bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021‒07‒18
eighty-two papers selected by
Farah Jaber-Hijazi
University of the West of Scotland
  1. Practical Considerations When Interpreting FDG PET/CT Imaging for Staging and Treatment Response Assessment in Melanoma Patients.
  2. miR-138-5p induces aggressive traits by targeting Trp53 expression in murine melanoma cells, and correlates with poor prognosis of melanoma patients.
  3. Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib.
  4. Outcomes after retreatment with MAPK inhibitors and immune checkpoint inhibitors in melanoma patients.
  5. Imaging findings of melanoma metastasis in the gallbladder.
  6. Lipid mediator lipoxin A4 and its analog BML-111 exert antitumor effects in melanoma.
  7. CAMKK2 defines ferroptosis sensitivity of melanoma cells by regulating AMPK-Nrf2 pathway.
  8. Activation of PKG restricts melanoma growth and invasion by interfering with the EGF/EGFR pathway.
  9. TFPI2 Promotes Perivascular Migration in an Angiotropism Model of Melanoma.
  10. Melanoma Mimicking Atypical Fibroxanthoma: Report of an Unusual Case.
  11. Pseudoprogression with Neoadjuvant Immunotherapy for Cutaneous Melanoma.
  12. Identification of CXCL13 as an Immune-Related Biomarker Associated with Tumorigenesis and Prognosis in Cutaneous Melanoma Patients.
  13. Molecular landscape of Hereditary Melanoma.
  14. Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases.
  15. Paclitaxel anticancer activity is enhanced by the MEK 1/2 inhibitor PD98059 in vitro and by PD98059-loaded nanoparticles in BRAFV600E melanoma-bearing mice.
  16. Plasma proteome alterations by MAPK inhibitors in BRAFV600-mutated metastatic cutaneous melanoma.
  17. Solute carrier transporter superfamily member SLC16A1 is a potential prognostic biomarker and associated with immune infiltration in skin cutaneous melanoma.
  18. Impact of multiple lymphatic basin drainage in truncal melanoma patients.
  19. Case of large lentigo maligna melanoma of the scalp treated with 5% and 3.75% Imiquimod.
  20. LncRNA LINC01116 facilitates melanoma 1 progression via sequestering miR-3612 and up-regulating GDF11 and SDC3.
  21. NCK1-AS1 promotes the progression of melanoma by accelerating cell proliferation and migration via targeting miR-526b-5p/ADAM15 axis.
  22. In vivo two-photon-excited cellular fluorescence of melanin, NAD(P)H, and keratin enables an accurate differential diagnosis of seborrheic keratosis and pigmented cutaneous melanoma.
  23. Genetic variants of EML1 and HIST1H4E in myeloid cell-related pathway genes independently predict cutaneous melanoma-specific survival.
  24. Melanosis, melanoma, and melanosarcoma: concepts and terms in 19th century ophthalmology.
  25. Impact of prior treatment with immune checkpoint inhibitors on dacarbazine efficacy in metastatic melanoma.
  26. Silencing Osteopontin Expression Inhibits Proliferation, Invasion and Induce Altered Protein Expression in Melanoma Cells.
  27. Electrospinning: New Strategies for the Treatment of Skin Melanoma.
  28. Cannabinoids and their derivatives in struggle against melanoma.
  29. No Overall Survival Difference in the Immunotherapy Era for Rare Subtypes of Melanoma.
  30. Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma.
  31. Predictive factors of neoadjuvant immune checkpoint blockade in melanoma.
  32. Sperm-Specific Glycolysis Enzyme Glyceraldehyde-3-Phosphate Dehydrogenase Regulated by Transcription Factor SOX10 to Promote Uveal Melanoma Tumorigenesis.
  33. Nodular melanoma on lip with retrograde in-transit metastases on face.
  34. A Prospective Study of Intraarterial Infusion Chemotherapy in Advanced WT BRAF Melanoma Patients.
  35. A Standardized Analysis of Tertiary Lymphoid Structures in Human Melanoma: Disease Progression- and Tumor Site-Associated Changes With Germinal Center Alteration.
  36. Durable complete remission of leptomeningeal melanoma by intrathecal methotrexate maintained with systemic ipilimumab.
  37. Adjuvant pembrolizumab-related hyperprogression in stage III melanoma.
  38. To assess the relationship between distance travelled to dermatology clinic and Breslow thickness of melanoma at diagnosis.
  39. A Novel Autophagy-Related lncRNA Gene Signature to Improve the Prognosis of Patients with Melanoma.
  40. BCAT1 knockdown-mediated suppression of melanoma cell proliferation and migration is associated with reduced oxidative phosphorylation.
  41. Aqueous extracts of Sanghuangporus vaninii induce S-phase arrest and apoptosis in human melanoma A375 cells.
  42. A Solitary Melanoma Metastasis Confined to the Submandibular Gland.
  43. Skin-whitening mechanism of cumin (Cuminum cyminum L.) extract.
  44. Implication of integrin α2β1 in senescence of SK-Mel-147 human melanoma cells.
  45. Do AI models recognise rare, aggressive skin cancers? An assessment of a direct-to-consumer app in the diagnosis of Merkel cell carcinoma and amelanotic melanoma.
  46. Prognostic variables in patients with thick melanomas. Analysis of 362 cases.
  47. Randomized Study of Wound Drainage on Early Complications After Lymph Node Dissection for Melanoma.
  48. August 2021: On the epistemology of Breslow thickness and histopathologic melanoma subtype.
  49. Heptazoline exerts antiproliferative effects on human melanoma cells by inducing apoptosis, cell cycle arrest and targeting MAPK signalling pathway.
  50. A Case Series of Multiple Primary Malignancies Among Patients With Advanced Melanoma.
  51. Synchronous and metachronous malignant melanomas arising in a human immunodeficiency virus-positive patient after the commencement of highly active antiretroviral therapy treatment: a case report.
  52. Adjuvant anti-PD-1 antibody treatment in stage III/IV melanoma: real-world experience and health economic considerations.
  53. Potential effect of EGCG on the anti-tumor efficacy of metformin in melanoma cells.
  54. Stage-specific trends in incidence and survival of cutaneous melanoma in the Netherlands (2003-2018): A nationwide population-based study.
  55. Malignant Melanoma within a Cellular Blue Nevi Presenting as a Vascular Malformation and the Connection to Sporadic KRAS Mutations.
  56. The BRD4 inhibitor JQ1 promotes melanoma cell apoptosis by regulating mitochondrial dynamics.
  57. The combination therapy with the cytotoxic T lymphocyte-associated antigen-4 and programmed death 1 antibody-induced asthma in a patient with advanced melanoma.
  58. PRAME expression in melanocytic lesions of the conjunctiva.
  59. Educational Case: Malignant Melanoma.
  60. Long-term outcomes after enucleation or plaque brachytherapy of choroidal melanomas touching the optic disc.
  61. Malignant melanoma without primary, presenting as solitary pulmonary nodule: a case report.
  62. Female sex is associated with higher rates of dermatologic adverse events among patients with melanoma receiving immune checkpoint inhibitor therapy: a retrospective cohort study.
  63. A secondary role for hypoxia and HIF1 in the regulation of (IFNγ-induced) PD-L1 expression in melanoma.
  64. Histological regression in melanoma: impact on sentinel lymph node status and survival.
  65. Life Interrupted: Experiences of adolescents, young adults and their family living with malignant melanoma.
  66. THE demographics and trends in pediatric melanoma in the United States: An analysis of the National Cancer Database.
  67. Primary Cilia Are Preserved in Cellular Blue and Atypical Blue Nevi and Lost in Blue Nevus-like Melanoma.
  68. Assessing exposure to dermoscopy in plastic surgery training programs.
  69. Reduction in the number of early melanomas diagnosed during the COVID-19 pandemic: a single-center cohort study.
  70. Melanocytic hyperplasia associated with surgical scars in basal cell carcinoma re-excision specimens: a single-center retrospective study.
  71. Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.
  72. Optimized protocol for immunophenotyping of melanoma and tumor-bearing skin from mouse.
  73. Clinical and immunologic implications of COVID-19 in patients with melanoma and renal cell carcinoma receiving immune checkpoint inhibitors.
  74. Special issue: "Biology of skin pigmentation and pigmentary diseases".
  75. Visceral hepatic leishmaniasis in a melanoma patient in FDG-PET.
  76. Transverse Needling After Autologous Mini-Punch Grafts Improves Repigmentation in Stable Non-Segmental Vitiligo.
  77. Altered circulating memory T cells in vitiligo cases followed NB-UVB therapy.
  78. Spinal Nerve Root Extradural Melanocytoma Progressing to Malignant Melanoma: A Case Report with Review of Literature.
  79. An update on Congenital Melanocytic Nevus Syndrome: a case report and literature review.
  80. [Optical coherence tomography for the differential diagnosis of unclear nail pigmentation].
  81. Is targeted UVB as effective as excimer light phototherapy in treatment of vitiligo?
  82. Editorial: Immunology of Vitiligo.
  1. Semin Nucl Med. 2021 Jul 07. pii: S0001-2998(21)00042-8. [Epub ahead of print]
    Practical Considerations When Interpreting FDG PET/CT Imaging for Staging and Treatment Response Assessment in Melanoma Patients.
    Christophe Van de Wiele, Gebreurs Juanito, Borght K Vander, Lawal Ismaheel, Bart De Spiegeleer, Sathekge Mike, Maes Alex.
      While FDG PET/CT bears a high sensitivity and specificity for the staging of stage III and IV melanoma as well as for the purpose of melanoma recurrence detection, overall results tend to vary from one part of the body to another as well as for melanoma from cutaneous or choroidal origin. In this paper, organ or site-related differences in sensitivity and specificity in melanoma patients, both from cutaneous and choroidal origin, as well as their impact on clinical decision making are discussed. Furthermore, with the advent of immunotherapy for the treatment of malignant melanoma, post-treatment related potential false positive findings have emerged, the knowledge of which is essential for accurate treatment response assessment. These post-treatment related potential false positive findings are summarized in this paper so as to help the nuclear medicine physician in avoiding erroneous interpretation of acquired FDG PET/CT images in melanoma patients receiving immuntherapy.
    DOI:  https://doi.org/10.1053/j.semnuclmed.2021.06.010
  2. Neoplasia. 2021 Jul 08. pii: S1476-5586(21)00041-5. [Epub ahead of print]23(8): 823-834
    miR-138-5p induces aggressive traits by targeting Trp53 expression in murine melanoma cells, and correlates with poor prognosis of melanoma patients.
    Adriana Taveira da Cruz, Aline Hunger, Fabiana Henriques Machado de Melo, Ana Carolina Monteiro, Geneviève Catherine Paré, Dulce Lai, Débora Kristina Alves-Fernandes, Ana Luisa Pedroso Ayub, Esteban Mauricio Cordero, José Franco da Silveira Filho, Regine Schneider-Stock, Bryan Eric Strauss, Victor Tron, Miriam Galvonas Jasiulionis.
      Deregulation of miRNAs contributes to the development of distinct cancer types, including melanoma, an aggressive form of skin cancer characterized by high metastatic potential and poor prognosis. The expression of a set of 580 miRNAs was investigated in a model of murine melanoma progression, comprising non-metastatic (4C11-) and metastatic melanoma (4C11+) cells. A significant increase in miR-138-5p expression was found in the metastatic 4C11+ melanoma cells compared to 4C11-, which prompted us to investigate its role in melanoma aggressiveness. Functional assays, including anoikis resistance, colony formation, collective migration, serum-deprived growth capacity, as well as in vivo tumor growth and experimental metastasis were performed in 4C11- cells stably overexpressing miR-138-5p. miR-138-5p induced an aggressive phenotype in mouse melanoma cell lines leading to increased proliferation, migration and cell viability under stress conditions. Moreover, by overexpressing miR-138-5p, low-growing and non-metastatic 4C11- cells became highly proliferative and metastatic in vivo, similar to the metastatic 4C11+ cells. Luciferase reporter analysis identified the tumor suppressor Trp53 as a direct target of miR-138-5p. Using data sets from independent melanoma cohorts, miR-138-5p and P53 expression were also found deregulated in human melanoma samples, with their levels negatively and positively correlated with prognosis, respectively. Our data shows that the overexpression of miR-138-5p contributes to melanoma metastasis through the direct suppression of Trp53.
    Keywords:  Aggressiveness; Melanoma; Metastasis; Trp53; miR-138-5p
    DOI:  https://doi.org/10.1016/j.neo.2021.05.015
  3. Eur J Cancer. 2021 Jul 06. pii: S0959-8049(21)00358-0. [Epub ahead of print]154 57-65
    Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib.
    Philippe Saiag, Caroline Robert, Jean-Jacques Grob, Laurent Mortier, Olivier Dereure, Céleste Lebbe, Sandrine Mansard, Florent Grange, Eve-Marie Neidhardt, Thierry Lesimple, Laurent Machet, Christophe Bedane, Hervé Maillard, Sophie Dalac-Rat, Charlée Nardin, Alexandra Szenik, Amine Denden, Caroline Dutriaux.
      BACKGROUND: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups.METHODS: Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan-Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis.
    RESULTS: Between March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33-8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with <3 metastatic sites, ECOG = 0 and no BM had the highest probability of PFS at 6 months (83%, 95% CI 76-87) and 12 months (56%, 95% CI 47-64), respectively.
    CONCLUSIONS: This is the largest prospective study in advanced BRAF V600-mutant melanoma patients treated with D + T, conducted in conditions close to 'real-world practice'. We confirm previous findings that LDH, ECOG PS and ≥3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor.
    Keywords:  BRAF V600-mutation; Dabrafenib; Melanoma; Regression tree; Trametinib
    DOI:  https://doi.org/10.1016/j.ejca.2021.05.031
  4. Future Oncol. 2021 Jul 13.
    Outcomes after retreatment with MAPK inhibitors and immune checkpoint inhibitors in melanoma patients.
    Oana D Persa, Cornelia Mauch.
      Background: When patients with advanced melanoma progress after MAPK inhibitor (MAPKI) and immune checkpoint inhibitor (ICI) treatment, they can either undergo chemotherapy or rechallenge with previously used treatments. Methods: The outcomes of 48 patients retreated with MAPKIs and 50 patients retreated with ICIs following progression were retrospectively analyzed. Results: Upon retreatment with MAPKIs, the disease control rate was 60%. Univariate analysis of possible risk factors associated with short progression-free survival upon MAPKI treatment showed elevated lactate dehydrogenase to be associated with decreased progression-free survival. Disease control rate after ICI retreatment was 24%. Melanoma of unknown primary was associated with prolonged progression-free survival upon ICI retreatment. Conclusion: Retreatment with MAPKIs or ICIs is a feasible option for patients with advanced melanoma.
    Keywords:  immune checkpoint inhibitor; melanoma; treatment resistance
    DOI:  https://doi.org/10.2217/fon-2021-0446
  5. Rev Esp Enferm Dig. 2021 Jul 13.
    Imaging findings of melanoma metastasis in the gallbladder.
    Louise Torres, Caroline Lorenzoni Ghezzi, Alice Schuch, Gabriela Schneider Galvão.
      Cutaneous melanoma is a common and aggressive neoplasm, and metastases to the gastrointestinal tract mainly affect the small intestine, colon, and stomach. Gallbladder metastasis is uncommon. We present a case of melanoma metastasis in the gallbladder in a 40-year-old man with a previous diagnosis of cutaneous melanoma in the dorsal region. The purpose of this article is to reinforce the importance of imaging exams, adding PET scan as another useful method in patients with melanoma in follow-up.
    DOI:  https://doi.org/10.17235/reed.2021.8176/2021
  6. Ann Transl Med. 2021 May;9(9): 802
    Lipid mediator lipoxin A4 and its analog BML-111 exert antitumor effects in melanoma.
    Yu Du, Jianing Yang, Tangfeng Su, Zhu Shen, Juan Li.
