bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021–07–11
53 papers selected by
Farah Jaber-Hijazi, University of the West of Scotland
  1. The LncRNA MIR155HG is Upregulated by SP1 in Melanoma Cells and Drives Melanoma Progression via Modulating the MiR-485-3p/PSIP1 Axis.
  2. GJB5 association with BRAF mutation and survival in cutaneous malignant melanoma.
  3. Early melanoma invasivity correlates with gut fungal and bacterial profiles.
  4. What's new in pediatric melanoma and Spitz tumors? Pretty much everything.
  5. BRAF-inhibitor therapy related encephalitis in a patient with metastatic melanoma.
  6. Volume increase of spleen in melanoma patients undergoing immune checkpoint blockade.
  7. Type 2 innate lymphoid cells: a novel actor in anti-melanoma immunity.
  8. A Non-cutaneous Form of Melanoma in a Goat during Meat Inspection: a Case Report.
  9. Prior Therapy With Pegylated-Interferon Alfa-2b Improves the Efficacy of Adjuvant Pembrolizumab in Resectable Advanced Melanoma.
  10. 9-Gene Signature Correlated With CD8+ T Cell Infiltration Activated by IFN-γ: A Biomarker of Immune Checkpoint Therapy Response in Melanoma.
  11. SFPQ promotes an oncogenic transcriptomic state in melanoma.
  12. STAT3-induced ZBED3-AS1 promotes the malignant phenotypes of melanoma cells by activating PI3K/AKT signaling pathway.
  13. The Research on the Treatment of Metastatic Skin Cutaneous Melanoma by Huanglian Jiedu Decoction Based on the Analysis of Immune Infiltration Analysis.
  14. Retrospective study of ultraviolet indices and incidence of melanoma in the United States.
  15. LncRNA MSC-AS1 motivates the development of melanoma by binding to miR-302a-3p and recruiting IGF2BP2 to elevate LEF1 expression.
  16. Health Care Utilization and Costs Associated With Systemic First-Line Metastatic Melanoma Therapies in the United States.
  17. Rosmarinic acid inhibits proliferation and migration, promotes apoptosis and enhances cisplatin sensitivity of melanoma cells through inhibiting ADAM17/EGFR/AKT/GSK3β axis.
  18. Interferon-α1b for the treatment of metastatic melanoma: results of a retrospective study.
  19. The role of Hypoxia-Inducible Factor-1alpha and its signaling in melanoma.
  20. Anti-tumor efficacy of a combination therapy with PD-L1 targeted alpha therapy and adoptive cell transfer of PD-1 deficient melanoma-specific human T-lymphocytes.
  21. Bilirubin Restrains the Anticancer Effect of Vemurafenib on BRAF-Mutant Melanoma Cells Through ERK-MNK1 Signaling.
  22. A PDZ Protein GIPC3 Positively Modulates Hedgehog Signaling and Melanoma Growth.
  23. Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers.
  24. Surfactin exerts an anti-cancer effect through inducing allergic reactions in melanoma skin cancer.
  25. Knockdown of DEAD-box RNA helicase 52 (DDX52) suppresses the proliferation of melanoma cells in vitro and of nude mouse xenografts by targeting c-Myc.
  26. A mutual information-based in vivo monitoring of adaptive response to targeted therapies in melanoma.
  27. Melanoma Extension for Community Healthcare Outcomes: A Feasibility Study of Melanoma Screening Implementation in Primary Care Settings.
  28. De Novo Mutation in Non-Tyrosine Kinase Domain of ROS1 as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma.
  29. Targeting HIF-activated collagen prolyl 4-hydroxylase expression disrupts collagen deposition and blocks primary and metastatic uveal melanoma growth.
  30. An In Vitro-In Vivo Evaluation of the Antiproliferative and Antiangiogenic Effect of Flavone Apigenin against SK-MEL-24 Human Melanoma Cell Line.
  31. Biocompatible gum arabic-gold nanorod composite as an effective therapy for mistreated melanomas.
  32. Choroidal malignant melanoma masquerading as orbital cellulitis.
  33. False positive FDG uptake in melanoma patients treated with talimogene laherparepvec (T-VEC).
  34. Stereotactic radiosurgery with immunotherapy is associated with improved overall survival in patients with metastatic melanoma or non-small cell lung cancer: a National Cancer Database analysis.
  35. A prospective, comprehensive registry that integrates the molecular analysis of pediatric and adolescent melanocytic lesions.
  36. Fluorescent in situ hybridization (FISH): A useful diagnostic tool for childhood conjunctival melanoma.
  37. Exploring the implications of the first COVID-19 lockdown on patients with melanoma: a national survey.
  38. Survival Outcomes Following Discontinuation of Ipilimumab and Nivolumab for Advanced Melanoma in a Population-based Cohort.
  39. Optimizing Detection of Lymphatic Invasion in Primary Cutaneous Melanoma With the Use of D2-40 and a Paired Melanocytic Marker.
  40. The regional distribution of melanosomes in the epidermis affords a localized intensive photoprotection for basal keratinocyte stem cells.
  41. Primary malignant melanoma of uterine cervix treated with pembrolizumab as adjuvant immunotherapy.
  42. Lysine Demethylases: Promising Drug Targets in Melanoma and Other Cancers.
  43. Subcutaneous sarcoidosis induced by pembrolizumab in a melanoma patient mimicking subcutaneous metastasis at 18F-FDG PET/CT.
  44. Male genital vitiligo.
  45. Dissecting immune cell stat regulation network reveals biomarkers to predict ICB therapy responders in melanoma.
  46. The cell membrane as the barrier in the defense against nanoxenobiotics: Zinc oxide nanoparticles interactions with native and model membrane of melanoma cells.
  47. The utility of ICG fluorescence for sentinel lymph node identification in head and neck melanoma.
  48. Impact of the COVID-19 pandemic on melanoma diagnosis.
  49. Large Plaque-type Blue Nevus with GNAQ Q209P Mutation, Involving Mammary Gland Tissue: Under-Recognized Mammary Condition as an Origin of Primary Mammary Melanocytic Tumors.
  50. Hair Follicle Stem Cells for Tissue Regeneration.
  51. Ganglionar tuberculosis infection evolving to hemophagocytic lymphohistiocytosis after anti-programmed cell death 1 treatment for high-risk melanoma: a case report.
  52. Incidental discovery of cilio-choroidal melanoma following initial presentation of liver metastases.
  53. Histopathology and immunohistochemistry of choroidal melanocytoma demonstrated by local resection: A case report.
  1. Anticancer Agents Med Chem. 2021 Mar 21.
    The LncRNA MIR155HG is Upregulated by SP1 in Melanoma Cells and Drives Melanoma Progression via Modulating the MiR-485-3p/PSIP1 Axis.
    Jia Huo, Yuan Wang, Yanfei Zhang, Wei Wang, Peiwen Yang, Wenwei Zhao, Miaomiao Zhang, Lu Cui, Dingwei Zhang.
       BACKGROUND: MIR155HG is a long non-coding RNA (lncRNA) that has been shown to be dysregulated in a range of tumor types, but the functions of this lncRNA in melanoma remain to be explored.
    OBJECTIVES: We explored the functions of lncRNA MIR155HG in melanoma progression.
    METHODS: The expression of miR155HG was analyzed in clinical melanoma. Bioinformatics analysis was performed to assess the potential tumor-related functions of miR155HG. The interaction of miR155HG and SP1 and the inhibition of PSIP1 by miR-485-3p were analyzed by ChIP, luciferase reporter experiments, and biological effects in melanoma were explored by colony formation assays, EdU cell proliferation assays, Transwell analysis and intracranial melanoma mouse model.
    RESULTS: Herein, we found that MIR155HG was markedly upregulated in melanoma cell lines and tissues. We further determined that the SP1 transcription factor was responsible for driving MIR155HG upregulation in melanoma. Elevated MIR155HG levels were linked to decreased overall survival (OS) in melanoma patients, and we further determined that MIR155HG expression was an independent predictor of melanoma patient prognosis. When MIR155HG was knocked down in melanoma cells, this impaired their proliferative, migratory, and invasive activity. Using predictive bioinformatics analyses, we identified miR-485-3p as a microRNA (miRNA) capable of binding to both MIR155HG and the 3' UTR of PSIP1.
    CONCLUSION: Together, these results suggest that MIR155HG is capable of promoting melanoma cell proliferation via the miR-485-3p/PSIP1 axis. These novel findings provide new insights into the development of melanoma, potentially highlighting future avenues for therapeutic intervention.
    Keywords:  MIR155HG; Melanoma; PSIP1; SP1; miR-485-3p; progression
    DOI:  https://doi.org/10.2174/1871520621666210322092906
  2. Br J Dermatol. 2021 Jul 08.
    GJB5 association with BRAF mutation and survival in cutaneous malignant melanoma.
    M Scatolini, A Patel, E Grosso, M Mello-Grand, P Ostano, R Coppo, M Vitiello, T Venesio, A Zaccagna, A Pisacane, I Sarotto, D Taverna, L Poliseno, D Bergamaschi, G Chiorino.
       BACKGROUND: Gap junctional intercellular communication is crucial for epidermal cellular homeostasis. Inability to establish melanocyte-keratinocytes contacts and loss of intercellular junction's integrity may contribute to melanoma development. Connexins, laminins and desmocollins have been implicated in the control of melanoma growth, where their reduced expression has been reported in metastatic lesions.
    OBJECTIVES: The aim of this study was to investigate Connexin 31.1 (GJB5) expression and identify any association with BRAF mutational status, melanoma patient prognosis and MAPK inhibitors (MAPKi) treatment.
    MATERIAL AND METHODS: GJB5 expression was measured at RNA and protein level in melanoma clinical samples and established cell lines treated or not with BRAF and MEK inhibitors, as well as in cell lines which developed MAPK inhibitors resistance. Findings were further validated and confirmed by analysis of independent datasets.
    RESULTS: Our analysis reveals significant downregulation of GJB5 expression in metastatic melanoma lesions compared to primary ones and in BRAF mutated versus BRAF wild-type melanomas. Likewise, GJB5 expression is significantly lower in BRAFV600E compared with BRAFWT cell lines and increases upon MAPKi treatment. MAPKi-resistant melanoma cells display a similar expression pattern compared to BRAFWT cells, with increased GJB5 expression associated with morphological changes. Enhancement of BRAFV600E expression in BRAFWT melanoma cells significantly upregulates miR-335-5p expression with consequent downregulation of GJB5, one of its targets. Furthermore, overexpression of miR-335-5p in two BRAFWT cell lines confirms specific GJB5 protein downregulation. RT-qPCR analysis also revealed upregulation of miR-335 in BRAFV600E melanoma cells, which is significantly downregulated in cells resistant to MEK inhibitors. Our data were further validated using the TCGA-SKCM dataset, where BRAF mutations associate with increased miR-335 expression and inversely correlate with GJB5 expression. In clinical samples, GJB5 underexpression is also associated with patient overall worse survival, especially at early stages.
    CONCLUSION: We identified a significant association between metastases / BRAF mutation and low GJB5 expression in melanoma. Our results identify a novel mechanism of Gap-junctional protein regulation, suggesting a prognostic role for GJB5 in cutaneous melanoma.
    DOI:  https://doi.org/10.1111/bjd.20629
  3. Br J Dermatol. 2021 Jul 06.
    Early melanoma invasivity correlates with gut fungal and bacterial profiles.
    F Vitali, R Colucci, M Di Paola, M Pindo, C De Filippo, S Moretti, D Cavalieri.
       BACKGROUND: The microbiome is emerging as a crucial player of the immune checkpoint in cancer. Melanoma is a highly immunogenic tumour, and the gut microbiome composition has been correlated to prognosis and evolution of advanced melanoma and proposed as biomarker for immune checkpoint therapy.
    OBJECTIVES: We investigated the gut fungal and bacterial composition in early-stage melanoma and correlated microbial profiles with histopathological features.
    METHODS: Bacterial 16S rRNA and fungal ITS region sequencing was performed from faecal samples of patients affected by stage I and II melanoma, and healthy controls. A meta-analysis with gut microbiota data from metastatic melanoma patients was also carried out.
