bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021–05–23
fifty-four papers selected by
Farah Jaber-Hijazi, University of the West of Scotland
  1. The Arp2/3 complex is critical for colonisation of the mouse skin by melanoblasts.
  2. The protective role of MC1R in chromosome stability and centromeric integrity in melanocytes.
  3. The genetic and epigenetic basis of distinct melanoma types.
  4. Epigenetic regulation during melanocyte development and homeostasis.
  5. Histone variant dictates fate biasing of neural crest cells to melanocyte lineage.
  6. Transcriptional co-activator regulates melanocyte differentiation and oncogenesis by integrating cAMP and MAPK/ERK pathways.
  7. Melanosome biogenesis in the pigmentation of mammalian skin.
  8. Conjunctival melanoma: New insights in tumour genetics and immunology, leading to new therapeutic options.
  9. Avian Coloration Genetics: Recent Advances and Emerging Questions.
  10. Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders.
  11. Epithelial-to-mesenchymal-like transition events in melanoma.
  12. The complex role of AIM2 in autoimmune diseases and cancers.
  13. Lentigo maligna: defining margins and predictors of recurrence utilising clinical, dermoscopic, confocal microscopy and histopathology features.
  14. Nicotinamide N-Methyltransferase Gene Silencing Enhances Chemosensitivity of Melanoma Cell Lines.
  15. Screening for second malignancies in mycosis fungoides: Non-Hodgkin lymphoma, Hodgkin lymphoma, lung cancer, bladder cancer, and melanoma.
  16. Clinicopathologic and molecular characterization of melanomas mutated for CTNNB1 and MAPK.
  17. Health Risks Associated With Excessive Exposure to Solar Ultraviolet Radiation Among Outdoor Workers in South Africa: An Overview.
  18. Estimated Effect of COVID-19 Lockdown on Skin Tumor Size and Survival: An Exponential Growth Model.
  19. Tips for difficult to diagnose hypomelanotic melanomas on reflectance confocal microscopy.
  20. In-transit metastatic cutaneous melanoma: current management and future directions.
  21. Management of Hyperpigmentation: Current Treatments and Emerging Therapies.
  22. Risk factors for cardiovascular mortality and melanoma-specific mortality among patients with melanoma: a SEER based study.
  23. Granulomatous colitis in a patient with metastatic melanoma under immunotherapy: a case report and literature review.
  24. Initial Stage of Cutaneous Primary Melanoma Plays a Key Role in the Pattern and Timing of Disease Recurrence.
  25. Semi-automated total body photography supports robust delivery of skin cancer monitoring services during the SARS-COV2/COVID-19 pandemic.
  26. Ultrasound-Mediated Microbubble Destruction Inhibits Skin Melanoma Growth by Affecting YAP1 Translation Using Ribosome Imprinting Sequencing.
  27. Cul4b Promotes Progression of Malignant Cutaneous Melanoma Patients by Regulating CDKN2A.
  28. Knockdown of NLE1 inhibits development of malignant melanoma in vitro and in vivo NLE1 promotes development of malignant melanoma.
  29. The effect of gluten on skin and hair: a systematic review.
  30. Differential diagnosis and management of hyperpigmentation.
  31. Immunoglobulin superfamily receptor Junctional adhesion molecule 3 (Jam3) requirement for melanophore survival and patterning during formation of zebrafish stripes.
  32. Inducible modulation of miR-204 levels in a zebrafish melanoma model.
  33. Metastatic endo and perineural involvement of the ulnar nerve from malignant melanoma: ultrasound (US) and magnetic resonance imaging (MRI) findings.
  34. Skin Melanoma Detection in Microscopic Images Using HMM-Based Asymmetric Analysis and Expectation Maximization.
  35. Linking Parkinson's Disease and Melanoma: Interplay Between α-Synuclein and Pmel17 Amyloid Formation.
  36. LAG3-PD-1 Inhibitor Combo Impresses in Melanoma.
  37. Inhibition of plasminogen activator inhibitor-1 blocks programmed death ligand 1 endocytosis and improves the response of melanoma cells to immune checkpoint blockade.
  38. Real-World Survival in Patients with Metastatic Melanoma after Discontinuation of Anti-PD-1 Immunotherapy for Objective Response or Adverse Effects: A Retrospective Study.
  39. Use of BRAF immunohistochemistry as a screening test in detecting BRAFV600E mutation in melanomas.
  40. Metastatic malignant melanoma in an endometrial polyp.
  41. [Development of destructive thyroiditis and diabetes mellitus after three injections of pembrolizumab for skin melanoma].
  42. Vigilance to misleading information is required to avoid delayed diagnosis: Case series of acral melanomas.
  43. Treatment Following Progression in Metastatic Melanoma: the State of the Art from Scientific Literature to Clinical Need.
  44. Outcomes after stereotactic radiosurgery of brain metastases in patients with malignant melanoma and validation of the melanoma molGPA.
  45. Inhibitory Effects of Euphorbia ebracteolata Hayata Extract ECB on Melanoma-Induced Hyperplasia of Blood Vessels in Zebrafish Embryos.
  46. Early time to recurrence predicts worse survival in patients with localized or regionally advanced cutaneous melanoma.
  47. Multiple eruptive squamous cell carcinomas: a possible clinical sign in melanoma patients treated with vemurafenib.
  48. Ocular safety profile of BRAF and MEK inhibitors: data from the World Health Organization Pharmacovigilance Database.
  49. Malignant Melanoma in Children and Adolescents Treated in Pediatric Oncology Centers: An Australian and New Zealand Children's Oncology Group (ANZCHOG) Study.
  50. Successful rechallenge therapy for BRAF/MEK inhibitor-resistant multiple brain metastases of melanoma.
  51. Use of hydrochlorothiazide and risk of skin cancer in a large nested case-control study in Spain.
  52. Lentiginous melanoma - should we change the paradigm?
  53. Outcomes for systemic therapy in older patients with metastatic melanoma: Results from the Dutch Melanoma Treatment Registry.
  54. Development and Pilot Screen of Novel High Content Assay for Down Regulators of Expression of Heterogenous Nuclear Ribonuclear Protein H2.
  1. Development. 2020 Jan 01. pii: dev.194555. [Epub ahead of print]
    The Arp2/3 complex is critical for colonisation of the mouse skin by melanoblasts.
    Vassilis Papalazarou, Karthic Swaminathan, Farah Jaber-Hijazi, Heather Spence, Ines Lahmann, Colin Nixon, Manuel Salmeron-Sanchez, Hans-Henning Arnold, Klemens Rottner, Laura M Machesky.
      The Arp2/3 complex is essential for the assembly of branched filamentous actin but its role in physiology and development is surprisingly little understood. Melanoblasts deriving from the neural crest migrate along the developing embryo and traverse the dermis to reach the epidermis colonising the skin and eventually homing within the hair follicles. We have previously established that Rac1 and Cdc42 direct melanoblast migration in vivo. We hypothesised that the Arp2/3 complex might be the main downstream effector of these small GTPases. Arp3 depletion in the melanocyte lineage results in severe pigmentation defects in dorsal and ventral regions of the mouse skin. Arp3 null melanoblasts demonstrate proliferation and migration defects and fail to elongate as their wild-type counterparts. Conditional deletion of Arp3 in primary melanocytes causes improper proliferation, spreading, migration and adhesion to extracellular matrix. Collectively, our results suggest that the Arp2/3 complex is absolutely indispensable in the melanocyte lineage in mouse development, and indicate a significant role in developmental processes that require tight regulation of actin-mediated motility.
    Keywords:  Actin cytoskeleton; Arp2/3; Development; Melanoblasts; Migration; Skin pigmentation
    DOI:  https://doi.org/10.1242/dev.194555
  2. Cell Death Discov. 2021 May 18. 7(1): 111
    The protective role of MC1R in chromosome stability and centromeric integrity in melanocytes.
    Xin Li, Weiwei Mao, Jie Chen, Colin R Goding, Rutao Cui, Zhi-Xiang Xu, Xiao Miao.
      Variants in the melanocortin-1 receptor (MC1R) gene, encoding a trimeric G-protein-coupled receptor and activated by α-melanocyte-stimulating hormone (α-MSH), are frequently associated with red or blonde hair, fair skin, freckling, and skin sensitivity to ultraviolet (UV) light. Several red hair color variants of MC1R are also associated with increased melanoma risk. MC1R variants affect melanoma risk independent of phenotype. Here, we demonstrated that MC1R is a critical factor in chromosome stability and centromere integrity in melanocytes. α-MSH/MC1R stimulation prevents melanocytes from UV radiation-induced damage of chromosome stability and centromere integrity. Mechanistic studies indicated that α-MSH/MC1R-controlled chromosome stability and centromeric integrity are mediated by microphthalmia-associated transcription factor (Mitf), a transcript factor needed for the α-MSH/MC1R signaling and a regulator in melanocyte development, viability, and pigment production. Mitf directly interacts with centromere proteins A in melanocytes. Given the connection among MC1R variants, red hair/fair skin phenotype, and melanoma development, these studies will help answer a question with clinical relevance "why red-haired individuals are so prone to developing melanoma", and will lead to the identification of novel preventive and therapeutic strategies for melanomas, especially those with redheads.
    DOI:  https://doi.org/10.1038/s41420-021-00499-9
  3. J Dermatol. 2021 May 18.
    The genetic and epigenetic basis of distinct melanoma types.
    Junna Oba, Scott E Woodman.
      Melanoma represents the deadliest skin cancer. Recent therapeutic developments, including targeted and immune therapies have revolutionized clinical management and improved patient outcome. This progress was achieved by rigorous molecular and functional studies followed by robust clinical trials. The identification of key genomic alterations and gene expression profiles have propelled the understanding of distinct characteristics within melanoma subtypes. The aim of this review is to summarize and highlight the main genetic and epigenetic findings of melanomas and highlight their pathological and therapeutic importance.
    Keywords:  epithelial-to-mesenchymal transition; gene expression; genomic alteration; melanoma subtypes; phenotypic switching
    DOI:  https://doi.org/10.1111/1346-8138.15957
  4. Exp Dermatol. 2021 May 18.
    Epigenetic regulation during melanocyte development and homeostasis.
    Ramile Dilshat, Hong Nhung Vu, Eiríkur Steingrímsson.
      Melanocytes originate in the neural crest as precursor cells which then migrate and proliferate to reach their destination where they differentiate into pigment-producing cells. Melanocytes not only determine the color of hair, skin and eyes but also protect against the harmful effects of UV irradiation. The establishment of the melanocyte lineage is regulated by a defined set of transcription factors and signaling pathways that direct the specific gene expression programs underpinning melanoblast specification, survival, migration, proliferation and differentiation. In addition, epigenetic modifiers and replacement histones play key roles in regulating gene expression and its timing during the different steps of this process. Here we discuss the evidence for the role of epigenetic regulators in melanocyte development and function and how they interact with transcription factors and signaling pathways to establish and maintain this important cell lineage.
    DOI:  https://doi.org/10.1111/exd.14391
  5. Development. 2020 Jan 01. pii: dev.182576. [Epub ahead of print]
    Histone variant dictates fate biasing of neural crest cells to melanocyte lineage.
    Desingu Ayyappa Raja, Yogaspoorthi Subramaniam, Ayush Aggarwal, Vishvabandhu Gotherwal, Aswini Babu, Jyoti Tanwar, Rajender K Motiani, Sridhar Sivasubbu, Rajesh S Gokhale, Vivek T Natarajan.
      In the neural crest lineage, progressive fate-restriction and stem cell assignment are critical for both development and regeneration. While the fate-commitment events have distinct transcriptional footprints, fate-biasing is often transitory and metastable, and is thought to be moulded by epigenetic programs. Hence molecular basis of specification is difficult to define. In this study, we establish a role of a histone variant H2a.z.2 in specification of melanocyte lineage from multipotent neural crest cells. Silencing of H2a.z.2 reduces the number of melanocyte precursors in developing zebrafish embryos, and from mouse embryonic stem cells in vitro. We demonstrate that this histone variant occupies nucleosomes in the promoter of key melanocyte determinant Mitf, and enhances its induction. CRISPR-Cas9 based targeted mutagenesis of this gene in zebrafish drastically reduces adult melanocytes, as well as their regeneration. Thereby our study establishes the role of a histone variant upstream to the core gene regulatory network in the neural crest lineage. This epigenetic mark is a key determinant of cell fate and facilitates gene activation by external instructive signals thereby establishing melanocyte fate identity.
