bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021‒07‒04
118 papers selected by
Farah Jaber-Hijazi
University of the West of Scotland
  1. Mechanical Intermittent Compression Affects the Progression Rate of Malignant Melanoma Cells in a Cycle Period-Dependent Manner.
  2. Knockdown of enhancer of rudimentary homolog expression attenuates proliferation, cell cycle and apoptosis of melanoma cells.
  3. Knockdown of enhancer of rudimentary homolog expression attenuates proliferation, cell cycle and apoptosis of melanoma cells.
  4. Malignant Melanoma Metastasis to the Appendix as the First Presentation of Lentigo Maligna Melanoma.
  5. Location, location, location: Melanoma cells "living at the edge".
  6. Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances.
  7. Safety and efficacy of autologous tumor lysate particle-loaded dendritic cell vaccination in combination with systemic therapies in patients with recurrent and metastatic melanoma.
  8. First line treatment of BRAF mutated advanced melanoma: Does one size fit all?
  9. LRG1 Promotes Metastatic Dissemination of Melanoma through Regulating EGFR/STAT3 Signalling.
  10. AP-2alpha-mediated activation of E2F and EZH2 drives melanoma metastasis.
  11. Imaging Mass Spectrometry-Based Proteomic Analysis to Differentiate Melanocytic Nevi and Malignant Melanoma.
  12. NecroX-5 Can Suppress Melanoma Metastasis by Reducing the Expression of Rho-Family GTPases.
  13. Identifying High-Risk Tumors within AJCC Stage IB-III Melanomas Using a Seven-Marker Immunohistochemical Signature.
  14. Adjuvant therapy in stage IIIA melanoma.
  15. Safety and efficacy of autologous tumor lysate particle-loaded dendritic cell vaccination in combination with systemic therapies in patients with recurrent and metastatic melanoma.
  16. Biomarkers for Diagnosis, Prognosis and Response to Immunotherapy in Melanoma.
  17. Translation of a circulating miRNA signature of melanoma into a solid tissue assay to improve diagnostic accuracy and precision.
  18. Indocyanine Green Fluorescence Imaging with Lymphoscintigraphy Improves the Accuracy of Sentinel Lymph Node Biopsy in Melanoma.
  19. Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 3rd-5th, 2020, Italy).
  20. Immunotherapy Discontinuation in Metastatic Melanoma: Lessons from Real-Life Clinical Experience.
  21. Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma.
  22. Tolerance and Effectiveness of Targeted Therapies in Aged Patients with Metastatic Melanoma.
  23. Recent advancements in the management of retinoblastoma and uveal melanoma.
  24. Monosomy 3 Is Linked to Resistance to MEK Inhibitors in Uveal Melanoma.
  25. Circulating Tumor DNA as a Marker for Treatment Response in Metastatic Melanoma Patients Using Next-Generation Sequencing-A Prospective Feasibility Study.
  26. The review of the light parameters and mechanisms of Photobiomodulation on melanoma cells.
  27. Adjuvant therapy in stage IIIA melanoma - Authors' reply.
  28. Knocking out the Vitamin D Receptor Enhances Malignancy and Decreases Responsiveness to Vitamin D3 Hydroxyderivatives in Human Melanoma Cells.
  29. Cutaneous melanoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.
  30. The Challenge of Melanocytic Lesions in Pediatric Patients: Clinical-Pathological Findings and the Diagnostic Value of PRAME.
  31. Metastatic Risk Factors Associated with Class 1A Uveal Melanoma Patients.
  32. Successful encorafenib desensitization in a patient with recurrent metastatic melanoma.
  33. Toxicity, Response and Survival in Older Patients with Metastatic Melanoma Treated with Checkpoint Inhibitors.
  34. Cost-Effectiveness Analysis of Dabrafenib Plus Trametinib and Vemurafenib as First-Line Treatment in Patients with BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma in China.
  35. Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression.
  36. Clinical-dermoscopic similarities between atypical nevi and early stage melanoma.
  37. Chimeric Antigen Receptor (CAR) T Cell Therapy for Metastatic Melanoma: Challenges and Road Ahead.
  38. Talimogene laherparepvec (TVEC) pseudolymphomatous reaction mimicking metastatic melanoma.
  39. CD36 promotes vasculogenic mimicry in melanoma by mediating adhesion to the extracellular matrix.
  40. Predictive and Prognostic Value of BRAF and NRAS Mutation of 159 Sentinel Lymph Node Cases in Melanoma-A Retrospective Single-Institute Study.
  41. ZNF224 is a mediator of TGF-β pro-oncogenic function in melanoma.
  42. Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations.
  43. PDCD1 Polymorphisms May Predict Response to Anti-PD-1 Blockade in Patients With Metastatic Melanoma.
  44. Therapeutic Advancements Across Clinical Stages in Melanoma, With a Focus on Targeted Immunotherapy.
  45. Nectin-1 Expression Correlates with the Susceptibility of Malignant Melanoma to Oncolytic Herpes Simplex Virus In Vitro and In Vivo.
  46. The Role of Interferons in Melanoma Resistance to Immune Checkpoint Blockade: Mechanisms of Escape and Therapeutic Implications.
  47. Predictive Evaluation on Cytological Sample of Metastatic Melanoma: The Role of BRAF Immunocytochemistry in the Molecular Era.
  48. Frequency, Treatment and Outcome of Immune-Related Toxicities in Patients with Immune-Checkpoint Inhibitors for Advanced Melanoma: Results from an Institutional Database Analysis.
  49. Identification ACTA2 and KDR as key proteins for prognosis of PD-1/PD-L1 blockade therapy in melanoma.
  50. The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma.
  51. Electrochemotherapy with Bleomycin Enhances Radiosensitivity of Uveal Melanomas: First In Vitro Results in 3D Cultures of Primary Uveal Melanoma Cell Lines.
  52. Artesunate combined with verteporfin inhibits uveal melanoma by regulation of the MALAT1/yes-associated protein signaling pathway.
  53. Metastatic Merkel cell carcinoma and malignant melanoma in a single sentinel lymph node.
  54. Nomogram Incorporating the WNT/β-Catenin Signaling Pathway for Predicting the Survival of Cutaneous Melanoma.
  55. Slow transcription of the 99a/let-7c/125b-2 cluster results in differential miRNA expression and promotes melanoma phenotypic plasticity.
  56. Triple Combination Therapy With PD-1/PD-L1, BRAF, and MEK Inhibitor for Stage III-IV Melanoma: A Systematic Review and Meta-Analysis.
  57. Landmark Series on Disparities in Surgical Oncology: Melanoma.
  58. Hyperacute toxicity with combination ipilimumab and anti-PD1 immunotherapy.
  59. Giant Congenital Melanocytic Nevi in a Pakistani Newborn.
  60. Patient engagement in melanoma research: from bench to bedside.
  61. Immune marker signature helps to predict survival in uveal melanoma.
  62. Intramammary melanoma micrometastasis within a silicone-implanted breast.
  63. Memory-like differentiation enhances NK cell responses to melanoma.
  64. A case of high-risk ciliary body melanoma arising in an eye following resection of an iridociliary melanocytoma.
  65. UVB mutagenesis differs in Nras- and Braf-mutant mouse models of melanoma.
  66. Severe progressive scarring pembrolizumab-induced lichen planopilaris in a patient with metastatic melanoma.
  67. Standard-Dose Pembrolizumab Plus Alternate-Dose Ipilimumab in Advanced Melanoma: KEYNOTE-029 Cohort 1C, a Phase 2 Randomized Study of Two Dosing Schedules.
  68. Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.
  69. Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600mut melanoma patients.
  70. Diagnostic assessment of deep learning for melanocytic lesions using whole-slide pathological images.
  71. Characterizing the Clinical Implications of Histologic Regression in Melanoma Requires Clear Diagnostic Criteria That Are Consistently Applied.
  72. Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy.
  73. Uveal Melanoma and Secondary Angle-Closure Crisis: A Case Report and Literature Review.
  74. Ensemble Method of Convolutional Neural Networks with Directed Acyclic Graph Using Dermoscopic Images: Melanoma Detection Application.
  75. A Randomized Trial of Precision Prevention Materials to Improve Primary and Secondary Melanoma Prevention Activities among Individuals with Limited Melanoma Risk Phenotypes.
  76. Targeting Melanoma-Initiating Cells by Caffeine: In Silico and In Vitro Approaches.
  77. Novel Chemically Modified Curcumin (CMC) Analogs Exhibit Anti-Melanogenic Activity in Primary Human Melanocytes.
  78. Racial diversity in melanoma research from 2015 to 2020: a cross-sectional study.
  79. Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin αvβ3 and the MC1 Receptor-Suitable for the Specific Visualization of Melanomas?
  80. Early maternal separation enhances melanoma progression in adult female mice by immune mechanisms.
  81. VECTOR: An Integrated Correlation Network Database for the Identification of CeRNA Axes in Uveal Melanoma.
  82. In Vitro Effects of Selective COX and LOX Inhibitors and Their Combinations with Antineoplastic Drugs in the Mouse Melanoma Cell Line B16F10.
  83. Mediastinal Malignant Melanoma Markedly Shrinking in Response to Nivolumab.
  84. Staged Eye-Plaque Brachytherapy: A Novel Approach for Large Uveal Melanoma.
  85. Development of Radiofluorinated Nicotinamide/Picolinamide Derivatives as Diagnostic Probes for the Detection of Melanoma.
  86. Inhibitory activity of acteoside in melanoma via regulation of the ERβ-Ras/Raf1-STAT3 pathway.
  87. PRP4 Promotes Skin Cancer by Inhibiting Production of Melanin, Blocking Influx of Extracellular Calcium, and Remodeling Cell Actin Cytoskeleton.
  88. Early rise in brain damage markers and high ICOS expression in CD4+ and CD8+ T cells during checkpoint inhibitor-induced encephalomyelitis.
  89. Expression Profiles of ASIC1/2 and TRPV1/4 in Common Skin Tumors.
  90. The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival.
  91. microRNAs in the Regulation of Melanogenesis.
  92. Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate melanoma progression.
  93. The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis.
  94. Endocrine Toxicity and Outcomes in Patients With Metastatic Malignancies Treated With Immune Checkpoint Inhibitors.
  95. Light- and Melanin Nanoparticle-Induced Cytotoxicity in Metastatic Cancer Cells.
  96. B16 melanomas evade antitumor immunity by the loss of epitope presentation and the acquisition of tumor resistance to granzyme B.
  97. Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family.
  98. Systemic administration of polymersomal oncolytic peptide LTX-315 combining with CpG adjuvant and anti-PD-1 antibody boosts immunotherapy of melanoma.
  99. Canine Transforming Growth Factor-β Receptor 2-Ig: A Potential Candidate Biologic for Melanoma Treatment That Reverses Transforming Growth Factor-β1 Immunosuppression.
  100. Pigmented Lesion Assay for Suspected Melanoma Lesions: A Health Technology Assessment.
  101. Melanoma origins: data from early-stage tumours supports de novo and naevus-associated melanomas as distinct subtypes.
  102. Real-time fluorescence imaging of anthocyanins complexed with diphenylboric acid 2-aminoethyl inside B16-F10 melanoma cells.
  103. Fractional versus Full Ablative CO2 Laser in Recipient site of Non-Cultured Melanocytes and Keratinocyte Transplantation in Treatment of Vitiligo.
  104. [Determination of dacarbazine in the urine of mice with melanoma by high performance liquid chromatography].
  105. A Novel Treatment for Giant Congenital Melanocytic Nevi Combining Inactivated Autologous Nevus Tissue by High Hydrostatic Pressure and a Cultured Epidermal Autograft: First-in-Human, Open, Prospective Clinical Trial.
  106. STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation.
  107. Deubiquitination of MITF-M Regulates Melanocytes Proliferation and Apoptosis.
  108. Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/- Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets.
  109. Preliminary Study: Proteomic Profiling Uncovers Potential Proteins for Biomonitoring Equine Melanocytic Neoplasm.
  110. Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial.
  111. Up-down regulation of HIF-1α in cancer progression.
  112. Y2O3 Nanoparticles and X-ray Radiation-Induced Effects in Melanoma Cells.
  113. Teledermoscopy: A Helpful Detection Tool for Amelanotic and Hypomelanotic Melanoma.
  114. Chitosan nanoparticles containing limonene and limonene-rich essential oils: potential phytotherapy agents for the treatment of melanoma and breast cancers.
  115. NGS-Based Analysis of Atypical Deep Penetrating Nevi.
  116. Comparative transcriptomics of albino and warningly-coloured caterpillars.
  117. Role of gut microbiome on immunotherapy efficacy in melanoma.
  118. A comparative pilot study of dipstick versus open-spray cryotherapy techniques as depigmentation treatments for vitiligo.
  1. Diagnostics (Basel). 2021 Jun 18. pii: 1112. [Epub ahead of print]11(6):
    Mechanical Intermittent Compression Affects the Progression Rate of Malignant Melanoma Cells in a Cycle Period-Dependent Manner.
    Takashi Morikura, Shogo Miyata.
      Static mechanical compression is a biomechanical factor that affects the progression of melanoma cells. However, little is known about how dynamic mechanical compression affects the progression of melanoma cells. In the present study, we show that mechanical intermittent compression affects the progression rate of malignant melanoma cells in a cycle period-dependent manner. Our results suggest that intermittent compression with a cycle of 2 h on/2 h off could suppress the progression rate of melanoma cells by suppressing the elongation of F-actin filaments and mRNA expression levels related to collagen degradation. In contrast, intermittent compression with a cycle of 4 h on/4 h off could promote the progression rate of melanoma cells by promoting cell proliferation and mRNA expression levels related to collagen degradation. Mechanical intermittent compression could therefore affect the progression rate of malignant melanoma cells in a cycle period-dependent manner. Our results contribute to a deeper understanding of the physiological responses of melanoma cells to dynamic mechanical compression.
    Keywords:  cancer progression; in vitro model; malignant melanoma; mechanical intermittent compression
    DOI:  https://doi.org/10.3390/diagnostics11061112
  2. Melanoma Res. 2021 Aug 01. 31(4): 309-318
    Knockdown of enhancer of rudimentary homolog expression attenuates proliferation, cell cycle and apoptosis of melanoma cells.
    Muzhang Xiao, Ningning Tang, Yu Yan, Zhelin Li, Shupeng Shi, Siqi He, Zizi Chen, Ke Cao, Jia Chen, Jianda Zhou, Xiang Chen.
      Early stage or localized melanoma can be surgically resected with satisfactory outcome, whereas advanced malignant melanoma responds to treatment poorly and has a negative prognosis even after surgery, radiotherapy and other comprehensive treatments. Gene therapy targeting various biological signaling pathways has become an increasingly popular area in melanoma research. However, for gene therapy success, it is important to reveal the molecular mechanisms of melanoma tumorigenesis and development. The present study examined the effects of downregulating enhancer of rudimentary homolog (ERH) expression on the proliferation, metastasis and cell cycle of melanoma cells. ERH expression levels in melanoma tissues and cells were determined. Then, ERH gene expression in melanoma cell lines was downregulated or overexpressed by the lentiviral RNA interference technique. Furthermore, we performed cell counting kit-8, clone formation, scratch, transwell migration, subcutaneous tumorigenesis and venous metastasis assays as well as carried out flow cytometry analysis to explore the effects of ERH expression on cell proliferation, cell cycle, apoptosis and metastasis. We found that ERH expression in melanoma tissues and cells was markedly higher than in normal melanin nevus. Suppressing ERH expression by RNA interference in melanoma A375, WM35 and SK28 cell lines inhibited their proliferation and induced cell apoptosis. The cell cycle was also found to be blocked in the G1 phase. However, the metastatic properties of melanoma cells in vitro and in vivo remained largely unaltered by ERH knockdown. Our results show that ERH expression is increased in melanoma. Meanwhile, the proliferation and cell cycle transformation abilities are impaired potentially by downregulating the ERH expression in melanoma cells. Therefore, targeting ERH might serve as a novel therapeutic approach for malignant melanoma.
    DOI:  https://doi.org/10.1097/CMR.0000000000000747
  3. Melanoma Res. 2021 Jun 29.
    Knockdown of enhancer of rudimentary homolog expression attenuates proliferation, cell cycle and apoptosis of melanoma cells.
    Muzhang Xiao, Ningning Tang, Yu Yan, Zhelin Li, Shupeng Shi, Siqi He, Zizi Chen, Ke Cao, Jia Chen, Jianda Zhou, Xiang Chen.
      Early stage or localized melanoma can be surgically resected with satisfactory outcome, whereas advanced malignant melanoma responds to treatment poorly and has a negative prognosis even after surgery, radiotherapy and other comprehensive treatments. Gene therapy targeting various biological signaling pathways has become an increasingly popular area in melanoma research. However, for gene therapy success, it is important to reveal the molecular mechanisms of melanoma tumorigenesis and development. The present study examined the effects of downregulating enhancer of rudimentary homolog (ERH) expression on the proliferation, metastasis and cell cycle of melanoma cells. ERH expression levels in melanoma tissues and cells were determined. Then, ERH gene expression in melanoma cell lines was downregulated or overexpressed by the lentiviral RNA interference technique. Furthermore, we performed cell counting kit-8, clone formation, scratch, transwell migration, subcutaneous tumorigenesis and venous metastasis assays as well as carried out flow cytometry analysis to explore the effects of ERH expression on cell proliferation, cell cycle, apoptosis and metastasis. We found that ERH expression in melanoma tissues and cells was markedly higher than in normal melanin nevus. Suppressing ERH expression by RNA interference in melanoma A375, WM35 and SK28 cell lines inhibited their proliferation and induced cell apoptosis. The cell cycle was also found to be blocked in the G1 phase. However, the metastatic properties of melanoma cells in vitro and in vivo remained largely unaltered by ERH knockdown. Our results show that ERH expression is increased in melanoma. Meanwhile, the proliferation and cell cycle transformation abilities are impaired potentially by downregulating the ERH expression in melanoma cells. Therefore, targeting ERH might serve as a novel therapeutic approach for malignant melanoma.
    DOI:  https://doi.org/10.1097/CMR.0000000000000747
  4. Arch Iran Med. 2021 Apr 01. 24(4): 330-332
    Malignant Melanoma Metastasis to the Appendix as the First Presentation of Lentigo Maligna Melanoma.
    Shokouh Taghipour Zahir, Koorosh Rahmani, Seyed Abolfazl Hosseini.
      Malignant melanoma is a malignant neoplasm of the skin and mucosal tissues, and its behavior is not predictable. Thus, it could metastasize via mysterious routes. Here, we report a rare case of acute abdomen and acute appendicitis which involved metastatic malignant melanoma in a 63-year-old man without a history of previously treated malignant melanoma.
    Keywords:  Appendicitis; Malignant melanoma; Metastasis
    DOI:  https://doi.org/10.34172/aim.2021.46
  5. Exp Dermatol. 2021 Jun 29.
    Location, location, location: Melanoma cells "living at the edge".
    Oscar Maiques, Victoria Sanz-Moreno.
      Abnormal cell migration and invasion underlie metastatic dissemination, one of the major challenges for cancer treatment. Melanoma is one the deadliest and most aggressive forms of skin cancer due in part to its migratory and metastatic potential. Cancer cells use a variety of migratory strategies regulated by cytoskeletal remodelling. In particular, we discuss the importance of amoeboid invasive melanoma strategies, since they have been identified at the edge of human melanomas. We hypothesize that the presence of amoeboid melanoma cells will favour tumour progression since they are invasive and metastatic; they support immunosuppression; they harbour cancer stem cell properties and they are involved in therapy resistance. The Rho-ROCK-Myosin II pathway is key to maintain amoeboid melanoma invasion but this pathway is further regulated by pro-tumorigenic/pro-metastatic/pro-survival signalling pathways such as JAK-STAT3, TGFβ-SMAD, NF-κB, Wnt11/5-FDZ7 and BRAFV600E -MEK-ERK. These pathways support amoeboid behaviour and are actionable in the clinic. After melanoma wide surgical margin removal, we propose that possible remaining melanoma cells should be eradicated using anti-amoeboid therapies.
    Keywords:  CANCER; CELL MIGRATION; Cell signalling; Cytoskeleton; INFLAMMATION; MELANOMA
    DOI:  https://doi.org/10.1111/exd.14423
  6. Int J Mol Sci. 2021 Jun 15. pii: 6395. [Epub ahead of print]22(12):
    Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances.
    Strahil Strashilov, Angel Yordanov.
      Melanoma develops from malignant transformations of the pigment-producing melanocytes. If located in the basal layer of the skin epidermis, melanoma is referred to as cutaneous, which is more frequent. However, as melanocytes are be found in the eyes, ears, gastrointestinal tract, genitalia, urinary system, and meninges, cases of mucosal melanoma or other types (e.g., ocular) may occur. The incidence and morbidity of cutaneous melanoma (cM) are constantly increasing worldwide. Australia and New Zealand are world leaders in this regard with a morbidity rate of 54/100,000 and a mortality rate of 5.6/100,000 for 2015. The aim of this review is to consolidate and present the data related to the aetiology and pathogenesis of cutaneous melanoma, thus rendering them easier to understand. In this article we will discuss these problems and the possible impacts on treatment for this disease.
    Keywords:  aetiology; melanoma; pathogenesis; skin melanoma
    DOI:  https://doi.org/10.3390/ijms22126395
  7. Melanoma Res. 2021 Jun 29.
    Safety and efficacy of autologous tumor lysate particle-loaded dendritic cell vaccination in combination with systemic therapies in patients with recurrent and metastatic melanoma.
    Alexandra M Adams, Robert C Chick, Timothy J Vreeland, Guy T Clifton, Diane F Hale, Patrick M McCarthy, Anne E O'Shea, Phillip M Kemp Bohan, Annelies T Hickerson, Hyohyun Park, Amanda JoEllen Sloan, John Hyngstrom, Adam C Berger, James W Jakub, Jeffrey J Sussman, Montaser Shaheen, Thomas Wagner, Mark B Faries, George E Peoples.
      Immunotherapy has revolutionized the treatment of melanoma, yet survival remains poor for patients with metastatic disease. The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine has been shown to be safe adjuvant therapy for patients with resected stage III/IV melanoma who complete the primary vaccine series. Here, we describe an open-label trial of patients with metastatic melanoma treated with TLPLDC vaccine in addition to standard of care (SoC) therapies. The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles, which are phagocytosed by autologous dendritic cells ex vivo. Patients who recurred while enrolled in a phase IIb trial of adjuvant TLPLDC vaccine (crossover cohort) and patients with measurable metastatic melanoma cohort were offered TLPLDC vaccine along with SoC therapies. Tumor response was measured by RECIST 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated by intention-to-treat analysis. Fifty-four patients were enrolled (28 in crossover cohort; 26 in metastatic melanoma cohort). The vaccine was well-tolerated with no grade ≥3 adverse events when given with SoC therapies to include checkpoint inhibitors, BRAF/MEK inhibitors, tyrosine kinase inhibitors, intralesional therapy and/or radiation. In the crossover arm, OS was 76.5% and PFS was 57.1% (median follow-up of 13.9 months). In the metastatic melanoma arm, OS was 85.7% and PFS was 52.2% (median follow-up 8.5 months). The TLPLDC vaccine is well-tolerated and safe in combination with SoC therapies. Future trials will determine the efficacy of TLPLDC in combination with SoC therapies in metastatic melanoma.
    DOI:  https://doi.org/10.1097/CMR.0000000000000758
  8. Cancer Treat Rev. 2021 Jun 18. pii: S0305-7372(21)00101-8. [Epub ahead of print]99 102253
    First line treatment of BRAF mutated advanced melanoma: Does one size fit all?
    Federica Giugliano, Edoardo Crimini, Paolo Tarantino, Paola Zagami, Jacopo Uliano, Chiara Corti, Dario Trapani, Giuseppe Curigliano, Paolo A Ascierto.
      In the last decade, immunotherapy and target therapy have revolutionized the prognosis of patients with BRAF-V600 mutation-positive metastatic melanoma. To date, three different combinations of BRAF/MEK inhibitors have been approved for this population, showing comparable efficacy and unique toxicity profiles. Several immune-checkpoint inhibitors, including pembrolizumab, nivolumab and the combination of nivolumab plus ipilimumab, are also available options for untreated metastatic melanoma patients. A novel approach has emerged by combining immune-checkpoint inhibitors and targeted agents, based on preclinical hints of synergy, prompting clinical results from large randomized trials. Specifically, the triplet of atezolizumab, vemurafenib and cobimetinib has been recently approved by FDA for patients with untreated BRAF-mutant metastatic melanoma. With a wide variety of available treatment options in this setting, it is paramount to establish criteria to select the most effective and safe frontline tailored approaches, for each patient. Results from ongoing studies are awaited, to maximise the benefits in survival outcomes and quality of life for patients, balancing adverse events and clinical benefit. The purpose of this review is to summarize the current landscape of standard and experimental treatment strategies for the first line treatment of patients with BRAF-mutated advanced melanoma and discuss the best patient-centered tailored strategies in the first-line setting.
    Keywords:  BRAFV600; First line; Immunotherapy; Metastatic melanoma; Target therapy
    DOI:  https://doi.org/10.1016/j.ctrv.2021.102253
  9. Cancers (Basel). 2021 Jun 30. pii: 3279. [Epub ahead of print]13(13):
    LRG1 Promotes Metastatic Dissemination of Melanoma through Regulating EGFR/STAT3 Signalling.
    Yuet Ping Kwan, Melissa Hui Yen Teo, Jonathan Chee Woei Lim, Michelle Siying Tan, Graciella Rosellinny, Walter Wahli, Xiaomeng Wang.
      Although less common, melanoma is the deadliest form of skin cancer largely due to its highly metastatic nature. Currently, there are limited treatment options for metastatic melanoma and many of them could cause serious side effects. A better understanding of the molecular mechanisms underlying the complex disease pathophysiology of metastatic melanoma may lead to the identification of novel therapeutic targets and facilitate the development of targeted therapeutics. In this study, we investigated the role of leucine-rich α-2-glycoprotein 1 (LRG1) in melanoma development and progression. We first established the association between LRG1 and melanoma in both human patient biopsies and mouse melanoma cell lines and revealed a significant induction of LRG1 expression in metastatic melanoma cells. We then showed no change in tumour cell growth, proliferation, and angiogenesis in the absence of the host Lrg1. On the other hand, there was reduced melanoma cell metastasis to the lungs in Lrg1-deficient mice. This observation was supported by the promoting effect of LRG1 in melanoma cell migration, invasion, and adhesion. Mechanistically, LRG1 mediates melanoma cell invasiveness in an EGFR/STAT3-dependent manner. Taken together, our studies provided compelling evidence that LRG1 is required for melanoma metastasis but not growth. Targeting LRG1 may offer an alternative strategy to control malignant melanoma.
