bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021–09–19
seventy papers selected by
Farah Jaber-Hijazi, University of the West of Scotland
  1. Response to the Comment by Suijkerbuijk et al. "Survival of stage IV melanoma in Belgium and the Netherlands".
  2. Cutaneous Melanoma More Likely to Be Invasive in Fairer Skin Phototypes: A Retrospective Observational Study.
  3. Tumor cell intrinsic TLR4 signaling promotes melanoma progression and metastatic dissemination.
  4. Protein signatures of NK cell-mediated melanoma killing predict response to immunotherapies.
  5. Crucial role of glucosylceramide synthase in the regulation of stem cell-like cancer cells in B16F10 murine melanoma.
  6. Retrospective analysis of adjuvant therapy using dabrafenib plus trametinib in Japanese patients with advanced melanoma: analysis of 36 cases.
  7. Non-coding RNAs in melanoma: Biological functions and potential clinical applications.
  8. "Suffocating" tumors by blocking adaptation to hypoxia: a new headway in melanoma immunotherapy.
  9. PITX1 inhibits the growth and proliferation of melanoma cells through regulation of SOX family genes.
  10. COX-2 Silencing in Canine Malignant Melanoma Inhibits Malignant Behaviour.
  11. The Prognostic Significance of Baseline Neutrophil-to-Lymphocyte Ratio in Melanoma Patients Receiving Immunotherapy.
  12. Oligoprogression After Immunotherapy and Targeted Therapy in Metastatic Melanoma.
  13. Primary Sites of Uveal Melanoma Associated with Distinct Survival Outcomes and Clinicopathological Features: A SEER Population-Based Study of 4359 Cases.
  14. Prognosis in Thin Melanoma Patients: Is Slightly Less Than Excellent Still Okay?
  15. Cutaneous Melanoma and Sentinel Lymph Node Biopsy; An Epidemiology Study of Population Level Data.
  16. METTL3 induces PLX4032 resistance in melanoma by promoting m6A-dependent EGFR translation.
  17. Carboplatin activates the cGAS-STING pathway by upregulating the TREX-1 (three prime repair exonuclease 1) expression in human melanoma.
  18. Prognostic Value and Immunological Characteristics of a Novel RNA Binding Protein Signature in Cutaneous Melanoma.
  19. LncRNA BASP1-AS1 interact with YBX1 to regulate Notch transcription and drives the malignancy of melanoma.
  20. Immune checkpoint inhibitors in melanoma.
  21. Overexpression of microRNA-130a represses uveal melanoma cell migration and invasion through inactivation of the Wnt/β-catenin signaling pathway by downregulating USP6.
  22. Prognostic score model-based signature genes for predicting the prognosis of metastatic skin cutaneous melanoma.
  23. Primary sellar melanocytoma.
  24. The changing landscape in management of desmoplastic melanoma.
  25. Three neoplasms in a Eurasian otter (Lutra lutra): malignant melanoma, trichoblastoma and mammary gland adenoma.
  26. Identification of Immune Cell Infiltration Landscape and Their Prognostic Significance in Uveal Melanoma.
  27. Discontinuation of anti-PD-1 monotherapy in advanced melanoma - outcomes of daily clinical practice.
  28. The Downregulation of eIF3a Contributes to Vemurafenib Resistance in Melanoma by Activating ERK via PPP2R1B.
  29. Resident memory CD8+ T cells in regional lymph nodes mediate immunity to metastatic melanoma.
  30. Cellular senescence promotes cancer metastasis by enhancing soluble E-cadherin production.
  31. Skin cancer classification via convolutional neural networks: systematic review of studies involving human experts.
  32. Dual Inhibition of Histone Deacetylases and the Mechanistic Target of Rapamycin Promotes Apoptosis in Cell Line Models of Uveal Melanoma.
  33. Melanocytic nevi on the hyponychium with dermoscopic features of longitudinal brush pigmentation in children.
  34. Characterization of m6A-Related Genes Landscape in Skin Cutaneous Melanoma to Aid Immunotherapy and Assess Prognosis.
  35. Combination immunotherapy of chlorogenic acid liposomes modified with sialic acid and PD-1 blockers effectively enhances the anti-tumor immune response and therapeutic effects.
  36. Conjunctival Pyogenic Granuloma Masquerading as Malignant Melanoma.
  37. CXCL9 as a key biomarker of vitiligo activity and prediction of the success of cultured melanocyte transplantation.
  38. Regression in melanoma is significantly associated with a lower regional recurrence rate and better recurrence-free survival.
  39. Fractionated stereotactic radiotherapy for uveal melanoma: Long-term outcome and control rates.
  40. Intelligent and spatiotemporal drug release based on multifunctional nanoparticle-integrated dissolving microneedle system for synergetic chemo-photothermal therapy to eradicate melanoma.
  41. Primary Tumor Location Predicts Survival in Melanoma: A Retrospective Cohort Study of 239,257 Melanoma Patients.
  42. PD-1 Blockade on Tumor Microenvironment-Resident ILC2s Promotes TNF-α Production and Restricts Progression of Metastatic Melanoma.
  43. Cooperation between melanoma cell states promotes metastasis through heterotypic cluster formation.
  44. Mesenchymal stromal cells as carriers of IL-12 reduce primary and metastatic tumors of murine melanoma.
  45. Association of Plasma Circulating Tumor DNA With Diagnosis of Metastatic Uveal Melanoma.
  46. Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression.
  47. Outcome of pretransplant melanoma after solid organ transplantation: an observational study.
  48. Differences in the skin microbial community between patients with active and stable vitiligo based on 16S rRNA gene sequencing.
  49. Expression and localization of Sox10 during hair follicle morphogenesis and induced hair cycle.
  50. Prospective study of clinical characteristics of melanoma patients with retinopathy caused by a high-dose interferon α-2b.
  51. Identification of the Role of Wnt/β-Catenin Pathway Through Integrated Analyses and in vivo Experiments in Vitiligo.
  52. Direct Reprogramming of Mouse Fibroblasts into Melanocytes.
  53. Incidence of melanoma and nonmelanoma skin cancers in Indian and the global regions.
  54. Polybrominated diphenyl ethers BDE-47 and BDE-99 modulate murine melanoma cell phenotype in vitro.
  55. Reconstruction of a Giant Congenital Melanocytic Nevus Defect With a Submental Flap in a Global Health Setting.
  56. A practical guide on the use of imiquimod cream to treat lentigo maligna.
  57. Excellent improvement of inflammatory acne vulgaris with monochromatic excimer light in a vitiligo patient.
  58. Influence of Ethnicities and Skin Color Variations in Different Populations: A Review.
  59. scRNA-seq of human vitiligo reveals complex networks of subclinical immune activation and a role for CCR5 in Treg function.
  60. S100A9-Targeted Cowpea Mosaic Virus as a Prophylactic and Therapeutic Immunotherapy against Metastatic Breast Cancer and Melanoma.
  61. Artificial Melanogenesis by Confining Melanin/Polydopamine Production inside Polymersomes.
  62. Acute neutrophilic gastritis induced by nivolumab used as a treatment of non- metastatic malignant melanoma.
  63. A new approach using a numerical diagnostic criterion for vitiligo diagnosis with HMB-45 and Melan-A staining.
  64. Developmental chromatin programs determine oncogenic competence in melanoma.
  65. Pyomelanin Synthesis in Alternaria alternata Inhibits DHN-Melanin Synthesis and Decreases Cell Wall Chitin Content and Thickness.
  66. Immunotherapy and Prevention of Cancer by Nanovaccines Loaded with Whole-Cell Components of Tumor Tissues or Cells.
  67. Functional analysis of peripheral and intratumoral neoantigen-specific TCRs identified in a patient with melanoma.
  68. Neutrophil mediated postoperative photoimmunotherapy against melanoma skin cancer.
  69. Microneedling-assisted topical tranexamic acid solution versus 4% hydroquinone for treating melasma: A split-face randomized study.
  70. The Application of Skin Care Product in Melasma Treatment.
  1. J Eur Acad Dermatol Venereol. 2021 Sep 17.
    Response to the Comment by Suijkerbuijk et al. "Survival of stage IV melanoma in Belgium and the Netherlands".
    B Reyn, E Van Eycken, M Louwman, K Henau, K Schreuder, L Brochez, M Garmyn, N A Kukutsch.
      With interest we read the letter by K.P.M Suijkerbuijk et al., giving their comments and opinion on our findings concerning differences in melanoma incidence and survival between Belgium and the Netherlands. More specifically in their interpretation of the data they stated a remarkable difference between the 610 stage IV melanoma patients during 12 years included in our study (i.e. 50 patients/year) and 700 stage IV patients registered each year by the Dutch Melanoma Treatment Registry (DMTR) .
    Keywords:  melanoma; stage IV; survival
    DOI:  https://doi.org/10.1111/jdv.17666
  2. Skinmed. 2021 ;19(4): 280-283
    Cutaneous Melanoma More Likely to Be Invasive in Fairer Skin Phototypes: A Retrospective Observational Study.
    Liam Mercieca, Susan Aquilina, Neville Calleja, Michael J Boffa.
      Fitzpatrick skin phototype is one of the factors determining melanoma development, with fairer skin phototypes I and II known to be associated with a higher risk. This study aimed to identify any associations between skin phototype and the histologic subtype, Breslow's thickness, and the site of melanoma. Patients diagnosed with melanoma for over an 18-month period were included. Data were gathered from the Malta National Cancer Registry. There were 167 registered cutaneous melanoma patients, of which 135 were included in the study. Melanomas in patients with skin phototypes I and II were more likely to be invasive than in situ when compared to patients with skin phototypes III and IV (P = 0.00027). There was also an association between skin phototype and histologic type of melanoma (P = 0.005), with melanoma in situ being the most common subtype in patients with skin type III. This study confirms that fairer skin phototypes have an increased risk of melanoma. It also shows that in our population, melanoma in skin phototypes I and II is more likely to be invasive rather than in situ compared to melanoma in darker skin phototypes. Further studies are required to confirm these findings and identify possible reasons.
  3. Int J Cancer. 2021 Sep 16.
    Tumor cell intrinsic TLR4 signaling promotes melanoma progression and metastatic dissemination.
    Meri Rogava, Andreas Dominik Braun, Tetje Cornelia van der Sluis, Naveen Shridhar, Thomas Tüting, Evelyn Gaffal.
      Most melanoma-associated deaths result from the early development of metastasis. Toll like receptor 4 (TLR4) expression on non-tumor cells is well known to contribute to tumor development and metastatic progression. The role of TLR4 expression on tumor cells however is less well understood. Here we describe TLR4 as a driver of tumor progression and metastatic spread of melanoma cells by employing a transplantable mouse melanoma model. HCmel12 melanoma cells lacking functional TLR4 showed increased sensitivity to TNF-α induced cell killing in vitro compared to cells with intact TLR4. Interestingly, TLR4 knockout melanoma cells also showed impaired migratory capacity in vitro and a significantly reduced ability to metastasize to the lungs after subcutaneous transplantation in vivo. Finally, we demonstrate that activation of TLR4 also promotes migration in a subset of human melanoma cell lines. Our work describes TLR4 as an important mediator of melanoma migration and metastasis and provides a rationale for therapeutic inhibition of TLR4 in melanoma. This article is protected by copyright. All rights reserved.
    Keywords:  TLR4; dedifferentiation; melanoma; metastasis; migration
    DOI:  https://doi.org/10.1002/ijc.33804
  4. Cancer Res. 2021 Sep 13. pii: canres.CAN-21-0164-A.2021. [Epub ahead of print]
    Protein signatures of NK cell-mediated melanoma killing predict response to immunotherapies.
    Sabrina Cappello, Hsu-Min Sung, Christian Ickes, Christine S Gibhardt, Adina Vultur, Hilal Bhat, Zhongwen Hu, Patricia Brafford, Andreas Denger, Ioana Stejerean-Todoran, Rixa-Mareike Köhn, Verena Lorenz, Nicolas Künzel, Gabriela Salinas, Hedwig Stanisz, Tobias J Legler, Peter Rehling, Michael P Schön, Karl S Lang, Volkhard Helms, Meenhard Herlyn, Markus Hoth, Carsten Kummerow, Ivan Bogeski.
      Despite impressive advances in melanoma-directed immunotherapies, resistance is common and many patients still succumb to metastatic disease. In this context, harnessing natural killer (NK) cells, which have thus far been sidelined in the development of melanoma immunotherapy, could provide therapeutic benefits for cancer treatment. To identify molecular determinants of NK cell-mediated melanoma killing (NKmK), we quantified NK cell cytotoxicity against a panel of genetically diverse melanoma cell lines and observed highly heterogeneous susceptibility. Melanoma protein microarrays revealed a correlation between NKmK and the abundance and activity of a subset of proteins, including several metabolic factors. Oxidative phoshorylation, measured by oxygen consumption rate, negatively correlated with melanoma cell sensitivity towards NKmK, and proteins involved in mitochondrial metabolism and EMT were confirmed to regulate NKmK. Two- and three-dimensional killing assays and melanoma xenografts established that the PI3K/Akt/mTOR signaling axis controls NKmK via regulation of NK cell-relevant surface proteins. A "protein-killing signature" based on the protein analysis predicted NKmK of additional melanoma cell lines and the response of melanoma patients to anti-PD-1 checkpoint therapy. Collectively, these findings identify novel NK cell-related prognostic biomarkers and may contribute to improved and personalized melanoma-directed immunotherapies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0164
  5. Mol Carcinog. 2021 Sep 13.
    Crucial role of glucosylceramide synthase in the regulation of stem cell-like cancer cells in B16F10 murine melanoma.
    Sweta Ghosh, Subir Kumar Juin, Suchandra Bhattacharyya Majumdar, Subrata Majumdar.
      Cancer stem cells render a complex cascade of events that facilitates highly invasive melanoma malignancy. Interplay between immunocytes and cancer stem cells within tumor microenvironment with the participation of sphingolipid signaling mediators skews the immune evasion strategies toward metastatic neoplasm. In this context, we aimed to explore the functional aspect of glucosylceramide synthase (GCS), a key enzyme of sphingolipid biosynthesis in the maintenance of melanoma stem cell-like cancer cells (CSCs). Our findings demonstrated that tumor hypoxia was responsible for elevated GCS expression in melanoma, which was correlated with substantially increased melanoma CSCs. Moreover, hypoxia-induced TGF-β from TAMs and Tregs promoted GCS induction in B16F10 murine melanoma CSCs via PKCα signaling and facilitated the expansion of melanoma CSCs. Interestingly, GCS ablation hindered the immunosuppressiveness of TAMs and Tregs. Therefore, our study for the first time demonstrated a novel paracrine pathway of melanoma CSC maintenance and tumorigenicity, exploiting the bidirectional signaling with immunocytes. Furthermore, our study showed that the combinatorial immunotherapy involving immunomodulators like Mw and DTA-1 repressed CSC pool affecting GCS functions in advanced-stage B16F10 murine melanoma tumor. Moreover, GCS inhibition sensitized conventional chemotherapeutic drug-resistant melanoma CSCs to the genotoxic drugs paving the way toward selective melanoma treatment. Better therapeutic efficacy with inhibition of GCS and CSC depletion suggests a crucial role of GCS in melanoma treatment, therefore, implying its application concerning clinical challenges of chemotherapy resistance leading to prolonged survival.