    RESULTS: We found a combination of gut fungal and bacterial profiles significantly discriminating M patients from controls. In melanoma patients, we observed an abundance of Prevotella copri and yeasts belonging to the Saccharomycetales order. We found bacterial and fungal community correlated to melanoma invasiveness, whereas specific fungal profile correlated to melanoma regression. Bacteroides was identified as general marker of immunogenicity, being shared by regressive and invasive melanoma. In addition, the bacterial community from stage I and II patients were different in structure and richer than those from metastatic melanoma patients.
    CONCLUSIONS: Gut microbiota composition in early-stage melanoma changes along the gradient from in situ to invasive (and metastatic) melanoma. Changes in the microbiota and mycobiota are correlated to the histological features of early-stage melanoma, and to the clinical course and response to immune therapies of advanced stage melanoma, through a direct or indirect immunomodulation.
    DOI:  https://doi.org/10.1111/bjd.20626
  4. Cancer. 2021 Jul 06.
    What's new in pediatric melanoma and Spitz tumors? Pretty much everything.
    Vernon K Sondak, Jane L Messina.
       LAY SUMMARY: Pathologists sometimes have great difficulty in determining whether a mole biopsied from the skin of a child is benign or malignant. New molecular technologies have helped pathologists to identify pediatric melanomas, but there are still some atypical moles that cannot be definitively classified as benign or malignant. With further research, it is hoped that the number of these atypical tumors can be decreased and that the treatment for all children with moles and melanoma can be improved.
    Keywords:  Spitz nevus; Spitzoid melanoma; atypical Spitz tumor; melanoma; pediatric
    DOI:  https://doi.org/10.1002/cncr.33749
  5. Oncologist. 2021 Jul 05.
    BRAF-inhibitor therapy related encephalitis in a patient with metastatic melanoma.
    Nalan Akgul Babacan, Edwin Peguero, Peter Forsyth, Zeynep Eroglu.
       INTRODUCTION: BRAF-inhibitors such as encorafenib and vemurafenib in combination with MEK inhibitors are commonly used for the treatment of patients with BRAFV600-mutant melanoma.
    CASE PRESENTATION: A patient with relapsed metastatic melanoma with a BRAFV600 mutation was started on treatment with vemurafenib and cobimetinib. Within two weeks of treatment-start, he was hospitalized and diagnosed with encephalitis through a lumbar puncture and treated with corticosteroids, with subsequent normalization of CSF findings. When he recovered and was switched to encorafenib treatment, the same symptoms recurred and patient was treated with high dose steroids and IVIG, again with improvement in his CSF. He has not had a relapse of his symptoms since BRAF-inhibitor treatment was permanently discontinued.
    CONCLUSION: This is the first known report of a patient who has developed encephalitis due to treatment with BRAF-inhibitors.
    Keywords:  BRAF-inhibitors; encephalitis; melanoma
    DOI:  https://doi.org/10.1002/onco.13896
  6. Immunotherapy. 2021 Jul 07.
    Volume increase of spleen in melanoma patients undergoing immune checkpoint blockade.
    Laura Susok, Dominik Reinert, Carsten Lukas, Eggert Stockfleth, Thilo Gambichler.
      Aim: To find out whether treatment with immune checkpoint inhibitors (ICIs) results in volume increase of the spleen. Patient & methods: We studied 49 stage III and IV melanoma patients with an indication for ICIs. Computer tomographic-assisted volumetry of spleens was performed. Results: After 3 months, median spleen volume was significantly increased when compared with the baseline volume. At 3 months, the increase of spleen volume was significantly associated with the use of ipilimumab and ipilimumab plus nivolumab. There was no significant association between spleen volume increase and clinical parameters. Conclusion: The median spleen volume of patients with cutaneous melanoma increases during the first months of ICI treatment, which was particularly attributable to the use of anti-CTLA-4 and anti-CTLA-4/anti-PD-1 regimens.
    Keywords:  CTLA-4; PD-1; immunotherapy; ipilimumab; melanoma; nivolumab; pembrolizumab; spleen; spleenic
    DOI:  https://doi.org/10.2217/imt-2021-0022
  7. Oncoimmunology. 2021 ;10(1): 1943168
    Type 2 innate lymphoid cells: a novel actor in anti-melanoma immunity.
    Nicolas Jacquelot, Gabrielle T Belz.
      Immunity to melanoma is thought to be mainly mediated by adaptive immune cells. To what extent innate immunity, particularly innate lymphoid cells, drive the immune response and impact melanoma prognosis and therapeutic responsiveness is not well understood. In a recent article published in Nature Immunology, we uncovered a critical role that ILC2 play in the control of melanoma. Using both complementary mouse models and human samples, we showed that ILC2-derived granulocyte macrophage-colony stimulating factor (GM-CSF) drives eosinophil tumor recruitment and activation. We found that ILC2 express PD-1 which inhibits ILC2 effector function and impairs anti-tumor responses. We further demonstrated that the combination of IL-33 and anti-PD-1 blocking antibodies improved anti-tumor responses through the expansion of splenic and tumor-infiltrating ILC2 and eosinophils. These findings have revealed an essential mechanism involving ILC2 and eosinophils necessary for anti-melanoma immunity and immunotherapy responses.
    Keywords:  ILC2; anti-PD-1; eosinophils; immunotherapy; melanoma
    DOI:  https://doi.org/10.1080/2162402X.2021.1943168
  8. Arch Razi Inst. 2021 Jul;76(2): 407-410
    A Non-cutaneous Form of Melanoma in a Goat during Meat Inspection: a Case Report.
    A Hatefi, M Seyedrasouli, D Mohajeri, M Ahmadian.
      Malignant melanoma is a neoplasm that originates from melanocytes. This tumor is observed in cutaneous and non-cutaneous forms, and it is considered one of the most life-threatening types of cancers. Non-cutaneous melanoma is a complex of unique and malignant complications that are easily separable from cutaneous type. Since the ultraviolet radiation from the sun damages DNA and is an oxidative stress factor in melanoma and there are more melanocytes in the basal layer of skin than other parts of the body, the cutaneous form has more prevalence. Most of the time, non-cutaneous form is the result of cutaneous metastasis but both forms can occur primarily. Furthermore, non-cutaneous form usually happens in mucosal layers, intestines, and eyes; moreover, the main reasons are ectopic melanocytes or their unwanted regressive growing. Malignant melanoma can occur in all domestic animals; however, they seem to be rare in sheep and goats. Herein, we describe a rare case of the primary non-cutaneous form of malignant melanoma in a three-year-old indigenous female goat. During meat inspection procedures in a slaughterhouse in Tabriz, Iran, we encountered numerous round firm black masses on visceral surfaces and serous membranes of the abdominal and thoracic cavities. The liver and lungs were prominently affected. Samples were taken from involved parts, and malignant melanoma was confirmed in the histopathological examination due to pleomorphism and polymorphism and melanin pigments in cells with eosinophilic cytoplasm. According to what was stated in the "manual on meat inspection for developing countries", the carcass was not convenient for human use and condemned by the inspector.
    Keywords:  Goat; Meat inspection; Melanoma; Slaughterhouse
    DOI:  https://doi.org/10.22092/ari.2020.127673.1388
  9. Front Oncol. 2021 ;11 675873
    Prior Therapy With Pegylated-Interferon Alfa-2b Improves the Efficacy of Adjuvant Pembrolizumab in Resectable Advanced Melanoma.
    Dong-Dong Jia, Yanling Niu, Honglin Zhu, Sizhen Wang, Tonghui Ma, Tao Li.
      Combination immunotherapy can overcome the limited objective response rates of PD-1 blockade. Interferon alpha (IFN-α) has been proven to be effective in modulating immune responses and may enhance the clinical responses to PD-1 blockade. According to clinical practice guidelines, IFN-α was recommended as adjuvant therapy for stage IIB/C melanoma patients. However, the impact of prior IFN-α therapy on the efficacy of subsequent PD-1 blockade in melanoma has not been previously reported. Therefore, we performed a retrospective analysis for melanoma patients and addressed whether prior IFN-α therapy enhanced adjuvant pembrolizumab as later-line treatment. Fifty-six patients with resectable stage III/IV melanoma who received adjuvant therapy with pembrolizumab were retrospectively enrolled in this study. Notably, 25 patients received adjuvant pegylated IFN-α (PEG-IFN-α) in the prior line of treatment while 31 patients did not receive prior PEG-IFN-α therapy. Cox regression analysis showed that prior PEG-IFN-α therapy was associated with the efficacy of later-line adjuvant pembrolizumab (hazard ratio=0.37, 95% CI 0.16-0.89; P = 0.026). The recurrence rates after treatment with adjuvant pembrolizumab were significantly reduced in the prior PEG-IFN-α group (P < 0.001). The Kaplan-Meier analysis also showed that recurrence-free survival (RFS) after adjuvant pembrolizumab therapy was prolonged by prior PEG-IFN-α treatment (median RFSPem 8.5 months vs. 4.5 months; P = 0.0372). These findings indicated that prior PEG-IFN-α could enhance the efficacy of adjuvant pembrolizumab. The long-lasting effects of PEG-IFN-α provide a new rationale for designing combination or sequential immunotherapy.
    Keywords:  adjuvant pembrolizumab; advanced melanoma; interferon alpha; recurrence-free survival; sequential therapy
    DOI:  https://doi.org/10.3389/fonc.2021.675873
  10. Front Immunol. 2021 ;12 622563
    9-Gene Signature Correlated With CD8+ T Cell Infiltration Activated by IFN-γ: A Biomarker of Immune Checkpoint Therapy Response in Melanoma.
    Kexin Yan, Yuxiu Lu, Zhangyong Yan, Yutao Wang.
       Purpose: To identify CD8+ T cell-related factors and the co-expression network in melanoma and illustrate the interactions among CD8+ T cell-related genes in the melanoma tumor microenvironment.
    Method: We obtained melanoma and paracancerous tissue mRNA matrices from TCGA-SKCM and GSE65904. The CIBERSORT algorithm was used to assess CD8+ T cell proportions, and the "estimate" package was used to assess melanoma tumor microenvironment purity. Weighted gene co-expression network analysis was used to identify the most related co-expression modules in TCGA-SKCM and GSE65904. Subsequently, a co-expression network was built based on the joint results in the two cohorts. Subsequently, we identified the core genes of the two most relevant modules of CD8+T lymphocytes according to the module correlation, and constructed the signature using ssGSEA. Later, we compared the signature with the existing classical pathways and gene sets, and confirmed the important prognostic significance of the signature in this paper.
    Results: Nine co-expressed genes were identified as CD8+ T cell-related genes enriched in the cellular response to interferon-gamma process and antigen processing and presentation of peptide antigen. In the low expression level group, inflammation and immune responses were weaker. Single-cell sequencing and immunohistochemistry indicated that these nine genes were highly expressed in CD8+ T cells group.
    Conclusion: We identified nine-gene signature, and the signature is considered as the biomarker for T lymphocyte response and clinical response to immune checkpoint inhibitors for melanoma.
    Keywords:  CD8+ T cells; immune microenvironment; immunotherapy; melanoma; weighted gene co-expression network analysis (WGCNA)
    DOI:  https://doi.org/10.3389/fimmu.2021.622563
  11. Oncogene. 2021 Jul 03.
    SFPQ promotes an oncogenic transcriptomic state in melanoma.
    O Bi, C A Anene, J Nsengimana, M Shelton, W Roberts, J Newton-Bishop, J R Boyne.
      The multifunctional protein, splicing factor, proline- and glutamine-rich (SFPQ) has been implicated in numerous cancers often due to interaction with coding and non-coding RNAs, however, its role in melanoma remains unclear. We report that knockdown of SFPQ expression in melanoma cells decelerates several cancer-associated cell phenotypes, including cell growth, migration, epithelial to mesenchymal transition, apoptosis, and glycolysis. RIP-seq analysis revealed that the SFPQ-RNA interactome is reprogrammed in melanoma cells and specifically enriched with key melanoma-associated coding and long non-coding transcripts, including SOX10, AMIGO2 and LINC00511 and in most cases SFPQ is required for the efficient expression of these genes. Functional analysis of two SFPQ-enriched lncRNA, LINC00511 and LINC01234, demonstrated that these genes independently contribute to the melanoma phenotype and a more detailed analysis of LINC00511 indicated that this occurs in part via modulation of the miR-625-5p/PKM2 axis. Importantly, analysis of a large clinical cohort revealed that elevated expression of SFPQ in primary melanoma tumours may have utility as a prognostic biomarker. Together, these data suggest that SFPQ is an important driver of melanoma, likely due to SFPQ-RNA interactions promoting the expression of numerous oncogenic transcripts.