    Keywords:  EGFR; STAT3; leucine-rich α-2-glycoprotein-1; melanoma; metastasis
    DOI:  https://doi.org/10.3390/cancers13133279
  10. Cancer Res. 2021 Jul 01. pii: canres.0772.2021. [Epub ahead of print]
    AP-2alpha-mediated activation of E2F and EZH2 drives melanoma metastasis.
    Jeffrey R White, Dakota T Thompson, Kelsey E Koch, Boris S Kiriazov, Anna C Beck, Dana M van der Heide, Benjamin G Grimm, Mikhail V Kulak, Ronald J Weigel.
      In melanoma metastasis, the role of the AP-2alpha transcription factor, which is encoded by TFAP2A, is controversial as some findings have suggested tumor suppressor activity while other studies have shown high TFAP2A expression in node-positive melanoma associated with poor prognosis. Here we demonstrate that AP-2alpha facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathway including EZH2. A BioID screen found that AP-2alpha interacts with members of the nucleosome remodeling and deacetylase (NuRD) complex. Loss of AP-2alpha removed activating chromatin marks in the promoters of EZH2 and other E2F target genes through activation of the NuRD repression complex. In melanoma cells, treatment with tazemetostat, an FDA-approved and highly specific EZH2 inhibitor, substantially reduced anchorage-independent colony formation and demonstrated heritable anti-metastatic effects, which were dependent on AP-2alpha. Single cell RNA-seq analysis of a metastatic melanoma mouse model revealed hyperexpansion of Tfap2aHigh/E2F-activated cell populations in transformed melanoma relative to progenitor melanocyte stem cells. These findings demonstrate that melanoma metastasis is driven by the AP-2alpha/EZH2 pathway and suggest that AP-2alpha expression can be used as a biomarker to predict responsiveness to EZH2 inhibitors for the treatment of advanced melanomas.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0772
  11. Cancers (Basel). 2021 Jun 26. pii: 3197. [Epub ahead of print]13(13):
    Imaging Mass Spectrometry-Based Proteomic Analysis to Differentiate Melanocytic Nevi and Malignant Melanoma.
    Rita Casadonte, Mark Kriegsmann, Katharina Kriegsmann, Isabella Hauk, Rolf R Meliß, Cornelia S L Müller, Jörg Kriegsmann.
      The discrimination of malignant melanoma from benign nevi may be difficult in some cases. For this reason, immunohistological and molecular techniques are included in the differential diagnostic toolbox for these lesions. These methods are time consuming when applied subsequently and, in some cases, no definitive diagnosis can be made. We studied both lesions by imaging mass spectrometry (IMS) in a large cohort (n = 203) to determine a different proteomic profile between cutaneous melanomas and melanocytic nevi. Sample preparation and instrument setting were tested to obtain optimal results in term of data quality and reproducibility. A proteomic signature was found by linear discriminant analysis to discern malignant melanoma from benign nevus (n = 113) with an overall accuracy of >98%. The prediction model was tested in an independent set (n = 90) reaching an overall accuracy of 93% in classifying melanoma from nevi. Statistical analysis of the IMS data revealed mass-to-charge ratio (m/z) peaks which varied significantly (Area under the receiver operating characteristic curve > 0.7) between the two tissue types. To our knowledge, this is the largest IMS study of cutaneous melanoma and nevi performed up to now. Our findings clearly show that discrimination of melanocytic nevi from melanoma is possible by IMS.
    Keywords:  MALDI; classification; imaging mass spectrometry; melanoma; nevi; proteomics
    DOI:  https://doi.org/10.3390/cancers13133197
  12. J Clin Med. 2021 Jun 25. pii: 2790. [Epub ahead of print]10(13):
    NecroX-5 Can Suppress Melanoma Metastasis by Reducing the Expression of Rho-Family GTPases.
    Gue-Tae Moon, Ji-Hyun Lee, Sang-Hyun Jeong, Song-Wan Jin, Young-Min Park.
      NecroX-5 (NX-5) is a cell-permeable necrosis inhibitor with cytoprotective effects. Although it has been reported to inhibit lung and breast cancer metastasis by modulating migration, its therapeutic effect on melanoma metastasis is still unknown. In this study, we examined the anti-metastatic effect of NX-5 on melanoma cell lines and its related therapeutic mechanism. The anti-metastatic effect of NX-5 on melanoma cell lines was determined using a transwell migration assay. We performed a quantitative real-time polymerase chain reaction and western blot analysis to measure changes in the expression of mRNA and protein, respectively, for major mediators of Rho-family GTPases after NX-5 treatment in melanoma cells. In addition, after constructing the 3D melanoma model, the expression of Rho-family GTPases was measured by immunohistochemistry. NX-5 (10 μM and 20 μM) treatment significantly reduced melanoma cell migration (p < 0.01). Additionally, NX-5 (20 μM) treatment significantly decreased the mRNA and protein expression levels of Cdc42, Rac1, and RhoA in melanoma cells compared with the untreated group (p < 0.001 and p < 0.05, respectively). Immunohistochemistry for our 3D melanoma model showed that Cdc42, Rac1, and RhoA were constitutively expressed in the nuclei of melanoma cells of the untreated group, and NX-5 treatment decreased their expression. These results demonstrate that NX-5 can suppress melanoma metastasis by reducing the expression of Rho-family GTPases.
    Keywords:  Cdc42; NecroX-5; Rac1; Rho-family GTPase; RhoA; melanoma; metastasis
    DOI:  https://doi.org/10.3390/jcm10132790
  13. Cancers (Basel). 2021 Jun 10. pii: 2902. [Epub ahead of print]13(12):
    Identifying High-Risk Tumors within AJCC Stage IB-III Melanomas Using a Seven-Marker Immunohistochemical Signature.
    Robin Reschke, Philipp Gussek, Mirjana Ziemer.
      BACKGROUND: We aim to validate a seven-marker immunohistochemical signature, consisting of Bax, Bcl-X, PTEN, COX-2, (loss of) ß-Catenin, (loss of) MTAP and (presence of) CD20, in an independent patient cohort and test clinical feasibility.METHODS: We performed staining of the mentioned antibodies in tissue of 88 primary melanomas and calculated a risk score for each patient. Data were correlated with clinical parameters and outcome (recurrence-free, distant metastasis-free and melanoma-specific survival).
    RESULTS: The seven-marker signature was able to identify high-risk patients within stages IB-III melanoma patients that have a significantly higher risk of disease recurrence, metastasis, and death. In particular, the high sensitivity of relapse prediction (>94%) in sentinel negative patients (stages IB-IIC) was striking (negative predictive value of 100% for melanoma-specific survival and distant metastasis-free survival, and 97.5% for relapse-free survival). For stage III patients (positive nodal status), the negative predictive value was 100% with the seven-marker signature.
    CONCLUSIONS: The seven-marker signature can help to further select high-risk patients in stages IIB-C but also in earlier stages IB-IIA and be a useful tool for therapy decisions in the adjuvant and future neo-adjuvant settings. Stage III patients with measurable lymph node disease classified as high-risk with the seven-marker signature are potential candidates for neoadjuvant immunotherapy.
    Keywords:  biomarker; immunotherapy; melanoma; relapse; targeted therapy
    DOI:  https://doi.org/10.3390/cancers13122902
  14. Lancet Oncol. 2021 Jul;pii: S1470-2045(21)00346-6. [Epub ahead of print]22(7): e299
    Adjuvant therapy in stage IIIA melanoma.
    Elif Hindié.
      
    DOI:  https://doi.org/10.1016/S1470-2045(21)00346-6
  15. Melanoma Res. 2021 Aug 01. 31(4): 378-388
    Safety and efficacy of autologous tumor lysate particle-loaded dendritic cell vaccination in combination with systemic therapies in patients with recurrent and metastatic melanoma.
    Alexandra M Adams, Robert C Chick, Timothy J Vreeland, Guy T Clifton, Diane F Hale, Patrick M McCarthy, Anne E O'Shea, Phillip M Kemp Bohan, Annelies T Hickerson, Hyohyun Park, Amanda JoEllen Sloan, John Hyngstrom, Adam C Berger, James W Jakub, Jeffrey J Sussman, Montaser Shaheen, Thomas Wagner, Mark B Faries, George E Peoples.
      Immunotherapy has revolutionized the treatment of melanoma, yet survival remains poor for patients with metastatic disease. The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine has been shown to be safe adjuvant therapy for patients with resected stage III/IV melanoma who complete the primary vaccine series. Here, we describe an open-label trial of patients with metastatic melanoma treated with TLPLDC vaccine in addition to standard of care (SoC) therapies. The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles, which are phagocytosed by autologous dendritic cells ex vivo. Patients who recurred while enrolled in a phase IIb trial of adjuvant TLPLDC vaccine (crossover cohort) and patients with measurable metastatic melanoma cohort were offered TLPLDC vaccine along with SoC therapies. Tumor response was measured by RECIST 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated by intention-to-treat analysis. Fifty-four patients were enrolled (28 in crossover cohort; 26 in metastatic melanoma cohort). The vaccine was well-tolerated with no grade ≥3 adverse events when given with SoC therapies to include checkpoint inhibitors, BRAF/MEK inhibitors, tyrosine kinase inhibitors, intralesional therapy and/or radiation. In the crossover arm, OS was 76.5% and PFS was 57.1% (median follow-up of 13.9 months). In the metastatic melanoma arm, OS was 85.7% and PFS was 52.2% (median follow-up 8.5 months). The TLPLDC vaccine is well-tolerated and safe in combination with SoC therapies. Future trials will determine the efficacy of TLPLDC in combination with SoC therapies in metastatic melanoma.
    DOI:  https://doi.org/10.1097/CMR.0000000000000758
  16. Cancers (Basel). 2021 Jun 09. pii: 2875. [Epub ahead of print]13(12):
    Biomarkers for Diagnosis, Prognosis and Response to Immunotherapy in Melanoma.
    Rossella Puglisi, Maria Bellenghi, Giada Pontecorvi, Giulia Pallante, Alessandra Carè, Gianfranco Mattia.
      Cutaneous Melanoma classification is constantly looking for specific and sensitive biomarkers capable of having a positive effect on diagnosis, prognosis and risk assessment, eventually affecting clinical outcome. Classical morphological, immunohistochemical and the well-known BRAF and NRAS genetic biomarkers do not allow the correct categorization of patients, being melanoma conditioned by high genetic heterogeneity. At the same time, classic prognostic methods are unsatisfactory. Therefore, new advances in omics and high-throughput analytical techniques have enabled the identification of numerous possible biomarkers, but their potentiality needs to be validated and standardized in prospective studies. Melanoma is considered an immunogenic tumor, being the first form of cancer to take advantage of the clinical use of the immune-checkpoint blockers. However, as immunotherapy is effective only in a limited number of patients, biomarkers associated with different responses are essential to select the more promising therapeutic approach and maximize clinical benefits. In this review, we summarize the most utilized biomarkers for Cutaneous Melanoma diagnosis, focusing on new prognostic and predictive biomarkers mainly associated with immunotherapy.
    Keywords:  BRAF; NRAS; biomarkers; immunotherapy; melanoma
    DOI:  https://doi.org/10.3390/cancers13122875
  17. Biomark Med. 2021 Jun 29.
    Translation of a circulating miRNA signature of melanoma into a solid tissue assay to improve diagnostic accuracy and precision.
    Ryan Van Laar, Samuel King, Richard McCoy, Mirette Saad, Sian Fereday, Ingrid Winship, Catherine Uzzell, Anthony Landgren.
      Aim: Successful treatment of cutaneous melanoma depends on early and accurate diagnosis of clinically suspicious melanocytic skin lesions. Multiple international studies have described the challenge of providing accurate and reproducible histopathological assessments of melanocytic lesions, highlighting the need for new diagnostic tools including disease-specific biomarkers. Previously, a 38-miRNA signature (MEL38) was identified in melanoma patient plasma and validated as a novel biomarker. In this study, MEL38 expression in solid tissue biopsies representing the benign nevi to metastatic melanoma spectrum is examined. Patients & methods: Nanostring digital gene expression assessment of the MEL38 signature was performed on 308 formalin-fixed paraffin-embedded biopsies of nevi, melanoma in situ and invasive melanoma. Genomic data were interrogated using hierarchical clustering, univariate and multivariate statistical approaches. Classification scores computed from the MEL38 signature were analyzed for their association with demographic data and histopathology results, including MPATH-DX class, AJCC disease stage and tissue subtype. Results: The MEL38 score can stratify higher-risk melanomas (MPATH-Dx class V or more advanced) from lower-risk skin lesions (class I-IV) with an area under the curve of 0.97 (p < 0.001). The genomic score ranges from 0 to 10 and is positively correlated with melanoma progression, with an intraclass correlation coefficient of 0.85 with stage 0-IV disease. Using an optimized classification threshold of ≥2.7 accurately identifies higher-risk melanomas with 89% sensitivity and 94% specificity. Multivariate analysis showed the score to be a significant predictor of malignancy, independent of technical and clinical covariates. Application of the MEL38 signature to Spitz nevi reveals an intrasubtype profile, with elements in common to both nevi and melanoma. Conclusion: Melanoma-specific circulating miRNAs maintain their association with malignancy when measured in the hypothesized tissue of origin. The MEL38 signature is an accurate and reproducible metric of melanoma status, based on changes in miRNA expression that occur as the disease develops and spreads. Inclusion of the MEL38 score into routine practice would provide physicians with previously unavailable, personalized genomic information about their patient's skin lesions. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, healthcare resource utilization and patient outcomes.
    Keywords:  cancer; diagnostics; genomics; melanoma; pathology; prediction; skin cancer; translational medicine; validation
    DOI:  https://doi.org/10.2217/bmm-2021-0289
  18. Plast Reconstr Surg. 2021 Jul 01. 148(1): 83e-93e
    Indocyanine Green Fluorescence Imaging with Lymphoscintigraphy Improves the Accuracy of Sentinel Lymph Node Biopsy in Melanoma.
    Rebecca Knackstedt, Brian R Gastman.
      BACKGROUND: Despite advances in melanoma management, there remains room for improvement in the accuracy of sentinel lymph node biopsy. The authors analyzed a prospective cohort of patients with primary cutaneous melanoma who underwent sentinel lymph node biopsy with lymphoscintigraphy and indocyanine green fluorescence to evaluate the quality and accuracy of this technique.METHODS: Consecutive primary cutaneous melanoma patients who underwent sentinel lymph node biopsy with radioisotope lymphoscintigraphy and indocyanine green fluorescence from 2012 to 2018 were prospectively enrolled. Analysis was performed of melanoma characteristics, means of identifying sentinel lymph nodes, sentinel lymph node status, and recurrence.
    RESULTS: Five hundred ninety-four melanomas and 1827 nodes were analyzed; 1556 nodes (85.2 percent) were identified by radioactivity/fluorescence, 255 (14 percent) by radioactivity only, and 16 (0.9 percent) with indocyanine green only. There were 163 positive sentinel nodes. One hundred forty-seven (90.2 percent) were identified by radioactivity/fluorescence, 13 (8 percent) by radioactivity only, and three (0.6 percent) with fluorescence only. Of the 128 patients with a positive biopsy, eight patients' (6.3 percent) nodes were identified by radioactivity only and four (3.4 percent) with fluorescence only. There were 128 patients with a positive biopsy, 454 with a negative biopsy, and 12 patients who had a negative biopsy with subsequent nodal recurrence. Mean follow-up was 2.8 years.
    CONCLUSIONS: In the study of the largest cohort of patients with primary cutaneous melanoma who underwent a sentinel lymph node biopsy with radioisotope lymphoscintigraphy and indocyanine green-based technology, the quality and accuracy of this technique are demonstrated. This has important implications for melanoma patients, as the adoption of this approach with subsequent accurate staging, adjuvant workup, and treatment may improve survival outcomes. .
    CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II.
    DOI:  https://doi.org/10.1097/PRS.0000000000008096
  19. J Transl Med. 2021 Jun 30. 19(1): 278
    Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 3rd-5th, 2020, Italy).
    Paolo A Ascierto, Christian Blank, Reinhard Dummer, Marc S Ernstoff, Soldano Ferrone, Bernard A Fox, Thomas F Gajewski, Claus Garbe, Patrick Hwu, Pawel Kalinski, Michelle Krogsgaard, Roger S Lo, Jason J Luke, Bart Neyns, Michael A Postow, Sergio A Quezada, Michele W L Teng, Giorgio Trinchieri, Alessandro Testori, Corrado Caracò, Iman Osman, Igor Puzanov, Magdalena Thurin.
      Advances in immune checkpoint therapy and targeted therapy have led to improvement in overall survival for patients with advanced melanoma. Single agent checkpoint PD-1 blockade and combination with BRAF/MEK targeted therapy demonstrated benefit in overall survival (OS). Superior response rates have been demonstrated with combined PD-1/CTLA-4 blockade, with a significant OS benefit compared with single-agent PD-1 blockade. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers but they have yet to be fully characterized and implemented clinically. Overall, the progress in melanoma therapeutics and translational research will help to optimize treatment regimens to overcome resistance and develop robust biomarkers to guide clinical decision-making. During the Melanoma Bridge meeting (December 3rd-5th, 2020, Italy) we reviewed the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine.
    Keywords:  Adjuvant; Anti-CTLA-4; Anti-PD-1; BRAF inhibitor; Biomarkers; Combination strategies; Immunotherapy; MEK inhibitor; Melanoma; Neoadjuvant; Target therapy
    DOI:  https://doi.org/10.1186/s12967-021-02951-x
  20. Cancers (Basel). 2021 Jun 20. pii: 3074. [Epub ahead of print]13(12):
    Immunotherapy Discontinuation in Metastatic Melanoma: Lessons from Real-Life Clinical Experience.
    Nethanel Asher, Noa Israeli-Weller, Ronnie Shapira-Frommer, Guy Ben-Betzalel, Jacob Schachter, Tomer Meirson, Gal Markel.
      BACKGROUND: Immunotherapy has revolutionized outcomes for melanoma patients, by significantly prolonging survival and probably even curing a fraction of metastatic patients. In daily practice, treatment for responding patients is often discontinued due to treatment-limiting toxicity, or electively, following a major tumor response. To date, the criteria for a safe stop and the optimal duration of treatment remain unclear.PATIENTS AND METHODS: This is a real-world single-site cohort of 106 advanced melanoma patients who were treated with immunotherapy and who discontinued treatments in the absence of disease progression. Here, we describe their long-term outcomes, and analyze the differential characteristics between patients who ultimately experienced progression and those who remained in unmaintained durable response.
    RESULTS: Patients were treated with anti-PD-1 monotherapy (81%) or in combination with ipilimumab (19%) for a median of 15.2 m (range, 0.7-42.3 m). Upon discontinuation, 75.5% had achieved a complete response (CR). After a median follow-up of 20.8 m (range, 6-58) from discontinuation, 32% experienced disease progression. Median time to progression was 8.5 m (range, 1.5-37). Response to re-induction with anti-PD-1 was observed in 47%. On multivariate analysis, achieving a non-CR response, immunotherapy given in advanced line, and shorter treatment duration were significantly associated with lesser progression-free survival.
    CONCLUSIONS: This is one of the few reports on real-world melanoma patients who discontinued immunotherapy while responding to treatment. This study reveals the key factors to bear in mind when considering an elective treatment cessation. Specifically, patients with non-CR as best response and patients treated in an advanced-line setting should be treated for longer periods, and elective discontinuation should not take place prior to 18 m.
    Keywords:  complete response; immunotherapy; melanoma; treatment discontinuation
    DOI:  https://doi.org/10.3390/cancers13123074
  21. J Immunother Cancer. 2021 Jul;pii: e002703. [Epub ahead of print]9(7):
    Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma.
    Troels Holz Borch, Katja Harbst, Aynal Haque Rana, Rikke Andersen, Evelina Martinenaite, Per Kongsted, Magnus Pedersen, Morten Nielsen, Julie Westerlin Kjeldsen, Anders Handrup Kverneland, Martin Lauss, Lisbet Rosenkrantz Hölmich, Helle Hendel, Özcan Met, Göran Jönsson, Marco Donia, Inge Marie Svane.
      PURPOSE: Despite impressive response rates following adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma, improvement is needed to increase the efficacy and broaden the applicability of this treatment. We evaluated the use of vemurafenib, a small-molecule BRAF inhibitor with immunomodulatory properties, as priming before TIL harvest and adoptive T cell therapy in a phase I/II clinical trial.METHODS: 12 patients were treated with vemurafenib for 7 days before tumor excision and during the following weeks until TIL infusion. TILs were grown from tumor fragments, expanded in vitro and reinfused to the patient preceded by a lymphodepleting chemotherapy regimen and followed by interleukin-2 infusion. Extensive immune monitoring, tumor profiling and T cell receptor sequencing were performed.
    RESULTS: No unexpected toxicity was observed, and treatment was well tolerated. Of 12 patients, 1 achieved a complete response, 8 achieved partial response and 3 achieved stable disease. A PR and the CR are ongoing for 23 and 43 months, respectively. In vitro anti-tumor reactivity was found in TILs from 10 patients, including all patients achieving objective response. Serum and tumor biomarker analyses indicate that baseline cytokine levels and the number of T cell clones may predict response to TIL therapy. Further, TCR sequencing suggested skewing of TCR repertoire during in vitro expansion, promoting certain low frequency clonotypes.
    CONCLUSIONS: Priming with vemurafenib before infusion of TILs was safe and feasible, and induced objective clinical responses in this cohort of patients with checkpoint inhibitor-resistant metastatic melanoma. In this trial, vemurafenib treatment seemed to decrease attrition and could be considered to bridge the waiting time while TILs are prepared.
    Keywords:  adoptive; clinical trials as topic; immunotherapy; lymphocytes; melanoma; tumor-infiltrating
    DOI:  https://doi.org/10.1136/jitc-2021-002703
  22. Cancers (Basel). 2021 Jun 18. pii: 3042. [Epub ahead of print]13(12):
    Tolerance and Effectiveness of Targeted Therapies in Aged Patients with Metastatic Melanoma.
    Ondine Becquart, Bastien Oriano, Stéphane Dalle, Laurent Mortier, Marie Thérèse Leccia, Caroline Dutriaux, Sophie Dalac, Henri Montaudié, Julie De Quatrebarbes, Florence Brunet-Possenti, Philippe Saiag, Thierry Lesimple, Marie Beylot-Barry, Francois Aubin, Pierre-Emmanuel Stoebner, Jean-Philippe Arnault, Brigitte Dreno, Raphael Porcher, Celeste Lebbe, Bernard Guillot.
      PURPOSE: Melanoma's incidence is increasing, and elderly people could be significantly impacted since the majority occurs in people over 65 years of age. Combined BRAF and MEK targeted therapies (TT) are current standard regimen for BRAF mutated metastatic melanoma (MM). Except for subgroups of pivotal trials, little data are available for TT in this population.MATERIALS AND METHODS: Outcomes were explored in real life patients from MelBase, a French multicentric biobank dedicated to the prospective follow-up of unresectable stage III or IV melanoma. Patients treated by BRAF TT and/or MEK TT combined or not, were included from 2013 to 2017 in 2 groups: group 1 ≤ 65-year-old (yo), group 2 > 65 yo, analyzed for tolerance and efficacy.
    RESULTS: 353 patients were included: 231 in group 1, 122 in group 2. Median follow-up was 12 months (M). Median time of treatment was 6.9 M. A total of 80% had at least one Adverse Effect (AE). Most frequent AE (all grades) were mainly skin and subcutaneous, general, and gastrointestinal disorders. A total of 31% of AE were grade 3-4: 28% in group 1 and 39% in group 2 (p = 0.05). No differences were observed in all AE grades proportion, dose modifications, interruptions, and discontinuations. For each group, median overall survival was 20.3 M (CI 95%: 15.5-27.9) and 16.3 M (CI: 14.5-26.9), respectively (p = 0.8). Median progression free survival was 7.8 M (6.4-9.9) and 7.7 M (CI: 5.8-11.3) (p = 0.4). Objective response rate was 59% and 50% (p = 0.6).
    CONCLUSION: This study on a large multicentric cohort is the first to assess that TT is well tolerated in elderly BRAF-mutated patients such as in patients younger than 65. Efficacy was similar between groups with outcomes reaching those from pivotal studies. There is thus no argument against using TT in elderly people, although an onco-geriatric opinion is welcome for the most vulnerable.
    Keywords:  elderly people; melanoma; side effects; targeted therapy
    DOI:  https://doi.org/10.3390/cancers13123042
  23. Fac Rev. 2021 ;10 51
    Recent advancements in the management of retinoblastoma and uveal melanoma.
    Amy C Schefler, Ryan S Kim.
      Retinoblastoma in children and uveal melanoma in adults can pose a serious threat to both vision and life. For many decades, enucleation was often the only option to treat these intraocular malignancies. For retinoblastoma, intra-arterial chemotherapy is often utilized as the primary treatment at advanced academic centers and has dramatically improved local tumor control and eye salvage rates. For uveal melanoma, both plaque brachytherapy and proton beam irradiation have served as widely utilized therapies with a local failure rate of approximately 1-10%, depending on the series. Major recent advancements have allowed for a better understanding of the genomics of uveal melanoma and the impact of certain mutations on metastatic susceptibility. Gene expression profile stratifies uveal melanomas into two classes: low-risk (class 1) and high-risk (class 2). A loss-of-function mutation of BAP1 is associated with a class 2 gene expression profile and therefore confers worse prognosis due to elevated risk of metastasis. On the other hand, gain-of-function mutations of EIF1AX and SF3B1 correspond to a gene expression profile of class 1A and class 1B and confer a better prognosis. Preferentially expressed antigen in melanoma (PRAME) is an antigen that increases metastatic susceptibility when expressed in uveal melanoma cells. In addition to plaque brachytherapy and proton beam irradiation, both of which have demonstrated superb clinical outcomes, scientists are actively investigating newer therapeutic modalities as either primary therapy or adjuvant treatment, including a novel nanoparticle therapy and immunotherapy.
    Keywords:  Ocular; chemotherapy; genetics; melanoma; radiotherapy; retinoblastoma; tumor; uveal
    DOI:  https://doi.org/10.12703/r/10-51
  24. Int J Mol Sci. 2021 Jun 23. pii: 6727. [Epub ahead of print]22(13):
    Monosomy 3 Is Linked to Resistance to MEK Inhibitors in Uveal Melanoma.
    Svenja Mergener, Jens T Siveke, Samuel Peña-Llopis.
      The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor.
    Keywords:  BRCA1-associated protein 1; MAPK; eIF2 signaling; eIF2alpha; monosomy 3; ocular melanoma; targeted therapy
    DOI:  https://doi.org/10.3390/ijms22136727
  25. Cancers (Basel). 2021 Jun 21. pii: 3101. [Epub ahead of print]13(12):
    Circulating Tumor DNA as a Marker for Treatment Response in Metastatic Melanoma Patients Using Next-Generation Sequencing-A Prospective Feasibility Study.