    Keywords:  TGF-β; cancer stem cell; glucosylceramide synthase; hypoxia; melanoma
    DOI:  https://doi.org/10.1002/mc.23347
  6. Melanoma Res. 2021 Sep 13.
    Retrospective analysis of adjuvant therapy using dabrafenib plus trametinib in Japanese patients with advanced melanoma: analysis of 36 cases.
    Ryo Amagai, Yusuke Muto, Hiroshi Kato, Shigeto Matsushita, Takeo Maekawa, Satoshi Fukushima, Koji Yoshino, Hiroshi Uchi, Yasuhiro Fujisawa, Yuki Yamamoto, Kentaro Ohuchi, Yumi Kambayashi, Taku Fujimura.
      Patients with resected stage IIIB, IIIC and IIID melanomas have a high risk of recurrence. Therefore, an appropriate protocol for stage III melanoma is needed. Since adjuvant dabrafenib plus trametinib (D+T) combined therapy and anti-PD1 antibody (Ab) therapy reduce the risk of recurrence in patients with resected stage III BRAF-mutated melanoma, selecting the adjuvant therapy for BRAF-mutated melanoma is controversial. The efficacy and safety profiles of D+T combined therapy in the adjuvant setting were retrospectively analyzed in 36 Japanese. BRAF-mutated advanced melanoma patients. The relapse-free rate (RFR) at 12 months was 82.1% (95% confidential interval (CI), 63.9-92.6%). In the 21 patients who completed the protocol, the RFR at 12 months was 85.7% (95% CI, 64.5-95.9%). In the seven patients whose protocol was interrupted by adverse events, the RFR was 71.4% (95% CI, 35.2-92.4%). The incidence rate of any AEs for all patients was 69.7% (95% CI, 52.5-82.8%), including 13 cases of pyrexia, five cases of skin rash and four cases of liver dysfunction. The present study suggested that D+T therapy in the adjuvant setting is a useful and very tolerable protocol for BRAF-mutated melanoma in the Japanese population.
    DOI:  https://doi.org/10.1097/CMR.0000000000000770
  7. Mol Ther Oncolytics. 2021 Sep 24. 22 219-231
    Non-coding RNAs in melanoma: Biological functions and potential clinical applications.
    Qiu Peng, Jia Wang.
      Malignant melanoma (MM) is a malignant tumor that originates from melanocytes and has a high mortality rate. Therefore, early diagnosis and treatment are very important for survival. So far, the exact molecular mechanism leading to the occurrence of melanoma, especially the molecular metastatic mechanism, remains largely unknown. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNA (circRNAs), have been investigated and found to play vital roles in regulating tumor occurrence and development, including melanoma. In this review, we summarize the progress of recent research on the effects of ncRNAs on melanoma and attempt to elucidate the role of ncRNAs as molecular markers or potential targets that will provide promising application perspectives on melanoma.
    Keywords:  circRNAs; lncRNAs; melanoma; microRNAs; non-coding RNAs
    DOI:  https://doi.org/10.1016/j.omto.2021.05.012
  8. Oncoimmunology. 2021 ;10(1): 1968611
    "Suffocating" tumors by blocking adaptation to hypoxia: a new headway in melanoma immunotherapy.
    Bassam Janji, Salem Chouaib.
      We recently reported that inhibiting Hypoxia-inducible Factor-1α (Hif1a) transcriptional activity improves melanoma immunotherapy by driving immune cells into the tumor microenvironment (TME). This Author's View provides additional perspectives on how hypoxia inhibitors combined with immunotherapy can be used as innovative approaches to improve the therapeutic benefit of melanoma patients.
    Keywords:  CCL5/Rantes; CD8 T-lymphocytes; Hypoxia; NK cells; anti-PD-1/PD-L1; cancer immunotherapy; chemokines; cold/hot tumors; hypoxia-inducible factor; immune landscape; melanoma
    DOI:  https://doi.org/10.1080/2162402X.2021.1968611
  9. Sci Rep. 2021 Sep 15. 11(1): 18405
    PITX1 inhibits the growth and proliferation of melanoma cells through regulation of SOX family genes.
    Takahito Ohira, Suguru Nakagawa, Jumpei Takeshita, Hiroyuki Aburatani, Hiroyuki Kugoh.
      Melanoma is one of the most aggressive types of cancer wherein resistance to treatment prevails. Therefore, it is important to discover novel molecular targets of melanoma progression as potential treatments. Here we show that paired-like homeodomain transcription factor 1 (PITX1) plays a crucial role in the inhibition of melanoma progression through regulation of SRY-box transcription factors (SOX) gene family mRNA transcription. Overexpression of PITX1 in melanoma cell lines resulted in a reduction in cell proliferation and an increase in apoptosis. Additionally, analysis of protein levels revealed an antagonistic cross-regulation between SOX9 and SOX10. Interestingly, PITX1 binds to the SOX9 promoter region as a positive regulatory transcription factor; PITX1 mRNA expression levels were positively correlated with SOX9 expression, and negatively correlated with SOX10 expression in melanoma tissues. Furthermore, transcription of the long noncoding RNA (lncRNA), survival-associated mitochondrial melanoma-specific oncogenic noncoding RNA (SAMMSON), was decreased in PITX1-overexpressing cells. Taken together, the findings in this study indicate that PITX1 may act as a negative regulatory factor in the development and progression of melanoma via direct targeting of the SOX signaling.
    DOI:  https://doi.org/10.1038/s41598-021-97791-6
  10. Front Vet Sci. 2021 ;8 633170
    COX-2 Silencing in Canine Malignant Melanoma Inhibits Malignant Behaviour.
    Tatiany L Silveira, Lisa Y Pang, Alexandra Di Domenico, Emerson S Veloso, Istéfani L D Silva, Helen L Del Puerto, Enio Ferreria, David J Argyle.
      Metastatic melanoma is a very aggressive form of cancer in both humans and dogs. Dogs primarily develop oral melanoma of mucosal origin. Although oral melanoma in humans is rare, both diseases are highly aggressive with frequent metastases. This disease represents a "One Health" opportunity to improve molecular and mechanistic understanding of melanoma progression. Accumulating evidence suggests that cyclooxygenase-2 (COX-2) may play a critical role in the malignant behaviour of melanoma. In this study we analysed 85 histologically confirmed melanomas from canine patients and showed that COX-2 is overexpressed in both oral and cutaneous melanomas and that COX-2 expression correlates with established markers of poor prognosis. To determine the role of COX-2 in melanoma we developed two melanoma cell lines with stable integration of an inducible doxycycline-regulated expression vector containing a COX-2 targeted micro-RNA (miRNA). Using this system, we showed that cellular proliferation, migration and invasion are COX-2 dependent, establishing a direct relationship between COX-2 expression and malignant behaviour in canine melanoma. We have also developed a powerful molecular tool to aid further dissection of the mechanisms by which COX-2 regulates melanoma progression.
    Keywords:  COX-2; canine; malignant; melanoma; one health
    DOI:  https://doi.org/10.3389/fvets.2021.633170
  11. J Immunother. 2021 Sep 13.
    The Prognostic Significance of Baseline Neutrophil-to-Lymphocyte Ratio in Melanoma Patients Receiving Immunotherapy.
    Yayun Li, Yu Meng, Huiyan Sun, Lin Ye, Furong Zeng, Xiang Chen, Guangtong Deng.
      Immunotherapy has revolutionized the treatment in metastatic melanoma, but alternative biomarkers that are economical, simple and reliable still need to be clarified. In this study, we aimed to comprehensively analyze the prognostic significance of baseline neutrophil-to-lymphocyte ratio (NLR) in melanoma patients with immunotherapy. We searched PubMed, Embase, and Cochrane Library until September 16, 2020. Hazard ratio (HR) and 95% confidence intervals (CIs) were pooled to investigate the association of baseline NLR with overall survival (OS) and progression-free survival (PFS). Sensitivity analysis, subgroup analyses, publication bias assessment, and the Duval and Tweedie trim-and-fill method were used to evaluate the stability of results. A total of 18 studies including 2054 patients were included in our analysis. Pooled data demonstrated that higher baseline NLR was associated with a poorer OS (HR=2.46, 95% CI=1.77, 3.43) and PFS (HR=2.38, 95% CI=1.95, 2.89) of melanoma patients receiving immunotherapy. Subgroup analysis according to immunotherapy type showed that the prognostic effects of baseline NLR existed in all the subtypes of immunotherapy, including anticytotoxic T lymphocyte-associated protein 4 therapy (OS HR=2.26, 95% CI=1.43, 3.59; PFS HR=2.68, 95% CI=1.79, 4.02), antiprogrammed cell death-1 therapy (OS HR=3.08, 95% CI=2.21, 4.27; PFS HR=2.01, 95% CI=1.64, 2.47), and combination therapy (OS HR=1.75, 95% CI=1.13, 2.72; PFS HR=3.13, 95% CI=1.63, 6.03). Conclusions were still consistent in subgroup analyses stratified by study year, region, study type, sample size, analysis of HR and cuttoff of baseline NLR. Altogether, baseline NLR is a promising prognostic biomarker for melanoma patients receiving immunotherapy.
    DOI:  https://doi.org/10.1097/CJI.0000000000000392
  12. Oncology (Williston Park). 2021 Sep 16. 35(9): 562-566
    Oligoprogression After Immunotherapy and Targeted Therapy in Metastatic Melanoma.
    Nora Sobrevilla-Moreno, Daniel Rivera-Sánchez, Dorian García-Ortega, Diego López-Macías, Alexandra Garcilazo-Reyes, Miguel Álvarez-Avitia.
      
    DOI:  https://doi.org/10.46883/ONC.2021.3509.0562
  13. Int J Gen Med. 2021 ;14 5221-5232
    Primary Sites of Uveal Melanoma Associated with Distinct Survival Outcomes and Clinicopathological Features: A SEER Population-Based Study of 4359 Cases.
    Xin Liang, Yan Rong, Junming Wang, Hong Zhang.
       Objective: We sought to investigate clinicopathological characteristics correlated with the prognosis of uveal melanoma (UM) patients and find the driving factors of prognosis for ciliary/iris melanoma relative to choroid melanoma.
    Materials and Methods: We collected patients with uveal melanoma between 1983 and 2012 from the Surveillance, Epidemiology, and End Results (SEER) database. Primary outcomes were evaluated as cancer-specific survival (CSS) and overall survival (OS). The Kaplan-Meier analysis was applied for the univariate analysis of CSS and OS and corresponding survival curves. Cox proportional hazards regression was used for multivariate analysis to value hazard ratio (HR) of ciliary body/iris melanoma subgroup versus choroid melanoma subgroup.
    Results: A total of 4359 eligible patients were collected in our study. Novel potential prognostic factors for CSS and OS of UM were identified. Age at diagnosis, sex, primary tumor site, histologic subtype, tumor size, the extent of disease, and treatment were the independent prognostic factors for UM patients (P < 0.05). Interestingly, when concerned with the primary site of UM, we found that the ciliary body/iris melanoma subgroup showed significant differences in prognosis (both CSS and OS), sex, histologic type, the extent of disease, and treatment options relative to choroid melanoma subgroup (P < 0.05). Subsequently, stratification analyses suggested that the distinct survival outcomes between the ciliary body/iris melanoma and choroid melanoma subgroups mainly attributed to patient sex, age, tumor size, the extent of disease, and treatment options (P < 0.05).
    Conclusion: Age, sex, primary tumor site, histologic subtype, tumor size, the extent of disease, and treatment options are independent prognostic indicators for UM patients. Besides, the ciliary body/iris melanoma subgroup shows worse survival outcomes than choroid melanoma. Our findings offer inspiration to the individual treatment for UM patients with different primary sites.
    Keywords:  cancer-specific survival; choroid melanoma; ciliary body/iris melanoma; overall survival; uveal melanoma
    DOI:  https://doi.org/10.2147/IJGM.S328910
  14. Ann Surg Oncol. 2021 Sep 15.
    Prognosis in Thin Melanoma Patients: Is Slightly Less Than Excellent Still Okay?
    Michael E Egger.
      
    DOI:  https://doi.org/10.1245/s10434-021-10772-x
  15. Ir Med J. 2021 08 19. 114(7): 402
    Cutaneous Melanoma and Sentinel Lymph Node Biopsy; An Epidemiology Study of Population Level Data.
    L Scanlon, A J P Clover.
      Aims Cutaneous melanoma accounts for 90% of all melanoma cases diagnosed. In addition, the incidence of cutaneous melanoma is increasing by approximately 3-7% yearly, and it is the most rapidly increasing cancer diagnosed in white populations worldwide. The aim of this study is to assess the survival benefit of Sentinel Lymph Node Biopsy (SLNB) in cutaneous melanoma in an Irish population. Methods Population based data was obtained from the National Cancer Registry of Ireland (NCRI) on all patients with a cutaneous melanoma diagnosed over a 20-year period 1994-2014 and predictors of Overall Survival (OS) were assessed. Results 13302 patients were identified with a melanoma diagnosis between 1994-2014. OS varied with gender, age, smoking and marital status, anatomical location and TMN stage. 2196 (17%) patients underwent SLNB, which included 710 patients in the stage 1 melanoma category (<11% of this group). Undergoing a SLNB was not an independent predictor of improved OS (p=0.440). However, a positive SLNB result was an independent predictor of OS (0.001). Conclusion This Irish population-based data re-affirms demographic indicators of poorer survival. A positive SLNB result indicates poorer survival; however, the precedent itself is not a predictor of OS.
  16. Cancer Lett. 2021 Sep 13. pii: S0304-3835(21)00462-6. [Epub ahead of print]
    METTL3 induces PLX4032 resistance in melanoma by promoting m6A-dependent EGFR translation.
    Poshan Yugal Bhattarai, Garam Kim, Muna Poudel, Sung-Chul Lim, Hong Seok Choi.
      Acquired resistance often limits therapeutic efficacy of the BFAF (V600E) kinase inhibitor PLX4032 in patients with advanced melanoma. Epitranscriptomic modification of mRNAs by N (Vasan et al., 2019) [6]-methyladenosine (m6A) modification contributes to melanoma pathogenesis; however, its role in acquired PLX4032 resistance remains unexplored. Here, we showed that m6A methyltransferase METTL3 expression is upregulated in A375R cells, a PLX4032-resistant subline of A375 melanoma cells, compared with the parental cells. Moreover, METTL3 increased the m6A modification of epidermal growth factor receptor (EGFR) mRNA in A375R cells, which promoted its translation efficiency. In turn, increased EGFR expression facilitated rebound activation of the RAF/MEK/ERK pathway in A375R cells, inducing PLX4032 resistance. In contrast, knockout of METTL3 in A375R cells reduced EGFR expression and restored PLX4032 sensitivity. PLX4032 treatment following METTL3 knockout induced apoptosis and reduced colony formation in A375R cells and reduced A375R cell-derived tumor growth in BALB/c nude mice. These findings indicate that METTL3 promotes rebound activation of the RAF/MEK/ERK pathway through EGFR upregulation and highlight a critical role for METTL3-induced m6A modification in acquired PLX4032 resistance in melanoma, implicating METTL3 as a potential candidate for targeted chemotherapy.