    Keywords:  Epigenetic regulation; Fate-bias; Gene regulatory network; Histone variant; Melanocyte; Pigmentation; Specification
    DOI:  https://doi.org/10.1242/dev.182576
  6. Cell Rep. 2021 May 18. pii: S2211-1247(21)00475-7. [Epub ahead of print]35(7): 109136
    Transcriptional co-activator regulates melanocyte differentiation and oncogenesis by integrating cAMP and MAPK/ERK pathways.
    Jelena Ostojić, Young-Sil Yoon, Tim Sonntag, Billy Nguyen, Joan M Vaughan, Maxim Shokhirev, Marc Montminy.
      The cyclic AMP pathway promotes melanocyte differentiation by activating CREB and the cAMP-regulated transcription co-activators 1-3 (CRTC1-3). Differentiation is dysregulated in melanomas, although the contributions of CRTC proteins is unclear. We report a selective differentiation impairment in CRTC3 KO melanocytes and melanoma cells, due to downregulation of oculo-cutaneous albinism II (OCA2) and block of melanosome maturation. CRTC3 stimulates OCA2 expression by binding to CREB on a conserved enhancer, a regulatory site for pigmentation and melanoma risk. CRTC3 is uniquely activated by ERK1/2-mediated phosphorylation at Ser391 and by low levels of cAMP. Phosphorylation at Ser391 is constitutively elevated in human melanoma cells with hyperactivated ERK1/2 signaling; knockout of CRTC3 in this setting impairs anchorage-independent growth, migration, and invasiveness, whereas CRTC3 overexpression supports cell survival in response to the mitogen-activated protein kinase (MAPK) inhibitor vemurafenib. As melanomas expressing gain-of-function mutations in CRTC3 are associated with reduced survival, our results suggest that CRTC3 inhibition may provide therapeutic benefit in this setting.
    Keywords:  CREB; CRTC3; ERK; OCA2; cAMP; melanoma; melanosome; phospho-diesterase; pigmentation
    DOI:  https://doi.org/10.1016/j.celrep.2021.109136
  7. Integr Comp Biol. 2021 May 22. pii: icab078. [Epub ahead of print]
    Melanosome biogenesis in the pigmentation of mammalian skin.
    Linh Le, Julia Sirés-Campos, Graça Raposo, Cédric Delevoye, Michael S Marks.
      Melanins, the main pigments of the skin and hair in mammals, are synthesized within membrane-bound organelles of melanocytes called melanosomes. Melanosome structure and function are determined by a cohort of resident transmembrane proteins, many of which are expressed only in pigment cells, that localize specifically to melanosomes. Defects in the genes that encode melanosome-specific proteins or components of the machinery required for their transport in and out of melanosomes underlie various forms of ocular or oculocutaneous albinism, characterized by hypopigmentation of the hair, skin and eyes and by visual impairment. We review major components of melanosomes, including the enzymes that catalyze steps in melanin synthesis from tyrosine precursors, solute transporters that allow these enzymes to function, and structural proteins that underlie melanosome shape and melanin deposition. We then review the molecular mechanisms by which these components are biosynthetically delivered to newly forming melanosomes-many of which are shared by other cell types that generate cell type-specific lysosome-related organelles. We also highlight unanswered questions that need to be addressed by future investigation.
    Keywords:  Hermansky-Pudlak syndrome; albinism; endosome; ion channels; lysosome; melanin; melanocyte; membrane transport; organelles; transporters
    DOI:  https://doi.org/10.1093/icb/icab078
  8. Prog Retin Eye Res. 2021 May 17. pii: S1350-9462(21)00032-X. [Epub ahead of print] 100971
    Conjunctival melanoma: New insights in tumour genetics and immunology, leading to new therapeutic options.
    Niels J Brouwer, Robert M Verdijk, Steffen Heegaard, Marina Marinkovic, Bita Esmaeli, Martine J Jager.
      Recent developments in oncology have led to a better molecular and cellular understanding of cancer, and the introduction of novel therapies. Conjunctival melanoma (CoM) is a rare but potentially devastating disease. A better understanding of CoM, leading to the development of novel therapies, is urgently needed. CoM is characterized by mutations that have also been identified in cutaneous melanoma, e.g. in BRAF, NRAS and TERT. These mutations are distinct from the mutations found in uveal melanoma (UM), affecting genes such as GNAQ, GNA11, and BAP1. Targeted therapies that are successful in cutaneous melanoma may therefore be useful in CoM. A recent breakthrough in the treatment of patients with metastatic cutaneous melanoma was the development of immunotherapy. While immunotherapy is currently sparsely effective in intraocular tumours such as UM, the similarities between CoM and cutaneous melanoma (including in their immunological tumour micro environment) provide hope for the application of immunotherapy in CoM, and preliminary clinical data are indeed emerging to support this use. This review aims to provide a comprehensive overview of the current knowledge regarding CoM, with a focus on the genetic and immunologic understanding. We elaborate on the distinct position of CoM in contrast to other types of melanoma, and explain how new insights in the pathophysiology of this disease guide the development of new, personalized, treatments.
    Keywords:  Conjunctival melanoma; Eye disease; Immunotherapy; Ocular oncology; Oncogenetics; Targeted therapy
    DOI:  https://doi.org/10.1016/j.preteyeres.2021.100971
  9. J Hered. 2021 May 08. pii: esab015. [Epub ahead of print]
    Avian Coloration Genetics: Recent Advances and Emerging Questions.
    Rosalyn Price-Waldman, Mary Caswell Stoddard.
      The colorful phenotypes of birds have long provided rich source material for evolutionary biologists. Avian plumage, beaks, skin, and eggs-which exhibit a stunning range of cryptic and conspicuous forms-inspired early work on adaptive coloration. More recently, avian color has fueled discoveries on the physiological, developmental, and-increasingly-genetic mechanisms responsible for phenotypic variation. The relative ease with which avian color traits can be quantified has made birds an attractive system for uncovering links between phenotype and genotype. Accordingly, the field of avian coloration genetics is burgeoning. In this review, we highlight recent advances and emerging questions associated with the genetic underpinnings of bird color. We start by describing breakthroughs related to 2 pigment classes: carotenoids that produce red, yellow, and orange in most birds and psittacofulvins that produce similar colors in parrots. We then discuss structural colors, which are produced by the interaction of light with nanoscale materials and greatly extend the plumage palette. Structural color genetics remain understudied-but this paradigm is changing. We next explore how colors that arise from interactions among pigmentary and structural mechanisms may be controlled by genes that are co-expressed, co-expressed or co-regulated. We also identify opportunities to investigate genes mediating within-feather micropatterning and the coloration of bare parts and eggs. We conclude by spotlighting 2 research areas-mechanistic links between color vision and color production, and speciation-that have been invigorated by genetic insights, a trend likely to continue as new genomic approaches are applied to non-model species.
    Keywords:  Carotenoids; Genotype to phenotype; Molecular adaptation and selection; Psittacofulvins; Self-assembly; Structural color
    DOI:  https://doi.org/10.1093/jhered/esab015
  10. Front Med (Lausanne). 2021 ;8 665647
    Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders.
    Laura Mercurio, Cristina Albanesi, Stefania Madonna.
      PhosphoInositide-3 Kinase (PI3K) represents a family of different classes of kinases which control multiple biological processes in mammalian cells, such as cell growth, proliferation, and survival. Class IA PI3Ks, the main regulators of proliferative signals, consists of a catalytic subunit (α, β, δ) that binds p85 regulatory subunit and mediates activation of AKT and mammalian Target Of Rapamycin (mTOR) pathways and regulation of downstream effectors. Dysregulation of PI3K/AKT/mTOR pathway in skin contributes to several pathological conditions characterized by uncontrolled proliferation, including skin cancers, psoriasis, and atopic dermatitis (AD). Among cutaneous cancers, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) display PI3K/AKT/mTOR signaling hyperactivation, implicated in hyperproliferation, and tumorigenesis, as well as in resistance to apoptosis. Upregulation of mTOR signaling proteins has also been reported in psoriasis, in association with enhanced proliferation, defective keratinocyte differentiation, senescence-like growth arrest, and resistance to apoptosis, accounting for major parts of the overall disease phenotypes. On the contrary, PI3K/AKT/mTOR role in AD is less characterized, even though recent evidence demonstrates the relevant function for mTOR pathway in the regulation of epidermal barrier formation and stratification. In this review, we provide the most recent updates on the role and function of PI3K/AKT/mTOR molecular axis in the pathogenesis of different hyperproliferative skin disorders, and highlights on the current status of preclinical and clinical studies on PI3K-targeted therapies.
    Keywords:  AKT; PI3K; apoptosis; atopic dermatitis; hyperproliferation; non-melanoma skin cancer; psoriasis
    DOI:  https://doi.org/10.3389/fmed.2021.665647
  11. FEBS J. 2021 May 17.
    Epithelial-to-mesenchymal-like transition events in melanoma.
    Dennis Pedri, Panagiotis Karras, Ewout Landeloos, Jean-Christophe Marine, Florian Rambow.
      Epithelial-to-mesenchymal transition (EMT), a process through which epithelial tumor cells acquire mesenchymal phenotypic properties, contributes to both metastatic dissemination and therapy resistance in cancer. Accumulating evidence indicates that non-epithelial tumors, including melanoma, can also gain mesenchymal-like properties that increase their metastatic propensity and decrease their sensitivity to therapy. In this review, we discuss recent findings, illustrating the striking similarities -but also knowledge gaps- between the biology of mesenchymal-like state(s) in melanoma and mesenchymal state(s) from epithelial cancers. Based on this comparative analysis, we suggest hypothesis-driven experimental approaches to further deepen our understanding of the EMT-like process in melanoma and how such investigations may pave the way towards the identification of clinically-relevant biomarkers for prognosis and new therapeutic strategies.
    Keywords:  EMT; melanoma; phenotype switching
    DOI:  https://doi.org/10.1111/febs.16021
  12. Immun Inflamm Dis. 2021 May 20.
    The complex role of AIM2 in autoimmune diseases and cancers.
    Huan Zhu, Ming Zhao, Christopher Chang, Vera Chan, Qianjin Lu, Haijing Wu.
      Absent in melanoma 2 (AIM2) is a novel member of interferon (IFN)-inducible PYHIN proteins. In innate immune cells, AIM2 servers as a cytoplasmic double-stranded DNA sensor, playing a crucial role in the initiation of the innate immune response as a component of the inflammasome. AIM2 expression is increased in patients with systemic lupus erythematosus (SLE), psoriasis, and primary Sjogren's syndrome, indicating that AIM2 might be involved in the pathogenesis of autoimmune diseases. Meanwhile, AIM2 also plays an antitumorigenesis role in an inflammasome independent-manner. In melanoma, AIM2 is initially identified as a tumor suppressor factor. However, AIM2 is also found to contribute to lung tumorigenesis via the inflammasome-dependent release of interleukin 1β and regulation of mitochondrial dynamics. Additionally, AIM2 reciprocally dampening the cGAS-STING pathway causes immunosuppression of macrophages and evasion of antitumor immunity during antibody treatment. To summarize the complicated effect and role of AIM2 in autoimmune diseases and cancers, herein, we provide an overview of the emerging research progress on the function and regulatory pathway of AIM2 in innate and adaptive immune cells, as well as tumor cells, and discuss its pathogenic role in autoimmune diseases, such as SLE, psoriasis, primary Sjogren's syndrome, and cancers, such as melanomas, non-small-cell lung cancer, colon cancer, hepatocellular carcinoma, renal carcinoma, and so on, hopefully providing potential therapeutic and diagnostic strategies for clinical use.
