bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021–08–01
sixty papers selected by
Farah Jaber-Hijazi, University of the West of Scotland
  1. SIRT7 gene knockout using CRISPR/Cas9 system enhances melanin production in the melanoma cells.
  2. CLEC12B decreases melanoma proliferation by repressing STAT3.
  3. Melanoma and Sarcoidosis in Patients Receiving or Not Antineoplastic Therapy.
  4. The significance of imaging examinations during follow-up for malignant melanoma.
  5. Clinical and Molecular Correlates of NLRC5 Expression in Patients With Melanoma.
  6. Treatment-specific evaluation of the modified Glasgow-Prognostic-Score in patients with advanced cutaneous melanoma.
  7. ANXA10 promotes melanoma metastasis by suppressing E3 ligase TRIM41-directed PKD1 degradation.
  8. uPAR controls vasculogenic mimicry ability expressed by drug-resistant melanoma cells.
  9. Search for effective treatments in patients with advanced refractory melanoma continues: can novel intratumoral therapies deliver?
  10. Primary malignant melanoma of the gastroesophageal junction: A rare and unusual disease.
  11. Chloroacridine derivatives as potential anticancer agents which may act as tricarboxylic acid cycle enzyme inhibitors.
  12. Editorial: Advancements in Molecular Diagnosis and Treatment of Melanoma.
  13. Retrograde Balloon-Assisted Deep Enteroscopy in the Diagnosis of Metastatic Melanoma.
  14. Clinical Trials in Metastatic Uveal Melanoma: Immunotherapy.
  15. Metastatic Malignant Melanoma With Occult Primary Presenting as Breast Mass: A Case Report and Literature Review.
  16. Squaring the circle: circRNAs in melanoma.
  17. Presumed complement-mediated, checkpoint inhibitor-induced, thrombotic microangiopathy in a patient with metastatic melanoma.
  18. A chondroitin sulfate proteoglycan 4‑specific monoclonal antibody inhibits melanoma cell invasion in a spheroid model.
  19. Fermitin family member 2 promotes melanoma progression by enhancing the binding of p-α-Pix to Rac1 to activate the MAPK pathway.
  20. An Integrative Analysis of The Micro-RNAs Contributing in Stemness, Metastasis and B-Raf Pathways in Malignant Melanoma and Melanoma Stem Cell.
  21. Retraction notice for: "Baicalein restrains proliferation, migration, and invasion of human malignant melanoma cells by down-regulating colon cancer associated transcript-1" [Braz J Med Biol Res (2019) 52(12): e8934].
  22. Periocular invasive melanoma manifestation in a patient using bimatoprost: case report and literature review.
  23. Life-threatening myositis after one dose of nivolumab in a patient with nonmetastatic completely resected cutaneous melanoma.
  24. Pyroptosis-Related Gene Signatures Can Robustly Diagnose Skin Cutaneous Melanoma and Predict the Prognosis.
  25. Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma.
  26. Survival in Patients With Sentinel Node-Positive Melanoma With Extranodal Extension.
  27. Real Life Clinical Management and Survival in Advanced Cutaneous Melanoma: The Italian Clinical National Melanoma Registry Experience.
  28. Retraction: Effects of microRNA-708 on Epithelial-Mesenchymal Transition, Cell Proliferation and Apoptosis in Melanoma Cells by Targeting LEF1 Through the Wnt Signaling Pathway.
  29. Cytologic diagnosis of metastatic melanoma by FNA: A practical review.
  30. Abdominal metastatic melanoma invading transverse colon and stomach.
  31. Mitochondrial Voltage-Dependent Anion Channel 1-Hexokinase-II Complex-Targeted Strategy for Melanoma Inhibition Using Designed Multiblock Peptide Amphiphiles.
  32. 18F-FDG PET/CT and 68Ga-FAPI-4 PET/CT Findings of Bilateral Knee Osteoarthritis in a Patient With Uveal Malignant Melanoma.
  33. Heart Dissemination: A Clinical Case of Melanoma.
  34. AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma.
  35. Rapid signaling reactivation after targeted BRAF inhibition predicts the proliferation of individual melanoma cells from an isogenic population.
  36. Oral Amelanotic Melanoma: A Systematic Review of Case Reports and Case Series.
  37. Ultrasound Biomicroscopy Documented Anterior Uveal Melanoma Regression after Ruthenium-106 Plaque Therapy.
  38. Uveal Melanoma in Asians: A Review.
  39. Giant gastric metastasis of malignant melanoma.
  40. The Human Melanoma Proteome Atlas-Complementing the melanoma transcriptome.
  41. Direct identification of neoantigen-specific TCRs from tumor specimens by high-throughput single-cell sequencing.
  42. To suture or not to suture? Does globe immobilisation technique affect clinical outcome in stereotactic radiosurgery for uveal melanoma?
  43. Overcoming PD-1 Blockade Resistance With CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients With Metastatic Melanoma.
  44. [SARS-CoV-2 Spike-like Pigmented Peripheral Structures: A Dermoscopic Finding in Dysplastic Nevi and Incipient Melanomas].
  45. A Novel Stimuli-Responsive Injectable Antibacterial Hydrogel to Achieve Synergetic Photothermal/Gene-Targeted Therapy towards Uveal Melanoma.
  46. Outcomes for posterior uveal melanoma: Validation of American Brachytherapy Society Guidelines.
  47. Clinical and histologic features associated with lentigo maligna clearance after imiquimod treatment.
  48. The human melanoma proteome atlas-Defining the molecular pathology.
  49. Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss.
  50. Ki-67 and p53 expression in head and neck mucosal melanoma: A clinicopathologic analysis of predictors of outcome.
  51. Antimetastatic Effects of Ganoderma lucidum Polysaccharide Peptide on B16-F10-luc-G5 Melanoma Mice With Sleep Fragmentation.
  52. Photochemical reaction to increase melanogenesis using Buddleja officinalis and blue light-emitting diode irradiation in B16F10.
  53. The major mechanism of melanoma mutations is based on deamination of cytosine in pyrimidine dimers as determined by circle damage sequencing.
  54. Oncogenic activity and cellular functionality of melanoma associated antigen A3.
  55. Effects of background color and feeding status on the expression of genes associated with body color regulation in the goldfish Carassius auratus.
  56. Photodynamic Therapy of Vitiligo: A Pilot Study.
  57. RASGRF2 gene fusions identified in a variety of melanocytic lesions with distinct morphological features.
  58. Changes in expression of PD-L1 on peripheral T cells in patients with melanoma and lung cancer treated with PD-1 inhibitors.
  59. Bimatoprost drug delivery with laser and microneedling for the management of COVID-19 prone positioning-induced atrophy and hypopigmentation.
  60. Topical pentoxifylline can be an effective and safe adjunctive therapy to NBUVB therapy in treating vitiligo: A split-side clinical trial.
  1. Biochim Biophys Acta Mol Basis Dis. 2021 Jul 22. pii: S0925-4439(21)00152-6. [Epub ahead of print] 166219
    SIRT7 gene knockout using CRISPR/Cas9 system enhances melanin production in the melanoma cells.
    Mohd Farhan Siddiqui, Moon-Moo Kim.
      Melanin is a prominent pigment of skin and hair, and its deficiency can cause various disorders such as hair graying and albinism. The improvement of melanin production at a genetic level could offer an effective and permanent solution. Recently, SIRT7 has evoked an interest in the study of hair follicle stem cells, but its role in melanin synthesis remains unclear. In the present study, we have first successfully developed SIRT7 gene KO melanoma cells using the CRISPR/Cas9 system. It was found that the SIRT7 gene KO enhanced melanin production in melanoma cells. To validate the role of SIRT7 in melanin production, RT-PCR, western blot, and immunofluorescence staining assays were performed. The expression levels of melanin-producing genes and proteins (MITF, TRP1, TRP-2, TYR, TH) were significantly increased in SIRT7 gene KO cells compared to normal cells. In addition, a melanin production was increased in KO cells higher than in normal cells through the image analysis. All these results suggest that SIRT7 could play an essential role in regulating melanin production, providing an alternative drug target to treat pigmentary disorders.
    Keywords:  CRISPR/Cas9; SIRT7, knockout; melanin; melanoma cells
    DOI:  https://doi.org/10.1016/j.bbadis.2021.166219
  2. J Invest Dermatol. 2021 Jul 23. pii: S0022-202X(21)01464-0. [Epub ahead of print]
    CLEC12B decreases melanoma proliferation by repressing STAT3.
    Henri Montaudié, Laura Sormani, Bérengère Dadone-Montaudié, Marjorie Heim, Nathalie Cardot-Leccia, Meri K Tulic, Guillaume Beranger, Anne-Sophie Gay, Delphine Debayle, Yann Cheli, Jérémy H Raymond, Pierre Sohier, Valérie Petit, Stéphane Rocchi, Franck Gesbert, Lionel Larue, Thierry Passeron.
      The potential role of CLEC12B, a gene predominantly expressed by skin melanocytes discovered through transcriptomic analysis, in melanoma is unknown. Here we show that CLEC12B expression is lower in melanoma and melanoma metastases than in melanocytes and benign melanocytic lesions, and that its decrease correlates with a poor prognosis. We further show that CLEC12B recruits SHP2 phosphatase through its ITIM domain, inactivates STAT1/3/5, increases p53/p21/p27 expression/activity and modulates melanoma cell proliferation. The growth of human melanoma cells overexpressing CLEC12B in nude mice, after subcutaneous injection, is significantly decreased compare to the vehicle control group, and is associated with decreased STAT3 phosphorylation and increased p53 levels in the tumors. Reducing the level of CLEC12B had the opposite effect. We show that CLEC12B represses activation of the STAT pathway and negatively regulates the cell cycle, providing a proliferative asset to melanoma cells.
    Keywords:  CLEC12B; SHP2; STAT1; STAT3; STAT5; melanoma
    DOI:  https://doi.org/10.1016/j.jid.2021.05.035
  3. Case Rep Oncol. 2021 May-Aug;14(2):14(2): 1059-1065
    Melanoma and Sarcoidosis in Patients Receiving or Not Antineoplastic Therapy.
    Panagiotis Gouveris, Dionysia N Zouki, Evangelos G Sarris, Likourgos Kolilekas, Dimitrios Tryfonopoulos, George Papaxoinis, Stamatina Demiri.
      Sarcoidosis and sarcoid-like reactions have been associated with many solid tumors including malignant melanoma. There are reports of melanoma patients who develop sarcoidosis without having received any antineoplastic treatment, but there are also melanoma patients who have received immunotherapy or targeted therapy and, therefore, develop drug-associated sarcoidosis. Herein, we describe 2 cases of thoracic sarcoidosis which occurred in asymptomatic patients with known malignant melanoma. The first patient had metastatic disease, and she was under melanoma treatment with BRAF/MEK inhibitors at the time of sarcoidosis diagnosis. The second case involves a patient with early stage melanoma who had received no antineoplastic treatment. In both cases, the thoracic lesions were suspicious for metastatic involvement, and it was the biopsy which gave the diagnosis of granulomatous disease. Sarcoidosis induced by immune checkpoint or BRAF/MEK inhibitors seems to be more frequent in real-world studies than in large phase 3 melanoma trials. Sarcoidosis can mimic metastasis, predominately in mediastinum, representing a diagnostic pitfall. Therefore, biopsies must always be performed to exclude the metastatic spread before initiation of any antineoplastic treatment.
    Keywords:  BRAF/MEK inhibitors; Melanoma; Sarcoid-like reactions; Sarcoidosis; Targeted therapy
    DOI:  https://doi.org/10.1159/000516035
  4. Eur J Dermatol. 2021 Jun 01. 31(3): 357-363
    The significance of imaging examinations during follow-up for malignant melanoma.
    Melánia Pozsgai, Klára Németh, Péter Oláh, Rolland Gyulai, Zsuzsanna Lengyel.