    DOI:  https://doi.org/10.1038/s41388-021-01912-4
  12. RNA Biol. 2021 Jul 09.
    STAT3-induced ZBED3-AS1 promotes the malignant phenotypes of melanoma cells by activating PI3K/AKT signaling pathway.
    Yang Wang, Nan Lou, Min Zuo, Fuqiang Zhu, Yan He, Zhiqiang Cheng, Xiaomei Wang.
      Melanoma is considered as the most frequent primary malignancy occurring in skin. Accumulating studies have suggested that long non-coding RNAs (lncRNAs) play critical parts in multiple cancers. In this study, we explored the molecular mechanism of ZBED3 antisense RNA 1 (ZBED3-AS1) in melanoma. We observed that ZBED3-AS1 expression was remarkably up-regulated in melanoma tissues, and high ZBED3-AS1 level was linked to unsatisfactory survival of melanoma patients. Then, we discovered that ZBED3-AS1 was overexpressed in melanoma cells compared with human epidermal melanocytes. In addition, loss-of-function assays verified that ZBED3-AS1 knockdown restrained cell proliferation, migration, epithelial-mesenchymal transition (EMT) and stemness in melanoma. In addition, signal transducer and activator of transcription 3 (STAT3), which also showed tumor-facilitating functions in melanoma, was confirmed as a transcriptional activator of ZBED3-AS1. Moreover, ZBED3-AS1 enhanced the expression of AT-rich interaction domain 4B (ARID4B) through sequestering miR-381-3p. Importantly, we further confirmed that ZBED3-AS1 promoted the malignant progression of melanoma by regulating miR-381-3p/ARID4B axis to activate the phosphatidylinositol 3-kinase/AKT serine/threonine kinase (PI3K/AKT) signaling pathway. In a word, our research might provide a novel therapeutic target for melanoma.
    Keywords:  ARID4B; Melanoma; PI3K/AKT; ZBED3-AS1; miR-381-3p
    DOI:  https://doi.org/10.1080/15476286.2021.1950463
  13. Evid Based Complement Alternat Med. 2021 ;2021 9952060
    The Research on the Treatment of Metastatic Skin Cutaneous Melanoma by Huanglian Jiedu Decoction Based on the Analysis of Immune Infiltration Analysis.
    Ding Li, Shi-Fang Li, Xiao-Yuan Li, Xiao-Wei Sun, Tian-Yue Sun, Guo-Jie Hu.
       Objective: To explore the potential mechanism of Huanglian Jiedu Decoction (HJD) treatment and prevention of metastatic Cutaneous Melanoma (CM) occurrence and metastasis based on network pharmacological methods and immune infiltration analysis.
    Methods: The GEO database was used to obtain metastatic CM disease targets, the TCMSP database and the HERB database were used to obtain HJD action targets, core genes were screened by protein interaction network, and the potential mechanism of HJD in the treatment of metastatic CM was explored by enrichment analysis, prognostic analysis and immune infiltration analysis.
    Results: HJD treatment of metastatic CM involved 60 targets, enrichment analysis showed that HJD treatment of metastatic CM involved Chemokine signaling pathway, NF-kappa B signaling pathway, and Fluid shear stress and atherosclerosis, etc. Prognostic analysis revealed that HJD had a certain ability to improve the prognosis of metastatic CM patients. Immune infiltration analysis showed that HJD could inhibit the immune cell infiltration of metastatic CM patients by acting on related targets.
    Conclusions: Our study identified the potential mechanism of HJD in the treatment of metastatic CM through network pharmacology, and revealed the mechanism of HJD in the prevention of Skin Cutaneous Melanoma metastasis through immune infiltration analysis and prognostic analysis.
    DOI:  https://doi.org/10.1155/2021/9952060
  14. Int J Dermatol. 2021 Jul 09.
    Retrospective study of ultraviolet indices and incidence of melanoma in the United States.
    Yu Wang, Shari R Lipner.
      
    DOI:  https://doi.org/10.1111/ijd.15773
  15. Exp Dermatol. 2021 Jul 04.
    LncRNA MSC-AS1 motivates the development of melanoma by binding to miR-302a-3p and recruiting IGF2BP2 to elevate LEF1 expression.
    Yan Ma, Yuanyuan Jin, Can Li, Yilun Liu, Dehuai Wang.
      Melanoma is considered as the most common malignancy among skin cancers. The roles of many long non-coding RNAs (lncRNAs) have been clearly identified in multiple tumors. Nevertheless, lncRNA MSC antisense RNA 1 (MSC-AS1) has not been deeply investigated melanoma. In the present study, RT-qPCR and western blot analyses were used to measure the expression of RNAs and proteins. Functional and in vivo assays were implemented to detect the function of genes in melanoma. RNA pull down, RIP and luciferase reporter assays were applied for determining interactions between RNA and protein molecules. It was observed that MSC-AS1 and lymphoid enhancer binding factor 1 (LEF1) were remarkably up-regulated while microRNA-302a-3p (miR-302a-3p) down-regulated in melanoma cell lines. The silencing of MSC-AS1 hindered cell proliferation, migration and epithelial-mesenchymal transition (EMT) in vitro and tumor growth in vivo. Furthermore, MSC-AS1 regulated LEF1 expression through sponging miR-302a-3p and recruiting insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2). Eventually, LEF1 overexpression rescued cell progression impaired by MSC-AS1 knockdown. In summary, our research identified the MSC-AS1/miR-302a-3p/IGF2BP2/LEF1 axis in melanoma development, which indicated that MSC-AS1 is a potential biomarker in the treatment of melanoma.
    Keywords:  IGF2BP2; LEF1; MSC-AS1; Melanoma; miR-302a-3p
    DOI:  https://doi.org/10.1111/exd.14427
  16. JCO Oncol Pract. 2021 Jul 06. OP2100140
    Health Care Utilization and Costs Associated With Systemic First-Line Metastatic Melanoma Therapies in the United States.
    Sascha van Boemmel-Wegmann, Joshua D Brown, Vakaramoko Diaby, Jinhai Huo, Natalie Silver, Haesuk Park.
       PURPOSE: US Food and Drug Administration approvals of immune checkpoint inhibitors and targeted therapies revolutionized the treatment of metastatic melanoma. Our aim was to assess health care resource utilization and costs for patients with metastatic melanoma treated with systemic therapies in first line between January 2012 and December 2017.
    METHODS: We conducted a retrospective cohort study of patients with metastatic melanoma using MarketScan data. We included patients diagnosed with melanoma and secondary malignant neoplasm who used pembrolizumab, nivolumab, ipilimumab, ipilimumab plus nivolumab, BRAF-inhibitor (BRAF-i) plus MEK inhibitor (MEK-i), BRAF-i or MEK-i monotherapy, or chemotherapy in first line. We compared health care utilization and costs per patient per month (PPPM) using two-part and generalized linear models.
    RESULTS: We identified 1,870 patients, including 185 pembrolizumab, 103 nivolumab, 689 ipilimumab, 185 nivolumab plus ipilimumab, 214 BRAF-i plus MEK-i, 240 BRAF-i or MEK-i monotherapy, and 254 chemotherapy users. Highest PPPM rates of hospitalizations, emergency room visits, and outpatient visits were observed in patients with ipilimumab plus nivolumab therapy (adjusted difference v pembrolizumab [aDiff], 0.18, 0.12, and 0.88, respectively; all P < .001). Ipilimumab monotherapy users (aDiff, 0.07 and 0.93; all P < .001) and chemotherapy users (aDiff, 0.10 and 2.63; all P < .001) showed higher PPPM rates of hospitalizations and outpatient visits compared with pembrolizumab users, respectively. Utilization rates in nivolumab, BRAF-i plus MEK-i, and BRAF-i or MEK-i groups were similar to the pembrolizumab group. Highest PPPM total costs and drug-related costs were observed in the ipilimumab group ($80,139 US dollars [USD] and $70,051 USD; all P < .001), followed by the ipilimumab plus nivolumab ($71,689 USD and $56,217 USD; all P < .001) and the BRAF-i plus MEK-i group ($31,184 USD and $19,648 USD; all P < .001). PPPM costs in the nivolumab group were similar to the pembrolizumab group.
    CONCLUSION: Significant differences in health care resource utilization and costs were found across first-line metastatic melanoma regimens. Utilization rates were highest in patients using ipilimumab-containing therapies. High drug costs constituted a major fraction of total PPPM health care costs.
    DOI:  https://doi.org/10.1200/OP.21.00140
  17. Bioengineered. 2021 Dec;12(1): 3065-3076
    Rosmarinic acid inhibits proliferation and migration, promotes apoptosis and enhances cisplatin sensitivity of melanoma cells through inhibiting ADAM17/EGFR/AKT/GSK3β axis.
    Lin Huang, Jiangyan Chen, Jin Quan, Debing Xiang.
      Rosmarinic acid (RA), a naturally occurring polyphenolic compound, exerts multiple biological properties including anti-cancer. The metalloprotease, a disintegrin and metalloproteinase 17 (ADAM17), can activate ligands of the epidermal growth factor receptor (EGFR) and contribute to tumor progression. We aimed to investigate whether RA could exhibit anti-cancer effects in melanoma cells through down-regulating ADAM17. The human melanoma A375 cells were exposed to RA, then cell viability, migration, invasion, apoptosis, melanin content and the expression of ADAM17/EGFR/AKT/GSK3β were evaluated. The viability of cells exposed to RA in the presence of cisplatin (Cis) was measured by CCK-8. Cells were overexpressed with ADAM17 in the absence or presence of RA and ADAM17 inhibitor (TACE prodomain; TPD) co-treatment, then the above cellular processes were also observed. Results showed that A375 cells treated with RA showed significant lower cell viability, proliferation, migrative and invasive abilities, melanin content and expression of related proteins including MMP2 and MMP9, compared with normal cells. RA enhanced the ratio of TUINEL-positive cells, the expression of pro-apoptotic proteins, but reduced Bcl-2 expression. RA co-treatment increased the inhibitory effect of Cis on cell viability. RA inhibited the expression of ADAM17/EGFR/AKT/GSK3β, which was further suppressed by TPD. Moreover, ADAM17 overexpression blocked all the effects of RA whereas TPD treatment generated an opposite function. In conclusion, RA exerted obvious inhibitory effect on melanoma cell proliferation, migration and invasion, but promotive effect on cells apoptosis. Addition, the showing of this characteristic of RA may rely on inhibiting the expression of ADAM17/EGFR/AKT/GSK3β axis.
    Keywords:  ADAM17; Rosmarinic acid; cisplatin; melanoma
    DOI:  https://doi.org/10.1080/21655979.2021.1941699
  18. Anticancer Drugs. 2021 Jul 04.
    Interferon-α1b for the treatment of metastatic melanoma: results of a retrospective study.
    Qiong Shi, Lin Liu, Weigang Zhang, Yanhong Zhao, Yu Liu, Guannan Zhu, Weinan Guo, Tao Zhao, Jianhong Zhao, Lei Wang, Chunying Li, Tianwen Gao.
       OBJECTIVES: Recombinant human interferon-α1b (IFN-α1b) is the first genetic engineered drug of China and is approved for cancer treatment by Chinese Food and Drug Administration. Although recombinant IFN-α1b is biologically and therapeutically active, its long-term efficacy against advanced melanoma is unknown.
    METHODS: Ninety patients who were diagnosed with stage IV melanoma and received recombinant IFN-α1b therapy in our department were included in this study. The safety and efficacy of IFN-α1b were analyzed.