    Marina Berger, Andrea Thueringer, Doritt Franz, Nadia Dandachi, Emina Talakić, Georg Richtig, Erika Richtig, Peter Michael Rohrer, Lukas Koch, Ingrid Hildegard Wolf, Catharina Koch, Barbara Margaretha Rainer, Maximilian Koeller, Martin Pichler, Hanno Gerritsmann, Karl Kashofer, Ariane Aigelsreiter.
      We prospectively performed a longitudinal analysis of circulating tumor DNA (ctDNA) from 149 plasma samples and CT scans in Stage III and IV metastatic melanoma patients (n = 20) treated with targeted agents or immunotherapy using two custom next-generation sequencing (NGS) Ion AmpliSeq™ HD panels including 60 and 81 amplicons in 18 genes, respectively. Concordance of matching cancer-associated mutations in tissue and plasma was 73.3%. Mutant allele frequency (MAF) levels showed a range from 0.04% to 28.7%, well detectable with NGS technologies utilizing single molecule tagging like the AmpliSeq™ HD workflow. Median followup time of the tissue and/or plasma positive cohort (n = 15) was 24.6 months and median progression-free survival (PFS) was 7.8 months. Higher MAF ≥ 1% at baseline was not significantly associated with a risk of progression (Odds Ratio = 0.15; p = 0.155). Although a trend could be seen, MAF levels did not differ significantly over time between patients with and without a PFS event (p = 0.745). Depending on the cell-free DNA amount, NGS achieved a sensitivity down to 0.1% MAF and allowed for parallel analysis of multiple mutations and previously unknown mutations. Our study indicates that NGS gene panels could be useful for monitoring disease burden during therapy with ctDNA in melanoma patients.
    Keywords:  circulating tumor DNA; custom panels; metastatic melanoma; next-generation sequencing; treatment monitoring
    DOI:  https://doi.org/10.3390/cancers13123101
  26. Photodermatol Photoimmunol Photomed. 2021 Jun 28.
    The review of the light parameters and mechanisms of Photobiomodulation on melanoma cells.
    Zeqing Chen, Shijie Huang, Muqing Liu.
      Photobiomodulation (PBM) that uses low-intensity visible or near-infrared light to produce beneficial effects on cells or tissues, such as brain therapy, wound healing. Still there is no consistent recommendation on the parameters (dose, light mode, wavelength, irradiance) and protocols (repetition, treatment duration) for its clinical application. Herein, we summarize the current PBM parameters for the treatment of melanoma, and we also discuss the potential photoreceptors and downstream signaling mechanisms in the PBM treatment of melanoma cells. It is hypothesized that PBM may inhibit the melanoma cells by activating mitochondria, OPNs, and other receptors. Regardless of the underlying mechanisms, PBM has been shown to be beneficial in treating melanoma. Through further in-depth studies of the underlying potential mechanisms, it can strengthen the applications of PBM for the therapy of melanoma.
    Keywords:  Melanoma; Mitochondria; Opsins; Photobiomodulation
    DOI:  https://doi.org/10.1111/phpp.12715
  27. Lancet Oncol. 2021 Jul;pii: S1470-2045(21)00354-5. [Epub ahead of print]22(7): e300
    Adjuvant therapy in stage IIIA melanoma - Authors' reply.
    Alexander M M Eggermont, Stefan Suciu, Caroline Robert.
      
    DOI:  https://doi.org/10.1016/S1470-2045(21)00354-5
  28. Cancers (Basel). 2021 Jun 22. pii: 3111. [Epub ahead of print]13(13):
    Knocking out the Vitamin D Receptor Enhances Malignancy and Decreases Responsiveness to Vitamin D3 Hydroxyderivatives in Human Melanoma Cells.
    Ewa Podgorska, Tae-Kang Kim, Zorica Janjetovic, Krystyna Urbanska, Robert C Tuckey, Sejong Bae, Andrzej T Slominski.
      Vitamin D3 is not only involved in calcium and phosphate metabolism in humans, but it can also affect proliferation and differentiation of normal and cancer cells, including melanoma. The mechanism of the anti-cancer action of vitamin D3 is not fully understood. The nuclear vitamin D receptor (VDR) is crucial for the phenotypic effects of vitamin D hydroxyderivatives. VDR expression shows an inverse correlation with melanoma progression and poor outcome of the disease. In this study we knocked out the VDR in a human melanoma cell line using CRISPR methodology. This enhanced the proliferation of melanoma cells grown in monolayer culture, spheroids or colonies and their migration. Activated forms of vitamin D, including classical 1,25(OH)2D3, 20(OH)D3 and 1,20(OH)2D3, inhibited cell proliferation, migration rate and the ability to form colonies and spheroids in the wild-type melanoma cell line, while VDR KO cells showed a degree of resistance to their action. These results indicate that expression of VDR is important for the inhibition of melanoma growth induced by activated forms of vitamin D. In conclusion, based on our previous clinicopathological analyses and the current study, we suggest that the VDR can function as a melanoma tumor suppressor gene.
    Keywords:  active forms of vitamin D; malignancy; melanoma; vitamin D; vitamin D receptor
    DOI:  https://doi.org/10.3390/cancers13133111
  29. Pediatr Blood Cancer. 2021 Jun;68 Suppl 4 e28992
    Cutaneous melanoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.
    Andrea Ferrari, Ricardo Lopez Almaraz, Yves Reguerre, Maja Cesen, Luca Bergamaschi, Alice Indini, Dominik T Schneider, Jan Godzinski, Ewa Bien, Teresa Stachowicz-Stencel, Thomas K Eigentler, Stefano Chiaravalli, Malgorzata A Krawczyk, Alberto Pappo, Daniel Orbach, Gianni Bisogno, Ines B Brecht.
      Cutaneous melanoma is rare in children and, like other very rare pediatric tumors, it suffers from a shortage of knowledge and clinical expertise. The clinical management of pediatric melanoma is often challenging. Its clinical and pathological diagnosis may be difficult, and there is no standard treatment. In the absence of specific treatment guidelines, young patients are generally treated following the same principle as for adults, but concern remains about their access to clinical trials and new drugs, which have been shown to dramatically change the natural history of advanced melanoma. This paper presents the internationally recognized recommendations for the diagnosis and treatment of children and adolescents with cutaneous melanoma, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded project called PARTNER (Paediatric Rare Tumours Network - European Registry). Main recommendations for melanoma are to discuss pediatric patients in multidisciplinary teams that include both pediatric oncologists and specialists in adult melanoma; to enroll patients in prospective trials, if available; to collect data in national-international databases; and to develop an effective international collaboration between pediatric and adult melanoma groups in order to facilitate the transfer of potentially effective new agents from the adult to the pediatric setting.
    Keywords:  EXPeRT; PARTNER; adolescents; children; cutaneous melanoma; diagnosis; guidelines; recommendations; therapy
    DOI:  https://doi.org/10.1002/pbc.28992
  30. Front Oncol. 2021 ;11 688410
    The Challenge of Melanocytic Lesions in Pediatric Patients: Clinical-Pathological Findings and the Diagnostic Value of PRAME.
    Giuseppina Rosaria Umano, Maria Elena Errico, Vittoria D'Onofrio, Giulia Delehaye, Letizia Trotta, Claudio Spinelli, Silvia Strambi, Renato Franco, Giuseppe D'Abbronzo, Andrea Ronchi, Alfonso Papparella.
      Pediatric melanoma is a rare disease especially in children aged younger than 10 years old. Recent estimates report a rise of disease incidence in both adults and children. Diagnostic work-up is challenging in pediatric melanoma, as it displays a wide range of clinical presentations. Immunohistochemical biomarkers have been reported as predictors of malignancy in melanoma, however data specific to pediatric melanoma are poor. Our study aims to contribute to provide evidence of pediatric melanoma clinical features and differential diagnosis in this patient population. We describe our experience with a retrospective case series of pigmented skin lesions including malignant melanoma, atypical spitzoid tumor, and benign nevi in children and adolescents aged less than 16 years. We described the clinical and demographic characteristics of the cohort and evaluated the immunohistochemical expression of the PReferentially expressed Antigen in MElanoma (PRAME) for differential diagnosis of melanoma in children. The series displayed a similar distribution of melanoma between males and females, and the most common site of melanoma onset were the upper and lower limbs. In our cohort, PRAME was negative in most cases. Focal and slight positivity (from 1 to 5% of the neoplastic cells) was observed in four cases (two Spitz nevi and two atypical Spitz tumors). A moderate positivity in 25% of the neoplastic cells was observed in one case of atypical Spitz tumor. Immunohistochemical expression of PRAME might be useful in the differential diagnosis of malignant melanoma.
    Keywords:  PRAME; atypical spitzoid tumor; children; immunohistochemistry; melanoma
    DOI:  https://doi.org/10.3389/fonc.2021.688410
  31. Cancers (Basel). 2021 Jun 30. pii: 3292. [Epub ahead of print]13(13):
    Metastatic Risk Factors Associated with Class 1A Uveal Melanoma Patients.
    Alexej Ballhausen, Elizabeth Urias, Stephen K Gruschkus, Michelle Williams, Maura S Glover, Yong Qin, Dan S Gombos, Sapna P Patel.
      In uveal melanoma (UM), gene expression profiling (GEP) is commonly used to classify metastatic risk into three groups (Class 1A, 1B, and 2). Class 1A patients have a lower metastatic risk of 2% at 5 years compared to other groups. We aimed to describe clinical features associated with the development of metastasis in this low-risk group. This single-center IRB-approved retrospective case series review included all UM patients between February 2006 and March 2019 with an archived or fresh specimen classified as Class 1A. Cox regression and receiver operating characteristics analyses were used to identify factors associated with metastasis development and OS. Among 73 UM patients with Class 1A, the 5-year cumulative incidence of local recurrence and distant metastasis was 4.2% and 17.0%, respectively. Stage III disease (HR 20.7; 95% confidence interval (95% CI) 1.4-300.6; p = 0.0264) was found to be independently associated with metastatic recurrence, while primary therapy was associated with OS (enucleation vs. brachytherapy, HR 13.5; 95% CI 1.3-147.6; p = 0.0348). Combined clinical decision-making utilizing factors such as GEP class, American Joint Committee on Cancer (AJCC) stage, and COMS size could have a significant clinical impact by improving risk stratification and adapting follow-up intervals in UM Class 1A patients.
    Keywords:  Class 1A; GEP; metastasis; risk factors; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13133292
  32. Melanoma Res. 2021 Aug 01. 31(4): 402-404
    Successful encorafenib desensitization in a patient with recurrent metastatic melanoma.
    Grace D Cullen, Heidi D Finnes, Svetomir N Markovic, Gerald W Volcheck.
      Type I hypersensitivity reactions (HSR) to dabrafenib are rare but have been previously described. We present a case where a 72-year-old woman with recurrent, metastatic BRAF-mutated melanoma developed a type I HSR to dabrafenib. We, therefore, developed a desensitization protocol with encorafenib, a similar class agent, to allow the patient to continue with treatment. Patients with a history of HSR to dabrafenib may be considered for encorafenib desensitization when other therapeutic options are limited.
    DOI:  https://doi.org/10.1097/CMR.0000000000000757
  33. Cancers (Basel). 2021 Jun 05. pii: 2826. [Epub ahead of print]13(11):
    Toxicity, Response and Survival in Older Patients with Metastatic Melanoma Treated with Checkpoint Inhibitors.
    Nienke A de Glas, Esther Bastiaannet, Frederiek van den Bos, Simon P Mooijaart, Astrid A M van der Veldt, Karlijn P M Suijkerbuijk, Maureen J B Aarts, Franchette W P J van den Berkmortel, Christian U Blank, Marye J Boers-Sonderen, Alfonsus J M van den Eertwegh, Jan-Willem B de Groot, John B A G Haanen, Geke A P Hospers, Hilde Jalving, Djura Piersma, Rozemarijn S van Rijn, Albert J Ten Tije, Gerard Vreugdenhil, Michel W J M Wouters, Johanneke E A Portielje, Ellen W Kapiteijn.
      BACKGROUND: Previous trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included. The aim of this study was to describe the treatment patterns and outcomes of "real-world" older patients with metastatic melanoma and to identify predictors of outcome.METHODS: We included patients aged ≥65 years with metastatic melanoma from the Dutch Melanoma Treatment Registry. We described the reasons for hospital admissions and treatment discontinuation. Additionally, we assessed predictors of toxicity and response using logistic regression models and survival using Cox regression models.
    RESULTS: We included 2216 patients. Grade ≥3 toxicity was not associated with age, comorbidities or WHO status. Patients aged ≥75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. Response rates were similar to previous trials (40.3% and 43.6% in patients aged 65-75 and ≥75, respectively, for anti-PD1 treatment) and did not decrease with age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity.
    CONCLUSION: Response rates and toxicity outcomes of checkpoint inhibitors did not change with increasing age or comorbidity. However, the impact of grade I-II toxicity on quality of life deserves further study as older patients discontinue treatment more frequently.
    Keywords:  geriatric oncology; immunotherapy; melanoma; older adults; response; toxicity
    DOI:  https://doi.org/10.3390/cancers13112826
  34. Int J Environ Res Public Health. 2021 Jun 08. pii: 6194. [Epub ahead of print]18(12):
    Cost-Effectiveness Analysis of Dabrafenib Plus Trametinib and Vemurafenib as First-Line Treatment in Patients with BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma in China.
    Tianfu Gao, Jia Liu, Jing Wu.
      Objective: To evaluate the cost-effectiveness of dabrafenib plus trametinib combination therapy versus vemurafenib as first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma from a healthcare system perspective in China. Methods: This study employed a partitioned survival model with three health states (progression-free survival, post-progression survival and dead) to parameterize the data derived from Combi-v trial and extrapolated to 30 years. Health states' utilities were measured by EQ-5D-3L, also sourced from the Combi-v trial. Costs including drug acquisition costs, disease management costs and adverse event costs were based on the Chinese Drug Bidding Database and physician survey in China. The primary outcomes of the model were lifetime costs, life-years (LYs), quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted, respectively. Result: Dabrafenib plus trametinib is projected to increase a patient's life expectancy by 0.95 life-years over vemurafenib (3.03 vs. 2.08) and 1.09 QALY gains (2.48 vs. 1.39) with an incremental cost of $3833. The incremental cost-effectiveness ratio (ICER) was $3511 per QALY. In the probabilistic sensitivity analyses, at a threshold of $33,357 per QALY (three times the gross domestic product (GDP) per capita in China in 2020), the probability of dabrafenib plus trametinib being cost-effective was 90%. In the deterministic sensitivity analyses, the results were most sensitive to the dabrafenib plus trametinib drug costs, vemurafenib drug costs and discount rate of cost. Conclusion: Dabrafenib plus trametinib therapy yields more clinical benefits than vemurafenib. Using a threshold of $33,357 per QALY, dabrafenib plus trametinib is very cost-effective as compared with vemurafenib in China.
    Keywords:  China; cost-effectiveness; dabrafenib plus trametinib; melanoma; vemurafenib
    DOI:  https://doi.org/10.3390/ijerph18126194
  35. J Immunol Res. 2021 ;2021 9920234
    Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression.
    Mieszko Lachota, Anton Lennikov, Karl-Johan Malmberg, Radoslaw Zagozdzon.
      Tumor-infiltrating immune cells are capable of effective cancer surveillance, and their abundance is linked to better prognosis in numerous tumor types. However, in uveal melanoma (UM), extensive immune infiltrate is associated with poor survival. This study aims to decipher the role of different tumor-infiltrating cell subsets in UM in order to identify potential targets for future immunotherapeutic treatment. We have chosen the TCGA-UVM cohort as a training dataset and GSE22138 as a testing dataset by mining publicly available databases. The abundance of 22 immune cell types was estimated using CIBERSORTx. Then, to determine the significance of tumor-infiltrating cell subsets in UM, we built a multicell type prognostic signature, which was validated in the testing cohort. The created signature was built upon the negative prognostic role of CD8+ T cells and M0 macrophages and the positive role of neutrophils. Based on the created signature score, we divided the patients into low- and high-risk groups. Kaplan-Meier, Cox, and ROC analyses demonstrated superior performance of our risk score compared to either clinical or pathologic characteristics of both cohorts. Further, we found the molecular pathways associated with cancer immunoevasion and metastasis to be enriched in the high-risk group, explaining both the lack of adequate immune surveillance despite increased infiltration of CD8+ T cells as well as the higher metastatic potential. Genes associated with tryptophan metabolism (IDO1 and KYNU) and metalloproteinases were among the most differentially expressed between the high- and low-risk groups. Our correlation analyses interpreted in context of published in vitro data strongly suggest the central role of CD8+ T cells in shifting the UM tumor microenvironment towards suppressive and metastasis-promoting. Therefore, we propose further investigations of IDO1 and metalloproteinases as novel targets for immunotherapy in lymphocyte-rich metastatic UM patients.
    DOI:  https://doi.org/10.1155/2021/9920234
  36. Exp Ther Med. 2021 Aug;22(2): 854
    Clinical-dermoscopic similarities between atypical nevi and early stage melanoma.
    Cristina-Raluca Jitian Mihulecea, Simona Frățilă, Maria Rotaru.
      Atypical (Clark) nevi are benign tumors that may be considered precursors of melanoma. Many studies acknowledge a linear progression from typical to atypical nevi that eventually transform into melanoma. It is often challenging to differentiate a Clark nevus from melanoma, especially in its early stages, due to their clinical, dermoscopic, and histological resemblance. Dermoscopy is a powerful tool in early melanoma diagnosis, but it is a subjective method of examination. Therefore, the use of dermoscopic algorithms and checklists can overcome this issue. In the case of a difficult diagnosis, since both dermoscopy and histopathological exam are subjective methods of examination, modern molecular biology techniques can be used to distinguish between benign and malignant tumors. This study aimed to test the accuracy of specific clinical and dermoscopic criteria in order to distinguish between benign and malignant tumors, with a secondary objective to provide an overview of the clinical and dermoscopic features of atypical nevi and melanoma. In the present study, dermoscopic algorithms did not necessarily help distinguish benign and malignant tumors but demonstrated that nevi and melanoma have similar characteristics.
    Keywords:  atypical nevi; dermoscopy; early diagnosis; histology; melanoma
    DOI:  https://doi.org/10.3892/etm.2021.10286
  37. Cells. 2021 Jun 09. pii: 1450. [Epub ahead of print]10(6):
    Chimeric Antigen Receptor (CAR) T Cell Therapy for Metastatic Melanoma: Challenges and Road Ahead.
    Tahereh Soltantoyeh, Behnia Akbari, Amirali Karimi, Ghanbar Mahmoodi Chalbatani, Navid Ghahri-Saremi, Jamshid Hadjati, Michael R Hamblin, Hamid Reza Mirzaei.
      Metastatic melanoma is the most aggressive and difficult to treat type of skin cancer, with a survival rate of less than 10%. Metastatic melanoma has conventionally been considered very difficult to treat; however, recent progress in understanding the cellular and molecular mechanisms involved in the tumorigenesis, metastasis and immune escape have led to the introduction of new therapies. These include targeted molecular therapy and novel immune-based approaches such as immune checkpoint blockade (ICB), tumor-infiltrating lymphocytes (TILs), and genetically engineered T-lymphocytes such as chimeric antigen receptor (CAR) T cells. Among these, CAR T cell therapy has recently made promising strides towards the treatment of advanced hematological and solid cancers. Although CAR T cell therapy might offer new hope for melanoma patients, it is not without its shortcomings, which include off-target toxicity, and the emergence of resistance to therapy (e.g., due to antigen loss), leading to eventual relapse. The present review will not only describe the basic steps of melanoma metastasis, but also discuss how CAR T cells could treat metastatic melanoma. We will outline specific strategies including combination approaches that could be used to overcome some limitations of CAR T cell therapy for metastatic melanoma.
    Keywords:  chimeric antigen receptor T cells; immunotherapy; metastatic melanoma
    DOI:  https://doi.org/10.3390/cells10061450
  38. J Cutan Pathol. 2021 Jun 29.
    Talimogene laherparepvec (TVEC) pseudolymphomatous reaction mimicking metastatic melanoma.
    Ania Henning, Doreen Agnese, Catherine G Chung.
      Talimogene laherparepvec (TVEC) is a genetically modified herpes simplex virus-1 approved as an intralesional oncolytic immunotherapy for the treatment of advanced melanoma. Cutaneous reactions at the site of injection may mimic recurrent or progressive melanoma; histopathological findings have included chronic granulomatous dermatitis, neutrophilic dermatitis, lymphocytic dermatitis and pigment incontinence. We report a 39-year-old male with metastatic stage IIIc melanoma treated with TVEC with clinical regression of melanoma lesions that later developed pink nodules at sites of prior injection. Histopathology demonstrated a nodular mononuclear infiltrate that stained strongly and diffusely with CD45 and CD20 with a surrounding rim of CD3-positive T-cells. Immunoglobulin gene rearrangement was negative for a clonal B cell population. To our knowledge, this is the first report of a pseudolymphomatous reaction mimicking recurrent melanoma after TVEC therapy. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1111/cup.14094
  39. BMC Cancer. 2021 Jul 02. 21(1): 765
    CD36 promotes vasculogenic mimicry in melanoma by mediating adhesion to the extracellular matrix.
    Carmela Martini, Mark DeNichilo, Danielle P King, Michaelia P Cockshell, Brenton Ebert, Brian Dale, Lisa M Ebert, Anthony Woods, Claudine S Bonder.
      BACKGROUND: The formation of blood vessels within solid tumors directly contributes to cancer growth and metastasis. Until recently, tumor vasculature was thought to occur exclusively via endothelial cell (EC) lined structures (i.e. angiogenesis), but a second source of tumor vasculature arises from the cancer cells themselves, a process known as vasculogenic mimicry (VM). While it is generally understood that the function of VM vessels is the same as that of EC-lined vessels (i.e. to supply oxygen and nutrients to the proliferating cancer cells), the molecular mechanisms underpinning VM are yet to be fully elucidated.METHODS: Human VM-competent melanoma cell lines were examined for their VM potential using the in vitro angiogenesis assays (Matrigel), together with inhibition studies using small interfering RNA and blocking monoclonal antibodies. Invasion assays and adhesion assays were used to examine cancer cell function.
    RESULTS: Herein we demonstrate that CD36, a cell surface glycoprotein known to promote angiogenesis by ECs, also supports VM formation by human melanoma cancer cells. In silico analysis of CD36 expression within the melanoma cohort of The Cancer Genome Atlas suggests that melanoma patients with high expression of CD36 have a poorer clinical outcome. Using in vitro 'angiogenesis' assays and CD36-knockdown approaches, we reveal that CD36 supports VM formation by human melanoma cells as well as adhesion to, and invasion through, a cancer derived extracellular matrix substrate. Interestingly, thrombospondin-1 (TSP-1), a ligand for CD36 on ECs that inhibits angiogenesis, has no effect on VM formation. Further investigation revealed a role for laminin, but not collagen or fibronectin, as ligands for CD36 expressing melanoma cells.
    CONCLUSIONS: Taken together, this study suggests that CD36 is a novel regulator of VM by melanoma cancer cells that is facilitated, at least in part, via integrin-α3 and laminin. Unlike angiogenesis, VM is not perturbed by the presence of TSP-1, thus providing new information on differences between these two processes of tumor vascularization which may be exploited to combat cancer progression.
    Keywords:  CD36; Integrin; Laminin; Melanoma; Thrombospondin; Tumor microenvironment; Vasculogenic mimicry
    DOI:  https://doi.org/10.1186/s12885-021-08482-4
  40. Cancers (Basel). 2021 Jun 30. pii: 3302. [Epub ahead of print]13(13):
    Predictive and Prognostic Value of BRAF and NRAS Mutation of 159 Sentinel Lymph Node Cases in Melanoma-A Retrospective Single-Institute Study.
    Gabriella Liszkay, Zoltán Mátrai, Kata Czirbesz, Nóra Jani, Eszter Bencze, István Kenessey.
      PURPOSE: To assess the prognostic role of sentinel lymph node status (SLN) in melanoma patients, a statistical comparison was performed with the application of already known prognostic factors, mutational occurrence of BRAF and NRAS in the primary tumor, as well as disease outcome.METHODS: Our retrospective single-center study involved 159 melanoma cases, who underwent SLN biopsy. The following clinico-pathological data were collected: age, gender, location of primary tumor, Breslow thickness, ulceration degree, histological subtype, mitosis count, lymphovascular and perineural invasion, presence of tumor-infiltrating lymphocytes, regression signs, mutations of BRAF and NRAS of the primary tumors, and SLN status.
    RESULTS: From the studied clinico-pathological factors, only Breslow thickness increased the risk of SLN positivity (p = 0.025) by multivariate analysis, while neither BRAF nor NRAS mutation of the primary tumor proved to be a predictor of the SLN status. While the NRAS-mutant subgroup showed the most unfavorable outcome for progression-free and distant metastasis-free survival, their rate of positive SLNs proved to be relatively lower than that of patient groups with BRAF mutation and double-wild-type phenotypes.
    CONCLUSION: Similarly to the importance of SLN positivity, NRAS mutation of the primary tumor proved to be an independent prognostic factor of progression. Therefore, despite negative SLN, this NRAS-mutant subgroup of patients still requires closer monitoring to detect disease progression.
    Keywords:  BRAF; NRAS; melanoma; progression; sentinel lymph node
    DOI:  https://doi.org/10.3390/cancers13133302
  41. Hum Mol Genet. 2021 Jun 28. pii: ddab173. [Epub ahead of print]
    ZNF224 is a mediator of TGF-β pro-oncogenic function in melanoma.
    Elena Cesaro, Arianna Pastore, Alessia Polverino, Lorenzo Manna, Giuseppina Divisato, Cristina Quintavalle, Maddalena Di Sanzo, Maria Concetta Faniello, Michela Grosso, Paola Costanzo.
      The zinc finger protein ZNF224 plays a dual role in cancer, operating as both tumor suppressor and oncogenic factor depending on cellular and molecular partners. In this research we investigated the role of ZNF224 in melanoma, a highly invasive and metastatic cancer, and provided evidence for the involvement of ZNF224 in the TGF-β signaling as a mediator of the TGF-β pro-oncogenic function. Our results showed that ZNF224, whose expression increased in melanoma cell lines after TGF-β stimulation, potentiated the activation induced by TGF-β on its target genes involved in epithelial-mesenchymal transition (EMT). Accordingly, overexpression of ZNF224 enhanced the tumourigenic properties of melanoma cells, promoting cell proliferation and invasiveness, while ZNF224 knockdown had the opposite effect. Moreover, ZNF224 positively modulates the expression of TGF-β itself and its type 1 and 2 receptors (TβR1 and TβR2), thus highlighting a possible mechanism by which ZNF224 could enhance the endogenous TGFβ/Smad signalling. Our findings unveil a positive regulatory loop between TGF-β and ZNF224 to promote EMT, consequently increasing the tumour metastatic potential.
    DOI:  https://doi.org/10.1093/hmg/ddab173
  42. NPJ Precis Oncol. 2021 Jun 10. 5(1): 50
    Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations.