      Background: LipoxinA4 (LXA4) is an anti-inflammatory lipid mediator which was recently proposed to have antitumor potential. However, the therapeutic effect of LXA4 in melanoma is still unclear. This work aimed to investigate the function of LXA4 and its analog in melanoma invasion through in vivo and in vitro experiments.Methods: The expression of the LXA4 receptor (ALXR) was detected in melanoma tissues and A375 human melanoma cells, using benign melanocytic nevi tissues and human melanocytes as negative controls, respectively. The invasive and apoptotic abilities of A375 cells in the presence or absence of LXA4 were examined by cell invasion assay and flow cytometric analysis. Finally, mice melanoma models were established, and the antitumor effects of BML-111 [5(S), 6(R)-7-trihydroxymethyl heptanoate], an agonist of ALXR, were examined in vivo.
    Results: ALXR was abundantly expressed in human melanoma tissues. The ALXR messenger RNA (mRNA) and protein expression levels were higher in A375 melanoma cells than in the controls (P<0.05). LXA4 could significantly attenuate the invasion ability of A375 cells (P<0.05). This trend was further enhanced by BML-111, which tended to control the tumor development in A375 melanoma models.
    Conclusions: LXA4 and its analog BML-111 exert antitumor effects in vivo and in vitro, and may be potential therapeutic options for patients with invasive melanoma.
    Keywords:  BML-111; Lipoxin A4 (LXA4); melanoma
    DOI:  https://doi.org/10.21037/atm-21-1873
  7. J Invest Dermatol. 2021 Jul 06. pii: S0022-202X(21)01416-0. [Epub ahead of print]
    CAMKK2 defines ferroptosis sensitivity of melanoma cells by regulating AMPK-Nrf2 pathway.
    Sijia Wang, Xiuli Yi, Zhenjie Wu, Sen Guo, Wei Dai, Huina Wang, Qiong Shi, Kang Zeng, Weinan Guo, Chunying Li.
      Melanoma is the most lethal skin cancer caused by malignant transformation of epidermal melanocyte. Recent progress in targeted therapy and immunotherapy has significantly improved the treatment outcome, but the survival of patients with advanced melanoma remains suboptimal. Ferroptosis, a cell death modality triggered by iron-dependent lipid peroxidation, reportedly participates in cancer pathogenesis and can mediate the effect of anti-PD-1 immunotherapy in melanoma. However, the detailed regulatory mechanism of ferroptosis remains far from understood. Herein, we report that CAMKK2 defines ferroptosis sensitivity of melanoma cells by regulating AMPK-Nrf2 pathway. We first found that CAMKK2 was prominently activated in ferroptosis. Then we proved that CAMKK2 negatively regulated ferroptosis via the activation of Nrf2 and the suppression of lipid peroxidation. Subsequent mechanistic studies revealed that AMPK connected CAMKK2 up-regulation to Nrf2-dependent anti-oxidative machinery in ferroptosis. Additionally, the suppression of CAMKK2 increased the efficacy of ferroptosis inducer and anti-PD-1 immunotherapy in pre-clinical xenograft tumor model by inhibiting AMPK-Nrf2 pathway and promoting ferroptosis. Taken together, CAMKK2 plays a protective role in ferroptosis by activating AMPK-Nrf2 pathway. Targeting CAMKK2 could be a potential approach to increase the efficacy of ferroptosis inducers and immunotherapy for melanoma treatment.
    Keywords:  AMPK; CAMKK2; ferroptosis; lipid peroxidation; melanoma
    DOI:  https://doi.org/10.1016/j.jid.2021.05.025
  8. J Invest Dermatol. 2021 Jul 12. pii: S0022-202X(21)01420-2. [Epub ahead of print]
    Activation of PKG restricts melanoma growth and invasion by interfering with the EGF/EGFR pathway.
    Marika Quadri, Antonella Comitato, Elisabetta Palazzo, Natascia Tiso, Andreas Rentsch, Giovanni Pellacani, Alessandra Marconi, Valeria Marigo.
      Drug resistance mechanisms still characterize metastatic melanoma, despite new treatments have been recently developed. Targeting of the cGMP/protein kinase G (PKG) pathway is emerging as a therapeutic approach in cancer research. In this study, we evaluated the anticancer effects of two polymeric linked dimeric (PDL) cGMP analogues able to bind and activate PKG, called PKG-activator (PA) 4 and 5. PA5 was identified as the most effective compound on melanoma cell lines as well as on patient-derived metastatic melanoma cells cultured as three-dimensional spheroids and in a zebrafish melanoma model. PA5 was able to significantly reduce cell viability, size, and invasion of melanoma spheroids. Importantly, PA5 showed a tumor specific outcome because no toxic effect was observed in healthy melanocytes exposed to the cGMP analogue. We defined that, by triggering PKG, PA5 interfered with the EGF pathway as shown by lower EGFR phosphorylation and reduction of activated, phosphorylated forms of AKT and ERK1/2 in melanoma cells. Finally, PA5 significantly reduced the metastatic process in zebrafish. These studies open future perspectives for the cGMP analogue PA5 as a potential therapeutic strategy for melanoma.
    Keywords:  EGFR pathway; Melanoma; PKG; Spheroids; Zebrafish; cGMP analogue
    DOI:  https://doi.org/10.1016/j.jid.2021.06.011
  9. Front Oncol. 2021 ;11 662434
    TFPI2 Promotes Perivascular Migration in an Angiotropism Model of Melanoma.
    Jing Mo, Xiulan Zhao, Wei Wang, Nan Zhao, Xueyi Dong, Yanhui Zhang, Runfen Cheng, Baocun Sun.
      Purpose: Angiotropism is the process by which cancer cells attach to and migrate along blood vessels to acquire vasculature, disseminate, and metastasize. However, the molecular basis for such vessel-tumor interactions has not been fully elucidated, partly due to limited experimental models. In this study, we aimed to observe and explore the molecular mechanism underlying angiotropism in melanoma.Methods: To monitor the interactions of human melanoma cells with the vasculature in vivo, a murine coxenograft model was employed by co-injecting highly and poorly invasive melanoma cells subcutaneously. To identify key pathways and genes involved in the angiotropic phenotype of melanoma, analysis of differentially expressed genes (DEGs) and gene set enrichment analysis (GSEA) were performed. The role of tissue factor pathway inhibitor 2 (TFPI2) in angiotropism was evaluated by immunostaining, adhesion assay, shRNA, and in vivo tumorigenicity. Angiotropism and TFPI2 expression were examined in surgical specimens of melanoma by immunohistochemical staining. Data from The Cancer Genome Atlas (TCGA) were analyzed to explore the expression and prognostic implications of TFPI2 in uveal and cutaneous melanoma.
    Results: Highly invasive melanoma cells spread along the branches of intratumor blood vessels to the leading edge of invasion in the coxenograft model, resembling angiotropic migration. Mechanisms underlying angiotropism were primarily associated with molecular function regulators, regulation of cell population proliferation, developmental processes, cell differentiation, responses to cytokines and cell motility/locomotion. TFPI2 downregulation weakened the perivascular migration of highly invasive melanoma cells. High levels of TFPI2 were correlated with worse and better survival in uveal and cutaneous melanoma, respectively.
    Conclusion: These results provide a straightforward in vivo model for the observation of angiotropism and suggest that TFPI2 could inhibit the angiotropic phenotype of melanoma.
    Keywords:  TFPI2; angiogenesis; angiotropism; melanoma; metastasis
    DOI:  https://doi.org/10.3389/fonc.2021.662434
  10. J Cutan Pathol. 2021 Jul 13.
    Melanoma Mimicking Atypical Fibroxanthoma: Report of an Unusual Case.
    Yanqing Wang, Ying Guo.
      Melanoma may mimic a variety of skin lesions clinically and histopathologically, and presents diagnostic challenges. In this article, we describe a case of melanoma in an 89-year-old man with a very rare histopathologic presentation, namely the presence of pleomorphic and multinucleated giant cells with abundant cytoplasm, highly resembling an atypical fibroxanthoma. The differential diagnoses in conjunction with the findings in immunohistochemical study are also discussed. This article is protected by copyright. All rights reserved.
    Keywords:  atypical fibroxanthoma; melanoma; mimic; multinucleate giant cells
    DOI:  https://doi.org/10.1111/cup.14096
  11. Case Rep Oncol. 2021 May-Aug;14(2):14(2): 881-885
    Pseudoprogression with Neoadjuvant Immunotherapy for Cutaneous Melanoma.
    Diogo Garcia, Juliana Rodrigues Beal, Daniel Mamere Alvarez, Ricardo Silvestre E Silva Macarenco, Gustavo Schvartsman.
      Immune checkpoint inhibitors (ICI) have drastically changed the landscape of metastatic melanoma management, thus significantly improving survival. Clinically, assessing treatment response may be challenging in a portion of cases due to a massive influx of immune cells into the tumor microenvironment, causing a transient increase in the target lesion size. This phenomenon, coined pseudoprogression, can occur in 5-10% of metastatic patients, and it is commonly followed by a tumor regression. Its incidence, however, may be underestimated, given its ephemeral nature and often being documented in visceral metastatic lesions, which are only assessed by imaging scans every 2-3 months. More recently, ICI has been studied in the neoadjuvant setting, yielding durable pathological responses in patients with cutaneous melanoma. Here, we report a case of a large retroauricular melanoma mass with regional lymph node involvement treated with ipilimumab and nivolumab combination therapy that developed pseudoprogression. Initially documented as an increase in size along with inflammatory features, followed by a dramatic clinical improvement. A complete regression was pathologically documented after 3 months and the patient remains disease-free for 14 months after treatment initiation. In conclusion, we document a pseudoprogression case during neoadjuvant ICI treatment and raise the question of whether the incidence of this phenomenon is higher when observed in superficial lesions, which can be assessed by routine physical exam.
    Keywords:  CTLA-4 receptor; Immunotherapy; Melanoma; PD-1 receptor; RECIST
    DOI:  https://doi.org/10.1159/000516036
  12. Med Sci Monit. 2021 Jul 11. 27 e932052
    Identification of CXCL13 as an Immune-Related Biomarker Associated with Tumorigenesis and Prognosis in Cutaneous Melanoma Patients.
    Zebing Si, Honghe Hu.
      BACKGROUND Melanoma is one of the most lethal tumors and its treatment is still challenging. It is urgent to detect novel therapy targets in melanoma. MATERIAL AND METHODS The GEO dataset was used to obtain a list of DEGS (differentially-expressed genes). Integrative bioinformatics analyses, including HPRD database, TCGA data, and TIMER, were performed to determine the role of CXCL13 in SKCM (skin cutaneous melanoma) progression and the immune environment. Furthermore, Pearson correlation coefficient analysis was used to measure correlations between CXCL13 and its co-expressed genes. Survival analysis, GO, and KEGG enrichment analysis were performed to investigate the role of CXCL13 in SKCM. RESULTS A total of 41 DEGs were identified in 3 GEO datasets, and 4 out of 41 DEGs are hub genes. Among the 4 hub genes, CXCL13 is involved in the most KEGG terms. CXCL13 is co-expressed with well-known immune checkpoint blockade targets, and it was associated with better overall survival. In addition, CXCL13 levels in infiltrating immune cells (neutrophil and myeloid dendritic cells) affect prognosis and survival in SKCM. Functional enrichment analysis clarified that CXCL13-co-expressed top 30 genes were associated with immune signaling pathways. Network analysis identified CXCL13 as a hub gene that interacts with CXCR5 to participate in immune-related biological process. CONCLUSIONS This study found that CXCL13 is associated with SKCM tumorigenesis and prognosis and immune infiltrations. Our result suggests that CXCL13 has great potential in development of novel immunotherapy targets in melanoma.
    DOI:  https://doi.org/10.12659/MSM.932052
  13. Crit Rev Oncol Hematol. 2021 Jul 07. pii: S1040-8428(21)00213-4. [Epub ahead of print] 103425
    Molecular landscape of Hereditary Melanoma.
    Joyce Ribeiro Moura Brasil Arnaut, Isabella Dos Santos Guimaraes, Anna Cláudia Evangelista Dos Santos, Flora de Moraes Lino da Silva, Jorge Ricardo Machado, Andreia Cristina de Melo.
      Melanoma is considered the most lethal skin cancer and its incidence has increased during the past decades. About 10% of cases are classified as hereditary melanoma. Genetic predisposition usually manifests itself clinically as early onset and multiple cutaneous melanomas. Several genes have been identified as involved to melanoma susceptibility, some of them still with unknown clinical relevance. Beyond melanoma, the affected families are also more prone to develop other malignancies, such as pancreatic cancer. The identification of risk families and involved genes is of great importance, since different forms of oncological surveillance are recommended. However, well established guidelines to standardize both the selection of individuals and the genetic panel to be requested are still lacking. Given the importance of the genetic counseling and testing in the context of clinical suspicion of hereditary melanoma, this paper aims to review the literature regarding genetic panel indications worldwide.
    Keywords:  CDKN2A; familial melanoma; genetic counseling; genetic testing; hereditary melanoma; melanoma; melanoma genetics
    DOI:  https://doi.org/10.1016/j.critrevonc.2021.103425
  14. Clin Cancer Res. 2021 Jun 10.
    Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases.
    Anna Maria Di Giacomo, Vanna Chiarion-Sileni, Michele Del Vecchio, Pier Francesco Ferrucci, Michele Guida, Pietro Quaglino, Massimo Guidoboni, Paolo Marchetti, Ornella Cutaia, Giovanni Amato, Alessia Covre, Roberto Camerini, Luana Calabrò, Monica Valente, Diana Giannarelli, Mario Mandalà, Michele Maio.
      PURPOSE: Phase II trials have shown encouraging activity with ipilimumab plus fotemustine and ipilimumab plus nivolumab in melanoma brain metastases. We report the primary analysis and 4-year follow-up of the NIBIT-M2 study, the first phase III trial comparing these regimens with fotemustine in patients with melanoma with brain metastases.EXPERIMENTAL DESIGN: This phase III study recruited patients 18 years of age and older with BRAF wild-type or mutant melanoma, and active, untreated, asymptomatic brain metastases from nine centers, randomized (1:1:1) to fotemustine, ipilimumab plus fotemustine, or ipilimumab plus nivolumab. The primary endpoint was overall survival (OS).
    RESULTS: From January, 2013 to September, 2018, 27, 26, and 27 patients received fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab. Median OS was 8.5 months [95% confidence interval (CI), 4.8-12.2] in the fotemustine arm, 8.2 months (95% CI, 2.2-14.3) in the ipilimumab plus fotemustine arm (HR vs. fotemustine, 1.09; 95% CI, 0.59-1.99; P = 0.78), and 29.2 months (95% CI, 0-65.1) in the ipilimumab plus nivolumab arm (HR vs. fotemustine, 0.44; 95% CI, 0.22-0.87; P = 0.017). Four-year survival rate was significantly higher for ipilimumab plus nivolumab than fotemustine [(41.0%; 95% CI, 20.6-61.4) vs. 10.9% (95% CI, 0-24.4; P = 0.015)], and was 10.3% (95% CI, 0-22.6) for ipilimumab plus fotemustine. In the fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab arms, respectively, 11 (48%), 18 (69%), and eight (30%) patients had treatment-related grade 3 or 4 adverse events, without treatment-related deaths.
    CONCLUSIONS: Compared with fotemustine, ipilimumab plus nivolumab significantly improved overall and long-term survival of patients with melanoma with asymptomatic brain metastases.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-1046
  15. Int J Pharm. 2021 Jul 09. pii: S0378-5173(21)00681-5. [Epub ahead of print] 120876
    Paclitaxel anticancer activity is enhanced by the MEK 1/2 inhibitor PD98059 in vitro and by PD98059-loaded nanoparticles in BRAFV600E melanoma-bearing mice.
    Aml I Mekkawy, Youssef W Naguib, Suhaila O Alhaj-Suliman, Emad I Wafa, Kareem Ebeid, Timothy Acri, Aliasger K Salem.