      Currently, there is a general lack of consensus regarding optimal strategy and imaging during follow-up for patients suffering from melanoma. Our aim was to analyse the utility of various imaging procedures, in particular CT scans, during the follow-up of patients with different stages of melanoma. A retrospective analysis of the medical records of patients suffering from melanoma diagnosed between 2001 and 2011 was carried out at the Department of Dermatology, University of Pécs. Patients with in situ (Stage 0) and metastatic (Stage IV) melanoma were excluded from the analysis, as well as patients who succumbed during the first three years of follow-up. In total, 649 melanoma patients met the inclusion criteria. During the entire follow-up period, 90 recurrences were detected. The vast majority (n = 71; 79%) of the total metastatic cases (n = 90) were diagnosed within the first three years. In 35% of the cases, metastases were detected by CT. Although more than 66% of the CT scans were performed for Stage I patients, only three cases were positive (0.1%) within this population. On the basis of our results, intensive radiological work-up is not deemed necessary during the surveillance of patients in the early stages (IA-IIA) of melanoma. Initial and regular follow-up imaging examinations (preferably CT scans) may be recommended from Stage IIB of the disease.
    Keywords:  computed tomography scan; follow-up; melanoma
    DOI:  https://doi.org/10.1684/ejd.2021.4054
  5. Front Bioeng Biotechnol. 2021 ;9 690186
    Clinical and Molecular Correlates of NLRC5 Expression in Patients With Melanoma.
    Lei Lv, Qinqin Wei, Zhiwen Wang, Yujia Zhao, Ni Chen, Qiyi Yi.
      NLRC5 is an important regulator in antigen presentation and inflammation, and its dysregulation promotes tumor progression. In melanoma, the impact of NLRC5 expression on molecular phenotype, clinical characteristics, and tumor features is largely unknown. In the present study, public datasets from the Cancer Cell Line Encyclopedia (CCLE), Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and cBioPortal were used to address these issues. We identify that NLRC5 is expressed in both immune cells and melanoma cells in melanoma samples and its expression is regulated by SPI1 and DNA methylation. NLRC5 expression is closely associated with Breslow thickness, Clark level, recurrence, pathologic T stage, and ulceration status in melanoma. Truncating/splice mutations rather than missense mutations in NLRC5 could compromise the expression of downstream genes. Low expression of NLRC5 is associated with poor prognosis, low activity of immune-related signatures, low infiltrating level of immune cells, and low cytotoxic score in melanoma. Additionally, NLRC5 expression correlates with immunotherapy efficacy in melanoma. In summary, these findings suggest that NLRC5 acts as a tumor suppressor in melanoma via modulating the tumor immune microenvironment. Targeting the NLRC5 related pathway might improve efficacy of immunotherapy for melanoma patients.
    Keywords:  CTLA-4; NLRC5; PD-1; immunotherapy; melanoma; prognosis
    DOI:  https://doi.org/10.3389/fbioe.2021.690186
  6. J Eur Acad Dermatol Venereol. 2021 Jul 26.
    Treatment-specific evaluation of the modified Glasgow-Prognostic-Score in patients with advanced cutaneous melanoma.
    N Pflug, M Vitus, J Knuever, S Hamacher, C Mauch, M Schlaak, S Theurich.
      Therapeutic options for patients with metastatic melanoma have greatly improved with the introduction of immune checkpoint-inhibition (ICI) and targeted therapies (TT).(1-4) However, a substantial proportion of patients does not respond or experiences toxicities. Thus, prognostic and predictive biomarkers including metabolic host factors are needed. The modified Glasgow-prognostic-score (mGPS) is a well-established immuno-nutritional prognostic assessment in various cancers(5-8), but not yet assessed in melanoma.
    Keywords:  biomarker; immune checkpoint-inhibition; immunometabolism; melanoma; modified Glasgow-Prognostic-Score; prognosis; targeted therapy
    DOI:  https://doi.org/10.1111/jdv.17533
  7. Cancer Lett. 2021 Jul 26. pii: S0304-3835(21)00360-8. [Epub ahead of print]
    ANXA10 promotes melanoma metastasis by suppressing E3 ligase TRIM41-directed PKD1 degradation.
    Xuerui Zhang, Zhaoqing Hu, Xinran Wang, Lin Li, Banghui Zhu, Xiaolei Lin, Jing Zhang, Zichun Hua.
      Melanoma is a highly metastatic cancer that requires effective and targeted curative therapy. Annexin A10 (ANXA10), a member of the annexin family, is a calcium- and phospholipid-binding protein. Considerable evidence indicates that ANXA10 is involved in tumour progression, but little is known about its role in melanoma development. In this study, we find that ANXA10 expression is significantly upregulated, and correlates with melanoma progression. ANXA10 knockout profoundly reduces cell migration and the metastatic activity of melanoma. In addition, ANXA10 knockout induces the N- to E-cadherin switch by upregulating SMAD6, an inhibitory SMAD in the TGF-β/SMAD pathway. The negative regulation of SMAD6 by ANXA10 is dependent on PKD1. ANXA10 interacts with PKD1 and inhibits E3 ligase TRIM41-targeted PKD1 degradation. In B16F10 melanoma cells, protein levels of ANXA10 and PKD1 are inversely correlated with SMAD6 level, but correlated with cell migration. Interestingly, ANXA10 and SMAD6 levels are inversely correlated in clinical samples of melanoma progression. Our findings suggest that the ANXA10-PKD1-SMAD6 axis is a new target for therapeutic strategies against melanoma metastasis.
    Keywords:  ANXA10; Cadherin switch; Melanoma metastasis; PKD1; SMAD6
    DOI:  https://doi.org/10.1016/j.canlet.2021.07.033
  8. Oncol Res. 2021 Jul 27.
    uPAR controls vasculogenic mimicry ability expressed by drug-resistant melanoma cells.
    Elena Andreucci, Anna Laurenzana, Silvia Peppicelli, Alessio Biagioni, Francesca Margheri, Jessica Ruzzolini, Francesca Bianchini, Gabriella Fibbi, Mario Del Rosso, Chiara Nediani, Simona Serratì, Livia Fucci, Michele Guida, Lido Calorini.
      Malignant melanoma is a highly aggressive skin cancer characterized by an elevated grade of tumor cell plasticity. Such plasticity allows melanoma cells adaptation to different hostile conditions and guarantees tumor survival and disease progression, including aggressive features such as drug resistance. Indeed, almost 50% of melanoma rapidly develop resistance to the BRAFV600E inhibitor vemurafenib, with fast tumor dissemination, a devastating consequence for patients' outcomes. Vasculogenic mimicry (VM), the ability of cancer cells to organize themselves in perfused vascular-like channels, might sustain tumor spread by providing vemurafenib-resistant cancer cells with supplementary ways to enter into circulation and disseminate. Thus, this research aims to determine if vemurafenib resistance goes with the acquisition of VM ability by aggressive melanoma cells, and identify a driving molecule for both vemurafenib resistance and VM. We used two independent experimental models of drug-resistant melanoma cells, the first one represented by a chronic adaptation of melanoma cells to extracellular acidosis, known to drive a particularly aggressive and vemurafenib-resistant phenotype, the second one generated with chronic vemurafenib exposure. By performing in vitro tube formation assay and evaluating the expression levels of the VM markers EphA2 and VE-cadherin by western blotting and flow cytometer analyses, we demonstrated that vemurafenib-resistant cells obtained by both models are characterized by an increased ability to perform VM. Moreover, by exploiting the CRISPR-Cas9 technique and using the urokinase plasminogen activator receptor (uPAR) inhibitor M25, we identified uPAR as a driver of VM expressed by vemurafenib-resistant melanoma cells. Thus, uPAR targeting may be successfully leveraged as a new complementary therapy to inhibit VM in drug-resistant melanoma patients, to counteract the rapid progression and dissemination of the disease.
    DOI:  https://doi.org/10.3727/096504021X16273798026651
  9. J Immunother Cancer. 2021 Jul;pii: e002820. [Epub ahead of print]9(7):
    Search for effective treatments in patients with advanced refractory melanoma continues: can novel intratumoral therapies deliver?
    Yana G Najjar.
      Most patients with advanced melanoma ultimately fail immune checkpoint inhibitor (ICI) therapy because of primary or acquired resistance. There remains a critical unmet need for new therapies that function via alternative immune activation mechanisms to safely trigger an antitumor immune response in patients with ICI-refractory disease. This commentary discusses the recent failures and hope for novel intratumoral therapies under development in the advanced refractory melanoma setting, outlining key mechanistic differences that may be critical to yielding success in this difficult-to-treat population.
    Keywords:  immunotherapy; melanoma; oncolytic viruses
    DOI:  https://doi.org/10.1136/jitc-2021-002820
  10. Med J Armed Forces India. 2021 Jul;77(3): 367-370
    Primary malignant melanoma of the gastroesophageal junction: A rare and unusual disease.
    C R Rakesh, A K Sharma, Nishant Pathak, G P S Gahlot.
      Malignant melanoma, an aggressive tumor of skin, is also seen rarely in extra cutaneous sites like the gastrointestinal tract (GIT). Primary melanoma of the GIT by itself is a rare tumor; often metastatic at presentation and if found non-metastatic, it is rarely resectable. We are reporting a histopathologically confirmed case of primary malignant melanoma affecting the 'gastroesophageal junction', which we operated on.
    Keywords:  Birmingham approach; Gastroesophageal junction; Primary malignant melanoma
    DOI:  https://doi.org/10.1016/j.mjafi.2020.03.011
  11. Biomed Pharmacother. 2020 Oct;pii: S0753-3322(20)30708-3. [Epub ahead of print]130 110515
    Chloroacridine derivatives as potential anticancer agents which may act as tricarboxylic acid cycle enzyme inhibitors.
    Miroslawa Cichorek, Anna Ronowska, Krystyna Dzierzbicka, Monika Gensicka-Kowalewska, Milena Deptula, Iwona Pelikant-Malecka.
       PURPOSE: This paper concerns the cytotoxicity of 9-chloro-1-nitroacridine (1a) and 9-chloro-4-methyl-1-nitroacridine (1b) against two biologically different melanoma forms: melanotic and amelanotic. Melanomas are tumors characterized by high heterogeneity and poor susceptibility to chemotherapies. Among new analogs synthesized by us, compound 1b exhibited the highest anticancer potency. Because of that, in this study, we analyzed the mechanism of action for 1a and its 4-methylated derivative, 1b, against a pair of biological melanoma forms, with regard to proliferation, cell death mechanism and energetic state.
    METHODS: Cytotoxicity was evaluated by XTT assay. Cell death was estimated by plasma membrane structure changes (phosphatidylserine externalization), caspase activation, and ROS presence. The energetic state of cells was estimated based on NAD and ATP levels, and the activity of tricarboxylic acid cycle enzymes (pyruvate dehydrogenase complex, aconitase, isocitrate dehydrogenase).
    RESULTS: The chloroacridines affect biological forms of melanoma in different ways. Amelanotic (Ab) melanoma (with inhibited melanogenesis and higher malignancy) was particularly sensitive to the action of the chloroacridines. The Ab melanoma cells died through apoptosis and through death without caspase activation. Diminished activity of TAC enzymes was noticed among Ab melanoma cells together with ATP/NAD depletion, especially in the case of 1b.
    CONCLUSION: Our data show that the biological forms of the tumors responded to 1a and its 4-methylated analog in different ways. 1a and 1b could be inducers of regulated melanoma cell death, especially the amelanotic form. Although the mechanism of the cell death is not fully understood, 1b may act by interfering with the TAC enzymes and blocking specific pathways leading to tumor growth. This could encourage further investigation of its anticancer activity, especially against the amelanotic form of melanoma.
    Keywords:  Amelanotic melanoma; Apoptosis; Cell death; Chloroacridine; Melanotic melanoma; Tricarboxylic acid cycle enzymes
    DOI:  https://doi.org/10.1016/j.biopha.2020.110515
  12. Front Oncol. 2021 ;11 728113
    Editorial: Advancements in Molecular Diagnosis and Treatment of Melanoma.
    Giuseppe Palmieri, Igor Puzanov, Daniela Massi, Paolo Antonio Ascierto.
      
    Keywords:  cancer progression; immunotherapy; melanoma; molecular diagnosis; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2021.728113
  13. Case Rep Gastrointest Med. 2021 ;2021 5572230
    Retrograde Balloon-Assisted Deep Enteroscopy in the Diagnosis of Metastatic Melanoma.