    Keywords:  Acquired resistance; Epitranscriptomic modification; N(6)-methyladenosine; RAF/MEK/ERK pathway
    DOI:  https://doi.org/10.1016/j.canlet.2021.09.015
  17. Bioengineered. 2021 Dec;12(1): 6448-6458
    Carboplatin activates the cGAS-STING pathway by upregulating the TREX-1 (three prime repair exonuclease 1) expression in human melanoma.
    Zhourui Ma, Qianwei Xiong, Hongliang Xia, Wei Liu, Shu Dai, Shizhong Cai, Zhenhong Zhu, Xiangming Yan.
      Human melanoma is a highly aggressive type of cancer, causing significant mortalities despite the advances in treatment. Carboplatin is a cisplatin analog necessary for the treatment of various cancers and can also be used to treat human melanoma. We assessed the effects and mechanisms leading to inhibited proliferation and induced apoptosis of human melanoma after carboplatin therapy in vitro and in vivo. TREX1, cGAS/STING, and apoptotic protein expressions were determined through RT-qPCR and western blot assays. Cell proliferation was validated through MTT assays. The study used SK-MEL-1 and SK-HEP-1 tumor cell line inoculations along with carboplatin in nude mice to validate the results. The TREX1 levels were down-regulated in human melanoma cell lines. TREX1 overexpression-induced apoptosis and decreased proliferation in the human melanoma cell lines. TREX1 overexpression also activated the cGAS/STING pathway to induce apoptosis and decrease cell growth. Carboplatin activated TREX1, induced apoptosis, and decreased proliferation in the human melanoma cancerous cell lines. Finally, carboplatin reduced the in-vivo tumor size and weight. In conclusion, the study revealed that carboplatin activated TREX1 and cGAS/STING pathways to upregulate apoptosis. The work also provides in vitro and in vivo evidence to understand the effects of TREX overexpression on tumor suppression. Targeting of TREX1/cGAS/STING pathway could be an effective therapeutic alternative to human melanoma.
    Keywords:  Apoptosis; carboplatin; metastatic melanoma; stimulator of interferon genes (STING); three-prime repair exonuclease 1 (TREX1)
    DOI:  https://doi.org/10.1080/21655979.2021.1972198
  18. Front Genet. 2021 ;12 723796
    Prognostic Value and Immunological Characteristics of a Novel RNA Binding Protein Signature in Cutaneous Melanoma.
    Jun Tian, Chongzhi Ma, Li Yang, Yang Sun, Yuan Zhang.
       Background: The existing studies indicate that RNA binding proteins (RBPs) are closely correlated with the genesis and development of cancers. However, the role of RBPs in cutaneous melanoma remains largely unknown. Therefore, the present study aims to establish a reliable prognostic signature based on RBPs to distinguish cutaneous melanoma patients with different prognoses and investigate the immune infiltration of patients.
    Methods: After screening RBPs from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, Cox and least absolute shrinkage and selection operator (LASSO) regression analysis were then used to establish a prediction model. The relationship between the signature and the abundance of immune cell types, the tumor microenvironment (TME), immune-related pathways, and immune checkpoints were also analyzed.
    Results: In total, 7 RBPs were selected to establish the prognostic signature. Patients categorized as a high-risk group demonstrated worse overall survival (OS) rates compared to those of patients categorized as a low-risk group. The signature was validated in an independent external cohort and indicated a promising prognostic ability. Further analysis indicated that the signature wasan independent prognostic indicator in cutaneous melanoma. A nomogram combining risk score and clinicopathological features was then established to evaluate the 3- and 5-year OS in cutaneous melanoma patients. Analyses of immune infiltrating, the TME, immune checkpoint, and drug susceptibility revealed significant differences between the two groups. GSEA analysis revealed that basal cell carcinoma, notch signaling pathway, melanogenesis pathways were enriched in the high-risk group, resulting in poor OS.
    Conclusion: We established and validated a robust 7-RBP signature that could be a potential biomarker to predict the prognosis and immunotherapy response of cutaneous melanoma patients, which provides new insights into cutaneous melanoma immunotherapeutic strategies.
    Keywords:  cutaneous melanoma; immune cell infiltration; prognosis; prognostic signature; tumor microenvironment
    DOI:  https://doi.org/10.3389/fgene.2021.723796
  19. Cancer Sci. 2021 Sep 17.
    LncRNA BASP1-AS1 interact with YBX1 to regulate Notch transcription and drives the malignancy of melanoma.
    YaLing Li, YaLi Gao, XueLi Niu, MingSui Tang, JingYi Li, Bing Song, XiuHao Guan.
      Melanoma is a fatal skin malignant tumor with a poor prognosis, we found that LncRNA BASP1-AS1 is essential for the development and prognosis of melanoma. Firstly, the methylation, RNA-Seq, CNV, mutation data, and sample follow-up information of melanoma from TCGA were analyzed using WGCNA and selected 366 samples common to the three omics for multi-group clustering analysis. Then a 4-gene prognostic model (BASP1-AS1, LOC100506098, ARHGAP27P1, and LINC01532) was constructed in the TCGA cohort and validated using the GSE65904 series. The expression of BASP1-AS1 was up-regulated in melanoma tissues and various melanoma cell lines. Functionally, the ectopic expression of BASP1-AS1 promoted cell proliferation, migration, and invasion in both A375 and SK-MEL-2 cells. Mechanically, BASP1-AS1 interacted with YBX1 and recruited it to the promoter of NOTCH3, initiating its transcription process. The activation of the Notch signaling then resulted in the transcription of multiple oncogenes, including c-MYC, PCNA, CDK4, which contributed to melanoma progression. Thus, BASP1-AS1 could act as a potential biomarker for cutaneous malignant melanoma.
    Keywords:  BASP1-AS1; NOTCH3; YBX1; melanoma; signature
    DOI:  https://doi.org/10.1111/cas.15140
  20. Lancet. 2021 Sep 11. pii: S0140-6736(21)01206-X. [Epub ahead of print]398(10304): 1002-1014
    Immune checkpoint inhibitors in melanoma.
    Matteo S Carlino, James Larkin, Georgina V Long.
      Immune checkpoint inhibitors target the dysfunctional immune system, to induce cancer-cell killing by CD8-positive T cells. Immune checkpoint inhibitors, specifically anti-CTLA4 and anti-PD-1 antibodies, have revolutionised the management of many cancers, particularly advanced melanoma, for which tumour regression and long-term durable cancer control is possible in nearly 50% of patients, compared with less than 10% historically. Despite the absence of adequately powered trial data, combined anti-CTLA4 and anti-PD-1 checkpoint inhibition has the highest 5-year overall survival rate of all therapies in advanced melanoma, and has high activity in melanoma brain metastases. A phase 3 study has shown the addition of an anti-LAG3 antibody to nivolumab improves progression-free survival, but its effect on overall survival and how this combination compares to combined anti-CTLA4 and anti-PD-1 checkpoint inhibition is unknown. At present, there are no highly sensitive and specific biomarkers of response to immune checkpoint inhibitors, and clinical factors, such as volume and sites of disease, serum lactate dehydrogenase, and BRAF mutation status, are used to select initial therapy for patients with advanced melanoma. Immune checkpoint inhibitors can induce autoimmune toxicities by virtue of their mechanism of action. These toxicities, termed immune-related adverse events, occur most frequently with combined anti-CTLA4 and anti-PD-1 checkpoint inhibition; can have a variety of presentations; can affect any organ system (most often the skin, colon, endocrine system, and liver); and appear to mimic classic autoimmune diseases. Immune-related adverse events require prompt recognition and management, which may be different from the autoimmune disease it mimics. Immune checkpoint inhibitors appear to be safe for use in patients with HIV, viral hepatitis, and patients with mild-to-moderate pre-existing autoimmune diseases. Patients with organ transplants can respond to immune checkpoint inhibitors but have a high chance of transplant loss. PD-1 inhibitors are now an established standard of care as adjuvant therapy in high-risk resected stage III or IV melanoma. Neoadjuvant checkpoint inhibition for resectable stage III melanoma, which is currently limited to clinical trials, is emerging as a highly effective therapy.
    DOI:  https://doi.org/10.1016/S0140-6736(21)01206-X
  21. Cancer Gene Ther. 2021 Sep 14.
    Overexpression of microRNA-130a represses uveal melanoma cell migration and invasion through inactivation of the Wnt/β-catenin signaling pathway by downregulating USP6.
    Shuai Wu, Mei Han, Chao Zhang.
      Uveal melanoma (UM) is a neoplasm arising from melanocytes of the ciliary body, choroid, and iris of the eye, which is the most common primary malignant intraocular tumor. microRNA-130a (miR-130a) has been confirmed to be underexpressed in many types of cancers. Here we aimed to investigate the mechanism whereby miR-130a affects the Wnt/β-catenin signaling pathway by targeting ubiquitin-specific protease 6 (USP6) in UM. Ocular specimens of 62 patients with UM and 42 participants subjected to enucleation due to trauma were collected. In the normal uveal tissues and those from metastatic and non-metastatic UM, we evaluated miR-130a expression by RT-qPCR and then measured mRNA and protein expression of recombinant human mothers against decapentaplegic homolog 4 (SMAD4), USP6, related factors of the Wnt/β-catenin signaling pathway, and epidermal growth factor receptor (EGFR) by RT-qPCR and western blot analysis. Subsequently, the interaction between miR-130a and USP6 was identified by bioinformatics analysis and dual-luciferase reporter gene assay. Next, UM cell migration and invasion abilities, as well as tumor growth in nude mice, were measured through gain- and loss-of-function studies of miR-130a and USP6. miR-130a expression was downregulated in uveal tissues from patients with UM, especially in metastatic uveal tissues. The overall survival of UM patients with low miR-130a expression was shorter than those with high miR-130a expression. USP6 was a target of miR-130a and the overexpression of miR-130a or inhibition of USP6 in UM MUM-2B and MUM-2C cell lines inhibited the expression of Wnt, β-catenin, and EGFR, and activated SMAD4 expression, while reducing UM cell migration and invasion abilities in vitro. The above changes could be reversed by overexpressing USP6 in vitro, whereas overexpressed miR-130a could inhibit the tumor growth in nude mice. Taken together, overexpressed miR-130a inhibited USP6 expression to repress UM cell migration and invasion abilities through inactivating the Wnt/β-catenin signaling pathway, which could be a potential candidate for treatment of UM.
    DOI:  https://doi.org/10.1038/s41417-021-00377-7
  22. Math Biosci Eng. 2021 Jun 08. 18(5): 5125-5145
    Prognostic score model-based signature genes for predicting the prognosis of metastatic skin cutaneous melanoma.
    Jiaping Wang.
       PURPOSE: Cutaneous melanoma (SKCM) is the most invasive malignancy of skin cancer. Metastasis to distant lymph nodes or other system is an indicator of poor prognosis in melanoma patients. The aim of this study was to identify reliable prognostic biomarkers for SKCMs.
    METHODS: Four RNA-sequencing datasets associated with SKCMs were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database as well as corresponding clinical information. Differentially expressed genes (DEGs) were screened between primary and metastatic samples by using MetaDE tool. Weighted gene co-expression network analysis (WGCNA) was conducted to screen functional modules. A prognostic score (PS)-based predictive model and nomogram model were constructed to identify signature genes and independent clinicopathologic factors.
    RESULTS: Based on MetaDE analysis and WGCNA, a total of 456 overlapped genes were identified as hub genes related to SKCMs progression. Functional enrichment analysis revealed these genes were mainly involved in the hippo signaling pathway, signaling pathways regulating pluripotency of stem cells, pathways in cancer. In addition, eight optimal DEGs (RFPL1S, CTSV, EGLN3, etc.) were identified as signature genes by using PS model. Cox regression analysis revealed that pathologic stage T, N and recurrence were independent prognostic factors. Three clinical factors and PS status were incorporated to construct a nomogram predictive model for estimating the three years and five-year survival probability of individuals.
    CONCLUSIONS: The prognosis prediction model of this study may provide a promising method for decision making in clinic and prognosis predicting of SKCM patients.
    Keywords:   WGCNA ; cutaneous melanoma ; metastasis ; nomogram model ; prognosis
    DOI:  https://doi.org/10.3934/mbe.2021261
  23. Pituitary. 2021 Sep 13.
    Primary sellar melanocytoma.
    M Claus, M Van Der Linden, J Van Dorpe, B Lapauw, G T'Sjoen.
       PURPOSE: We present an up-to-date review of all published cases of sellar melanocytoma, a benign melanocytic neoplasm arising from melanocytes present in the leptomeninges surrounding the pituitary.
    METHODS: Both the Medline and Embase databases were searched for case reports or case series of patients with a sellar mass consisting of melanocytes.
    RESULTS: All 14 identified patients developed symptoms due to compression of the surrounding structures. Symptoms included pituitary dysfunction and visual impairment. All patients received a transsphenoidal resection as first-line treatment. The diagnosis is made on pathological examination but deciding whether a sellar melanocytic tumor is best classified as a melanocytoma or a melanoma is not straightforward.
    DISCUSSION: Genetic analyses can help differentiate between central nervous system origin and metastasis of a cutaneous melanoma with the presence of a GNAQ and GNA11 mutations or a BRAF mutation, respectively. First choice treatment is complete resection, and in case of incomplete resection or recurrence additional radiotherapy is advised.
    Keywords:  Leptomeninges; Pituitary tumor; Sellar melanocytoma; Transsphenoidal surgery
    DOI:  https://doi.org/10.1007/s11102-021-01186-9
  24. J Surg Oncol. 2021 Sep 17.
    The changing landscape in management of desmoplastic melanoma.
    Jonathan A Dunne, George Adigbli.
      
    DOI:  https://doi.org/10.1002/jso.26677
  25. J Vet Med Sci. 2021 Sep 15.
    Three neoplasms in a Eurasian otter (Lutra lutra): malignant melanoma, trichoblastoma and mammary gland adenoma.
    Naoyuki Fuke, Nguyen Van Diep, Takuya Hirai, Mathurot Suwanruengsri, Uda Zahli Izzati, Ryoji Yamaguchi.
      An eighteen-year-old female Eurasian otter became emaciated and died. Necropsy examination revealed nose and thoracic cutaneous masses, abdominal subcutaneous mass, and multiple nodules in the liver and lungs. Malignant melanoma was found in the nose cutaneous mass and to have metastasized to the liver, lungs, kidneys, adrenal glands, mammary glands and left mandibular lymph node. The neoplastic cells were labeled for vimentin, melanoma, and S100. The cutaneous mass in the thoracic area consisted of spindle shaped neoplastic epithelial cells and was diagnosed as trichoblastoma. Mammary gland adenoma was observed in the abdominal subcutaneous mass. This is the first report of primary three neoplasms of malignant melanoma, trichoblastoma and mammary gland adenoma in a Eurasian otter.