      Melanoma, the most malignant form of skin cancer, shows resistance to traditional anticancer drugs including paclitaxel (PTX). Furthermore, over 50% of melanoma cases express the BRAFV600E mutation which activates the MAPK pathway increasing cell proliferation and survival. In the current study, we investigated the capacity of the combination therapy of PTX and the MAPK inhibitor, PD98059, to enhance the cytotoxicity of PTX against melanoma and therefore improve treatment outcomes. Synergistic in vitro cytotoxicity was observed when soluble PTX and PD98059 were used to treat the A375 melanoma cell line as evidenced by a significant reduction in the cell viability and IC50 value for PTX. Then, in further studies, TPGS-emulsified PD98059-loaded PLGA nanoparticles (NPs) were prepared, characterized in vitro and assessed for therapeutic efficacy when used in combination with soluble PTX. The average particle size (180 nm d.), zeta potential (-34.8 mV), polydispersity index (0.081), encapsulation efficiency (20%), particle yield (90.8%), and drug loading (6.633 µg/mg) of the prepared NPs were evaluated. Also, cellular uptake and in vitro cytotoxicity studies were performed with these PD98059-loaded NPs and compared to soluble PD98059. The PD98059-loaded NPs were superior to soluble PD98059 in terms of both cellular uptake and in vitro cytotoxicity in A375 cells. In in vivo studies, using A375 challenged mice, we report improved survival in mice treated with soluble PTX and PD98059-loaded NPs. Our findings suggest the potential for using this combinatorial therapy in the management of patients with metastatic melanoma harboring the BRAF mutation as a means to improve survival outcomes.
    Keywords:  BRAF mutation; MEK1/2; PD98059; melanoma; nanoparticles; paclitaxel
    DOI:  https://doi.org/10.1016/j.ijpharm.2021.120876
  16. Neoplasia. 2021 Jul 08. pii: S1476-5586(21)00042-7. [Epub ahead of print]23(8): 783-791
    Plasma proteome alterations by MAPK inhibitors in BRAFV600-mutated metastatic cutaneous melanoma.
    Haris Babačić, Hanna Eriksson, Maria Pernemalm.
      Approximately half of metastatic cutaneous melanomas (CM) harbor a mutation in the BRAF protooncogene, upregulating the mitogen-activated protein kinase (MAPK)-pathway. The development of inhibitors targeting the MAPK pathway (MAPKi), i.e., BRAF- and MEK-inhibitors (BRAFi and MEKi), have substantially improved the survival in BRAFV600E/K-mutated stage IV metastatic CM. However, most patients develop resistance to treatment and no predictive biomarkers exist in practice. This study aimed at discovering plasma proteome changes during treatment MAPKi in patients with metastatic (stage IV) CM. Matched plasma samples before (pre) and during treatment (trm) from 23 patients with stage IV CM, treated with BRAF-inhibitors (BRAFi) alone or BRAF- and MEK- inhibitors combined (BRAFi and MEKi), were collected and analyzed with targeted proteomics by proximity extension assays. Additionally, plasma from 9 patients treated with BRAFi and MEKi was analyzed with in-depth high-resolution isoelectric focusing liquid-chromatography mass-spectrometry proteomics. Alterations of plasma proteins involved in granzyme and interferon gamma pathways were detected in patients treated with BRAFi, and cell adhesion-, neutrophil degranulation-, and proteolysis pathways in patients treated with BRAFi and MEKi. Several proteins were associated with progression-free survival after MAPKi treatment. We show that the majority of the altered plasma proteins were traceable to BRAFV600E-mutant metastatic CM tissue at mRNA level in 154 patients from the TCGA, further strengthening their involvement in tumoral response to treatment. This wide screen of plasma proteins unravels proteins that may serve as predictive and/or prognostic biomarkers of MAPKi treatment, opening a window of opportunity for plasma biomarker discovery in MAPKi-treatment of BRAFV600-mutant metastatic CM.
    Keywords:  BRAF and MEK inhibitors; Biomarkers; Melanoma; Mitogen-activated protein kinase; Plasma proteins; Targeted therapy; V600E mutation
    DOI:  https://doi.org/10.1016/j.neo.2021.06.002
  17. Channels (Austin). 2021 Dec;15(1): 483-495
    Solute carrier transporter superfamily member SLC16A1 is a potential prognostic biomarker and associated with immune infiltration in skin cutaneous melanoma.
    Jiaheng Xie, Zhechen Zhu, Yuan Cao, Shujie Ruan, Ming Wang, Jingping Shi.
      Melanoma is a type of cancer with a relatively poor prognosis. The development of immunotherapy for the treatment of patients with melanoma has drawn considerable attention in recent years. It is of great clinical significance to identify novel promising prognostic biomarkers and to explore their roles in the immune microenvironment. The solute carrier (SLC) superfamily is a group of transporters predominantly expressed on the cell membrane and are involved in substance transport. SLC16A1 is a member of the SLC family, participating in the transport of lactate, pyruvate, amino acids, ketone bodies, etc. The role of SLC16A1 in tumor immunity has been recently elucidated, while its role in melanoma remains unclear. In this study, bioinformatics analysis was performed to explore the role of SLC16A1 in melanoma. The results showed that high SLC16A1 expression was correlated with decreased overall survival in patients with melanoma. The genes co-expressed with SLC16A1 were significantly enriched in metabolic regulation, protein ubiquitination, and substance localization. Moreover, SLC16A1 was correlated with the infiltration of immune cells. In conclusion, SLC16A1 is a robust prognostic biomarker for melanoma and may be used as a novel target in immunotherapy.
    Keywords:  bioinformatics; immunotherapy; melanoma; solute carrier; transporter
    DOI:  https://doi.org/10.1080/19336950.2021.1953322
  18. J Plast Reconstr Aesthet Surg. 2021 Jun 18. pii: S1748-6815(21)00334-X. [Epub ahead of print]
    Impact of multiple lymphatic basin drainage in truncal melanoma patients.
    Z Š Zorica Špirić, D S Dragi Stanimirović, N N Nikolina Nikodinović, M V Marina Vukčević.
      INTRODUCTION: In many patients with cutaneous melanoma that affects the trunk area, there is lymphatic drainage to multiple basins (MLBD). This study aimed to examine whether MLBD is associated with disease outcomes.METHODS: Lymphatic mapping and sentinel lymph node (SLN) biopsy were performed in 161 patients with truncal melanoma. The number and location of draining nodal basins were established during the preoperative lymphoscintigraphy using technetium-99 m rhenium sulphide nanocolloid.
    RESULTS: MLBD was present in 59 (37%) patients, and single lymphatic basin drainage (SLBD) in 102 (63%) patients. Patients with MLBD showed no increased risk for SLN metastasis compared to patients with SLBD (27% versus 29%, respectively). There was no significant difference in disease-free survival (DFS) between patients with MLBD and those with SLBD. Five-year DFS was 64% for patients with MLBD and SLBD. Multivariate analysis showed that the presence of ulceration (p = 0.01) was an independent predictor of SLN metastasis, while melanoma thickness (p = 0.01) and SLN metastasis (p = 0.01) were independent predictors of DFS. In patients with a negative SLN, five-year DFS was 74% for patients with MLBD and 73% for those with SLBD. Multivariate analysis showed that melanoma thickness (p = 0.00) was an independent predictor of DFS.
    CONCLUSION: MLBD does not negatively impact the disease outcome in patients with truncal melanoma.
    Keywords:  Lymphatic drainage; Melanoma; Metastasis; Sentinel lymph node; Survival
    DOI:  https://doi.org/10.1016/j.bjps.2021.06.001
  19. An Bras Dermatol. 2021 Jul 12. pii: S0365-0596(21)00168-9. [Epub ahead of print]
    Case of large lentigo maligna melanoma of the scalp treated with 5% and 3.75% Imiquimod.
    Miriam Rovesti, Alfredo Zucchi, Claudio Feliciani, Francesca Satolli.
      The paper presents a case of lentigo maligna melanoma of the scalp in an elderly patient treated for the nodular part with surgery and the residual melanoma in situ with 5% Imiquimod and subsequently with 3.75% Imiquimod (each concentration for 4 months, 5 times per week), with complete regression of the lesion. 3.75% Imiquimod, which is already used for the treatment of actinic keratosis, could be a useful weapon with the same effectiveness and fewer side effects compared to 5% Imiquimod.
    Keywords:  Dermoscopy; Imiquimod; Melanoma
    DOI:  https://doi.org/10.1016/j.abd.2020.08.025
  20. Arch Med Res. 2021 Jul 13. pii: S0188-4409(21)00143-0. [Epub ahead of print]
    LncRNA LINC01116 facilitates melanoma 1 progression via sequestering miR-3612 and up-regulating GDF11 and SDC3.
    Kai Wang, Min Li, Tong Zhang, Chengyang Xu, Feifei Yu, Hongyan Duan.
      BACKGROUND: Melanoma is the deadliest cutaneous malignant tumor with high risks. Though increasing evidence has widely referred to the involvement of long non-coding RNAs (lncRNAs) in the mechanism of tumor development, including melanoma, the functional roles of most lncRNAs in melanoma remain to be explored. In this study, we focus on disclosing the role of long intergenic non-protein coding RNA 1116 (LINC01116) in melanoma.METHODS: Firstly, we detected LINC01116 expression through RT-qPCR. Functional analysis and animal experiments were carried out to assess the role of LINC01116 in vivo and in vitro. Western blot analysis was employed for detection of important markers regarding epithelial mesenchymal transition (EMT). In addition, RNA pulls down, RIP and luciferase reporter assays were performed to probe into the regulatory mechanism of LINC01116.
    RESULTS: LINC01116 was significantly up regulated in melanoma cells. LINC01116 deficiency abrogated cell proliferation, migration, invasion and EMT in melanoma. Moreover, LINC01116 enhanced growth differentiation factor 11 (GDF11) and syndecan 3 (SDC3) expression through sponging microRNA-3612 (miR-3612). The oncogenic role of the LINC01116/miR-3612/GDF11/SDC3 axis in melanoma was finally demonstrated.
    CONCLUSION: Conclusively, LINC01116 sequestered miR-3612 and targeted GDF11 and SDC3 to contribute to the progression of melanoma.
    Keywords:  GDF11; LINC01116; Melanoma; SDC3; miR-3612
    DOI:  https://doi.org/10.1016/j.arcmed.2021.06.008
  21. Cancer Cell Int. 2021 Jul 12. 21(1): 367
    NCK1-AS1 promotes the progression of melanoma by accelerating cell proliferation and migration via targeting miR-526b-5p/ADAM15 axis.
    Quan Lin, Yan Jia, Duo Zhang, Hongjuan Jin.
      BACKGROUND: Long non-coding RNAs (lncRNAs) are vital regulators of gene expression and cellular processes in multiple cancers, including melanoma. Nevertheless, the function of lncRNA NCK1-antisense 1 (NCK1-AS1) in melanoma remains unknown.METHODS: RT-qPCR was used to analyze the expression of NCK1-AS1, microRNA-526b-5p (miR-526b-5p) and ADAM metallopeptidase domain 15 (ADAM15). Cell proliferation was determined by CCK-8, colony formation and EdU assays. Cell migration was assessed by transwell migration and wound healing assays. Mechanism experiments including luciferase reporter, RIP and RNA pull down assays were conducted to demonstrate the interactions between RNAs. Xenograft model was established to verify the function of NCK1-AS1 and miR-526b-5p in melanoma in vivo.
    RESULTS: NCK1-AS1 was overexpressed in melanoma cell lines and NCK1-AS1 knockdown hampers the proliferation and migration of melanoma cells. Besides, miR-526b-5p binds to NCK1-AS1 in melanoma and ADAM15 was validated as its downstream target. Further, the inhibitory effects of NCK1-AS1 knockdown on cell proliferation and migration in melanoma were reversed by the depletion of miR-526b-5p and further counteracted by ADAM15 knockdown. The growth of melanoma tumors was hindered by the down-regulation of NCK1-AS1 or up-regulation of miR-526b-5p.
    CONCLUSION: NCK1-AS1 facilitates cell proliferation and migration in melanoma via targeting miR-526b-5p/ADAM15 axis.
    Keywords:  ADAM15; Melanoma; Migration; NCK1-AS1; Proliferation; miR-526b-5p
    DOI:  https://doi.org/10.1186/s12935-021-02055-y
  22. J Biomed Opt. 2021 Jul;26(7):
    In vivo two-photon-excited cellular fluorescence of melanin, NAD(P)H, and keratin enables an accurate differential diagnosis of seborrheic keratosis and pigmented cutaneous melanoma.
    Łukasz Szyc, Constantin Scharlach, Holger Haenssle, Christine Fink.
      SIGNIFICANCE: Seborrheic keratoses (SKs) are harmless pigmented skin lesions (PSLs) that may be confused clinically not only with other benign conditions but also with cutaneous melanoma (CM). As SKs are one of the most common neoplasms in adults, the importance of their correct diagnosis is high. Misclassifying SK as malignant is not rare and leads to a high number of unnecessary biopsies. On the other hand, misdiagnosing CM as SK may have a large impact on prognosis or therapy.AIM: In the non-invasive technique of dermatofluoroscopy, the fluorophores in melanocytes and keratinocytes are excited in vivo with nanosecond laser pulses and the resulting spectrally resolved, melanin-dominated fluorescence signals are used to differentiate between pigmented benign lesions and CM.
    APPROACH: In this single-center, non-interventional study, 33 PSLs of 20 patients were scanned with dermatofluoroscopy in vivo. For all included cases, dermatofluoroscopic signals were compared to pathology classification.
    RESULTS: The characteristic spectral features of SK were identified, where the signals are dominated by keratin, NAD(P)H, and melanin. The fluorescence spectra of SKs differed substantially from those of CM: a characteristic spectrum of SK has been identified in 27 of 28 SKs.
    CONCLUSIONS: The high-accuracy differential diagnosis between CM and SK is possible with dermatofluoroscopy.
    Keywords:  fluorescence; malignant melanoma; melanin; seborrheic keratosis
    DOI:  https://doi.org/10.1117/1.JBO.26.7.075002
  23. Am J Cancer Res. 2021 ;11(6): 3252-3262
    Genetic variants of EML1 and HIST1H4E in myeloid cell-related pathway genes independently predict cutaneous melanoma-specific survival.
    Yuanmin He, Hongliang Liu, Sheng Luo, Christopher I Amos, Jeffrey E Lee, Keming Yang, Abrar A Qureshi, Jiali Han, Qingyi Wei.
      Both in vivo and in vitro evidence has supported a key role of myeloid cells in immune suppression in melanoma and in promoting melanocytic metastases. Some single-nucleotide polymorphisms (SNPs) have been shown to predict cutaneous melanoma-specific survival (CMSS), but the association between genetic variation in myeloid cell-related genes and cutaneous melanoma (CM) patient survival remains unknown.METHODS: we investigated associations between SNPs in myeloid cell-related pathway genes and CMSS in a discovery dataset of 850 CM patients and replicated the findings in another dataset of 409 CM patients.
    RESULTS: we identified two SNPs (EML1 rs10151787 A>G and HIST1H4E rs2069018 T>C) as independent prognostic factors for CMSS, with adjusted allelic hazards ratios of 1.56 (95% confidence interval =1.19-2.05, P=0.001) and 1.66 (1.22-2.26, P=0.001), respectively; so were their combined unfavorable alleles in a dose-response manner in both discovery and replication datasets (P trend<0.001 and 0.002, respectively). Additional functional analysis revealed that both EML1 rs10151787 G and HIST1H4E rs2069018 C alleles were associated with elevated mRNA expression levels in normal tissues.
    CONCLUSIONS: Our findings suggest that EML1 rs10151787 A>G and HIST1H4E rs2069018 T>C are independent prognostic biomarkers for CMSS.
    Keywords:  Cutaneous melanoma; myeloid cell; prognostic factors; single-nucleotide polymorphism; survival
  24. J BUON. 2021 May-Jun;26(3):26(3): 1176-1178
    Melanosis, melanoma, and melanosarcoma: concepts and terms in 19th century ophthalmology.
    Konstantinos Laios, Spyros N Michaleas, Marianna Karamanou, George Androutsos.
      
  25. Br J Cancer. 2021 Jul 14.
    Impact of prior treatment with immune checkpoint inhibitors on dacarbazine efficacy in metastatic melanoma.
    Sarah Bouchereau, Louise Chaplain, Magali Fort, Alain Beauchet, Thomas Sidibé, Marie Chapalain, Leire Gonzalez-Lara, Christine Longvert, Astrid Blom, Philippe Saiag, Elisa Funck-Brentano.