    Keywords:  AIM2; autoimmune diseases; cGAS-STING; cancers
    DOI:  https://doi.org/10.1002/iid3.443
  13. J Eur Acad Dermatol Venereol. 2021 May 17.
    Lentigo maligna: defining margins and predictors of recurrence utilising clinical, dermoscopic, confocal microscopy and histopathology features.
    Phoebe Star, Robert V Rawson, Martin Drummond, Serigne Lo, Richard A Scolyer, Pascale Guitera.
       BACKGROUND: Lentigo maligna (LM) is a subtype of melanoma in situ with poorly defined margins and a high recurrence rate. The biological behaviour of LM appears to differ widely between cases, from biologically indolent to biologically active variants, with some patients experiencing multiple recurrences. It is not known whether this is secondary to inadequate margins, field cancerisation or the innate biology of the lesion itself.
    OBJECTIVES: a) describe the margins of LM in detail by analysing LM in three zones, i.e., centre, edge and surround using reflectance confocal microscopy (RCM) and histopathology; b) ascertain association of histological distance of LM and atypical melanocytic hyperplasia from the surgical margin with multi recurrent (MR) disease and c) identify features (clinical, dermoscopy, RCM and histopathology) associated with MR LM.
    METHODS: (1) Descriptive observational study comparing the centre, edge and surround of LM on histopathology and RCM; (2) Retrospective cohort study comparing parameters associated with MR and non-recurrent (NR) LM.
    RESULTS: 30 patients (median follow up time 6.2 yrs) were included. On histopathology, confluent or near confluent lentiginous proliferation, melanocyte density >15 per 0.5mm and adnexal spread were best for distinguishing surround from edge of LM. On RCM, predominant melanocytes, lentiginous proliferation, and pleomorphism distinguished surround from centre/edge. MR patients had a median histological distance of LM from the surgical margin of 2mm (versus NR patients with an average distance of 4mm). MR patients had a greater proportion of more florid features, compared with NR on histopathology at both the centre and edge but were similar in the surround.
    CONCLUSION: This data may help pathologists and confocalists better define margins of LM. More florid features in MR patients, despite a similar background of sun damaged skin, suggests the innate biology of the lesion rather than the field of cancerisation may explain MR LM.
    Keywords:  Lentigo maligna; margins; recurrence; reflectance confocal microscopy
    DOI:  https://doi.org/10.1111/jdv.17349
  14. Pigment Cell Melanoma Res. 2021 May 21.
    Nicotinamide N-Methyltransferase Gene Silencing Enhances Chemosensitivity of Melanoma Cell Lines.
    Roberto Campagna, Eleonora Salvolini, Veronica Pompei, Valentina Pozzi, Alessia Salvucci, Elisa Molinelli, Valerio Brisigotti, Davide Sartini, Anna Campanati, Annamaria Offidani, Monica Emanuelli.
      Melanoma accounts for less than 5% of all cutaneous neoplasms but is responsible for the greater part of skin cancer-related deaths. Therefore, the identification of molecules that could serve as therapeutic target is urgent. This study focused on the enzyme nicotinamide N-methyltransferase (NNMT). The effect of NNMT knockdown on cell proliferation and migration of A375 melanoma cells was evaluated by MTT and wound healing assays, respectively. Viability of A375 cells downregulating NNMT was also explored under treatment with dacarbazine, a chemotherapeutic drug approved for advanced melanoma treatment. The impact of enzyme knockdown on cell proliferation and chemosensitivity was also investigated in WM-115 melanoma cells. Results obtained demonstrated that NNMT silencing led to a significant reduction of cell proliferation and migration of A375 cells. Moreover, enzyme downregulation was associated with an increase of melanoma cells sensitivity to treatment with dacarbazine. Analogous effects induced by enzyme knockdown on cell proliferation and chemosensitivity were also found in WM-115 cell line. Our data seem to demonstrate that NNMT could represent a promising molecular target for the effective treatment of this form of skin cancer.
    Keywords:  Nicotinamide N-methyltransferase; cell migration; cell proliferation; chemosensitivity; cutaneous melanoma
    DOI:  https://doi.org/10.1111/pcmr.12993
  15. J Eur Acad Dermatol Venereol. 2021 May 20.
    Screening for second malignancies in mycosis fungoides: Non-Hodgkin lymphoma, Hodgkin lymphoma, lung cancer, bladder cancer, and melanoma.
    Amrita Goyal, Daniel O'Leary, Kavita Goyal, Nathan Rubin, Murali Janakiram.
       BACKGROUND: Patients with mycosis fungoides (MF) are at increased risk of developing non-Hodgkin lymphoma (NHL),Hodgkin lymphoma (HL), lung cancer, bladder cancer, and melanoma. There are no guidelines for screening MF patients for second malignancies.
    MATERIALS/METHODS: We identified 742 patients with MF and second malignancies in the Surveillance Epidemiology and End Result-18 database.
    RESULTS: The majority of second malignancy patients were white and male, mean ages 55-67 years at diagnosis of MF, and mean age of 61-72 years at diagnosis of second malignancy. MF/NHL, MF/lung cancer, and MF/bladder, cancer tended to be diagnosed at earlier stages of the second malignancy than patients with NHL, lung cancer, or bladder cancers alone and have improved survival. There was no improvement in stage at diagnosis or survival for MF/melanoma patients.
    CONCLUSIONS: Improvements in survival in MF/NHL, MF/lung cancer, and MF/bladder cancer patients may reflect underlying biology or the importance of increased contact with the healthcare system. MF/melanoma data suggests that patients require pigmented-lesion focused skin exams. Tools for screening include regular lymph node exams, pigmented-lesion focused exams, and detailed review of systems questions. With these simple interventions, we hope to identify second malignancies sooner and potentially avoid them.
    Keywords:  Hodgkin lymphoma; Mycosis fungoides; bladder cancer; lung cancer; melanoma; non-Hodgkin lymphoma
    DOI:  https://doi.org/10.1111/jdv.17384
  16. Virchows Arch. 2021 May 20.
    Clinicopathologic and molecular characterization of melanomas mutated for CTNNB1 and MAPK.
    Bénédicte Oulès, Samia Mourah, Barouyr Baroudjian, Fanélie Jouenne, Julie Delyon, Baptiste Louveau, Aurélia Gruber, Céleste Lebbé, Maxime Battistella.
      Wnt/β-catenin signaling plays crucial roles in melanocyte biology and may be implicated in melanoma progression. In this study, we retrospectively examined a real-life cohort of melanomas mutated for β-catenin (CTNNB1), in association or not with a MAPK mutation (of BRAF or NRAS), and analyzed their clinical, histopathological, and molecular characteristics. Our results indicate that, regardless of the presence of a concurrent MAPK mutation, CTNNB1mut cutaneous primary melanomas display more proliferative hallmarks (increased Breslow thickness, mitotic index, and ulceration) than their CTNNB1 wild-type counterparts. Accordingly, they often progress to the metastatic stage. Furthermore, concurrent CTNNB1 and MAPK mutations do not necessarily confer a deep penetrating nevi phenotype. Altogether, this study provides evidence that CTNNB1 mutations in melanomas are associated with specific clinical and pathological features.
    Keywords:  BRAF mutation; CTNNB1 mutation; Cutaneous melanoma; Deep penetrating nevus; NRAS mutation
    DOI:  https://doi.org/10.1007/s00428-021-03119-0
  17. Front Public Health. 2021 ;9 678680
    Health Risks Associated With Excessive Exposure to Solar Ultraviolet Radiation Among Outdoor Workers in South Africa: An Overview.
    Caradee Y Wright, Mary Norval.
      Exposure of outdoor workers to high levels of solar ultraviolet radiation (UVR) poses significant, well-known health risks including skin cancer and eye diseases. In South Africa, little is known about how many workers are potentially overexposed to solar UVR and what the associated impacts on their health might be. In this overview, the geography and solar UVR environment in South Africa are considered, as well as the different outdoor occupational groups likely to be affected by excessive solar UVR exposure. Sunburn, pterygium, cataract, keratinocyte cancers, and melanoma are discussed in the context of outdoor workers. Few studies in South Africa have considered these health issues and the most effective ways to reduce solar UVR exposure for those working outside. Several countries have developed policies and guidelines to support sun safety in the workplace which include training and education, in addition to the provision of personal protective equipment and managerial support. Several gaps in occupational sun protection and workplace sun safety for South Africa are identified. Legislation needs to recognize solar UVR exposure as an occupational health hazard, with sun safety guidelines and training provided for employers and employees.
    Keywords:  cataract; employment; environmental health; keratinocyte cancers; melanoma; personal sun safety; skin cancer; sun exposure
    DOI:  https://doi.org/10.3389/fpubh.2021.678680
  18. Actas Dermosifiliogr. 2020 Oct;111(8): 629-638
    Estimated Effect of COVID-19 Lockdown on Skin Tumor Size and Survival: An Exponential Growth Model.
    A Tejera-Vaquerizo, J Cañueto, A Toll, J Santos-Juanes, A Jaka, C Ferrandiz, O Sanmartín, S Ribero, D Moreno-Ramírez, F Almazán, M J Fuente, S Podlipnik, E Nagore.
       Background and objectives: Spain is in a situation of indefinite lockdown due to the ongoing coronavirus disease 2019 (COVID-19) pandemic. One of the consequences of this lockdown is delays in medical and surgical procedures for common diseases. The aim of this study was to model the impact on survival of tumor growth caused by such delays in patients with squamous cell carcinoma (SCC) and melanoma.
    Material and methods: Multicenter, retrospective, observational cohort study. We constructed an exponential growth model for both SCC and melanoma to estimate tumor growth between patient-reported onset and surgical excision at different time points.
    Results: Data from 200 patients with SCC of the head and neck and 1000 patients with cutaneous melanoma were included. An exponential growth curve was calculated for each tumor type and we estimated tumor size after 1, 2, and 3 months of potential surgical delay. The proportion of patients with T3 SCC (diameter > 4 cm or thickness > 6 mm) increased from 41.5% (83 patients) in the initial study group to an estimated 58.5%, 70.5%, and 72% after 1, 2, and 3 months of delay. Disease-specific survival at 2, 5, and 10 years in patients whose surgery was delayed by 3 months decreased by 6.2%, 8.2%, and 5.2%, respectively. The proportion of patients with ultrathick melanoma (> 6 mm) increased from 6.9% in the initial study group to 21.9%, 30.2%, and 30.2% at 1, 2, and 3 months. Five- and 10-year disease-specific survival both decreased by 14.4% in patients treated after a potential delay of 3 months.
    Conclusions: In the absence of adequate diagnosis and treatment of SCC and melanoma in the current lockdown situation in Spain, we can expect to see to a considerable increase in large and thick SCCs and melanomas. Efforts must be taken to encourage self-examination and facilitate access to dermatologists in order to prevent further delays.
    Keywords:  COVID-19 virus disease; Cutaneous squamous cell carcinoma; Early diagnosis; Lockdown; Melanoma; Prognosis
    DOI:  https://doi.org/10.1016/j.adengl.2020.09.008
  19. J Dermatol. 2021 May 17.
    Tips for difficult to diagnose hypomelanotic melanomas on reflectance confocal microscopy.
    Maria Antonietta Pizzichetta, Vincenzo Canzonieri, Pietro Rubegni, Paola Corneli, Fabio Puglisi, Iris Zalaudek, Elisa Cinotti.
      Amelanotic/hypomelanotic melanoma (AHM) represents a clinical diagnostic challenge. Dermoscopy improves AHM diagnosis thanks to visualization of little pigment and vascular pattern. Reflectance confocal microscopy (RCM) increases further the diagnostic accuracy of AHM but few and small studies have described in detail RCM features of AHM. We evaluated dermoscopic and RCM features of nine cases of difficult to diagnose hypomelanotic melanomas (HMs) to find clues for their diagnosis. The RCM score was suggestive of melanoma in all cases. The major criteria of nonedged papillae and/or cytological atypia at the dermo-epidermal junction were seen in all cases. Among the minor criteria, roundish pagetoid cells, including hyporeflective pagetoid cells, were found in four out of nine lesions. Dermoscopically, four out of nine HMs did not show prevalent suspicious criteria while revealing suspicious RCM features that were visible only after careful RCM examination by zooming mosaic images. RCM can improve HM diagnostic accuracy but only after extensive evaluation of images. Atypical cells were less reflective and the architectural irregularity was less visible than in pigmented melanoma and zooming was needed to identify both features.