    RESULTS: IFN-α1b was overall well tolerated, with only 7.8% of the patients showing grade 3 toxicity and none with grade 4 toxicity or treatment-related death. The most common adverse effect was fever (78.9%). Furthermore, increasing the drug dosage showed no increase in the incidence of adverse events. The median overall survival (mOS) of the cohort was 14.1 months (95% confidence interval, 11.3-16.9 months). There was no significant difference of the mOS between samples of various primary sites. In the 42 patients who had not received prior adjuvant interferon therapy, the objective response rate, disease control rate and clinical benefit rate were 7.1, 28.5 and 21.4%, respectively.
    CONCLUSION: Our findings suggest that systemic IFN-α1b treatment is a relatively safe therapy and could prolong the survival of patients with unresectable metastatic melanoma.
    DOI:  https://doi.org/10.1097/CAD.0000000000001120
  19. Biomed Pharmacother. 2021 Jul 02. pii: S0753-3322(21)00655-7. [Epub ahead of print]141 111873
    The role of Hypoxia-Inducible Factor-1alpha and its signaling in melanoma.
    Mohammad Malekan, Mohammad Ali Ebrahimzadeh, Fateme Sheida.
      Adaptation to the loss of O2 is regulated via the activity of hypoxia-inducible factors such as Hypoxia-Inducible Factor-1 (HIF-1). HIF-1 acts as a main transcriptional mediator in the tissue hypoxia response that regulates over 1000 genes related to low oxygen tension. The role of HIF-1α in oncogenic processes includes angiogenesis, tumor metabolism, cell proliferation, and metastasis, which has been examined in various malignancies, such as melanoma. Melanoma is accompanied by a high death rate and a cancer type whose incidence has risen over the last decades. The linkage between O2 loss and melanogenesis had extensively studied over decades. Recent studies revealed that HIF-1α contributes to melanoma progression via different signaling pathways such as PI3K/Akt/mTOR, RAS/RAF/MEK/ERK, JAK/STAT, Wnt/β-catenin, Notch, and NF-κB. Also, various microRNAs (miRs) are known to mediate the HIF-1α role in melanoma. Therefore, HIF-1α offers a diagnostic/prognostic biomarker and a candidate for targeted therapy in melanoma.
    Keywords:  Diagnostic/prognostic biomarker; HIF-1α; Hypoxia; Melanoma; Melanoma treatment; Signaling pathways
    DOI:  https://doi.org/10.1016/j.biopha.2021.111873
  20. Oncoimmunology. 2021 ;10(1): 1940676
    Anti-tumor efficacy of a combination therapy with PD-L1 targeted alpha therapy and adoptive cell transfer of PD-1 deficient melanoma-specific human T-lymphocytes.
    L Marotte, M Capitao, C Deleine, T Beauvais, G Cadiou, J Perrin, M Chérel, E Scotet, Y Guilloux, F Bruchertseifer, A Morgenstern, A Jarry, J Gaschet, N Labarriere.
      The optimization of adoptive transfer approaches of anti-tumor T cells requires both the functional improvement of the injected T cells and the modulation of the tumor microenvironment, favoring the recruitment of these T cells and their activation. We have recently shown the therapeutic benefit of two approaches tested individually in a melanoma model wich were on one hand the adoptive transfer of specific T cells deficient for the expression of the inhibitory receptor PD-1, and on the other hand PD-L1 targeted alpha therapy (TAT). In this study, we sought to investigate the efficacy of these two therapies combined, compared to each monotherapy, in order to evaluate the synergy between these two approaches, in the same melanoma model. Here we used melanoma-specific T-cell clones, previously validated for the edition of PDCD1 gene and with previously demonstrated superior anti-tumor activity than their wild-type counterparts, after adoptive transfer in NSG mice engrafted with PD-L1 expressing human melanoma tumors. We also used a previously validated TAT approach, using a 213Bi-anti-human-PD-L1 mAb, alone or in combination with adoptive cell transfer, in the same mouse model. We confirmed previous results obtained with each monotherapy and documented the safety and the superior ability of a combination between the adoptive transfer of PD-1 deficient T cells and TAT targeting PD-L1 to control the growth of melanoma tumors in NSG mice. This study provides the first proof-of-concept of the efficacy of a combination therapy using TAT, adoptive cell transfer and genomic editing of IC-coding genes.
    Keywords:  PD-1; adoptive cell transfer; gene editing; melanoma; pd-l1; targeted alpha therapy
    DOI:  https://doi.org/10.1080/2162402X.2021.1940676
  21. Front Oncol. 2021 ;11 698888
    Bilirubin Restrains the Anticancer Effect of Vemurafenib on BRAF-Mutant Melanoma Cells Through ERK-MNK1 Signaling.
    Yufan Tan, Xiaoyu Zhong, Xizhi Wen, Leyi Yao, Zhenlong Shao, Wenshuang Sun, Jiawen Wu, Guanmei Wen, Daolin Tang, Xiaoshi Zhang, Yuning Liao, Jinbao Liu.
      Melanoma, the most threatening cancer in the skin, has been considered to be driven by the carcinogenic RAF-MEK1/2-ERK1/2 signaling pathway. This signaling pathway is usually mainly dysregulated by mutations in BRAF or RAS in skin melanomas. Although inhibitors targeting mutant BRAF, such as vemurafenib, have improved the clinical outcome of melanoma patients with BRAF mutations, the efficiency of vemurafenib is limited in many patients. Here, we show that blood bilirubin in patients with BRAF-mutant melanoma treated with vemurafenib is negatively correlated with clinical outcomes. In vitro and animal experiments show that bilirubin can abrogate vemurafenib-induced growth suppression of BRAF-mutant melanoma cells. Moreover, bilirubin can remarkably rescue vemurafenib-induced apoptosis. Mechanically, the activation of ERK-MNK1 axis is required for bilirubin-induced reversal effects post vemurafenib treatment. Our findings not only demonstrate that bilirubin is an unfavorable for patients with BRAF-mutant melanoma who received vemurafenib treatment, but also uncover the underlying mechanism by which bilirubin restrains the anticancer effect of vemurafenib on BRAF-mutant melanoma cells.
    Keywords:  BRAF-mutant melanoma; ERK; MNK1; bilirubin; vemurafenib
    DOI:  https://doi.org/10.3389/fonc.2021.698888
  22. J Invest Dermatol. 2021 Jul 02. pii: S0022-202X(21)01414-7. [Epub ahead of print]
    A PDZ Protein GIPC3 Positively Modulates Hedgehog Signaling and Melanoma Growth.
    Sathya Narayanan Patmanathan, Bing Teck Tong, Jia Hao Jackie Teo, Yong Zheng Jonathan Ting, Nguan Soon Tan, Siew Hoon Kenice Sim, Yng-Cun Ta, Wei-Meng Woo.
      The Hedgehog (Hh) pathway is essential for animal development but aberrant activation promotes cancer growth. Here we show that GIPC3, a PDZ domain-containing protein with putative adaptor protein function, positively modulates Hh target gene expression in normal fibroblasts and melanoma cells and supports melanoma tumor growth. Using overexpression and epistasis studies, we show that Gipc3 potentiates Hh transcriptional output and it modulates GLI-dependent transcription independently of Sufu. While we find GIPC3 protein does not interact with Hh pathway components, Ingenuity Pathway Analyses of GIPC3-interacting proteins identified by co-immunoprecipitation and mass spectrometry show an association with cancer pathogenesis. Subsequent interrogation of TCGA and The Human Protein Atlas databases reveals GIPC3 upregulation in many cancers. Using expression screens in selected groups of GIPC3-upregulated cancers with reported Hh pathway activation, we find a significant positive correlation of GIPC3 expression with Hh pathway components GLI1, GLI2, and GPR161, in melanoma lines. Consistently, GIPC3 knockdown in melanoma lines significantly reduces GLI1 and GLI2 expression, cell viability, colony formation, and allograft tumor growth. Our findings highlight previously unidentified roles of Gipc3 in potentiating Hh response and melanoma tumorigenesis, and suggest that GIPC3 modulation on Hh signaling may be targeted to reduce melanoma growth.
    Keywords:  GIPC; Gli; Hedgehog pathway; PDZ protein; cancer; melanoma
    DOI:  https://doi.org/10.1016/j.jid.2021.04.033
  23. Eur J Cancer. 2021 Jul 02. pii: S0959-8049(21)00303-8. [Epub ahead of print]153 234-241
    Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers.
    Dirk Schadendorf, Caroline Robert, Reinhard Dummer, Keith T Flaherty, Hussein A Tawbi, Alexander M Menzies, Hiya Banerjee, Mike Lau, Georgina V Long.
       BACKGROUND: Dabrafenib plus trametinib has demonstrated clinical benefit across multiple BRAF-mutant tumours, leading to approval for resected stage III and metastatic melanoma, non-small-cell lung cancer (NSCLC) and anaplastic thyroid cancer. Pyrexia is a common adverse event in patients treated with dabrafenib plus trametinib. Here, we characterise the incidence, patterns and management of pyrexia in patients receiving dabrafenib plus trametinib in clinical trials.
    METHODS: Patients (N = 1076) included in the analysis received dabrafenib plus trametinib in the following clinical trials: phase II registration trial in advanced NSCLC (N = 82), phase III COMBI-AD study in resectable stage III melanoma (N = 435) and phase III COMBI-d and COMBI-v studies in unresectable or metastatic melanoma (N = 209 and N = 350, respectively).
    RESULTS: Among the 1076 patients enrolled in the clinical trials, 61.3% developed pyrexia, 5.7% developed grade 3/4 pyrexia and 15.6% developed a protocol-defined serious pyrexia event. Among the 660 patients with pyrexia, 33.0% had 1 occurrence, 19.8% had 2 occurrences and 47.1% had ≥3 occurrences. The incidence of pyrexia was highest early in treatment and decreased with time on treatment. Temporary dose interruption of dabrafenib or trametinib was the most common and effective management strategy.
    CONCLUSIONS: Pyrexia is the most common adverse event associated with dabrafenib plus trametinib but is manageable with dose interruption.
    TRIAL REGISTRATION: ClinicalTrials.gov (Phase II NSCLC, NCT01336634; COMBI-AD, NCT01682083; COMBI-d, NCT01584648; COMBI-v, NCT01597908).
    Keywords:  Adverse event; BRAF V600–mutant melanoma; BRAF inhibitor; MEK inhibitor; Pyrexia
    DOI:  https://doi.org/10.1016/j.ejca.2021.05.005
  24. Int Immunopharmacol. 2021 Jul 04. pii: S1567-5769(21)00570-1. [Epub ahead of print]99 107934
    Surfactin exerts an anti-cancer effect through inducing allergic reactions in melanoma skin cancer.
    Hee-Yun Kim, Hanchul Jung, Hyung-Min Kim, Hyun-Ja Jeong.
      Surfactin is a mast cell degranulator, that increases the immune response via the degranulation of mast cells. Recently, numerous studies reported that allergic reactions play an important role in the reduction of melanoma development. So, this study aimed to investigate the anti-cancer effects of surfactin in a melanoma skin cancer in vivo model and a melanoma cell line, B16F10. Oral administration of surfactin significantly increased survival rate and reduced tumor growth and tumor weight on melanoma skin cancer in vivo model. Surfactin significantly increased infiltration of mast cells and levels of histamine. Surfactin significantly enhanced levels of IgE and immune-enhancing mediators, such as interferon-γ, interleukin (IL)-2, IL-6, IL-12, and tumor necrosis factor-α in serum and melanoma tissues. Activities of caspase-3, 8, and 9 were significantly enhanced by oral administration of surfactin. In vitro model, surfactin significantly increased B16F10 cell death via activation of caspase-3, 8, and 9 in a dose-dependent manner. Overall, our results indicate that surfactin has a significant anti-cancer effect on melanoma skin cancer through indirectly or directly inducing apoptosis of B16F10 melanoma cells. Also, these findings suggest that it will contribute to a novel perception into the role of allergic reactions in melanoma.