      BACKGROUND: Despite its low efficacy, chemotherapy with dacarbazine remains an option in metastatic melanoma patients after failure of immune checkpoint inhibitors (ICI) ± targeted therapy. Some observations suggested an increased efficacy of chemotherapy in melanoma or lung cancer patients previously treated with ICI; we aimed to evaluate the efficacy of dacarbazine in a controlled-group study of patients pre-treated or not with ICI.METHODS: We retrospectively collected data from all consecutive patients treated with dacarbazine for advanced cutaneous melanoma without brain metastasis, in our skin cancer centre between June 2006 and September 2019. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall response rates (ORR), overall survival (OS) and safety of dacarbazine.
    RESULTS: Among 72 patients, 17 (23.6%) received dacarbazine after ICI and 55 (76.3%) without prior ICI. Despite less favourable prognostic factors in patients ICI-pre-treated, median PFS was 4.27 months (range 0.89-43.69) in this group versus 2.04 months (range 1.25-39.25) P = 0.03 in non-ICI-pre-treated patients; ORR were 35.3% and 12.7%, respectively. The median OS and the occurrence of adverse events were similar in both groups.
    CONCLUSION: Dacarbazine seems to offer a short-lived benefit in patients with progressive advanced disease despite ICI (±targeted therapy), and could be an alternative before considering best supportive care.
    DOI:  https://doi.org/10.1038/s41416-021-01486-8
  26. Pathol Oncol Res. 2021 ;27 581395
    Silencing Osteopontin Expression Inhibits Proliferation, Invasion and Induce Altered Protein Expression in Melanoma Cells.
    Tímea Kiss, Krisztina Jámbor, Viktória Koroknai, István Szász, Helga Bárdos, Attila Mokánszki, Róza Ádány, Margit Balázs.
      Osteopontin (OPN) is a multifunctional phosphoprotein that is expressed in different types of cancers, including melanoma. OPN overexpression is associated with tumor progression and metastasis formation; however, the role of OPN in cell invasion and metastasis formation is not completely understood. In this study we aimed to define OPN expression in melanoma tissues and cell lines and investigate the effect of OPN expression on cell proliferation and invasion after inhibiting OPN expression with small interfering RNA (siRNA). OPN gene expression was determined by qRT-PCR, while protein expression was examined using a Proteome Profiler Oncology Array. siRNA-mediated OPN knockdown led to decreased OPN expression in melanoma cell lines, which was associated with decreased cell proliferation and invasion. Proteome profile analysis revealed significantly different protein expression between the original and transfected cell lines. The altered expression of the differently expressed proteins was validated at the mRNA level. Furthermore, OPN-specific siRNA was able to reduce OPN expression and inhibit the invasiveness of melanoma cells. Our results revealed for the first time that silencing the OPN gene influences proliferation and invasion of melanoma cells by effecting EGFR, tenascin C, survivin, galectin-3 and enolase 2 expression. To predict protein-protein interactions along with putative pathways we used STRING analysis for the differentially expressed proteins. These proteins formed multiple clusters, including extracellular matrix organization, regulation of angiogenesis, cell death and cell migration, PI3K-Akt, MAPK and focal adhesion signaling pathways. Taken together these data suggest that OPN might be an ideal target for drug development and therapies.
    Keywords:  invasion; melanoma progression; osteopontin expression; osteopontin knockdown; proliferation; protein expression profile
    DOI:  https://doi.org/10.3389/pore.2021.581395
  27. Mini Rev Med Chem. 2021 Jul 11.
    Electrospinning: New Strategies for the Treatment of Skin Melanoma.
    Javier Mauricio Anaya Mancipe, Franz Acker Lobianco, Marcos Lopes Dias, Rossana Mara da Silva Moreira Thiré.
      Recent studies have shown significant growth of skin cancer cases in northern regions of the world, in which its presence was not common. Skin cancer is one of the cancers that mostly affects the world population, ranking fifth in studies conducted in the United States (USA). Melanoma is cancer that has the highest number of deaths worldwide since it is the most resistant skin cancer to current treatments. This is why alternatives for its treatment have been investigated considering nanomedicine concepts. This study approaches the role of this field in the creation of promising electrospun devices, composed of nanoparticles and nanofibers, among other structures, capable of directing and/or loading active drugs and/or materials with the objective of inhibiting the growth of melanoma cells or even eliminating those cells.
    Keywords:  Dressings; Drug Delivery; Electrospinning; Nanofibers; Skin Melanoma; nanomedicine
    DOI:  https://doi.org/10.2174/1389557521666210712111809
  28. Pharmacol Rep. 2021 Jul 15.
    Cannabinoids and their derivatives in struggle against melanoma.
    Paweł Marzęda, Małgorzata Drozd, Paula Wróblewska-Łuczka, Jarogniew J Łuszczki.
      Melanoma is one of the most aggressive malignances in human. Recently developed therapies improved overall survival rate, however, the treatment of melanoma still remains a challenging issue. This review attempts to summarize recent advances in studies on cannabinoids used in the setting of melanoma treatment. Searches were carried out in PubMed, Google Scholar, Scopus, Research Gate. Conclusions after analysis of available data suggest that cannabinoids limit number of metastasis, and reduce growth of melanoma. The findings indicate that cannabinoids induce apoptosis, necrosis, autophagy, cell cycle arrest and exert significant interactions with tumor microenvironment. Cannabinoids should be rather considered as a part of multi-targeted anti-tumor therapy instead of being standalone agent. Moreover, cannabinoids are likely to improve quality of life in patients with cancer, due to different supportive effects, like analgesia and/or anti-emetic effects. In this review, it was pointed out that cannabinoids may be potentially useful in the melanoma therapy. Nevertheless, due to limited amount of data, great variety of cannabinoids available and lack of clinical trials, further studies are required to determine an exact role of cannabinoids in the treatment of melanoma.
    Keywords:  Antitumor effect; CB1 receptor; CB2 receptor; Cannabinoids; Melanoma
    DOI:  https://doi.org/10.1007/s43440-021-00308-1
  29. Pathol Oncol Res. 2021 ;27 639004
    No Overall Survival Difference in the Immunotherapy Era for Rare Subtypes of Melanoma.
    Mohammed Safi, Dario Trapani, Mohammed Alradhi, Xiu Shan, Liu Jiwei.
      
    Keywords:  SEER database; epidimiology; immunotherapy; melanoma; survival
    DOI:  https://doi.org/10.3389/pore.2021.639004
  30. J Clin Oncol. 2021 Jul 13. JCO2100675
    Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma.
    Adi Diab, Scott S Tykodi, Gregory A Daniels, Michele Maio, Brendan D Curti, Karl D Lewis, Sekwon Jang, Ewa Kalinka, Igor Puzanov, Alexander I Spira, Daniel C Cho, Shanhong Guan, Erika Puente, Tuan Nguyen, Ute Hoch, Sue L Currie, Wei Lin, Mary A Tagliaferri, Jonathan Zalevsky, Mario Sznol, Michael E Hurwitz.
      PURPOSE: Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma.METHODS: A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers.
    RESULTS: At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response.
    CONCLUSION: BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.
    DOI:  https://doi.org/10.1200/JCO.21.00675
  31. Hum Vaccin Immunother. 2021 Jul 13. 1-9
    Predictive factors of neoadjuvant immune checkpoint blockade in melanoma.
    Melissa Sarver, Michael C Brown, Kristen E Rhodin, April K S Salama, Georgia M Beasley.
      This review describes the current body of literature and ongoing clinical trials examining neoadjuvant immune checkpoint inhibitors (ICI) for patients with resectable stage III and IV melanoma. Based on prior success in treating metastatic melanoma and as adjuvant therapy, ICIs are being explored in the neoadjuvant setting. There have been initial trials and there are many ongoing trials examining neoadjuvant ICI. Herein, we will review the clinical feasibility and efficacy of various neoadjuvant ICI regimens, explore pathologic and cellular responses, and present factors associated with predictive tumor response.
    Keywords:  Melanoma; immune therapy; lymph nodes; neoadjuvant
    DOI:  https://doi.org/10.1080/21645515.2021.1943987
  32. Front Cell Dev Biol. 2021 ;9 610683
    Sperm-Specific Glycolysis Enzyme Glyceraldehyde-3-Phosphate Dehydrogenase Regulated by Transcription Factor SOX10 to Promote Uveal Melanoma Tumorigenesis.
    Xia Ding, Lihua Wang, Mingjiao Chen, Yue Wu, Shengfang Ge, Jin Li, Xianqun Fan, Ming Lin.
      Melanoma cells exhibit increased aerobic glycolysis, which represents a major biochemical alteration associated with malignant transformation; thus, glycolytic enzymes could be exploited to selectively target cancer cells in cancer therapy. Sperm-specific glyceraldehyde-3-phosphate dehydrogenase (GAPDHS) switches glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate by coupling with the reduction of NAD+ to NADH. Here, we demonstrated that GAPDHS displays significantly higher expression in uveal melanoma (UM) than in normal controls. Functionally, the knockdown of GAPDHS in UM cell lines hindered glycolysis by decreasing glucose uptake, lactate production, adenosine triphosphate (ATP) generation, cell growth and proliferation; conversely, overexpression of GAPDHS promoted glycolysis, cell growth and proliferation. Furthermore, we identified that SOX10 knockdown reduced the activation of GAPDHS, leading to an attenuated malignant phenotype, and that SOX10 overexpression promoted the activation of GAPDHS, leading to an enhanced malignant phenotype. Mechanistically, SOX10 exerted its function by binding to the promoter of GAPDHS to regulate its expression. Importantly, SOX10 abrogation suppressed in vivo tumor growth and proliferation. Collectively, the results reveal that GAPDHS, which is regulated by SOX10, controls glycolysis and contributes to UM tumorigenesis, highlighting its potential as a therapeutic target.
    Keywords:  SOX10; glycolysis; glycolytic enzyme; sperm-specific glyceraldehyde-3-phosphate dehydrogenase; uveal melanoma
    DOI:  https://doi.org/10.3389/fcell.2021.610683
  33. Indian J Dermatol Venereol Leprol. 2021 Jul 07. pii: 10.25259/IJDVL_64_20. [Epub ahead of print] 1-3
    Nodular melanoma on lip with retrograde in-transit metastases on face.
    Krishnendu Mondal, Rupali Mandal.
      
    DOI:  https://doi.org/10.25259/IJDVL_64_20
  34. J Surg Res. 2021 Jul 10. pii: S0022-4804(21)00381-4. [Epub ahead of print]
    A Prospective Study of Intraarterial Infusion Chemotherapy in Advanced WT BRAF Melanoma Patients.
    Stefano Guadagni, Odysseas Zoras, Giammaria Fiorentini, Francesco Masedu, Konstantinos Lasithiotakis, Donatella Sarti, Antonietta Rosella Farina, Andrew Reay Mackay, Marco Clementi.
      BACKGROUND: Treatment strategies for advanced cutaneous melanoma (CM) patients, resistant or not treatable with novel target and immunotherapeutic drugs, remain a significant challenge, particularly for patients with unresectable stage IIIC/D disease localized to inferior limbs and pelvis, for whom specific outcomes are rarely considered.MATERIALS AND METHODS: This is a prospective study of multidisciplinary treatments, including locoregional melphalan chemotherapy, in 62 BRAF wild-type CM patients with locoregional metastases in the inferior limbs and pelvis, including inguinal regions. Patients were either in progression following or ineligible for, or not treatable with novel immunotherapy. For exclusively inferior limb-localised disease, patients received locoregional melphalan chemotherapy performed by hyperthermic isolated limb perfusion (n = 19) or isolated limb infusion (n = 19), and for synchronous lesions localised to inferior limbs and pelvis, received hypoxic pelvic and limb perfusion (n = 24). Additional multidisciplinary therapy included local, locoregional and systemic treatments and the primary endpoint was tumour response.
    RESULTS: The objective response rate following first cycle of locoregional chemotherapy was 37.1% at 3 mo and median progression-free survival was 4-mo, with 12.9% procedure-related complications, 30.6% low-grade haematological toxicity and 11.3% severe limb toxic tissue reactions. Multivariate logistic regression showed that the odds of response were significantly higher for patients ≤ 75 y of age and for patients with locoregional metastases exclusively located in the inferior limbs.
    CONCLUSION: In this subgroup of CM patients with BRAF wild-type status, locoregional metastases localized to inferior limbs and pelvis, in progression following or ineligible for immunotherapy, melphalan locoregional chemotherapy demonstrated a safe and effective profile.
    TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01920516; date of trial registration: August 6, 2013.
    Keywords:  BRAF wild-type; Locoregional metastases, Hyperthermic isolated limb perfusion, Isolated limb infusion, Hypoxic pelvic and limb perfusion; Melphalan; Novel immunotherapies; Recurrent melanoma
    DOI:  https://doi.org/10.1016/j.jss.2021.05.054
  35. Front Immunol. 2021 ;12 675146
    A Standardized Analysis of Tertiary Lymphoid Structures in Human Melanoma: Disease Progression- and Tumor Site-Associated Changes With Germinal Center Alteration.
    Franziska Werner, Christine Wagner, Martin Simon, Katharina Glatz, Kirsten D Mertz, Heinz Läubli, Johannes Griss, Stephan N Wagner.
      There is increasing evidence that tertiary lymphoid structures (TLS) control not only local adaptive B cell responses at melanoma tumor sites but also the cellular composition and function of other immune cells. In human melanoma, however, a comprehensive analysis of TLS phenotypes, density and spatial distribution at different disease stages is lacking. Here we used 7-color multiplex immunostaining of whole tissue sections from 103 human melanoma samples to characterize TLS phenotypes along the expression of established TLS-defining molecular and cellular components. TLS density and spatial distribution were determined by referring TLS counts to the tissue area within defined intra- and extratumoral perimeters around the invasive tumor front. We show that only a subgroup of primary human melanomas contains TLS. These TLS rarely formed germinal centers and mostly located intratumorally within 1 mm distance to the invasive tumor front. In contrast, melanoma metastases had a significantly increased density of secondary follicular TLS. They appeared preferentially in stromal areas within an extratumoral 1 mm distance to the invasive tumor front and their density varied over time and site of metastasis. Interestingly, secondary follicular TLS in melanoma often lacked BCL6+ lymphatic cells and canonical germinal center polarity with the formation of dark and light zone areas. Our work provides an integrated qualitative, quantitative and spatial analysis of TLS in human melanoma and shows disease progression- and site-associated changes in TLS phenotypes, density and spatial distribution. The frequent absence of canonical germinal center polarity in melanoma TLS highlights the induction of TLS maturation as a potential additive to future immunotherapy studies. Given the variable evaluation strategies used in previous TLS studies of human tumors, an important asset of this study is the standardized quantitative evaluation approach that provides a high degree of reproducibility.
    Keywords:  TLS maturation; Tertiary Lymphoid Structures (TLS); automated imaging and analysis; germinal center polarity; human melanoma; multiplex immunohistochemistry (mIHC); spatial distribution; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2021.675146
  36. Immunotherapy. 2021 Jul 14.
    Durable complete remission of leptomeningeal melanoma by intrathecal methotrexate maintained with systemic ipilimumab.
    Carmen Dietrich, Martin Salzmann, Andreas Steinbrecher, Rudolf Herbst, Jessica C Hassel.
      Leptomeningeal disease (LMD) is a complication of metastasized melanoma, with poor prognosis even in the era of immunotherapy. We present the case of a 37-year-old man who was diagnosed with stage IV melanoma with lymphonodular, splenic and pulmonary metastases. Treatment with dabrafenib and trametinib led to a complete remission, but subsequent symptomatic LMD. Treatment was changed to intrathecal methotrexate, leading to aseptic meningitis, but also a remission of LMD. Followed by ipilimumab monotherapy, a durable, complete remission was observed. Symptomatic LMD may not be amenable to immunotherapy alone, as quick responses may be needed. With little evidence and few retrospective trials demonstrating the challenging treatment of LMD, intrathecal chemotherapy, potentially in combination, may still be considered a viable option.
    Keywords:  immunotherapy; intrathecal chemotherapy; leptomeningeal disease; melanoma
    DOI:  https://doi.org/10.2217/imt-2021-0031
  37. J Dtsch Dermatol Ges. 2021 Jul 13.
    Adjuvant pembrolizumab-related hyperprogression in stage III melanoma.
    Nadine L Ammann, Glenn Geidel, Stefan W Schneider, Christoffer Gebhardt.
      
    DOI:  https://doi.org/10.1111/ddg.14535
  38. J Eur Acad Dermatol Venereol. 2021 Jul 09.
    To assess the relationship between distance travelled to dermatology clinic and Breslow thickness of melanoma at diagnosis.