    Keywords:  amelanotic melanoma; confocal microscopy; dermoscopy; melanoma; skin neoplasm
    DOI:  https://doi.org/10.1111/1346-8138.15815
  20. Clin Exp Metastasis. 2021 May 17.
    In-transit metastatic cutaneous melanoma: current management and future directions.
    Ayushi Patel, Michael J Carr, James Sun, Jonathan S Zager.
      Management of in-transit melanoma encompasses a variety of possible treatment pathways and modalities. Depending on the location of disease, number of lesions, burden of disease and patient preference and characteristics, some treatments may be more beneficial than others. After full body radiographic staging is performed to rule out metastatic disease, curative therapy may be performed through surgical excision, intraarterial regional perfusion and infusion therapies, intralesional injections, systemic therapies or various combinations of any of these. While wide excision is limited in indication to superficial lesions that are few in number, the other listed therapies may be effective in treating unresectable disease. Where intraarterial perfusion based therapies have been shown to successfully treat extremity disease, injectable therapies can be used in lesions of the head and neck. Although systemic therapies for in-transit melanoma have limited specific data to support their primary use for in-transit disease, there are patients who may not be eligible for any of the other options, and current clinical trials are exploring the use of concurrent and sequential use of regional and systemic therapies with early results suggesting a synergistic benefit for oncologic response and outcomes.
    Keywords:  In transit melanoma; Isolated limb infusion; Melanoma; Metastatic melanoma; Regional perfusion chemotherapy; T-VEC
    DOI:  https://doi.org/10.1007/s10585-021-10100-3
  21. Pigment Cell Melanoma Res. 2021 May 17.
    Management of Hyperpigmentation: Current Treatments and Emerging Therapies.
    Avni Nautiyal, Sarika Wairkar.
      Hyperpigmentation of the skin refers to a dermatological condition which alters the color of the skin, making it discoloured or darkened. The treatments for hyperpigmentation disorders often take very long to show results and have poor patient compliance. The first-line treatment for hyperpigmentation involves topical formulations of conventional agents such as hydroquinone, kojic acid, glycolic acid followed by oral formulations of therapeutic agents like tranexamic acid, melatonin, cysteamine hydrochloride. The second-line approaches include chemical peels and laser therapy given under the observation of expert professionals. However, these therapies pose certain limitations and adverse effects like erythema, skin peeling and drying and require long treatment duration to show visible effects. These shortcomings of the conventional treatments provided scope for further research on newer alternatives for managing hyperpigmentation. Some of these therapies include novel formulations like solid lipid nanocarriers, liposomes, phytochemicals, platelet-rich plasma, microneedling. This review focuses on elaborating on several hyperpigmentation disorders and their mechanisms, the current, novel and emerging treatment options for management of hyperpigmentation.
    Keywords:  Topical formulations; chemical peels; hyperpigmentation; laser therapy; novel therapies
    DOI:  https://doi.org/10.1111/pcmr.12986
  22. Eur J Cancer Prev. 2021 May 18.
    Risk factors for cardiovascular mortality and melanoma-specific mortality among patients with melanoma: a SEER based study.
    Alaa Ahmed Elshanbary, Mohamed Sayed Zaazouee, Mohamed Abdelmonem, Yasmine Adel Mohammed, Walid Abdel-Aziz.
       OBJECTIVE: This study aims to identify the risk factors for cardiovascular mortality in melanoma patients.
    METHODS: Data of melanoma patients were obtained from the Surveillance, Epidemiology, and End Results database. We used Person's chi-square test to assess the relationships between categorical variables. We used Kaplan-Meier test in the univariate analysis and Cox regression test for the multivariate analysis. Analyses were conducted using the SPSS software.
    RESULTS: We analyzed data of 194 503 melanoma patients. Among them, 28 818 (14.8 %) died due to cardiovascular diseases. Cardiovascular-specific survival was higher in younger patients, women, married, localized disease, superficial spreading melanoma and in patients who had surgery. It was lower in patients who received chemotherapy or radiotherapy. The multivariate analysis revealed a higher risk of cardiovascular mortality in patients aged 50-64 years [hazard ratio (HR), 7.297; 95% confidence interval (CI), 6.68-7.97], patients aged ≥65 years (HR, 43.309; 95% CI, 39.706-47.240), men (HR, 1.535; 95% CI, 1.475-1.597), Blacks (HR, 1.29; 95% CI, 1.044-1.594), separated (HR, 1.286; 95% CI, 1.058-1.562), widowed (HR, 1.829; 95% CI, 1.706-1.961), patients with no or unknown history of chemotherapy (HR, 1.302; 95% CI, 1.071-1.583) or radiotherapy (HR, 1.477; 95% CI, 1.217-1.793) and patients with no surgery (HR, 1.468; 95% CI, 1.264-1.706).
    CONCLUSIONS: In patients with melanoma, the risk of cardiovascular death is higher in older patients, men, Blacks, separated, widowed and patients with nodular or lentigo maligna melanoma. The risk is lower in married, patients with superficial spreading or acral lentiginous melanoma, and patients who had chemotherapy, radiotherapy or surgery.
    DOI:  https://doi.org/10.1097/CEJ.0000000000000690
  23. BMC Gastroenterol. 2021 May 19. 21(1): 227
    Granulomatous colitis in a patient with metastatic melanoma under immunotherapy: a case report and literature review.
    Stratigoula Sakellariou, Dionysia N Zouki, Dimitrios C Ziogas, Despoina Pouloudi, Helen Gogas, Ioanna Delladetsima.
       BACKGROUND: Immune checkpoint inhibitors (ICPIs) have changed the way advanced malignancies are currently confronted, improving cancer patients' outcomes but also generating distinct immune-related (ir) adverse events. ICPIs-induced colitis is a common complication showing different clinical and histological manifestations. In the literature review, 14 cases with ICPIs related colon granulomas have been reported in 5 studies with either limited or unavailable information regarding histology. Granulomatous reactions can be mistakenly perceived as disease recurrence or progression. Better understanding and identification of this infrequent histological display can help to avoid misdiagnosis and mismanagement.
    CASE PRESENTATION: A 63-year-old female patient with metastatic melanoma was admitted to the hospital with symptoms of nausea, persistent diarrhea and shivering fever under consecutive treatments with ICPIs, initially pembrolizumab and subsequently ipilimumab. Sigmoidoscopy was performed revealing mucosal edema, hyperemia and erosions of the rectum and sigmoid colon. Histological evaluation of sigmoid colon mucosa biopsies revealed an unusual colitis pattern characterized by multiple intracryptal granulomas attributed to ICPIs therapy. Steroids were administered and the patient recovered. ICPIs treatment was discontinued. The patient was subsequently treated with chemotherapy but follow up radiology showed disease progression. A re-challenge with another ICPI regimen was decided and the patient is currently under immunotherapy with stable disease regarding melanoma status and without any sign of colitis recurrence.
    CONCLUSIONS: The present report provides detailed histological description of a distinctive ICPIs-induced granulomatous colitis and highlights the need for awareness of the distinct adverse events and reaction patterns in the context of immunotherapy.
    Keywords:  Granulomatous colitis; Immune checkpoint inhibitors-related adverse events; Immune checkpoint inhibitors-related colitis; Intracryptal granulomas; Ipilimumab-related granulomas
    DOI:  https://doi.org/10.1186/s12876-021-01812-7
  24. Acta Derm Venereol. 2021 May 18.
    Initial Stage of Cutaneous Primary Melanoma Plays a Key Role in the Pattern and Timing of Disease Recurrence.
    Sümeyre Seda Ertekin, Sebastian Podlipnik, Constanza Riquelme-Mc Loughlin, Alicia Barreiro-Capurro, Ana Arance, Cristina Carrera, Josep Malvehy, Susana Puig.
      Given recent developments in the treatment of metastatic melanoma, early detection of disease recurrence is crucial. The aim of this single-centre retrospective cohort study was to investigate the impact of the initial stage of primary melanoma on the pattern and timing of disease recurrence and post-recurrence survival. Patients diagnosed with cutaneous melanoma with initial stage IA-IIID, between January 1996 and December 2018 and who developed disease recurrence until May 2019 were included (n = 784). Earlier stage at diagnosis was associated with a higher proportion of locoregional and a lower proportion of distant metastasis (p = 0.01). The median time to first metastasis decreased with the more advanced stages at initial diagnosis: 3.32 years (interquartile range (IQR) 1.72-6.14 years) for stage I, 1.85 years (IQR 0.99-3.78 years) for stage II and 1.19 years (IQR 0.70-2.42 years) for stage III disease (p < 0.001). These findings add evidence that American Joint Committee on Cancer stages at initial diagnosis of melanoma play a key role in the pattern and timing of disease recurrence and may be helpful to improve surveillance strategies in the follow-up of patients with melanoma.
    Keywords:   cutaneous malignant; disease progression; follow-up studies; metastasis, survival; recurrence; melanoma
    DOI:  https://doi.org/10.2340/00015555-3832
  25. Dermatol Online J. 2021 Apr 15. pii: 13030/qt2202r5hk. [Epub ahead of print]27(4):
    Semi-automated total body photography supports robust delivery of skin cancer monitoring services during the SARS-COV2/COVID-19 pandemic.
    Elizabeth D Drugge, Rebecca M Sarac, Patricia Fay, Rhett J Drugge.
       BACKGROUND: The SARS-CoV-2/COVID-19 pandemic dramatically impacted the delivery of healthcare, including dermatological services. In the initial stages of the pandemic, reduced patient flow produced a dramatic drop in the volume of skin cancer screening. Consistent with COVID-19 precautions, our practice conducted visual skin examinations (VSE) utilizing semi-automated total body photography (TBP).
    METHODS: A cross-sectional study of patient characteristics and self-reported melanoma risk factors associated with TBP usage was conducted on all patients from May to November 2020 in a single practitioner private dermatology setting. The process and histopathology-confirmed outcomes were compared to those in the same 6-month period in 2019.
    RESULTS: For the May-November 2020 timeframe, those who opted for the home TBP (35%) compared to clinic TBP were younger, had higher self-reported skin cancer risk, and were more likely to have had previous TBP sessions. Overall, the number of TBP sessions increased, while dermoscopy usage and biopsy number decreased. There was no change in the number and distribution of skin cancer diagnoses compared to the same period in 2019. The Melanoma-In-Situ:Invasive Melanoma (MIS:INV) ratio was above the U.S. ratio reported for 2020 of 0.95:1 (95,710 MIS:100,350 INV).
    CONCLUSION: Semi-automated TBP was successfully implemented during the pandemic without affecting skin cancer detection.
  26. Front Oncol. 2021 ;11 619167
    Ultrasound-Mediated Microbubble Destruction Inhibits Skin Melanoma Growth by Affecting YAP1 Translation Using Ribosome Imprinting Sequencing.
    Tianhong Wei, Lan Li, Zhiyou He.
      Cutaneous melanoma (CMM) is a skin tumor with a high degree of malignancy. BRAF resistance imposes great difficulty to the treatment of CMM, and partially contributes to the poor prognosis of CMM. YAP is involved in the growth and drug resistance of a variety of tumors, and mechanical signals may affect the activation of YAP1. As a novel ultrasound treatment technology, ultrasound-mediated microbubble destruction (UMMD) has been reported to have a killing effect on isolated CMM cells. In this study, the tumor tissue samples were collected from 64 CMM patients. We found that YAP1 mRNA expression was irrelevant to the clinicopathological characteristics and prognostic survival of the CMM patients. The drug-resistant cell line was constructed and subcutaneously implanted into nude mice, which were further separately treated with UMMD, ultrasound (US), and microbubbles (MB). The result showed that UMMD significantly inhibited the growth of tumor tissues. Ribosome imprinting sequencing (Ribo-seq) is a genetic technology for studying protein translation at genetic level. Ribo-seq, RNA-seq, and RT-qPCR were applied to detect YAP1 expression in CMM mouse tumor tissues. Ribo-seq data revealed that UMMD greatly up-regulated the expression of YAP1, interestingly, the up-regulated YAP1 was found to be negatively correlated with the weight of tumor tissues, while no significant change in YAP1 expression was detected by RNA-seq or RT-qPCR assay. These results indicated that UMMD could inhibit the tumor growth of drug-resistant CMM by affecting the translation efficiency of YAP1, providing a strong basis for the clinical treatment of UMMD in CMM.