    Keywords:  Apoptosis; Histamine; IgE; Mast cells; Melanoma; Surfactin
    DOI:  https://doi.org/10.1016/j.intimp.2021.107934
  25. Bioengineered. 2021 Dec;12(1): 3539-3549
    Knockdown of DEAD-box RNA helicase 52 (DDX52) suppresses the proliferation of melanoma cells in vitro and of nude mouse xenografts by targeting c-Myc.
    Qiang Wang, Leqi Qian, Mengyuan Tao, Jiaqi Liu, Fa-Zhi Qi.
      The ATP-dependent protein DEAD-box RNA helicase 52 (DDX52) is an important regulator in RNA biology and has been implicated in the development of prostate and lung cancer. However, its biological functions and clinical importance in malignant melanoma (MM) are still unclear. Understanding the potential mechanism underlying the regulation of MM progression by DDX52 might lead to novel therapeutic strategies. The aim of the present study was to investigate the role of DDX52 in the regulation of MM progression and its clinical relevance. DDX52 expression in normal and MM tissues was evaluated by GEO analysis and immunohistochemistry. The effects of DDX52 on cell growth were evaluated in MM cells with downregulated DDX52 expression. In this study, we found that DDX52 was markedly overexpressed in MM tissues compared with nontumor tissues and was associated with shorter overall survival in patients; therefore, DDX52 might be a prognostic marker in MM. Downregulation of DDX52 expression in the MM cell lines A2058 and MV3 markedly inhibited cell proliferation and colony formation. Additionally, knockdown of DDX52 in MM cells caused significant regression of established tumors in nude mice and delayed the onset time. Moreover, downregulation of DDX52 markedly suppressed c-Myc mRNA and protein expression, and an RNA immunoprecipitation assay confirmed the association between DDX52 and c-Myc. Restoration of c-Myc expression partly rescued the effects of DDX52 deficiency in MM cells. In conclusion, our study found that DDX52 mediated oncogenesis by promoting the transcriptional activity of c-Myc and could be a therapeutic target in MM.
    Keywords:  DDX52; Melanoma; c-Myc; proliferation
    DOI:  https://doi.org/10.1080/21655979.2021.1950283
  26. Neoplasia. 2021 Jul 05. pii: S1476-5586(21)00050-6. [Epub ahead of print]23(8): 775-782
    A mutual information-based in vivo monitoring of adaptive response to targeted therapies in melanoma.
    Aurore Bugi-Marteyn, Fanny Noulet, Nicolas Liaudet, Rastine Merat.
      The mechanisms of adaptive resistance to genetic-based targeted therapies of solid malignancies have been the subject of intense research. These studies hold great promise for finding co-targetable hub/pathways which in turn would control the downstream non-genetic mechanisms of adaptive resistance. Many such mechanisms have been described in the paradigmatic BRAF-mutated melanoma model of adaptive response to BRAF inhibition. Currently, a major challenge for these mechanistic studies is to confirm in vivo, at the single-cell proteomic level, the existence of dependencies between the co-targeted hub/pathways and their downstream effectors. Moreover, the drug-induced in vivo modulation of these dependencies needs to be demonstrated. Here, we implement such single-cell-based in vivo expression dependency quantification using immunohistochemistry (IHC)-based analyses of sequential biopsies in two xenograft models. These mimic phase 2 and 3 trials in our own therapeutic strategy to prevent the adaptive response to BRAF inhibition. In this mechanistic model, the dependencies between the targeted Li2CO3-inducible hub HuR and the resistance effectors are more likely time-shifted and transient since the minority of HuRLow cells, which act as a reservoir of adaptive plasticity, switch to a HuRHigh state as they paradoxically proliferate under BRAF inhibition. Nevertheless, we show that a copula/kernel density estimator (KDE)-based quantification of mutual information (MI) efficiently captures, at the individual level, the dependencies between HuR and two relevant resistance markers pERK and EGFR, and outperforms classic expression correlation coefficients. Ultimately, the validation of MI as a predictive IHC-based metric of response to our therapeutic strategy will be carried in clinical trials.
    Keywords:  Adaptive resistance; BRAF inhibitor; ELAVL1/HuR; Information theory; Melanoma; Mutual information
    DOI:  https://doi.org/10.1016/j.neo.2021.06.009
  27. Cureus. 2021 May 29. 13(5): e15322
    Melanoma Extension for Community Healthcare Outcomes: A Feasibility Study of Melanoma Screening Implementation in Primary Care Settings.
    Mirna Becevic, Emily Smith, Mojgan Golzy, Ramakrishna Bysani, Adam Rosenfeld, Ellen R Mutrux, Kimberly Hoffman, Emmanuelle Wallach, Jane A McElroy, Karen Edison.
      Introduction Melanoma incidence rates are rising faster than the rates of any other malignancy. As a major global public health concern, melanoma can be identified by a visual exam not requiring expensive invasive procedures. However, non-dermatologists lack specialized training and skills to identify high-risk patients and implement melanoma skin screenings during regular exams. Most patients from rural and underserved areas have inadequate access to specialty dermatologic care, which can potentially lead to later-stage melanomas and poor patient outcomes. The objective of this study was to identify facilitators and barriers to the implementation of risk surveys and melanoma skin screenings in primary care settings through live interactive education and the telementoring project - Melanoma ECHO (Extension for Community Healthcare Outcomes).  Methods This cross-sectional study was designed with theoretical concepts from dissemination and implementation research. Monthly Melanoma ECHO sessions were integrated into an ongoing Dermatology ECHO at the University of Missouri, Columbia, Missouri, USA, from April 2018 to February 2019. Ten primary care providers, medical doctors/doctors of osteopathic medicine (MDs/DOs), nurse practitioners (NPs), and physician assistants (PAs), from across Missouri participated. Eleven virtual monthly melanoma-related didactics and case-based discussions were provided to participants. Information regarding risk factors, risk surveys, and screening techniques was provided. Ongoing telementoring and guidance were also provided for de-identified real-life patient cases. The main outcomes and measures of the study were to identify the facilitators and barriers of risk survey and melanoma skin screenings in primary care settings and to quantify the number of high-risk patients identified by participating providers and the number of new melanomas detected by visual exams during the study period. Results The primary reason why six out of 10 providers reported participation in Melanoma ECHO was that implementing melanoma skin screenings in their practice was made easier as it increased their confidence. Nine providers reported increased knowledge, and eight cited professional networking as other facilitators. The main perceived barrier to melanoma skin screening was lack of administrative and nursing support, and six providers indicated that lack of time to incorporate skin exams was also a barrier. Combined, ten participants reported identifying 976 high-risk patients during the study period and detecting 36 new melanomas. Discussion and conclusion Our findings indicate that primary care providers may benefit from attending regularly scheduled and focused specialized telementoring sessions, such as Melanoma ECHO. Ongoing support from specialists may help providers practicing in rural and isolated areas with the successful integration of risk surveys and melanoma skin screenings in primary care settings. Further Melanoma ECHO sessions with a more diverse group of primary care providers are needed to better understand the generalizability of the results.
    Keywords:  collaborative learning; continuing health education; early screening; melanoma diagnosis; virtual learning
    DOI:  https://doi.org/10.7759/cureus.15322
  28. Front Oncol. 2021 ;11 666145
    De Novo Mutation in Non-Tyrosine Kinase Domain of ROS1 as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma.
    Si-Cong Ma, Hong-Bo Zhu, Jian Wang, Yan-Pei Zhang, Xue-Jun Guo, Li-Li Long, Ze-Qin Guo, De-Hua Wu, Zhong-Yi Dong, Xue Bai.
       Purpose: Despite the success of targeted therapy in c-ros oncogene 1 (ROS1)-rearranged cancers, especially non-small cell lung cancer (NSCLC), the clinical significance of ROS1 de novo mutation has not yet been understood. We sought to elucidate the predictive effect of ROS1 mutation for immune checkpoint inhibitor (ICI) therapy in melanoma.
    Methods: The Cancer Genome Atlas [TCGA (n = 10967)] and Memorial Sloan Kettering Cancer Center [MSK (n = 10,945)] datasets, as well as two clinical cohorts of melanoma received ICI [CA209-038 (n = 73) and MEL-IPI (n = 110)], were included to explore the prevalence, prognostic effect, and immunotherapeutic predictive effect of ROS1 mutation in melanoma. Overall survival (OS) was defined as the primary outcome.
    Results: Overall, melanoma accounted for the highest proportion of ROS1 mutation (~20%) which made up the majority (~95%) of the ROS1-alterated cases. Remarkably, ROS1 mutation yielded longer OS from ICI than the wild-type counterpart in the MSK melanoma population [hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.30-0.74], and two external melanoma cohorts (CA209-038: HR 0.42, 95% CI 0.20-0.89; MEL-IPI: HR 0.55, 95% CI 0.34-0.91), without affecting the prognosis of patients. Elevated tumor mutational burden and enrichment of DNA damage repair was observed in ROS1 mutated patients, providing an explanation for the favorable responses to ICI therapy. Precisely, ROS1 mutation in non-protein tyrosine kinase (PTK) domain but not PTK mutation was responsible for the immunotherapy-specific responses of the ROS1 mutated patients in melanoma.
    Conclusions: Collectively, ROS1 mutation, specifically the non-PTK mutation, is a potential predictor of ICI therapy in melanoma, which is distinct from the well-established role of ROS1 rearrangement for targeted therapy in NSCLC.
    Keywords:  ROS1 mutation; immune checkpoint inhibitor; melanoma; tumor mutational burden; tyrosine kinase domain
    DOI:  https://doi.org/10.3389/fonc.2021.666145
  29. Oncogene. 2021 Jul 03.
    Targeting HIF-activated collagen prolyl 4-hydroxylase expression disrupts collagen deposition and blocks primary and metastatic uveal melanoma growth.
    Stefan Kaluz, Qing Zhang, Yuki Kuranaga, Hua Yang, Satoru Osuka, Debanjan Bhattacharya, Narra S Devi, Jiyoung Mun, Wei Wang, Ruiwen Zhang, Mark M Goodman, Hans E Grossniklaus, Erwin G Van Meir.
      Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults, and patients that develop metastases (~50%) survive <1 year, highlighting the urgent need for new therapies. TCGA has recently revealed that a hypoxia gene signature is associated with poor UM patient prognosis. Here we show that expression of hypoxia-regulated collagen prolyl-4-hydroxylase genes P4HA1 and P4HA2 is significantly upregulated in UM patients with metastatic disease and correlates with poor prognosis, suggesting these enzymes might be key tumor drivers. We targeted hypoxia-induced expression of P4HA1/2 in UM with KCN1, a hypoxia inducible factor-1 (HIF-1) pathway inhibitor and found potent inhibition of primary and metastatic disease and extension of animal survival, without overt side effects. At the molecular level, KCN1 antagonized hypoxia-induced expression of P4HA1 and P4HA2, which regulate collagen maturation and deposition in the extracellular matrix. The treatment decreased prolyl hydroxylation, induced proteolytic cleavage and rendered a disordered structure to collagen VI, the main collagen produced by UM, and reduced UM cell invasion. Together, these data demonstrate that extracellular collagen matrix formation can be targeted in UM by inhibiting hypoxia-induced P4HA1 and P4HA2 expression, warranting further development of this strategy in patients with uveal melanoma.
    DOI:  https://doi.org/10.1038/s41388-021-01919-x
  30. Anal Cell Pathol (Amst). 2021 ;2021 5552664
    An In Vitro-In Vivo Evaluation of the Antiproliferative and Antiangiogenic Effect of Flavone Apigenin against SK-MEL-24 Human Melanoma Cell Line.
    Alexandra Ghiƫu, Ioana Zinuca Pavel, Stefana Avram, Brigitta Kis, Daliana Minda, Cristina Adriana Dehelean, Valentina Buda, Roxana Folescu, Corina Danciu.
      One of the most important class of natural compounds with successful preclinical results in the management of cancer is the flavonoids. Due to the plethora of biological activities, apigenin (4',5,7 trihydroxyflavone) is a main representant of the flavone subclass. Although the antiproliferative and antiangiogenic effects of apigenin were studied on a significant number of human and murine melanoma cell lines, in order to complete the data existing in the literature, the aim of this study is to evaluate the in vitro effect of apigenin on SK-MEL-24 human melanoma cell line as well as in vivo on tumor angiogenesis using the aforementioned cell line on the chorioallantoic membrane assay. Results have shown that in the range of tested doses, the phytocompound presents significant antiproliferative, cytotoxic, and antimigratory potential at 30 μM, respectively, 60 μM. Moreover, the phytocompound in both tested concentrations limited melanoma cell growth and migration and induced a reduced angiogenic reaction limiting melanoma cell development.