    S Vasudevan, E Flashner-Abramson, Heba Alkhatib, Sangita Roy Chowdhury, I A Adejumobi, D Vilenski, S Stefansky, A M Rubinstein, N Kravchenko-Balasha.
      BRAFV600E melanoma patients, despite initially responding to the clinically prescribed anti-BRAFV600E therapy, often relapse, and their tumors develop drug resistance. While it is widely accepted that these tumors are originally driven by the BRAFV600E mutation, they often eventually diverge and become supported by various signaling networks. Therefore, patient-specific altered signaling signatures should be deciphered and treated individually. In this study, we design individualized melanoma combination treatments based on personalized network alterations. Using an information-theoretic approach, we compute high-resolution patient-specific altered signaling signatures. These altered signaling signatures each consist of several co-expressed subnetworks, which should all be targeted to optimally inhibit the entire altered signaling flux. Based on these data, we design smart, personalized drug combinations, often consisting of FDA-approved drugs. We validate our approach in vitro and in vivo showing that individualized drug combinations that are rationally based on patient-specific altered signaling signatures are more efficient than the clinically used anti-BRAFV600E or BRAFV600E/MEK targeted therapy. Furthermore, these drug combinations are highly selective, as a drug combination efficient for one BRAFV600E tumor is significantly less efficient for another, and vice versa. The approach presented herein can be broadly applicable to aid clinicians to rationally design patient-specific anti-melanoma drug combinations.
    DOI:  https://doi.org/10.1038/s41698-021-00190-3
  43. Front Immunol. 2021 ;12 672521
    PDCD1 Polymorphisms May Predict Response to Anti-PD-1 Blockade in Patients With Metastatic Melanoma.
    Sagun Parakh, Ashan Musafer, Sabrina Paessler, Tom Witkowski, Connie S N Li Wai Suen, Candani S A Tutuka, Matteo S Carlino, Alexander M Menzies, Richard A Scolyer, Jonathan Cebon, Alexander Dobrovic, Georgina V Long, Oliver Klein, Andreas Behren.
      A significant number of patients (pts) with metastatic melanoma do not respond to anti-programmed cell death 1 (PD1) therapies. Identifying predictive biomarkers therefore remains an urgent need. We retrospectively analyzed plasma DNA of pts with advanced melanoma treated with PD-1 antibodies, nivolumab or pembrolizumab, for five PD-1 genotype single nucleotide polymorphisms (SNPs): PD1.1 (rs36084323, G>A), PD1.3 (rs11568821, G>A), PD1.5 (rs2227981, C>T) PD1.6 (rs10204225, G>A) and PD1.9 (rs2227982, C>T). Clinico-pathological and treatment parameters were collected, and presence of SNPs correlated with response, progression free survival (PFS) and overall survival (OS). 115 patients were identified with a median follow up of 18.7 months (range 0.26 - 52.0 months). All were Caucasian; 27% BRAF V600 mutation positive. At PD-1 antibody commencement, 36% were treatment-naïve and 52% had prior ipilimumab. The overall response rate was 43%, 19% achieving a complete response. Overall median PFS was 11.0 months (95% CI 5.4 - 17.3) and median OS was 31.1 months (95% CI 23.2 - NA). Patients with the G/G genotype had more complete responses than with A/G genotype (16.5% vs. 2.6% respectively) and the G allele of PD1.3 rs11568821 was significantly associated with a longer median PFS than the AG allele, 14.1 vs. 7.0 months compared to the A allele (p=0.04; 95% CI 0.14 - 0.94). No significant association between the remaining SNPs and responses, PFS or OS were observed. Despite limitations in sample size, this is the first study to demonstrate an association of a germline PD-1 polymorphism and PFS in response to anti-PD-1 therapy in pts with metastatic melanoma. Extrinsic factors like host germline polymorphisms should be considered with tumor intrinsic factors as predictive biomarkers for immune checkpoint regulators.
    Keywords:  PD1; immunotherapy; metastatic melanoma; polymorphism; predictive biomarker
    DOI:  https://doi.org/10.3389/fimmu.2021.672521
  44. Front Oncol. 2021 ;11 670726
    Therapeutic Advancements Across Clinical Stages in Melanoma, With a Focus on Targeted Immunotherapy.
    Claudia Trojaniello, Jason J Luke, Paolo A Ascierto.
      Melanoma is the most fatal skin cancer. In the early stages, it can be safely treated with surgery alone. However, since 2011, there has been an important revolution in the treatment of melanoma with new effective treatments. Targeted therapy and immunotherapy with checkpoint inhibitors have changed the history of this disease. To date, more than half of advanced melanoma patients are alive at 5 years; despite this breakthrough, approximately half of the patients still do not respond to treatment. For these reasons, new therapeutic strategies are required to expand the number of patients who can benefit from immunotherapy or combination with targeted therapy. Current research aims at preventing primary and acquired resistance, which are both responsible for treatment failure in about 50% of patients. This could increase the effectiveness of available drugs and allow for the evaluation of new combinations and new targets. The main pathways and molecules under study are the IDO inhibitor, TLR9 agonist, STING, LAG-3, TIM-3, HDAC inhibitors, pegylated IL-2 (NKTR-214), GITR, and adenosine pathway inhibitors, among others (there are currently about 3000 trials that are evaluating immunotherapeutic combinations in different tumors). Other promising strategies are cancer vaccines and oncolytic viruses. Another approach is to isolate and remove immune cells (DCs, T cells, and NK cells) from the patient's blood or tumor infiltrates, add specific gene fragments, expand them in culture with growth factors, and re-inoculate into the same patient. TILs, TCR gene transfer, and CAR-T therapy follow this approach. In this article, we give an overview over the current status of melanoma therapies, the clinical rationale for choosing treatments, and the new immunotherapy approaches.
    Keywords:  advanced melanoma; immune checkpoint inhibitor (ICI); immune system; immunotherapy; target therapy
    DOI:  https://doi.org/10.3389/fonc.2021.670726
  45. Cancers (Basel). 2021 Jun 19. pii: 3058. [Epub ahead of print]13(12):
    Nectin-1 Expression Correlates with the Susceptibility of Malignant Melanoma to Oncolytic Herpes Simplex Virus In Vitro and In Vivo.
    Barbara Schwertner, Georg Lindner, Camila Toledo Stauner, Elisa Klapproth, Clara Magnus, Anette Rohrhofer, Stefanie Gross, Beatrice Schuler-Thurner, Veronika Öttl, Nicole Feichtgruber, Konstantin Drexler, Katja Evert, Michael P Krahn, Mark Berneburg, Barbara Schmidt, Philipp Schuster, Sebastian Haferkamp.
      Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus, is approved for intralesional injection of unresectable stage IIIB/IVM1a melanoma. However, it is still unclear which parameter(s) predict treatment response or failure. Our study aimed at characterizing surface receptors Nectin-1 and the herpes virus entry mediator (HVEM) in addition to intracellular molecules cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) as potential bio-markers for oncolytic virus treatment. In 20 melanoma cell lines, oncolytic activity of T-VEC was correlated with the expression of Nectin-1 but not HVEM, as evaluated via flow cytometry and immunohistochemistry. Knockout using CRISPR/Cas9 technology confirmed the superior role of Nectin-1 over HVEM for entry and oncolytic activity of T-VEC. Neither cGAS nor STING as evaluated by Western Blot and immunohistochemistry correlated with T-VEC induced oncolysis. The role of these biomarkers was retrospectively analyzed for the response of 35 cutaneous melanoma metastases of 21 patients to intralesional T-VEC injection, with 21 (60.0%) of these lesions responding with complete (n = 16) or partial regression (n = 5). Nectin-1 expression in pretreatment biopsies significantly predicted treatment outcome, while the expression of HVEM, cGAS, and STING was not prognostic. Altogether, Nectin-1 served as biomarker for T-VEC-induced melanoma regression in vitro and in vivo.
    Keywords:  T-VEC; herpes simplex virus; malignant melanoma; nectin-1; oncolytic
    DOI:  https://doi.org/10.3390/cancers13123058
  46. Br J Dermatol. 2021 Jun 29.
    The Role of Interferons in Melanoma Resistance to Immune Checkpoint Blockade: Mechanisms of Escape and Therapeutic Implications.
    K M Hargadon.
      Immune checkpoint blockade therapy has achieved unprecedented success in the treatment of metastatic melanoma, though its efficacy is often limited by innate and acquired mechanisms of resistance. Type I and type II interferons act as key determinants of checkpoint blockade therapeutic outcome, and tumor-intrinsic and -extrinsic factors that disrupt interferon activity confer resistance to various checkpoint inhibitors. This review highlights our current understanding of the mechanisms by which tumors disrupt interferon function in the context of immune checkpoint blockade, and it discusses therapeutic strategies to overcome these mechanisms of resistance and improve the clinical reach of checkpoint blockade therapy in melanoma patients.
    DOI:  https://doi.org/10.1111/bjd.20608
  47. Diagnostics (Basel). 2021 Jun 18. pii: 1110. [Epub ahead of print]11(6):
    Predictive Evaluation on Cytological Sample of Metastatic Melanoma: The Role of BRAF Immunocytochemistry in the Molecular Era.
    Andrea Ronchi, Marco Montella, Federica Zito Marino, Michele Caraglia, Anna Grimaldi, Giuseppe Argenziano, Elvira Moscarella, Gabriella Brancaccio, Teresa Troiani, Stefania Napolitano, Renato Franco, Immacolata Cozzolino.
      BACKGROUND: Cutaneous malignant melanoma is an aggressive neoplasm. In advanced cases, the therapeutic choice depends on the mutational status of BRAF. Fine needle aspiration cytology (FNA) is often applied to the management of patients affected by melanoma, mainly for the diagnosis of metastases. The evaluation of BRAF mutational status by sequencing technique on cytological samples may be inconvenient, as it is a time and biomaterial-consuming technique. Recently, BRAF immunocytochemistry (ICC) was applied for the evaluation of BRAF V600E mutational status. Although it may be useful mainly in cytological samples, data about BRAF ICC on cytological samples are missing.METHODS: We performed BRAF ICC on a series of 50 FNA samples of metastatic melanoma. BRAF molecular analysis was performed on the same cytological samples or on the corresponding histological samples. Molecular analysis was considered the gold standard.
    RESULTS: BRAF ICC results were adequate in 49 out of 50 (98%) cases, positive in 15 out of 50 (30%) cases and negative in 34 out of 50 (68%) of cases. Overall, BRAF ICC sensitivity, specificity, positive predictive value and negative predictive value results were 88.2%, 100%, 100% and 94.1%, respectively. The diagnostic performance of BRAF ICC results was perfect when molecular evaluation was performed on the same cytological samples. Hyperpigmentation represents the main limitation of the technique.
    CONCLUSIONS: BRAF ICC is a rapid, cost-effective method for detecting BRAF V600E mutation in melanoma metastases, applicable with high diagnostic performance to cytological samples. It could represent the first step to evaluate BRAF mutational status in cytological samples, mainly in poorly cellular cases.
    Keywords:  BRAF; fine needle aspiration; immunocytochemistry; melanoma
    DOI:  https://doi.org/10.3390/diagnostics11061110
  48. Cancers (Basel). 2021 Jun 11. pii: 2931. [Epub ahead of print]13(12):
    Frequency, Treatment and Outcome of Immune-Related Toxicities in Patients with Immune-Checkpoint Inhibitors for Advanced Melanoma: Results from an Institutional Database Analysis.
    Florentia Dimitriou, Ramon Staeger, Melike Ak, Matias Maissen, Ken Kudura, Marjam J Barysch, Mitchell P Levesque, Phil F Cheng, Reinhard Dummer, Joanna Mangana.
      Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs), which may result in treatment discontinuation. We sought to describe the onset, frequency, and kinetics of irAEs in melanoma patients in a real-life setting and to further investigate the prognostic role of irAEs in treatment outcomes. In this retrospective single-center cohort study, we included 249 melanoma patients. Onset, grade, and resolution of irAEs and their treatment were analyzed. A total of 191 (74.6%) patients in the non-adjuvant and 65 (25.3%) in the adjuvant treatment setting were identified. In the non-adjuvant setting, 29 patients (59.2%) with anti-CTLA4, 43 (58.1%) with anti-PD1, and 54 (79.4%) with anti-PD1/anti-CTLA4 experienced some grade of irAE and these had an improved outcome. In the adjuvant setting, the frequency of irAEs was 84.6% in anti-CTLA4 and 63.5% in anti-PD1, but no correlation with disease relapse was observed. Patients with underlying autoimmune conditions have a risk of disease exacerbation. Immunomodulatory agents had no impact on treatment efficacy. IrAEs are correlated with increased treatment efficacy in the non-adjuvant setting. Application of steroids and immunomodulatory agents, such as anti-TNF-alpha or anti-IL6, did not affect ICI efficacy. These data support irAEs as possible prognostic markers for ICI treatment.
    Keywords:  immune-related adverse events; immunotherapy; infliximab; melanoma; tocilizumab
    DOI:  https://doi.org/10.3390/cancers13122931
  49. Animal Model Exp Med. 2021 Jun;4(2): 138-150
    Identification ACTA2 and KDR as key proteins for prognosis of PD-1/PD-L1 blockade therapy in melanoma.
    Yuchen Wang, Zhaojun Li, Zhihui Zhang, Xiaoguang Chen.
      Programmed cell death protein 1 (PD-1) /programmed cell death ligand 1 (PD-L1) blockade is an important therapeutic strategy for melanoma, despite its low clinical response. It is important to identify genes and pathways that may reflect the clinical outcomes of this therapy in patients. We analyzed clinical dataset GSE96619, which contains clinical information from five melanoma patients before and after anti-PD-1 therapy (five pairs of data). We identified 704 DEGs using these five pairs of data, and then the number of DEGs was narrowed down to 286 in patients who responded to treatment. Next, we performed KEGG pathway enrichment and constructed a DEG-associated protein-protein interaction network. Smooth muscle actin 2 (ACTA2) and tyrosine kinase growth factor receptor (KDR) were identified as the hub genes, which were significantly downregulated in the tumor tissue of the two patients who responded to treatment. To confirm our analysis, we demonstrated similar expression tendency to the clinical data for the two hub genes in a B16F10 subcutaneous xenograft model. This study demonstrates that ACTA2 and KDR are valuable responsive markers for PD-1/PD-L1 blockade therapy.
    Keywords:  PD‐1/PD‐L1 blockade therapy; expression profiling data; hub genes; melanoma
    DOI:  https://doi.org/10.1002/ame2.12154
  50. BMC Cancer. 2021 Jul 01. 21(1): 761
    The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma.
    Oliver Coen, Pippa Corrie, Helen Marshall, Ruth Plummer, Christian Ottensmeier, Jane Hook, Sue Bell, Gurdeep S Sagoo, David Meads, Janine Bestall, Galina Velikova, Ferdia A Gallagher, Alexandra Smith, Helen Howard, Ellen Mason, Eszter Katona, Shobha Silva, Michelle Collinson, Simon Rodwell, Sarah Danson.
      BACKGROUND: Immunotherapy is revolutionising the treatment of patients diagnosed with melanoma and other cancers. The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)), showed a survival advantage over standard chemotherapy. Subsequently the anti-programmed cell death protein 1 (PD-1) antibodies, nivolumab and pembrolizumab were shown to be more effective than ipilimumab. Ipilimumab combined with nivolumab gives an incremental gain in overall survival compared with nivolumab alone but increases the risk of severe, potentially life-threatening toxicities. In contrast to ipilimumab monotherapy, anti-PD-1 antibodies are licensed to be continued until disease progression. Follow-up of patients recruited to the first trials evaluating 2 years of pembrolizumab showed that three-quarters of responding patients continue responding after stopping treatment. Suggestive of early response, we hypothesised that continuing anti-PD-1 treatment beyond 1 year in progression-free patients may be unnecessary and so designed the DANTE trial.METHODS: DANTE is a multicentre, randomised, phase III, non-inferiority trial to evaluate the duration of anti-PD-1 therapy in patients with metastatic (unresectable stage III and stage IV) melanoma. It uses a two-stage recruitment strategy, registering patients before they complete 1 year of first-line anti-PD-1 +/- CTLA-4 therapy and randomising eligible patients who have received 12 months of treatment and are progression-free at 1 year. At randomisation, 1208 patients are assigned (1:1) to either 1) continue anti-PD-1 treatment until disease progression/ unacceptable toxicity/ for at least 2 years in the absence of disease progression/ unacceptable toxicity or 2) to stop treatment. Randomisation stratifies for baseline prognostic factors. The primary outcome is progression-free survival at 3, 6, 9 and 12 months and then, 6-monthly for up to 4-years. Secondary outcomes collected at all timepoints include overall survival, response-rate and duration and safety, with quality of life and cost-effectiveness outcomes collected 3-monthly for up to 18-months. Sub-studies include a qualitative analysis of patient acceptance of randomisation and sample collection to inform future translational studies into response/ toxicity biomarkers.
    DISCUSSION: DANTE is a unique prospective trial investigating the optimal duration of anti-PD-1 therapy in metastatic melanoma patients. Outcomes will inform future use of these high burden drugs.
    TRIAL REGISTRATION: ISRCTN15837212 , 31 July 2018.
    Keywords:  Anti-PD-1; Checkpoint inhibitor; Efficacy; Immunotherapy; Metastatic melanoma; Quality of life; Safety; Schedule
    DOI:  https://doi.org/10.1186/s12885-021-08509-w
  51. Cancers (Basel). 2021 Jun 21. pii: 3086. [Epub ahead of print]13(12):
    Electrochemotherapy with Bleomycin Enhances Radiosensitivity of Uveal Melanomas: First In Vitro Results in 3D Cultures of Primary Uveal Melanoma Cell Lines.
    Miltiadis Fiorentzis, Ekaterina A Sokolenko, Nikolaos E Bechrakis, Saskia Ting, Kurt W Schmid, Ali Sak, Martin Stuschke, Berthold Seitz, Utta Berchner-Pfannschmidt.
      Electrochemotherapy (ECT) is emerging as a complementary treatment modality for local tumor control in various cancer entities. Irradiation is an established therapeutic option for oncologic patients, which is commonly combined with chemotherapy due to its insufficient targeting ability. The efficiency of radiotherapy for tumors can be enhanced with different radiosensitizers. ECT can potentiate the radiosensitizing effect of chemotherapeutic agents such as bleomycin. The present study aims to evaluate the radiosensitizing effect of concomitant ECT with bleomycin on 3D tumor spheroids with primary and radioresistant uveal melanoma cell lines (UPMD2, UPMM3, UM92.1, Mel270) and irradiation. The changes in the spheroid growth and the cell viability as well the cytotoxic long-term effect of the combination treatment were evaluated with various combinations of electroporation settings and bleomycin concentrations as well as radiotherapy doses. A broad range of radiosensitivity was documented among the spheroids from different uveal melanoma cell lines. The primary cell lines showed a higher radiosensitivity and required lower irradiation and bleomycin doses. The maximal tumor control with a reduction of cell survival <10% was achieved with a 5 Gy irradiation only in the primary uveal melanoma cell lines and in combination with all tested ECT settings, whereas the same result could be obtained in UM92.1 spheroids only after ECT with 20 Gy irradiation. Based on the spheroid growth and the measurement of the cross-sectional area, the Mel270 spheroids, originating from a previously irradiated recurrent uveal melanoma, required higher doses of bleomycin and ECT settings after irradiation with 5 Gy in order to achieve a significant growth reduction. No significant difference could be demonstrated for the reduction of cell viability in the combination therapy with 20 Gy and 1000 V/cm between 1 and 2.5 µg/mL bleomycin even in Mel270 spheroids, underlying the importance of a drug delivery system to potentiate the radiosensitizing effect of agents in lower doses. ECT should be further assessed for its applicability in clinical settings as a therapeutic radiosensitizing option for radioresistant tumors and a sufficient local tumor control with lower chemotherapy and irradiation doses.
    Keywords:  3D tumor spheroids; bleomycin; cytotoxic effects; electrochemotherapy; long-time survival; radiation therapy; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13123086
  52. Oncol Lett. 2021 Aug;22(2): 597
    Artesunate combined with verteporfin inhibits uveal melanoma by regulation of the MALAT1/yes-associated protein signaling pathway.
    Xudong Jiu, Yang Liu, Jin Wen.
      Uveal melanoma (UM) is the most common ocular malignancy and has no effective clinical treatment. Therefore, novel drugs to suppress UM tumor progression are urgently required. The present study aimed to clarify the underlying mechanism of the inhibitory effects of artesunate on UM. By using plasmid transfection and detecting apoptotic level, the present study identified artesunate as a potential candidate for UM treatment. Compared with those in the vehicle (DMSO)-treated control cells, artesunate enhanced the apoptotic rate and increased lactate dehydrogenase release, reactive oxygen species and IL1b and IL18 levels in C918 cells. Overexpression of yes-associated protein (YAP) or metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in C918 cells reversed the effects of artesunate and reduced the apoptotic rate compared with those observed in cells transfected with the negative control plasmid. Notably, verteporfin enhanced the effects of artesunate on C918 cells by increasing the apoptotic rate, indicating that combined therapy was more effective compared with treatment with artesunate alone. In conclusion, the results of the present study demonstrated that artesunate elevated the apoptotic rate and suppressed C918 cell viability by regulating the MALAT1/YAP signaling pathway, and these effects were enhanced by supplementation with verteporfin. These results suggested that artesunate may exert an inhibitory effect on C918 cells and that the MALAT1/YAP signaling may serve important role in mediating these effects, providing evidence of its potential for treating UM in the clinic.
    Keywords:  MALAT1; apoptosis; artesunate; combination therapy; uveal melanoma; yes-associated protein
    DOI:  https://doi.org/10.3892/ol.2021.12858
  53. SAGE Open Med Case Rep. 2021 ;9 2050313X211023685
    Metastatic Merkel cell carcinoma and malignant melanoma in a single sentinel lymph node.
    Amanda Hamilton, Prasad Jayaratne, Mark Zonta.
      Merkel cell carcinoma (MCC) and malignant melanoma are aggressive skin cancers that usually arise in sun-exposed parts of the body. This report describes an 85-year-old man who underwent a wide local excision and sentinel lymph node biopsy for primary MCC and was subsequently found to have metastatic MCC and malignant melanoma within the left inguinal sentinel lymph node. Dual diagnoses of aggressive cutaneous carcinomas, although rare, may become more common in regions of high ultraviolet exposure and an ageing population. Currently, there are no guidelines for treating synchronous MCC and melanoma, however, immunotherapy with PD-1 inhibitors and anti-CTLA-4 receptor antagonists have shown therapeutic effect against these two cancers and should be considered in treatment planning.
    Keywords:  BRAF; Merkel cell carcinoma; Metastatic; immunotherapy; melanoma; neuroendocrine; radiation and chemotherapy; sentinel lymph node biopsy; wide local excision
    DOI:  https://doi.org/10.1177/2050313X211023685
  54. Int J Gen Med. 2021 ;14 2751-2761
    Nomogram Incorporating the WNT/β-Catenin Signaling Pathway for Predicting the Survival of Cutaneous Melanoma.
    Yu-Xin Zhou, Xin Wang, De-Quan Pang, Ying-Man Wang, Jing Bai, Fei Tian, Duo Han, Shuwei Shi, Lei Hu.
      Background: Accurate prediction of the survival of cutaneous melanoma (CM) permits the selection of the optimal treatment. Currently, the TNM stage has limitations in predicting the survival of CM. There is evidence that the WNT/β-catenin signaling pathway has the potential to predict the CM prognosis. However, it still needs further investigation.Objective: This study aims to establish a nomogram incorporating the WNT/β-catenin signaling pathway to improve the predicted accuracy of the overall survival (OS) of CM.
    Methods: Two hundred and eighty CM patients were recruited and followed up. The clinicopathological characteristics and the key genes of the WNT/β-catenin signaling pathway (VEGF, β-catenin, and DKK1) were chosen as potential variables associated with the OS. In the training cohort (n = 190), a nomogram was built to estimate the 1-, 3-, and 5-year OS, and its discriminations and calibrations were valid by the verification cohort (n = 90). The predicted accuracies of the nomogram with or without the Wnt/β-catenin pathway and TNM stage were compared.
    Results: A nomogram integrating independent risk factors (ulceration, lymph node metastasis, distant metastasis, Breslow thickness, dermal mitoses, β-catenin, VEGF, and DKK1), which were evaluated by a multivariate analysis, was constructed to predict the 1-, 3-, and 5-year OS of CM patients. Good discrimination and calibration were obtained regardless of the training or validation datasets. The nomogram incorporating the Wnt/β-catenin signaling pathway showed the highest accuracy [area under the curve (AUC)=0.914, 0.852, 0.785] compared with the nomogram without the Wnt/β-catenin signaling pathway (AUC=0.693, 0.640, 0.615) and the TNM stage (AUC=0.726, 0.693, 0.673).
    Conclusion: The prognostic value of the established nomogram incorporating the WNT/β-catenin signaling pathway was better than it without WNT/β-catenin signaling pathway and TNM stage, which might be beneficial in the development of optimal treatment options.
    Keywords:  TNM; WNT/β-catenin signaling pathway; cutaneous melanoma; nomogram; overall survial
    DOI:  https://doi.org/10.2147/IJGM.S309616
  55. J Invest Dermatol. 2021 Jun 26. pii: S0022-202X(21)01406-8. [Epub ahead of print]
    Slow transcription of the 99a/let-7c/125b-2 cluster results in differential miRNA expression and promotes melanoma phenotypic plasticity.
    Danna Sheinboim, Shivang Parikh, Roma Parikh, Amitai Menuchin, Guy Shapira, Oxana Kapitansky, Nadav Elkoshi, Shmuel Ruppo, Lital Shaham, Tamar Golan, Sharona Elgavish, Yuval Nevo, Rachel E Bell, Hagar Malcov, Noam Shomron, Jeffrey W Taub, Shai Izraeli, Carmit Levy.
      Almost half of human miRNAs are encoded in clusters. Although transcribed as a single unit, the levels of individual mature miRNAs often differ. The mechanisms underlying differential biogenesis of clustered miRNAs and the resulting physiological implications are mostly unknown. Here, we report that the melanoma master transcription regulator MITF regulates the differential expression of the 99a/let-7c/125b-2 cluster by altering the distribution of RNA polymerase II (Pol-II) along the cluster. We discovered that MITF interacts with TRIM28, a known inhibitor of Pol-II transcription elongation, at the let-7c region resulting in Pol-II pausing and causing its elevated expression, whereas low levels of Pol-II occupation over miR-99a and miR-125b-2 regions decreases their biogenesis. Furthermore, we showed that this differential expression affects the phenotypic state of melanoma cells. RNA-seq analysis of proliferative melanoma cells that express miR-99a and miR-125b mimics revealed a transcriptomic shift toward an invasive phenotype. Conversely, expression of a let-7c mimic in invasive melanoma cells induced a shift to a more proliferative state. We confirmed direct target genes of these miRNAs: FGFR3, BAP1, Bcl2, TGFBR1, and CDKN1A. Our study demonstrates a MITF-governed biogenesis mechanism that results in differential expression of clustered 99a/let-7c/125b-2 miRNAs that control melanoma progression.