    Keywords:  Eurasian otter; malignant melanoma; spindle cell trichoblastoma; triple neoplasms
    DOI:  https://doi.org/10.1292/jvms.21-0279
  26. Front Cell Dev Biol. 2021 ;9 713569
    Identification of Immune Cell Infiltration Landscape and Their Prognostic Significance in Uveal Melanoma.
    Han Zhao, Yun Chen, Peijun Shen, Lan Gong.
      Uveal melanoma (UVM) is the most common primary intraocular cancer in adults. Increasing evidence has demonstrated that immune cell infiltration (ICI) is crucial in predicting patient outcomes and therapeutic efficacy. Thus, describing the immune cell infiltrative landscape of UVM tumors may yield a novel prognostic marker and provide direction for immunotherapeutic selection. In this study, the gene expression data and clinical information of UVM patients were obtained from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. The ICI landscape of UVM was analyzed using the CIBERSORT and ESTIMATE algorithms. Two ICI phenotypes were defined, and the ICI scores were calculated by using principal component analysis algorithms. We found that a subtype with high ICI scores had poorer prognosis and increased expression levels of immune checkpoint-related genes. This study demonstrates that ICI scores are an independent prognostic biomarker and highlights their value in predicting immunotherapeutic outcomes.
    Keywords:  ICI scores; immune cell infiltration; immunotherapy; prognosis; tumor microenvironment; uveal melanoma
    DOI:  https://doi.org/10.3389/fcell.2021.713569
  27. Int J Cancer. 2021 Sep 14.
    Discontinuation of anti-PD-1 monotherapy in advanced melanoma - outcomes of daily clinical practice.
    Michiel C T van Zeijl, Alfons J M van den Eertwegh, Michel W J M Wouters, Liesbeth C de Wreede, Maureen J B Aarts, Franchette W P J van den Berkmortel, Jan-Willem B de Groot, Geke A P Hospers, Ellen Kapiteijn, Djura Piersma, Rozemarijn S van Rijn, Karijn P M Suijkerbuijk, Albert J Ten Tije, Astrid A M van der Veldt, Gerard Vreugdenhil, Jacobus J M van der Hoeven, John B A G Haanen.
      
    Keywords:  Discontinuation; advanced melanoma; anti-PD-1; immunotherapy; real-world
    DOI:  https://doi.org/10.1002/ijc.33800
  28. Front Pharmacol. 2021 ;12 720619
    The Downregulation of eIF3a Contributes to Vemurafenib Resistance in Melanoma by Activating ERK via PPP2R1B.
    Shi-Long Jiang, Zhi-Bin Wang, Tao Zhu, Ting Jiang, Jiang-Feng Fei, Chong Liu, Chao Luo, Yan Cheng, Zhao-Qian Liu.
      Vemurafenib, a BRAF V600E inhibitor, provides therapeutic benefits for patients with melanoma, but the frequent emergence of drug resistance remains a challenge. An understanding of the mechanisms underlying vemurafenib resistance may generate novel therapeutic strategies for patients with melanoma. Here, we showed that eIF3a, a translational regulatory protein, was an important mediator involved in vemurafenib resistance. eIF3a was expressed at significantly lower levels in vemurafenib-resistant A375 melanoma cells (A375R) than in parental A375 cells. Overexpression of eIF3a enhanced the sensitivity to BRAF inhibitors by reducing p-ERK levels. Furthermore, eIF3a controlled ERK activity by regulating the expression of the phosphatase PPP2R1B via a translation mechanism, thus determining the sensitivity of melanoma cells to vemurafenib. In addition, a positive correlation between eIF3a and PPP2R1B expression was also observed in tumor samples from the Human Protein Atlas and TCGA databases. In conclusion, our studies reveal a previously unknown molecular mechanism of BRAF inhibitor resistance, which may provide a new strategy for predicting vemurafenib responses in clinical treatment.
    Keywords:  ERK; PPP2R1B; eIF3a; melanoma; vemurafenib resistance
    DOI:  https://doi.org/10.3389/fphar.2021.720619
  29. Immunity. 2021 Sep 14. pii: S1074-7613(21)00351-4. [Epub ahead of print]54(9): 2117-2132.e7
    Resident memory CD8+ T cells in regional lymph nodes mediate immunity to metastatic melanoma.
    Aleksey K Molodtsov, Nikhil Khatwani, Jennifer L Vella, Kathryn A Lewis, Yanding Zhao, Jichang Han, Delaney E Sullivan, Tyler G Searles, Nicholas K Preiss, Tamer B Shabaneh, Peisheng Zhang, Aaron R Hawkes, Brian T Malik, Fred W Kolling, Edward J Usherwood, Sandra L Wong, Joseph D Phillips, Keisuke Shirai, Christina V Angeles, Shaofeng Yan, Tyler J Curiel, Yina H Huang, Chao Cheng, Mary Jo Turk.
      The nature of the anti-tumor immune response changes as primary tumors progress and metastasize. We investigated the role of resident memory (Trm) and circulating memory (Tcirm) cells in anti-tumor responses at metastatic locations using a mouse model of melanoma-associated vitiligo. We found that the transcriptional characteristics of tumor-specific CD8+ T cells were defined by the tissue of occupancy. Parabiosis revealed that tumor-specific Trm and Tcirm compartments persisted throughout visceral organs, but Trm cells dominated lymph nodes (LNs). Single-cell RNA-sequencing profiles of Trm cells in LN and skin were distinct, and T cell clonotypes that occupied both tissues were overwhelmingly maintained as Trm in LNs. Whereas Tcirm cells prevented melanoma growth in the lungs, Trm afforded long-lived protection against melanoma seeding in LNs. Expanded Trm populations were also present in melanoma-involved LNs from patients, and their transcriptional signature predicted better survival. Thus, tumor-specific Trm cells persist in LNs, restricting metastatic cancer.
    Keywords:  CD69; CD8 T cells; CXCR6; Cancer; TCR; TRP-2; Trm; parabiosis; scRNA-seq; vitiligo
    DOI:  https://doi.org/10.1016/j.immuni.2021.08.019
  30. iScience. 2021 Sep 24. 24(9): 103022
    Cellular senescence promotes cancer metastasis by enhancing soluble E-cadherin production.
    Koichiro Kawaguchi, Kaori Komoda, Ryuta Mikawa, Azusa Asai, Masataka Sugimoto.
      Cellular senescence acts as a potent tumor-suppression mechanism in mammals; however, it also promotes tumor progression in a non-cell-autonomous manner. We provided insights into the mechanism underlying senescence-dependent metastatic cancer development. The elimination of senescent cells suppressed the lung metastasis of melanoma cells. Using an antibody array screening of humoral factor(s) that depend on cellular senescence, we identified soluble E-cadherin (seCad) as a potential mediator of the senescence-induced melanoma metastasis. seCad enhanced the invasive activity of melanoma cells both in vitro and in vivo, and gene expression profiling revealed that seCad induced genes associated with poor prognosis in patients with melanoma. An analysis of sera from patients revealed that serum seCad is associated with distant metastasis. Our data suggest that senescent cells promote metastatic lung cancer through seCad, and that seCad may be a potential diagnostic marker as well as a therapeutic target for metastatic lung cancer.
    Keywords:  cancer; cell biology
    DOI:  https://doi.org/10.1016/j.isci.2021.103022
  31. Eur J Cancer. 2021 Sep 08. pii: S0959-8049(21)00444-5. [Epub ahead of print]156 202-216
    Skin cancer classification via convolutional neural networks: systematic review of studies involving human experts.
    Sarah Haggenmüller, Roman C Maron, Achim Hekler, Jochen S Utikal, Catarina Barata, Raymond L Barnhill, Helmut Beltraminelli, Carola Berking, Brigid Betz-Stablein, Andreas Blum, Stephan A Braun, Richard Carr, Marc Combalia, Maria-Teresa Fernandez-Figueras, Gerardo Ferrara, Sylvie Fraitag, Lars E French, Frank F Gellrich, Kamran Ghoreschi, Matthias Goebeler, Pascale Guitera, Holger A Haenssle, Sebastian Haferkamp, Lucie Heinzerling, Markus V Heppt, Franz J Hilke, Sarah Hobelsberger, Dieter Krahl, Heinz Kutzner, Aimilios Lallas, Konstantinos Liopyris, Mar Llamas-Velasco, Josep Malvehy, Friedegund Meier, Cornelia S L Müller, Alexander A Navarini, Cristián Navarrete-Dechent, Antonio Perasole, Gabriela Poch, Sebastian Podlipnik, Luis Requena, Veronica M Rotemberg, Andrea Saggini, Omar P Sangueza, Carlos Santonja, Dirk Schadendorf, Bastian Schilling, Max Schlaak, Justin G Schlager, Mildred Sergon, Wiebke Sondermann, H Peter Soyer, Hans Starz, Wilhelm Stolz, Esmeralda Vale, Wolfgang Weyers, Alexander Zink, Eva Krieghoff-Henning, Jakob N Kather, Christof von Kalle, Daniel B Lipka, Stefan Fröhling, Axel Hauschild, Harald Kittler, Titus J Brinker.
       BACKGROUND: Multiple studies have compared the performance of artificial intelligence (AI)-based models for automated skin cancer classification to human experts, thus setting the cornerstone for a successful translation of AI-based tools into clinicopathological practice.
    OBJECTIVE: The objective of the study was to systematically analyse the current state of research on reader studies involving melanoma and to assess their potential clinical relevance by evaluating three main aspects: test set characteristics (holdout/out-of-distribution data set, composition), test setting (experimental/clinical, inclusion of metadata) and representativeness of participating clinicians.
    METHODS: PubMed, Medline and ScienceDirect were screened for peer-reviewed studies published between 2017 and 2021 and dealing with AI-based skin cancer classification involving melanoma. The search terms skin cancer classification, deep learning, convolutional neural network (CNN), melanoma (detection), digital biomarkers, histopathology and whole slide imaging were combined. Based on the search results, only studies that considered direct comparison of AI results with clinicians and had a diagnostic classification as their main objective were included.
    RESULTS: A total of 19 reader studies fulfilled the inclusion criteria. Of these, 11 CNN-based approaches addressed the classification of dermoscopic images; 6 concentrated on the classification of clinical images, whereas 2 dermatopathological studies utilised digitised histopathological whole slide images.
    CONCLUSIONS: All 19 included studies demonstrated superior or at least equivalent performance of CNN-based classifiers compared with clinicians. However, almost all studies were conducted in highly artificial settings based exclusively on single images of the suspicious lesions. Moreover, test sets mainly consisted of holdout images and did not represent the full range of patient populations and melanoma subtypes encountered in clinical practice.
    Keywords:  Artificial intelligence; Convolutional neural network(s); Deep learning; Dermatology; Digital biomarkers; Machine learning; Malignant melanoma; Skin cancer classification
    DOI:  https://doi.org/10.1016/j.ejca.2021.06.049
  32. Invest Ophthalmol Vis Sci. 2021 Sep 02. 62(12): 16
    Dual Inhibition of Histone Deacetylases and the Mechanistic Target of Rapamycin Promotes Apoptosis in Cell Line Models of Uveal Melanoma.
    Ruchi P Patel, Joanna R Thomas, Katherine M Curt, Christina M Fitzsimmons, Pedro J Batista, Susan E Bates, Michael M Gottesman, Robert W Robey.
       Purpose: Over 90% of uveal melanomas harbor pathogenic variants of the GNAQ or GNA11 genes that activate survival pathways. As previous studies found that Ras-mutated cell lines were vulnerable to a combination of survival pathway inhibitors and the histone-deacetylase inhibitor romidepsin, we investigated whether this combination would be effective in models of uveal melanoma.
    Methods: A small-scale screen of inhibitors of bromodomain-containing protein 4 (BRD4; OTX-015), extracellular signal-related kinase (ERK; ulixertinib), mechanistic target of rapamycin (mTOR; AZD-8055), or phosphoinositide 3-kinase (PI3K; GDC-0941) combined with a clinically relevant administration of romidepsin was performed on a panel of uveal melanoma cell lines (92.1, Mel202, MP38, and MP41) and apoptosis was quantified by flow cytometry after 48 hours. RNA sequencing analysis was performed on Mel202 cells treated with romidepsin alone, AZD-8055 alone, or the combination, and protein changes were validated by immunoblot.
    Results: AZD-8055 with romidepsin was the most effective combination in inducing apoptosis in the cell lines. Increased caspase-3 and PARP cleavage were noted in the cell lines when they were treated with romidepsin and mTOR inhibitors. RNA sequencing analysis of Mel202 cells revealed that apoptosis was the most affected pathway in the romidepsin/AZD-8055-treated cells. Increases in pro-apoptotic BCL2L11 and decreases in anti-apoptotic BIRC5 and BCL2L1 transcripts noted in the sequencing analysis were confirmed at the protein level in Mel202 cells.
    Conclusions: Our data suggest that romidepsin in combination with mTOR inhibition could be an effective treatment strategy against uveal melanoma due in part to changes in apoptotic proteins.
    DOI:  https://doi.org/10.1167/iovs.62.12.16
  33. Pediatr Dermatol. 2021 Sep 13.
    Melanocytic nevi on the hyponychium with dermoscopic features of longitudinal brush pigmentation in children.
    Jongeun Lee, Jaihee Bae, Dongyoun Lee.
      The dermoscopic features of longitudinally aligned pigmentation on the hyponychium were previously described in pediatric patients with longitudinal melanonychia. We report four cases of biopsy-proven acral melanocytic nevi on the hyponychium with a longitudinal brush pigmentation (LBP) pattern in dermoscopy. This LBP pattern on the hyponychium may be a counterpart of the fibrillar pattern of acral melanocytic nevi. Therefore, the LBP pattern in dermoscopy may provide a useful clue for distinguishing benign melanocytic nevi from melanoma in pediatric patients.
    Keywords:  dermatopathology; melanocytic nevi
    DOI:  https://doi.org/10.1111/pde.14794
  34. Int J Gen Med. 2021 ;14 5345-5361
    Characterization of m6A-Related Genes Landscape in Skin Cutaneous Melanoma to Aid Immunotherapy and Assess Prognosis.
    Jinzhi Meng, Xing Huang, Yue Qiu, Miao Yu, Jinfeng Lu, Jun Yao.
       Background: Skin cutaneous melanoma (SKCM) is the most malignant tumor among skin cancers. Immunotherapy has shown a great role in the advantageous prognosis of SKCM. However, only a small percentage of people can benefit from immunotherapy. To date, there has been insufficient evidence to reveal the prognostic value of m6A in SKCM and its relationship with the infiltration of immune cells and the efficacy of immunotherapy.
    Methods: Here, we synthetically analyzed 23 m6A regulators from SKCM samples collected from the TCGA and GEO databases. We defined three m6A modification patterns and constructed m6A scores using principal component analysis (PCA).