    DOI:  https://doi.org/10.1155/2021/5552664
  31. Int J Biol Macromol. 2021 Jun 30. pii: S0141-8130(21)01401-X. [Epub ahead of print]185 551-561
    Biocompatible gum arabic-gold nanorod composite as an effective therapy for mistreated melanomas.
    Jenifer P Gonçalves, Anderson F da Cruz, Ábner M Nunes, Mario R Meneghetti, Heloise R de Barros, Beatriz S Borges, Lia C A S de Medeiros, Maurilio J Soares, Mayara P Dos Santos, Marco T Grassi, Gustavo R Rossi, Daniel L Bellan, Stellee M P Biscaia, Aline M Cristal, João L A Buzzo, Yasmin C Ribeiro, Alexandra Acco, Mateus B Cardoso, Fernanda F Simas, Edvaldo S Trindade, Izabel C Riegel-Vidotti, Carolina C de Oliveira.
      Advanced melanoma patients that are not included in common genetic classificatory groups lack effective and safe therapeutic options. Chemotherapy and immunotherapy show unsatisfactory results and devastating adverse effects for these called triple wild-type patients. New approaches exploring the intrinsic antitumor properties of gold nanoparticles might reverse this scenario as a safer and more effective alternative. Therefore, we investigated the efficacy and safety of a composite made of gum arabic-functionalized gold nanorods (GA-AuNRs) against triple wild-type melanoma. The natural polymer gum arabic successfully stabilized the nanorods in the biological environment and was essential to improve their biocompatibility. In vivo results obtained from treating triple wild-type melanoma-bearing mice showed that GA-AuNRs remarkably reduced primary tumor growth by 45%. Furthermore, GA-AuNRs induced tumor histological features associated with better prognosis while also reducing superficial lung metastasis depth and the incidence of intrapulmonary metastasis. GA-AuNRs' efficacy comes from their capacity to reduce melanoma cells ability to invade the extracellular matrix and grow into colonies, in addition to a likely immunomodulatory effect induced by gum arabic. Additionally, a broad safety investigation found no evidence of adverse effects after GA-AuNRs treatment. Therefore, this study unprecedentedly reports GA-AuNRs as a potential nanomedicine for advanced triple wild-type melanomas.
    Keywords:  Antimetastatic; Antitumor; Gold nanorod; Gum arabic; Natural polysaccharide; Triple wild-type melanoma
    DOI:  https://doi.org/10.1016/j.ijbiomac.2021.06.172
  32. Orbit. 2021 Jul 07. 1-2
    Choroidal malignant melanoma masquerading as orbital cellulitis.
    Sana Qureshi, Dane H Slentz, Victor M Elner, Hakan Demirci.
      
    Keywords:  Malignant melanoma; ocular oncology; orbital cellulitis; phthisis bulbi
    DOI:  https://doi.org/10.1080/01676830.2021.1916046
  33. J Surg Oncol. 2021 Jul 08.
    False positive FDG uptake in melanoma patients treated with talimogene laherparepvec (T-VEC).
    Evalyn E A P Mulder, Emma H A Stahlie, Daniëlle Verver, Clara Lemstra, Lukas B Been, Antien L Mooyaart, Tessa Brabander, Erik Vegt, Frederik A Verburg, Astrid A M van der Veldt, Cornelis Verhoef, Alexander C J van Akkooi, Dirk J Grünhagen.
      Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy and has been approved for the local treatment of unresectable (stage IIIB/C and IVM1a) cutaneous melanoma. During T-VEC treatment, tumor response is often evaluated using [18F]2-fluoro-2-deoxy- d-glucose(FDG) positron emission tomography/computed tomography (PET/CT). In a Dutch cohort (n = 173), almost one-third of patients developed new-onset FDG uptake in uninjected locoregional lymph nodes during T-VEC. In 36 out of 53 (68%) patients with new nodal FDG uptake, nuclear medicine physicians classified this FDG uptake as "suspected metastases" without clinical or pathological confirmation in the majority of patients. These false positive results indicate that new-onset FDG uptake in locoregional lymph nodes during T-VEC treatment does not necessarily reflect progressive disease, but may be associated with immune infiltration. In current clinical practice, physicians should be aware of the high false positive rate of FDG uptake during treatment with T-VEC in patients with melanoma. Therefore, pathological examination of lymph node lesions with new FDG uptake is recommended to differentiate between progressive disease and immune infiltration after treatment with T-VEC.
    Keywords:  FDG-PET/CT; cutaneous melanoma; false positive FDG uptake; talimogene laherparevec (T-VEC)
    DOI:  https://doi.org/10.1002/jso.26607
  34. Clin Transl Oncol. 2021 Jul 08.
    Stereotactic radiosurgery with immunotherapy is associated with improved overall survival in patients with metastatic melanoma or non-small cell lung cancer: a National Cancer Database analysis.
    J M Jiang, R Kabarriti, N P Brodin, N Ohri, C Guha, S Kalnicki, M Garg.
       PURPOSE: Immunotherapy is now a first-line treatment for metastatic non-small cell lung cancer (NSCLC) and melanomaQuery. It is important to understand the relationship between immunotherapy and radiation to the brain. The aim of this study was to assess the role of stereotactic radiosurgery (SRS) or WBRT in addition to immunotherapy in patients with melanoma or NSCLC metastatic to the brain.
    METHODS/PATIENTS: Using the National Cancer Database, 2951 patients with NSCLC and 936 patients with melanoma treated with immunotherapy were identified. Patients were classified as having received immunotherapy alone, immunotherapy with SRS, or immunotherapy with whole-brain radiation therapy (WBRT). Kaplan-Meier, multivariate Cox regression analyses, and propensity matching were performed to evaluate the impact of adding SRS to immunotherapy on overall survival (OS). Immortal survival bias was accounted for by only including patients who received radiation before immunotherapy and time zero was defined as the start of immunotherapy.
    RESULTS: 205(6.9%) and 75(8.0%) patients received immunotherapy with no radiation, 822(27.9%) and 326(34.8%) received SRS and immunotherapy, and 1924(65.2%) and 535(57.2%) received WBRT and immunotherapy for NSCLC and melanoma, respectively. Adding SRS to immunotherapy was associated with improved OS in multivariate analyses (NSCLC HR = 0.81, 95% CI 0.66-0.99, p = 0.044; melanoma HR = 0.63, 95% CI 0.45-0.90, p = 0.011). The addition of WBRT to immunotherapy did not improve OS in patients with melanoma nor NSCLC.
    CONCLUSIONS: This analysis suggests that treatment with SRS and immunotherapy is associated with improved OS compared to immunotherapy alone for patients with melanoma or NSCLC metastatic to the brain.
    Keywords:  Immunotherapy; Melanoma; National cancer database; Non small cell lung cancer; Stereotactic radiosurgery; Whole-brain radiation
    DOI:  https://doi.org/10.1007/s12094-021-02675-w
  35. Cancer. 2021 Jul 06.
    A prospective, comprehensive registry that integrates the molecular analysis of pediatric and adolescent melanocytic lesions.
    Alberto S Pappo, Valerie McPherson, Haitao Pan, Fang Wang, Lu Wang, Teresa Wright, Margaret Hussong, Dana Hawkins, Sue C Kaste, Andrew M Davidoff, Armita Bahrami.
       BACKGROUND: Childhood melanocytic tumors represent a diagnostic and therapeutic challenge, and additional research is needed to better define the natural history of these tumors.
    METHODS: The authors developed a comprehensive, prospective registry called Molecular Analysis of Childhood Melanocytic Tumors for children and adolescents with an atypical Spitz tumor/Spitz melanoma (AST/SM), conventional or adult-type melanoma (CM), melanoma arising in a giant congenital nevus (MCM), or atypical melanocytic proliferation of other types (OT) to better define the clinical behavior of these lesions by incorporating an integrated clinicopathologic and molecular analysis using centralized pathology review and various platforms, including fluorescence in situ hybridization; array comparative genomic hybridization; and whole genome, exome, and capture targeted panels.
    RESULTS: From May 2016 to November 2019, 70 children were enrolled with a median age at diagnosis of 9.1 years. Thirty-seven had AST/SM, 17 had CM, 4 had MCM, and 12 had OT. Patients with AST/SM were younger (median age, 7 years), and their tumor most commonly arose in the extremities and trunk. The most common gene rearrangements included MAP3K8 and ALK. None of the 33 patients who underwent a TERT promoter mutation analysis had a mutation, and all patients were alive. Among the CM patients, the median age was 13 years; 11 had a BRAFV600E mutation, and 7 had a TERT promoter mutation. Three patients died of their disease. All 4 patients with MCM harbored an NRASQ61 mutation and died of their disease. The OT group was heterogenous, and all patients survived.
    CONCLUSIONS: The incorporation of an integrated clinicopathologic and genomic analysis identifies distinct subgroups of pediatric melanocytic lesions that have different clinical behaviors. The integration of this combined diagnostic modality can help to individualize diagnoses and treatments for these patients.
    Keywords:  Spitz melanoma; TERT; atypical Spitz; melanoma; pediatric melanocytic lesions
    DOI:  https://doi.org/10.1002/cncr.33750
  36. Eur J Ophthalmol. 2021 Jul 09. 11206721211030775
    Fluorescent in situ hybridization (FISH): A useful diagnostic tool for childhood conjunctival melanoma.
    Raquel María Moral, Carlos Monteagudo, Javier Muriel, Lucía Moreno, Ana María Peiró.
       INTRODUCTION: Conjunctival melanoma is extremely rare in children and has low rates of resolution. Definitive histopathological diagnosis based exclusively on microscopic findings is sometimes difficult. Thus, early diagnosis and adequate treatment are essential to improve clinical outcomes.
    CLINICAL CASE: We present the first case in which the fluorescent in situ hybridization (FISH) diagnostic technique was applied to a 10-year-old boy initially suspected of having amelanotic nevi in his right eye. Based on the 65% of tumor cells with 11q13 (CCND1) copy number gain and 33% with 6p25 (RREB1) gain as measured by the FISH analysis, and on supporting histopathological findings, the diagnosis of conjunctival melanoma could be made. Following a larger re-excision, adjuvant therapy with Mitomycin C (MMC), cryotherapy and an amniotic membrane graft, the patient has remained disease-free during 9 years of long-term follow-up.
    CASE DISCUSSION: Every ophthalmologist should remember to consider and not forget the possibility of using FISH analyses during the differential diagnosis of any suspicious conjunctival lesions. Genetic techniques, such as FISH, have led to great advances in the classification of ambiguous lesions. Evidence-based guidelines for diagnosing conjunctival melanoma in the pediatric population are needed to determine the most appropriate strategy for this age group.
    Keywords:  Conjunctival melanoma; childhood; fluorescent in situ hybridization
    DOI:  https://doi.org/10.1177/11206721211030775
  37. Clin Exp Dermatol. 2021 Jul 08.
    Exploring the implications of the first COVID-19 lockdown on patients with melanoma: a national survey.
    S A Raza, D Cannon, G Nuttall, F R Ali.
      The impact of the COVID-19 pandemic upon melanoma care remains as yet poorly understood. We undertook a UK-wide national survey, in conjunction with a patient support group (Melanoma UK), to explore patient perceptions of the impact of the pandemic upon treatment and outpatient care of their melanoma. Our findings suggest that following the onset of COVID-19, a significant minority of treatments and appointments have been delayed, there has been a shift from face-to-face to virtual outpatient consultations and there may be a rise in psychological comorbidities in melanoma patients. We would urge clinicians to consider mental health interventions as part of a holistic care package.