    William Barge, Mark R Albertini, Christopher Cold, Daniel Abbott, Deepak Gopal.
      A 74-year-old male with a history of metastatic melanoma presents with persistently abnormal small bowel findings on PET-CT scan. The patient had persistent FDG uptake near the ileocolic junction on imaging, concerning for metastatic melanoma. Capsule endoscopy demonstrated ulcerated mucosa in the distal ileum. This area was biopsied and tattooed via retrograde double-balloon enteroscopy to confirm the diagnosis of metastatic melanoma and facilitate subsequent small bowel resection. The case illustrates a unique case of metastatic melanoma to the small bowel and the utility of capsule endoscopy and balloon-assisted enteroscopy to assist in diagnosis and management of metastatic disease.
    DOI:  https://doi.org/10.1155/2021/5572230
  14. Ocul Oncol Pathol. 2021 Jun;7(3): 168-176
    Clinical Trials in Metastatic Uveal Melanoma: Immunotherapy.
    Marlana Orloff.
       Background: Uveal melanoma (UM) is a rare subtype of melanoma that generally has a poor prognosis once it has metastasized. Clinical trials evaluating immune checkpoint inhibitors (ICIs) in UM have demonstrated response rates lower than those seen in cutaneous melanoma. Despite lower efficacy demonstrated in initial ICI studies, there are a number of ongoing clinical trials investigating novel immunotherapy approaches in UM.
    Summary: This review aims to summarize important ongoing clinical trials investigating immunotherapeutic approaches in UM and previous trials that have evaluated a number of immunologic interventions. A thorough clinical trial investigation was conducted through clinicaltrials.gov using the disease search terms "uveal melanoma" and "ocular melanoma," excluding non-immunotherapy-related trials. Here, we report on ICI, vaccine, adoptive T cells, and combination immunotherapy trials in UM.
    Key Messages: There is an increasing effort in the search for new, effective therapies for this difficult-to-treat disease, with immunotherapeutic approaches being of particular interest. Increasing knowledge of UM biology and development of new biomarkers will direct future drug development and trial design.
    Keywords:  Immune checkpoint inhibitor; Immunotherapy; T cell; Uveal melanoma; Vaccine
    DOI:  https://doi.org/10.1159/000513336
  15. Cureus. 2021 Jun;13(6): e15886
    Metastatic Malignant Melanoma With Occult Primary Presenting as Breast Mass: A Case Report and Literature Review.
    Rebecca M Harsten, Rebecca Fisher, Nazar Al-Sanjari, Philip Idaewor, Abdalla Saad Abdalla Al-Zawi.
      Skin malignant melanoma (MM) is a malignant neoplasm that arises from the melanocytes in the basal layer of the epidermis. It is considered an aggressive neoplasm and is responsible for 75% of skin cancer deaths. Here we present a case of a young female patient who presented with a left breast mass and investigations revealed multiple disease foci from an occult MM.
    Keywords:  braf gene; breast ca; breast lump; malignant melanoma; mel a; pembrolizumab
    DOI:  https://doi.org/10.7759/cureus.15886
  16. Oncogene. 2021 Jul 30.
    Squaring the circle: circRNAs in melanoma.
    Nicol Mecozzi, Olga Vera, Florian A Karreth.
      Non-coding RNAs are emerging as critical molecules in the genesis, progression, and therapy resistance of cutaneous melanoma. This includes circular RNAs (circRNAs), a class of non-coding RNAs with distinct characteristics that forms through non-canonical back-splicing. In this review, we summarize the features and functions of circRNAs and introduce the current knowledge of the roles of circRNAs in melanoma. We also highlight the various mechanisms of action of the well-studied circRNA CDR1as and describe how it acts as a melanoma tumor suppressor. We further discuss the utility of circRNAs as biomarkers, therapeutic targets, and therapeutic agents in melanoma and outline challenges that must be overcome to comprehensively characterize circRNA functions.
    DOI:  https://doi.org/10.1038/s41388-021-01977-1
  17. BMJ Case Rep. 2021 Jul 26. pii: e242075. [Epub ahead of print]14(7):
    Presumed complement-mediated, checkpoint inhibitor-induced, thrombotic microangiopathy in a patient with metastatic melanoma.
    Thiago P Muniz, Christopher J Patriquin, Samuel D Saibil.
      Immune checkpoint inhibitors (ICIs) are associated with a variety of immune-related adverse events (irAEs), but haematological irAEs are rare. We report a case of presumed complement-mediated thrombotic microangiopathy (CM-TMA) in a 78-year-old man with metastatic melanoma following treatment with ICIs. Following two doses of combination nivolumab and ipilimumab therapy, he developed microangiopathic haemolytic anaemia, thrombocytopenia and increased creatinine. ADAMTS13 activity was preserved, CH50 was high, haptoglobin was depleted and a blood film demonstrated fragments. Given this constellation of findings, a diagnosis of CM-TMA was made. Immunotherapy was held and the patient received steroids and supportive care. Six months after his last dose of immunotherapy, he has no evidence of melanoma or CM-TMA. CM-TMA should be suspected in patients on ICI with unexplained anaemia and thrombocytopenia with preserved ADAMTS13 activity. Suspicion of complement dysregulation may have therapeutic implications, such as the necessity of complement pathway inhibition.
    Keywords:  haematology (incl blood transfusion); oncology; skin cancer
    DOI:  https://doi.org/10.1136/bcr-2021-242075
  18. Int J Oncol. 2021 Sep;pii: 70. [Epub ahead of print]59(3):
    A chondroitin sulfate proteoglycan 4‑specific monoclonal antibody inhibits melanoma cell invasion in a spheroid model.
    Karolina Uranowska, Mahzeiar Samadaei, Tanja Kalic, Matthias Pinter, Heimo Breiteneder, Christine Hafner.
      The overexpression of chondroitin sulfate proteoglycan 4 (CSPG4) is associated with several tumor types, including malignant melanoma, squamous cell carcinoma, triple‑negative breast carcinoma, oligodendrocytomas or gliomas. Due to its restricted distribution in normal tissues, CSPG4 has been considered a potential target for several antitumor approaches, including monoclonal antibody (mAb) therapies. The aim of the present study was to characterize the impact of the CSPG4‑specific mAb clone 9.2.27 on its own or in combination with the commonly used BRAF‑selective inhibitor, PLX4032, on different functions of melanoma cells to assess the potential synergistic effects. The BRAF V600‑mutant human melanoma cell lines, M14 (CSPG4‑negative) and WM164 (CSPG4‑positive), were exposed to the CSPG4‑specific 9.2.27 mAb and/or PLX4032. Cell viability and colony formation capacity were evaluated. A 3D‑cell culture spheroid model was used to assess the invasive properties of the treated cells. In addition, flow cytometric analysis of apoptosis and cell cycle analyses were performed. Incubation of the WM164 cell line with CSPG4‑specific 9.2.27 mAb decreased viability, colony formation ability and the invasive capacity of CSPG4‑positive tumor cells, which was not the case for the CSPG4‑negative M14 cell line. Combined treatment of the WM164 cells with 9.2.27 mAb plus PLX4032 did not exert any significant additional effect in comparison to treatment with PLX4032 alone in the clonogenic and invasion assays. M14 cell cycle distribution was not influenced by the CSPG4‑specific 9.2.27 mAb. By contrast, the exposure of WM164 cells to the mAb resulted in an arrest of the cells in the S phase. Moreover, combined treatment of the WM164 cells led to a significantly increased accumulation of cells in the subG1 phase, combined with a decrease of cells in the G2/M phase. On the whole, findings of the present study indicate that the CSPG4‑specific 9.2.27 mAb exerts an anti‑invasive effect on CSPG4‑positive melanoma spheroids, which is not enhanced by BRAF inhibition. These findings provide the basis for further investigations on the effects of anti‑CSPG4‑based treatments of CSPG4‑positive tumors.
    Keywords:  BRAF inhibitor; BRAF‑mutated melanoma; CSPG4; CSPG4‑positive tumors; CSPG4‑specific antibody; cell invasion inhibition; melanoma; monoclonal antibody; spheroids
    DOI:  https://doi.org/10.3892/ijo.2021.5250
  19. Oncogene. 2021 Jul 28.
    Fermitin family member 2 promotes melanoma progression by enhancing the binding of p-α-Pix to Rac1 to activate the MAPK pathway.
    Shaobin Huang, Wuguo Deng, Peng Wang, Yue Yan, Chuanbo Xie, Xiaoling Cao, Miao Chen, Changlin Zhang, Dingbo Shi, Yunxian Dong, Pu Cheng, Hailin Xu, Wenkai Zhu, Zhicheng Hu, Bing Tang, Jiayuan Zhu.
      We identified fermitin family member 2 (FERMT2, also known as kindlin-2) as a potential target in A375 cell line by siRNA library screening. Drugs that target mutant BRAF kinase lack durable efficacy in the treatment of melanoma because of acquired resistance, thus the identification of novel therapeutic targets is needed. Immunohistochemistry was used to identify kindlin-2 expression in melanoma samples. The interaction between kindlin-2 and Rac1 or p-Rac/Cdc42 guanine nucleotide exchange factor 6 (α-Pix) was investigated. Finally, the tumor suppressive role of kindlin-2 was validated in vitro and in vivo. Analysis of clinical samples and Oncomine data showed that higher levels of kindlin-2 predicted a more advanced T stage and M stage and facilitated metastasis and recurrence. Kindlin-2 knockdown significantly inhibited melanoma growth and migration, whereas kindlin-2 overexpression had the inverse effects. Further study showed that kindlin-2 could specifically bind to p-α-Pix(S13) and Rac1 to induce a switch from the inactive Rac1-GDP conformation to the active Rac1-GTP conformation and then stimulate the downstream MAPK pathway. Moreover, we revealed that a Rac1 inhibitor suppressed melanoma growth and metastasis and the combination of the Rac1 inhibitor and vemurafenib resulted in a better therapeutic outcome than monotherapy in melanoma with high kindlin-2 expression and BRAF mutation. Our results demonstrated that kindlin-2 promoted melanoma progression, which was attributed to specific binding to p-α-Pix(S13) and Rac1 to stimulate the downstream MAPK pathway. Thus, kindlin-2 could be a potential therapeutic target for treating melanoma.
    DOI:  https://doi.org/10.1038/s41388-021-01954-8
  20. Cell J. 2021 Aug;23(3): 261-272
    An Integrative Analysis of The Micro-RNAs Contributing in Stemness, Metastasis and B-Raf Pathways in Malignant Melanoma and Melanoma Stem Cell.
    Parisa Sahranavardfard, Zahra Madjd, Amir Nader Emami Razavi, Ali Reza Ghanadan, Javad Firouzi, Pardis Khosravani, Saeid Ghavami, Esmaeil Ebrahimie, Marzieh Ebrahimi.
       Objective: Epithelial-mesenchymal transition (EMT) and the stemness potency in association with BRAF mutation are in dispensable to the progression of melanoma. Recently, microRNAs (miRNAs) have been introduced as the regulator of a multitude of oncogenic functions in most of tumors. Therefore identifying and interpreting the expression patterns of these miRNAs is essential. The present study sought to find common miRNAs regulating all three important pathways in melanoma development.
    Materials and Methods: In this experimental study, 18 miRNAs that importantly contribute to EMT and have a role in regulating self-renewal and the BRAF pathway were selected based on current literature and cross-analysis with available databases. Subsequently, their expression patterns were evaluated in 20 melanoma patients, normal tissues, serum from patients and control subjects, and melanospheres. Pattern discovery and integrative regulatory network analysis were used to find the most important miRNAs in melanoma progression.
    Results: Among 18 selected miRNAs, miR-205, -141, -203, -15b, and -9 were differentially expressed in tumor samples than normal tissues. Among them, miR-205, -15b, and -9 significantly expressed in serum samples and healthy donors. Attribute Weighting and decision trees (DT) analysis presented evidence that the combination of miR-205, -203, -9, and -15b can regulate self-renewal and EMT process, by affecting CDH1, CCND1, and VEGF expression.
    Conclusion: We suggested here that miR-205, -15b, -203, -9 pattern as the key miRNAs linked to melanoma status, the pluripotency, proliferation, and motility of malignant cells. However, further investigations are required to find the mechanisms underlying the combinatory effects of the above mentioned miRNAs.