    Keywords:  MITF; Transcription; melanoma; miRNA biogenesis; tumor invasion
    DOI:  https://doi.org/10.1016/j.jid.2021.03.036
  56. Front Oncol. 2021 ;11 693655
    Triple Combination Therapy With PD-1/PD-L1, BRAF, and MEK Inhibitor for Stage III-IV Melanoma: A Systematic Review and Meta-Analysis.
    Ye Liu, Xilan Zhang, Guoying Wang, Xinchang Cui.
      Triple combination of anti-PD-1/PD-L1 immunotherapy and anti-BRAF plus anti-MEK targeted therapy is a promising antitumor strategy and is increasingly being used in clinical trials. To evaluate the safety and efficacy of triple combination of PD-1/PD-L1, BRAF, and MEK inhibition in patients diagnosed with stage III-IV melanoma, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs). The PubMed, EMBASE, and Cochrane Library were searched for all studies published from inception to January 2021. The progression free survival (PFS), overall survival (OS), overall response rate (ORR), and risk of adverse events (AEs) were extracted by two independent investigators and pooled hazard ratio (HR) or risk ratio (RR) with 95% CI were determined using the random-effects model for data synthesis. Overall, five randomized controlled trials encompassing 1,266 patients with stage III-IV melanoma were selected. Triple combination therapy significantly improved PFS (HR = 0.71; 95% CI = 0.59 to 0.86; P = 0.0005) and 2-year OS (RR = 1.12; 95% CI = 1.03 to 1.23; P = 0.01), but had no impact on ORR (RR = 1.09; 95% CI = 0.91 to 1.30; P = 0.37) when compared with controlled treatment group. In addition, triple combination therapy was associated with increased risks of hypothyroidism, arthralgia, myalgia, ALT increased, AST increased, asthenia, and pyrexia compared with control group. Triple combination therapy of PD-1/PD-L1, BRAF, and MEK inhibition achieved better survival benefits but had higher incidence of some adverse events over two-drug combination or monotherapy. Further randomized controlled clinical trials are needed to verify our results.Systematic Review Registration: PROSPERO 2021 CRD42021235845 Available from https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021235845.
    Keywords:  BRAF inhibition; MEK inhibition; PD-1/PD-L1; melanoma; meta-analysis; triple combination therapy
    DOI:  https://doi.org/10.3389/fonc.2021.693655
  57. Ann Surg Oncol. 2021 Jun 30.
    Landmark Series on Disparities in Surgical Oncology: Melanoma.
    Elliot A Asare, Umang Swami, John H Stewart.
      BACKGROUND: Although the lifetime risk of melanoma is disproportionately higher in whites, blacks have a poorer overall survival with an absolute survival difference of 25%. Significant progress has been made in melanoma treatment in the past decade; however, these successes may not be available or accessible to all segments of the population.METHODS: In this review, we highlight important studies in melanoma as well as informative retrospective studies from databases and nonmelanoma cancers where appropriate.
    RESULTS: There are no level I evidence-based studies on disparities in melanoma, and most likely there will never be, but the studies presented herein and clinical experience demonstrate that disparities in clinical outcomes from melanoma exists.
    CONCLUSIONS: By becoming aware of the disparities, we can help mitigate them by engagement, education, and corrective and empowering actions through awareness campaigns, appropriate clinical trial design, encouraging participation in clinical trials, increasing the diversity of providers, and advocacy.
    DOI:  https://doi.org/10.1245/s10434-021-10273-x
  58. Eur J Cancer. 2021 Jun 25. pii: S0959-8049(21)00324-5. [Epub ahead of print]153 168-178
    Hyperacute toxicity with combination ipilimumab and anti-PD1 immunotherapy.
    Helen Dearden, Lewis Au, Daniel Y Wang, Lisa Zimmer, Zeynep Eroglu, Jessica L Smith, Marcello Cuvietto, Chloe Khoo, Victoria Atkinson, Serigne Lo, Georgina V Long, Shahneen Sandhu, Paolo A Ascierto, Matteo S Carlino, Douglas B Johnson, James Larkin, Alexander M Menzies.
      BACKGROUND: Combination ipilimumab and nivolumab is approved for several malignancies. Toxicity most often occurs 6-10 weeks into treatment. Whether very early toxicity is harder to manage or influences efficacy is unknown.METHODS: Consecutive metastatic melanoma patients who developed hyperacute toxicity, defined as Grade 2+ irAE within 21 days of receiving ipilimumab + anti-PD-1 were retrospectively identified from nine centres.
    RESULTS: A total of 82 patients developed hyperacute toxicity (estimated incidence 9%), at a median 10 days (range 1-21). Toxicities included colitis (N = 23), rash (17), hepatitis (9), endocrine (9), pneumonitis (6) and neurotoxicity (4) and were G2 (38%), G3 (52%), G4 (6%) and G5 (2% myocarditis). Fifty-nine percent required treatment beyond oral steroids, including IV steroids (28%), infliximab and other immunosuppression (30%). A total of 29% patients developed an additional hyperacute toxicity and 26% another toxicity >21 days after treatment commencement but before further immunotherapy. The objective response rate (ORR) was 54%, and after a median 11.6 mo follow-up, median PFS was 7.4 mo. Increasing levels of immunosuppression was associated with a reduced PFS (12-month PFS 62% no immunosuppression versus 49% oral steroids versus 33% IV steroids versus 20% further immunosuppressants, p = 0.006). There was no significant difference in ORR or PFS by duration of immunosuppression.
    CONCLUSIONS: Hyperacute toxicities from combination immunotherapy have a wide spectrum and can be severe. Many patients require significant immunosuppression for prolonged durations and remain at risk of further severe toxicity. Melanoma outcomes in such patients appear similar to those of trial populations, although greater immunosuppression requirements may be associated with inferior outcomes.
    Keywords:  Combination; Immunotherapy; Ipilimumab; Melanoma; Nivolumab; Pembrolizumab; Toxicity
    DOI:  https://doi.org/10.1016/j.ejca.2021.04.045
  59. Cureus. 2021 May 24. 13(5): e15210
    Giant Congenital Melanocytic Nevi in a Pakistani Newborn.
    Hina Mumtaz Hashmi, Nazia Shamim, Vinod Kumar, Sidra Idrees.
      Congenital melanocytic nevi arise from overgrowth or disrupted migration of melanocyte precursor in the neural crest. They are also known as coat-sleeve, stocking, bathing trunk or garment nevi. The colour ranges from brown to black, with the lesions presenting as flat to raised nevi. Lesions presenting at birth with a diameter greater than 20cm are labelled giant congenital melanocytic nevi. Risk increases with an increase in the number of satellite lesions near the giant nevus. Management includes regular clinical follow-up monitoring of changes in the lesion and surgical procedures in cases with risk of melanoma and psychological support. The purpose of this case presentation is to describe a rare issue of giant congenital melanocytic nevi in a newborn, along with a literature review and discussion on possible management options.
    Keywords:  giant congenital melanocytic nevi; melanoma; neurocutaneous melanosis; nevomelanocytes; satellite lesions
    DOI:  https://doi.org/10.7759/cureus.15210
  60. Future Oncol. 2021 Jul 02.
    Patient engagement in melanoma research: from bench to bedside.
    Ann Tivey, Prerana Huddar, Rohan Shotton, Imogen Cheese, Susanna Daniels, Paul Lorigan, Rebecca J Lee.
      Advances in research have transformed the management of melanoma in the past decade. In parallel, patient advocacy has gained traction, and funders are increasingly prioritizing patient and public involvement. Here we discuss the ways in which patients and the public can be engaged in different stages of the research process, from developing, prioritizing and refining the research question to preclinical studies and clinical trials, then finally to ongoing research in the clinic. We discuss the challenges and opportunities that exist at each stage in order to ensure that a representative population of patients and the public contribute to melanoma research both now and in the future.
    Keywords:  PPI; advocacy; clinical trial; melanoma; patient engagement; research; risk
    DOI:  https://doi.org/10.2217/fon-2020-1165
  61. Math Biosci Eng. 2021 May 10. 18(4): 4055-4070
    Immune marker signature helps to predict survival in uveal melanoma.
    Li-Sha Pan, Zacharia Ackbarkha, Jing Zeng, Min-Li Huang, Zhen Yang, Hao Liang.
      The detailed molecular function of tumor microenvironment (TEM) in uveal melanoma (UVM) remains unclear. This study generated the immune index and the stromal index scores by ESTIMATE algorithm based on RNA-sequencing data with 80 UVM patients. There was no correlation between the immune stromal index and clinical parameters. The differentially expressed genes related to the immune stromal index were calculated and were described by functional annotations and protein-protein interaction network diagrams. After univariate and multivariate Cox regression analyses, there were four genes (HLA-J, MMP12, HES6, and ADAMDEC1) with significant prognostic significance. The prognostic model was constructed using these four characteristic genes, and the KM curve and tROC curve were described to show that the model had a better ability to predict survival outcomes and prognosis. The verification results in GSE62075 showed that HLA-J and HES6 were expressed differently in the cancer group than in the non-cancer group. This study indicates that the risk signature based on the immune index can be used as an indicator to evaluate the prognosis of patients with UVM.
    Keywords:   immune index ; prognosis ; stromal index ; tumor microenvironment ; uveal melanoma
    DOI:  https://doi.org/10.3934/mbe.2021203
  62. BMJ Case Rep. 2021 Jul 02. pii: e240793. [Epub ahead of print]14(7):
    Intramammary melanoma micrometastasis within a silicone-implanted breast.
    Anna Payne, Ted Welman, Matthew Stodell.
      We present the case of a 53-year-old woman with silicone breast implants who underwent excision of an abdominal melanoma and sentinel lymph node biopsy. Two lymph nodes were excised; both lying in the breast parenchyma adjacent to the intact right breast capsule. The lymph node histology revealed a subcapsular melanoma deposit along with silicone lymphadenopathy in the sentinel node. This case highlights that sentinel lymph nodes can be located in alternative locations to the common lymphatic basins and, therefore, the importance of preoperative lymphoscintigraphy. We also discuss subclinical breast implant rupture as a causative factor for silicone lymphadenopathy.
    Keywords:  dermatological; malignant disease and immunosuppression; plastic and reconstructive surgery; skin; skin cancer
    DOI:  https://doi.org/10.1136/bcr-2020-240793
  63. Clin Cancer Res. 2021 Jun 29. pii: clincanres.0851.2021. [Epub ahead of print]
    Memory-like differentiation enhances NK cell responses to melanoma.
    Nancy D Marin, Bradley A Krasnick, Michelle Becker-Hapak, Leah Conant, Simon P Goedegebuure, Melissa M Berrien-Elliott, Keenan J Robbins, Jennifer A Foltz, Mark Foster, Pamela Wong, Celia C Cubitt, Jennifer Tran, Christopher B Wetzel, Miriam Jacobs, Alice Zhou, David Russler-Germain, Lynne Marsala, Timothy Schappe, Ryan C Fields, Todd A Fehniger.
      PURPOSE: Treatment of advanced melanoma (AM) is a clinical challenge. NK cells are a promising cellular therapy for T cell-refractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK cell anti-tumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers in the NK cell therapeutics field, resulting in potent cytotoxicity and enhanced cytokine production against blood cancer targets. However, the pre-clinical activity of ML NK against solid tumors remains largely undefined.EXPERIMENTAL DESIGN: Phenotypic and functional alterations of blood and AM infiltrating NK cells were evaluated using mass cytometry. ML NK from healthy donors (HD) and AM patients were evaluated for their ability to produce IFN-g and kill melanoma targets in vitro and in vivo using a xenograft model.
    RESULTS: NK cells in AM exhibited a decreased cytotoxic potential compared to blood NK cells. ML NK cells differentiated from HD and AM patients displayed enhanced ability of IFN-g production and cytotoxicity against melanoma targets. This included ML differentiation enhancing melanoma patients' NK cell responses against autologous targets. The ML NK cell response against melanoma was partially dependent on the NKG2D and NKp46 activating receptors. Further, in xenograft NSG mouse models, human ML NK cells demonstrated superior control of melanoma, compared to conventional NK cells.
    CONCLUSIONS: Blood NK cells from healthy donors or AM patients can be differentiated into ML NK cells for use as a novel immunotherapeutic treatment for advanced melanoma, which warrants testing in early phase clinical trials.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-0851
  64. Retin Cases Brief Rep. 2021 Jun 24.
    A case of high-risk ciliary body melanoma arising in an eye following resection of an iridociliary melanocytoma.
    Terry Lee, Ekaterina Semenova, Alan D Proia, Miguel A Materin.
      PURPOSE: To report a case of a benign iridociliary melanocytoma recurring as malignant melanoma after excision.METHODS: Observational case report with clinical data, slit lamp exam findings, ultrasound biomicroscopy (UBM) results, and histopathological and genetic analyses.
    RESULTS: A 40-year-old African-American woman initially presented with a superonasal iridociliary mass with a maximal thickness of 2.5 mm. Visual acuity of the involved eye was 20/25, IOP was 52 mmHg on maximal pressure-lowering medications, and Humphrey Visual Field testing revealed an inferior altitudinal defect. Fine needle aspiration biopsy (FNAB) and incisional biopsy followed by tumor excision confirmed a benign melanocytoma. After five years of stability, possible recurrence was detected on ultrasound biomicroscopy (UBM) as an increase in ciliary body thickness. The new lesion grew to a thickness of 5.1 mm over the next 18 months of observation. FNAB and gene expression profile (GEP) of the recurrent lesion diagnosed a malignant melanoma with high metastatic potential (Class 2). The patient underwent plaque brachytherapy and has ongoing regression of the tumor.
    CONCLUSION: Transformation of benign iridociliary melanocytoma to melanoma is rare. To the best of the authors' knowledge, this is the first documented case of a melanoma arising in an eye after initial excision of a melanocytoma. Close monitoring of these patients is warranted even years after the initial excision.
    DOI:  https://doi.org/10.1097/ICB.0000000000001178
  65. Life Sci Alliance. 2021 Sep;pii: e202101135. [Epub ahead of print]4(9):
    UVB mutagenesis differs in Nras- and Braf-mutant mouse models of melanoma.
    Robert L Bowman, Rebecca C Hennessey, Tirzah J Weiss, David A Tallman, Emma R Crawford, Brandon M Murphy, Amy Webb, Souhui Zhang, Krista Md La Perle, Craig J Burd, Ross L Levine, A Hunter Shain, Christin E Burd.
      BRAF-mutant melanomas are more likely than NRAS-mutant melanomas to arise in anatomical locations protected from chronic sun damage. We hypothesized that this discrepancy in tumor location is a consequence of the differential sensitivity of BRAF and NRAS-mutant melanocytes to ultraviolet light (UV)-mediated carcinogenesis. We tested this hypothesis by comparing the mutagenic consequences of a single neonatal, ultraviolet-AI (UVA; 340-400 nm) or ultraviolet-B (UVB; 280-390 nm) exposure in mouse models heterozygous for mutant Braf or homozygous for mutant Nras Tumor onset was accelerated by UVB, but not UVA, and the resulting melanomas contained recurrent mutations affecting the RING domain of MAP3K1 and Actin-binding domain of Filamin A. Melanomas from UVB-irradiated, Braf-mutant mice averaged twice as many single-nucleotide variants and five times as many dipyrimidine variants than tumors from similarly irradiated Nras-mutant mice. A mutational signature discovered in UVB-accelerated tumors mirrored COSMIC signatures associated with human skin cancer and was more prominent in Braf- than Nras-mutant murine melanomas. These data show that a single UVB exposure yields a greater burden of mutations in murine tumors driven by oncogenic Braf.
    DOI:  https://doi.org/10.26508/lsa.202101135
  66. Australas J Dermatol. 2021 Jul 03.
    Severe progressive scarring pembrolizumab-induced lichen planopilaris in a patient with metastatic melanoma.
    Aarthy K Uthayakumar, Emily Rudd, Mariana Noy, Justin Weir, James Larkin, Louise Fearfield.
      Lichenoid reactions are one of the many cutaneous immune-related adverse events seen with the use of immune checkpoint inhibitors, particularly anti-PD1 inhibitors. We present a rare care of severe lichen planopilaris secondary to pembrolizumab, with progression even after cessation of immunotherapy. It is important to recognise the significant long-term impact of these cutaneous adverse effects on patient's quality of life.
    Keywords:  cutaneous immune-related adverse effects; lichen planopilaris; lichenoid reaction; scarring alopecia
    DOI:  https://doi.org/10.1111/ajd.13660
  67. Clin Cancer Res. 2021 Jul 01. pii: clincanres.0793.2021. [Epub ahead of print]
    Standard-Dose Pembrolizumab Plus Alternate-Dose Ipilimumab in Advanced Melanoma: KEYNOTE-029 Cohort 1C, a Phase 2 Randomized Study of Two Dosing Schedules.
    Georgina V Long, Caroline Robert, Marcus O Butler, Felix Couture, Matteo S Carlino, Steven O'Day, Victoria Atkinson, Jonathan S Cebon, Michael P Brown, Stephane Dalle, Andrew G Hill, Geoffrey T Gibney, Steven McCune, Alexander M Menzies, Cuizhen Niu, Nageatte Ibrahim, Blanca Homet Moreno, Adi Diab.
      PURPOSE: Standard-dose pembrolizumab plus alternative-dose ipilimumab (1 mg/kg Q3W for 4 doses) was tolerable and had robust antitumor activity in advanced melanoma in cohort B of the phase 1 KEYNOTE-029 study. Cohort C evaluated standard-dose pembrolizumab with two other alternative ipilimumab regimens.EXPERIMENTAL DESIGN: Patients with treatment-naive unresectable stage III/IV melanoma were randomly assigned 1:1 to pembrolizumab 200 mg Q3W for {less than or equal to}24 months plus ipilimumab 50 mg Q6W for 4 doses (PEM200+IPI50), or the same pembrolizumab regimen plus ipilimumab 100 mg Q12W for 4 doses (PEM200+IPI100). Primary end points were incidence of grade 3-5 treatment-related adverse events (TRAEs) and objective response rate (ORR) per RECIST v1.1 by independent central review. Per protocol-defined thresholds, grade 3-5 TRAE incidence {less than or equal to}26% indicated meaningful toxicity reduction and ORR {greater than or equal to}48% indicated no decrease in efficacy versus data reported for other PD-1 inhibitor/ipilimumab combinations.
    RESULTS: Median follow-up on February 18, 2019, was 16.3 months in PEM200+IPI50 (N=51) and 16.4 months in PEM200+IPI100 (N=51). Grade 3-5 TRAEs occurred in 12 (24%) patients in PEM200+IPI50 and 20 (39%) in PEM200+IPI100. One patient in PEM200+IPI50 died from treatment-related autoimmune myocarditis. Immune-mediated AEs or infusion reactions occurred in 21 (42%) patients in PEM200+IPI50 and 28 (55%) in PEM200+IPI100. ORR was 55% in PEM200+IPI50; 61% in PEM200+IPI100.
    CONCLUSIONS: Pembrolizumab 200 mg Q3W plus ipilimumab 50 mg Q6W or 100 mg Q12W demonstrated antitumor activity above the predefined threshold; pembrolizumab plus ipilimumab 50 mg Q6W had lower incidence of grade 3-5 TRAEs than the predefined threshold, suggesting a reduction in toxicity.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-0793
  68. Eur J Cancer. 2021 Jun 28. pii: S0959-8049(21)00267-7. [Epub ahead of print]153 213-222
    Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.
    Adriana Hepner, Victoria G Atkinson, James Larkin, Rebecca A Burrell, Matteo S Carlino, Douglas B Johnson, Lisa Zimmer, Katy K Tsai, Oliver Klein, Serigne N Lo, Andrew Haydon, Prachi Bhave, Megan Lyle, Lalit Pallan, Ines Pires da Silva, Camille Gerard, Olivier Michielin, Georgina V Long, Alexander M Menzies.
      PURPOSE: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown.METHODS: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined.
    RESULTS: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%, P = 0.655). Time to AR was 11 months (95% confidence interval [CI], 8-15 months). After a median follow-up of 16 months (95% CI, 10-25 months), responders to reinduction had a median progression-free survival of 14 months (95% CI, 13, NR months), and in the whole cohort, the median overall survival from reinduction was 17 months (95% CI, 12-NR months). Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred.
    CONCLUSIONS: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.
    Keywords:  Immunotherapy; Ipilimumab; Melanoma; Programmed death-1
    DOI:  https://doi.org/10.1016/j.ejca.2021.04.021
  69. Ann Dermatol Venereol. 2021 Jun 25. pii: S0151-9638(21)00054-5. [Epub ahead of print]
    Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600mut melanoma patients.
    M Raynal, J-C Alvarez, P Saiag, A Beauchet, C Funck-Brentano, E Funck-Brentano.
      BACKGROUND: Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mut melanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE.METHODS: We analysed PCD/T in patients treated with D+T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results.
    RESULTS: We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0ng/mL; interquartile range (IQR) [4-945]) and of PCT (median: 8.6ng/mL; IQR [5-39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P=0.06). However, no difference was observed between mean PCD/T of progressing patients (n=21; 125±183ng/mL and 9.3±3.6ng/mL, respectively) and responders (complete, partial or stable response) (n=13; 159±225ng/mL, P=0.58 and 10.6±24.4ng/mL, P=0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n=16) was significantly higher for female subjects (n=18; 11.5±4.8ng/mL) than for male subjects (8.8ng/mL±2.9, P=0.01), but no difference was observed between sex and CPD (P=0.32).
    CONCLUSION: Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment.
    Keywords:  Dabrafenib; Drug monitoring; Melanoma; Molecular targeted therapies; Trametinib
    DOI:  https://doi.org/10.1016/j.annder.2021.04.005
  70. Transl Oncol. 2021 Jun 27. pii: S1936-5233(21)00153-4. [Epub ahead of print]14(9): 101161
    Diagnostic assessment of deep learning for melanocytic lesions using whole-slide pathological images.
    Wei Ba, Rui Wang, Guang Yin, Zhigang Song, Jinyi Zou, Cheng Zhong, Jingrun Yang, Guanzhen Yu, Hongyu Yang, Litao Zhang, Chengxin Li.
      BACKGROUND: Deep learning has the potential to improve diagnostic accuracy and efficiency in medical image recognition. In the current study, we developed a deep learning algorithm and assessed its performance in discriminating melanoma from nevus using whole-slide pathological images (WSIs).METHODS: The deep learning algorithm was trained and validated using a set of 781 WSIs (86 melanomas, 695 nevi) from PLA General Hospital. The diagnostic performance of the algorithm was tested on an independent test set of 104 WSIs (29 melanomas, 75 nevi) from Tianjin Chang Zheng Hospital. The same test set was also diagnostically classified by 7 expert dermatopathologists.
    RESULTS: The deep learning algorithm receiver operating characteristic (ROC) curve achieved a sensitivity 100% at the specificity of 94.7% in the classification of melanoma and nevus on the test set. The area under ROC curve was 0.99. Dermatopathologists achieved a mean sensitivity and specificity of 95.1% (95% confidence interval [CI]: 92.0%-98.2%) and 96.0% (95% CI: 94.2%-97.8%), respectively. At the operating point of sensitivity of 95.1%, the algorithm revealed a comparable specificity with 7 dermatopathologists (97.3% vs. 96.0%, P = 0.11). At the operating point of specificity of 96.0%, the algorithm also achieved a comparable sensitivity with 7 dermatopathologists (96.5% vs. 95.1%, P = 0.30). A more transparent and interpretable diagnosis could be generated by highlighting the regions of interest recognized by the algorithm in WSIs.
    CONCLUSION: The performance of the deep learning algorithm was on par with that of 7 expert dermatopathologists in interpreting WSIs with melanocytic lesions. By pre-screening the suspicious melanoma regions, it might serve as a supplemental diagnostic tool to improve working efficiency of pathologists.
    Keywords:  Artificial intelligence; Deep learning algorithm; Melanoma; Nevus; Whole-slide pathological images
    DOI:  https://doi.org/10.1016/j.tranon.2021.101161
  71. JAMA Dermatol. 2021 Jun 30.
    Characterizing the Clinical Implications of Histologic Regression in Melanoma Requires Clear Diagnostic Criteria That Are Consistently Applied.
    Mark C Mochel, David E Elder.
      
    DOI:  https://doi.org/10.1001/jamadermatol.2021.2137
  72. Nat Cancer. 2021 Mar;2(3): 300-311
    Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy.
    Jichang Han, Yanding Zhao, Keisuke Shirai, Aleksey Molodtsov, Fred W Kolling, Jan L Fisher, Peisheng Zhang, Shaofeng Yan, Tyler G Searles, Justin M Bader, Jiang Gui, Chao Cheng, Marc S Ernstoff, Mary Jo Turk, Christina V Angeles.
      While T-cell responses to cancer immunotherapy have been avidly studied, long-lived memory has been poorly characterized. In a cohort of metastatic melanoma survivors with exceptional responses to immunotherapy, we probed memory CD8+ T-cell responses across tissues, and across several years. Single-cell RNA sequencing revealed three subsets of resident memory T (TRM) cells shared between tumors and distant vitiligo-affected skin. Paired T-cell receptor sequencing further identified clonotypes in tumors that co-existed as TRM in skin and as effector memory T (TEM) cells in blood. Clonotypes that dispersed throughout tumor, skin, and blood preferentially expressed a IFNG / TNF-high signature, which had a strong prognostic value for melanoma patients. Remarkably, clonotypes from tumors were found in patient skin and blood up to nine years later, with skin maintaining the most focused tumor-associated clonal repertoire. These studies reveal that cancer survivors can maintain durable memory as functional, broadly-distributed TRM and TEM compartments.
    DOI:  https://doi.org/10.1038/s43018-021-00180-1
  73. Case Rep Ophthalmol. 2021 May-Aug;12(2):12(2): 476-480
    Uveal Melanoma and Secondary Angle-Closure Crisis: A Case Report and Literature Review.
    Tung Thanh Hoang, Tuan Anh Hoang, Peter McCluskey, John Grigg.
      A 66-years-old Vietnamese healthy female patient presented with prolonged severe right ocular pain and complete vision loss in that eye. Anterior segment assessment including gonioscopy identified angle-closure configuration. A suspected ciliary body melanoma was seen through the pupil. Posterior segment examination revealed a large tumor mass and 360° retinal detachment (kissing configuration). An ultrasound examination was consistent with a uveal tumor. The painful, blind right eye with a tumor mass was enucleated. Histopathology confirmed a type A uveal spindle cell melanoma associated with total serous retinal detachment without evidence of tumor necrosis, epithelioid cells, scleral, or optic nerve infiltration. There was no evidence of metastasis after 1-year of follow-up. It is critically important to differentiate primary and secondary angle closure, especially in cases with life-threatening ocular malignancy as uveal melanoma.