    Keywords:  YAP1; drug resistance; ribosomal blot sequencing; skin melanoma; ultrasound-mediated microbubble destruction
    DOI:  https://doi.org/10.3389/fonc.2021.619167
  27. Tohoku J Exp Med. 2021 ;254(1): 33-39
    Cul4b Promotes Progression of Malignant Cutaneous Melanoma Patients by Regulating CDKN2A.
    Chao Zhang, Can Cao, Xiu-Li Liu, Tan Jun, Pei Liu.
      Although several molecular targeted therapy and immunotherapy have been developed, cutaneous melanoma prognosis is still not satisfying. Cul4b promotes the progression of several malignant tumors by regulating cell proliferation. However, its prognostic role in malignant cutaneous melanoma has not been evaluated. In this study, immunohistochemistry was performed to assess the expression of Cul4b in a consecutive patient cohort. The prognostic role of Cul4b was estimated with univariate and multivariate analysis. Cul4b was knocked down in melanoma cell line to evaluate its role in promoting cell proliferation. The results revealed that Cul4b was highly expressed in some of the cutaneous malignant melanoma patients and high expression of Cul4b was associated with poor melanoma-specific overall survival and poor disease-free survival. Cul4b expression was associated with Breslow categories, Clark level, and Ki67 expression. Univariate and multivariate analysis revealed that Cul4b is an independent prognosis risk factor of cutaneous melanoma. Downregulation of Cul4b inhibited the proliferation ability of melanoma cells and downregulated the expression of CDKN2A. These results suggest that Cul4b plays an essential role in cutaneous melanoma progression and may serve as a promising treatment target.
    Keywords:  CDKN2A; Cul4b; cutaneous melanoma; proliferation
    DOI:  https://doi.org/10.1620/tjem.254.33
  28. Exp Cell Res. 2021 May 18. pii: S0014-4827(21)00168-3. [Epub ahead of print] 112636
    Knockdown of NLE1 inhibits development of malignant melanoma in vitro and in vivo NLE1 promotes development of malignant melanoma.
    Zhaozhou Ren, Feifei Ni, Tao Zhang, Xiangnan Yuan, Jianjun Li, Wan'an Xiao.
      Melanoma, which originates from neural crest derived melanocytes, causes severe pain and even death to numerous patients. Previous studies reported that Notchless Homolog 1 (NLE1) plays an important role in cell proliferation, transcription and signal transduction. However, the clinical significance and biological behavior of NLE1 in melanoma remain a mystery. Thus, the role of NLE1 in melanoma was investigated in vitro and in vivo. The expression of NLE1 in melanoma was elevated and the expression level was positively correlated with lymphatic metastasis and tumor stage. In addition, NLE1 knockdown by shRNA specifically inhibited proliferation, enhanced the apoptotic sensitivity and hindered migration of melanoma cells in vitro. Mice xenograft model further showed that NLE1 knockdown could inhibit the tumor formation of melanoma in vivo. Additionally, the induction of apoptosis of melanoma cells by NLE1 knockdown required the participation of a series of apoptosis-related proteins. Besides, NLE1 can activate the PI3K/AKT signaling pathway. In summary, NLE1 was involved in the development and progression of melanoma, which may be a novel potential target for molecular therapy of melanoma.
    Keywords:  Cell proliferation; Melanoma; Migration; NLE1; PI3K/AKT pathway
    DOI:  https://doi.org/10.1016/j.yexcr.2021.112636
  29. Dermatol Online J. 2021 Apr 15. pii: 13030/qt2qz916r0. [Epub ahead of print]27(4):
    The effect of gluten on skin and hair: a systematic review.
    Katheryn A Bell, Aunna Pourang, Natasha A Mesinkovska, Michael A Cardis.
      Non-celiac gluten sensitivity is often clinically indistinguishable from celiac disease, and patients show improvement or resolution of their symptoms with a gluten-free diet. In contrast to celiac disease, the effects of gluten on the skin and hair in the context of non-celiac gluten sensitivity are not as clear. This review aims to describe the impact of gluten on the skin and hair in patients with non-celiac gluten sensitivity and those without a definitive celiac disease diagnosis. A literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guidelines for systematic reviews. Forty-two publications met inclusion criteria with five studies describing the skin manifestations of non-celiac gluten sensitivity. Trials identifying the impact of a gluten-free diet on skin disease, as well as dermatologic conditions and their associations with antigliadin antibodies were also identified. Dermatologic manifestations in patients with non-celiac gluten sensitivity vary and may be non-specific. It may be appropriate for some of these patients with skin manifestations to trial a gluten-free diet. Dermatologic conditions that may respond positively to a gluten-free diet include psoriasis, atopic dermatitis, vitiligo, and palmoplantar pustulosis, while linear IgA disease does not appear to improve with this dietary change.
  30. Clin Exp Dermatol. 2021 May 17.
    Differential diagnosis and management of hyperpigmentation.
    J Yoo.
      There is an increasing recognition of ethnic dermatology to reflect the rising skin of colour (SOC) population. Hyperpigmentary disorder is one of the commonest skin concerns in SOC but there have been limited training available in this field of dermatology. Variations in skin colour is genetically determined by the amount of melanin content, eumelanin:pheomelanin ratio and size of melanosomes but also influenced by extrinsic factors such as ultraviolet (UV) and hormones. Hyperpigmentation is a broad terminology describing increased pigmentation and making a correct diagnosis is an important first step in the successful management of hyperpigmentary disorder. A systematic approach based on its pathogenesis (e.g., reactive vs. non-reactive, increased melanin vs. increased number of cells or epidermal vs. dermal pigmentation) aided by a detailed history and clinical examination would be best way to diagnose a hyperpigmentary disorder. Based on its pathogenesis, management can be planned. For epidermal hyperpigmentation caused by increased melanin, topical skin lightening agents targeting inhibition of tyrosinase or melanosome transfer as well as increasing keratinocyte turnover can be used. Hydroquinone-containing cream is the gold standard treatment for epidermal hyperpigmentation. Alternative treatments include laser toning or chemical peels. However, increased dermal pigmentation is more challenging to target with topical treatments. If hyperpigmentation is due to the increased number of melanocytes or keratinocytes, high-fluence treatment with laser would be most appropriate.
    DOI:  https://doi.org/10.1111/ced.14747
  31. Dev Biol. 2021 Apr 29. pii: S0012-1606(21)00102-0. [Epub ahead of print]476 314-327
    Immunoglobulin superfamily receptor Junctional adhesion molecule 3 (Jam3) requirement for melanophore survival and patterning during formation of zebrafish stripes.
    Dae Seok Eom, Larissa B Patterson, Raegan R Bostic, David M Parichy.
      Adhesive interactions are essential for tissue patterning and morphogenesis yet difficult to study owing to functional redundancies across genes and gene families. A useful system in which to dissect roles for cell adhesion and adhesion-dependent signaling is the pattern formed by pigment cells in skin of adult zebrafish, in which stripes represent the arrangement of neural crest derived melanophores, cells homologous to melanocytes. In a forward genetic screen for adult pattern defects, we isolated the pissarro (psr) mutant, having a variegated phenotype of spots, as well as defects in adult fin and lens. We show that psr corresponds to junctional adhesion protein 3b (jam3b) encoding a zebrafish orthologue of the two immunoglobulin-like domain receptor JAM3 (JAM-C), known for roles in adhesion and signaling in other developing tissues, and for promoting metastatic behavior of human and murine melanoma cells. We found that zebrafish jam3b is expressed post-embryonically in a variety of cells including melanophores, and that jam3b mutants have defects in melanophore survival. Jam3b supported aggregation of cells in vitro and was required autonomously by melanophores for an adherent phenotype in vivo. Genetic analyses further indicated both overlapping and non-overlapping functions with the related receptor, Immunoglobulin superfamily 11 (Igsf11) and Kit receptor tyrosine kinase. These findings suggest a model for Jam3b function in zebrafish melanophores and hint at the complexity of adhesive interactions underlying pattern formation.
    Keywords:  Cell adhesion; Iridophore; JAM3; Melanophore; Pigment pattern; Zebrafish
    DOI:  https://doi.org/10.1016/j.ydbio.2021.04.007
  32. Biol Open. 2020 Jan 01. pii: bio.053785. [Epub ahead of print]
    Inducible modulation of miR-204 levels in a zebrafish melanoma model.
    Samanta Sarti, Raffaella De Paolo, Chiara Ippolito, Angela Pucci, Letizia Pitto, Laura Poliseno.
      Here, we present miniCoopR-I, an inducible upgrade of the constitutive miniCoopR vector. We developed miniCoopR-I-sponge-204 and miniCoopR-I-pre-miR-204 vectors and we successfully tested them for their ability to achieve time (embryo/juvenile/adult)- and space (melanocytic lineage)- restricted inhibition/overexpression of miR-204, a positive modulator of pigmentation previously discovered by us. Furthermore, melanoma-free survival curves performed on induced fish at adult stage indicate that miR-204 overexpression accelerates the development of BRAFV600E-driven melanoma. miniCoopR-I allows to study the impact that coding and non-coding modulators of pigmentation exert on melanomagenesis in adult zebrafish, uncoupling it from the impact that they exert on melanogenesis during embryonic development.
    Keywords:  Melanoma model; MiR-204; MiniCoopR-I; Pigmentation; Zebrafish
    DOI:  https://doi.org/10.1242/bio.053785
  33. Eur Rev Med Pharmacol Sci. 2021 May;pii: 25829. [Epub ahead of print]25(9): 3478-3482
    Metastatic endo and perineural involvement of the ulnar nerve from malignant melanoma: ultrasound (US) and magnetic resonance imaging (MRI) findings.
    I Simonetti, F Sandomenico, M P Rocco, R Fusco, S V Setola, V Granata, D M Iasevoli, P A Ascierto, R Grassi, A Petrillo.
      Malignant melanoma metastases occur in about 15% of patients. The most common localizations are lymph nodes, lungs, pancreas, bones. The central nervous system and the perineural region are rarely affected. In case of distant metastases, the survival rate is lower (about 25%). Involvement of peripheral nerve metastases from melanoma is reported in the literature just in one case. We report the ultrasound (US) integrated with Color-Doppler Ultrasound (CDU), elastosonography, and magnetic resonance imaging (MRI) findings of a rare case of metastatic endo- and perineural involvement of the ulnar nerve from cutaneous melanoma. Our purpose is to increase the clinicians' and radiologists' awareness on the possibility of metastatic spread to the peripheral nervous system and improve the differential diagnosis with other peripheral nerve sheath tumors.
    DOI:  https://doi.org/10.26355/eurrev_202105_25829
  34. IEEE J Biomed Health Inform. 2021 May 18. PP
    Skin Melanoma Detection in Microscopic Images Using HMM-Based Asymmetric Analysis and Expectation Maximization.
    Rozita Rastghalam, Habibollah Danyali, Mohammad Sadegh Helfroush, M Emre Celebi, Mojgan Mokhtari.
      Melanoma is one of the deadliest types of skin cancer with increasing incidence. The most definitive diagnosis method is the histopathological examination of the tissue sample. In this paper, a melanoma detection algorithm is proposed based on decision-level fusion and a Hidden Markov Model (HMM), whose parameters are optimized using Expectation Maximization (EM) and asymmetric analysis. The texture heterogeneity of the samples is determined using asymmetric analysis. A fusion-based HMM classifier trained using EM is introduced. For this purpose, a novel texture feature is extracted based on two local binary patterns, namely local difference pattern (LDP) and statistical histogram features of the microscopic image. Extensive experiments demonstrate that the proposed melanoma detection algorithm yields a total error of less than 0.04%.