    Results: We found significant differences in overall survival (OS) and immune infiltration between different m6A subclusters. Besides, m6A score was positively correlated with regulatory T-cell and helper T-cell content, which may account for the association of high m6A scores with superior prognosis. Multivariate Cox regression analysis revealed that the m6A score was an independent prognostic indicator. Moreover, patients with high m6A scores showed a better response to immunotherapy, and this result was further validated in two independent immunotherapy cohorts receiving anti-PD-1/PD-L1 therapy.
    Conclusion: The findings suggested the m6A score can screen suitable candidates for immunotherapy and can predict immunotherapy response. This analysis of different m6A patterns in a large sample of SKCM expanded our understanding of TME and provided new ideas for prognostic assessment and personalized immunotherapy strategies for SKCM patients.
    Keywords:  M6A-related genes; immunotherapy; prognosis; skin cutaneous melanoma
    DOI:  https://doi.org/10.2147/IJGM.S328522
  35. Drug Deliv. 2021 Dec;28(1): 1849-1860
    Combination immunotherapy of chlorogenic acid liposomes modified with sialic acid and PD-1 blockers effectively enhances the anti-tumor immune response and therapeutic effects.
    Xixi Li, Shunyao Zhu, Ping Yin, Shuangshuang Zhang, Juewen Xu, Qin Zhang, Senlin Shi, Ting Zhang.
      Melanoma is one of the most common malignant tumors. The anti-PD-1 antibody is used for the treatment of metastatic melanoma. Treatment success is only 35-40% and a range of immune-related adverse reactions can occur. Combination of anti-PD1 antibody therapy with other oncology therapies has been attempted. Herein, we assessed whether chlorogenic acid liposomes modified with sialic acid (CA-SAL) combined with anti-PD1 antibody treatment was efficacious as immunotherapy for melanoma. CA-SAL liposomes were prepared and characterized. In a mouse model of B16F10 tumor, mice were treated with an anti-PD1 antibody, CA-SAL, or combination of CA-SAL + anti-PD1 antibody, and compared with no treatment controls. The tumor inhibition rate, tumor-associated macrophages (TAMs) phenotype, T-cell activity, and safety were investigated. We observed a significant decrease in the proportion of M2-TAMs and CD4+Fop3+ T cells, while there was a significant increase in the proportion of M1-TAMs and CD8+ T cells, and in the activity of T cells, and thus in the tumor inhibition rate. No significant toxicity was observed in major organs. CA-SAL and anti-PD1 Ab combination therapy presented synergistic anti-tumor activity, which enhanced the efficacy of the PD-1 checkpoint blocker in a mouse model of melanoma. In summary, combination immunotherapy of CA-SAL and anti-PD1 Ab has broad prospects in improving the therapeutic effect of melanoma, and may provide a new strategy for clinical treatment.
    Keywords:  Combination immunotherapy; anti-PD-1 antibody; chlorogenic acid; melanoma; sialic acid
    DOI:  https://doi.org/10.1080/10717544.2021.1971797
  36. Cureus. 2021 Aug;13(8): e17029
    Conjunctival Pyogenic Granuloma Masquerading as Malignant Melanoma.
    Priyanka R Rao, Amjad U Furniturewala, Indumati Gopinathan, Akshay Gopinathan Nair.
      Pyogenic granuloma is a common, benign, vascular growth that often appears as a rapidly growing mass on mucus membrane-lined surfaces such as the conjunctiva. Conjunctival pyogenic granulomas are common following trauma, burst chalazion or ill-fitting prosthesis. Also known as 'lobular capillary hemangiomas', these lesions typically appear bright red, fleshy and pedunculated. Treatment options include excision, topical steroid therapy and topical beta-blocker therapy. In this communication, the authors describe a rapidly enlarging, pedunculated black coloured conjunctival mass lesion in a 44-year-old woman, who had a recent history of chalazia. Given the location and the clinical appearance, a melanocytic tumour was suspected and the mass was excised. Histopathology and immunohistochemical studies confirmed the diagnosis to be consistent with that of a a necrotic pyogenic granuloma. Pigmented lesions of the conjunctiva, especially rapidly enlarging ones, need to be viewed with a high degree of suspicion to rule out malignant melanoma. Rarely though, benign lesions such as pyogenic granulomas that undergo necrosis may masquerade as conjunctival melanomas.
    Keywords:  chalazion; conjunctiva; eye cancer; eyelid tumor; melanoma; pigmented tumor
    DOI:  https://doi.org/10.7759/cureus.17029
  37. Sci Rep. 2021 Sep 14. 11(1): 18298
    CXCL9 as a key biomarker of vitiligo activity and prediction of the success of cultured melanocyte transplantation.
    Fuquan Lin, Wenting Hu, Wen Xu, Miaoni Zhou, Ai-E Xu.
      This study aimed to investigate the potential biomarkers of vitiligo by evaluating the disease activity and curative effect of autologous cultured pure melanocyte transplantation (CMT) on patients. Altogether, 36patients with stable vitiligo were treated with CMT. Blister fluid samples were collected from patients with stable vitiligo. Patients with active vitiligo were matched with healthy controls. The chemokine levels in the serum and blister fluid samples were measured using Luminex. The curative effect on patients with stable vitiligo was evaluated 6 months after treatment. Treatment responses were defined according to the extent of repigmentation as effective (if 50% or more repigmentation was achieved) or ineffective (if less than 50% or worse repigmentation was achieved). Patients received re-transplantation if the initial treatment was ineffective. The levels of C-X-C motif chemokine ligand (CXCL)9 and CXCL10 in blister fluid samples were significantly lower in stable patients than in active participants. Receiver operating characteristic analysis revealed that the levels of CXCL9 and CXCL10 were sensitive and specific in diagnosing active vitiligo. Further, 65.6% (21/32) of patients who received CMT had effective treatment responses. The high CXCL9 level in the blister fluid was a significant predictor of ineffective treatment responses. The treatment response was significantly enhanced after treatment. Four patients with ineffective treatment responses received anti-inflammatory treatment and re-transplantation. The CXCL9 and CXCL10 levels in the blister fluid were related to the presence of active vitiligo. Also, the CXCL9 level was a predictor of the effectiveness of CMT in treating vitiligo.
    DOI:  https://doi.org/10.1038/s41598-021-97296-2
  38. J Surg Oncol. 2021 Sep 17.
    Regression in melanoma is significantly associated with a lower regional recurrence rate and better recurrence-free survival.
    Sarayu Subramanian, Gang Han, Natalie Olson, Stanley P Leong, Mohammed Kashani-Sabet, Richard L White, Jonathan S Zager, Vernon K Sondak, Jane L Messina, Barbara Pockaj, Heidi E Kosiorek, John Vetto, Graham Fowler, Schlomo Schneebaum, Dale Han.
       BACKGROUND AND OBJECTIVES: The prognostic significance of regression in predicting melanoma recurrences is unknown. We present a large multicenter study correlating regression with recurrence.
    METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with regression data. Clinicopathologic factors were correlated with overall and first-site of recurrence and with recurrence-free survival (RFS).
    RESULTS: There were 4790 patients and the median follow-up was 39.6 months. Regression and recurrences were seen in 1081 (22.6%) and 773 (16.1%) cases, respectively. First-site locoregional and distant recurrences were seen in 412 (8.6%) and 352 (7.3%) patients, respectively. Regression was seen in 15.8% and 24.7% of all cases with and without recurrences (p < 0.0001), respectively, while regression was seen in 14.3% and 17.9% of first-site locoregional and distant recurrent cases, respectively, compared with 23.3% and 22.9% of patients with regression and without first-site locoregional and distant recurrences, respectively (p = 0.29). On multivariable analysis, after controlling for age, gender, thickness, ulceration, lymphovascular invasion, and sentinel lymph node status, regression significantly predicted improved RFS (p = 0.004) and fewer first-site regional recurrences (p = 0.017).
    CONCLUSION: Our data suggest that regression is a favorable prognostic marker in melanoma and predicts significantly better RFS and decreased first-site regional recurrences.
    Keywords:  melanoma; recurrence rate; recurrence-free survival; regression; survival
    DOI:  https://doi.org/10.1002/jso.26678
  39. Acta Ophthalmol. 2021 Sep 16.
    Fractionated stereotactic radiotherapy for uveal melanoma: Long-term outcome and control rates.
    Jackelien G M van Beek, Caroline M van Rij, Sara J Baart, Serdar Yavuzyigitoglu, Michael J Bergmann, Dion Paridaens, Nicole C Naus, Emine Kiliç.
       PURPOSE: The aim of our study is to evaluate local tumour control rates, radiation side-effects, visual preservation and disease-free survival (DFS) of uveal melanoma (UM) patients treated with fractionated stereotactic radiotherapy (fSRT).
    METHODS: A retrospective study of UM patients, who were treated with fSRT (N = 189), was performed by the Rotterdam Ocular Melanoma Study group (ROMS), the Netherlands, between 1999 and 2014 with a follow-up of at least 5 years.
    RESULTS: The 1-, 3-, 5-, 10- and 15-year local tumour control rates were as follows: 99.4%, 92.8%, 92.2%, 89.3% and 89.3%, respectively. Cataract (67.8%) was the most common side-effect of fSRT followed by retinopathy (35.1%), maculopathy (23.8%), vitreous haemorrhage (20.1%), neovascular glaucoma (NVG) (20.0%) and optic neuropathy (12.4%). Patients with anterior located UMs developed cataract more frequently (p = 0.047, multivariable analysis). By multivariable analysis, significant factors for secondary enucleation were tumour recurrence (p < 0.001) and NVG (p < 0.001). In multivariable analysis, risk factors for a worse DFS were larger UM (p = 0.024) and tumours with subretinal fluid (SRF) at baseline (p = 0.038). The 5-year DFS was 77.0% and the best corrected visual acuity decreased significantly after treatment. After 5 years, 22.0% of patients and after 10 years 17.6% of patients had a visual acuity of ≤0.3 logMAR.
    CONCLUSION: Fractionated stereotactic radiotherapy is a good treatment option for small-, medium- and large-sized tumours with 5-year local tumour control of 92.2%. After 5 years, 22.0% of the patients had a good vision. Independently of tumour location, the visual acuity decreased significantly after treatment. Overall, the 5-year DFS was 77.0%.
    Keywords:  fractionated stereotactic radiotherapy; local tumour control; side-effects; uveal melanoma
    DOI:  https://doi.org/10.1111/aos.15029
  40. Acta Biomater. 2021 Sep 13. pii: S1742-7061(21)00597-3. [Epub ahead of print]
    Intelligent and spatiotemporal drug release based on multifunctional nanoparticle-integrated dissolving microneedle system for synergetic chemo-photothermal therapy to eradicate melanoma.
    Yiting Zhao, Yixian Zhou, Dan Yang, Xinyi Gao, Ting Wen, Jintao Fu, Xinguo Wen, Guilan Quan, Xin Pan, Chuanbin Wu.
      Cutaneous melanoma is one of the most common malignant skin cancer with high lethality. Chemotherapy and photothermal therapy are important and extensively studied treatment modalities for melanoma. However, these therapies still face some challenges, which severely restrict their further applications, such as unsatisfactory efficacy of monotherapy, nonspecific uptake and release during drug delivery, and unexpected adverse effects from system administration. Recently, the strategies of collaboration, functional modification, stimuli-responsive design, and topical administration all show great prospect for solving above problems. In this research, a multifunctional nanoparticle-integrated dissolving microneedle drug delivery system was constructed, in which the nanoparticles were prepared based on the framework with the incorporation of photothermal agent (CuS) into Zeolitic imidazolate framework-8 and functionalized by hyaluronic acid. This system can co-load multi-modal drugs, improve specific uptake and distribution of targeted tumor, deliver drug locally, and release drug intelligently and spatiotemporally, thereby promising a low-dose administration with high efficiency. The high inhibiting tumor performance and excellent systematic safety were verified both in vitro and in vivo. Together, this smart design overcame the drawbacks of monotherapy and conventional system administration. We believe the nanoparticle-integrated dissolving microneedles will be in prospect of clinical application for more superficial tumors with further delicate optimization. STATEMENT OF SIGNIFICANCE: Melanoma is one of the most common skin cancers with high lethality. Extensively studied chemotherapy and photothermal therapy still face some challenges, such as the limited therapeutic efficacy and the severe system adverse effects. In order to overcome these drawbacks, the multifunctional nanoparticle-integrated dissolving microneedles (DMNs) were designed. Especially, the nanoparticles could co-load multi-modal drugs, improve specific uptake, and release drug intelligently and spatiotemporally. The microneedles could increase the drug accumulation in tumor, thus achieving excellent therapeutic efficacy and reducing side effects. This system paved the way to a less invasive, more focused and efficient therapeutic strategy for melanoma therapy.
    Keywords:  Cellular uptake; Dissolving microneedles; Specific distribution; Superficial tumor; Synergistic therapy
    DOI:  https://doi.org/10.1016/j.actbio.2021.09.009
  41. Skinmed. 2021 ;19(4): 288-296
    Primary Tumor Location Predicts Survival in Melanoma: A Retrospective Cohort Study of 239,257 Melanoma Patients.
    Carolina Puyana, Jeffrey Rajkumar, Maria M Tsoukas.
      The link between primary tumor location and overall survival in melanoma has been studied in the past, but its associated population and prognostic significance is less understood. The purpose of this study was to characterize melanoma demographics and disease-specific survival (DSS) in relation to primary tumor site. Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program were retrospectively analyzed; from 1973 to 2015, 239,257 patients diagnosed with cutaneous melanoma were included in the study and separated into three cohorts based on primary tumor site. The effect of primary location on melanoma survival was evaluated using Cox proportional hazards models. Tumors were predominantly localized and had a depth of ≤1 mm. Patients diagnosed with tumors originating in the upper and lower extremities had significantly increased DSS probability compared to those of the head and neck. Characteristics, including woman sex, married or widowed status, treated on the Pacific coast, and increasing year of diagnosis, were associated with greater DSS. Conversely, non-white or Hispanic origin, higher age at diagnosis, tumors with increased depth, or nodular or acral melanoma histology were associated with lower DSS. Primary tumor site is a significant predictive factor of DSS in cutaneous melanoma along with additional characteristics supported in our study.
  42. Front Immunol. 2021 ;12 733136
    PD-1 Blockade on Tumor Microenvironment-Resident ILC2s Promotes TNF-α Production and Restricts Progression of Metastatic Melanoma.
    Emily Howard, Benjamin P Hurrell, Doumet Georges Helou, Christine Quach, Jacob D Painter, Pedram Shafiei-Jahani, Marshall Fung, Parkash S Gill, Pejman Soroosh, Arlene H Sharpe, Omid Akbari.
      While pulmonary ILC2s represent one of the major tissue-resident innate lymphoid cell populations at steady state and are key drivers of cytokine secretion in their occupational niche, their role in pulmonary cancer progression remains unclear. As the programmed cell death protein-1 (PD-1) plays a major role in cancer immunotherapy and immunoregulatory properties, here we investigate the specific effect of PD-1 inhibition on ILC2s during pulmonary B16 melanoma cancer metastasis. We demonstrate that PD-1 inhibition on ILC2s suppresses B16 tumor growth. Further, PD-1 inhibition upregulates pulmonary ILC2-derived TNF-α production, a cytotoxic cytokine that directly induces cell death in B16 cells, independent of adaptive immunity. Together, these results highlight the importance of ILC2s and their anti-tumor role in pulmonary B16 cancer progression during PD-1 inhibitory immunotherapy.