    Keywords:  Epithelial-Mesenchymal Transition; Melanoma; MicroRNA; Network Analysis
    DOI:  https://doi.org/10.22074/cellj.2021.7311
  21. Braz J Med Biol Res. 2021 Jul 23. pii: S0100-879X2021000700952. [Epub ahead of print]54(7): e8934retraction
    Retraction notice for: "Baicalein restrains proliferation, migration, and invasion of human malignant melanoma cells by down-regulating colon cancer associated transcript-1" [Braz J Med Biol Res (2019) 52(12): e8934].
      [This retracts the article doi: 10.1590/1414-431X20198934].
    DOI:  https://doi.org/10.1590/1414-431X2020e8934retraction
  22. Orbit. 2021 Jul 28. 1-8
    Periocular invasive melanoma manifestation in a patient using bimatoprost: case report and literature review.
    Adam P Deveau, Flávia Nagel da Silva, Thai Yen Ly, Ahsen Hussain.
      Prostaglandin F2a analogs (PGAs) are considered efficacious in the first-line treatment of glaucoma. They have however been associated with a number of periocular side effects. We present a case of periocular hyperpigmentation and progression to lentigo maligna melanoma (LMM) in a patient using bimatoprost eye drops. We conducted a literature review regarding the etiology and pathophysiology of periocular pigmentation in this setting.A 71-year-old female Caucasian patient with open-angle glaucoma using bimatoprost exclusively in her right eye noticed an ipsilateral lower eyelid/upper cheek area dark lesion after commencing treatment. Examination demonstrated a heterogeneously pigmented lesion. Excisional biopsy demonstrated extensive lentigo maligna (melanoma in situ) with superficially invasive malignant melanoma in the lesion center. The patient underwent successful staged excision and reconstruction. Literature review has demonstrated case reports supporting periocular hyperpigmentation; however, there has been no description of progression to periocular lentigo maligna and melanoma in a patient using bimatoprost.
    Keywords:  Bimatoprost; eyelid; lentigo maligna; lentigo maligna melanoma; melanoma; prostaglandin
    DOI:  https://doi.org/10.1080/01676830.2021.1955392
  23. Acta Neurol Belg. 2021 Jul 30.
    Life-threatening myositis after one dose of nivolumab in a patient with nonmetastatic completely resected cutaneous melanoma.
    Tomaž Rus, Milica Gregorič Kramberger, Gregor Brecl Jakob, Lea Leonardis, Marija Meznaric.
      
    Keywords:  Adjuvant therapy; Adverse events; Immune checkpoint inhibitors; Nivolumab-induced myositis; Nonmetastatic melanoma
    DOI:  https://doi.org/10.1007/s13760-021-01760-9
  24. Front Oncol. 2021 ;11 709077
    Pyroptosis-Related Gene Signatures Can Robustly Diagnose Skin Cutaneous Melanoma and Predict the Prognosis.
    Anji Ju, Jiaze Tang, Shuohua Chen, Yan Fu, Yongzhang Luo.
      Skin cutaneous melanoma (SKCM) is a chronically malignant tumor with a high mortality rate. Pyroptosis, a kind of pro-inflammatory programmed cell death, has been linked to cancer in recent studies. However, the value of pyroptosis in the diagnosis and prognosis of SKCM is not clear. In this study, it was discovered that 20 pyroptosis-related genes (PRGs) differed in expression between SKCM and normal tissues, which were related to diagnosis and prognosis. Firstly, based on these genes, nine machine-learning algorithms were shown to perform well in constructing diagnostic classifiers, including K-Nearest Neighbor (KNN), logistic regression, Support Vector Machine (SVM), Artificial Neural Network (ANN), decision tree, random forest, XGBoost, LightGBM, and CatBoost. Secondly, the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied and the prognostic model was constructed based on 9 PRGs. Subgroups in low and high risks determined by the prognostic model were shown to have different survival. Thirdly, functional enrichment analyses were performed by applying the gene set enrichment analysis (GSEA), and results suggested that the risk was related to immune response. In conclusion, the expression signatures of pyroptosis-related genes are effective and robust in the diagnosis and prognosis of SKCM, which is related to immunity.
    Keywords:  classifier; diagnosis; immunity; prognosis; prognostic model; pyroptosis-related genes; skin cutaneous melanoma
    DOI:  https://doi.org/10.3389/fonc.2021.709077
  25. Oncogene. 2021 Jul 24.
    Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma.
    Beike Wang, Wei Zhang, Gao Zhang, Lawrence Kwong, Hezhe Lu, Jiufeng Tan, Norah Sadek, Min Xiao, Jie Zhang, Marilyne Labrie, Sergio Randell, Aurelie Beroard, Eric Sugarman, Vito W Rebecca, Zhi Wei, Yiling Lu, Gordon B Mills, Jeffrey Field, Jessie Villanueva, Xiaowei Xu, Meenhard Herlyn, Wei Guo.
      Targeting MAPK pathway using a combination of BRAF and MEK inhibitors is an efficient strategy to treat melanoma harboring BRAF-mutation. The development of acquired resistance is inevitable due to the signaling pathway rewiring. Combining western blotting, immunohistochemistry, and reverse phase protein array (RPPA), we aim to understanding the role of the mTORC1 signaling pathway, a center node of intracellular signaling network, in mediating drug resistance of BRAF-mutant melanoma to the combination of BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) therapy. The mTORC1 signaling pathway is initially suppressed by BRAFi and MEKi combination in melanoma but rebounds overtime after tumors acquire resistance to the combination therapy (CR) as assayed in cultured cells and PDX models. In vitro experiments showed that a subset of CR melanoma cells was sensitive to mTORC1 inhibition. The mTOR inhibitors, rapamycin and NVP-BEZ235, induced cell cycle arrest and apoptosis in CR cell lines. As a proof-of-principle, we demonstrated that rapamycin and NVP-BEZ235 treatment reduced tumor growth in CR xenograft models. Mechanistically, AKT or ERK contributes to the activation of mTORC1 in CR cells, depending on PTEN status of these cells. Our study reveals that mTOR activation is essential for drug resistance of melanoma to MAPK inhibitors, and provides insight into the rewiring of the signaling networks in CR melanoma.
    DOI:  https://doi.org/10.1038/s41388-021-01911-5
  26. J Natl Compr Canc Netw. 2021 Jul 26. pii: jnccn20357. [Epub ahead of print]
    Survival in Patients With Sentinel Node-Positive Melanoma With Extranodal Extension.
    Andrea Maurichi, Francesco Barretta, Roberto Patuzzo, Rosalba Miceli, Gianfranco Gallino, Ilaria Mattavelli, Consuelo Barbieri, Andrea Leva, Martina Angi, Francesco Baldo Lanza, Giuseppe Spadola, Mara Cossa, Francesco Nesa, Umberto Cortinovis, Laura Sala, Lorenza Di Guardo, Carolina Cimminiello, Michele Del Vecchio, Barbara Valeri, Mario Santinami.
       BACKGROUND: Prognostic parameters in sentinel node (SN)-positive melanoma are important indicators to identify patients at high risk of recurrence who should be candidates for adjuvant therapy. We aimed to evaluate the presence of melanoma cells beyond the SN capsule-extranodal extension (ENE)-as a prognostic factor in patients with positive SNs.
    METHODS: Data from 1,047 patients with melanoma and positive SNs treated from 2001 to 2020 at the Istituto Nazionale dei Tumori in Milano, Italy, were retrospectively investigated. Kaplan-Meier survival and crude cumulative incidence of recurrence curves were estimated. A multivariable logistic model was used to investigate the association between ENE and selected predictive factors. Cox models estimated the effect of the selected predictors on survival endpoints.
    RESULTS: Median follow-up was 69 months. The 5-year overall survival rate was 62.5% and 71.7% for patients with positive SNs with and without ENE, respectively. The 5-year disease-free survival rate was 54.0% and 64.0% for patients with positive SNs with and without ENE, respectively. The multivariable logistic model showed that age, size of the main metastatic focus in the SN, and numbers of metastatic non-SNs were associated with ENE (all P<.0001). The multivariable Cox regression models showed the estimated prognostic effects of ENE associated with age, ulceration, size of the main metastatic focus in the SN, and number of metastatic non-SNs (all P<.0001) on disease-free survival and overall survival.
    CONCLUSIONS: ENE was a significant prognostic factor in patients with positive-SN melanoma. This parameter may be useful in clinical practice as a selection criterion for adjuvant treatment in patients with stage IIIA disease with a tumor burden <1 mm in the SN. We recommend its inclusion as an independent prognostic determinant in future updates of melanoma guidelines.
    DOI:  https://doi.org/10.6004/jnccn.2020.7693
  27. Front Oncol. 2021 ;11 672797
    Real Life Clinical Management and Survival in Advanced Cutaneous Melanoma: The Italian Clinical National Melanoma Registry Experience.
    Clinical National Melanoma Registry Study Group at the Italian Melanoma Intergroup
       Background: Cutaneous melanoma (CM) is one of the most aggressive types of skin cancer. Currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice. Data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility. The aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CM in several Italian centers, which are part of the Clinical National Melanoma Registry (CNMR).
    Methods: Melanoma-specific survival and overall survival were calculated. Multivariate Cox regression models were used to estimate the hazard ratios adjusting for confounders and other prognostic factors.
    Results: The median follow-up time was 36 months (range 1.2-185.1). 787 CM were included in the analysis with completed information about therapies. All types of immunotherapy showed a significant improved survival compared with all other therapies (p=0.001). 75% was the highest reduction of death reached by anti-PD-1 (HR=0.25), globally immunotherapy was significantly associated with improved survival, either for anti-CTLA4 monotherapy or combined with anti-PD-1 (HR=0.47 and 0.26, respectively) and BRAFI+MEKI (HR=0.62).
    Conclusions: The nivolumab/pembrolizumab in combination of ipilimumab and the addition of ant-MEK to the BRAFi can be considered the best therapies to improve survival in a real-world-population. The CNMR can complement clinical registries with the intent of improving cancer management and standardizing cancer treatment.
    Keywords:  cutaneous melanoma; immunotherapy; ipilimumab; medical record systems; survival analysis
    DOI:  https://doi.org/10.3389/fonc.2021.672797
  28. Pathol Oncol Res. 2021 ;27 1609917
    Retraction: Effects of microRNA-708 on Epithelial-Mesenchymal Transition, Cell Proliferation and Apoptosis in Melanoma Cells by Targeting LEF1 Through the Wnt Signaling Pathway.
      [This retracts the article DOI: 10.1007/s12253-017-0334-z.].
    DOI:  https://doi.org/10.3389/pore.2021.1609917
  29. Cancer Cytopathol. 2021 Jul 26.
    Cytologic diagnosis of metastatic melanoma by FNA: A practical review.
    Andrea Ronchi, Marco Montella, Federica Zito Marino, Giuseppe Argenziano, Elvira Moscarella, Gabriella Brancaccio, Giuseppe Ferraro, Giovanni Francesco Nicoletti, Teresa Troiani, Renato Franco, Immacolata Cozzolino.
      Malignant melanoma (MM) is a highly aggressive neoplasm with a growing worldwide incidence. It is not uncommon that the disease is already metastatic at the time of the first diagnosis. Regional lymph nodes and skin are the first and most common metastatic sites, followed by distant visceral sites (lungs, liver, and central nervous system) and bone. In this clinical setting, fine-needle aspiration (FNA) often represents the first diagnostic approach. FNA is a useful tool to obtain a rapid and accurate diagnosis, in conjunction with ancillary techniques and molecular analysis, as recommended by recent guidelines. The aim of this review was to describe the cytomorphology, immunocytochemical tools, and molecular tools used for the diagnosis of MM metastases on FNA.
    Keywords:   BRAF ; fine-needle aspiration; immunocytochemistry; melanoma; sentinel node
    DOI:  https://doi.org/10.1002/cncy.22488
  30. Rev Esp Enferm Dig. 2021 Jul 28.
    Abdominal metastatic melanoma invading transverse colon and stomach.