    DOI:  https://doi.org/10.1109/JBHI.2021.3081185
  35. Mov Disord. 2021 May 22.
    Linking Parkinson's Disease and Melanoma: Interplay Between α-Synuclein and Pmel17 Amyloid Formation.
    Dexter N Dean, Jennifer C Lee.
      Parkinson's disease (PD) is a neurodegenerative disorder associated with the death of dopaminergic neurons within the substantia nigra of the brain. Melanoma is a cancer of melanocytes, pigmented cells that give rise to skin tone, hair, and eye color. Although these two diseases fundamentally differ, with PD leading to cell degeneration and melanoma leading to cell proliferation, epidemiological evidence has revealed a reciprocal relationship where patients with PD are more susceptible to melanoma and patients with melanoma are more susceptible to PD. The hallmark pathology observed in PD brains is intracellular inclusions, of which the primary component is proteinaceous α-synuclein (α-syn) amyloid fibrils. α-Syn also has been detected in cultured melanoma cells and tissues derived from patients with melanoma, where an inverse correlation exists between α-syn expression and pigmentation. Although this has led to the prevailing hypothesis that α-syn inhibits enzymes involved in melanin biosynthesis, we recently reported an alternative hypothesis in which α-syn interacts with and modulates the aggregation of Pmel17, a functional amyloid that serves as a scaffold for melanin biosynthesis. In this perspective, we review the literature describing the epidemiological and molecular connections between PD and melanoma, presenting both the prevailing hypothesis and our amyloid-centric hypothesis. We offer our views of the essential questions that remain unanswered to motivate future investigations. Understanding the behavior of α-syn in melanoma could not only provide novel approaches for treating melanoma but also could reveal insights into the role of α-syn in PD. © 2021 International Parkinson and Movement Disorder Society.
    Keywords:  aggregation; cross-propagation; fibrils; functional amyloid; melanosomes
    DOI:  https://doi.org/10.1002/mds.28655
  36. Cancer Discov. 2021 May 19.
    LAG3-PD-1 Inhibitor Combo Impresses in Melanoma.
      Immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA4 have dramatically improved melanoma treatment-and the LAG3 immune checkpoint inhibitor relatlimab may soon be added to the mix. In a phase III trial, adding relatlimab to the PD-1 inhibitor nivolumab more than doubled progression-free survival, and the combination had relatively manageable side effects.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NB2021-0347
  37. J Invest Dermatol. 2021 May 14. pii: S0022-202X(21)01230-6. [Epub ahead of print]
    Inhibition of plasminogen activator inhibitor-1 blocks programmed death ligand 1 endocytosis and improves the response of melanoma cells to immune checkpoint blockade.
    Yu-Ju Tseng, Chih-Hung Lee, Wei-Yu Chen, Jenq-Lin Yang, Hong-Tai Tzeng.
      Immune checkpoint molecules especially programmed death 1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1) act as a major mechanism of cancer immune evasion. Although anti-PD-1/PD-L1 monotherapy increases therapeutic efficacy in melanoma treatment, only a subset of patients exhibits long-term tumor remission, and the underlying mechanism of resistance to PD-1/PD-L1 inhibitors remains unclear. In this study, we demonstrated that cell surface retention of PD-L1 inversely correlated with plasminogen activator inhibitor-1 (PAI-1) expression in vitro, in vivo and in clinical specimens. Moreover, extracellular PAI-1 induced the internalization of surface-expressed PD-L1 by triggering clathrin-mediated endocytosis. The endocytosed PD-L1 was transported to lysosomes for degradation by endo-lysosomal systems, resulting in the reduction of surface PD-L1. Notably, inhibition of PAI-1 by pharmacological inhibitor with tiplaxtinin led to elevated PD-L1 expression on the plasma membrane, both in vitro and in vivo. Strikingly, targeting PAI-1 by tiplaxtinin treatment synergizes with anti-PD-L1 immune checkpoint blockade therapy in a syngeneic murine model of melanoma. Our findings demonstrate a role for PAI-1 activity in immune checkpoint modulation by promoting surface PD-L1 for lysosomal degradation, and provides an insight on the combination of PAI-1 inhibition and anti-PD-L1 immunotherapy as a promising therapeutic regimen for melanoma treatment.
    Keywords:  PAI-1; PD-L1; endocytosis; immunotherapy; melanoma
    DOI:  https://doi.org/10.1016/j.jid.2021.03.030
  38. J Oncol. 2021 ;2021 5524685
    Real-World Survival in Patients with Metastatic Melanoma after Discontinuation of Anti-PD-1 Immunotherapy for Objective Response or Adverse Effects: A Retrospective Study.
    Julie Valentin, Thomas Ferté, Valérie Dorizy-Vuong, Léa Dousset, Sorilla Prey, Caroline Dutriaux, Anne Pham-Ledard, Marie Beylot-Barry, Emilie Gérard.
       Objective: Anti-PD-1 has dramatically improved the survival of patients with advanced melanoma. However, there is a lack of data on maintenance of the response after treatment discontinuation. We aimed to evaluate the progression-free survival (PFS) of patients with metastatic melanoma after anti-PD-1 interruption for objective response (OR) or limiting toxicity during clinical trials.
    Methods: All patients with advanced melanoma who stopped single-agent anti-PD-1 antibodies for objective response or toxicity were included between April 2014 and January 2019 in our institution (data cut-off, September 10th, 2019). Clinical and biological factors associated with relapse were studied.
    Results: The median follow-up after introduction of treatment was 36.5 months [4.6-62.4], and the median follow-up after discontinuation of treatment was 15.7 months (2.5-45.1). Out of 65 patients, 28 patients stopped immunotherapy for limiting adverse effects (AEs) (43.1%), 25 for complete response (CR) (38.4%), and 12 for partial response (PR) or long-term stable disease (SD) (18.5%). Twelve patients relapsed (18.5%) after a median time of 9 months [1.9-40.9 months]. Seven relapsed after discontinuation for AEs, 3 after discontinuation for CR, and 2 after discontinuation for PR/SD. The median PFS after therapy discontinuation was not reached. No statistical association was found between recurrence and age, sex, increased LDH, BRAF status, presence of brain metastases, previous treatments, radiotherapy, or time on anti-PD-1 treatment.
    Conclusion: This cohort shows a global recurrence rate of 18.5% and confirms a long-lasting response after anti-PD-1 cessation regardless of the cause of discontinuation.
    DOI:  https://doi.org/10.1155/2021/5524685
  39. Niger J Clin Pract. 2021 May;24(5): 770-773
    Use of BRAF immunohistochemistry as a screening test in detecting BRAFV600E mutation in melanomas.
    S Gun, M Kefeli, L Yildiz.
       Objective: BRAF mutation is detected in 50-70% of melanomas. The molecular methods used to detect BRAF mutations are 80-90% sensitive, specific, and expensive methods. Immunohistochemistry is a relatively common, rapid, relatively inexpensive method in pathology practice compared to molecular techniques.
    Aims: We aimed to compare immunohistochemical and molecular methods in our case of malign melanoma in which we investigated BRAF mutation with "real time PCR" method and to investigate the compatibility of molecular test results of BRAF immunohistochemistry results as a preliminary test.
    Methods: Selected blocks of 30 patients with metastatic melanoma who came to our department for BRAF mutation detection were subjected to real time PCR molecular method and immunohistochemical study was performed with BRAF primer antibody.
    Results: BRAF mutation was detected by molecular method in 7 of 30 cases (23.33%).
    Conclusion: In all of these 7 cases, positive immunohistochemical staining was identified (100%). In conclusion, the use of BRAF immunohistochemistry as a screening test in the detection of mutant disease will allow the cost-effective use of molecular testing.
    Keywords:  BRAF; immunohistochemistry; melanoma; molecular methods
    DOI:  https://doi.org/10.4103/njcp.njcp_415_19
  40. Dermatol Online J. 2021 Apr 15. pii: 13030/qt9m97010n. [Epub ahead of print]27(4):
    Metastatic malignant melanoma in an endometrial polyp.
    Keely Ulmer, Jennifer Powers, Audai Alrwashdeh, Abbey Hardy-Fairbanks.
      Melanocytic metastasis to gynecologic organs is rare with most metastases to the ovaries. Metastases to the uterus, or in this case report, a uterine polyp, is exceedingly rare with only 17 cases reported in the literature. Post-menopausal bleeding is the most common presentation of metastatic melanoma in the endometrium, followed by uterine bleeding or abnormal postnatal bleeding in the premenopausal population. We present an 81-year-old woman with metastatic melanoma confined to an endometrial polyp leading to the diagnosis of widespread dissemination of the patient's acral melanoma resected 6 years prior. Although rare, metastatic melanoma should be considered as a cause for abnormal bleeding, especially in the post-menopausal patient with a history of melanoma.
  41. Probl Endokrinol (Mosk). 2021 Feb 09. 67(2): 20-27
    [Development of destructive thyroiditis and diabetes mellitus after three injections of pembrolizumab for skin melanoma].
    A A Glibka, G A Mel Nichenko, M S Mikhina, N V Mazurina, G Yu Kharkevich.
      The exponential rise in the use of immune checkpoint inhibitors (Ipilimumab, Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, and Avelumab) as the new standard for cancer treatment increase the incidence the immune-related adverse events due to immune activation. Endocrine immune-related adverse events are the third most commonly reported. Thyroid gland is most susceptible to autoimmune dysfunctions from immune checkpoint inhibitors and associated with the use of anti-PD-1 monoclonal antibodies. Hypophysitis develops more often during therapy with anti-CTLA-4 monoclonal antibodies. But such immune-related adverse events as diabetes mellitus, hypoparathyroidism are rare (about 1% of cases).We present a clinical case of the patient with skin melanoma who was prescribed therapy with immune checkpoints inhibitors (Pembrolizumab). Immune-related adverse events developed with damage to the endocrine organs after 3 Pembrolizumab injections. Of greatest interest is the development of two endocrine immune-related adverse events at once: destructive thyroiditis (with a short phase of thyrotoxicosis and subsequent persistent hypothyroidism) and diabetes mellitus. We tried to reflect the chronology of diseases and their features as fully as possible for endocrinologists, oncologists, therapists, family doctors and other medical doctors of related specialties.
    DOI:  https://doi.org/10.14341/probl12698
  42. Ann Med Surg (Lond). 2021 May;65 102270
    Vigilance to misleading information is required to avoid delayed diagnosis: Case series of acral melanomas.
    Sumadi Lukman Anwar, Ery Kus Dwianingsih, Tania Maharani Chandra, Arini Rizky Wijayanti, Haryo Widhanto, Adryan Kalya Ndraha Khairindra, Herjuna Hardiyanto, Suwardjo Suwardjo.
       Introduction: Melanoma is considered a rare cancer among Asians with a wide range of mucocutaneous manifestations. Failure to recognize a lesion as melanoma at first presentation might delay surgery aimed at complete resection. Acral melanoma has been related with the highest rate of misdiagnosis (~30%) causing further delayed diagnosis. Reliability of patient' history taking in melanoma has not yet been systematically reported.
    Presented cases: Two patients visited our oncology clinic with pigmented lesions in their soles. A 66-year-old man disclosed it appeared since a year ago after accidently hitting a stone while farming. Physical examination showed a black-brown irregular 100 × 80 mm lesion covering the distal third of the right sole with ulceration in the central lesion. The second patient was a geriatric woman with a black-purple 25 × 27 mm lesion with slight protrusion and ulceration in the central, irregular border, and partial hyperkeratosis. She explained the lesion emerged two years ago after she accidently stepped on a nail. Both patients were then diagnosed with acral melanomas and were treated with wide-excision, closure with skin grafting, and inguinal dissection.