    Keywords:  Secondary angle closure; Serous retinal detachment; Uveal melanoma
    DOI:  https://doi.org/10.1159/000513133
  74. Sensors (Basel). 2021 Jun 10. pii: 3999. [Epub ahead of print]21(12):
    Ensemble Method of Convolutional Neural Networks with Directed Acyclic Graph Using Dermoscopic Images: Melanoma Detection Application.
    Arthur Cartel Foahom Gouabou, Jean-Luc Damoiseaux, Jilliana Monnier, Rabah Iguernaissi, Abdellatif Moudafi, Djamal Merad.
      The early detection of melanoma is the most efficient way to reduce its mortality rate. Dermatologists achieve this task with the help of dermoscopy, a non-invasive tool allowing the visualization of patterns of skin lesions. Computer-aided diagnosis (CAD) systems developed on dermoscopic images are needed to assist dermatologists. These systems rely mainly on multiclass classification approaches. However, the multiclass classification of skin lesions by an automated system remains a challenging task. Decomposing a multiclass problem into a binary problem can reduce the complexity of the initial problem and increase the overall performance. This paper proposes a CAD system to classify dermoscopic images into three diagnosis classes: melanoma, nevi, and seborrheic keratosis. We introduce a novel ensemble scheme of convolutional neural networks (CNNs), inspired by decomposition and ensemble methods, to improve the performance of the CAD system. Unlike conventional ensemble methods, we use a directed acyclic graph to aggregate binary CNNs for the melanoma detection task. On the ISIC 2018 public dataset, our method achieves the best balanced accuracy (76.6%) among multiclass CNNs, an ensemble of multiclass CNNs with classical aggregation methods, and other related works. Our results reveal that the directed acyclic graph is a meaningful approach to develop a reliable and robust automated diagnosis system for the multiclass classification of dermoscopic images.
    Keywords:  computer-aided system; deep learning; dermoscopic images; directed acyclic graph; ensemble method; fusion-based model; melanoma detection; multiclass classification; skin cancer
    DOI:  https://doi.org/10.3390/s21123999
  75. Cancers (Basel). 2021 Jun 23. pii: 3143. [Epub ahead of print]13(13):
    A Randomized Trial of Precision Prevention Materials to Improve Primary and Secondary Melanoma Prevention Activities among Individuals with Limited Melanoma Risk Phenotypes.
    John Charles A Lacson, Scarlet H Doyle, Lu Qian, Jocelyn Del Rio, Stephanie M Forgas, Stella Valavanis, Rodrigo Carvajal, Guillermo Gonzalez-Calderon, Youngchul Kim, Richard G Roetzheim, Steven K Sutton, Susan T Vadaparampil, Peter A Kanetsky.
      Inherited variation at MC1R is associated with elevated melanoma risk among non-Hispanic whites (NHWs). MC1R genetic testing may unmask previously unrecognized disease risk, especially among individuals with few melanoma phenotypic risk factors. We recruited NHW individuals with limited phenotypic risk factors from two primary care clinics in west-central Florida. Participants (n = 1134) were randomized within MC1R genotype risk group (average/higher) to receive mailed precision prevention (i.e., intervention) or generic prevention materials. Participants reported hours of weekday and weekend sun exposure, frequency of intentional outdoor tanning and sun protection behaviors, number of sunburns, indoor tanning episodes, and skin examinations at baseline, and after 6 and 12 months. Among MC1R higher-risk participants, the intervention increased the likelihood of often or always wearing a shirt with sleeves (OR = 1.49, p = 0.03) and seeking shade or using an umbrella (OR = 1.42, p = 0.046), and it decreased the number of sunburns among their young children (β = -0.13, p = 0.03). Intervention effects were not noted among MC1R average-risk participants. Moderation analyses identified intervention effects within subgroups in average-risk and higher-risk participants. Precision prevention information conveying MC1R testing results can increase the practice of some sun protection behaviors among at-risk individuals with limited melanoma risk phenotypes and may provide a cross-generational tool to counteract increasing incidence of melanoma.
    Keywords:  MC1R; genetic testing; intervention trial; melanoma; precision prevention; prevention; public health genetics; randomized trial; sun-resistant
    DOI:  https://doi.org/10.3390/cancers13133143
  76. Molecules. 2021 Jun 13. pii: 3619. [Epub ahead of print]26(12):
    Targeting Melanoma-Initiating Cells by Caffeine: In Silico and In Vitro Approaches.
    Claudio Tabolacci, Martina Cordella, Stefania Rossi, Marialaura Bonaccio, Adriana Eramo, Carlo Mischiati, Simone Beninati, Licia Iacoviello, Antonio Facchiano, Francesco Facchiano.
      The beneficial effects of coffee on human diseases are well documented, but the molecular mechanisms of its bioactive compounds on cancer are not completely elucidated. This is likely due to the large heterogeneity of coffee preparations and different coffee-based beverages, but also to the choice of experimental models where proliferation, differentiation and immune responses are differently affected. The aim of the present study was to investigate the effects of one of the most interesting bioactive compounds in coffee, i.e., caffeine, using a cellular model of melanoma at a defined differentiation level. A preliminary in silico analysis carried out on public gene-expression databases identified genes potentially involved in caffeine's effects and suggested some specific molecular targets, including tyrosinase. Proliferation was investigated in vitro on human melanoma initiating cells (MICs) and cytokine expression was measured in conditioned media. Tyrosinase was revealed as a key player in caffeine's mechanisms of action, suggesting a crucial role in immunomodulation through the reduction in IL-1β, IP-10, MIP-1α, MIP-1β and RANTES secretion onto MICs conditioned media. The potent antiproliferative effects of caffeine on MICs are likely to occur by promoting melanin production and reducing inflammatory signals' secretion. These data suggest tyrosinase as a key player mediating the effects of caffeine on melanoma.
    Keywords:  bioactive compounds; caffeine; immunomodulatory signals; melanin; melanoma
    DOI:  https://doi.org/10.3390/molecules26123619
  77. Int J Mol Sci. 2021 Jun 03. pii: 6043. [Epub ahead of print]22(11):
    Novel Chemically Modified Curcumin (CMC) Analogs Exhibit Anti-Melanogenic Activity in Primary Human Melanocytes.
    Shilpi Goenka, Sanford R Simon.
      Hyperpigmentation is a dermatological condition characterized by the overaccumulation and/or oversecretion of melanin pigment. The efficacy of curcumin as an anti-melanogenic therapeutic has been recognized, but the poor stability and solubility that have limited its use have inspired the synthesis of novel curcumin analogs. We have previously reported on comparisons of the anti-melanogenic activity of four novel chemically modified curcumin (CMC) analogs, CMC2.14, CMC2.5, CMC2.23 and CMC2.24, with that of parent curcumin (PC), using a B16F10 mouse melanoma cell model, and we have investigated mechanisms of inhibition. In the current study, we have extended our findings using normal human melanocytes from a darkly pigmented donor (HEMn-DP) and we have begun to study aspects of melanosome export to human keratinocytes. Our results showed that all the CMCs downregulated the protein levels of melanogenic paracrine mediators, endothelin-1 (ET-1) and adrenomedullin (ADM) in HaCaT cells and suppressed the phagocytosis of FluoSphere beads that are considered to be melanosome mimics. All the three CMCs were similarly potent (except CMC2.14, which was highly cytotoxic) in inhibiting melanin production; furthermore, they suppressed dendricity in HEMn-DP cells. CMC2.24 and CMC2.23 robustly suppressed cellular tyrosinase activity but did not alter tyrosinase protein levels, while CMC2.5 did not suppress tyrosinase activity but significantly downregulated tyrosinase protein levels, indicative of a distinctive mode of action for the two structurally related CMCs. Moreover, HEMn-DP cells treated with CMC2.24 or CMC2.23 partially recovered their suppressed tyrosinase activity after cessation of the treatment. All the three CMCs were nontoxic to human dermal fibroblasts while PC was highly cytotoxic. Our results provide a proof-of-principle for the novel use of the CMCs for skin depigmentation, since at low concentrations, ranging from 5 to 25 µM, the CMCs (CMC2.24, CMC2.23 and CMC2.5) were more potent anti-melanogenic agents than PC and tetrahydrocurcumin (THC), both of which were ineffective at melanogenesis at similar doses, as tested in HEMn-DP cells (with PC being highly toxic in dermal fibroblasts and keratinocytes). Further studies to evaluate the efficacy of CMCs in human skin tissue and in vivo studies are warranted.
    Keywords:  HEMn-DP cells; HaCaT cells; chemically modified curcumins; dendricity; melanogenesis; melanosome uptake; tyrosinase
    DOI:  https://doi.org/10.3390/ijms22116043
  78. Int J Dermatol. 2021 Jul 02.
    Racial diversity in melanoma research from 2015 to 2020: a cross-sectional study.
    Melissa A Nickles, Vishnutheertha Kulkarni, Swati P Garg, Mit M Patel, Allison Kirchner, Arpan V Prabhu.
      
    DOI:  https://doi.org/10.1111/ijd.15763
  79. Pharmaceuticals (Basel). 2021 Jun 07. pii: 547. [Epub ahead of print]14(6):
    Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin αvβ3 and the MC1 Receptor-Suitable for the Specific Visualization of Melanomas?
    Xia Cheng, Ralph Hübner, Valeska von Kiedrowski, Gert Fricker, Ralf Schirrmacher, Carmen Wängler, Björn Wängler.
      Combining two peptides addressing two different receptors to a heterobivalent peptidic ligand (HBPL) is thought to enable an improved tumor-targeting sensitivity and thus tumor visualization, compared to monovalent peptide ligands. In the case of melanoma, the Melanocortin-1 receptor (MC1R), which is stably overexpressed in the majority of primary malignant melanomas, and integrin αvβ3, which is involved in lymph node metastasis and therefore has an important role in the transition from local to metastatic disease, are important target receptors. Thus, if a radiolabeled HBPL could be developed that was able to bind to both receptor types, the early diagnosis and correct staging of the disease would be significantly increased. Here, we report on the design, synthesis, radiolabeling and in vitro and in vivo testing of different SiFAlin-modified HBPLs (SiFA = silicon fluoride acceptor), consisting of an MC1R-targeting (GG-Nle-c(DHfRWK)) and an integrin αvβ3-affine peptide (c(RGDfK)), being connected by a symmetrically branching framework including linkers of differing length and composition. Kit-like 18F-radiolabeling of the HBPLs 1-6 provided the labeled products [18F]1-[18F]6 in radiochemical yields of 27-50%, radiochemical purities of ≥95% and non-optimized molar activities of 17-51 GBq/μmol within short preparation times of 25 min. Besides the evaluation of radiotracers regarding logD(7.4) and stability in human serum, the receptor affinities of the HBPLs were investigated in vitro on cell lines overexpressing integrin αvβ3 (U87MG cells) or the MC1R (B16F10). Based on these results, the most promising compounds [18F]2, showing the highest affinity to both target receptors (IC50 (B16F10) = 0.99 ± 0.11 nM, IC50 (U87MG) = 1300 ± 288 nM), and [18F]4, exhibiting the highest hydrophilicity (logD(7.4) = -1.39 ± 0.03), were further investigated in vivo and ex vivo in a xenograft mouse model bearing both tumors. For both HBPLs, clear visualization of B16F10, as well as U87MG tumors, was feasible. Blocking studies using the respective monospecific peptides demonstrated both peptide binders of the HBPLs contributing to tumor uptake. Despite the somewhat lower target receptor affinities (IC50 (B16F10) = 6.00 ± 0.47 nM and IC50 (U87MG) = 2034 ± 323 nM) of [18F]4, the tracer showed higher absolute tumor uptakes ([18F]4: 2.58 ± 0.86% ID/g in B16F10 tumors and 3.92 ± 1.31% ID/g in U87MG tumors; [18F]2: 2.32 ± 0.49% ID/g in B16F10 tumors and 2.33 ± 0.46% ID/g in U87MG tumors) as well as higher tumor-to-background ratios than [18F]2. Thus, [18F]4 demonstrates to be a highly potent radiotracer for the sensitive and bispecific imaging of malignant melanoma by PET/CT imaging and impressively illustrates the suitability of the underlying concept to develop heterobivalent integrin αvβ3- and MC1R-bispecific radioligands for the sensitive and specific imaging of malignant melanoma by PET/CT.
    Keywords:  18F; MC1R; PET/CT imaging; SiFAlin; heterobivalent peptidic ligands; malignant melanoma; αvβ3
    DOI:  https://doi.org/10.3390/ph14060547
  80. Ann N Y Acad Sci. 2021 Jun 28.
    Early maternal separation enhances melanoma progression in adult female mice by immune mechanisms.
    Francisco Stefânio Barreto, Wesley Lyeverton Correia Ribeiro, Bruno Coêlho Cavalcanti, Paulo Goberlânio de Barros Silva, Caren Nádia Soares, Germana Silva Vasconcelos, Ana Paula Negreiros Nunes, Manoel Odorico de Moraes Filho, Danielle S Macedo.
      Maternal separation (MS) is a risk factor for major depressive disorder. Both cancer and depression seem to share a common biological link. Here, we evaluated the progression of melanoma and the underlying mechanisms related to this progression, namely cell proliferation and apoptosis, in adult female mice exposed to MS. Female C57BL/6 mice were exposed to MS for 60 min/day during the first 2 postnatal weeks (here called MS mice) or left undisturbed (here called non-MS mice). Melanoma cells were inoculated subcutaneously into the axillary region of adult animals, and tumor progression was evaluated for 25 days. Adult MS mice presented depressive-like behavior and working memory deficits. MS accelerated murine melanoma growth by mechanisms related to decreased apoptosis and increased cell proliferation rate, such as increased expression of IL-6 and mTOR. MS stimulated eukaryotic elongation factor 2 expression and increased the number of circulating monocytes and DNA damage in peripheral blood leukocytes, an effect associated with oxidative DNA damage. In conclusion, MS accelerated the progression of murine melanoma by mechanisms related to tumor proliferation and apoptosis, revealing a relationship between adverse childhood experiences and cancer progression, particularly melanoma.
    Keywords:  IL-6; adverse childhood experiences; cancer progression; mTOR; melanoma; stress-related disorders
    DOI:  https://doi.org/10.1111/nyas.14625
  81. Genes (Basel). 2021 Jun 29. pii: 1004. [Epub ahead of print]12(7):
    VECTOR: An Integrated Correlation Network Database for the Identification of CeRNA Axes in Uveal Melanoma.
    Cristina Barbagallo, Antonio Di Maria, Adriana Alecci, Davide Barbagallo, Salvatore Alaimo, Lorenzo Colarossi, Alfredo Ferro, Cinzia Di Pietro, Michele Purrello, Alfredo Pulvirenti, Marco Ragusa.
      Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults and, although its genetic background has been extensively studied, little is known about the contribution of non-coding RNAs (ncRNAs) to its pathogenesis. Indeed, its competitive endogenous RNA (ceRNA) regulatory network comprising microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and mRNAs has been insufficiently explored. Thanks to UM findings from The Cancer Genome Atlas (TCGA), it is now possible to statistically elaborate these data to identify the expression relationships among RNAs and correlative interaction data. In the present work, we propose the VECTOR (uVeal mElanoma Correlation NeTwORk) database, an interactive tool that identifies and visualizes the relationships among RNA molecules, based on the ceRNA model. The VECTOR database contains: i) the TCGA-derived expression correlation values of miRNA-mRNA, miRNA-lncRNA and lncRNA-mRNA pairs combined with predicted or validated RNA-RNA interactions; ii) data of sense-antisense sequence overlapping; iii) correlation values of Transcription Factor (TF)-miRNA, TF-lncRNA, and TF-mRNA pairs associated with ChiPseq data; iv) expression data of miRNAs, lncRNAs and mRNAs both in UM and physiological tissues. The VECTOR web interface can be queried, by inputting the gene name, to retrieve all the information about RNA signaling and visualize this as a graph. Finally, VECTOR provides a very detailed picture of ceRNA networks in UM and could be a very useful tool for researchers studying RNA signaling in UM. The web version of Vector is freely available at the URL reported at the end of the Introduction.
    Keywords:  bioinformatics; cancer; ceRNA; lncRNA; miRNA; ncRNA; network
    DOI:  https://doi.org/10.3390/genes12071004
  82. Int J Mol Sci. 2021 Jun 17. pii: 6498. [Epub ahead of print]22(12):
    In Vitro Effects of Selective COX and LOX Inhibitors and Their Combinations with Antineoplastic Drugs in the Mouse Melanoma Cell Line B16F10.
    Ines Da-Costa-Rocha, Jose M Prieto.
      The constitutive expression or overactivation of cyclooxygenase (COX) and lipoxygenase (LOX) enzymes results in aberrant metabolism of arachidonic acid and poor prognosis in melanoma. Our aim is to compare the in vitro effects of selective COX-1 (acetylsalicylic acid), COX-2 (meloxicam), 5-LOX (MK-886 and AA-861), 12-LOX (baicalein) and 15-LOX (PD-146176) inhibition in terms of proliferation (SRB assay), mitochondrial viability (MTT assay), caspase 3-7 activity (chemiluminescent assay), 2D antimigratory (scratch assay) and synthesis of eicosanoids (EIA) in the B16F10 cell line (single treatments). We also explore their combinatorial pharmacological space with dacarbazine and temozolomide (median effect method). Overall, our results with single treatments show a superior cytotoxic efficacy of selective LOX inhibitors over selective COX inhibitors against B16F10 cells. PD-146176 caused the strongest antiproliferation effect which was accompanied by cell cycle arrest in G1 phase and an >50-fold increase in caspases 3/7 activity. When the selected inhibitors are combined with the antineoplastic drugs, only meloxicam provides clear synergy, with LOX inhibitors mostly antagonizing. These apparent contradictions between single and combination treatments, together with some paradoxical effects observed in the biosynthesis of eicosanoids after FLAP inhibition in short term incubations, warrant further mechanistical in vitro and in vivo scrutiny.
    Keywords:  cell migration; cyclooxygenases; cytotoxicity; eicosanoids; lipoxygenases; melanoma; synergy
    DOI:  https://doi.org/10.3390/ijms22126498
  83. Intern Med. 2021 Jun 26.
    Mediastinal Malignant Melanoma Markedly Shrinking in Response to Nivolumab.
    Hiroyuki Sakaguchi, Azusa Tanimoto, Shigeki Sato, Naohiro Yanagimura, Chiaki Suzuki, Yohei Takumi, Akihiro Nishiyama, Kaname Yamashita, Shinji Takeuchi, Koshiro Ohtsubo, Seiji Yano.
      Primary malignant melanoma (MM) of the mediastinum is rare, and there is a lack of consensus regarding the preferred treatment because non-cutaneous MM demonstrates an inferior response to systemic therapy. Herein, we describe the case of a 73-year-old man with MM of the anterior mediastinum with multiple liver metastases. Even though the size of lesions increased rapidly following diagnosis, nivolumab monotherapy caused remarkable tumor shrinkage. This is the first report of mediastinal MM showing a significant response to nivolumab. We, therefore, suggest that immunotherapy may be one of the treatment options for primary mediastinal MM.
    Keywords:  malignant melanoma; mediastinal tumor; nivolumab
    DOI:  https://doi.org/10.2169/internalmedicine.7452-21
  84. Adv Radiat Oncol. 2021 Jul-Aug;6(4):6(4): 100712
    Staged Eye-Plaque Brachytherapy: A Novel Approach for Large Uveal Melanoma.
    Neil Chevli, Amy C Schefler, Maria E Bretana, Ramiro Pino, E Brian Butler, Bin S Teh.
      
    DOI:  https://doi.org/10.1016/j.adro.2021.100712
  85. Int J Mol Sci. 2021 Jun 16. pii: 6432. [Epub ahead of print]22(12):
    Development of Radiofluorinated Nicotinamide/Picolinamide Derivatives as Diagnostic Probes for the Detection of Melanoma.
    Yi-Hsuan Lo, Ting-Yu Chang, Chuan-Lin Chen, Ming-Hsien Lin, Hsin-Ell Wang, Chi-Wei Chang, Ren-Shyan Liu, Chun-Yi Wu.
      Regarding the increased incidence and high mortality rate of malignant melanoma, practical early-detection methods are essential to improve patients' clinical outcomes. In this study, we successfully prepared novel picolinamide-benzamide (18F-FPABZA) and nicotinamide-benzamide (18F-FNABZA) conjugates and determined their biological characteristics. The radiochemical yields of 18F-FPABZA and 18F-FNABZA were 26 ± 5% and 1 ± 0.5%, respectively. 18F-FPABZA was more lipophilic (log P = 1.48) than 18F-FNABZA (log P = 0.68). The cellular uptake of 18F-FPABZA in melanotic B16F10 cells was relatively higher than that of 18F-FNABZA at 15 min post-incubation. However, both radiotracers did not retain in amelanotic A375 cells. The tumor-to-muscle ratios of 18F-FPABZA-injected B16F10 tumor-bearing mice increased from 7.6 ± 0.4 at 15 min post-injection (p.i.) to 27.5 ± 16.6 at 3 h p.i., while those administered with 18F-FNABZA did not show a similarly dramatic increase throughout the experimental period. The results obtained from biodistribution studies were consistent with those derived from microPET imaging. This study demonstrated that 18F-FPABZA is a promising melanin-targeting positron emission tomography (PET) probe for melanotic melanoma.
    Keywords:  melanin-targeting probe; melanoma; radiofluorinated nicotinamide–benzamide derivative (18F-FNABZA); radiofluorinated picolinamide–benzamide derivative (18F-FPABZA)
    DOI:  https://doi.org/10.3390/ijms22126432
  86. Arch Biochem Biophys. 2021 Jun 23. pii: S0003-9861(21)00227-7. [Epub ahead of print] 108978
    Inhibitory activity of acteoside in melanoma via regulation of the ERβ-Ras/Raf1-STAT3 pathway.
    Yuanyuan Wu, Mengnan Zeng, Ruiqi Xu, Beibei Zhang, Shengchao Wang, Benke Li, Yuxuan Kan, Bing Cao, Xiaoke Zheng, Weisheng Feng.
      BACKGROUND: Melanoma is an aggressive cancer with a rapidly increasing incidence rate worldwide. Acteoside has been shown to have antitumor effects in multiple human cancers; however, the underlying function and mechanisms of acteoside in melanoma remain unclear.PURPOSE: This study explored the inhibitory effect of acteoside on melanoma and the possible mechanisms.
    METHODS: Acteoside (15 mg/kg, 30 mg/kg) was administered to mice daily for 21 days. ICI182,780 (0.5 mg/kg) was intraperitoneally injected 30 min before acteoside administration three times a week to evaluate whether the effects elicited by acteoside were mediated via the estrogen receptor. Tumor growth and metabolism, cardiac function, ROS and apoptosis levels in the spleen, serum inflammatory factors, and immune cells in the spleen were monitored. STAT3, p-STAT3, CD31, and survivin levels in tumor tissues were measured via immunofluorescence. Ras, Raf1, STAT3, p-STAT3, Bcl-2, Bax, cleaved caspase-3, and cleaved caspase-9 levels in tumor tissues were determined via Western Blotting.
    RESULTS: The results showed that acteoside inhibited melanoma growth, alleviated inflammation levels in mice, attenuated ROS and apoptosis levels in the spleen, downregulated the levels of CD31, survivin, Ras, Raf1, p-STAT3, and Bcl-2, and upregulated the levels of ERβ, Bax, cleaved caspase-3, and cleaved caspase-9. Moreover, the effect of acteoside was blocked by ICI182,780.
    CONCLUSION: Acteoside may promote the apoptosis of tumor cells by regulating the ERβ-Ras/Raf1-STAT3 signaling axis, thus inhibiting the occurrence and development of melanoma.
    Keywords:  Acteoside; ERβ; ICI182,780; Melanoma; STAT3
    DOI:  https://doi.org/10.1016/j.abb.2021.108978
  87. Int J Mol Sci. 2021 Jun 29. pii: 6992. [Epub ahead of print]22(13):
    PRP4 Promotes Skin Cancer by Inhibiting Production of Melanin, Blocking Influx of Extracellular Calcium, and Remodeling Cell Actin Cytoskeleton.
    Muhammad Bilal Ahmed, Salman Ul Islam, Young Sup Lee.
      Pre-mRNA processing factor 4B (PRP4) has previously been shown to induce epithelial-mesenchymal transition (EMT) and drug resistance in cancer cell lines. As melanin plays an important photoprotective role in the risk of sun-induced skin cancers, we have investigated whether PRP4 can induce drug resistance and regulate melanin biosynthesis in a murine melanoma (B16F10) cell line. Cells were incubated with a crucial melanogenesis stimulator, alpha-melanocyte-stimulating hormone, followed by transfection with PRP4. This resulted in the inhibition of the production of melanin via the downregulation of adenylyl cyclase-cyclic adenosine 3',5'-monophosphate (AC)-(cAMP)-tyrosinase synthesis signaling pathway. Inhibition of melanin production by PRP4 leads to the promotion of carcinogenesis and induced drug resistance in B16F10 cells. Additionally, PRP4 overexpression upregulated the expression of β-arrestin 1 and desensitized the extracellular calcium-sensing receptor (CaSR), which in turn, inhibited the influx of extracellular Ca2+ ions. The decreased influx of Ca2+ was confirmed by a decreased expression level of calmodulin. We have demonstrated that transient receptor potential cation channel subfamily C member 1 was involved in the influx of CaSR-induced Ca2+ via a decreasing level of its expression. Furthermore, PRP4 overexpression downregulated the expression of AC, decreased the synthesis of cAMP, and modulated the actin cytoskeleton by inhibiting the expression of Ras homolog family member A (RhoA). Our investigation suggests that PRP4 inhibits the production of melanin in B16F10 cells, blocks the influx of Ca2+ through desensitization of CaSR, and modulates the actin cytoskeleton through downregulating the AC-cAMP pathway; taken together, these observations collectively lead to the promotion of skin carcinogenesis.
    Keywords:  PRP4; actin cytoskeleton; cAMP; calcium-sensing receptor; drug resistance; melanocyte
    DOI:  https://doi.org/10.3390/ijms22136992
  88. J Immunother Cancer. 2021 Jul;pii: e002732. [Epub ahead of print]9(7):
    Early rise in brain damage markers and high ICOS expression in CD4+ and CD8+ T cells during checkpoint inhibitor-induced encephalomyelitis.
    Sara Bjursten, Ankur Pandita, Zhiyuan Zhao, Charlotta Fröjd, Lars Ny, Christer Jensen, Tobias Ullerstam, Henrik Jespersen, Jan Borén, Malin Levin, Henrik Zetterberg, Anna Rudin, Max Levin.