    Miquel Ángel Escribano-Pons, Juan José Segura-Sampedro, Cristina Pineño-Flores, José Carlos Rodriguez Pino, Francesc Xavier González-Argenté, Rafael Morales-Soriano.
      Gastrointestinal melanoma metastases are not uncommon, with jejunum and ileum being the most common locations (58%), followed by gastric (26%), colonic (22%), duodenal (12%) and rectum metastases (5%).
    DOI:  https://doi.org/10.17235/reed.2021.8052/2021
  31. ACS Appl Mater Interfaces. 2021 Jul 26.
    Mitochondrial Voltage-Dependent Anion Channel 1-Hexokinase-II Complex-Targeted Strategy for Melanoma Inhibition Using Designed Multiblock Peptide Amphiphiles.
    Fan Zhang, Angelina Angelova, Vasil M Garamus, Borislav Angelov, Shuyang Tu, Liangliang Kong, Xinlei Zhang, Na Li, Aihua Zou.
      Targeted therapies of melanoma are of urgent need considering the resistance of this aggressive type of cancer to chemotherapeutics. The voltage-dependent anion channel 1 (VDAC1)-hexokinase-II (HK-II) complex is an emerging target for novel anticancer therapies based on induced mitochondria-mediated apoptosis. The low cell membrane permeability of the anticancer 12-mer peptide N-Ter (RDVFTKGYGFGL) derived from the N-terminal fragment of the VDAC1 protein impedes the intracellular targeting. Here, novel multiblock VDAC1-derived cationic amphiphilic peptides (referred to as Pal-N-Ter-TAT, pFL-N-Ter-TAT, and Pal-pFL-N-Ter-TAT) are designed with a self-assembly propensity and cell-penetrating properties. The created multiblock amphiphilic peptides of partial α-helical conformations form nanoparticles of ellipsoid-like shapes and are characterized by enhanced cellular uptake. The amphiphilic peptides can target mitochondria and dissociate the VDAC1-HK-II complex at the outer mitochondrial membrane, which result in mitochondria-mediated apoptosis. The latter is associated with decrease of the mitochondrial membrane potential, cytochrome c release, and changes of the expression levels of the apoptotic proteins in A375 melanoma cells. Importantly, the mitochondrial VDAC1-derived amphiphilic peptides have a comparable IC50 value for melanoma cells to a small-molecule drug, sorafenib, which has been previously used in clinical trials for melanoma. These results demonstrate the potential of the designed peptide constructs for efficient melanoma inhibition.
    Keywords:  VDAC1-derived amphiphilic peptides; cell-penetrating peptides (CPP); human melanoma cells; mitochondria-mediated apoptosis; protein−protein interaction inhibition; self-assembly; targeting VDAC1−HK-II complex
    DOI:  https://doi.org/10.1021/acsami.1c04385
  32. Clin Nucl Med. 2021 Jul 26.
    18F-FDG PET/CT and 68Ga-FAPI-4 PET/CT Findings of Bilateral Knee Osteoarthritis in a Patient With Uveal Malignant Melanoma.
    Özge Erol Fenercioğlu, Ediz Beyhan, Nurhan Ergül, Esra Arslan, Tevfik Fikret Çermik.
       ABSTRACT: We present the findings of 68Ga-FAPI-4 PET/CT and 18F-FDG PET/CT of a metastatic malignant melanoma patient with osteoarthritis. A 65-year-old woman with a history of metastatic uveal malignant melanoma was referred to 18F-FDG PET/CT for restaging after enucleation and chemotherapy. 18F-FDG PET/CT imaging showed high radiotracer uptake in liver metastases; additionally mild uptake due to osteoarthritis was observed in both knees. However, although 68Ga-FAPI-4 showed lower uptake in liver lesions, it showed a more prominent uptake in both knee joints compared with 18F-FDG.
    DOI:  https://doi.org/10.1097/RLU.0000000000003854
  33. Case Rep Med. 2021 ;2021 8562402
    Heart Dissemination: A Clinical Case of Melanoma.
    Diogo André, Teresa André, Fabiana Gouveia, Rafael Nascimento, António Chaves, Maria Braza O.
      Introduction. Primitive malignant heart tumours are rare, specific cases. The presence of cardiac metastases, often in the pericardium, besides indicating disseminated oncological disease, represents a diagnostic challenge since they tend to be asymptomatic. Malignant cutaneous melanoma (MCM) is the neoplasm that most often affects the heart. Patients and Methods. The authors describe a case report of a 59-year-old female patient with a history of non-insulin-treated diabetes mellitus, arterial hypertension, dyslipidemia, and remitting cutaneous malignant melanoma who underwent skin excision, lymphadenectomy, and adjuvant chemotherapy in 1996. In April 2014, she resorted to emergency service due to epigastric pain and progressive tiredness. Due to the persistence of the complaints, abdominal ultrasound was performed, which showed a large pericardial effusion, corroborated later by teleradiography and echocardiography. The patient underwent pericardiocentesis, which isolated neoplastic cells. A computed tomography study of the chest, abdomen, and pelvis revealed bilateral and pericardial pleural effusion, as well as alterations suggestive of pericardial and pulmonary metastasis. Later, fine-needle aspiration puncture of the left posterior cervical nodule confirmed histologically malignant melanoma metastasis. Discussion. Given the natural history of melanoma that when metastasized has an overall survival of 15-20% for 5 years, its metastatic spread may occur several years after its surgical excision. Thus, patients with a history of melanoma and heart failure who develop new cardiac symptoms of unknown aetiology should undergo imaging studies such as echocardiography, computed tomography, and magnetic resonance imaging.
    DOI:  https://doi.org/10.1155/2021/8562402
  34. J Exp Med. 2021 Sep 06. pii: e20200962. [Epub ahead of print]218(9):
    AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma.
    Keitaro Fukuda, Ken Okamura, Rebecca L Riding, Xueli Fan, Khashayar Afshari, Nazgol-Sadat Haddadi, Sean M McCauley, Mehmet H Guney, Jeremy Luban, Takeru Funakoshi, Tomonori Yaguchi, Yutaka Kawakami, Anastasia Khvorova, Katherine A Fitzgerald, John E Harris.
      The STING and absent in melanoma 2 (AIM2) pathways are activated by the presence of cytosolic DNA, and STING agonists enhance immunotherapeutic responses. Here, we show that dendritic cell (DC) expression of AIM2 within human melanoma correlates with poor prognosis and, in contrast to STING, AIM2 exerts an immunosuppressive effect within the melanoma microenvironment. Vaccination with AIM2-deficient DCs improves the efficacy of both adoptive T cell therapy and anti-PD-1 immunotherapy for "cold tumors," which exhibit poor therapeutic responses. This effect did not depend on prolonged survival of vaccinated DCs, but on tumor-derived DNA that activates STING-dependent type I IFN secretion and subsequent production of CXCL10 to recruit CD8+ T cells. Additionally, loss of AIM2-dependent IL-1β and IL-18 processing enhanced the treatment response further by limiting the recruitment of regulatory T cells. Finally, AIM2 siRNA-treated mouse DCs in vivo and human DCs in vitro enhanced similar anti-tumor immune responses. Thus, targeting AIM2 in tumor-infiltrating DCs is a promising new treatment strategy for melanoma.
    DOI:  https://doi.org/10.1084/jem.20200962
  35. Sci Rep. 2021 Jul 29. 11(1): 15473
    Rapid signaling reactivation after targeted BRAF inhibition predicts the proliferation of individual melanoma cells from an isogenic population.
    Payam Khoshkenar, Emily Lowry, Amir Mitchell.
      Cancer cells within tumors display a high degree of phenotypic variability. This variability is thought to allow some of the cells to survive and persist after seemingly effective drug treatments. Studies on vemurafenib, a signaling inhibitor that targets an oncogenic BRAF mutation common in melanoma, suggested that cell-to-cell variation in drug resistance, measured by long-term proliferation, originates from epigenetic differences in gene expression that pre-exist treatment. However, it is still unknown whether reactivation of signaling downstream to the inhibited BRAF, thought to be a key step for resistance, is heterogeneous across cells. While previous studies established that signaling reactivation takes place many hours to days after treatment, they monitored reactivation with bulk-population assays unsuitable for detecting cell-to-cell heterogeneity. We hypothesized that signaling reactivation is heterogeneous and is almost instantaneous for a small subpopulation of resistant cells. We tested this hypothesis by monitoring signaling dynamics at a single-cell resolution and observed that despite highly uniform initial inhibition, roughly 15% of cells reactivated signaling within an hour of treatment. Moreover, by tracking cell lineages over multiple days, we established that these cells indeed proliferated more than neighboring cells, thus establishing that rapid signaling reactivation predicts long-term vemurafenib resistance.
    DOI:  https://doi.org/10.1038/s41598-021-94941-8
  36. Head Neck Pathol. 2021 Jul 26.
    Oral Amelanotic Melanoma: A Systematic Review of Case Reports and Case Series.
    Shivani P Bansal, Sonal Sunil Dhanawade, Ankita Satish Arvandekar, Vini Mehta, Rajiv S Desai.
      Oral amelanotic melanoma (OAM) is a rare, non-pigmented mucosal neoplasm representing less than 2% of all melanoma. The present study analyses the available data on OAM and describes its clinicopathological features, identifying potential prognostic factors. Online electronic databases such as PubMed-Medline, Embase, and Scopus were searched using appropriate keywords from the earliest available date till 31st March 2021 without restriction on language. Additional sources like Google Scholar, major journals, unpublished studies, conference proceedings, and cross-references were explored. 37 publications were included for quantitative synthesis, comprising 55 cases. The mean age of the patients was 59.56 years, and the lesions were more prevalent in males than in females. OAM's were most prevalent in the maxilla (67.2%) with ulceration, pinkish-red color, nodular mass, and pain. 2 patients (3.36%) were alive at their last follow-up, and 25 were dead (45.4%). Univariate survival analysis of clinical variables revealed that age older than 68 years (p = 0.003), mandibular gingiva (p = 0.007), round cells (p = 0.004), and surgical excision along with chemotherapy & radiation therapy (p = 0.001) were significantly associated with a lower survival rate. Oral Amelanotic Melanoma is a neoplasm with a poor prognosis, presenting a 6.25% possibility of survival after 5 years. Patients older than 68 years, lesions in the mandibular gingiva, round cells, and surgical excision along with chemotherapy and radiotherapy, presented the worst prognosis. However, they did not represent independent prognostic determinants for these patients.
    Keywords:  Amelanotic; Immunohistochemistry; Melanoma; Mucosal melanoma; Oral amelanotic melanoma; Oral cavity; Prognosis
    DOI:  https://doi.org/10.1007/s12105-021-01366-w
  37. Ocul Oncol Pathol. 2021 Jun;7(3): 224-232
    Ultrasound Biomicroscopy Documented Anterior Uveal Melanoma Regression after Ruthenium-106 Plaque Therapy.
    Biljana Kuzmanović Elabjer, Mladen Bušić, Andrej Pleše, Mirjana Bjeloš, Daliborka Miletić, Nenad Vukojević.
       Introduction: Ultrasound biomicroscopy (UBM) is the only widely used method for the evaluation of anterior uveal melanoma (AUM).
    Objective: Documentation of regression of AUM treated with ruthenium-106 (Ru-106) plaque types CCB and CCC using UBM.
    Methods: This single institution-based retrospective case series involved 10 Caucasian patients with AUM followed after brachytherapy with UBM from January 2014 until February 2019. The largest prominence of the tumor perpendicular to the sclera or the cornea (including scleral/corneal thickness) (D) and the largest basal dimension (B) were measured in millimeters with UBM for all patients prior to the brachytherapy and at 4-month interval follow-up. Tumor regression was calculated as a percentage of decrease in the initial D and B values.
    Results: The study involved 10 patients with a mean age of 64.4 years (yr) (range 46-80 yr). D ranged from 1.82 to 5.5 mm (median 2.99 mm) and B from 2.32 to 12.38 mm (median 4.18 mm). The apical radiation dose in all patients was 100 Gy. The median follow-up was 42.02 months. Regression for D was 21.11 ± 13.66%, 31.09 ± 14.66%, and 34.92 ± 19.86% at 1st, 2nd, and 3rd year of the follow-up, respectively, while for B it was 21.58 ± 16.05%, 28.98 ± 17.71%, and 32.06 ± 18.96%, respectively. Tumor recurrence was documented in 2/10 patients.