    Discussion: Both patients reported history of traumas in lesions later confirmed as acral melanomas. Although history taking can provide up to 80% of the information for accurate diagnosis, in ambivalent cases, careful anamnesis, clinical examination, and biopsy are required to confirm diagnosis of acral melanoma. Early disease identification to establish definitive diagnosis of cancer is generally associated with better clinical outcomes. In suspected cases, vigilance toward misleading information in history taking is required.
    Keywords:  Acral; Delayed diagnosis; History taking; Melanoma; Misleading
    DOI:  https://doi.org/10.1016/j.amsu.2021.102270
  43. Curr Oncol Rep. 2021 May 19. 23(7): 84
    Treatment Following Progression in Metastatic Melanoma: the State of the Art from Scientific Literature to Clinical Need.
    F Serra, S Barruscotti, T Dominioni, A Zuccarini, P Pedrazzoli, S Chiellino.
       INTRODUCTION: In the last few years, the advent of targeted therapy and immunotherapy has improved the management and the prognosis of metastatic melanoma, but the spread of resistance mechanisms can lead to disease progression. The clinical management in this setting can be challenging because the oncologist has to decide what is the best treatment strategy among therapy beyond progression (TBP), therapy change, and the rechallenge approach. This review of the relevant scientific literature is intended to clarify which patients with progressing metastatic melanoma will benefit from continuation of ongoing therapy and which ones will not. The data are based on a total of about 4300 patients coming from the main retrospective studies in the chosen field. The article body is divided into four sections which analyze respectively the targeted therapy beyond progression, the immunotherapy beyond progression, the possible treatment sequences, and finally the rechallenge strategy.
    RECENT FINDINGS: Despite the possible approaches of TBP or rechallenge, the patient may not have an optimal response and may need new therapy, which is currently missing. To broaden the pharmacological offer in the fight against melanoma, cancer research is studying new disease targets, like the NRAS, PI3K, and cKIT pathways or combination treatment of targeted therapy plus immunotherapy. Despite the limitations of this work, mainly due to the limited number of studies, their retrospective nature and the lack of comparative studies, the analysis performed allows us to draw some important conclusions: therapy beyond progression, both targeted therapy and immunotherapy, represents a valid treatment option with positive effects on disease control and survival outcomes for patients with low clinical risk, expressed as low disease burden, normal LDH levels, and good performance status; moreover, the prognosis and quality of life of these patients improve when TBP is associated with locoregional treatments. In patients with progressive metastatic melanoma and high clinical risk (high disease burden, high LDH levels, and poor performance status), it is recommended to change therapy, without ever forgetting the possibility of enrolling the patient in a clinical trial. Finally, an efficacious treatment alternative is the rechallenge strategy; this approach consists in a re-treatment with the same drug after a variable interval of discontinuation. Preliminary studies seem to have demonstrated that patients retreated with targeted therapy achieved a greater benefit if they had a low clinical risk and if the drug doublet (BRAF + MEK inhibitors) was used. On the side of immunotherapy, the rechallenge strategy produced a major benefit in patients who prior experienced a severe toxic episode.
    Keywords:  Immunotherapy; Rechallenge; Targeted therapy; Therapy change; Treatment beyond progression
    DOI:  https://doi.org/10.1007/s11912-021-01065-3
  44. Clin Transl Oncol. 2021 May 15.
    Outcomes after stereotactic radiosurgery of brain metastases in patients with malignant melanoma and validation of the melanoma molGPA.
    K A Kessel, A Deichl, J Gempt, B Meyer, C Posch, C Diehl, C Zimmer, S E Combs.
       INTRODUCTION: Malignant melanoma is the third most common primary in the diagnosis of brain metastases. Stereotactic radiosurgery (SRS) is a well-established treatment option in limited brain disease. We analyzed outcomes of SRS with a particular focus on the graded prognostic assessment (GPA, melanoma molGPA), prognostic factors, and toxicity.
    METHODS: We evaluated 173 brain metastases in 83 patients with malignant melanoma. All were treated with SRS median dose of 20 Gy prescribed to the 80 or 100% isodose line between 2002 and 2019. All patients were followed-up regularly, including contrast-enhanced brain imaging as well as clinical examination, initially 6 weeks after treatment, then in quarterly follow-up.
    RESULTS: The median age was 61 years (range 27-80); 36 female and 47 male patients were treated. After a median follow-up of 5.7 months, median OS (overall survival) was 9.7 months 95%-KI 4.7-14.7). LC (local control) at 6 months, 12, 24 months was 89%, 86%, and 72%, respectively (median was not reached). Median DBC (distant brain control) was 8.2 months (95%-KI 4.7-11.7). For OS, a KPS ≥ 80%, a positive BRAF mutation status, a small PTV (planning target volume), the absence of extracranial metastases, as well as a GPA and melanoma molGPA > 2 were prognostic factors. In the MVA, a small PTV and a melanoma molGPA > 2 remained significant.
    CONCLUSION: The present survival outcomes support the use of the disease-specific melanoma molGPA as reliable prognostic score. Favorable outcomes for SRS compared to other studies were observed. In the treatment of brain metastases of malignant melanoma patients, a multidisciplinary approach consisting of surgery, SRS, chemotherapy, and immunotherapy should be considered.
    Keywords:  Brain metastases; GPA; Melanoma; Prognostic factors; Radiosurgery; SRS
    DOI:  https://doi.org/10.1007/s12094-021-02607-8
  45. Evid Based Complement Alternat Med. 2021 ;2021 5543259
    Inhibitory Effects of Euphorbia ebracteolata Hayata Extract ECB on Melanoma-Induced Hyperplasia of Blood Vessels in Zebrafish Embryos.
    Wenjing Dong, Xinyue Han, Chao Bao, Saijilahu Tai, Yuxia Bai, Liang Xu, Jingfeng Yang, TinChung Leung, Wuliji Ao, Wu Dong.
      Melanoma is a serious malignant form of skin cancer. Euphorbiaceae compound B (ECB, 2,4-dihydroxy-6-methoxy-3-methylacetophenone) is an acetophenone compound that is isolated from Euphorbia ebracteolata Hayata (EEH), an herbaceous perennial, and has antitumor activity. Here, we transplanted human melanoma cells into zebrafish embryos to establish a zebrafish/melanoma model. We showed that this model can be used to evaluate the therapeutic effect of EEH and ECB and discussed its potential mechanism of action. The results showed that ECB was an active ingredient of EEH in inhibiting melanoma-induced hyperplasia of blood vessels in zebrafish embryos, similar to the angiogenic inhibitor vatalanib. ECB inhibited the number and length of subintestinal veins (p < 0.05), as well as the distribution of melanoma in zebrafish embryos (p < 0.05). More importantly, unlike vatalanib, ECB only inhibited melanoma-induced abnormal and excessive growth of blood vessels in xenografts. In addition, ECB inhibited the mRNA expression of vegfr2 and vegfr3 in zebrafish. Both vegfr2 and vegfr3 are essential genes that regulate blood vessel formation and upregulate the expression of p53 and casp3a genes in zebrafish. Together, the above-mentioned results indicate that ECB has a potential antimelanoma effect in vivo, which may be mediated by inhibiting vascular endothelial growth factor receptors.
    DOI:  https://doi.org/10.1155/2021/5543259
  46. Dermatol Ther. 2021 May 16. e14981
    Early time to recurrence predicts worse survival in patients with localized or regionally advanced cutaneous melanoma.
    Chengcai Liang, Wanming Hu, Jingjing Li, Xiaoshi Zhang, Zhiwei Zhou, Yao Liang.
       OBJECTIVES: To investigate the prognostic significance of time to recurrence (TTR) for overall survival (OS) and survival after recurrence (SAR) in patients with localized or regionally advanced cutaneous melanoma.
    METHODS: A total of 731 cutaneous melanoma patients with an initial diagnosis of 8th American Joint Committee on Cancer (AJCC) clinical stage I-III were included in this study. The prognostic factors associated with OS and SAR were estimated through Kaplan-Meier and Cox regression analysis.
    RESULTS: Of the total cohort, 329 patients (45%) died, and 418 patients (57%) experienced recurrence. The median follow-up and TTR were 55.6 months and 9.6 months, respectively. A total of 141 patients (19%) experienced recurrence in <6 months, and 277 patients (38%) experienced recurrence in ≥6 months. Patients with stage III and positive lymph node dissection (LND) were more common in the early TTR group than in the late TTR group. Both the OS and SAR rates at 5 years and 10 years in the early TTR group were significantly poorer than those in the late TTR group (p<0.001 and p=0.008, respectively). Furthermore, early TTR, along with truncal tumour, higher TNM stage and therapeutic variables (extended resection, LND and adjuvant therapy), were significant independent predictors of worse OS and SAR in multivariate analysis (all p<0.05).
    CONCLUSIONS: Early TTR predicts worse survival and could be considered an independent prognostic factor for patients with localized or regionally advanced cutaneous melanoma. TTR should be evaluated in all patients with recurrence to guide post-recurrence risk stratification and follow-up schedules. This article is protected by copyright. All rights reserved.
    Keywords:  cutaneous melanoma; overall survival (OS); survival after recurrence (SAR); time to recurrence (TTR)
    DOI:  https://doi.org/10.1111/dth.14981
  47. Eur J Dermatol. 2021 Apr 01. 31(2): 279-280
    Multiple eruptive squamous cell carcinomas: a possible clinical sign in melanoma patients treated with vemurafenib.
    Andrija Jovic, Danica Tiodorovic, Danijela Popovic, Natasa Vidovic, Zorana Zlatanovic, Sladjana Cekic, Hristina Kocic, Giovanni Damiani.
      
    DOI:  https://doi.org/10.1684/ejd.2020.3952
  48. Ophthalmology. 2021 May 14. pii: S0161-6420(21)00366-3. [Epub ahead of print]
    Ocular safety profile of BRAF and MEK inhibitors: data from the World Health Organization Pharmacovigilance Database.
    Camille Mettler, Dominique Monnet, Nora Kramkimel, Jean-Marc Tréluyer, Luc Mouthon, Antoine Brézin, Nicolas Dupin, Marie-Blanche Valnet-Rabier, Laurent Chouchana, Benjamin Terrier.
       PURPOSE: BRAF (BRAFi) and MEK (MEKi) inhibitors significantly improved metastatic melanoma prognosis. Ocular adverse effects (OAEs) represent an uncommon but disabling toxicity of these drugs. We aimed to characterize the ocular safety profile of BRAFi and/or MEKi and to detect possible safety signals.
    METHODS: We performed a retrospective, observational, pharmacovigilance study using VigiBase, the WHO global safety database. OAEs were classified according to the eye segments and to the inflammatory pattern based on to the Standardized of Uveitis Nomenclature. Associations between BRAFi monotherapy, MEKi monotherapy and BRAFi+MEKi combination therapy and OAE reporting were was assessed using the disproportionality analysis. Results were expressed with the Reporting Odds Ratio (ROR) and its 95% confidence interval (CI).
    RESULTS: From January, 2010 to October, 2019, 1,568 OAE cases were reported with BRAFi and/or MEKi. Among them 1,006 cases with sufficient data were included, corresponding to 310 (30.8%), 124 (12.3%) and 572 (56.9%) cases reported with BRAFi, MEKi or BRAFi+MEKi combination therapy, respectively. BRAFi monotherapy was significantly associated with the reporting of iris and ciliary body abnormalities [ROR 8.7 (95% CI 6.0-12.5)], diffuse abnormalities [ROR 7.1 (5.4-9.4)], anterior uveitis [ROR 8.6 (6.0-12.1)] and panuveitis [ROR 7.1 (5.4-9.4)]. MEKi monotherapy was associated with the reporting of retinal and choroid abnormalities [ROR 9.5 (7.4-12.2)], diffuse abnormalities [ROR 2.5 (1.1-6.1)] and panuveitis [ROR 2.5 (1.1-6.1)]. Combinations of BRAFi and MEKi therapies were associated with OAEs reporting from both drugs, with a possible synergistic or additive effect for diffuse abnormalities and panuveitis.