    S B Bowe, C G Gallagher, Moc O'Connell, L P Paul.
      Malignant Melanoma (MM) is the 4th most common cancer in Ireland1 . Irish guidelines recommend that suspicious pigmented lesions should be referred urgently for specialist assessment1 . Access to dermatologists and specialist centres varies widely across Ireland. Our dermatology department is in Waterford City which has a higher than average incidence of MM when compared to the national average2 .
    Keywords:  Breslow thickness; Melanoma; age; distance
    DOI:  https://doi.org/10.1111/jdv.17515
  39. Biomed Res Int. 2021 ;2021 8848227
    A Novel Autophagy-Related lncRNA Gene Signature to Improve the Prognosis of Patients with Melanoma.
    Yi Ding, Tian Li, Min Li, Tuersong Tayier, MeiLin Zhang, Long Chen, ShuMei Feng.
      Objective: Autophagy and long noncoding RNAs (lncRNAs) have been the focus of research on the pathogenesis of melanoma. However, the autophagy network of lncRNAs in melanoma has not been reported. The purpose of this study was to investigate the lncRNA prognostic markers related to melanoma autophagy and predict the prognosis of patients with melanoma.Methods: We downloaded RNA sequencing data and clinical information of melanoma from the Cancer Genome Atlas. The coexpression of autophagy-related genes (ARGs) and lncRNAs was analyzed. The risk model of autophagy-related lncRNAs was established by univariate and multivariate Cox regression analyses, and the best prognostic index was evaluated combined with clinical data. Finally, gene set enrichment analysis was performed on patients in the high- and low-risk groups.
    Results: According to the results of the univariate Cox analysis, only the overexpression of LINC00520 was associated with poor overall survival, unlike HLA-DQB1-AS1, USP30-AS1, AL645929, AL365361, LINC00324, and AC055822. The results of the multivariate Cox analysis showed that the overall survival of patients in the high-risk group was shorter than that recorded in the low-risk group (p < 0.001). Moreover, in the receiver operating characteristic curve of the risk model we constructed, the area under the curve (AUC) was 0.734, while the AUC of T and N was 0.707 and 0.658, respectively. The Gene Ontology was mainly enriched with the positive regulation of autophagy and the activation of the immune system. The results of the Kyoto Encyclopedia of Genes and Genomes enrichment were mostly related to autophagy, immunity, and melanin metabolism.
    Conclusion: The positive regulation of autophagy may slow the transition from low-risk patients to high-risk patients in melanoma. Furthermore, compared with clinical information, the autophagy-related lncRNA risk model may better predict the prognosis of patients with melanoma and provide new treatment ideas.
    DOI:  https://doi.org/10.1155/2021/8848227
  40. Am J Cancer Res. 2021 ;11(6): 2670-2683
    BCAT1 knockdown-mediated suppression of melanoma cell proliferation and migration is associated with reduced oxidative phosphorylation.
    Bingxia Zhang, Fang Xu, Kaijuan Wang, Mengduan Liu, Jinxia Li, Qianwei Zhao, Liya Jiang, Zhendong Zhang, Yamei Li, Huiping Chen, Jianying Zhang, Xiaolei Tang, Jintao Zhang.
      Malignant melanoma has a high mutational rate. As a result, resistance to current therapies is common. Consequently, there is an unmet medical need to develop novel therapies. Recent data suggest that branched-chain amino acid transaminase 1 (BCAT1) is overexpressed in multiple cancers, and such overexpressed BCAT1 is necessary for individual cancer progression. Therefore, BCAT1 appears to be a good target in cancer treatment. Additionally, because its expression in healthy tissues is highly restricted in adults and is limited to the brain, ovary, and placenta, BCAT1 is especially an ideal target in cancer therapies. Currently, the function of BCAT1 in malignant melanoma has not been demonstrated. Therefore, we investigated the role of BCAT1 in the proliferation and migration of malignant melanomas using human samples and mouse malignant B16 melanoma cell line. Our data showed that BCAT1 was overexpressed in malignant melanoma tissues both in humans and mice. Besides, BCAT1 knockdown suppressed melanoma cell proliferation and migration, which was associated with reduced oxidative phosphorylation. Collectively, our data indicate that BCAT1 is a promising therapeutic target for the treatment of malignant melanomas.
    Keywords:  Malignant melanoma; branched-chain amino acid transaminase 1; branched-chain amino acids; glycolysis; migration; oxidative phosphorylation; proliferation
  41. Oncol Lett. 2021 Aug;22(2): 628
    Aqueous extracts of Sanghuangporus vaninii induce S-phase arrest and apoptosis in human melanoma A375 cells.
    Taihen Yu, Shi Zhong, Yuqing Sun, Haiyan Sun, Weiguo Chen, Yougui Li, Jianxun Zhu, Longxi Lu, Jinxi Huo.
      Sanghuangporus vaninii, also called 'Sanghuang' mushroom in Chinese, has various medicinal uses, but its effects on human melanoma cells have not been reported. The present study investigated the inhibitory ability and potential anticancer mechanism of the aqueous extracts of S. vaninii (SH). The results revealed that SH inhibited the proliferation of A375 human melanoma cells in a dose-dependent manner, and flow cytometry analysis suggested that SH induced A375 cell cycle arrest at S phase and apoptosis. Reverse transcription-quantitative PCR, western blotting and immunofluorescence analyses indicated that SH induced S-phase arrest by upregulating p21 expression, and p21 inhibited the expression of cyclin-cyclin-dependent kinases complexes at both the RNA and protein levels. In addition, SH induced apoptosis of A375 cells by inhibiting the expression levels of the anti-apoptosis gene Bcl-2. Therefore, the results suggested that SH may be a potential candidate for the treatment of human melanoma, thus providing new ideas for developing drugs that target melanoma.
    Keywords:  S-phase arrest; Sanghuangporus vaninii; apoptosis; aqueous extracts; human melanoma
    DOI:  https://doi.org/10.3892/ol.2021.12889
  42. Case Rep Oncol. 2021 May-Aug;14(2):14(2): 957-962
    A Solitary Melanoma Metastasis Confined to the Submandibular Gland.
    Senne Gorris, Celia Perdaens, Veerle Delvaux, Vincent Vander Poorten, Bart Neyns, Ilan Baron.
      Malignant melanoma is a type of cancer that most commonly originates from the skin, less frequently from mucosal surfaces, the eye, or meninges [Annu Rev Pathol. 2014;9(1):239-71]. In 2019, this type of malignancy was the third most frequent cancer to be diagnosed in males and the fifth most in females according to the American Cancer Society and the National Cancer Institute [CA Cancer J Clin. 2019;69(5):363-85]. The majority of the malignant melanomas in the head and neck region (85-90%) are cutaneous lesions, most often arising in the skin of the face [Head Neck. 2016;38:147-155]. In sharp contrast are the histological findings of metastatic melanoma with an unknown primary site: they are much more scarce and histologically difficult to diagnose. The literature is limited to case studies or small cohorts. In 2-6% of all patients suffering from metastatic melanoma, after clinical examination of the skin and mucosa, imaging, and other diagnostic examination, a primary tumor cannot be found [Eur J Cancer. 2004;40(9):1454-5]. A very small subgroup (0.5%) presents with a single focus of melanoma within the dermis or subcutaneous tissues [Arch Dermatol. 2000;136(11):1397-9]. We hereby report a case in this subgroup of a solitary melanoma metastasis found in the submandibular gland in a 59-year-old male. The tumor was discovered incidentally after surgical excision of this gland because of nodular enlargement.
    Keywords:  Case report; Immunotherapy; Metastatic melanoma; Submandibular gland; Unknown primary
    DOI:  https://doi.org/10.1159/000516796
  43. Pak J Pharm Sci. 2021 Jan;34(1): 77-84
    Skin-whitening mechanism of cumin (Cuminum cyminum L.) extract.
    Ya Wang, Guo-Ying Du, Tao Guo, Hong-Mei Zou, Dan Jia.
      Skin-whitening effect is closely linked with the melanogenesis inhibitory activity and free radical scavenging capacity. The purpose of the present study was to evaluate the skin-whitening effect of cumin (Cuminum cyminum L.) extract. The whitening activity was evaluated by cell-free mushroom tyrosinase assay, free radical scavenging assay, cell viability assay, cellular tyrosinase assay and melanin content assay using B16F10 murine melanoma cells. The results showed that cumin extract exhibited concentration-dependent inhibitory effect on both monophenolase and diphenolase activities of mushroom tyrosinase (IC50 values of 1.027mg/mL and 0.977mg/mL, respectively). Kinetic study on diphenolase showed that the cumin extract was a reversible mixed-type inhibitor, and the inhibition constant (KI) was determined to be 0.62mg/mL. In addition, cumin extract significantly suppressed melanin production and cellular tyrosinase activity of B16F10 melanoma cells in a concentration and time dependent manner without cytotoxicity. Moreover, cumin extract exerted strong scavenging capacity on DPPH, hydroxyl and superoxide anion radicals. Taken together, these results strongly suggest that cumin is a potential skin-whitening agent for the cosmetic industry.
  44. Aging (Albany NY). 2021 Jul 13. 13(undefined):
    Implication of integrin α2β1 in senescence of SK-Mel-147 human melanoma cells.
    Nadezhda I Kozlova, Galina E Morozevich, Albert E Berman.
      This investigation addressed the impact of integrin-initiated signaling pathways on senescence of tumor cells. In a model of human SK-Mel-147 melanoma cells, the silencing of integrin α2β1 strongly reduced cell proliferation and enhanced the percentage of SA-β-Gal-positive cells, a phenotypic feature of cellular senescence. These changes were accompanied by a significant increase in the activity of Akt and mTOR protein kinases and also in the expression of p53 and p21 oncosuppressors. Pharmacological inhibition of Akt and mTORC1 and genetic inhibition of p53 and p21 reduced the senescence of α2β1-depleted SK-Mel-147 cells to the level of control cells. Based on our earlier data on the non-canonical functions of Akt isomers in the invasion and anoikis of SK-Mel-147 cells, we investigated the role of Akt isomers in senescence induced by α2β1 suppression. The inhibition of Akt1 strongly reduced the percentage of SA-β-Gal-positive cells in the α2β1-depleted cell population, while the inhibition of Akt2 did not have a noticeable effect. Our data demonstrated for the first time that α2β1 is involved in the protection of tumor cells against senescence and that senescence, which is induced by the downregulation of α2β, is based on a signaling mechanism in which Akt1 performs a non-canonical function.
    Keywords:  Akt isoforms; integrins; senescence; signaling; tumor progression
    DOI:  https://doi.org/10.18632/aging.203309
  45. J Eur Acad Dermatol Venereol. 2021 Jul 09.
    Do AI models recognise rare, aggressive skin cancers? An assessment of a direct-to-consumer app in the diagnosis of Merkel cell carcinoma and amelanotic melanoma.
    L Steele, D Velazquez-Pimentel, B R Thomas.
      Machine learning (ML) models for skin cancer recognition have reported comparable or superior performance to dermatologists in controlled or restricted settings.1 One restriction is the number of disease classes. When trained models are deployed into real-world contexts, an important challenge will be the detection of rare but aggressive skin cancers that are not well-covered in training datasets, such as Merkel cell carcinoma (MCC) and amelanotic melanoma.
    Keywords:  Amelanotic; Artificial Intelligence; Machine Learning; Melanoma; Mobile Applications; Reproducibility of Results; Skin Neoplasms
    DOI:  https://doi.org/10.1111/jdv.17517
  46. Gac Med Mex. 2021 ;157(2): 207-211
    Prognostic variables in patients with thick melanomas. Analysis of 362 cases.
    Estefanía Aguilar-Romero, Jazmín D Chávez-Hernández, César Zepeda-Najar, Rosa A Salcedo-Hernández, Leonardo S Lino-Silva.
      Background: Melanoma epidemiological and prognostic studies are based on Caucasian populations, in whom the predominant subtype is superficially-spreading melanoma and in whom thin melanomas (Breslow < 3 mm) predominate. Mexican patients show a predominance of thick melanomas (Breslow ≥ 3 mm), and the acral subtype is the most common. There are no publications on prognostic factors in thick melanomas. We hypothesize that we will identify factors that determine the prognosis in this group of patients.Objective: To identify clinical-pathological factors associated with the prognosis of patients with thick melanomas in the Mexican population.
    Material and methods: Data on melanomas with Breslow > 3 mm were collected from 2010 to 2015. The prognostic influence of various clinical-pathological factors was analyzed.
    Results: The most common subtypes were acral melanoma in 271 patients (74.9 %) and nodular melanoma in 49 (13.5 %). Median Breslow thickness was 7 mm. 56.6 % of the patients had lymph node metastases (clinical stage [CS] III), 269 (74.3 %) had ulceration, and surgical margins were positive in 15 (4.1 %). Elevated neutrophil: lymphocyte ratio (≥ 2) was found in 188 (51.9 %). The variables associated with lower overall survival were CS (p < 0.001), Breslow thickness (p = 0.044), ulceration (p = 0.004), mitotic activity (p < 0.001), < 2-cm margin (p < 0.001) and an increased neutrophil: lymphocyte ratio (p = 0.037). In the multivariate analysis, the factors associated with overall survival were CS, mitotic activity, and surgical margin.
    Conclusions: In patients with thick melanomas, overall survival is influenced by mitotic activity, a positive margin, and clinical stage.
    Keywords:  Acral melanoma; Breslow; Melanoma; Melanoma acral; Mitotic index; Prognosis; Pronóstico; Índice mitósico
    DOI:  https://doi.org/10.24875/GMM.M21000543
  47. J Surg Res. 2021 Jul 07. pii: S0022-4804(21)00312-7. [Epub ahead of print]267 467-476
    Randomized Study of Wound Drainage on Early Complications After Lymph Node Dissection for Melanoma.
    Lars Frich, Robert Hermann, Åshild Berentzen, Truls Ryder.
      INTRODUCTION: The complication rate after axillary lymph node dissection (ALND) and inguinal lymph node dissection (ILND) in melanoma patients is high. The aim of this randomized non-inferiority study was to evaluate the effect of postoperative wound drainage on early complications after ALND and ILND.MATERIALS AND METHODS: Between 2018 and 2020, 104 stage III melanoma patients operated on with ALND or ILND were randomized to a study group with complete wound drain removal 3 wk after surgery or a control group with progressive drain removal. The primary end point was overall early complications graded according to the modified Clavien-Dindo classification. Secondary endpoints were length of hospital stay and prognostic factors for early complications.
    RESULTS: Of the 99 patients analyzed, ALND was performed in 58 patients and ILND in 41 patients. Overall, 62 patients (62.6%) developed early complications: 30 in the study group and 32 in the control group (P = 0.53). The confidence interval for the difference in proportions of patients without early complications in the two groups was -0.27 to 0.11 (P = 0.42), hence non-inferiority could be claimed. Length of hospital stay was 5 d in the study group compared to 6 in the control group (P < 0.01). ILND was associated with increased risk of early complications compared to ALND (75.6% versus 53.4%, P = 0.04).
    CONCLUSIONS: Complete drain removal 3 wk after ALN and ILND in stage III melanoma patients did not increase the risk of early complications compared to progressive drain removal.
    Keywords:  Axilla; Complications; Drain placement; Groin; Lymph node dissection; Melanoma
    DOI:  https://doi.org/10.1016/j.jss.2021.05.005
  48. J Am Acad Dermatol. 2021 Aug;pii: S0190-9622(21)01111-7. [Epub ahead of print]85(2): 318
    August 2021: On the epistemology of Breslow thickness and histopathologic melanoma subtype.
    Jonathan Kantor.
      
    DOI:  https://doi.org/10.1016/j.jaad.2021.06.011
  49. J BUON. 2021 May-Jun;26(3):26(3): 1184
    Heptazoline exerts antiproliferative effects on human melanoma cells by inducing apoptosis, cell cycle arrest and targeting MAPK signalling pathway.
    Wei Zhou, Ling Zhou, Min Wang, Zeming Liu, Danyang Chen, Liang Guo.