    Conclusion: The major regression of AUM, treated with Ru-106 plaque types CCB and CCC, was documented in the first 2 years after brachytherapy in our study group. In the following years, only minimal regression was documented that warns of the need for close monitoring and active search for local recurrences.
    Keywords:  Anterior uveal melanoma; Basal dimension; Brachytherapy; Tumor prominence; Ultrasound biomicroscopy; Uveal melanoma regression
    DOI:  https://doi.org/10.1159/000512030
  38. Ocul Oncol Pathol. 2021 Jun;7(3): 159-167
    Uveal Melanoma in Asians: A Review.
    Pradeep Manchegowda, Arun D Singh, Carol Shields, Swathi Kaliki, Parag Shah, Lingam Gopal, Pukhraj Rishi.
      Despite limited data, some differences in the clinical profile can be observed in Asian population when compared with presentation of uveal melanoma (UM) in white population. The incidence of UM is higher in Whites than in Asians. For the purpose of comparison with Asian population, data from North America, Europe, and Australia were considered as that of "white" population. The annual incidence of UM has been reported to be 5-6 cases/million in whites. The incidence in different parts of Asia is estimated at 0.2-0.6 per million. The age of presentation is around 40-55 years in Asians, which is younger when compared to that of whites (mean age of 58 years). At presentation, mean basal diameter of tumors in Asians is greater compared to whites but overall, medium-size tumors are most common. Clinical presentation is straightforward in majority of cases with retinal detachment, acute glaucoma, uveitis, cataract, or vitreous hemorrhage as common symptoms. Epithelioid cell-type variant carries the worst prognosis. Management options for choroidal melanoma include transpupillary thermotherapy, plaque radiotherapy, charged particle irradiation, local resection, enucleation, or orbital exenteration. Most commonly used modalities are enucleation and plaque radiotherapy.
    Keywords:  Asian; Choroid; Eye; Iris; Melanoma; Tumor; Uvea
    DOI:  https://doi.org/10.1159/000512738
  39. Oxf Med Case Reports. 2021 Jul;2021(7): omab050
    Giant gastric metastasis of malignant melanoma.
    Takaaki Yoshimoto, Takeshi Okamoto, Katsuyuki Fukuda.
      
    DOI:  https://doi.org/10.1093/omcr/omab050
  40. Clin Transl Med. 2021 Jul;11(7): e451
    The Human Melanoma Proteome Atlas-Complementing the melanoma transcriptome.
    Lazaro Hiram Betancourt, Jeovanis Gil, Aniel Sanchez, Viktória Doma, Magdalena Kuras, Jimmy Rodriguez Murillo, Erika Velasquez, Uğur Çakır, Yonghyo Kim, Yutaka Sugihara, Indira Pla Parada, Beáta Szeitz, Roger Appelqvist, Elisabet Wieslander, Charlotte Welinder, Natália Pinto de Almeida, Nicole Woldmar, Matilda Marko-Varga, Jonatan Eriksson, Krzysztof Pawłowski, Bo Baldetorp, Christian Ingvar, Håkan Olsson, Lotta Lundgren, Henrik Lindberg, Henriett Oskolas, Boram Lee, Ethan Berge, Marie Sjögren, Carina Eriksson, Dasol Kim, Ho Jeong Kwon, Beatrice Knudsen, Melinda Rezeli, Johan Malm, Runyu Hong, Peter Horvath, A Marcell Szász, József Tímár, Sarolta Kárpáti, Peter Horvatovich, Tasso Miliotis, Toshihide Nishimura, Harubumi Kato, Erik Steinfelder, Madalina Oppermann, Ken Miller, Francesco Florindi, Quimin Zhou, Gilberto B Domont, Luciana Pizzatti, Fábio C S Nogueira, Leticia Szadai, István Balázs Németh, Henrik Ekedahl, David Fenyö, György Marko-Varga.
      The MM500 meta-study aims to establish a knowledge basis of the tumor proteome to serve as a complement to genome and transcriptome studies. Somatic mutations and their effect on the transcriptome have been extensively characterized in melanoma. However, the effects of these genetic changes on the proteomic landscape and the impact on cellular processes in melanoma remain poorly understood. In this study, the quantitative mass-spectrometry-based proteomic analysis is interfaced with pathological tumor characterization, and associated with clinical data. The melanoma proteome landscape, obtained by the analysis of 505 well-annotated melanoma tumor samples, is defined based on almost 16 000 proteins, including mutated proteoforms of driver genes. More than 50 million MS/MS spectra were analyzed, resulting in approximately 13,6 million peptide spectrum matches (PSMs). Altogether 13 176 protein-coding genes, represented by 366 172 peptides, in addition to 52 000 phosphorylation sites, and 4 400 acetylation sites were successfully annotated. This data covers 65% and 74% of the predicted and identified human proteome, respectively. A high degree of correlation (Pearson, up to 0.54) with the melanoma transcriptome of the TCGA repository, with an overlap of 12 751 gene products, was found. Mapping of the expressed proteins with quantitation, spatiotemporal localization, mutations, splice isoforms, and PTM variants was proven not to be predicted by genome sequencing alone. The melanoma tumor molecular map was complemented by analysis of blood protein expression, including data on proteins regulated after immunotherapy. By adding these key proteomic pillars, the MM500 study expands the knowledge on melanoma disease.
    Keywords:  BRAF; acetylation stoichiometry; driver mutations; histopathology; metastatic melanoma; phosphorylation; posttranslational-modification; proteogenomics
    DOI:  https://doi.org/10.1002/ctm2.451
  41. J Immunother Cancer. 2021 Jul;pii: e002595. [Epub ahead of print]9(7):
    Direct identification of neoantigen-specific TCRs from tumor specimens by high-throughput single-cell sequencing.
    Yong-Chen Lu, Zhili Zheng, Frank J Lowery, Jared J Gartner, Todd D Prickett, Paul F Robbins, Steven A Rosenberg.
       BACKGROUND: Recognition of neoantigens by T cells plays a major role in cancer immunotherapy. Identification of neoantigen-specific T-cell receptors (TCRs) has become a critical research tool for studying T cell-mediated responses after immunotherapy. In addition, neoantigen-specific TCRs can be used to modify the specificity of T cells for T cell-based therapies targeting tumor-specific mutations. Although several techniques have been developed to identify TCR sequences, these techniques still require a significant amount of labor, making them impractical in the clinical setting.
    METHODS: Thanks to the availability of high-throughput single-cell sequencing, we developed a new process to isolate neoantigen-specific TCR sequences. This process included the isolation of tumor-infiltrating T cells from a tumor specimen and the stimulation of T cells by neoantigen-loaded dendritic cells, followed by single-cell sequencing for TCR and T-cell activation markers, interferon-γ and interleukin-2.
    RESULTS: In this study, potential neoantigen-specific TCRs were isolated from three melanoma and three colorectal tumor specimens. These TCRs were then synthesized and transduced into autologous T cells, followed by testing the recognition of neoantigens. A total of 28 neoantigen-specific TCRs were identified by this process. If identical TCR sequences were detected from two or more single cells, this approach was highly reliable (100%, 19 out of 19 TCRs).
    CONCLUSION: This single-cell approach provides an efficient process to isolate antigen-specific TCRs for research and clinical applications.
    Keywords:  adoptive; cell engineering; gastrointestinal neoplasms; immunotherapy; lymphocytes; melanoma; tumor-infiltrating
    DOI:  https://doi.org/10.1136/jitc-2021-002595
  42. Br J Neurosurg. 2021 Jul 27. 1-4
    To suture or not to suture? Does globe immobilisation technique affect clinical outcome in stereotactic radiosurgery for uveal melanoma?
    Hibba Quhill, Sachin M Salvi, Ian G Rennie, John Yianni, Matthias Radatz, Paul Rundle.
       INTRODUCTION: Stereotactic radiosurgery (SRS) is a valuable treatment option for uveal melanoma, offering excellent tumour control rates and eye preservation. Its efficacy relies upon accurate localisation of the tumour, which is challenging in the mobile eye. Various methods of globe immobilisation have been used, including non-invasive devices, such as eye movement tracking and suction cups, but common practice is to use local anaesthetic block with or without transconjunctival suturing of the extraocular muscles. Some studies have suggested that the addition of muscle suturing to local anaesthetic block provides better immobilisation of the globe, when compared to anaesthetic block alone. Controversy exists regarding the clinical relevance of this observation and ocular oncologists differ in their choice of immobilisation technique.
    METHODS: In order to establish if the addition of muscle suturing to local anaesthetic block improves clinical outcomes, we performed a retrospective review of all cases that underwent SRS for uveal melanoma over a 10-year period (May 2008 to May 2018). Based on surgeon preference, all patients received either local anaesthetic block plus muscle suturing (Group A) or local anaesthetic block alone (Group B) to induce globe akinesia. Outcomes assessed were primary treatment failure, tumour recurrence, secondary enucleation and death rate.
    RESULTS: In our cohort of 290 eyes; 118 patients were in group A and 172 patients were in group B. There were no cases of primary treatment failure in either group. With a minimum of 24 months follow-up, only 3 patients experienced tumour recurrence (1 in group A and 2 in group B). There was no significant difference in recurrence, enucleation and all-cause death rates between the two groups.
    CONCLUSION: Our retrospective review suggests that although extraocular muscle suturing may be considered by some units to provide superior globe immobilisation for SRS, it does not alter the clinical outcome.
    Keywords:  Stereotactic; immobilisation; ocular; suturing; uveal melanoma
    DOI:  https://doi.org/10.1080/02688697.2021.1958147
  43. Cancer Discov. 2021 Jul 29. pii: candisc.0425.2021. [Epub ahead of print]
    Overcoming PD-1 Blockade Resistance With CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients With Metastatic Melanoma.
    Antoni Ribas, Theresa Medina, John M Kirkwood, Yousef Zakharia, Rene Gonzalez, Diwakar Davar, Bartosz Chmielowski, Katie M Campbell, Riyue Bao, Heather Kelley, Aaron Morris, David Mauro, James E Wooldridge, Jason J Luke, George J Weiner, Arthur M Krieg, Mohammed M Milhem.
      Patients with advanced melanoma that is resistant to programmed death-1 (PD-1) blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong interferon response to induce and attract antitumor T cells. In the dose-escalation part of this phase 1b study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti-PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an interferon-γ gene signature following treatment, as well as increased systemic expression of the interferon-inducible chemokine CXCL10.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0425
  44. Actas Dermosifiliogr. 2021 Jul 15.
    [SARS-CoV-2 Spike-like Pigmented Peripheral Structures: A Dermoscopic Finding in Dysplastic Nevi and Incipient Melanomas].
    Alejandro Martin-Gorgojo, José Luis Ramírez-Bellver, Ricardo Ruiz-Rodríguez, Ángel Pizarro.
      
    DOI:  https://doi.org/10.1016/j.ad.2021.07.001
  45. Adv Sci (Weinh). 2021 Jul 31. e2004721
    A Novel Stimuli-Responsive Injectable Antibacterial Hydrogel to Achieve Synergetic Photothermal/Gene-Targeted Therapy towards Uveal Melanoma.
    Shaoyun Wang, Baohui Chen, Liping Ouyang, Donghui Wang, Ji Tan, Yuqin Qiao, Shengfang Ge, Jing Ruan, Ai Zhuang, Xuanyong Liu, Renbing Jia.
      Uveal melanoma (UM) is the most prevalent primary intraocular malignant tumor with a high lethal rate. Patients who undergo conventional enucleation treatments consistently suffer permanent blindness, facial defects, and mental disorders, therefore, novel therapeutic modalities are urgently required. Herein, an injectable and stimuli-responsive drug delivery antibacterial hydrogel (CP@Au@DC_AC50) is constructed via a facile grinding method that is inspired by the preparation process of traditional Chinese medicine. The incorporation of gold nanorods can enhance the mechanical strength of the hydrogel and realize photothermal therapy (PTT) and thermosensitive gel-sol transformation to release the gene-targeted drug DC_AC50 on demand in response to low-density near-infrared (NIR) light. The orthotopic model of UM is built successfully and indicates the excellent efficiency of CP@Au@DC_AC50 in killing tumors without damage to normal tissue because of its synergistic mild temperature PTT and gene-targeted therapy. Moreover, the eyeball infection model reveals the remarkable antibacterial properties of the hydrogel which can prevent endophthalmitis in the eyeball. There is negligible difference between the CP@Au@DC_AC50+NIR group and normal group. This NIR light-triggered gene-targeted therapy/PTT/antibacterial treatment pattern provides a promising strategy for building multifunctional therapeutic platform against intraocular tumors and exhibits great potential for the clinical treatment of UM.