    CONCLUSION: Our study characterizes ocular safety profile of BRAFi and/or MEKi. We identify possible safety signals for several OAEs, not previously reported with BRAFi and MEKi. Our data provide rationale for a personalized management of OAE in patients with BRAFi+MEKi combination therapy according to the type of ocular reaction.
    DOI:  https://doi.org/10.1016/j.ophtha.2021.05.008
  49. Front Oncol. 2021 ;11 660172
    Malignant Melanoma in Children and Adolescents Treated in Pediatric Oncology Centers: An Australian and New Zealand Children's Oncology Group (ANZCHOG) Study.
    Anne L Ryan, Charlotte Burns, Aditya K Gupta, Ruvishani Samarasekera, David S Ziegler, Maria L Kirby, Frank Alvaro, Peter Downie, Stephen J Laughton, Siobhan Cross, Timothy Hassall, Geoff B McCowage, Jordan R Hansford, Rishi S Kotecha, Nicholas G Gottardo.
       Objectives: Unlike adults, malignant melanoma in children and adolescents is rare. In adult melanoma, significant progress in understanding tumor biology and new treatments, including targeted therapies and immunotherapy have markedly improved overall survival. In sharp contrast, there is a paucity of data on the biology and clinical behavior of pediatric melanoma. We report a national case series of all pediatric and adolescent malignant melanoma presenting to ANZCHOG Childhood Cancer Centers in Australia and New Zealand.
    Methods: A retrospective, descriptive, multi-center study was undertaken to identify patients less than 18 years of age treated for cutaneous malignant melanoma over a twenty-year period (1994 to 2014). Data on clinical characteristics, histopathology, and extent of disease, treatment and follow-up are described.
    Results: A total of 37 cases of malignant melanoma were identified from all of the Australasian tertiary Childhood Cancer Centers. The median age was 10 years (range 1 month - 17 years). Clinically, the most common type of lesion was pigmented, occurring in sixteen (57%) patients, whilst amelanotic was seen in 7 patients (25%). In 11 (27.9%) the Breslow thickness was greater than 4mm. A total of 11 (29.7%) patients relapsed and 90% of these died of disease. Five-year event free survival (EFS) and overall survival were 63.2 (95% CI: 40.6 - 79.1) and 67.7% (95% CI: 45.1 - 82.6) respectively.
    Conclusion: Our data confirms that melanoma is a rare presentation of cancer to tertiary Australasian Childhood Cancer Centers with only 37 cases identified over two decades. Notably, melanoma managed in Childhood Cancer Centers is frequently at an advanced stage, with a high percentage of patients relapsing and the majority of these patients who relapsed died of disease. This study confirms previous clinical and prognostic information to support the early multidisciplinary management in Childhood Cancer Centers, in conjunction with expert adult melanoma centers, of this rare and challenging patient group.
    Keywords:  childhood; cutaneous melanoma; dermatology; outcome; rare tumors
    DOI:  https://doi.org/10.3389/fonc.2021.660172
  50. J Dermatol. 2021 May 21.
    Successful rechallenge therapy for BRAF/MEK inhibitor-resistant multiple brain metastases of melanoma.
    Hidehiko Fukushima, Yohei Iwata, Kenta Saito, Kazumitsu Sugiura.
      Combination therapy with BRAF and MEK inhibitors (BRAFi/MEKi) have dramatically improved prognosis among patients with BRAF-mutant metastatic melanoma compared with traditional treatment, such as chemotherapy. However, resistance to these targeted agents occurs invariably, thereby limiting their clinical efficacy. Recently, it has been reported that the ligand-independent phosphorylation of erythropoietin-producing hepatocellular receptor A2 (EphA2) at Ser-897 signaling is a driver of BRAF inhibitor resistance in melanoma. A melanoma patient with multiple metastases was treated with dabrafenib plus trametinib therapy and maintained complete remission for more than 2 years. As brain metastasis occurred, we had switched to nivolumab plus ipilimumab therapy. However, new lesions were observed after four cycles of nivolumab plus ipilimumab therapy, she was rechallenged with encorafenib plus binimetinib therapy, and she maintained progression-free status for more than 7 months. We performed immunohistochemical staining of EphA2, phospho-EphA2 (p-EphA2; Ser-897), and epidermal growth factor receptor (EGFR) of melanoma cells before and/or after dabrafenib and trametinib therapy. Immunohistochemical examination showed higher expression of EphA2, p-EphA2, and EGFR in the melanoma cells after dabrafenib plus trametinib therapy as compared with that before therapy. Our results may indicate that EphA2, p-EphA2, and EGFR can be critical factors for resistance and reversible response of BRAFi/MEKi in metastases of melanoma. Our case presents a possible treatment that can help overcome BRAFi/MEKi resistance and improve prognosis of melanoma.
    Keywords:  BRAF/MEK inhibitor-resistant melanoma; dabrafenib plus trametinib therapy; encorafenib plus binimetinib therapy; erythropoietin-producing hepatocellular receptor A2; phospho-EphA2
    DOI:  https://doi.org/10.1111/1346-8138.15969
  51. Pharmacoepidemiol Drug Saf. 2021 May 20.
    Use of hydrochlorothiazide and risk of skin cancer in a large nested case-control study in Spain.
    Luz M León-Muñoz, Talita Duarte-Salles, Ana Llorente, Yesika Díaz, Diana Puente, Anton Pottegård, Dolores Montero-Corominas, Consuelo Huerta.
       PURPOSE: Hydrochlorothiazide (HCTZ) use has been linked to skin cancer in northern European countries. We assessed the association between HCTZ exposure and risk of malignant melanoma (MM) and keratinocyte carcinoma (KC) in a European Mediterranean population.
    METHODS: Two parallel nested case-control studies were conducted in Spain using two electronic primary healthcare databases, each one providing data on both exposure and outcomes: SIDIAP and BIFAP. Cancer cases were matched to 10 controls by age and gender through risk-set sampling. The ORs and 95% CI for MM and KC associated with previous HCTZ use were estimated using conditional logistic regression. In BIFAP, KC cases were further identified as basal cell carcinoma (BCC) or squamous cell carcinoma (SCC).
    RESULTS: In adjusted analyses, both ever and cumulative high (≥50,000 mg) use of HCTZ were associated with an increased risk of KC. The risk estimates for high use were 1.30 (1.26-1.34) in SIDIAP and 1.20 (1.12-1.30) in BIFAP, with a lower risk for BCC (1.11 (1.02-1.21)) than for SCC (1.71 (1.45-2.02)). A dose-response relationship was observed between cumulative doses of HCTZ and KC risk. Inconsistent results were found for high use of HCTZ and risk of MM: 1.25 (1.09-1.43) in SIDIAP and 0.85 (0.64-1.13) in BIFAP.
    CONCLUSIONS: In this European Mediterranean population, a high cumulative use of HCTZ was related to an increased risk of KC with a clear dose-response pattern.
    Keywords:  HCTZ; Malignant melanoma; case-control; keratinocyte carcinoma; pharmacoepidemiology
    DOI:  https://doi.org/10.1002/pds.5295
  52. J Eur Acad Dermatol Venereol. 2021 Jun;35(6): 1246-1247
    Lentiginous melanoma - should we change the paradigm?
    P Pietkiewicz.
      
    DOI:  https://doi.org/10.1111/jdv.17291
  53. J Geriatr Oncol. 2021 May 18. pii: S1879-4068(21)00105-3. [Epub ahead of print]
    Outcomes for systemic therapy in older patients with metastatic melanoma: Results from the Dutch Melanoma Treatment Registry.
    Anouk Jochems, Esther Bastiaannet, Maureen J B Aarts, Alexander C J van Akkooi, Franchette W P J van den Berkmortel, Marye J Boers-Sonderen, Alfonsus J M van den Eertwegh, Nienke G de Glas, Jan Willem B de Groot, John B A G Haanen, Geke A P Hospers, Jacobus J M van der Hoeven, Djura Piersma, Rozemarijn S van Rijn, Karijn P M Suijkerbuijk, Albert J Ten Tije, Astrid A M van der Veldt, Gerard Vreugdenhil, Michiel C T van Zeijl, Ellen Kapiteijn, Michel W J M Wouters.
       BACKGROUND: The incidence of metastatic melanoma is increasing in all ages. Multiple trials with targeted drugs and immune checkpoint inhibitors showed improved survival in metastatic melanoma. However, patients aged ≥75 years are often under-represented in clinical trials, therefore raising questions on safety and efficacy of treatment.
    PATIENTS AND METHODS: We analyzed a real-world cohort of 3054 patients with metastatic melanoma stratified for age (≤65 years, 66-74 years and ≥ 75 years), and BRAF status, providing data on treatment strategies, toxicity, and survival. Kaplan Meier curves and Cox Proportional Hazard Models were used to present overall survival (OS) and Melanoma Specific Survival (MSS).
    RESULTS: Overall, 52.2% of patients were ≤ 65 years and 18.4% of patients ≥75 years. BRAF mutated tumors were found less often in patients ≥75 years: 34.5% versus 65% in patients ≤65 years. Patients ≥75 years received systemic therapy less frequently compared to their younger counterparts independent of the BRAF status. When receiving treatment, no statistical significant difference in grade 3 or 4 toxicity was observed. Three year Overall Survival rate was 13.7% (9.1-19.3) in patients ≥75 years versus 26.7% (23.1-30.4) in patients ≤65 years, with a Hazard Ratio (HR) of 1.71 (95%CI 1.50-1.95), p < 0.001. Three year Melanoma Specific Survival was 30.4% (22.0-39.2) versus 34.0% (29.7-38.2), HR 1.26 (95% CI 1.07-1.49), p = 0.005 with an adjusted HR of 1.21 (1.00-1.47), p = 0.049.
    CONCLUSION: Patients with metastatic melanoma ≥75 years are less frequently treated, but when treated there is no statistical significant increase in toxicity and only a borderline statistical significant difference in Melanoma Specific Survival was seen, compared to younger patients.
    Keywords:  Immune checkpoint inhibitors; Metastatic melanoma; Older patients; Outcome; Safety; Targeted therapy
    DOI:  https://doi.org/10.1016/j.jgo.2021.04.006
  54. Cell Physiol Biochem. 2021 May 19. 55(3): 265-276
    Development and Pilot Screen of Novel High Content Assay for Down Regulators of Expression of Heterogenous Nuclear Ribonuclear Protein H2.
    Juan Diez, Sumitha Rajendrarao, Shadi A Baajour, Praathibha Sripadhan, Timothy P Spicer, Louis D Scampavia, Dmitriy Minond.
       BACKGROUND/AIMS: Despite recent advances in melanoma drug discovery, the average overall survival of patients with late-stage metastatic melanoma is approximately 3 years, suggesting a need for new approaches and melanoma therapeutic targets. Previously we identified heterogeneous nuclear ribonucleoprotein H2 as a potential target of anti-melanoma compound 2155-14 (Palrasu et al., Cell Physiol Biochem 2019;53:656-686). In the present study, we endeavored to develop an assay to enable a high throughput screening campaign to identify drug-like molecules acting via down regulation of heterogeneous nuclear ribonucleoprotein H2 that can be used for melanoma therapy and research.
    METHODS: We established a cell-based platform using metastatic melanoma cell line WM266-4 expressing hnRNPH2 conjugated with green fluorescent protein to enable assay development and screening. High Content Screening assay was developed and validated in 384 well plate format, followed by miniaturization to 1,536 well plate format.
    RESULTS: All plate-based QC parameters were acceptable: %CV = 6.7±0.3, S/B = 21±2.1, Z' = 0.75±0.04. Pilot screen of FDA-approved drug library (n=1,400 compounds) demonstrated hit rate of 0.5%. Two compounds demonstrated pharmacological response and were authenticated by western blot analysis.
    CONCLUSION: We developed a highly robust HTS-amenable high content screening assay capable of monitoring down regulation of hnRNPH2. This assay is thus capable of identifying authentic down regulators of hnRNPH1 and 2 in a large compound collection and, therefore, is amenable to a large-scale screening effort.
    Keywords:  High content assay; High throughput screening; Heterogenous nuclear ribonuclear protein H; Melanoma
    DOI:  https://doi.org/10.33594/000000372
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