      The Editors of JBUON issue an Expression of Concern to 'Heptazoline exerts antiproliferative effects on human melanoma cells by inducing apoptosis, cell cycle arrest and targeting MAPK signalling pathway', by Wei Zhou, Ling Zhou, Min Wang, Zeming Liu, Danyang Chen, Liang Guo; JBUON 2020;25(1):479-484; PMID: 32277672. Following the publication of the above article, readers drew to our attention that part of the data was possibly unreliable. We sent emails to the authors with a request to provide the raw data to prove the originality, but received no reply. Therefore, as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause.
  50. Cureus. 2021 Jun;13(6): e15480
    A Case Series of Multiple Primary Malignancies Among Patients With Advanced Melanoma.
    Matthew I Ebia, Stephen Capone, Charité Ricker, Jacob S Thomas, Varsha Tulpule, Irene Kang, Anishka D'Souza, David R Freyer, Kimberly Miller, Gino K In.
      Multiple primary malignancies (MPM) are described as two or more primary tumors within the same individual. The impact of MPM on the tumor microenvironment among patients with melanoma is poorly understood. Here, we describe this unique group of patients who have both advanced melanoma and at least one other primary malignancy and report their survival outcomes. In this study, patients with advanced melanoma and a second primary malignancy were identified. Medical records were reviewed for cancer treatment history. Kaplan-Meier methods were used to derive survival curves and estimate overall survival (OS), and log-rank tests were used to compare OS. Among 11 MPM patients, the most common non-melanoma cancers were breast (n = 3) and thyroid (n = 3). Median OS was 153.5 months for all patients. Median OS for synchronous MPM (sMPM) and metachronous MPM (mMPM) were 83.1 and 196.7 months, respectively (p= 0.10). Median OS was not reached when melanoma was diagnosed first, and 153.5 months when diagnosed second (p= 0.45). For six patients receiving immunotherapy for melanoma, there was a 100% complete response rate. In conclusion, patients with melanoma are at risk of secondary malignancies, including breast and thyroid cancer. The timing of secondary malignancies may impact prognosis. Further study of the impact of immunotherapy on MPM is warranted.
    Keywords:  cancer survival; hereditary cancer; immunotherapy; melanoma; multiple primary malignancies
    DOI:  https://doi.org/10.7759/cureus.15480
  51. J Med Case Rep. 2021 Jul 14. 15(1): 367
    Synchronous and metachronous malignant melanomas arising in a human immunodeficiency virus-positive patient after the commencement of highly active antiretroviral therapy treatment: a case report.
    Sharad P Paul, Simon Briggs, Michael Hitchcock.
      BACKGROUND: We present an unusual case of a patient who developed four melanomas within a few months of diagnosis with human immunodeficiency virus and commencement of highly active antiretroviral therapy therapy. The patient had no previous history of melanoma, and previous skin checks were normal.CASE PRESENTATION: A 50-year-old Caucasian male drainlayer with Fitzpatrick type 2 skin presented for a routine skin examination. He had been diagnosed with human immunodeficiency virus 4 months earlier and commenced on highly active antiretroviral therapy therapy. He was found to have three melanomas (melanoma in situ stage) on excision biopsies, and when he presented for wider excisions of these sites a few weeks later, another new melanoma in situ was found. He had no other medical history of note, and no symptoms to report. He is being followed up 3-monthly.
    CONCLUSIONS: This case of a human immunodeficiency virus-positive person presenting with four cutaneous melanomas-occurring in both synchronous and metachronous fashion within a 4-month period-is being presented both for its uniqueness and also to highlight the increased need for close skin surveillance in human immunodeficiency virus-positive patients.
    Keywords:  Antiretroviral drugs; HIV; Melanoma; Skin cancer
    DOI:  https://doi.org/10.1186/s13256-021-02920-4
  52. J Dtsch Dermatol Ges. 2021 Jul 13.
    Adjuvant anti-PD-1 antibody treatment in stage III/IV melanoma: real-world experience and health economic considerations.
    Peter Koelblinger, Magdalena Hoellwerth, Marie-Therese Dernoscheg, Lukas Koch, Erika Richtig, Marina Wanner, Van-Anh Nguyen, Herwig Ostermann, Johann W Bauer, Martin Laimer.
      BACKGROUND: Anti-programmed death 1 (PD-1) antibodies have evolved as a new standard of care in the adjuvant treatment of completely resected melanoma. Real-world data on treatment efficacy and safety as well as cost-effectiveness are still limited.PATIENTS AND METHODS: Treatment outcomes were retrospectively analyzed in a continuous patient cohort receiving adjuvant nivolumab (91 patients) or pembrolizumab (9 patients). Based on the obtained clinical data, a semi-Markov model was developed to evaluate cost-effectiveness.
    RESULTS: After a median follow-up of 11.5 months, disease recurrence was observed in 39 patients (39 %). The site of first recurrence was locoregional in 17, distant in 19, and combined locoregional and distant in three patients. Twelve-month estimates for recurrence- and distant-metastasis-free survival were 64.8 % and 77.4 %, respectively. Sixteen patients experienced grade 3 or 4 treatment-related adverse events, while 22 patients discontinued treatment due to adverse events. The base-case Markov model yielded an incremental cost-effectiveness ratio of 13,330 € per quality-adjusted life year for adjuvant anti-PD-1 antibody treatment compared to a simulated observation cohort.
    CONCLUSIONS: Real-world outcomes of adjuvant anti-PD-1 antibody therapy in completely resected melanoma appear comparable to clinical trial data. Moreover, our data suggests this treatment strategy to be cost-effective according to Austrian health economic standards.
    DOI:  https://doi.org/10.1111/ddg.14511
  53. J Zhejiang Univ Sci B. 2021 Jul 15. pii: 1673-1581(2021)07-0548-15. [Epub ahead of print]22(7): 548-562
    Potential effect of EGCG on the anti-tumor efficacy of metformin in melanoma cells.
    An'an Xu, Jeehyun Lee, Yueling Zhao, Yuefei Wang, Xiaoli Li, Ping Xu.
      Metformin, a first-line drug for type 2 diabetes mellitus, has been recognized as a potential anti-tumor agent in recent years. Epigallocatechin-3-gallate (EGCG), as the dominant catechin in green tea, is another promising adjuvant agent for tumor prevention. In the present work, the potential effect of EGCG on the anti-tumor efficacy of metformin in a mouse melanoma cell line (B16F10) was investigated. Results indicated that EGCG and metformin exhibited a synergistic effect on cell viability, migration, and proliferation, as well as signal transducer and activator of transcription 3/nuclear factor-κB (STAT3/NF-κB) pathway signaling and the production of inflammation cytokines. Meanwhile, the combination showed an antagonistic effect on cell apoptosis and oxidative stress levels. The combination of EGCG and metformin also differentially affected the nucleus (synergism) and cytoplasm (antagonism) of B16F10 cells. Our findings provide new insight into the potential effects of EGCG on the anti-tumor efficacy of metformin in melanoma cells.
    Keywords:  Anti-tumor efficacy; Epigallocatechin-3-gallate (EGCG); Melanoma; Metformin
    DOI:  https://doi.org/10.1631/jzus.B2000455
  54. Eur J Cancer. 2021 Jul 10. pii: S0959-8049(21)00371-3. [Epub ahead of print]154 111-119
    Stage-specific trends in incidence and survival of cutaneous melanoma in the Netherlands (2003-2018): A nationwide population-based study.
    Brenda Leeneman, Kay Schreuder, Carin A Uyl-de Groot, Alexander C J van Akkooi, John B A G Haanen, Marlies Wakkee, Margreet G Franken, Marieke W J Louwman.
      OBJECTIVE: To examine stage-specific trends in the incidence and survival of cutaneous melanoma in the Netherlands between 2003 and 2018, as well as the uptake of the sentinel lymph node biopsy (SLNB) and novel drugs during that period.METHODS: Data were obtained from the nationwide population-based Netherlands Cancer Registry for all patients diagnosed with invasive primary cutaneous melanoma (n = 60,267). We presented age-standardized incidence rates, the proportion of patients with an SLNB, the proportion of patients who received a novel drug (for their primary diagnosis) and one- and five-year relative survival rates.
    RESULTS: Between 2003 and 2018, the incidence rate increased from 10.9 to 23.9 for men and from 15.6 to 27.3 for women. This increase reflected the increasing incidence rate of patients with stage I and III. The proportion of patients with an SLNB increased from 23% to 64%. A reasonable increase was observed in the proportion of patients with a positive outcome (from 2% to 11%). For patients with stage IV, there was a shift from chemotherapy towards novel drugs as from 2013. The five-year relative survival rate increased from 81% to 92% for men and from 88% to 96% for women. This increase reflected the increasing five-year relative survival rate of patients with stage II, III, and IV.
    CONCLUSION: We observed an increase in incidence for patients with stage I and III and an improvement in survival for patients with stage II, III and IV. These trends can be partly explained by the introduction of the SLNB and the novel drugs.
    Keywords:  Cutaneous melanoma; Immunotherapy; Incidence; Surgery; Survival; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ejca.2021.06.007
  55. Case Rep Dermatol. 2021 May-Aug;13(2):13(2): 310-316
    Malignant Melanoma within a Cellular Blue Nevi Presenting as a Vascular Malformation and the Connection to Sporadic KRAS Mutations.
    Felicia Tai, Vitor M Pereira, Sam Babak, Ivan Radovanovic, Shachar Sade, Tara Lynn Teshima.
      We present a case of malignant melanoma (MM) developing within a vascular malformation showing features of cellular blue nevi. A 47-year-old male presented with acute symptoms of a temporal and zygomatic mass, which were both previously asymptomatic upon development 30 years ago. These masses were diagnosed as vascular malformations upon imaging and were treated with sclerotherapy. Embolization and surgical excision were performed 3 years later due to symptomatic growth. Final pathology reports showed MM with congenital blue nevi. We hypothesize a possible linkage to a sporadic KRAS mutation, linking both presentations of vascular malformation, MM, and cellular blue nevi. A literature search for similar cases is also reported.
    Keywords:  Blue nevus; KRAS; Melanoma; Nevus; Vascular malformation
    DOI:  https://doi.org/10.1159/000517202
  56. Cancer Sci. 2021 Jul 12.
    The BRD4 inhibitor JQ1 promotes melanoma cell apoptosis by regulating mitochondrial dynamics.
    Liyuan Li, Yan Meng, Xiaolin Wu, Jiajing Li, Yuxin Sun.
      Although the role of bromodomain-containing protein 4 (BRD4) in ovarian cancer, pancreatic cancer, multiple lymphoma and many other diseases is well known, its function in cutaneous melanoma is only partially understood. Here, our results show that the BRD4 inhibitor JQ1 promotes the apoptosis of B16 melanoma cells by altering mitochondrial dynamics, thereby inducing mitochondrial dysfunction and increasing oxidative stress. We found that treatment of B16 cells with different concentrations of JQ1 (125 nM or 250 nM), significantly downregulated the expression of protein subunits involved in mitochondrial respiratory chain complexes I, III, IV, and V, increased reactive oxygen species (ROS), induced energy metabolism dysfunction, significantly enhanced apoptosis and activated the mitochondrial apoptosis pathway. At the same time, JQ1 inhibited the activation of AMP-activated protein kinase (AMPK), a metabolic energy sensor. In addition, we found that the mRNA and protein levels of mitochondrial dynamin-related protein 1 (DRP1) increased, whereas the levels of mitochondrial fusion protein 1 (MFN1) and optic atrophy protein 1 (OPA1) decreased. Mechanistically, we determined that JQ1 inhibited the expression of c-Myc and altered mitochondrial dynamics, eventually leading to changes in the mitochondrial function, metabolism, and apoptosis of B16 melanoma cells.
    Keywords:  BRD4; apoptosis; energy metabolism; melanoma; mitochondrial dynamics
    DOI:  https://doi.org/10.1111/cas.15061
  57. J Cancer Res Ther. 2021 Jul;17(3): 808-810
    The combination therapy with the cytotoxic T lymphocyte-associated antigen-4 and programmed death 1 antibody-induced asthma in a patient with advanced melanoma.
    Weiran Xu, Bin Lian, Chuanliang Cui, Jun Guo.
      The combination of programmed death 1 (PD-1) inhibitors and cytotoxic T lymphocyte-associated antigen-(CTLA-4) inhibitors have markedly improved the survival of melanoma patients. We report the case of a patient with advanced melanoma who developed asthma during anti-PD-1 and anti-CTLA-4 combination therapy. The patient was a 57-year-old woman enrolled in a clinical trial regarding novel CTLA-4 antibody and sintilimab treatment. The patient was diagnosed with asthma after three cycles of therapy. Subsequently, she was treated with corticosteroids, shortcostero β2 agonists, and antihistamines. The symptoms were relieved after 7 days. This is the first report of asthma in a patient treated with combination immunotherapy to the best of our knowledge. The mechanism remains to be further explored.
    Keywords:  Adverse event; immunotherapy; melanoma
    DOI:  https://doi.org/10.4103/jcrt.jcrt_419_21
  58. Histopathology. 2021 Jul 16.
    PRAME expression in melanocytic lesions of the conjunctiva.
    Daja Šekoranja, Gregor Hawlina, Jože Pižem.
      AIMS: PRAME (PReferentially expressed Antigen in MElanoma) is a tumour-associated antigen that is preferentially strongly expressed in most cutaneous melanomas but not or only focally in nevi. Our aim was to evaluate PRAME expression in melanocytic lesions of the conjunctiva.METHODS AND RESULTS: Surgical specimens of 114 conjunctival melanocytic nevi of different types (including 67 common, 25 combined deep penetrating and 21 inflamed juvenile nevi), 30 invasive melanomas, 10 in situ melanomas, 23 primary acquired melanoses (PAM) without atypia and 11 PAM with atypia were analysed for PRAME expression by immunohistochemistry. Nuclear positivity for PRAME in melanocytes was assessed as the percentage of positive nuclei: negative (0%), 1+ (1-25%), 2+ (26-50%), 3+ (51-75%) and 4+ (>75%). In 113 of 114 conjunctival melanocytic nevi, PRAME was either completely negative or focally 1+ positive. Diffuse 4+ PRAME expression was identified in 17 of 30 (57%) invasive melanomas, 7 of 10 (70%) in situ melanomas, 4 of 5 (80%) PAM with severe atypia, 0 of 3 PAM with moderate atypia, 0 od 3 PAM with mild atypia, 1 of 23 (4%) PAM without atypia and 0 of 114 nevi. Diffuse 4+ PRAME expression in invasive melanomas correlated with a higher mitotic count but was not related to age and gender of the patients, Breslow thickness, location or mutational status.
    CONCLUSION: Diffuse 4+ PRAME positivity is highly specific for malignant conjunctival melanocytic lesions. PRAME is therefore a useful ancillary marker to support the diagnosis of a suspected conjunctival melanoma.
    Keywords:  BRAFV600E; PRAME; conjunctiva; melanoma; melanosis; nevus
    DOI:  https://doi.org/10.1111/his.14452
  59. Acad Pathol. 2021 Jan-Dec;8:8 23742895211023954
    Educational Case: Malignant Melanoma.
    Eric M Bonar, Colleen Beatty, Melina B Flanagan.
      The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.
    Keywords:  malignant skin neoplasms; melanoma; organ system pathology; pathology competencies; skin; skin neoplasia
    DOI:  https://doi.org/10.1177/23742895211023954
  60. Brachytherapy. 2021 Jul 09. pii: S1538-4721(21)00431-1. [Epub ahead of print]
    Long-term outcomes after enucleation or plaque brachytherapy of choroidal melanomas touching the optic disc.
    Maria Fili, Melvin Astrahan, Gustav Stålhammar.
      PURPOSE: To investigate local and systemic outcomes after enucleation, brachytherapy with ruthenium-106, iodine-125, notched and non-notched plaques and transpupillary thermotherapy (TTT) of choroidal melanomas touching the optic disc.METHODS AND MATERIALS: All patients treated for choroidal melanoma touching the optic disc at St. Erik Eye Hospital, Stockholm, Sweden between 1984 and 2015 (n = 165) were included. Retrospective clinicopathological data was collected and 3D dosimetry performed.