      We report a case of rapid eradication of melanoma brain metastases and simultaneous near-fatal encephalomyelitis following double immune checkpoint blockade. Brain damage marker S-100B and C reactive protein increased before symptoms or signs of encephalomyelitis and peaked when the patient fell into a coma. At that point, additional brain damage markers and peripheral T cell phenotype was analyzed. The analyses were repeated four times during the patient's recovery. Axonal damage marker neurofilament light polypeptide (NFL) and astrocytic damage marker glial fibrillar acidic protein (GFAP) were very high in blood and cerebrospinal fluid and gradually normalized after immunosuppression and intensive care. The costimulatory receptor inducible T cell costimulatory receptor (ICOS) was expressed on a high proportion of CD4+ and CD8+T cells as encephalomyelitis symptoms peaked and then gradually decreased in parallel with clinical improvement. Both single and double immune checkpoint inhibitor-treated melanoma patients with other serious immune-related adverse events (irAE) (n=9) also expressed ICOS on a significantly higher proportion of CD4+ and CD8+T cells compared with controls without irAE (n=12). In conclusion, our results suggest a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalomyelitis and other serious irAE. In addition, brain damage markers in blood could facilitate early diagnosis of encephalitis.
    Keywords:  CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; autoimmunity; immunotherapy; melanoma
    DOI:  https://doi.org/10.1136/jitc-2021-002732
  89. Int J Mol Sci. 2021 Jun 02. pii: 6024. [Epub ahead of print]22(11):
    Expression Profiles of ASIC1/2 and TRPV1/4 in Common Skin Tumors.
    Kirsten Ackermann, Susanne Wallner, Christoph Brochhausen, Stephan Schreml.
      The acid-sensing ion channels ASIC1 and ASIC2, as well as the transient receptor potential vanilloid channels TRPV1 and TRPV4, are proton-gated cation channels that can be activated by low extracellular pH (pHe), which is a hallmark of the tumor microenvironment in solid tumors. However, the role of these channels in the development of skin tumors is still unclear. In this study, we investigated the expression profiles of ASIC1, ASIC2, TRPV1 and TRPV4 in malignant melanoma (MM), squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and in nevus cell nevi (NCN). We conducted immunohistochemistry using paraffin-embedded tissue samples from patients and found that most skin tumors express ASIC1/2 and TRPV1/4. Striking results were that BCCs are often negative for ASIC2, while nearly all SCCs express this marker. Epidermal MM sometimes seem to lack ASIC1 in contrast to NCN. Dermal portions of MM show strong expression of TRPV1 more frequently than dermal NCN portions. Some NCN show a decreasing ASIC1/2 expression in deeper dermal tumor tissue, while MM seem to not lose ASIC1/2 in deeper dermal portions. ASIC1, ASIC2, TRPV1 and TRPV4 in skin tumors might be involved in tumor progression, thus being potential diagnostic and therapeutic targets.
    Keywords:  basal cell carcinoma; melanoma; proton-sensitive ion channels; squamous cell carcinoma
    DOI:  https://doi.org/10.3390/ijms22116024
  90. Nat Commun. 2021 Jul 02. 12(1): 4098
    The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival.
    Sara Valpione, Piyushkumar A Mundra, Elena Galvani, Luca G Campana, Paul Lorigan, Francesco De Rosa, Avinash Gupta, John Weightman, Sarah Mills, Nathalie Dhomen, Richard Marais.
      Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes could therefore be indicative of the functional state of these cells and determine disease course at different stages in cancer progression. Here we show that the diversity of the TCR of tumor infiltrating T cell at baseline is prognostic in various cancers, whereas the TCR clonality of T cell infiltrating metastatic melanoma pre-treatment is predictive for activity and efficacy of PD1 blockade immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-021-24343-x
  91. Int J Mol Sci. 2021 Jun 05. pii: 6104. [Epub ahead of print]22(11):
    microRNAs in the Regulation of Melanogenesis.
    Yekatsiaryna Hushcha, Irene Blo, Lucia Oton-Gonzalez, Giulia Di Mauro, Fernanda Martini, Mauro Tognon, Monica De Mattei.
      Melanogenesis is the process leading to the synthesis of melanin, the main substance that influences skin color and plays a pivotal role against UV damage. Altered melanogenesis is observed in several pigmentation disorders. Melanogenesis occurs in specialized cells called melanocytes, physically and functionally related by means of autocrine and paracrine interplay to other skin cell types. Several external and internal factors control melanin biosynthesis and operate through different intracellular signaling pathways, which finally leads to the regulation of microphthalmia-associated transcription factor (MITF), the key transcription factor involved in melanogenesis and the expression of the main melanogenic enzymes, including TYR, TYRP-1, and TYRP-2. Epigenetic factors, including microRNAs (miRNAs), are involved in melanogenesis regulation. miRNAs are small, single-stranded, non-coding RNAs, of approximately 22 nucleotides in length, which control cell behavior by regulating gene expression, mainly by binding the 3' untranslated region (3'-UTR) of target mRNAs. This review collects data on the miRNAs involved in melanogenesis and how these miRNAs can modulate target gene expression. Bringing to light the biological function of miRNAs could lead to a wider understanding of epigenetic melanogenesis regulation and its dysregulation. This knowledge may constitute the basis for developing innovative treatment approaches for pigmentation dysregulation.
    Keywords:  melanocyte; melanogenesis; microRNA; skin pigmentation
    DOI:  https://doi.org/10.3390/ijms22116104
  92. iScience. 2021 Jun 25. 24(6): 102653
    Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate melanoma progression.
    Mahmoud AbuEid, Donna M McAllister, Laura McOlash, Megan Cleland Harwig, Gang Cheng, Donovan Drouillard, Kathleen A Boyle, Micael Hardy, Jacek Zielonka, Bryon D Johnson, R Blake Hill, Balaraman Kalyanaraman, Michael B Dwinell.
      Metabolic heterogeneity within the tumor microenvironment promotes cancer cell growth and immune suppression. We determined the impact of mitochondria-targeted complex I inhibitors (Mito-CI) in melanoma. Mito-CI decreased mitochondria complex I oxygen consumption, Akt-FOXO signaling, blocked cell cycle progression, melanoma cell proliferation and tumor progression in an immune competent model system. Immune depletion revealed roles for T cells in the antitumor effects of Mito-CI. While Mito-CI preferentially accumulated within and halted tumor cell proliferation, it also elevated infiltration of activated effector T cells and decreased myeloid-derived suppressor cells (MDSC) as well as tumor-associated macrophages (TAM) in melanoma tumors in vivo. Anti-proliferative doses of Mito-CI inhibited differentiation, viability, and the suppressive function of bone marrow-derived MDSC and increased proliferation-independent activation of T cells. These data indicate that targeted inhibition of complex I has synchronous effects that cumulatively inhibits melanoma growth and promotes immune remodeling.
    Keywords:  Cancer; Cell biology; Components of the immune system
    DOI:  https://doi.org/10.1016/j.isci.2021.102653
  93. Neuro Oncol. 2021 Jul 03. pii: noab159. [Epub ahead of print]
    The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis.
    Cedric Tehranian, Laura Fankhauser, Patrick N Harter, Colin D H Ratcliffe, Pia S Zeiner, Julia M Messmer, Dirk C Hoffmann, Katharina Frey, Dana Westphal, Michael W Ronellenfitsch, Erik Sahai, Wolfgang Wick, Matthia A Karreman, Frank Winkler.
      BACKGROUND: Brain metastases (BM) are a frequent complication of malignant melanoma (MM), with limited treatment options and poor survival. Prevention of BM could be more effective and better tolerated than treating established BM in various conditions.METHODS: To investigate the temporo-spatial dynamics of PI3K/Akt/mTOR (PAM) pathway activation during BM formation and the preventive potential of its inhibition, in vivo molecular imaging with an Akt biosensor was performed, and long-term intravital multiphoton microscopy through a chronic cranial window in mice.
    RESULTS: In vivo molecular imaging revealed invariable PAM pathway activation during the earliest steps of brain colonization. In order to perform a long-term intravascular arrest and to extravasate, circulating MM cells needed to activate their PAM pathway during this process. However, the PAM pathway was quite heterogeneously activated in established human brain metastases, and its inhibition with the brain-penetrant PAM inhibitor GNE-317 resulted in only modest therapeutic effects in mice. In contrast, giving GNE-317 in preventive schedules that included very low doses effectively reduced growth rate and number of BM in two MM mouse models over time, and led to an overall survival benefit. Longitudinal intravital multiphoton microscopy found that the first, rate-limiting steps of BM formation - permanent intravascular arrest, extravasation, and initial perivascular growth - are most vulnerable to dual PI3K/mTOR inhibition.
    CONCLUSION: These findings establish a key role of PAM pathway activation for critical steps of early metastatic brain colonization and reveal its pharmacological inhibition as a potent avenue to prevent the formation of clinically relevant BM.
    Keywords:  PI3K/Akt/mTOR pathway; brain metastasis; dual PI3K/mTOR inhibition; extravasation; tertiary prevention
    DOI:  https://doi.org/10.1093/neuonc/noab159
  94. J Endocr Soc. 2021 Aug 01. 5(8): bvab100
    Endocrine Toxicity and Outcomes in Patients With Metastatic Malignancies Treated With Immune Checkpoint Inhibitors.
    Suleiman I Al Ashi, Bicky Thapa, Monica Flores, Ramsha Ahmed, Shab E Gul Rahim, Maryam Amir, Mohammad Alomari, Pravallika Chadalavada, Shannon L Morrison, James F Bena, Aleck Hercbergs, Ossama Lashin, Hamed Daw.
      Context: Immune checkpoint inhibitors (ICIs) have gained a revolutionary role in management of many advanced malignancies. However, immune-related endocrine events (irEEs), have been associated with their use. irEEs have nonspecific clinical presentations and variable timelines, making their early diagnosis challenging.Objective: To identify risk factors, timelines, and prognosis associated with irEEs development.
    Design and Setting: Retrospective observational study within the Cleveland Clinic center.
    Patients: Metastatic cancer adult patients who received ICIs were included.
    Methods: 570 charts were reviewed to obtain information on demographics, ICIs used, endocrine toxicities, cancer response to treatment with ICI, and overall survival.
    Main Outcome Measures: Incidence of irEEs, time to irEEs development and overall survival of patients who develop irEEs.
    Results: The final cohort included 551 patients. The median time for the diagnosis of irEEs was 9 weeks. Melanoma was associated with the highest risk for irEEs (31.3%). Ipilimumab appeared to have the highest percentage of irEEs (29.4%), including the highest risk of pituitary insufficiency (11.7%), the most severe (Grade 4 in 60%) and irreversible (100%) forms of irEEs. Forty-five percent of patients with irEEs had adequate cancer response to ICI compared to 28.3% of patients without irEEs (P = 0.002). Patients with irEEs had significantly better survival compared to patients without irEEs (P < 0.001).
    Conclusions: In the adult population with metastatic cancer receiving treatment with ICI, irEEs development may predict tumor response to immunotherapy and a favorable prognosis. Ipilimumab use, combination ICI therapy, and melanoma are associated with a higher incidence of irEEs.
    Keywords:  cancer; endocrine toxicities; immune-checkpoint inhibitors; immune-related adverse events
    DOI:  https://doi.org/10.1210/jendso/bvab100
  95. Pharmaceutics. 2021 Jun 26. pii: 965. [Epub ahead of print]13(7):
    Light- and Melanin Nanoparticle-Induced Cytotoxicity in Metastatic Cancer Cells.
    Victoria R Gabriele, Robabeh M Mazhabi, Natalie Alexander, Purna Mukherjee, Thomas N Seyfried, Njemuwa Nwaji, Eser M Akinoglu, Andrzej Mackiewicz, Guofu Zhou, Michael Giersig, Michael J Naughton, Krzysztof Kempa.
      Melanin nanoparticles are known to be biologically benign to human cells for a wide range of concentrations in a high glucose culture nutrition. Here, we show cytotoxic behavior at high nanoparticle and low glucose concentrations, as well as at low nanoparticle concentration under exposure to (nonionizing) visible radiation. To study these effects in detail, we developed highly monodispersed melanin nanoparticles (both uncoated and glucose-coated). In order to study the effect of significant cellular uptake of these nanoparticles, we employed three cancer cell lines: VM-M3, A375 (derived from melanoma), and HeLa, all known to exhibit strong macrophagic character, i.e., strong nanoparticle uptake through phagocytic ingestion. Our main observations are: (i) metastatic VM-M3 cancer cells massively ingest melanin nanoparticles (mNPs); (ii) the observed ingestion is enhanced by coating mNPs with glucose; (iii) after a certain level of mNP ingestion, the metastatic cancer cells studied here are observed to die-glucose coating appears to slow that process; (iv) cells that accumulate mNPs are much more susceptible to killing by laser illumination than cells that do not accumulate mNPs; and (v) non-metastatic VM-NM1 cancer cells also studied in this work do not ingest the mNPs, and remain unaffected after receiving identical optical energy levels and doses. Results of this study could lead to the development of a therapy for control of metastatic stages of cancer.
    Keywords:  cytotoxicity; hyperthermia; laser medical applications; melanin nanoparticles; melanoma
    DOI:  https://doi.org/10.3390/pharmaceutics13070965
  96. Cell Immunol. 2021 Jun 08. pii: S0008-8749(21)00113-1. [Epub ahead of print]367 104394
    B16 melanomas evade antitumor immunity by the loss of epitope presentation and the acquisition of tumor resistance to granzyme B.
    Jaeyeon Lee, Jiyoon Kim, Jeong-Im Sin.
      Melanomas exhibit the highest rate of heterogeneity among cancer cell types. In this study, we tested the two types of B16 melanoma cells (B16-S0-1 and B16-S1-1) showing resistance to antitumor immunity. These cells expressed Trp2 protein. Contrary to B16 and B16-S0-1 cells, B16-S1-1 cells failed to stimulate IFN-γ responses in Trp2-specific CD8+ T cells, suggesting that B16-S1-1 cells may have lost the ability to present antigen to Ag-specific CTLs in the context of MHC class I molecules. However, B16-S0-1 cells exhibited active Stat3 and decreased Bcl-2 expression, which were found to be not associated with immune escape. B16-S0-1 cells were more resistant to granzyme B-mediated caspase activation and apoptosis than B16 cells. Thus, these data show that B16 cells escape antitumor immune responses through the loss of epitope presentation to CTLs and the acquisition of tumor cell resistance to granzyme B-mediated caspase activation.
    Keywords:  Apoptosis; B16 melanoma; Caspase activation; Chemosensitivity; Granzyme B; Immune escape
    DOI:  https://doi.org/10.1016/j.cellimm.2021.104394
  97. Fam Cancer. 2021 Jul 03.
    Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family.
    Kevin M Brown, Mai Xu, Michael Sargen, Hyunbum Jang, Mingzhen Zhang, Tongwu Zhang, Bin Zhu, Kristie Jones, Jung Kim, Laura Mendoza, Nicholas K Hayward, Margaret A Tucker, Alisa M Goldstein, Xiaohong Rose Yang, Douglas R Stewart, Belynda Hicks, Dario Consonni, Angela C Pesatori, Maria Concetta Fargnoli, Ketty Peris, Alex Stratigos, Chiara Menin, Paola Ghiorzo, Susana Puig, Eduardo Nagore, , Thorkell Andresson, Ruth Nussinov, Donato Calista, Maria Teresa Landi.
      While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2 + binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A > C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.
    Keywords:  Familial cancer; In vitro characterization; Melanoma; Molecular modeling; NRAS gene; Rare variant
    DOI:  https://doi.org/10.1007/s10689-021-00267-9
  98. J Control Release. 2021 Jun 24. pii: S0168-3659(21)00319-9. [Epub ahead of print]336 262-273
    Systemic administration of polymersomal oncolytic peptide LTX-315 combining with CpG adjuvant and anti-PD-1 antibody boosts immunotherapy of melanoma.
    Yifeng Xia, Jingjing Wei, Songsong Zhao, Beibei Guo, Fenghua Meng, Bert Klumperman, Zhiyuan Zhong.
      Oncolytic peptide LTX-315 while showing clinical promise in treating solid tumors is limited to intratumoral administration, which is not applicable for inaccessible or metastatic tumors. The cationic and amphipathic nature of oncolytic peptides engenders formidable challenges to developing systems for their systemic delivery. Here, we describe cRGD-functionalized chimaeric polymersomes (cRGD-CPs) as a robust systemic delivery vehicle for LTX-315, which in combination with CpG adjuvant and anti-PD-1 boost immunotherapy of malignant B16F10 melanoma in mice. cRGD-CPs containing 14.9 wt% LTX-315 (cRGD-CPs-L) exhibited a size of 53 nm, excellent serum stability, and strong and selective killing of B16F10 cells (versus L929 fibroblasts) in vitro, which provoked similar immunogenic effects to free LTX-315 as revealed by release of danger-associated molecular pattern molecules. The systemic administration of cRGD-CPs-L gave a notable tumor accumulation of 4.8% ID/g and significant retardation of tumor growth. More interestingly, the treatment of B16F10 tumor-bearing mice was further boosted by co-administration of polymersomal CpG and anti-PD-1 antibody, in which two out of seven mice were cured as a result of strong immune response and long-term immune memory protection. The immunotherapeutic effect was evidenced by secretion of IL-6, IFN-γ and TNF-α, tumor infiltration of CD8+ CTLs and Th, and induction of TEM and TCM in spleen. This study opens a new avenue to oncolytic peptides, which enables durable immunotherapy of tumors via systemic administration.
    Keywords:  Anti-PD-1 antibody; Antimicrobial peptide; CpG; Melanoma; Polymersomes
    DOI:  https://doi.org/10.1016/j.jconrel.2021.06.032
  99. Front Vet Sci. 2021 ;8 656715
    Canine Transforming Growth Factor-β Receptor 2-Ig: A Potential Candidate Biologic for Melanoma Treatment That Reverses Transforming Growth Factor-β1 Immunosuppression.
    Hiroto Takeuchi, Satoru Konnai, Naoya Maekawa, Satoshi Takagi, Hiroshi Ohta, Noboru Sasaki, Sangho Kim, Tomohiro Okagawa, Yasuhiko Suzuki, Shiro Murata, Kazuhiko Ohashi.
      Cancer cells can evade host immune systems via multiple mechanisms. Transforming growth factor beta 1 (TGF-β1) is an immunosuppressive cytokine that induces regulatory T cell (Tregs) differentiation and is involved in immune evasion mechanisms in cancer. The inhibition of the TGF-β1 signaling pathway can suppress cancer progression and metastasis through the modulation of anticancer immune responses. However, to best of our knowledge, no implementation of treatments targeting TGF-β1 has been reported in dog cancers. This study aimed to examine whether TGF-β1 is upregulated in canine cancers. We measured TGF-β1 concentrations in culture supernatants of canine melanoma cell lines and in serum samples from dogs with oral malignant melanoma. TGF-β1 production was observed in several cell lines, and serum TGF-β1 levels were elevated in dogs with oral malignant melanoma. Interestingly, the addition of recombinant TGF-β1 to canine peripheral blood mononuclear cell cultures decreased Th1 cytokine production and increased differentiation of CD4+CD25+Foxp3+ lymphocytes, suggesting that TGF-β1 is immunosuppressive in canine immune systems. We developed a decoy receptor for TGF-β, namely TGF-βRII-Ig, by identifying an open reading frame of the canine TGFBR2 gene. TGF-βRII-Ig was prepared as a recombinant fusion protein of the extracellular region of canine TGF-βRII and the Fc region of canine IgG-B. As expected, TGF-βRII-Ig bound to TGF-β1. In the presence of TGF-β1, the treatment with TGF-βRII-Ig increased Th1 cytokine production and decreased the differentiation of CD4+CD25+Foxp3+ lymphocytes. Our results suggest that TGF-βRII-Ig competitively inhibits the immunosuppressive effects of TGF-β1 and thereby activates immune responses. This study demonstrated the potential of TGF-βRII-Ig as a novel biologic for canine melanoma.
    Keywords:  TGF-β1; biologic; cancer immunotherapy; canine; immunosuppression; melanoma
    DOI:  https://doi.org/10.3389/fvets.2021.656715
  100. Ont Health Technol Assess Ser. 2021 ;21(5): 1-81
    Pigmented Lesion Assay for Suspected Melanoma Lesions: A Health Technology Assessment.
    .
      Background: Early detection of melanoma is key, as survival rates are substantially better when the cancer is detected in its early stages. Currently, the standard of care is to biopsy any lesion suspected of melanoma for diagnostic confirmation by histopathology. As a result, most people who undergo biopsy receive negative melanoma results. If effective, a non-invasive alternative, such as pigmented lesion assay, could minimize the number of unnecessary biopsies performed. We conducted a health technology assessment of pigmented lesion assay for people with suspected melanoma lesions, which included an evaluation of diagnostic accuracy, clinical utility, the budget impact of publicly funding pigmented lesion assay, and the preferences and values of people who have undergone biopsy for suspected melanoma.Methods: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) and the Risk of Bias Assessment Tool for Non-randomized Studies (RoBANS). We assessed the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic literature search of the economic evidence. We also analyzed the budget impact of publicly funding pigmented lesion assay in adults with suspected melanoma in Ontario. To contextualize the potential value of pigmented lesion assay, we spoke with people who had undergone skin biopsy for melanoma. We also used the qualitative research synthesis from a report by the Canadian Agency for Drugs and Technologies in Health to provide context for the preferences and values of those with suspected melanoma.
    Results: We included seven studies in the clinical evidence review. Pigmented lesion assay has a sensitivity of 79% (95% confidence interval [CI] 58%-93%) and a specificity of 80% (95% CI 73%-85%; GRADE: Low). We found one published cost-effectiveness study with potentially serious limitations. Therefore, the cost-effectiveness of pigmented lesion assay compared with the standard care pathway is currently uncertain. Assuming a very low uptake, we estimated that the budget impact of publicly funding pigmented lesion assay in Ontario over the next 5 years is about $3.44 million if the test is used exclusively by primary care providers, or about $2.56 million if it is used exclusively by specialists. The people with whom we spoke who had experienced biopsy for suspected melanoma responded positively to the potential benefits of pigmented lesion assay, emphasizing its ease-of-use, potential increase in early detection of melanoma, and reduction in physical and emotional burden of unnecessary biopsies. Participants also felt that the accuracy of this tool was essential to ensure minimal false negatives.
    Conclusions: There is uncertainty because of the low-quality evidence for the diagnostic accuracy of pigmented lesion assay. The cost-effectiveness of pigmented lesion assay compared with standard care is also uncertain. We estimated that publicly funding pigmented lesion assay in Ontario over the next 5 years would result in additional costs of $3.44 million (if used exclusively by primary care providers) or $2.56 million (if used exclusively by specialists). For people who had experienced biopsy for suspected melanoma, it was felt that pigmented lesion assay could represent an effective tool to increase early detection and avoid unnecessary biopsies, if the tool was accurate.
  101. Br J Dermatol. 2021 Jul;185(1): 9-10
    Melanoma origins: data from early-stage tumours supports de novo and naevus-associated melanomas as distinct subtypes.
    J Wiggins, D Polsky.
      
    DOI:  https://doi.org/10.1111/bjd.20396
  102. Phytochemistry. 2021 Jun 25. pii: S0031-9422(21)00198-9. [Epub ahead of print]189 112849
    Real-time fluorescence imaging of anthocyanins complexed with diphenylboric acid 2-aminoethyl inside B16-F10 melanoma cells.
    Madalina Nistor, Monica Focsan, Luiza Gaina, Mihai Cenariu, Adela Pintea, Carmen Socaciu, Dumitrita Rugina.
      Anthocyanins (AN), natural compounds daily consumed by humans, have outstanding therapeutical potential if administered topically in melanoma pathology. However, the search for efficient therapy development is still in progress, owing to the lack of complete understanding of the AN intracellular path, once they are uptaken by the cells. This target is constrained by the need for an imaging strategy that would enable their intracellular detection and localization in-situ. In this light, diphenylboric acid 2-aminoethyl (DPBA), a non-fluorescent reagent, was here successfully used to form fluorescent complexes with AN. The AN used are the cyanidin aglycon as a free standard molecule (CY), and the glycosylated compounds, extracted and purified from chokeberry fruits (AE). In solution, it was observed that the fluorescence emission increased by 39% (CY@DPBA), and by 34% (AE@DPBA), which concludes that AN form fluorescent complexes with DPBA (CY@DPBA and AE@DPBA). In addition, using NMR (nuclear magnetic resonance) spectroscopy, and HRMS (high-resolution mass spectrometry) analysis, the structure of the CY@DPBA complex was efficiently elucidated. In-vitro experiments showed that the complexes formed after the treatment proved to be non-toxic on B16-F10 cells. The sub-cellular visualization of all AN was monitored by fluorescence microscopy and flow cytometry, demonstrating detectable signals of the non-metabolized CY and glycosylated CY inside melanoma cells. This study reports that the use of DPBA to image AN intracellularly is a sensitive, non-invasive and successful method that can extend its application in broad fields like drug development or metabolism-associated mechanisms.
    Keywords:  2-((diphenylboraneyl)oxy)ethan-1-amine; Anthocyanins; Fluorescence microscopy; HRMS; Melanoma B16–F10 cells; NMR
    DOI:  https://doi.org/10.1016/j.phytochem.2021.112849
  103. J Cosmet Dermatol. 2021 Jul 02.
    Fractional versus Full Ablative CO2 Laser in Recipient site of Non-Cultured Melanocytes and Keratinocyte Transplantation in Treatment of Vitiligo.
    Alzahraa Mohammed Gamal, Rasha Aly El-Barbary, Nayera Hassan Moftah.
      BACKGROUND: Melanocyte-keratinocyte transplant procedure (MKTP) or non-cultured epidermal cell suspension transplantation is a very popular surgical modality for treating stable vitiligo. The recipient-site preparation is one potential determinant in the repigmentation outcomes.OBJECTIVES: To assess the efficacy of fractional CO2 (FCO2 ) laser in recipient-site preparation before MKTP and comparing it to the frequently used full surface laser ablation.
    METHODS: This randomized comparative trial included 19 patients with 40 stable vitiligo lesions. In each patient, the treated sites were randomly categorized into two groups according to the recipient site ablation (either fractional or full ablative CO2 laser). Assessment of repigmentation was performed six months after the procedure.
    RESULTS: Both modalities achieved successful repigmentation of a median 80% and 77.5% for fractional and full ablation group respectively, with a non-statistically significant difference between them. The median of VASI change percent was -73% and -71% with fractional and full surface ablation, respectively.
    CONCLUSIONS: FCO2 laser ablation is effective for recipient-site preparation before cell suspension transplantation as well as the full ablative CO2 laser.
    Keywords:  MKTP; Stable vitiligo; cellular grafting; fractional CO2 laser; full ablative CO2 laser
    DOI:  https://doi.org/10.1111/jocd.14324
  104. Se Pu. 2020 Nov 08. 38(11): 1302-1307
    [Determination of dacarbazine in the urine of mice with melanoma by high performance liquid chromatography].
    Yuhua Yue, Bingjun Zhou, Jiayuan Ai, Shun Feng.