    Keywords:  PD-1; TNF - α; cancer; innate lymphoid cell 2; melanoma
    DOI:  https://doi.org/10.3389/fimmu.2021.733136
  43. Dev Cell. 2021 Sep 13. pii: S1534-5807(21)00677-8. [Epub ahead of print]
    Cooperation between melanoma cell states promotes metastasis through heterotypic cluster formation.
    Nathaniel R Campbell, Anjali Rao, Miranda V Hunter, Magdalena K Sznurkowska, Luzia Briker, Maomao Zhang, Maayan Baron, Silja Heilmann, Maxime Deforet, Colin Kenny, Lorenza P Ferretti, Ting-Hsiang Huang, Sarah Perlee, Manik Garg, Jérémie Nsengimana, Massimo Saini, Emily Montal, Mohita Tagore, Julia Newton-Bishop, Mark R Middleton, Pippa Corrie, David J Adams, Roy Rabbie, Nicola Aceto, Mitchell P Levesque, Robert A Cornell, Itai Yanai, Joao B Xavier, Richard M White.
      Melanomas can have multiple coexisting cell states, including proliferative (PRO) versus invasive (INV) subpopulations that represent a "go or grow" trade-off; however, how these populations interact is poorly understood. Using a combination of zebrafish modeling and analysis of patient samples, we show that INV and PRO cells form spatially structured heterotypic clusters and cooperate in the seeding of metastasis, maintaining cell state heterogeneity. INV cells adhere tightly to each other and form clusters with a rim of PRO cells. Intravital imaging demonstrated cooperation in which INV cells facilitate dissemination of less metastatic PRO cells. We identified the TFAP2 neural crest transcription factor as a master regulator of clustering and PRO/INV states. Isolation of clusters from patients with metastatic melanoma revealed a subset with heterotypic PRO-INV clusters. Our data suggest a framework for the co-existence of these two divergent cell populations, in which heterotypic clusters promote metastasis via cell-cell cooperation.
    Keywords:  TFAP2; circulating tumor cell cluster; cluster; cooperation; melanoma; metastasis; zebrafish
    DOI:  https://doi.org/10.1016/j.devcel.2021.08.018
  44. Sci Rep. 2021 Sep 15. 11(1): 18335
    Mesenchymal stromal cells as carriers of IL-12 reduce primary and metastatic tumors of murine melanoma.
    Natalia Kułach, Ewelina Pilny, Tomasz Cichoń, Justyna Czapla, Magdalena Jarosz-Biej, Marek Rusin, Alina Drzyzga, Sybilla Matuszczak, Stanisław Szala, Ryszard Smolarczyk.
      Due to immunosuppressive properties and confirmed tropism towards cancer cells mesenchymal stromal cells (MSC) have been used in many trials. In our study we used these cells as carriers of IL-12 in the treatment of mice with primary and metastatic B16-F10 melanomas. IL-12 has confirmed anti-cancer activity, induces a strong immune response against cancer cells and acts as an anti-angiogenic agent. A major limitation of the use of IL-12 in therapy is its systemic toxicity. The aim of the work was to develop a system in which cytokine may be administered intravenously without toxic side effects. In this study MSC were used as carriers of the IL-12. We confirmed antitumor effectiveness of the cells secreting IL-12 (MSC/IL-12) in primary and metastatic murine melanoma models. We observed inhibition of tumor growth and a significant reduction in the number of metastases in mice after MSC/IL-12 administration. MSC/IL-12 decreased vascular density and increased the number of anticancer M1 macrophages and CD8+ cytotoxic T lymphocytes in tumors of treated mice. To summarize, we showed that MSC are an effective, safe carrier of IL-12 cytokine. Administered systemically they exert therapeutic properties of IL-12 cytokine without toxicity. Therapeutic effect may be a result of pleiotropic (proinflammatory and anti-angiogenic) properties of IL-12 released by modified MSC.
    DOI:  https://doi.org/10.1038/s41598-021-97435-9
  45. JAMA Ophthalmol. 2021 Sep 16.
    Association of Plasma Circulating Tumor DNA With Diagnosis of Metastatic Uveal Melanoma.
    Jasmine H Francis, Julia Canestraro, A Rose Brannon, Christopher A Barker, Michael Berger, Alexander N Shoushtari, David H Abramson.
      
    DOI:  https://doi.org/10.1001/jamaophthalmol.2021.3708
  46. Nat Commun. 2021 Sep 13. 12(1): 5402
    Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression.
    Mathieu F Bakhoum, Jasmine H Francis, Albert Agustinus, Ethan M Earlie, Melody Di Bona, David H Abramson, Mercedes Duran, Ignas Masilionis, Elsa Molina, Alexander N Shoushtari, Michael H Goldbaum, Paul S Mischel, Samuel F Bakhoum, Ashley M Laughney.
      Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41467-021-25529-z
  47. Transpl Int. 2021 Sep 14.
    Outcome of pretransplant melanoma after solid organ transplantation: an observational study.
    Marion Patras, Evelyne Decullier, Céleste Lebbé, Julie Delyon, Jacques Dantal, Christophe Legendre, Manal Mazloum, Aurélie Du Thanh, Feriel Boukari, Emmanuel Morelon, Denis Jullien, Jean Kanitakis, Emilie Ducroux.
       BACKGROUND: The number of patients with a history of melanoma who are waiting a solid organ transplantation (SOT) is increasing. Few recommendations exist on the timing to transplantation after melanoma diagnosis. The aim of this study was to assess the melanoma recurrence-free survival after pretransplant melanoma (PTM).
    METHODS: We conducted a multicenter ambispective observational study. Organ transplant recipients (OTR) with a history of PTM and complete AJCC staging were included.
    RESULTS: Thirty-seven patients (predominantly men with a renal allograft) were included. Five melanomas were in situ, 21 stage IA, 4 stage IB, 5 stage II and 2 stage IIIB. The median post-transplantation follow-up time was 4 years. 62% of patients were followed more than 2 years. Recurrence-free survival since melanoma reached 89.9%, but varied significantly according to AJCC staging (p=0.0129). Three patients presented a recurrence.
    CONCLUSION: Despite the rather limited sample size and a wide range of follow-up, our findings concerning the recurrence-free survival appear reassuring for in situ and stage IA PTM; accordingly we suggest that a waiting time to transplantation is not mandatory in patients with in situ or stage IA PTM, especially whenever SOT I s urgently needed. Caution is however needed for patients with higher stage.
    Keywords:  Pretransplant melanoma; pretransplant malignancy; solid organ transplantation
    DOI:  https://doi.org/10.1111/tri.14109
  48. Australas J Dermatol. 2021 Sep 15.
    Differences in the skin microbial community between patients with active and stable vitiligo based on 16S rRNA gene sequencing.
    Haojie Lu, Jinhui Xu, Yebei Hu, Haixin Luo, Yi Chen, Bo Xie, Xiuzu Song.
       BACKGROUND/OBJECTIVE: Recent studies have described an association between altered skin microbial community and epidemiology of skin diseases, such as vitiligo, atopic dermatitis and psoriasis. In this study, we conducted microbiological analysis on patients at different stages of vitiligo to determine whether the dysbiosis is associated with disease progression.
    METHODS: To characterise the skin microbes in vitiligo patients, we profiled samples collected from 40 patients with active and stable vitiligo using the Novaseq sequencer. Alpha diversity was used to measure richness and uniformity, while Beta diversity (Non-Metric Multi-Dimensional Scaling) analysis was used to show the differences. Moreover, the species differences were evaluated by LEfSe analysis and the flora gene function was predicted using Statistical Analysis of Metagenomic Profiles (STAMP).
    RESULTS: The alpha diversity results showed no significant differences between active vitiligo and stable vitiligo, while beta diversity and LEfSe analysis results showed the differences in community composition. Streptomyces and Streptococcus were enriched in active vitiligo compared to stable vitiligo. In addition, the flora gene function of mixed acid fermentation was more pronounced in active vitiligo, while the function of lipid IVA biosynthesis was more significant in stable vitiligo.
    CONCLUSION: This study has shown the differences in epidermal microbes between active vitiligo and stable vitiligo. Our results suggest that maintaining the flora balance might be a potential therapeutic target for vitiligo.
    Keywords:  16S rRNA gene-targeted sequencing; Flora; Skin; Vitiligo
    DOI:  https://doi.org/10.1111/ajd.13721
  49. Int J Med Sci. 2021 ;18(15): 3498-3505
    Expression and localization of Sox10 during hair follicle morphogenesis and induced hair cycle.
    Jing Jing, Peng Xu, Jia-Li Xu, Yu-Xin Ding, Xiao-Shuang Yang, Xiao-Qin Jin, Li-Juan Zhou, Yu-Hong Chen, Xian-Jie Wu, Zhong-Fa Lu.
      Sox transcription factors play many diverse roles during development, including regulating stem cell states, directing differentiation, and influencing the local chromatin landscape. Sox10 has been implicated in the control of stem/progenitor activity and epithelial-mesenchymal transition, yet it has not been studied in relation to the hair follicle cycle or hair follicle stem cell (HFSC) control. To elucidate the role of Sox10 in hair follicle cycle control, we performed immunohistochemical and immunofluorescence analysis of its expression during hair morphogenesis, the postnatal hair cycle, and the depilation-induced murine hair follicle cycle. During hair follicle morphogenesis, Sox10 was expressed in the hair germ and peg. In telogen, we detected nuclear Sox10 in the hair bulge and germ cell cap, where HFSCs reside, while in anagen and catagen, Sox10 was detected in the epithelial portion, such as the strands of keratinocytes, the outer root sheath (ORS) in anagen, and the regressed epithelial strand of hair follicle in catagen. These results suggest that Sox10 may be involved in early hair follicle morphogenesis and postnatal follicular cycling.
    Keywords:  Sox10; hair follicle stem cell; morphogenesis
    DOI:  https://doi.org/10.7150/ijms.60728
  50. Melanoma Res. 2021 Sep 13.
    Prospective study of clinical characteristics of melanoma patients with retinopathy caused by a high-dose interferon α-2b.
    Shijie Lan, Zhihua Cui, Qiliang Yin, Zhigang Liu, Lingling Liang, Hua He, Hesong Liu, Zhen Guo, Yingying Yu, Di Wu.
      Retinopathy is a rare side effect of interferon α-2b treatment. The goal of this study was to prospectively investigate the clinical characteristics of Chinese patients with melanomas who developed retinopathy following high doses of interferon α-2b (HD-IFN) therapy. The study included 56 melanoma stage I-III patients that were treated with HD-IFN. Fourty-three patients developed HD-IFN-induced retinopathies. Forty-three melanoma patients (76%) developed retinopathy after being treated with HD-IFN. Among these patients, 49% had cotton-wool spots, 19% had retinal hemorrhage, and 30% had retinal hemorrhage. The median time of occurrence of retinopathy was 4 weeks after treatment, and the median time of duration was 4 weeks. No patient showed other symptoms except one who had blurred vision. A comparison of clinical characteristics (age, gender, primary site, stage, and ulceration) and laboratory examinations (white blood cell and platelet counts, hemoglobin, serum lactate dehydrogenase, alanine transaminase, aspartate aminotransferase, triiodothyronine, thyroxine, thyroid-stimulating hormone, and lipid) between the HD-IFN-induced retinopathy patients and nonretinopathy patients did not show any significant differences (P > 0.05). Although all patients that developed retinopathy had diabetes or hypertension, an equal percentage of patients were without retinopathy had diabetes or hypertension. HD-IFN therapy in patients with melanomas may induce mild retinopathy. Our results; however, do not necessarily suggest to discontinue the HD-IFN treatment because retinopathy is a reversible disorder.
    DOI:  https://doi.org/10.1097/CMR.0000000000000769
  51. Clin Cosmet Investig Dermatol. 2021 ;14 1089-1103
    Identification of the Role of Wnt/β-Catenin Pathway Through Integrated Analyses and in vivo Experiments in Vitiligo.
    Si-Jia Zhao, Hong Jia, Xiu-Lian Xu, Wen-Bo Bu, Qian Zhang, Xi Chen, Juan Ji, Jian-Fang Sun.
       Purpose: Vitiligo is an acquired depigmentation skin disease, which affects an average of 1% of the world's population. The purpose of this study is to identify the key genes and pathways responsible for vitiligo and find new therapeutic targets.
    Methods: The datasets GSE65127, GSE53146, and GSE75819 were downloaded from the Gene Expression Omnibus (GEO) database. R language was used to identify the differentially expressed genes (DEGs) between lesional skin of vitiligo and non-lesional skin. Next, the key pathways were obtained by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The protein-protein interaction (PPI) networks were conducted by STRING database and Cytoscape software. Subsequently, module analysis was performed by Cytoscape. Among these results, the Wnt/β-catenin pathway and melanogenesis pathway caught our attention. The expression level of β-catenin, microphthalmia-associated transcription factor (MITF) and tyrosinase (TYR) was detected by immunofluorescence in vitiligo lesions and healthy skin. Moreover, zebrafish was treated with XAV-939, an inhibitor of the Wnt/β-catenin pathway. After that, the area of melanin granules as a percentage of the head area was measured. The mRNA expression of β-catenin, lymphoid-enhancing factor 1(lef1), tyr and mitf were detected by q-PCR (quantitative polymerase chain reaction) in zebrafish (Danio rerio).
    Results: A total of 2442 DEGs were identified, including 1068 upregulated and 1374 downregulated DEGs. The key pathways were identified by GO and KEGG analyses, such as "NOD-like receptor signaling pathway", "Wnt signaling pathway", "Melanogenesis", "mTOR signaling pathway", "PI3K-Akt signaling pathway", "Calcium signaling pathway" and "Rap1 signaling pathway". The immunofluorescence results showed that the level of β-catenin, MITF and TYR was significantly downregulated in vitiligo lesional skin. In zebrafish, the mean percentage area of melanin granules and the expression of β-catenin, lef1, tyr and mitf were decreased after treated with XAV-939.
    Conclusion: The present study identified key genes and signaling pathways associated with the pathophysiology of vitiligo. Among them, the Wnt/β-catenin pathway played an essential role in pigmentation and could be a breakthrough point in vitiligo treatment.
    Keywords:  Rap1; Wnt/β-catenin; calcium signaling; melanogenesis; vitiligo; zebrafish
    DOI:  https://doi.org/10.2147/CCID.S319061
  52. J Vis Exp. 2021 Aug 27.
    Direct Reprogramming of Mouse Fibroblasts into Melanocytes.
    Yi-Xuan Zhang, Li-Ping Liu, Ming Jin, Hui Sun, Han-Lin Zhang, Yu-Mei Li.