    RESULTS: Ninety-five patients (58 %) had been treated with ruthenium-106 brachytherapy, 21 (13 %) with iodine-125 brachytherapy and 49 (30 %) with enucleation. Median follow-up was 12.3 years. In simulations, some tumor areas were underdosed with non-notched plaques. Fifty of 116 patients (43 %) underwent a secondary brachytherapy (n = 5), enucleation (n = 29) or TTT (n = 16). In multivariate Cox Regressions, there were no significant differences in the risk for tumor progression or lack of regression between radioisotopes and notched and non-notched plaques. Adding TTT did not reduce the risk for a second treatment. The number of clock hours of circumpapillary tumor growth did not correlate to the risk for treatment failure or mortality. There were no significant differences in melanoma-related mortality for any treatment including enucleation. Kaplan-Meier disease-specific survival was 77 % at 5 years, 72 % at 10 years and 67 % at 20 years.
    CONCLUSION: Plaque brachytherapy of choroidal melanomas touching the optic disc entails a two to threefold increased risk for treatment failure. This risk is similar between radioisotopes, notched and non-notched plaque designs and if TTT is used or not. The high rate of treatment failure does not lead to increased mortality.
    Keywords:  Brachytherapy; Dosimetry; Enucleation; Juxtapapillary; Transpupillary thermotherapy; Uveal melanoma
    DOI:  https://doi.org/10.1016/j.brachy.2021.05.162
  61. J Med Case Rep. 2021 Jul 16. 15(1): 347
    Malignant melanoma without primary, presenting as solitary pulmonary nodule: a case report.
    George Tsaknis, Muhammad Naeem, Advitya Singh, Siddharth Vijayakumar.
      BACKGROUND: Solitary pulmonary nodules are the most common incidental finding on chest imaging. Their management is very well defined by several guidelines, with risk calculators for lung cancer being the gold standard. Solitary intramuscular metastasis combined with a solitary pulmonary nodule from malignant melanoma without a primary site is rare.CASE PRESENTATION: A 57-year-old white male was referred to our lung cancer service with solitary pulmonary nodule. After positron-emission tomography, we performed an ultrasound-guided core needle biopsy of an intramuscular solitary lesion, not identified on computed tomography scan, and diagnosed metastatic malignant melanoma. The solitary pulmonary nodule was resected and also confirmed metastatic melanoma. There was no primary skin lesion. The patient received oral targeted therapy and is disease-free 5 years later.
    CONCLUSIONS: Clinicians dealing with solitary pulmonary nodules must remain vigilant for other extrathoracic malignancies even in the absence of obvious past history. Lung metastasectomy may have a role in metastatic malignant melanoma with unknown primary.
    Keywords:  Case report; Intramuscular metastasis; Malignant melanoma; Needle biopsy; Solitary pulmonary nodule
    DOI:  https://doi.org/10.1186/s13256-021-02933-z
  62. J Am Acad Dermatol. 2021 Jul 09. pii: S0190-9622(21)02087-9. [Epub ahead of print]
    Female sex is associated with higher rates of dermatologic adverse events among patients with melanoma receiving immune checkpoint inhibitor therapy: a retrospective cohort study.
    Ai-Tram N Bui, Amina Bougrine, Elizabeth I Buchbinder, Anita Giobbie-Hurder, Nicole R LeBoeuf.
      
    Keywords:  cutaneous adverse events; immune checkpoint inhibitor; immune-related adverse events; immunotherapy; melanoma; programmed cell death 1; programmed cell death ligand 1; sex differences
    DOI:  https://doi.org/10.1016/j.jaad.2021.06.885
  63. Cancer Immunol Immunother. 2021 Jul 15.
    A secondary role for hypoxia and HIF1 in the regulation of (IFNγ-induced) PD-L1 expression in melanoma.
    Anneloes van Duijn, Karin J Willemsen, Nathalie O P van Uden, Lieke Hoyng, Sterre Erades, Jan Koster, Rosalie M Luiten, Walbert J Bakker.
      Cancer cells are able to escape immune surveillance by upregulating programmed death ligand 1 (PD-L1). A key regulator of PD-L1 expression is transcriptional stimulation by the IFNγ/JAK/STAT pathway. Recent studies suggest that hypoxia can induce PD-L1 expression. As hypoxia presents a hallmark of solid tumor development, hypoxic control of PD-L1 expression may affect the efficacy of cancer immunotherapy. This study aims to explore the hypoxic regulation of PD-L1 expression in human melanoma, and its interaction with IFNγ-induced PD-L1 expression. Analysis of the cutaneous melanoma dataset from the cancer genome atlas revealed a significant correlation of the HIF1-signaling geneset signature with PD-L1 mRNA expression. However, this correlation is less pronounced than other key pathways known to control PD-L1 expression, including the IFNγ/JAK/STAT pathway. This secondary role of HIF1 in PD-L1 regulation was confirmed by analyzing single-cell RNA-sequencing data of 33 human melanoma tissues. Interestingly, PD-L1 expression in these melanoma tissues was primarily found in macrophages. However, also in these cells STAT1, and not HIF1, displayed the most pronounced correlation with PD-L1 expression. Moreover, we observed that hypoxia differentially affects PD-L1 expression in human melanoma cell lines. Knockdown of HIF1 expression indicated a minor role for HIF1 in regulating PD-L1 expression. A more pronounced influence of hypoxia was found on IFNγ-induced PD-L1 mRNA expression, which is controlled at a 952 bp PD-L1 promoter fragment. These findings, showing the influence of hypoxia on IFNγ-induced PD-L1 expression, are relevant for immunotherapy, as both IFNγ and hypoxia are frequently present in the tumor microenvironment.
    Keywords:  HIF1; Hypoxia; IFNγ; Immunotherapy; Melanoma; PD-L1
    DOI:  https://doi.org/10.1007/s00262-021-03007-1
  64. Mod Pathol. 2021 Jul 10.
    Histological regression in melanoma: impact on sentinel lymph node status and survival.
    Karina Aivazian, Tasnia Ahmed, Mary-Ann El Sharouni, Jonathan R Stretch, Robyn P M Saw, Andrew J Spillane, Kerwin F Shannon, Sydney Ch'ng, Omgo E Nieweg, John F Thompson, Serigne N Lo, Richard A Scolyer.
      Regression in melanoma is an immunological phenomenon that results in partial or complete replacement of the tumor with variably vascular fibrous tissue, often accompanied by pigment-laden macrophages and chronic inflammation. In some cases, tumor-infiltrating lymphocytes (TILs) may represent the earliest phase of this process. The prognostic significance of regression has long been a matter of debate, with inconsistent findings reported in the literature to date. This study sought to determine whether regression in primary cutaneous melanomas predicted sentinel lymph node (SLN) status and survival outcomes in a large cohort of patients managed at a single centre. Clinical and pathological parameters for 8,693 consecutive cases were retrieved. Associations between regression and SLN status, overall survival (OS), melanoma-specific survival (MSS) and recurrence-free survival (RFS) were investigated using logistic and Cox regression. Histological evidence of regression was present in 1958 cases (22.5%). Regression was significantly associated with lower Breslow thickness, lower mitotic rate, and absence of ulceration (p < 0.0001). Multivariable analysis showed that regression in combination with TILs independently predicted a negative SLN biopsy (OR 0.33; 95% C.I. 0.20-0.52; p < 0.0001). Patients whose tumors showed both regression and TILs had the highest 10-year OS (65%, 95% C.I. 59-71%), MSS (85%, 95% C.I. 81-89%), and RFS (60%, 95% C.I. 54-66%). On multivariable analyses, the concurrent presence of regression and TILs independently predicted the lowest risk of death from melanoma (HR 0.69; 95% C.I. 0.51-0.94; p = 0.0003) as well as the lowest rate of disease recurrence (HR 0.71; 95% C.I. 0.58-0.85; p < 0.0001). However, in contrast, in the subgroup analysis of Stage III patients, the presence of regression predicted the lowest OS and RFS, with MSS showing a similar trend. Overall, these findings indicate a prognostically favorable role of regression in primary cutaneous melanoma. However, in Stage III melanoma patients, regression may be a marker of more aggressive disease.
    DOI:  https://doi.org/10.1038/s41379-021-00870-2
  65. J Adv Nurs. 2021 Jul 10.
    Life Interrupted: Experiences of adolescents, young adults and their family living with malignant melanoma.
    Wendy McInally, Carol Gray-Brunton, Zoe Chouliara, Richard G Kyle.
      AIM: Melanoma is one of the most common human malignancies; yet, it is often thought of as a disease of adulthood rather than one affecting adolescents and young adults. This study sought to understand the experiences of adolescents, young adults and their family living with malignant melanoma.DESIGN: A qualitative study using Interpretive Phenomenological Analysis, through a multi-perspective design.
    METHODS: Data collection was conducted between January and August 2018 in each participant's Primary Care Centre when they were attending for an outpatient appointment. Each young person and a nominated family member were interviewed (n = 10) either individually (n = 4) or as a dyad (n = 6) according to their personal choice. In-depth semi-structured interviews were conducted and audio-recorded with the participant's consent. Interview data were transcribed verbatim and analysed.
    FINDINGS: The metanarrative 'Life Interrupted' was the core conceptual thread woven throughout the findings. It represents the interconnections and interrelationships between the adolescent or young adult and their family. Being able to recognize the disease and seek support was challenging with often limited physical, emotional or social support resulting in feelings of fear and isolation. Four super-ordinate themes were identified: (a) 'Is it Serious', (b) 'Too Much too Young', (c) 'Not the Same' and (d) 'Time to Live'.
    CONCLUSIONS: With the rising incidence of MM in the adolescents and young adults population globally, there are demands to improve healthcare professionals and nurse's knowledge and understanding of MM. As young people with MM experience their journey outside specialist cancer services, the care delivery for this patient group and their families require stronger links between services.
    IMPACT: This study will inform the improvement of care delivery for MM in order that this patient group is provided with the same access to service delivery as other adolescents and young adults with cancer.
    Keywords:  adolescents; experiences; family; interpretative phenomenological analysis; malignant melanoma; narrative; nursing; qualitative; research; young adults
    DOI:  https://doi.org/10.1111/jan.14959
  66. Pediatr Dermatol. 2021 Jul 11.
    THE demographics and trends in pediatric melanoma in the United States: An analysis of the National Cancer Database.
    Rame Yousif, Christina Boull, Pedram Gerami, Beatrice Nardone, Karina L Vivar, Walter Liszewski.
      BACKGROUND/OBJECTIVE: Relative to adults, rates of melanoma are lower in children. Due to its rarity, it is difficult to assess the incidence, trends, and outcomes of this malignancy. Much of our understanding comes from single institution or regional cancer registries which may not be large enough to detect subtleties in the burden of pediatric melanoma.METHODS: Data from the 2004 to 2016 National Cancer Database were analyzed; this database captures approximately 70% of all cancer diagnoses in the United States.
    RESULTS: Our analysis consisted of 1903 cases. A majority were White (89.8%), the mean age was 12.4 years, and the ratio of females: males was 1.2:1.0. The most common anatomic location was the trunk (31.1%). Between 2004 and 2016, a decreasing trend in the number of new melanoma cases was observed. Comparing histologic subtype by age, there was an increased percentage of nodular and epithelioid and spindle cell tumors in the pre-teen children and a greater percentage of superficial spreading tumors in teenagers. Overall, a majority of cases were stage 0 or I (56.9%), with relatively few stage IV cases (2.0%). A 5-year all-cause survival of greater than 90% was observed for stage I-III tumors, with stage IV tumors having a 5-year all-cause survival of 34.4%.
    CONCLUSION: Comparable to previous studies, pediatric melanoma occurred most often in Whites, females, and adolescents. However, we detected a decreasing trend in new cases, noted differences between histologic subtype and age, and observed a 5-year all-cause survival rate of greater than 90% for stage I-III tumors.
    Keywords:  cancer; dermatology; epidemiology; medical dermatology; melanoma; oncology; pediatrics
    DOI:  https://doi.org/10.1111/pde.14672
  67. Am J Surg Pathol. 2021 Jul 15.
    Primary Cilia Are Preserved in Cellular Blue and Atypical Blue Nevi and Lost in Blue Nevus-like Melanoma.
    Kathleen M Sheahon, Tyler Jankowski, Iwei Yeh, Jeffrey P North, Laura B Pincus, Philip E LeBoit, Timothy H McCalmont, Ursula E Lang.
      Distinguishing cellular blue nevi (CBNs) and atypical CBNs from blue nevus-like melanoma (BNLM) can be diagnostically challenging. Immunohistochemistry may inform the diagnosis in a subset of cases but is not always diagnostic. Further, ancillary molecular testing is expensive and often requires significant tissue to complete. Primary cilia are cell-surface organelles with roles in signal transduction pathways and have been shown to be preserved in conventional melanocytic nevi but lost in melanoma. Immunofluorescence staining of primary cilia can be performed using a single standard-thickness formalin-fixed paraffin-embedded tissue section and has a turnaround time similar to immunohistochemistry. The percentage of tumoral melanocytes retaining a primary cilium is quantified and reported as the ciliation index. In the current study, we explored the utility of the ciliation index in a series of 31 blue nevus-like lesions, including CBNs (12), atypical CBNs (15), and BNLM (4). The average ciliation index for the CBNs was 59±18%, with a median of 60 (range: 28 to 87). The average ciliation index for atypical CBNs was 59±23, with a median of 59 (range: 20 to 93). The average ciliation index for BNLM was 4±3, with a median of 3 (range: 1 to 8). There was no significant difference in ciliation index between the CBN and atypical CBN categories. There was a significant difference between CBN and BNLM and between atypical CBNs and BNLM (P<0.001 for each). Here, we show that ciliation index is a quantitative diagnostic tool useful in the setting of blue nevus-like neoplasms, with benefits including cost and time efficiency.
    DOI:  https://doi.org/10.1097/PAS.0000000000001739
  68. JPRAS Open. 2021 Sep;29 178-183
    Assessing exposure to dermoscopy in plastic surgery training programs.
    Gemma Percival, Christine Nicholas, Carmen E Webb, Claire F Temple-Oberle.
      Background: Dermoscopy is a noninvasive tool that improves the diagnostic accuracy of melanoma and other cutaneous malignancies; yet, it is not widely used by plastic surgeons, who commonly manage skin lesions. Thus, the purpose of this study was to explore current practice patterns and knowledge of dermoscopy among plastic surgeons and postgraduate plastic surgery trainees. Additionally, interest to establish a formal dermoscopy curriculum as part of plastic surgery residency training was evaluated.Methods: An online electronic questionnaire was developed and distributed through email to practicing plastic surgeons and plastic surgery trainees at two Canadian universities.
    Results: Of the 59 potential participants, 27 (46%) responded. While the majority of participants were familiar with dermoscopy (n = 26; 96%), only one respondent reported using dermoscopy in clinical practice. However, all respondents reported exposure to melanoma clinically (n = 26; one participant did not provide a response). A lack of training, along with lack of access to dermatoscopes, were the most frequently cited reasons for not using dermoscopy. Knowledge scores with regard to dermoscopic features were also low; coupled with a noted propensity toward diagnostic or excisional biopsy, whichcould raise the benign to malignant ratio. Overall, 89% (n = 24) of respondents expressed interest in dermoscopy training in plastic surgery postgraduate training.
    Conclusions: Few responding plastic surgeons or plastic surgery residents currently use dermoscopy in training or practice but are interested in formal dermoscopy training in residency.
    Keywords:  cutaneous malignancy; dermoscopy; melanoma; plastic surgery; post-graduate medical education; residency
    DOI:  https://doi.org/10.1016/j.jpra.2021.05.003
  69. J Eur Acad Dermatol Venereol. 2021 Jul 14.
    Reduction in the number of early melanomas diagnosed during the COVID-19 pandemic: a single-center cohort study.
    Erica Koch, Francisco Villanueva, Michael A Marchetti, Álvaro Abarzúa, Consuelo Cárdenas, Juan Camilo Castro, Francisco Dominguez, Katherine Droppelmann, Nicolás Droppelmann, Héctor Galindo, Augusto León, Jorge Madrid, Montserrat Molgó, Sebastián Mondaca, Pablo Montero, Pablo Uribe, Miguel A Villaseca, Eugenio Vinés, Cristian Navarrete-Dechent.