    DOI:  https://doi.org/10.1111/ced.14840
  38. Clin Oncol (R Coll Radiol). 2021 Jul 02. pii: S0936-6555(21)00229-6. [Epub ahead of print]
    Survival Outcomes Following Discontinuation of Ipilimumab and Nivolumab for Advanced Melanoma in a Population-based Cohort.
    D Ksienski, P T Truong, E S Wai, N S Croteau, A Chan, T Patterson, M Clarkson, S Hackett, S Irons, M Lesperance.
       AIMS: Induction ipilimumab and nivolumab followed by maintenance nivolumab improve overall survival compared with ipilimumab alone in patients with advanced melanoma, but immune-related adverse events (irAE) occur commonly. The need for induction discontinuation because of irAE and the relationship between irAE and survival in non-trials patients are unclear.
    MATERIALS AND METHODS: Patients with unresectable stage III-IV melanoma receiving first-line combination immunotherapy at one of six centres between December 2017 and February 2020 outside of trials were identified retrospectively. Landmark 12-week Kaplan-Meier analyses and log-rank tests were used to evaluate associations between discontinuation of induction therapy on overall survival and time to treatment failure (TTF). Multivariable analysis of factors influencing overall survival and TTF was undertaken.
    RESULTS: Among 95 patients, the median age was 62 years, 38.9% had Eastern Cooperative Oncology Group performance status ≥1 and 22.1% had brain metastases. The median follow-up for the whole cohort was 19.8 months by the reverse Kaplan-Meier method. Any grade and grade 3-4 irAE were noted in 78.9% and 44.2% of the cohort, respectively. 44.2% of patients completed induction immunotherapy, whereas 41.1% did not due to irAE. Twelve-week landmark overall survival and TTF were similar in patients who completed induction versus those who did not due to irAE. On multivariable analysis, any grade irAE (versus none) was associated with longer overall survival (hazard ratio = 0.35, 95% confidence interval 0.15-0.82, P = 0.02) and TTF (hazard ratio = 0.38, 95% confidence interval = 0.17-0.81, P = 0.01). Grade 3-4 irAE correlated with longer TTF (hazard ratio = 0.45, 95% confidence interval = 0.20-1.01, P = 0.05).
    CONCLUSION: In this population-based cohort, discontinuation of induction immunotherapy as a result of irAE did not adversely affect overall survival or TTF. irAE observed during ipilimumab and nivolumab induction were associated with improved survival outcomes.
    Keywords:  Adverse events; ipilimumab; melanoma; nivolumab
    DOI:  https://doi.org/10.1016/j.clon.2021.06.009
  39. Am J Dermatopathol. 2021 Jul 07.
    Optimizing Detection of Lymphatic Invasion in Primary Cutaneous Melanoma With the Use of D2-40 and a Paired Melanocytic Marker.
    Richard J Straker, Laura A Taylor, Madalyn G Neuwirth, Andrew J Sinnamon, Adrienne B Shannon, James Abbott, John T Miura, Emily Y Chu, Xiaowei Xu, Giorgos C Karakousis.
       ABSTRACT: Dual immunohistochemical (IHC) staining with D2-40 and S100 improves detection of lymphatic invasion (LI) in primary cutaneous melanoma. However, limited data exist evaluating this technique using other melanocytic markers, and thus, the optimal marker for detection of LI is unestablished. To address this knowledge gap, a case-control study was performed comparing melanoma specimens from 22 patients with known lymphatic spread (LS) with a control group of 11 patients without LS. Specimens underwent dual IHC staining with D2-40 and MART-1, SOX-10, and S100 to evaluate for LI. Receiver operating characteristic analysis was used to estimate each stain's accuracy for detection of LI. The LS group was more likely to be ≥65 years (P = 0.04), have a tumor thickness of ≥1 mm (P < 0.01), and have ulcerated tumors (P = 0.02). Detection of LI with D2-40/MART-1 significantly correlated with LS (P = 0.03), and the D2-40/MART-1 stain was most accurate for LI based on receiver operating characteristic curve analysis (area under the curve [AUC] 0.705) in comparison with D2-40/SOX-10 (AUC 0.575) and D2-40/S100 (AUC 0.633). These findings suggest that MART-1 may be the optimal melanocytic marker to combine with D2-40 for detection of LI in melanoma. Further studies are needed to determine the utility of routinely performing these stains for histopathologic analysis of melanoma.
    DOI:  https://doi.org/10.1097/DAD.0000000000002018
  40. J Dermatol Sci. 2021 Jun 29. pii: S0923-1811(21)00146-8. [Epub ahead of print]
    The regional distribution of melanosomes in the epidermis affords a localized intensive photoprotection for basal keratinocyte stem cells.
    Shan Jiang, Zhi-Kai Liao, Hai-Yan Jia, Xiao-Ming Liu, Jing Wan, Tie-Chi Lei.
      Human skin is a highly efficient self-renewing barrier that is critical to withstanding environmental insults. Undifferentiated keratinocyte stem cells reside in the basal layer of the epidermis and in hair follicles that continuously give rise to progenies ensuring epidermal turnover and renewal. Ultraviolet (UV) radiation is a proven cause of skin keratinocyte cancers, which preferentially occur at sun-exposed areas of the skin. Fortunately, melanocytes produce melanin that is packaged in specific organelles (termed melanosomes) that are then delivered to nearby keratinocytes, endowing the recipient cells with photoprotection. It has long been thought that melanosome transfer takes place stochastically from melanocytes to keratinocytes via an as-yet-unrecognized manner. However, recent studies have indicated that melanosomes are distributed regionally in the basal layer of the skin, affording localized intensive photoprotection for progenitor keratinocytes and stem cells that reside in the microenvironment of the basal epidermis. In this review, we summarize current knowledge about molecular and cellular mechanisms that are responsible for the selective transfer and exclusive degradation of melanosomes in the epidermis, emphasizing implications for skin carcinogenesis.
    Keywords:  Distribution; Keratinocyte; Melanosome; Photoprotection
    DOI:  https://doi.org/10.1016/j.jdermsci.2021.06.010
  41. Int Cancer Conf J. 2021 Jul;10(3): 254-258
    Primary malignant melanoma of uterine cervix treated with pembrolizumab as adjuvant immunotherapy.
    Reiko Suzuki, Hiraku Endo, Takamichi Sasaki, Takayoshi Nakamura, Hiroyuki Yamanaka, Shinji Hosonuma, Shiho Kuji, Imari Deura, Tatsuru Ohara, Haruhiro Kondo, Motohiro Chosokabe, Junki Koike, Hiroshi Kadono, Junichi Hasegawa, Nao Suzuki.
      This is the case report of primary malignant melanoma (MM) of uterine cervix treated by immune checkpoint inhibitor: the Pembrolizumab. Despite the merge of the novel drugs that has been strikingly improving prognosis of MM, we still struggle treatment of MM of uterine cervix that has aggressive characteristics with unknown etiology. We present our case to contribute its rarity of the disease case report, the primary MM of the uterine cervix that had poor response to pembrolizumab and had OS of 6 months. The treatment ineffectiveness is mainly considered for mucosal MM of low tumor mutation burden and its unusual type of pathology. Accumulation of retrospective studies exclusively on cervical melanoma needs to be proceeded to investigate on characteristics between poor and long survival to establish standardized treatment.
    Keywords:  Immune point check inhibitor; Malignant melanoma; Pembrolizumab; Uterine cervical melanoma
    DOI:  https://doi.org/10.1007/s13691-021-00477-z
  42. Front Genet. 2021 ;12 680633
    Lysine Demethylases: Promising Drug Targets in Melanoma and Other Cancers.
    Gaya Punnia-Moorthy, Peter Hersey, Abdullah Al Emran, Jessamy Tiffen.
      Epigenetic dysregulation has been implicated in a variety of pathological processes including carcinogenesis. A major group of enzymes that influence epigenetic modifications are lysine demethylases (KDMs) also known as "erasers" which remove methyl groups on lysine (K) amino acids of histones. Numerous studies have implicated aberrant lysine demethylase activity in a variety of cancers, including melanoma. This review will focus on the structure, classification and functions of KDMs in normal biology and the current knowledge of how KDMs are deregulated in cancer pathogenesis, emphasizing our interest in melanoma. We highlight the current knowledge gaps of KDMs in melanoma pathobiology and describe opportunities to increases our understanding of their importance in this disease. We summarize the progress of several pre-clinical compounds that inhibit KDMs and represent promising candidates for further investigation in oncology.
    Keywords:  cancer; epigenetics; histones; lysine demethylases; melanoma; small molecule inhibitors
    DOI:  https://doi.org/10.3389/fgene.2021.680633
  43. Rev Esp Med Nucl Imagen Mol (Engl Ed). 2021 Jul-Aug;40(4):pii: S2253-8089(20)30107-5. [Epub ahead of print]40(4): 255-256
    Subcutaneous sarcoidosis induced by pembrolizumab in a melanoma patient mimicking subcutaneous metastasis at 18F-FDG PET/CT.
    J Marcoval, A Bauer-Alonso, R Fornons-Servent, L Jiménez-Colomo, A Sabaté-Llobera, R M Penín.
      
    DOI:  https://doi.org/10.1016/j.remnie.2020.09.004
  44. Ann Dermatol Venereol. 2021 Jul 02. pii: S0151-9638(21)00066-1. [Epub ahead of print]
    Male genital vitiligo.
    J-N Dauendorffer, C Skayem, T Passeron.
      Vitiligo is a polygenetic multifactorial disease leading to melanocytic loss in skin and sometimes in hair. Genital areas may be involved and represent a specific therapeutic challenge. Surprisingly, data on male genital vitiligo remain scarce. This review aims to collate current knowledge on male genital vitiligo and to discuss the risks and benefits of the various therapeutic approaches. Male genital vitiligo is relatively frequent and often induces marked impairment of quality of life, with a specific impact on sex life. Prompt recognition of activity remains mandatory to halt disease progression, as repigmentation remains difficult to achieve in most cases. Thanks to progress in understanding of the pathophysiology of vitiligo, new therapeutic approaches are under development. Topical ruxolitinib, a JAK pathway inhibitor, is currently the product in the most advanced stage of development, with a very encouraging repigmentation rate on the face, although specific efficacy in genital area remains to be assessed. The next generation of treatments, such as topical WNT agonists, could be of great interest in genital vitiligo as they will not require combination with UV therapy and they may be able to enhance the differentiation and proliferation of melanocyte stem cells in this difficult-to-treat area.
    Keywords:  Genital; Penis; Scrotum; Vitiligo
    DOI:  https://doi.org/10.1016/j.annder.2021.06.003
  45. J Transl Med. 2021 Jul 08. 19(1): 296
    Dissecting immune cell stat regulation network reveals biomarkers to predict ICB therapy responders in melanoma.
    Jingwen Wang, Feng Li, Yanjun Xu, Xuan Zheng, Chunlong Zhang, Congxue Hu, Yingqi Xu, Wanqi Mi, Xia Li, Yunpeng Zhang.
       BACKGROUND: Immunotherapy is a revolutionary strategy in cancer therapy, but the resistance of which is one of the important challenges. Detecting the regulation of immune cells and biomarkers concerning immune checkpoint blockade (ICB) therapy is of great significance.
    METHODS: Here, we firstly constructed regulation networks for 11 immune cell clusters by integrating biological pathway data and single cell sequencing data in metastatic melanoma with or without ICB therapy. We then dissected these regulation networks and identified differently expressed genes between responders and non-responders. Finally, we trained and validated a logistic regression model based on ligands and receptors in the regulation network to predict ICB therapy response.
    RESULTS: We discovered the regulation of genes across eleven immune cell stats. Functional analysis indicated that these stat-specific networks consensually enriched in immune response corrected pathways and highlighted antigen processing and presentation as a core pathway in immune cell regulation. Furthermore, some famous ligands like SIRPA, ITGAM, CD247and receptors like CD14, IL2 and HLA-G were differently expressed between cells of responders and non-responders. A predictive model of gene sets containing ligands and receptors performed accuracy prediction with AUCs above 0.7 in a validation dataset suggesting that they may be server as biomarkers for predicting immunotherapy response.