      The loss of function of melanocytes leads to vitiligo, which seriously affects the physical and mental health of the affected individuals. Presently, there is no effective long-term treatment for vitiligo. Therefore, it is imperative to develop a convenient and effective treatment for vitiligo. Regenerative medicine technology for direct reprogramming of skin cells into melanocytes seems to be a promising novel treatment of vitiligo. This involves the direct reprogramming of the patient's skin cells into functional melanocytes to help ameliorate the loss of melanocytes in patients with vitiligo. However, this method needs to be first tested on mice. Although direct reprogramming is widely used, there is no clear protocol for direct reprogramming into melanocytes. Moreover, the number of available transcription factors is overwhelming. Here, a concentrated lentivirus packaging system protocol is presented to produce transcription factors selected for reprogramming skin cells to melanocytes, including Sox10, Mitf, Pax3, Sox2, Sox9, and Snai2. Mouse embryonic fibroblasts (MEFs) were infected with the concentrated lentivirus for all these transcription factors for the direct reprogramming of the MEFs into induced melanocytes (iMels) in vitro. Furthermore, these transcription factors were screened, and the system was optimized for direct reprogramming to melanocytes. The expression of the characteristic markers of melanin in iMels at the gene or protein level was significantly increased. These results suggest that direct reprogramming of fibroblasts to melanocytes could be a successful new therapeutic strategy for vitiligo and confirm the mechanism of melanocyte development, which will provide the basis for further direct reprogramming of fibroblasts into melanocytes in vivo.
    DOI:  https://doi.org/10.3791/62911
  53. J Cancer Res Ther. 2021 Jul-Sep;17(4):17(4): 906-911
    Incidence of melanoma and nonmelanoma skin cancers in Indian and the global regions.
    Satyanarayana Labani, Smita Asthana, Kushal Rathore, Kabir Sardana.
       Background: Incidence of common types of skin cancers in India is not reported and its comparison with global load would be helpful statistics.
    Aim: The aim of this study is to summarize and report recent skin cancer incidence in India and to compare it with the incidence globally.
    Materials and Methods: Age-specific rates and age-adjusted rates (AARs) of the incidence of skin cancer for all ages (0-75 years) were collected from India and the world, respectively, from the National Cancer Registry Programme and GLOBOCAN 2018.
    Results: The AAR per 100,000 of melanoma of the skin was highest in the North region of India for both males and females with 1.62 and with 1.21, respectively. The incidence of nonmelanoma of the skin or other skin cancers for males was highest in the East region with 6.2 and for females in Northeast with 3.49. Among nonmelanoma, northeast region showed the maximum incidence for both male (75.6) and female (43.6) sexes. Globally, AAR of melanoma of skin for males was highest in the Western Pacific region with 36.9 and for the females; AAR was highest in the European region with 31.7. The incidence of nonmelanoma of the skin or other skin cancers for males was highest in the Western pacific region with 225.4 and 68.6 for females.
    Conclusion: Summary of the incidence rates of melanoma and nonmelanoma skin cancers which shows that though there are regional variations of incidence in India is lower than that of in the West.
    Keywords:  Incidence; melanoma; nonmelanoma; skin cancer
    DOI:  https://doi.org/10.4103/jcrt.JCRT_785_19
  54. Environ Sci Pollut Res Int. 2021 Sep 17.
    Polybrominated diphenyl ethers BDE-47 and BDE-99 modulate murine melanoma cell phenotype in vitro.
    Gisleine Jarenko Steil, João Luiz Aldinucci Buzzo, Ciro Alberto de Oliveira Ribeiro, Francisco Filipak Neto.
      Cancer is one of the leading causes of mortality worldwide. Even with the advances of pharmaceutical industry and treatments, the mortality rate for various types of cancer remains high. In particular, phenotypic alterations of tumor cells concerning drug efflux, migratory and invasive capabilities may represent a hurdle for cancer treatment and contribute to poor prognosis. In the present study, we investigated the effects of polybrominated diphenyl ethers (PBDEs) used as flame retardants on phenotypic features of melanoma cells that are important for cancer. Murine melanoma B16-F1 (less metastatic) and B16-F10 (more metastatic) cells were exposed to 0.01-1.0 nM of BDE-47 (2,2',4,4'-tetrabromodiphenyl ether), BDE-99 (2,2',4,4',5-pentabromodiphenyl ether), and the mixture of both (at 0.01 nM) for 24 h (acute exposure) and 15 days (chronic exposure). The polybrominated diphenyl ethers (PBDEs) did not affect cell viability but led to increased drug efflux transporter activity, cell migration, and colony formation, as well as overexpression of Abcc2 (ATP-binding cassette subfamily C member 2), Mmp-2 (matrix metalloproteinase-2), Mmp-9 (matrix metalloproteinase-9), and Tp53 (tumor protein p53) genes and downregulation of Timp-3 (tissue inhibitor of metalloproteinase 3) gene in B16-F10 cells. These effects are consistent with increased aggressiveness and malignancy of tumors due to exposure to the flame retardants and raise some concerns on the effects such chemicals may have on melanoma treatment and cancer prognosis.
    Keywords:  B16-F10; Brominated compounds; Cancer; Gene expression; Malignancy; Melanoma
    DOI:  https://doi.org/10.1007/s11356-021-16455-0
  55. Cureus. 2021 Jul;13(7): e16751
    Reconstruction of a Giant Congenital Melanocytic Nevus Defect With a Submental Flap in a Global Health Setting.
    Amanda L Brown, Ariel N Servin, Lawrence J McCarthy, Brian A Mailey.
      Excision of a facial congenital melanocytic nevus (CMN) is a common reason for consultation in pediatric plastic surgery. Facial nevi are generally small and uncomplicated to remove and become more complex when large or giant. The available resources determine treatment and excision options. The indication for excision is generally based on esthetic criteria; however, the risk of melanoma increases with the nevi diameter. This patient with a giant CMN (GCMN) was encountered on an international medical mission trip. The palm-sized lesion spanned from her left zygomatic arch down to the jawline. Due to the esthetic impact and lack of resources to continue monitoring the lesion, complete excision was performed. The resultant defect was reconstructed with a pedicled submental flap. This article presents management and reconstruction of a facial GCMN encountered in the global setting and presents a brief literature review of GCMN.
    Keywords:  congenital facial defect; giant congenital melanocytic nevus; global surgery; head and neck reconstruction; pediatric craniofacial surgery; perforator flap; short term surgical missions; submental flap
    DOI:  https://doi.org/10.7759/cureus.16751
  56. Australas J Dermatol. 2021 Sep 16.
    A practical guide on the use of imiquimod cream to treat lentigo maligna.
    Pascale Guitera, Andreanne Waddell, Elizabeth Paton, Gerald B Fogarty, Angela Hong, Richard A Scolyer, Jonathan R Stretch, Brett A O'Donnell, Giovanni Pellacani.
      Lentigo maligna (LM) is a common in situ melanoma subtype arising on chronically sun-damaged skin and mostly affects the head and neck region. Localisation in cosmetically sensitive areas, difficulty to obtain wide resection margins and advanced patient age/comorbidities have encouraged investigation of less invasive therapeutic strategies than surgery in managing complex cases of LM. Radiotherapy and imiquimod have emerged as alternative treatment options in this context. The treatment of LM with imiquimod cream can be challenging due to the nature of the disease including its often large size, variegated appearance, involvement of adnexal structures, poorly defined peripheral edge and frequent localisation close to sensitive structures such as the eyes and lips, and elderly patients with multiple comorbidities. Prolonged and unpredictable inflammatory reaction and side effects and compliance with a patient-delivered therapy can also be challenging. In the literature to date, studies evaluating the use of imiquimod to treat LM have utilised varying methodologies and provided short follow-up and these limitations have impaired the development of clear guidelines for dosage and management of side effects. Based on our multidisciplinary experience and review of the literature, we propose practical clinical strategies for the use of imiquimod for treating LM, detailing optimal administration procedures in various clinical scenarios and long-term management, with the aim of facilitating optimal patient outcomes.
    Keywords:  Hutchinson's Melanotic Freckle; diagnosis; imiquimod; lentigo maligna; multidisciplinary consensus; pathology; treatment
    DOI:  https://doi.org/10.1111/ajd.13720
  57. Int J Dermatol. 2021 Sep 12.
    Excellent improvement of inflammatory acne vulgaris with monochromatic excimer light in a vitiligo patient.
    Ahmad Kamel Seddeik Abdel-Hameed, Ahmed Elsaeed Elsaadany.
      
    DOI:  https://doi.org/10.1111/ijd.15906
  58. Skin Pharmacol Physiol. 2021 Aug 05. 1
    Influence of Ethnicities and Skin Color Variations in Different Populations: A Review.
    Piyu Parth Naik, Syed Nadir Farrukh.
       BACKGROUND: In the world scientific tradition, skin color is the primary physical characteristic used to divide humans into groups. Human skin has a wide range of tones and colors, which can be seen in a wide range of demographic populations. Many factors influence the color of people's skin, but the pigment melanin is by far the most important. Melanin is produced by cells called melanocytes in the skin and is the primary determinant of skin color in people with darker skin. Indeed, >150 genes have now been identified as having a direct or indirect effect on skin color. Vitamin D has recently been discovered to regulate cellular proliferation and differentiation in a variety of tissues, including the skin. The mechanisms through which the active vitamin D metabolite 1,25 dihydroxyvitamin D3 (or calcitriol) affects keratinocyte development are numerous and overlap with the mechanisms by which calcium influences keratinocyte differentiation. Ultraviolet (UV) is the most major modifiable risk factor for skin cancer and many other environmental-influenced skin disorders when it is abundant in the environment. Although the UV component of sunlight is known to cause skin damage, few researches have looked at the impact of non-UV solar radiation on skin physiology in terms of inflammation, and there is less information on the role of visible light in pigmentation.
    SUMMARY: The quantity and quality of melanin are regulating by the expression of genes. The enzyme tyrosinase is primarily responsible for the genetic mechanism that controls human skin color. Genetics determines constitutive skin color, which is reinforced by facultative melanogenesis and tanning reactions. High quantities of melanin and melanogenic substances are typically accepted in darker skin to protect against UV radiation-induced molecular damage. Previous research has proposed that skin color variation is caused by a dynamic genetic mechanism, contributing to our understanding of how population demographic history and natural selection shape human genetic and phenotypic diversity. However, the most significant ethnic skin color difference is determined by melanin content. This current review aimed to assess the influence of skin color variations in skin structure and functions as well as difference in dermatological disease patterns. Also, this article reviewed several cases of skin color adaptation in different populations. Key Messages: Skin color impacts the composition and activity. Therefore, the contrast of dermatological ailments between distinct race-related categories is remarkable. Skin color adaptation is a challenging procedure. Refinement of skin color is an age-old craving of humans with ever-evolving drifts.
    Keywords:  Ethnicity; Genetic factors; Melanin; Skin color
    DOI:  https://doi.org/10.1159/000518826
  59. Sci Transl Med. 2021 Sep 08. 13(610): eabd8995
    scRNA-seq of human vitiligo reveals complex networks of subclinical immune activation and a role for CCR5 in Treg function.
    Kyle J Gellatly, James P Strassner, Kingsley Essien, Maggi Ahmed Refat, Rachel L Murphy, Anthony Coffin-Schmitt, Amit G Pandya, Andrea Tovar-Garza, Michael L Frisoli, Xueli Fan, Xiaolan Ding, Evangeline E Kim, Zainab Abbas, Patrick McDonel, Manuel Garber, John E Harris.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/scitranslmed.abd8995
  60. Adv Sci (Weinh). 2021 Sep 14. e2101796
    S100A9-Targeted Cowpea Mosaic Virus as a Prophylactic and Therapeutic Immunotherapy against Metastatic Breast Cancer and Melanoma.
    Young Hun Chung, Jooneon Park, Hui Cai, Nicole F Steinmetz.
      Prognosis and treatment of metastatic cancer continues to be one of the most difficult and challenging areas of oncology. Treatment usually consists of chemotherapeutics, which may be ineffective due to drug resistance, adverse effects, and dose-limiting toxicity. Therefore, novel approaches such as immunotherapy have been investigated to improve patient outcomes and minimize side effects. S100A9 is a calcium-binding protein implicated in tumor metastasis, progression, and aggressiveness that modulates the tumor microenvironment into an immunosuppressive state. S100A9 is expressed in and secreted by immune cells in the pre-metastatic niche, as well as, post-tumor development, therefore making it a suitable targeted for prophylaxis and therapy. In previous work, it is demonstrated that cowpea mosaic virus (CPMV) acts as an adjuvant when administered intratumorally. Here, it is demonstrated that systemically administered, S100A9-targeted CPMV homes to the lungs leading to recruitment of innate immune cells. This approach is efficacious both prophylactically and therapeutically against lung metastasis from melanoma and breast cancer. The current research will facilitate and accelerate the development of next-generation targeted immunotherapies administered as prophylaxis, that is, after surgery of a primary breast tumor to prevent outgrowth of metastasis, as well as, therapy to treat established metastatic disease.
    Keywords:  S100A9; breast cancer; immunotherapy; melanoma; metastasis
    DOI:  https://doi.org/10.1002/advs.202101796
  61. Macromol Biosci. 2021 Sep 12. e2100249
    Artificial Melanogenesis by Confining Melanin/Polydopamine Production inside Polymersomes.
    Claire E Meyer, Cora-Ann Schoenenberger, Riccardo P Wehr, Dalin Wu, Cornelia G Palivan.
      Melanin and polydopamine are potent biopolymers for the development of biomedical nanosystems. However, applications of melanin or polydopamine-based nanoparticles are limited by drawbacks related to a compromised colloidal stability over long time periods and associated cytotoxicity. To overcome these hurdles, a novel strategy is proposed that mimics the confinement of natural melanin in melanosomes. Melanosome mimics are developed by co-encapsulating the melanin/polydopamine precursors L-DOPA/dopamine with melanogenic enzyme Tyrosinase within polymersomes. The conditions of polymersome formation are optimized to obtain melanin/polydopamine polymerization within the cavity of the polymersomes. Similar to native melanosomes, polymersomes containing melanin/polydopamine show long-term colloidal stability, cell-compatibility, and potential for cell photoprotection. This novel kind of artificial melanogenesis is expected to inspire new applications of the confined melanin/polydopamine biopolymers.
    Keywords:  melanin; melanogenesis; melanosomes; polydopamine; polymersomes; tyrosinase
    DOI:  https://doi.org/10.1002/mabi.202100249
  62. Rev Esp Enferm Dig. 2021 Sep 15.
    Acute neutrophilic gastritis induced by nivolumab used as a treatment of non- metastatic malignant melanoma.
    Asunción Ojeda Gómez, Nuria Jiménez García, Jorge Barragán Martínez, Andrea García Soria, Julia Sáez Fuster, María Cabezas Macián, Mariana Fe García Sepulcre.