    Keywords:  antibacterial activity; gene-targeted therapy; injectable hydrogel; intelligent release; photothermal therapy; uveal melanoma
    DOI:  https://doi.org/10.1002/advs.202004721
  46. Brachytherapy. 2021 Jul 22. pii: S1538-4721(21)00441-4. [Epub ahead of print]
    Outcomes for posterior uveal melanoma: Validation of American Brachytherapy Society Guidelines.
    Kyle Meidenbauer, Zachary Richards, Renato J Yupari, James F Bena, Allan Wilkinson, John Suh, Arun D Singh.
       PURPOSE: To assess outcomes of small and medium choroidal melanoma (less than 5.0 mm in height) following Iodine-125 episcleral brachytherapy.
    METHODS AND MATERIALS: Patients with small and medium choroidal melanoma that underwent Iodine-125 brachytherapy with apical height of 1.0 mm to 5.0 mm and largest basal diameter of ≤16.0 mm were included. Data were extracted from the original dosimetry plans to determine doses to vision critical structures with the prescription point to the apical height (actual dose, ABS guidelines) and, after simulation, with the prescription point to the height of 5.0 mm (simulated dose, COMS protocol). Visual acuity (VA) outcomes with actual dose and that predicted with the simulated dose were estimated along with local recurrence, ocular survival, and survival at 5 years.
    RESULTS: A total of 339 patients with a mean age of 61.5 years with a mean follow up duration of 43.4 months were included. The mean dose reduction for lens, optic disc, and fovea was 34%, 39.4%, and 41.4%, respectively with actual dose when compared with simulated dose. The Kaplan-Meier estimations for 3 year event free rate of VA of 20/50 or better were 56% and 31% for actual dose and simulated dose, respectively. Only 3 events of local recurrence were observed (enucleated) yielding 5 year local control and ocular survival rate of 98%. Overall survival (OS) and metastasis free survival (MFS) were 95% and 87.5% at 5 years, respectively.
    CONCLUSIONS: Small and medium choroidal melanoma treated according to ABS has excellent outcomes. Brachytherapy planning using ABS guidelines as compared to COMS protocol may be associated with lower rates of radiation toxicity and vision loss.
    Keywords:  ABS guidelines; Brachytherapy; COMS protocol; Choroidal melanoma; Iodine-125; Vision loss
    DOI:  https://doi.org/10.1016/j.brachy.2021.05.165
  47. J Dermatolog Treat. 2021 Jul 27. 1-14
    Clinical and histologic features associated with lentigo maligna clearance after imiquimod treatment.
    R Kwak, C Joyce, A E Werchniak, J Y Lin, H C Tsibris.
       BACKGROUND: Imiquimod cream may be used as non-surgical treatment for lentigo maligna or as adjuvant therapy following excision to decrease risk of recurrence.
    OBJECTIVES: To evaluate histologic and clinical factors associated with clinical clearance of lentigo maligna treated with imiquimod.
    METHODS: We performed a retrospective review of all patients diagnosed with lentigo maligna and treated with imiquimod between 1997 and 2019 at our academic institution.
    RESULTS: We observed clinical clearance in 93% (66/71) of participants who received adjuvant imiquimod following surgery and 79% (19/24) in the primary non-surgical treatment group over a median of 38 months of follow-up. In the adjuvant therapy group, positive surgical margins were associated with a decreased rate of clinical clearance when compared to cases with close (<1mm) margins or background melanocytic dysplasia (83.3% vs. 100%, p = 0.01). The presence of an inflammatory response during treatment was associated with increased clearance (94.1% vs. 66.7%, p = 0.02).
    CONCLUSIONS: Adjuvant imiquimod treatment may decrease LM recurrence rates in cases with background melanocytic dysplasia or close margins. LM cases with positive surgical margins need close clinical follow-up given higher recurrence rates.
    Keywords:  imiquimod; lentigo maligna; melanoma
    DOI:  https://doi.org/10.1080/09546634.2021.1962001
  48. Clin Transl Med. 2021 Jul;11(7): e473
    The human melanoma proteome atlas-Defining the molecular pathology.
    Lazaro Hiram Betancourt, Jeovanis Gil, Yonghyo Kim, Viktória Doma, Uğur Çakır, Aniel Sanchez, Jimmy Rodriguez Murillo, Magdalena Kuras, Indira Pla Parada, Yutaka Sugihara, Roger Appelqvist, Elisabet Wieslander, Charlotte Welinder, Erika Velasquez, Natália Pinto de Almeida, Nicole Woldmar, Matilda Marko-Varga, Krzysztof Pawłowski, Jonatan Eriksson, Beáta Szeitz, Bo Baldetorp, Christian Ingvar, Håkan Olsson, Lotta Lundgren, Henrik Lindberg, Henriett Oskolas, Boram Lee, Ethan Berge, Marie Sjögren, Carina Eriksson, Dasol Kim, Ho Jeong Kwon, Beatrice Knudsen, Melinda Rezeli, Runyu Hong, Peter Horvatovich, Tasso Miliotis, Toshihide Nishimura, Harubumi Kato, Erik Steinfelder, Madalina Oppermann, Ken Miller, Francesco Florindi, Qimin Zhou, Gilberto B Domont, Luciana Pizzatti, Fábio C S Nogueira, Peter Horvath, Leticia Szadai, József Tímár, Sarolta Kárpáti, A Marcell Szász, Johan Malm, David Fenyö, Henrik Ekedahl, István Balázs Németh, György Marko-Varga.
      The MM500 study is an initiative to map the protein levels in malignant melanoma tumor samples, focused on in-depth histopathology coupled to proteome characterization. The protein levels and localization were determined for a broad spectrum of diverse, surgically isolated melanoma tumors originating from multiple body locations. More than 15,500 proteoforms were identified by mass spectrometry, from which chromosomal and subcellular localization was annotated within both primary and metastatic melanoma. The data generated by global proteomic experiments covered 72% of the proteins identified in the recently reported high stringency blueprint of the human proteome. This study contributes to the NIH Cancer Moonshot initiative combining detailed histopathological presentation with the molecular characterization for 505 melanoma tumor samples, localized in 26 organs from 232 patients.
    Keywords:  heterogeneity; histopathology; metastatic malignant melanoma; proteogenomics; subcellular localization
    DOI:  https://doi.org/10.1002/ctm2.473
  49. Oncogene. 2021 Jul 30.
    Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss.
    Shuning He, Mark W Zimmerman, Hillary M Layden, Alla Berezovskaya, Julia Etchin, Megan W Martel, Grace Thurston, Chang-Bin Jing, Ellen van Rooijen, Charles K Kaufman, Scott J Rodig, Leonard I Zon, E Elizabeth Patton, Marc R Mansour, A Thomas Look.
      Melanomas driven by loss of the NF1 tumor suppressor have a high risk of treatment failure and effective therapies have not been developed. Here we show that loss-of-function mutations of nf1 and pten result in aggressive melanomas in zebrafish, representing the first animal model of NF1-mutant melanomas harboring PTEN loss. MEK or PI3K inhibitors show little activity when given alone due to cross-talk between the pathways, and high toxicity when given together. The mTOR inhibitors, sirolimus, everolimus, and temsirolimus, were the most active single agents tested, potently induced tumor-suppressive autophagy, but not apoptosis. Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma.
    DOI:  https://doi.org/10.1038/s41388-021-01926-y
  50. Ann Diagn Pathol. 2021 Jul 20. pii: S1092-9134(21)00089-7. [Epub ahead of print]54 151789
    Ki-67 and p53 expression in head and neck mucosal melanoma: A clinicopathologic analysis of predictors of outcome.
    Gaofei Yin, Wei Guo, Hongfei Liu, Zhigang Huang, Xiaohong Chen.
       OBJECTIVE: To explore the prognostic value of Ki-67 and p53 in patients with head and neck mucosal melanoma by analyzing the relevant data from previous patients.
    METHODS: Data on Ki-67 and p53 immunohistochemical staining in 128 patients treated in Beijing Tongren Hospital between April 2005 and January 2021 were analyzed retrospectively. The correlation of Ki-67 and p53 expression with general clinical features and survival prognosis was analyzed.
    RESULTS: Median follow-up time was 21 months. There were 66 cases in the group with Ki-67 < 40% and 62 cases in the group with Ki-67 ≥ 40%, with 60 cases in the p53-negative group and 68 cases in the p53-positive group. Of the 128 patients, 67 died and 61 survived. There were 63 patients with distant metastasis and 33 patients with local recurrence. Ki-67 expression was related to distant metastasis but this was not an independent risk factor; however, it was an independent risk factor affecting the survival of patients. The survival time for patients with Ki-67 ≥ 40% was significantly shorter than for patients with Ki-67 < 40%. P53 expression had no significant effect on survival and prognosis.
    CONCLUSION: Ki-67 is related to the disease stage and overall survival of patients with head and neck mucosal melanoma. It may have a guiding significance for the prognosis of patients as those with higher Ki-67 levels had poorer prognosis. However, the incidence rate of this disease is low, and all of the results need to be verified with a larger dataset.
    Keywords:  Clinical pathology; Head and neck tumor; Ki-67; Mucosal melanoma
    DOI:  https://doi.org/10.1016/j.anndiagpath.2021.151789
  51. Front Pharmacol. 2021 ;12 650216
    Antimetastatic Effects of Ganoderma lucidum Polysaccharide Peptide on B16-F10-luc-G5 Melanoma Mice With Sleep Fragmentation.
    Haocheng Xian, Jiayi Li, Yimeng Zhang, Ditian Li, Yinan Zhu, Siyan Li, Zhelun Tan, Zhibin Lin, Xuejun Li, Yan Pan.
      Ganoderma lucidum (Lingzhi) polysaccharide peptide (GL-pp) is a component of the globally acknowledged traditional Chinese medicine Ganoderma lucidum; Ganoderma lucidum is known for its sedative, hypnotic, immune regulatory, antitumor, and other pharmacological effects. In recent years, sleep disorders have been linked to many diseases and human body disorders, including cancer. Some experimental studies in mice found that sleep fragmentation could promote tumor development and progression. However, effects on GL-pp on tumor metastasis under circumstances of sleep disorders have rarely been studied. Thus, in this study, we used mice with sleep fragmentation (SF) bearing B16-F10-luc-G5 melanoma tumors to investigate the effect of SF on melanoma metastasis. Furthermore, we investigated the antitumor and antimetastatic effects of GL-pp (80 mg/kg) in mice suffering from SF and bearing B16-F10-luc-G5. Then, whole proteomics was used to analyze the differences in protein expression in the lung tissue between SF mice bearing B16-F10-luc-G5 with and without GL-pp administration. High-throughput pyrosequencing of 16S rRNA was also used to analyze the impact of GL-pp on the gut microbiota composition in SF mice bearing B16-F10-luc-G5. Last, the effects of GL-pp on macrophage polarization and TNF-α serum levels were detected. Collectively, we found that SF significantly facilitated the B16-F10-luc-G5 melanoma tumor metastasis in mice, while GL-pp significantly reduced B16-F10-luc-G5 melanoma tumor metastasis under the condition of SF, in which proteomics and gut microbiota had been changed greatly.
    Keywords:  Ganoderma lucidum polysaccharide peptide; gut microbiota; proteomics; sleep fragmentation; tumor metastasis
    DOI:  https://doi.org/10.3389/fphar.2021.650216
  52. Photodiagnosis Photodyn Ther. 2021 Jul 23. pii: S1572-1000(21)00280-5. [Epub ahead of print] 102456
    Photochemical reaction to increase melanogenesis using Buddleja officinalis and blue light-emitting diode irradiation in B16F10.