    CONCLUSIONS: In summary, our study presented the gene-gene regulation landscape across 11 immune cell clusters and analysis of these networks revealed several important aspects and immunotherapy response biomarkers, which may provide novel insights into immune related mechanisms and immunotherapy response prediction.
    Keywords:  Immune single cells; Immunotherapy; Regulation networks
    DOI:  https://doi.org/10.1186/s12967-021-02962-8
  46. J Appl Toxicol. 2021 Jul 07.
    The cell membrane as the barrier in the defense against nanoxenobiotics: Zinc oxide nanoparticles interactions with native and model membrane of melanoma cells.
    Agnieszka Czyżowska, Anna Barbasz, Elżbieta Rudolphi-Szydło, Barbara Dyba.
      Currently, we are dealing with ever-increasing pollution of the environment with metal and metal oxide nanoparticles. One type of these, zinc oxide nanoparticles (ZnO-NPs), are increasingly used in areas such as cosmetology, electrical engineering, medicine, and even in the food and textile industries. As a consequence, ZnO-NPs may enter the human body in many ways. Their influence on the body is still not clear. Here, we define the mechanism of the initial toxicity of ZnO-NPs to cells based on interaction with the lipid part of the native and model cell membrane. The selected cell lines react differently to contact with nanoparticles. We found a disruption of the native membranes of B16-F0 cells and to a lesser extent of COLO 679. In turn, the membrane of COLO 679 cells was more peroxidated, and cell viability was much lower. A model of the lipid part of the membrane was created for B16-F0 cells and compared with previously published studies on immune cells. On the basis of physicochemical parameters obtained for individual lipids and a mix representing the native membrane of the tested cells, we concluded that exposure to nanoparticles resulted in a change within the model membranes (specifically with the polar parts of lipids). The greatest interaction has been noticed between ZnO-NPs and zwitterionic phospholipids (PC and PE), cholesterol, and negatively charged phosphatidylglycerol. Assessing the interactions between the membrane and nanoparticles will help to better understand the first steps of its toxicity mechanism.
    Keywords:  cytotoxicity; melanoma; model membrane; zinc oxide
    DOI:  https://doi.org/10.1002/jat.4216
  47. Am J Otolaryngol. 2021 Jun 25. pii: S0196-0709(21)00248-9. [Epub ahead of print]42(5): 103147
    The utility of ICG fluorescence for sentinel lymph node identification in head and neck melanoma.
    Nisha Patel, Meredith Allen, Khashayar Arianpour, Richard Keidan.
       PURPOSE: Perform an evidence-based review to determine the utility of indocyanine green fluorescence (ICG) to detect sentinel lymph nodes (SLN) in patients with head and neck melanoma compared to blue dye or radiocolloid injection (RI).
    MATERIALS AND METHODS: A systematic review of the literature was performed to identify patients with head and neck melanoma managed with ICG fluorescence. PubMed, Embase, and Cochrane Library databases were searched. Included studies were assessed for level of evidence. Patient demographics and data on SLN identification were determined.
    RESULTS: Twenty-two studies encompassing 399 patients (75% male, 25% female, average age 57.1 years) met inclusion criteria. Publications comprised of two case reports, four retrospective case series, twelve cohort studies, and four clinical trials. Most common site of melanoma was scalp/temple/forehead (35%), cheek/midface (22%), and ear (17%) with an average Breslow thickness of 3.32 mm. SLN was identified in 80.7% (n = 201/249) of patients using ICG-RI, 85.2% (n = 75/88) using RI alone, and 63.4% (n = 52/82) using blue dye-RI.
    CONCLUSIONS: ICG-99mTc-nanocolloid hybrid tracer may be a superior alternative to blue dye + adiocolloid and has theoretical advantages compared to RI alone. Additional prospective randomized controlled trials are needed to further compare these methods and obtain data on false negative rates, operating room time, and cost effectiveness to fully elucidate the utility of ICG-99mTc-nanocolloid over current methods used for SLN identification in this patient population.
    Keywords:  Head and neck cancer; ICG fluorescence; Indocyanine green; Melanoma; Radiotracer; Sentinel lymph node
    DOI:  https://doi.org/10.1016/j.amjoto.2021.103147
  48. J Eur Acad Dermatol Venereol. 2021 Jul 08.
    Impact of the COVID-19 pandemic on melanoma diagnosis.
    Paolo Gisondi, Simone Cazzaniga, Sara Di Leo, Stefano Piaserico, Francesco Bellinato, Miriam Pizzolato, Alessandro Gatti, Albino Eccher, Matteo Brunelli, Deborah Saraggi, Giampiero Girolomoni, Luigi Naldi.
      Many health-care systems have responded the COVID-19 pandemic by delaying and/or cancelling elective surgical procedures, particularly during the lockdown.1-3 There is a concern that this could have affected the early diagnosis of malignant melanoma (MM) that is critical to improve its prognosis.4,5 The objective of this observational study was to investigate whether a reduction in the incidence of new diagnoses of MM has occurred following the COVID-19 outbreak. All the consecutive histological diagnoses of MM were retrospectively collected in the pathological laboratories of 4 provinces of the Veneto region in northern Italy, namely Verona, Vicenza, Rovigo and Treviso, between 1st March and 31st October 2020 and the same period of 2019. All cases were stratified in three categories according to Breslow thickness: in situ, <1 mm and ≥1 mm. The date of MM excision was considered for all the time-related analyses. The period March-October 2020 was compared with the same period of 2019.
    Keywords:  COVID-19; SARS-CoV-2; lockdown; melanoma; surgery
    DOI:  https://doi.org/10.1111/jdv.17493
  49. Am J Dermatopathol. 2021 Jul 07.
    Large Plaque-type Blue Nevus with GNAQ Q209P Mutation, Involving Mammary Gland Tissue: Under-Recognized Mammary Condition as an Origin of Primary Mammary Melanocytic Tumors.
    Kosuke Satake, Tamotsu Sudo, Takashi Sugino, Shusuke Yoshikawa, Yoshio Kiyohara, Tomomi Hayashi, Kazuaki Nakashima, Keisuke Goto.
       ABSTRACT: Plaque-type blue nevus is a rare variant of blue nevi that was first described in 1954. This article presents clinical, macroscopic, histopathological, and genetic findings for a case of large plaque-type blue nevus expanding into the mammary gland tissue as well as the skin of the right breast. A 63-year-old woman presented with a congenital, large, blue-colored macule limited to the hypochondriac area of the right breast. A nodule 8 mm in diameter was also present in the mammary gland tissue. Magnetic resonance imaging was unable to detect diffuse melanin deposition in the mammary gland tissue, but pigmentation in the whole mammary parenchyma was observed in the cut surfaces of the mastectomy specimen. Histopathology revealed a sparse distribution of dendritic melanocytes in whole sections of the mammary fibrous tissue and partial sections of the dermis. The histopathological criteria for atypical cellular blue nevus were fulfilled for the mammary tumor. Nodal blue nevus was diagnosed in the sentinel lymph node. Sanger sequencing confirmed the GNAQ Q209P mutation, which was also identified in all 4 literature cases of plaque-type blue nevus, but rarely in conventional blue nevi and uveal melanoma. It should be noted that plaque-type blue nevus can expand into the mammary gland tissue, even if the pigmented lesion does not exist on the overlying breast skin. The mammary condition can be the origin of primary mammary melanocytic tumors. Mosaicism of the GNAQ Q209P mutation can be a characteristic genetic alteration to extensive blue nevi, including plaque-type blue nevus.
    DOI:  https://doi.org/10.1097/DAD.0000000000002010
  50. Tissue Eng Part B Rev. 2021 Jul 09.
    Hair Follicle Stem Cells for Tissue Regeneration.
    Alyssa Peterson, Lakshmi Nair.
      With the positive outcomes of various cell therapies currently under pre-clinical and clinical studies, there is a significant interest in novel stem cell sources with unique therapeutic properties. Studies over the past two decades or so demonstrated the feasibility to isolate multipotent/pluripotent stem cells from hair follicles. The easy accessibility, high proliferation and differentiation ability as well as lack of ethical concerns associated with this stem cell source make hair follicle stem cells (HFSCs) attractive candidate for cell therapy and tissue engineering. This review discusses the various stem cell types identified in rodent and human hair follicles and ongoing studies on the potential use of HFSCs for skin, bone, cardio-vascular, and nerve tissue engineering.
    DOI:  https://doi.org/10.1089/ten.TEB.2021.0098
  51. J Med Case Rep. 2021 Jul 08. 15(1): 350
    Ganglionar tuberculosis infection evolving to hemophagocytic lymphohistiocytosis after anti-programmed cell death 1 treatment for high-risk melanoma: a case report.
    Cesar M Costa, Luiza L Gadotti, Maria C Seiwald, Alessandra C R Salgues, Fernando Ganem, Ellen C T Nascimento, David E Uip, Celso Arrais-Rodrigues, Rodrigo R Munhoz.
       BACKGROUND: Hemophagocytic lymphohistiocytosis is a rare, potentially fatal syndrome of immune hyperactivation. Here we describe a ganglionar tuberculosis evolving to hemophagocytic lymphohistiocytosis following adjuvant immunotherapy in a melanoma patient.
    CASE PRESENTATION: A 76-year-old Caucasian male with melanoma started with fever, diffuse petechiae, splenomegaly, anemia, thrombocytopenia, hypofibrinogenemia, and hyperferritinemia 2 months following completion of adjuvant treatment with nivolumab. Positron emission tomography scan showed significant hypermetabolism in cervical, supraclavicular, mediastinal, and abdominal lymph nodes. Bone marrow aspiration demonstrated no alterations, except for a hypercellular pattern. Dexamethasone and intravenous immunoglobulin were started owing to suspicion of hemophagocytic lymphohistiocytosis. Core biopsy of the infracarinal lymph node revealed a chronic granulomatous inflammation and caseous necrosis, with positivity for Mycobacterium tuberculosis by polymerase chain reaction, and treatment for ganglionar tuberculosis was started.
    CONCLUSION: This case highlights the challenges involving programmed cell death 1 blockade in high-risk melanoma, in which infections, lymphoproliferative disorders, and sarcoidosis can mimic disease progression and trigger immune-related adverse events.
    Keywords:  Anti-PD-1; Ganglionar tuberculosis; Hemophagocytic lymphohistiocytosis; Immune checkpoint inhibitors; Immune-related adverse events; Immunotherapy; Melanoma; Nivolumab; PD-1 blockade; Tuberculosis
    DOI:  https://doi.org/10.1186/s13256-021-02900-8
  52. J Fr Ophtalmol. 2021 Jul 05. pii: S0181-5512(21)00312-0. [Epub ahead of print]
    Incidental discovery of cilio-choroidal melanoma following initial presentation of liver metastases.
    S Lemaitre, R Anguita, A K Arora.
      
    DOI:  https://doi.org/10.1016/j.jfo.2021.01.009
  53. Am J Ophthalmol Case Rep. 2021 Sep;23 101147
    Histopathology and immunohistochemistry of choroidal melanocytoma demonstrated by local resection: A case report.
    Hiroshi Goto, Naoyuki Yamakawa, Hiroyuki Komatsu.
       Purpose: To describe the clinical and histopathological features of a case of choroidal melanocytoma treated by local resection.
    Observations: A 73-year-old man was referred to our hospital with a clinical diagnosis of choroidal melanoma. His best corrected visual acuity at presentation was 20/20 OU. Ocular fundus examination of his right eye showed a pigmented intraocular tumor. Local resection of the tumor was performed under general anesthesia. Histopathological examination of the excised tumor showed proliferation of round to ovoid cells with abundant cytoplasm containing many melanosomes and uniform nuclei and these histopathological findings were compatible with a diagnosis of choroidal melanocytoma. Visual acuity of 20/200 OD has been maintained for over 4 years without local recurrence.
    Conclusions and Importance: Clinical diagnosis of choroidal melanocytoma, especially differentiation from melanoma, is difficult and challenging. Local resection of the tumor allowed study of the histopathological features of the choroidal melanocytoma and maintained tolerable vision in the current case.
    Keywords:  Choroid; Histopathology; Local resection; Melanocytoma
    DOI:  https://doi.org/10.1016/j.ajoc.2021.101147
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