      We present a 47 year-old man with a personal history of malignant melanoma (pT3bN2M0) radically removed, who was receiving adjuvant Nivolumab for prevention of recurrence. He was admitted to our service complaining of epigastric pain and hyporexia after receiving the 9º dose of Nivolumab. He underwent a preferential esophagogastroduodenoscopy which showed an intense inflammation limited to the stomach. Macroscopically all the mucosa was erythematosus, edematous, with friability and large ulcerations covered with fibrin. Multiple biopsies revealed inflammatory neutrophilic infiltration in the epithelium, cellular apoptosis and crypt microabscesses, all of which was related to Nivolumab drug-induced pangastritis. No form of Helicobacter Pylori was identified. A medical treatment with double dose of proton-pump inhibitor and definitive cessation of Nivolumab was established, becoming the patient rapidly asymptomatic. The immune checkpoint inhibitors are becoming a widespread treatment in the Oncology field. Nivolumab is a PD-L1 inhibitor, leading to the activation of the cytotoxic immune response carried out by LT-CD8 (1). Despite the immune-mediated adverse events related to the lower gastrointestinal tract are well known; the gastritis or the esophagitis remain sporadic effects (2). They can appear several months after the beginning of the treatment but also after its discontinuation. The differential diagnosis must be reached by excluding pathologies such as infectious gastritis, vasculitis, Crohn´s disease or Behçet syndrome, so as to the pathologist should always know the involvement of this treatment in order to achieve a reliable diagnosis (3). The role of Helicobater Pylori must be highlighted in this case. Since it is capable of simulating or even worsening the immune-mediated gastritis, not only its identification but also its eradication becomes essential (4). The treatment is based on the immediate cessation of the immunotherapy, the gastric acid suppression and high doses of corticosteroids in the most severe cases. The benefits of immunosuppressive treatment using infliximab have been well shown in refractory cases (5).
    DOI:  https://doi.org/10.17235/reed.2021.8295/2021
  63. Int J Clin Exp Pathol. 2021 ;14(8): 902-907
    A new approach using a numerical diagnostic criterion for vitiligo diagnosis with HMB-45 and Melan-A staining.
    Nuri Na, Joonsoo Park.
      This study aims to investigate the usefulness of the Melan-A and homatropine methyl bromide-45 (HMB-45) markers in identifying melanocytes and to evaluate cut-off values for the diagnosis of vitiligo. We also aim to identify the role of remaining melanocytes when using HMB-45. We counted and confirmed melanocytes and melanin in the samples using a high-magnification microscope. The Melan-A, HMB-45, and Fontana-Masson staining methods were utilized. Descriptive statistical analysis of quantitative traits was performed. For the comparison of the two diagnostic tools, receiver operating characteristic curve and the area under the curve were evaluated. We found out that there was no significant difference observed between the two methods. The cut-off value is <27 for HMB-45 and <15 for Melan-A per 100 cells in the basal cell layer. Thus, HMB-45 is as useful as Melan-A in the diagnosis of vitiligo.
    Keywords:  Depigmented diseases; HMB-45; Melan-A; melanocytes; vitiligo
  64. Science. 2021 09 03. 373(6559): eabc1048
    Developmental chromatin programs determine oncogenic competence in melanoma.
    Arianna Baggiolini, Scott J Callahan, Emily Montal, Joshua M Weiss, Tuan Trieu, Mohita M Tagore, Sam E Tischfield, Ryan M Walsh, Shruthy Suresh, Yujie Fan, Nathaniel R Campbell, Sarah C Perlee, Nathalie Saurat, Miranda V Hunter, Theresa Simon-Vermot, Ting-Hsiang Huang, Yilun Ma, Travis Hollmann, Satish K Tickoo, Barry S Taylor, Ekta Khurana, Richard P Koche, Lorenz Studer, Richard M White.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abc1048
  65. Front Microbiol. 2021 ;12 691433
    Pyomelanin Synthesis in Alternaria alternata Inhibits DHN-Melanin Synthesis and Decreases Cell Wall Chitin Content and Thickness.
    Chantal Fernandes, Marta Mota, Lillian Barros, Maria Inês Dias, Isabel C F R Ferreira, Ana P Piedade, Arturo Casadevall, Teresa Gonçalves.
      The genus Alternaria includes several of fungi that are darkly pigmented by DHN-melanin. These are pathogenic to plants but are also associated with human respiratory allergic diseases and with serious infections in immunocompromised individuals. The present work focuses on the alterations of the composition and structure of the hyphal cell wall of Alternaria alternata occuring under the catabolism of L-tyrosine and L-phenylalanine when cultured in minimal salt medium (MM). Under these growing conditions, we observed the released of a brown pigment into the culture medium. FTIR analysis demonstrates that the produced pigment is chemically identical to the pigment released when the fungus is grown in MM with homogentisate acid (HGA), the intermediate of pyomelanin, confirming that this pigment is pyomelanin. In contrast to other fungi that also synthesize pyomelanin under tyrosine metabolism, A. alternata inhibits DHN-melanin cell wall accumulation when pyomelanin is produced, and this is associated with reduced chitin cell wall content. When A. alternata is grown in MM containing L-phenylalanine, a L-tyrosine percursor, pyomelanin is synthesized but only at trace concentrations and A. alternata mycelia display an albino-like phenotype since DHN-melanin accumulation is inhibited. CmrA, the transcription regulator for the genes coding for the DHN-melanin pathway, is involved in the down-regulation of DHN-melanin synthesis when pyomelanin is being synthetized, since the CMRA gene and genes of the enzymes involved in DHN-melanin synthesis pathway showed a decreased expression. Other amino acids do not trigger pyomelanin synthesis and DHN-melanin accumulation in the cell wall is not affected. Transmission and scanning electron microscopy show that the cell wall structure and surface decorations are altered in L-tyrosine- and L-phenylalanine-grown fungi, depending on the pigment produced. In summary, growth in presence of L-tyrosine and L-phenylalanine leads to pigmentation and cell wall changes, which could be relevant to infection conditions where these amino acids are expected to be available.
    Keywords:  Alternaria alternata; DHN-melanin; L-phenylalanine; L-tyrosine; chitin; melanin; pyomelanin
    DOI:  https://doi.org/10.3389/fmicb.2021.691433
  66. Adv Mater. 2021 Sep 18. e2104849
    Immunotherapy and Prevention of Cancer by Nanovaccines Loaded with Whole-Cell Components of Tumor Tissues or Cells.
    Lin Ma, Lu Diao, Zuofu Peng, Yun Jia, Huimin Xie, Baisong Li, Jianting Ma, Meng Zhang, Lifang Cheng, Dawei Ding, Xuenong Zhang, Huabing Chen, Fengfeng Mo, Honglv Jiang, Guoqiang Xu, Fenghua Meng, Zhiyuan Zhong, Mi Liu.
      Tumor tissues/cells are the best sources of antigens to prepare cancer vaccines. However, due to the difficulty of solubilization and delivery of water-insoluble antigens in tumor tissues/cells, including water-insoluble antigens into cancer vaccines and delivering such vaccines efficiently to antigen-presenting cells (APCs) remain challenging. To solve these problems, herein, water-insoluble components of tumor tissues/cells are solubilized by 8 m urea and thus whole components of macrometer-sized tumor cells are reasssembled into nanosized nanovaccines. To induce maximized immunization efficacy, various antigens are loaded both inside and on the surface of nanovaccines. By encapsulating both water-insoluble and water-soluble components of tumor tissues/cells into nanovaccines, the nanovaccines are efficiently phagocytosed by APCs and showed better therapeutic efficacy than the nanovaccine loaded with only water-soluble components in melanoma and breast cancer. Anti-PD-1 antibody and metformin can improve the efficacy of nanovaccines. In addition, the nanovaccines can prevent lung cancer (100%) and melanoma (70%) efficiently in mice. T cell analysis and tumor microenvironment analysis indicate that tumor-specific T cells are induced by nanovaccines and both adaptive and innate immune responses against cancer cells are activated by nanovaccines. Overall, this study demonstrates a universal method to make tumor-cell-based nanovaccines for cancer immunotherapy and prevention.
    Keywords:  cancer immunotherapy; cancer prevention; cell lysate; drug delivery; nanovaccines; tumor tissues; whole cell components
    DOI:  https://doi.org/10.1002/adma.202104849
  67. J Immunother Cancer. 2021 Sep;pii: e002754. [Epub ahead of print]9(9):
    Functional analysis of peripheral and intratumoral neoantigen-specific TCRs identified in a patient with melanoma.
    Eva Bräunlein, Gaia Lupoli, Franziska Füchsl, Esam T Abualrous, Niklas de Andrade Krätzig, Dario Gosmann, Lukas Wietbrock, Sebastian Lange, Thomas Engleitner, Huan Lan, Stefan Audehm, Manuel Effenberger, Melanie Boxberg, Katja Steiger, Yinshui Chang, Kai Yu, Cigdem Atay, Florian Bassermann, Wilko Weichert, Dirk H Busch, Roland Rad, Christian Freund, Iris Antes, Angela M Krackhardt.
       BACKGROUND: Neoantigens derived from somatic mutations correlate with therapeutic responses mediated by treatment with immune checkpoint inhibitors. Neoantigens are therefore highly attractive targets for the development of therapeutic approaches in personalized medicine, although many aspects of their quality and associated immune responses are not yet well understood. In a case study of metastatic malignant melanoma, we aimed to perform an in-depth characterization of neoantigens and respective T-cell responses in the context of immune checkpoint modulation.
    METHODS: Three neoantigens, which we identified either by immunopeptidomics or in silico prediction, were investigated using binding affinity analyses and structural simulations. We isolated seven T-cell receptors (TCRs) from the patient's immune repertoire recognizing these antigens. TCRs were compared in vitro by multiparametric analyses including functional avidity, multicytokine secretion, and cross-reactivity screenings. A xenograft mouse model served to study in vivo functionality of selected TCRs. We investigated the patient's TCR repertoire in blood and different tumor-related tissues over 3 years using TCR beta deep sequencing.
    RESULTS: Selected mutated peptide ligands with proven immunogenicity showed similar binding affinities to the human leukocyte antigen complex and comparable disparity to their wild-type counterparts in molecular dynamic simulations. Nevertheless, isolated TCRs recognizing these antigens demonstrated distinct patterns in functionality and frequency. TCRs with lower functional avidity showed at least equal antitumor immune responses in vivo. Moreover, they occurred at high frequencies and particularly demonstrated long-term persistence within tumor tissues, lymph nodes and various blood samples associated with a reduced activation pattern on primary in vitro stimulation.
    CONCLUSIONS: We performed a so far unique fine characterization of neoantigen-specific T-cell responses revealing defined reactivity patterns of neoantigen-specific TCRs. Our data highlight qualitative differences of these TCRs associated with function and longevity of respective T cells. Such features need to be considered for further optimization of neoantigen targeting including adoptive T-cell therapies using TCR-transgenic T cells.
    Keywords:  CD8-positive T-lymphocytes; adaptive immunity; adoptive; antigens; immunologic; immunotherapy; neoplasm; receptors
    DOI:  https://doi.org/10.1136/jitc-2021-002754
  68. Nanoscale. 2021 Sep 17. 13(35): 14825-14836
    Neutrophil mediated postoperative photoimmunotherapy against melanoma skin cancer.
    Yunyun Wu, Xiaoqing Han, Runxiao Zheng, Hongda Cheng, Jiao Yan, Xiaqing Wu, Yaqing Hu, Bing Li, Zhenxin Wang, Xi Li, Haiyuan Zhang.
      Surgery is the primary treatment option for most melanoma; however, high tumor recurrence rate after surgical resection becomes the main cause of death in cancer patients. The development of efficient drug delivery nanosystems to inhibit postoperative tumor recurrence becomes very necessary. In the present study, IR780 molecules and TRP-2 peptide were encapsulated in the hydrophobic shell and hydrophilic interior of TAT peptide functionalized liposomes to form TLipIT NPs, which were further internalized into neutrophils (NEs) to achieve TLipIT/NEs. After being intravenously injected into postoperative B16F10-bearing mice, TLipIT/NEs could actively migrate toward the inflamed residual tumor and release TLipIT through neutrophil extracellular traps (NETs). Under NIR laser irradiation, the TLipIT exhibited both photothermal and photodynamic effects to induce immunogenic cell death for maturation of DCs, and simultaneously, to release TRP-2 peptide as a melanoma associated antigen to further strengthen the maturation of DCs, both of which prompts the activation of T cells and induces potent immune responses. TLipIT/NEs hold great potential for the inhibition of postoperative tumor recurrence.
    DOI:  https://doi.org/10.1039/d1nr04002b
  69. J Cosmet Dermatol. 2021 Sep 15.
    Microneedling-assisted topical tranexamic acid solution versus 4% hydroquinone for treating melasma: A split-face randomized study.
    Mohamed S Zaky, Zakaria M Obaid, Eman A Khalil, Mohamed L Elsaie.
       BACKGROUND: Melasma, also known as chloasma or mask of pregnancy, is a common, acquired, hyperpigmentary disorder usually affecting females. Tranexamic acid (TA), a derivative of amino acid lysine, has shown promising results over the past few years when used along with other therapies and when used as a stand-alone therapy.
    AIM OF THE WORK: In this study, we aimed to evaluate and compare the effectiveness of topically applied tranexamic acid after microneedling versus topically applied hydroquinone (HQ) 4% alone in patients with melasma.
    PATIENTS AND METHODS: Fifty selected patients were divided randomly according to the random number allocation method into two groups (25 patients each) of A (topical 4% hydroquinone, nightly application) and B (microneedling + topical 4% TA, every other week).
    RESULTS: After eight weeks of treatment, the mean modified MASI score of the HQ treated side changed from 6.604 ± 4.02 to 3.032 ± 1.19 with a mean decrease percentage of 54.8% ± 19.4%. This reduction in modified MASI score was found to be statistically significant, (p < 0.001). MASI score of group B (TA +microneedling) changed from 6.348 ± 3.84 to 3.712 ± 1.19 with mean decrease percentage of 57.4% ± 23.4% which was also statistically significant, (p < 0.001).
    CONCLUSION: We demonstrated safety and efficacy of both used modalities and with minimal side effects. Topical HQ application achieved minimal non-significant higher satisfactory results among raters and subjects.
    Keywords:  hydroquinone; melasma; microneedling; tranexamic acid
    DOI:  https://doi.org/10.1111/jocd.14440
  70. Clin Cosmet Investig Dermatol. 2021 ;14 1165-1171
    The Application of Skin Care Product in Melasma Treatment.
    Yu Wang, Jianmei Zhao, Lu Jiang, Yunzhu Mu.
      Melasma is an acquired and chronic hyperpigmentation disorder which is recognized as one of the most psychologically distressing and difficult to cure forms of skin hyperpigmentation. It is associated with substantial quality of life impairments. Treatments of melasma include local application, oral medication, physical laser therapy and program combination therapy. However, routine treatment usually leads to the damage of skin barrier function, resulting in adverse reactions such as erythema, pruritus, post-inflammatory pigmentation and even scar. Skin care products contain a variety of active ingredients, which are widely concerned by cosmetic dermatologists because of high safety, good tolerance and the effect of improving the damaged skin barrier. Using skin care products alone or in combination with routine treatment not only can improve the curative effect for melasma, reduce side effects and recurrence rate, but also improve patient satisfaction. This article mainly describes the application of skin care products in the treatment of melasma.
    Keywords:  melasma; skin care product; treatment
    DOI:  https://doi.org/10.2147/CCID.S323748
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