      Early detection of melanoma is an important intervention to reduce morbidity and mortality.1, 2 The COVID-19 pandemic has affected timely access to healthcare, potentially affecting patient outcomes. Marson et al. showed that the incidence of melanoma decreased during the pandemic using United States data.3 Lallas et al. demonstrated an overall 30.1% decrease in cancers diagnosed during the pandemic in Greece.4 We sought to evaluate whether melanomas diagnosed during the pandemic at our medical center differed in stage compared to the pre-pandemic time period.
    Keywords:  Breslow thickness; COVID-19; diagnosis; melanoma; pandemic; skin cancer; stage
    DOI:  https://doi.org/10.1111/jdv.17522
  70. J Cutan Pathol. 2021 Jul 16.
    Melanocytic hyperplasia associated with surgical scars in basal cell carcinoma re-excision specimens: a single-center retrospective study.
    Maya Farah, Shuji Suzuki, Jag Bhawan.
      BACKGROUND: Melanocytic hyperplasia (MH) overlying surgical scars has been reported but MH adjacent to the scar has not been previously addressed.METHODS: We evaluated scar-associated MH in 489 re-excision specimens of basal cell carcinoma. Melanocytic density, confluence, atypia, suprabasal scatter, follicular extension, distance from the scar, correlation with clinicopathologic parameters, and PRAME expression were recorded.
    RESULTS: One hundred seventy-seven of 489 (36%) cases exhibited MH beyond the scar extending to 6.65 mm median distance, with a median density of 13 melanocytes/0.5 mm (6-24 mm), confluence in 74 (42%) cases, atypia in 14 (8%), suprabasal melanocytes in 25 (14%), and follicular extension in 21 (12%). Mean age of MH group was significantly lower than non-MH group (p<0.0001). MH overlying the scar was significantly higher in specimens with elastosis compared to those without elastosis (p<0.0001). PRAME expression was absent in 14/20 cases and present in rare melanocytes in six cases.
    CONCLUSIONS: Increased melanocytic density with confluence, mild atypia, suprabasal scatter, and superficial follicular extension may be observed in re-excision specimens adjacent to surgical scars in the absence of a melanocytic neoplasm. These observations are helpful for appropriate interpretation of melanoma re-excision specimens to avoid potential pitfalls in diagnosis and unnecessary therapeutic measures. This article is protected by copyright. All rights reserved.
    Keywords:  basal cell carcinoma; excision; melanocytic hyperplasia; scar
    DOI:  https://doi.org/10.1111/cup.14098
  71. Genet Med. 2021 Jul 14.
    Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.
    B Dalmasso, L Pastorino, V Nathan, N N Shah, J M Palmer, M Howlie, P A Johansson, N D Freedman, B D Carter, L Beane-Freeman, B Hicks, A Molven, H Helgadottir, A Sankar, H Tsao, A J Stratigos, P Helsing, R Van Doorn, N A Gruis, M Visser, K A W Wadt, G Mann, E A Holland, E Nagore, M Potrony, S Puig, C Menin, K Peris, M C Fargnoli, D Calista, N Soufir, M Harland, T Bishop, P A Kanetsky, D E Elder, V Andreotti, I Vanni, W Bruno, V Höiom, M A Tucker, X R Yang, P A Andresen, D J Adams, M T Landi, N K Hayward, A M Goldstein, P Ghiorzo, , .
      PURPOSE: Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear.METHODS: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set.
    RESULTS: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018).
    CONCLUSION: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.
    DOI:  https://doi.org/10.1038/s41436-021-01240-8
  72. STAR Protoc. 2021 Sep 17. 2(3): 100627
    Optimized protocol for immunophenotyping of melanoma and tumor-bearing skin from mouse.
    Sai Sakktee Krisna, Christophe Goncalves, Natascha Gagnon, Fan Huang, Dany Plourde, Wilson H Miller, Jörg H Fritz, Sonia V Del Rincon.
      While isolating immune cells from spleens and lungs is routinely achieved using flow cytometry, it is challenging to isolate viable immune cells from skin. Here, we describe a step-by-step protocol for skin digestion using a murine melanoma model, which is amenable for detection of low abundant immune cell populations including group 2 innate lymphoid cells.
    Keywords:  Cancer; Cell isolation; Flow Cytometry/Mass Cytometry; Immunology; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2021.100627
  73. J Immunother Cancer. 2021 Jul;pii: e002835. [Epub ahead of print]9(7):
    Clinical and immunologic implications of COVID-19 in patients with melanoma and renal cell carcinoma receiving immune checkpoint inhibitors.
    Benjamin Switzer, John Haanen, Paul C Lorigan, Igor Puzanov, Samra Turajlic.
      The clinical and immunologic implications of the SARS-CoV-2 pandemic for patients with cancer receiving systemic anticancer therapy have introduced a multitude of clinical challenges and academic controversies. This review summarizes the current evidence, discussion points, and recommendations regarding the use of immune checkpoint inhibitors (ICIs) in patients with cancer during the SARS-CoV-2 pandemic, with a focus on patients with melanoma and renal cell carcinoma (RCC). More specifically, we summarize the theoretical concepts and available objective data regarding the relationships between ICIs and the antiviral immune response, along with recommended clinical approaches to the management of melanoma and RCC patient cohorts receiving ICIs throughout the course of the COVID-19 pandemic. Additional insights regarding the use of ICIs in the setting of current and upcoming COVID-19 vaccines and broader implications toward future pandemics are also discussed.
    Keywords:  COVID-19; immunotherapy; kidney neoplasms; melanoma; vaccination
    DOI:  https://doi.org/10.1136/jitc-2021-002835
  74. Pigment Cell Melanoma Res. 2021 Jul;34(4): 705-706
    Special issue: "Biology of skin pigmentation and pigmentary diseases".
    Shosuke Ito, Zalfa Abdel-Malek, Mauro Picardo.
      
    DOI:  https://doi.org/10.1111/pcmr.12997
  75. Curr Med Imaging. 2021 Jul 14.
    Visceral hepatic leishmaniasis in a melanoma patient in FDG-PET.
    Andreas Dunzinger, Carina Datinger, Almute Loidl, Bernhard Walcherberger, Roland Andreas Lengauer, Nariman Mehraban, Robert Pichler.
      BACKGROUND: Leishmaniasis is caused by protozoans that depend on female phlebotomine sandflies as vectors. The natural habitat of these sandflies is changing due to climate change. More patients will get immunocompromised due to cancer therapy.CASE REPORT: We report the case of a 72-year-old patient with melanoma in whom we found visceral leishmaniasis mimicking hepatic metastasis in routine FDG-PET/CT. The patient was hospitalized due to fever and pancytopenia in the general hospital Steyr. The diagnosis was made by biopsy of the iliac crest with cytological study and polymerase chain reaction. After treatment with amphotericin B, the patient recovered, and tests became negative, including FDG-PET/CT. Because of climate change and the increasing use of immunomodulatory medication, our awareness of such findings should grow.
    CONCLUSION: New pitfalls in diagnosis and surveillance of cancer patients because of altered environmental conditions and immunocompromised patients have to be considered.
    Keywords:  FDG-PET/CT; leishmaniasis; liver; visceral
    DOI:  https://doi.org/10.2174/1573405617666210714122602
  76. Clin Cosmet Investig Dermatol. 2021 ;14 827-835
    Transverse Needling After Autologous Mini-Punch Grafts Improves Repigmentation in Stable Non-Segmental Vitiligo.
    Magdy Ragab, Omneya El Zagh, Carmen Farid.
      Background: Repigmentation remains the primary target in vitiligo treatment. Melanocyte transfer procedures are often required for repigmenting stable, resistant vitiligo lesions necessitating procedural optimization and comparative evaluation. In the current study, we aimed to assess the additive value of weekly transverse needling sessions after mini-punch grafting for repigmenting stable non-segmental vitiligo lesions versus either procedure alone.Methods: Eighty lesions, included in 20 stable non-segmental vitiligo patients, were randomly allocated to each of the three treatment groups (line-1, mini-punch grafting; line-2, needling; and line-3, combined grafting and needling) and to a fourth control group receiving non-procedural treatment (line-4). Oral mini-pulse steroids and narrow-band ultraviolet-B sessions were administered to all patients for 3 months before and 6 months after the interventions. The extent of repigmentation was assessed using planimetry. Secondary outcomes were the time to first repigmentation response, cosmetic matching, and patient satisfaction. Blinding and allocation concealment were not feasible owing to the intervention nature and within subject design.
    Results: Mini-punch grafting followed by weekly needling for 6 months achieved the fastest response and highest extent of repigmentation. Mini-punch grafts and transverse needling alone provided better results than the control group. No steroid-associated side effects were reported.
    Conclusion: Weekly needling sessions after mini-punch grafting hastened and improved the repigmentation extent of stable, resistant, non-segmental vitiligo lesions and should be considered during treatment planning.
    Keywords:  narrow-band UVB; oral mini-pulse steroid; planimetry; stability; vitiligo surgery
    DOI:  https://doi.org/10.2147/CCID.S315407
  77. Photodermatol Photoimmunol Photomed. 2021 Jul 15.
    Altered circulating memory T cells in vitiligo cases followed NB-UVB therapy.
    Fuquan Lin, Xiukun Sun, Jiehao Lei, Xu Ai-E.
      BACKGROUND: Vitiligo represents a commonly diagnosed autoimmune disease caused the depletion of epidermal melanocytes. Many subsets of T cells contribute to vitiligopathogenesis, including resident and circulating memory T cells.OBJECTIVES: To analyze the amounts of CD4+ and CD8+ memory T-cell subsets in peripheral blood specimens fromvitiligo patients, as well as alterations caused by narrowband ultraviolet B (NB-UVB) phototherapy.
    METHODS: Circulating CD4+ and CD8+ central memory T (TCM ) and effector memory T (TEM ) cell frequencies in 33 patients with non-segmental vitiligo and 16 healthy donors were evaluated by flow cytometry. Related chemokine levels were also detected.
    RESULTS: Peripheral blood CD4+ TCM and CD8+ TCM counts were markedly reduced in vitiligo cases while there were higher in active vitiligo compared with stable vitiligo cases. Circulating CD8+ TCM frequency in vitiligo was closely related to disease duration. Interestingly, CD4+ TCM and CD8+ TCM frequencies, alongside CXCL9 and CXCL10 amounts in peripheral blood of patients with vitiligo were significantly decreased after NB-UVB phototherapy.
    CONCLUSIONS: Decreased frequencies of circulating CD4+ TCM and CD8+ TCM by NB-UVB suggest a possible immunosuppressive effect of phototherapy. The chemokines CXCL9 and CXCL10 are the bridge between circulating and skin resident memory T cells. NB-UVB blocks the homing of circulating memory T cells into vitiligo lesions by down regulating CXCL9 and CXCL10. Targeting the above proteins could provide novel, durable treatment options to cure and prevent flares of this disease.
    Keywords:  Memory T-cell; NB-UVB; Vitiligo
    DOI:  https://doi.org/10.1111/phpp.12719
  78. Asian J Neurosurg. 2021 Apr-Jun;16(2):16(2): 394-397
    Spinal Nerve Root Extradural Melanocytoma Progressing to Malignant Melanoma: A Case Report with Review of Literature.
    Salman T Shaikh, Gaurav S Gupta, Chandan B Mohanty, Chadrashekhar E Deopujari.
      Melanocytomas are rare benign pigmented tumors arising from the leptomeninges with a very remote chance of progressing to malignant melanoma. They have a predilection for occurring in the posterior fossa or in the intradural extramedullary region of the cervical spine. We report the first case of malignant transformation of a nerve root (extradural) melanocytoma wherein immunotherapy has been added for its treatment. Only four such cases of malignant transformation of central nervous system melanocytoma have been reported in the literature. Definite diagnosis in such cases is based on immunohistochemistry evaluation. Surgical resection with adjuvant radiotherapy and immunotherapy is the recommended treatment.
    Keywords:  Immunotherapy; melanoma; meningeal melanocytoma; nerve root; spine
    DOI:  https://doi.org/10.4103/ajns.AJNS_416_20
  79. J Cutan Pathol. 2021 Jul 13.
    An update on Congenital Melanocytic Nevus Syndrome: a case report and literature review.
    Lilaf Abdulmajid, Francesca Maria Bosisio, Hilde Brems, Greet De Vlieger, Marjan Garmyn, Heidi Segers, Philippe Demaerel, Katarina Segers, Katrien Jansen, Lieven Lagae, Magali Verheecke.
      Congenital melanocytic nevus syndrome (CMNS) is a rare condition characterized by pigmented skin lesions that is usually present at birth and is associated with an increased risk of neurological abnormalities and malignant melanoma. It mostly results from a post-zygotic NRAS mutation of neural-derived crest cells, leading to an uncontrolled cell growth. Due to the increased knowledge of the genetics underlying CMNS, targeted therapy becomes a promising treatment option. We present a case of CMNS in a newborn. Physical examination at birth showed a giant congenital melanocytic nevus, extending from the occipital to the lower lumbar region. An MRI-scan revealed multiple cerebral and cerebellar parenchymal lesions. Genetic analysis of the cutaneous lesions showed the presence of a NRAS Q61R mutation. The patient was treated with dermabrasion to reduce the color intensity of the nevus. However, this was complicated with recurrent wound infections and laborious wound healing. At the age of 1 year, the patient had an age-appropriate psychomotor development, without neurological deficits. This article is protected by copyright. All rights reserved.
    Keywords:  Congenital melanocytic nevus syndrome; NRAS mutation; histopathology; neurocutaneous disorder; targeted therapy
    DOI:  https://doi.org/10.1111/cup.14097
  80. Hautarzt. 2021 Jul 16.
    [Optical coherence tomography for the differential diagnosis of unclear nail pigmentation].
    Katja Dicke, Vasileios Dervenis, Thomas Dirschka, Julia Welzel, Sandra Schuh.
      In daily practice, nail pigmentation can be a diagnostic challenge, especially if the dermoscopic findings are nonspecific. We present examples of cases, in which optical coherence tomography-a rapid, noninvasive imaging method-showed typical changes that were indicative for the diagnosis.
    Keywords:  Glomus tumor; Hematoma; Melanoma; Pigmented nevus; Pseudomonas
    DOI:  https://doi.org/10.1007/s00105-021-04862-w
  81. Dermatol Ther. 2021 Jul 10. e15058
    Is targeted UVB as effective as excimer light phototherapy in treatment of vitiligo?
    Hera Tabassum, Imran Majid, Saher Imran.
      Excimer light (EL) and targeted UVB (TUVB) devices have been used successfully in repigmenting vitiligo. To compare the repigmenting efficacy and safety of EL with TUVB device in vitiligo. The study was conducted retrospectively on patients of vitiligo who had received either EL (Group A) or TUVB (Group B) from year 2015 to 2020. Data pertaining to 40 such age and sex matched patients from each group was retrieved with almost similar sites of involvement. Only patients whose phototherapy sessions had been given twice weekly for minimum of 30 sessions or until 90%-100% repigmentation were included in the study. The study was retrospective in nature and the principles outlined in the Declaration of Helsinki were followed during the study. The primary endpoint compared between the two groups was the extent of repigmentation achieved on different sites of body and adverse effects from treatment. Secondary endpoints compared included total number of doses, cumulative dose needed for complete repigmentation and number of doses needed for onset of repigmentation. There were 82.6% responders in Group A and 76.3% in Group B who had achieved at least 50% repigmentation. Excellent response (75%-100% repigmentation) was achieved in 68.1% lesions in Group A and 46.4% lesions in Group B. Patients in Group A needed less number of doses (13.75 vs. 19.37) and less cumulative dose (6.14 vs. 7.69 J/cm2 ) to achieve complete or near complete repigmentation. Adverse effects were negligible in both groups. Targeted phototherapy with EL demonstrated better repigmenting efficacy than TUVB in vitiligo.
    Keywords:  excimer light; repigmenting efficacy; targeted UVB; targeted phototherapy; vitligo
    DOI:  https://doi.org/10.1111/dth.15058
  82. Front Immunol. 2021 ;12 711080
    Editorial: Immunology of Vitiligo.
    Julien Seneschal, John E Harris, I Caroline Le Poole, Thierry Passeron, Reinhart Speeckaert, Katia Boniface.
      
    Keywords:  adaptive immunity; innate immunity; melanocytes; oxidative stress; tolerance; translational research; vitiligo
    DOI:  https://doi.org/10.3389/fimmu.2021.711080
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