      Dacarbazine (DTIC) is a first-line chemotherapy drug that is widely used in clinical practice for malignant melanoma. DTIC is metabolized by the liver in vivo. Some drugs are excreted in urine in the form of a prototype. Hence, DTIC in urine can be monitored to evaluate its utilization and conversion rate in the human body, and then to determine its therapeutic effect. Urine is the only body fluid that can be obtained in large quantities without damage, and it plays an important role in the analysis of body functions. However, the composition of urine is complex and there is large matrix interference, because of which trace analysis or trace component analysis is difficult. At present, the main analytical methods for DTIC are high performance liquid chromatography (HPLC) with/without mass spectrometry (MS). HPLC and HPLC-MS have the advantages of good separation effect, good selectivity, high detection sensitivity, automatic operation, and wide application range. Unfortunately, DTIC is a strongly polar and weakly basic compound; thus, it is difficult to achieve good separation and obtain good peak shapes by conventional reversed-phase chromatography. To overcome these defects, it is necessary to develop a novel method for the analysis of DTIC. In this study, mice were subjected to 12 h of fasting; then, blueberry anthocyanin was administered by gavage, and DTIC was administered by intraperitoneal injection. Then, morning urine was collected in a metabolic cage. Urine collection was continued every 4 days for a total of 5 times. Within 2 h, the collected urine was centrifuged (3000 g, 4℃) for 10 min to remove solids. The supernatant was stored in a refrigerator at-80℃. Before analysis, the urine samples were removed from the refrigerator and thawed naturally at room temperature. Then, the samples were treated by the acetone-sediment method, freeze-dried, dissolved in the mobile phase, and subjected to HPLC analysis with isocratic elution. The separation was performed on a Shimadzu-GL ODS column (250 mm×4.6 mm, 5 μm). The mobile phase was methanol/acetonitrile (1:1, v/v)-0.01 mol/L NaH2PO4 (pH 6.5; 20:80, v/v) at a flow rate of 1 mL/min. The detection wavelength, column temperature, and running time were 280 nm, 30℃, and 15 min, respectively. Under the optimized conditions, the retention time of DTIC was 5.3 min, and a good peak shape was obtained. The linearity ranged from 0.25 to 1000 μg/mL (r2=0.999). The limits of detection and quantification were calculated to be 0.12 μg/mL and 0.25 μg/mL based on signal-to-noise ratios of 3 and 10, respectively. At three spiked levels (50.0, 375, and 500 μg/mL), the average recoveries were 98.9%, 102%, and 99.1% with relative standard deviations (RSDs) of 3.2%, 1.3%, and 1.2% (n=5), respectively. The RSDs of the interday and intraday measurements were lower than 3.8% and 4.4%, respectively. The proposed method allowed for the accurate determination of DTIC in urine using a mixed organic solvent/phosphate buffer solution as the mobile phase, with equivalent elution for 15 min. This method was successfully applied to monitor the change in DTIC concentration in the urine of C57BL/6 mice in various stages of melanoma. The results demonstrate that the method is simple, reliable, and easy to apply.
    Keywords:  blueberry anthocyanin; dacarbazine; high performance liquid chromatography (HPLC); melanoma; nutritional adjuvant; urine
    DOI:  https://doi.org/10.3724/SP.J.1123.2020.01003
  105. Plast Reconstr Surg. 2021 Jul 01. 148(1): 71e-76e
    A Novel Treatment for Giant Congenital Melanocytic Nevi Combining Inactivated Autologous Nevus Tissue by High Hydrostatic Pressure and a Cultured Epidermal Autograft: First-in-Human, Open, Prospective Clinical Trial.
    Naoki Morimoto, Toshihito Mitsui, Michiharu Sakamoto, Atsushi Mahara, Kenichi Yoshimura, Jun Arata, Chizuru Jinno, Natsuko Kakudo, Kenji Kusumoto, Tetsuji Yamaoka.
      BACKGROUND: Giant congenital melanocytic nevi are large skin lesions associated with a risk of malignant transformation. The authors developed a novel treatment to reconstruct full-thickness skin defects by combining an inactivated nevus as the autologous dermis and a cultured epidermal autograft. The first-in-human trial of this treatment was performed.METHODS: Patients with melanocytic nevi that were not expected to be closed by primary closure were recruited. The full-thickness nevus of the target was removed and inactivated by high hydrostatic pressurization at 200 MPa for 10 minutes. The inactivated nevus was sutured to the original site, and a cultured epidermal autograft was grafted onto it 4 weeks later. Patients were followed for up to 52 weeks.
    RESULTS: Ten patients underwent reimplantation of the pressurized nevus, and one patient dropped out. The recurrence of nevus at 52 weeks was not detected by pathological diagnosis in any patients. The L* value at 52 weeks was significantly higher than that of the target nevus. One patient received skin grafting due to contracture of the reconstructed skin. The epithelized area of the reconstructed skin, as the percentage of the original target nevus, was 55.5 ± 19.4 percent at 12 weeks and 85.0 ± 32.4 percent at 52 weeks.
    CONCLUSIONS: The inactivated nevus caused inflammation and contracture for several months. However, no recurrence was observed, and combination therapy using an inactivated nevus with a cultured epidermal autograft may therefore be a novel treatment of giant congenital melanocytic nevi.
    CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.
    DOI:  https://doi.org/10.1097/PRS.0000000000008084
  106. J Immunother Cancer. 2021 Jul;pii: e002852. [Epub ahead of print]9(7):
    STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation.
    Takashi Nakamura, Takanori Sato, Rikito Endo, Shun Sasaki, Naomichi Takahashi, Yusuke Sato, Mamoru Hyodo, Yoshihiro Hayakawa, Hideyoshi Harashima.
      BACKGROUND: Resistance to an immune checkpoint inhibitor (ICI) is a major obstacle in cancer immunotherapy. The causes of ICI resistance include major histocompatibility complex (MHC)/histocompatibility locus antigen (HLA) class I loss, neoantigen loss, and incomplete antigen presentation. Elimination by natural killer (NK) cells would be expected to be an effective strategy for the treatment of these ICI-resistant tumors. We previously demonstrated that a lipid nanoparticle containing a stimulator of an interferon gene (STING) agonist (STING-LNP) efficiently induced antitumor activity via the activation of NK cells. Thus, we evaluated the potential of reducing ICI resistance by STING-LNPs.METHODS: Lung metastasis of a B16-F10 mouse melanoma was used as an anti-programmed cell death 1 (anti-PD-1)-resistant mouse model. The mice were intravenously injected with the STING-LNP and the mechanism responsible for the improvement of anti-PD-1 resistance by the STING-LNPs was analyzed by RT-qPCR and flow cytometry. The dynamics of STING-LNP were also investigated.
    RESULTS: Although anti-PD-1 monotherapy failed to induce an antitumor effect, the combination of the STING-LNP and anti-PD-1 exerted a synergistic antitumor effect. Our results indicate that the STING-LNP treatment significantly increased the expression of CD3, CD4, NK1.1, PD-1 and interferon (IFN)-γ in lung metastases. This change appears to be initiated by the type I IFN produced by liver macrophages that contain the internalized STING-LNPs, leading to the systemic activation of NK cells that express PD-1. The activated NK cells appeared to produce IFN-γ, resulting in an increase in the expression of the PD ligand 1 (PD-L1) in cancer cells, thus leading to a synergistic antitumor effect when anti-PD-1 is administered.
    CONCLUSIONS: We provide a demonstration to show that a STING-LNP treatment can overcome PD-1 resistance in a B16-F10 lung metastasis model. The mechanism responsible for this indicates that NK cells are activated by stimulating the STING pathway which, in turn, induced the expression of PD-L1 on cancer cells. Based on the findings reported herein, the STING-LNP represents a promising candidate for use in combination therapy with anti-PD-1-resistant tumors.
    Keywords:  adjuvants; combination; drug therapy; immunotherapy; killer cells; melanoma; natural; pharmaceutic
    DOI:  https://doi.org/10.1136/jitc-2021-002852
  107. Front Mol Biosci. 2021 ;8 692724
    Deubiquitination of MITF-M Regulates Melanocytes Proliferation and Apoptosis.
    Shuaishuai Hu, Shaocheng Bai, Yingying Dai, Naisu Yang, Jiali Li, Xiyu Zhang, Fan Wang, Bohao Zhao, Guolian Bao, Yang Chen, Xinsheng Wu.
      Microphthalmia-associated transcription factor-M (MITF-M) is the key gene in the proliferation and differentiation of melanocytes, which undergoes an array of post-translation modifications. As shown in our previous study, deubiquitinase USP13 is directly involved in melanogenesis. However, it is still ambiguous that the effect of USP13-mediated MITF-M expression on melanocytes proliferation and apoptosis. Herein, we found that MITF-M overexpressing melanocytes showed high cell proliferation, reduced apoptosis, and increased melanin levels. Besides, melanin-related genes, TYR, DCT, GPNMB, and PMEL, were significantly up-regulated in MITF-M overexpressing melanocytes. Furthermore, Exogenous USP13 significantly upregulated the endogenous MITF-M protein level, downregulated USP13 significantly inhibited MITF-M protein levels, without altering MITF-M mRNA expression. In addition, USP13 upregulation mitigated the MITF-M degradation and significantly increased the half-life of MITF-M. Also, USP13 stabilized the exogenous MITF protein levels. In conclusion, the MITF-M level was regulated by USP13 deubiquitinase in melanocytes, affecting melanocytes proliferation and apoptosis. This study provides the theoretical basis for coat color transformation that could be useful in the development of the new breed in fur animals.
    Keywords:  MITF-M; USP13; deubiquitination; interaction; melanocytes
    DOI:  https://doi.org/10.3389/fmolb.2021.692724
  108. Cancers (Basel). 2021 Jun 25. pii: 3186. [Epub ahead of print]13(13):
    Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/- Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets.
    Tuba N Gide, Inês Pires da Silva, Camelia Quek, Peter M Ferguson, Marcel Batten, Ping Shang, Tasnia Ahmed, Alexander M Menzies, Matteo S Carlino, Robyn P M Saw, John F Thompson, Richard A Scolyer, Georgina V Long, James S Wilmott.
      While immune checkpoint inhibitors targeting the CTLA-4 and PD-1 receptors have significantly improved outcomes of many patients with metastatic melanoma, there remains a group of patients who demonstrate no benefit. In this study, we sought to characterise patients who do not respond to anti-PD-1-based therapies based on their clinical, genetic and immune profiles. Forty patients with metastatic melanoma who did not respond to anti-PD-1 +/- anti-CTLA-4 treatment were identified. Targeted RNA sequencing (n = 37) was performed on pretreatment formalin-fixed paraffin-embedded (FFPE) melanoma specimens. Patients clustered into two groups based on the expression profiles of 26 differentially expressed genes: an immune gene rich group (n = 17) expressing genes associated with immune and T cell signalling, and a second group (n = 20) expressing genes associated with metabolism, signal transduction and neuronal signalling. Multiplex immunohistochemistry validated significantly higher densities of tumour-infiltrating lymphocytes (TILs) and macrophages in the immune gene-rich group. This TIL-high subset of patients also demonstrated higher expression of alternative immune-regulatory drug targets compared to the TIL-low group. Patients were also subdivided into rapid progressors and other progressors (cut-off 2 mo progression-free survival), with significantly lower TILs (p = 0.04) and CD68+ macrophages (p = 0.0091) in the rapid progressors. Furthermore, a trend towards a higher tumour burden was observed in rapid progressors (p = 0.06). These data highlight the need for a personalised and multilayer (clinical and molecular) approach for identifying the most appropriate treatments for anti-PD-1 resistant patients and provides insight into how individual treatment strategies can be achieved.
    Keywords:  RNA-sequencing; anti-CTLA-4; anti-PD-1; immunotherapy resistance; melanoma; tumour-infiltrating lymphocytes
    DOI:  https://doi.org/10.3390/cancers13133186
  109. Animals (Basel). 2021 Jun 27. pii: 1913. [Epub ahead of print]11(7):
    Preliminary Study: Proteomic Profiling Uncovers Potential Proteins for Biomonitoring Equine Melanocytic Neoplasm.
    Parichart Tesena, Amornthep Kingkaw, Wanwipa Vongsangnak, Surakiet Pitikarn, Narumon Phaonakrop, Sittiruk Roytrakul, Attawit Kovitvadhi.
      Equine melanocytic neoplasm (EMN) is a cutaneous neoplasm and is mostly observed in aged grey horses. This preliminary study aimed to identify potential proteins to differentiate normal, mild and severe EMN from serum proteomic profiling. Serum samples were collected from 25 grey horses assigned to three groups: normal (free of EMN; n = 10), mild (n = 6) and severe EMN (n = 9). To explore the differences in proteins between groups, proteomic profiling and analysis were employed. Accordingly, 8241 annotated proteins out of 8725 total proteins were compared between normal and EMN groups and inspected based on differentially expressed proteins (DEPs). Through DEP analysis, 95 significant DEPs differed between normal and EMN groups. Among these DEPs, 41 significant proteins were categorised according to protein functions. Based on 41 significant proteins, 10 were involved in metabolism and 31 in non-metabolism. Interestingly, phospholipid phosphatase6 (PLPP6) and ATPase subunit alpha (Na+/K+-ATPase) were considered as potential proteins uniquely expressed in mild EMN and related to lipid and energy metabolism, respectively. Non-metabolism-related proteins (BRCA1, phosphorylase B kinase regulatory subunit: PHKA1, tyrosine-protein kinase receptor: ALK and rho-associated protein kinase: ROCK1) correlated to melanoma development differed among all groups. The results of our study provide a foundation for early EMN biomonitoring and prevention.
    Keywords:  bioinformatics; equine melanocytic neoplasm; grey horse; potential proteins; serum proteomics
    DOI:  https://doi.org/10.3390/ani11071913
  110. Nutrients. 2021 Jun 04. pii: 1931. [Epub ahead of print]13(6):
    Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial.
    Harriet Johansson, Giuseppe Spadola, Giulio Tosti, Mario Mandalà, Alessandro M Minisini, Paola Queirolo, Valentina Aristarco, Federica Baldini, Emilia Cocorocchio, Elena Albertazzi, Leonardo Zichichi, Saverio Cinieri, Costantino Jemos, Giovanni Mazzarol, Patrizia Gnagnarella, Debora Macis, Ines Tedeschi, Emanuela Omodeo Salè, Luigia Stefania Stucci, Bernardo Bonanni, Alessandro Testori, Elisabetta Pennacchioli, Pier Francesco Ferrucci, Sara Gandini, On Behalf Of The Italian Melanoma Intergroup Imi.
      Patients with newly resected stage II melanoma (n = 104) were randomized to receive adjuvant vitamin D3 (100,000 IU every 50 days) or placebo for 3 years to investigate vitamin D3 protective effects on developing a recurrent disease. Median age at diagnosis was 50 years, and 43% of the patients were female. Median serum 25-hydroxy vitamin D (25OHD) level at baseline was 18 ng/mL, interquartile range (IQ) was 13-24 ng/mL, and 80% of the patients had insufficient vitamin D levels. We observed pronounced increases in 25OHD levels after 4 months in the active arm (median 32.9 ng/mL; IQ range 25.9-38.4) against placebo (median 19.05 ng/mL; IQ range 13.0-25.9), constantly rising during treatment. Remarkably, patients with low Breslow score (<3 mm) had a double increase in 25OHD levels from baseline, whereas patients with Breslow score ≥3 mm had a significantly lower increase over time. After 12 months, subjects with low 25OHD levels and Breslow score ≥3 mm had shorter disease-free survival (p = 0.02) compared to those with Breslow score <3 mm and/or high levels of 25OHD. Adjusting for age and treatment arm, the hazard ratio for relapse was 4.81 (95% CI: 1.44-16.09, p = 0.011). Despite the evidence of a role of 25OHD in melanoma prognosis, larger trials with vitamin D supplementation involving subjects with melanoma are needed.
    Keywords:  Breslow; cancer; melanoma; prognosis; single-nucleotide polymorphisms; vitamin D
    DOI:  https://doi.org/10.3390/nu13061931
  111. Gene. 2021 Jun 24. pii: S0378-1119(21)00391-7. [Epub ahead of print] 145796
    Up-down regulation of HIF-1α in cancer progression.
    Mohsen Rashid, Leila Rostami Zadeh, Behzad Baradaran, Ommoleila Molavi, Zeinab Ghesmati, Mehdi Sabzichi, Fatemeh Ramezani.
      Hypoxia induicible factor-1 alpha (HIF-1α) is a key transcription factor in cancer progression and target therapy in cancer. HIF-1α acts differently depending on presence or absence of Oxygen. In an oxygen-immersed environment, HIF-1α completely deactivated and destroyed by the ubiquitin proteasome pathway (UPP). In contrast, in the oxygen-free environment, it escapes destruction and enters to the nucleus of cells then upregulates many genes involved in cancer progression. Overexpressed HIF-1α and downstream genes support cancer progression through various mechanisms including angiogenesis, proliferation and survival of cells, metabolism reprogramming, invasion and metastasis, cancer stem cell maintenance, induction of genetic instability, and treatment resistance. HIF-1α can be provoked by signaling pathways unrelated to hypoxia during cancer progression. Therefore, cancer development and progression can be modulated by targeting HIF-1α and its downstream signaling molecules. In this regard, HIF-1α inhibitors which are categorized into the agents that regulate HIF-1α in gene, mRNA and protein levels used as an efficient way in cancer treatment. Also, HIF-1α expression can be negatively affected by the agents suppressing the activation of mTOR, PI3k/Akt and MAPK pathways.
    Keywords:  Cancer Progression; Cancer Stem Cells; Drug Resistance; HIF-1α; Invasion and Metastasis; Proliferation and apoptosis
    DOI:  https://doi.org/10.1016/j.gene.2021.145796
  112. Molecules. 2021 Jun 04. pii: 3403. [Epub ahead of print]26(11):
    Y2O3 Nanoparticles and X-ray Radiation-Induced Effects in Melanoma Cells.
    Ioana Porosnicu, Cristian M Butnaru, Ion Tiseanu, Elena Stancu, Cristian V A Munteanu, Bogdan I Bita, Octavian G Duliu, Felix Sima.
      The innovative strategy of using nanoparticles in radiotherapy has become an exciting topic due to the possibility of simultaneously improving local efficiency of radiation in tumors and real-time monitoring of the delivered doses. Yttrium oxide (Y2O3) nanoparticles (NPs) are used in material science to prepare phosphors for various applications including X-ray induced photodynamic therapy and in situ nano-dosimetry, but few available reports only addressed the effect induced in cells by combined exposure to different doses of superficial X-ray radiation and nanoparticles. Herein, we analyzed changes induced in melanoma cells by exposure to different doses of X-ray radiation and various concentrations of Y2O3 NPs. By evaluation of cell mitochondrial activity and production of intracellular reactive oxygen species (ROS), we estimated that 2, 4, and 6 Gy X-ray radiation doses are visibly altering the cells by inducing ROS production with increasing the dose while at 6 Gy the mitochondrial activity is also affected. Separately, high-concentrated solutions of 25, 50, and 100 µg/mL Y2O3 NPs were also found to affect the cells by inducing ROS production with the increase of concentration. Additionally, the colony-forming units assay evidenced a rather synergic effect of NPs and radiation. By adding the NPs to cells before irradiation, a decrease of the number of proliferating cell colonies was observed with increase of X-ray dose. DNA damage was evidenced by quantifying the γ-H2AX foci for cells treated with Y2O3 NPs and exposed to superficial X-ray radiation. Proteomic profile confirmed that a combined effect of 50 µg/mL Y2O3 NPs and 6 Gy X-ray dose induced mitochondria alterations and DNA changes in melanoma cells.
    Keywords:  A375 cell; X-ray irradiation; Y2O3 nanoparticles
    DOI:  https://doi.org/10.3390/molecules26113403
  113. Br J Dermatol. 2021 Jun 29.
    Teledermoscopy: A Helpful Detection Tool for Amelanotic and Hypomelanotic Melanoma.
    A Altayeb, S Dawood, A Atwan, C Mills.
      Amelanotic and hypomelanotic melanomas (AHM) comprise 2-8% of all melanomas. They are usually diagnosed late and are more advanced at diagnosis compared with pigmented melanomas (MM). As a result, AHMs are associated with higher mortality and morbidity (1). Some reports have described the dermoscopic features of amelanotic melanomas (AMM) and hypomelanotic melanomas (HMM) to aid the diagnosis of such lesions (2-4).
    DOI:  https://doi.org/10.1111/bjd.20609
  114. BMC Complement Med Ther. 2021 Jul 02. 21(1): 186
    Chitosan nanoparticles containing limonene and limonene-rich essential oils: potential phytotherapy agents for the treatment of melanoma and breast cancers.
    Hiva Alipanah, Mojtaba Farjam, Elham Zarenezhad, Ghazaal Roozitalab, Mahmoud Osanloo.
      BACKGROUND: Melanoma and breast cancers are two common cancers worldwide. Due to the side effects of chemotherapy drugs and the occurring resistance against them, the development of green drugs has been received more attention.METHODS: The anticancer effects of three essential oils from the Citrus family and their identified major constituents (limonene) were first investigated against melanoma and breast cancer cell lines (A-375 and MDA-MB-468). By preparing chitosan nanoparticles containing them, an attempt was then made to improve their effectiveness.
    RESULTS: Chitosan nanoparticles containing Citrus sinensis and Citrus limon essential oils with IC50s of 0.03 and 0.124 μg/mL on A-375 cells, and 23.65 and 40.32 μg/mL on MDA-MB-468 showed distinct anticancer efficacies.
    CONCLUSION: The prepared formulations could thus be considered as green anticancer agents in complementary medicine and therapies.
    Keywords:  Citrus; Cytostatic agents; Phytochemicals; Skin neoplasms; Triple negative breast neoplasms
    DOI:  https://doi.org/10.1186/s12906-021-03362-7
  115. Cancers (Basel). 2021 Jun 19. pii: 3066. [Epub ahead of print]13(12):
    NGS-Based Analysis of Atypical Deep Penetrating Nevi.
    Antonella Manca, Maria Cristina Sini, Anna Maria Cesinaro, Francesca Portelli, Carmelo Urso, Maria Lentini, Roberta Cardia, Llucia Alos, Martin Cook, Sara Simi, Panagiotis Paliogiannis, Vincenzo De Giorgi, Antonio Cossu, Giuseppe Palmieri, Daniela Massi.
      Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or epithelioid melanocytes with a distinctive wedge-shaped configuration showing activation of the WNT pathway, with unusual cyto-architectural features. It is unclear whether they show a distinct genomic profile associated with a diverse metastatic potential. We describe herein a cohort of 21 atypical DPNs analyzed by next-generation sequencing using the Ion AmpliSeq™ Comprehensive Cancer Panel. We found that β-catenin exon 3 was mutated in 95% and MAP kinase pathway genes in 71% of the cases. Less frequent mutations were observed in HRAS (19%) and MAP2K1 (24%). Isocitrate dehydrogenases 1 (IDH1) mutations, including R132C, V178I, and S278L, were identified in 38% of cases and co-existed with BRAF/HRAS mutations. The only case with progressive nodal disease carried alterations in the β-catenin pathway and mutations in IDH1 and NRAS (codon 61). By a comprehensive mutation analysis, we found low genetic heterogeneity and a lack of significant associations between specific gene mutations and histopathological features, despite atypical features. Whether the acquisition of an NRAS or IDH1 mutation in an atypical DPN may represent a molecular evolution implying a pathway to melanoma progression should be confirmed in a larger series.
    Keywords:  atypical deep penetrating nevus; borderline/atypical deep penetrating nevus; deep penetrating nevus (DPN); next-generation sequencing (NGS); β-catenin
    DOI:  https://doi.org/10.3390/cancers13123066
  116. Ecol Evol. 2021 Jun;11(12): 7507-7517
    Comparative transcriptomics of albino and warningly-coloured caterpillars.
    Juan A Galarza.
      Coloration is perhaps one of the most prominent adaptations for survival and reproduction of many taxa. Coloration is of particular importance for aposematic species, which rely on their coloring and patterning acting as a warning signal to deter predators. Most research has focused on the evolution of warning coloration by natural selection. However, little information is available for color mutants of aposematic species, particularly at the genomic level. Here, I compare the transcriptomes of albino mutant caterpillars of the aposematic wood tiger moth (Arctia plantaginis) to those of their full sibs having their distinctive orange-black warning coloration. The results showed >290 differentially expressed genes genome-wide. Genes involved in the immune system, structural constituents of cuticular, and immunity were mostly downregulated in the albino caterpillars. Surprisingly, higher expression was observed in core melanin genes from albino caterpillars, suggesting that melanin synthesis may be disrupted in terminal ends of the pathway during its final conversion. Taken together, these results suggest that caterpillar albinism may not be due to a depletion of melanin precursor genes. In contrast, the albino condition may result from the combination of faulty melanin conversion late in its synthesis and structural deficiencies in the cuticular preventing its deposition. The results are discussed in the context of how albinism may impact individuals of aposematic species in the wild.
    Keywords:  Arctia plantaginis; aposematism; gene expression; melanin
    DOI:  https://doi.org/10.1002/ece3.7581
  117. Hum Vaccin Immunother. 2021 Jun 30. 1-6
    Role of gut microbiome on immunotherapy efficacy in melanoma.
    Stefano Bibbò, Gianluca Ianiro, Federica Giambò, Carlo Romano Settanni, Giovanni Cammarota, Antonio Gasbarrini.
      The gut microbiota is considered a key component in many aspects of cancer pathophysiology and response to therapy. In particular, in recent years intriguing evidences has been emerging regarding the role of the intestinal microbiota in the response to immunotherapy and in promoting the development of adverse events, such as colitis. For this reason, studies are being carried out both on pre-clinical models and on humans to study how to predict the response to immunotherapy through the study of the microbiota or how to improve its clinical response through modulation. Promising data have recently been reported through modulation by probiotics or prebiotics, and in particular by fecal microbiota transplantation. The aim of this review is to analyze the evidence regarding the role of the microbiota in immunotherapy with a particular focus on melanoma.
    Keywords:  checkpoint inhibitors; colitis; fecal microbiota transplantation; immunotherapy; microbiota; oncology; prebiotic; probiotic
    DOI:  https://doi.org/10.1080/21645515.2021.1926759
  118. J Cosmet Dermatol. 2021 Jul 03.
    A comparative pilot study of dipstick versus open-spray cryotherapy techniques as depigmentation treatments for vitiligo.
    Marwa Abdallah, Haitham M Saleh.
      Depigmentation therapy is considered in patients with wide-spread vitiligo (>50% body surface area, BSA), especially if in exposed sites and those who have significant cosmetic disfigurement due to residual pigmentations. Remaining pigmented patches can be removed using depigmentation creams (20-40% monobenzyl ether of hydroquinone; MBEH), laser therapy or cryotherapy[1].
    Keywords:  cryotherapy; depigmentation; dipstick; open-spray; vitiligo
    DOI:  https://doi.org/10.1111/jocd.14328
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