    Hyejoung Cho, Byunggook Kim, Ok-Su Kim, Young Kim, Ying Yang, Jianan Song, Danyang Liu, Sangmi Jeon, Okjoon Kim.
      Recently, the incidence of vitiligo has increased because of stresses induced by external environment. Ultraviolet (UV) light therapy is the most commonly used method of treating the disease; however, UV light therapy requires a long treatment period, and prolonged exposure to UV radiation has side effects. The purpose of the present study was to investigate the effects of natural products and LED irradiation (LED-IR) on the synthesis of melanin. It was not possible to effectively increase intracellular melanin production through individual applications of Buddleja officinalis (BO), which is a natural substance selected through screening, or blue light irradiation (Blue-IR). However, when used in combination, these two agents stimulated adenylyl cyclase (AC) and melanin production was induced in the stimulated cells via the CREB/MITF/TYR pathway. Furthermore, the combined treatment with BO and Blue-IR generated low levels of cellular reactive oxygen species (ROS) and induced p38 phosphorylation, which in turn activated MITF in ROS-stimulated synthetic melanocytes, resulting in the promotion of melanogenic pathways other than the CREB/MITF/TYR pathway. In addition, this treatment combination affected melanin transport. These results suggested that the combined therapies can be used to treat melanin-deficiency skin diseases such as vitiligo.
    Keywords:  Buddleja officinalis; Vitiligo; blue Light emitting diode irradiation; melanogenesis; photochemotherapy
    DOI:  https://doi.org/10.1016/j.pdpdt.2021.102456
  53. Sci Adv. 2021 Jul;pii: eabi6508. [Epub ahead of print]7(31):
    The major mechanism of melanoma mutations is based on deamination of cytosine in pyrimidine dimers as determined by circle damage sequencing.
    Seung-Gi Jin, Dean Pettinga, Jennifer Johnson, Peipei Li, Gerd P Pfeifer.
      Sunlight-associated melanomas carry a unique C-to-T mutation signature. UVB radiation induces cyclobutane pyrimidine dimers (CPDs) as the major form of DNA damage, but the mechanism of how CPDs cause mutations is unclear. To map CPDs at single-base resolution genome wide, we developed the circle damage sequencing (circle-damage-seq) method. In human cells, CPDs form preferentially in a tetranucleotide sequence context (5'-Py-T<>Py-T/A), but this alone does not explain the tumor mutation patterns. To test whether mutations arise at CPDs by cytosine deamination, we specifically mapped UVB-induced cytosine-deaminated CPDs. Transcription start sites (TSSs) were protected from CPDs and deaminated CPDs, but both lesions were enriched immediately upstream of the TSS, suggesting a mutation-promoting role of bound transcription factors. Most importantly, the genomic dinucleotide and trinucleotide sequence specificity of deaminated CPDs matched the prominent mutation signature of melanomas. Our data identify the cytosine-deaminated CPD as the leading premutagenic lesion responsible for mutations in melanomas.
    DOI:  https://doi.org/10.1126/sciadv.abi6508
  54. Biochem Pharmacol. 2021 Jul 22. pii: S0006-2952(21)00313-0. [Epub ahead of print] 114700
    Oncogenic activity and cellular functionality of melanoma associated antigen A3.
    Paula Schäfer, Themistoklis Paraschiakos, Sabine Windhorst.
      Cancer testis antigen Melanoma associated antigen A3 (MAGE-A3) has been subject of research for many years. Being expressed in various tumor types and influencing proliferation, metastasis, and tumor pathogenicity, MAGE-A3 is an attractive target for cancer therapy, particularly because in healthy tissues, MAGE-A3 is only expressed in testes and placenta. MAGE-A3 acts as a cellular master regulator by stimulating E3 ubiquitin ligase tripartite motif-containing protein 28 (TRIM28), resulting in regulation of various cellular targets. These include tumor suppressor protein p53 and cellular energy sensor AMP-activated protein kinase (AMPK). The restricted expression of MAGE-A3 in tumor cells makes MAGE-A3 an attractive target for vaccine-based immune therapy. However, although phase I and phase II clinical trials involving MAGE-A3-specific immunotherapeutic interventions were promising, large phase III studies failed. This article gives an overview about the role of MAGE-A3 as a cellular master switch and discusses approaches to improve MAGE-A3-based immunotherapies.
    Keywords:  Cancer germline antigens; Cancer vaccine; Immunotherapy; Intracellular mechanism; MAGE-A3; Melanoma Associated Antigen A3
    DOI:  https://doi.org/10.1016/j.bcp.2021.114700
  55. Gen Comp Endocrinol. 2021 Jul 21. pii: S0016-6480(21)00153-2. [Epub ahead of print] 113860
    Effects of background color and feeding status on the expression of genes associated with body color regulation in the goldfish Carassius auratus.
    Tingshu Yang, Satoshi Kasagi, Akiyoshi Takahashi, Kanta Mizusawa.
      Alpha-melanocyte-stimulating hormone (α-MSH), a peptide derived from proopiomelanocortin (POMC), and melanin-concentrating hormone (MCH), act as neuromodulators and regulate food intake in vertebrates. In teleosts, these peptides are also involved competitively in body color regulation; α-MSH induces a dark body color, while MCH induces a pale body color. Similarly, members of the growth hormone (GH) family, somatolactin (SL) and prolactin (PRL), which are involved in the regulation of energy metabolism, are also associated with body color regulation in teleosts. Since these hormones are involved in both body color regulation and energy metabolism, it is possible that feeding status can affect body color. Here, we examined the effects of fasting on the response of goldfish body coloration to changes in background color. Goldfish were acclimated for one week in tanks with a white or black background under conditions of periodic feeding or fasting. The results showed that body color and expression levels of pmch1 and pomc were affected by background color, irrespective of feeding status. Expression levels of sla were higher in fish maintained in tanks with a black background than in tanks with a white background, and higher in the fasted fish compared to the fed fish. However, the pattern of slb expression was almost the opposite of that observed in sla expression. The expression levels of gh and prl in the pituitary, and pmch2a and pmch2b in the brain, were not affected by background color. These results suggest that MCH, α-MSH, SLα, and SLβ might be involved in body color regulation and that they are affected by background color in goldfish. The results also suggest that feeding status may affect body color regulation via SLα and SLβ, although these effects might be limited compared to the effect of background color.
    Keywords:  background color; body color; feeding; goldfish; hormone
    DOI:  https://doi.org/10.1016/j.ygcen.2021.113860
  56. Photodiagnosis Photodyn Ther. 2021 Jul 25. pii: S1572-1000(21)00266-0. [Epub ahead of print] 102439
    Photodynamic Therapy of Vitiligo: A Pilot Study.
    Hoda Rahimi, Roya Zeinali, Zohreh Tehranchinia.
       BACK GROUND: Vitiligo is an acquired autoimmune skin disorder with depigmented macules and patches. There are several possible treatments for vitiligo, none of which could be considered as a definitive cure. Photodynamic therapy (PDT) is a novel treatment with controversial outcomes in vitiligo patients.
    MATERIALS & METHODS: A total of 10 patches (5 patches on the trunk, 3 on the extremities, and 2 on the neck) were selected and received microderm abrasion. Then the lesion was covered with 5- aminolevulinic acid (ALA) for one hour. Afterwards, it received red light with a dose of 120 J/cm2.This cycle was repeated monthly for 5 sessions. Another vitiligo patch was considered as a control and received topical mometasone twice a day during the study. The therapeutic results were compared by a blind dermatologist.
    RESULTS: The median of repigmentation score, which was determined by a blind dermatologist, was 0.5 in the PDT group and 1 in the steroid group, which did not show any statistically significant difference.
    CONCLUSION: The results of this study demonstrated that PDT does not have any additional therapeutic effect in comparison with topical corticosteroids as the traditional treatment of vitiligo.
    DOI:  https://doi.org/10.1016/j.pdpdt.2021.102439
  57. Pigment Cell Melanoma Res. 2021 Jul 26.
    RASGRF2 gene fusions identified in a variety of melanocytic lesions with distinct morphological features.
    Aurélie Houlier, Daniel Pissaloux, Franck Tirode, Noémie Lopez Ramirez, Maud Plaschka, Julie Caramel, Ingrid Masse, Arnaud de la Fouchardiere.
      The WHO classification identifies nine classes of melanocytic proliferations according to location, UV-exposure, histological and genetic features. Only a minority of lesions remain unclassified. We describe five cases that harbored either an ERBIN-RASGRF2 or an ATP2B4-RASGRF2 in frame fusion transcript. These lesions were collected from different studies, unified only by the lack of identifiable known mutations, with a highly variable phenotype. One case was a large abdominal congenital nevus, three were slowly growing pigmented nodules and the last was an ulcerated nodule arising on the site of a preexisting small nevus, known since childhood. The latter was diagnosed as a 4mm thick melanoma with loss of BAP1 expression. The four other cases were compound, melanocytic proliferations with an unusual deep pattern of small dense nests of bland melanocytes encased in a fibrous background. The RASGRF2 fusion was confirmed by a break-apart FISH technique. Array-CGH performed in three cases found non-recurrent secondary copy number alterations. Follow-up was uneventful. In silico analysis identified a single RASGRF2 fusion in the TCGA pan-cancer database whereas RASGRF2 variants were stochastically distributed in all cancer subtypes.
    Keywords:   ATP2B4-RASGRF2 ; ERBIN-RASGRF2 ; RASGRF2 ; congenital nevus; gene fusion; melanoma
    DOI:  https://doi.org/10.1111/pcmr.13004
  58. Sci Rep. 2021 Jul 28. 11(1): 15312
    Changes in expression of PD-L1 on peripheral T cells in patients with melanoma and lung cancer treated with PD-1 inhibitors.
    Sarah J Dart, Alistair M Cook, Michael J Millward, Alison M McDonnell, Wee L Chin, Muhammad U Hakeem, Tarek M Meniawy, Samantha E Bowyer.
      Advances in cancer immunology have increased the use of immune checkpoint inhibitors in clinical practice, however not all patients respond, and treatment can have severe side-effects. Blood-based immunological biomarkers are an attractive method for predicting which patients will respond to therapy, however, reliable biomarkers for immune checkpoint blockade are lacking. This study aimed to identify patients before or early in treatment who would best respond to PD-1 inhibitors. We hypothesised that higher baseline PD-L1 and/or PD-1 on peripheral blood T cells could predict radiological response to PD-1 inhibitors. This pilot prospective cohort study assessed 26 patients with melanoma or non-small cell lung cancer, treated with pembrolizumab, nivolumab, or nivolumab/ipilimumab combined. Response was assessed by RECIST 1.1. Peripheral blood lymphocytes collected at baseline, after one cycle, 10 weeks and at discontinuation of therapy were analysed by flow cytometry. Patients with a higher proportion of PD-L1+ T cells at baseline had improved objective response to PD-1 inhibitor therapy, and patients with a lower proportion of regulatory T cells at baseline experienced more immune-related adverse events. These findings may prove useful to assist in clinical decision making. Further studies with larger cohorts are required to validate these findings.
    DOI:  https://doi.org/10.1038/s41598-021-93479-z
  59. JAAD Case Rep. 2021 Jul 15.
    Bimatoprost drug delivery with laser and microneedling for the management of COVID-19 prone positioning-induced atrophy and hypopigmentation.
    Britney N Wilson, Abdullah Aleisa, Christian Menzer, Anthony M Rossi.
      
    Keywords:  COVID-19; bimatoprost; facial ulcers; hypopigmented scar; laser therapy; proning; skin of color
    DOI:  https://doi.org/10.1016/j.jdcr.2021.07.004
  60. Exp Dermatol. 2021 Jul 26.
    Topical pentoxifylline can be an effective and safe adjunctive therapy to NBUVB therapy in treating vitiligo: A split-side clinical trial.
    Nasrin Saki, Elham Sheikhi Ghayur, Alireza Heiran, Mahsa Gholami, Shohreh Alipour.
      
    Keywords:  NBUVB; pentoxifylline; phototherapy; tacrolimus; vitiligo
    DOI:  https://doi.org/10.1111/exd.14436
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