bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021‒08‒22
fifty papers selected by
Farah Jaber-Hijazi
University of the West of Scotland
  1. Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4.
  2. Effect of estrogen in malignant melanoma.
  3. Melanoma medicine in the new millennium.
  4. The Role of Ferroptosis in Melanoma.
  5. The concepts of rechallenge and retreatment with immune checkpoint blockade in melanoma patients.
  6. [Transformation of choroidal nevus into melanoma].
  7. Multiregional genetic evolution of metastatic uveal melanoma.
  8. eIF4B enhances ATF4 expression and contributes to cellular adaptation to asparagine limitation in BRAF-mutated A375 melanoma.
  9. Long-term Overall Survival and Predictors in Anti-PD-1-naive Melanoma Patients With Brain Metastases Treated With Immune Checkpoint Inhibitors in the Real-world Setting: A Multicohort Study.
  10. Risk of skin cancer in patients with vitiligo in Denmark: A nationwide cohort study.
  11. Sentinel Lymph Node Biopsy in Cutaneous Melanoma-Where Do We Stand?
  12. [The role of CXC and CC chemokines in patients with uveal melanoma].
  13. Author Correction: Estimation of the timing of BAP1 mutation in uveal melanoma progression.
  14. Inhibition of melanogenesis by Aster yomena callus pellet extract in melanoma cells and patients with skin pigmentation.
  15. Residual melanoma in wide local excision specimens after 'complete' excision of primary cutaneous in situ and invasive melanomas.
  16. Impact of Prior Treatment on the Efficacy of Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma.
  17. Precision Nuclear Medicine: The Evolving Role of PET in Melanoma.
  18. Integrated analysis of the expression, involved functions, and regulatory network of RUNX3 in melanoma.
  19. Cost-effectiveness of ipilimumab versus high-dose interferon as an adjuvant therapy in resected high-risk melanoma.
  20. Effect of piceatannol against malignant melanoma in vivo and in vitro.
  21. Cutaneous immune-related adverse events in patients with metastatic melanoma on antiprogrammed cell death protein 1 and anticytotoxic T-lymphocyte-associated protein 4 therapy: A retrospective cohort study.
  22. N6-Methyladenosine Regulators and Related LncRNAs Are Potential to be Prognostic Markers for Uveal Melanoma and Indicators of Tumor Microenvironment Remodeling.
  23. TIL in Melanoma-Similar Approaches, Different Results, Unanswered Questions.
  24. Metastatic malignant melanoma of unknown primary site to the brain: A case report.
  25. Identification and validation of tumor microenvironment-related lncRNA prognostic signature for uveal melanoma.
  26. Combination of radiotherapy and targeted therapy for melanoma brain metastases: a systematic review.
  27. Collision Cutaneous Neoplasms Consisting of Melanoma and Basal Cell Carcinoma.
  28. Risk of Developing Melanoma With Systemic Agents Used to Treat Psoriasis: A Review of the Literature.
  29. The calcium-binding protein S100B reduces IL6 production in malignant melanoma via inhibition of RSK cellular signaling.
  30. The Bork-Baykal Phenomenon in Congenital Melanocytic Nevus.
  31. Is Fas-mediated apoptosis of melanocytes indispensable in vitiligo?
  32. Chemical composition of Miscanthus sinensis var. purpurascens flower absolute and its beneficial effects on skin wound healing and melanogenesis-related cell activities.
  33. Scoparone Induces Expression of Pluripotency Transcription Factors SOX2 and NANOG in Dermal Papilla Cells.
  34. Congenital Melanocytic Nevus Regression Lacking the Halo Phenomenon: The Influence of the Body Site.
  35. Is vitiligo associated with systemic aquaporin-3 deficiency?
  36. Tranexamic acid versus fractional carbon dioxide laser in post-acne hyperpigmentation.
  37. Clinical Evidence of Cell-Targeted Topical Therapy for Treating Skin Dyspigmentation.
  38. Polypodium leucotomos as an adjunct to the treatment of vitiligo.
  39. TGF-β2 and collagen play pivotal roles in the spheroid formation and anti-aging of human dermal papilla cells.
  40. Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy.
  41. Immunological Overkilling Followed by Cellular Replenishment: A Novel 2-Step Treatment for Halo Congenital Melanocytic Nevus.
  42. Human embryonic stem cell-derived melanocytes exhibit limited immunogenicity.
  43. Evaluation of the of the efficacy of Fractional Erbium-Doped Yttrium Aluminum Garnet Laser-Assisted Drug Delivery of Kojic Acid in the Treatment of Melasma; A split face, comparative clinical study.
  44. Knowledge about risks, benefits, and curative potential of immunotherapy among patients with advanced cancer.
  45. Specific mutations in the genes of MC1R and TYR have an important influence on the determination of pheomelanin pigmentation in Korean native chickens.
  46. Repigmentation of nipple-areola complex after ReCell® treatment on breast vitiligo.
  47. Psoriasis, Vitiligo, and Biologic Therapy: Case Report and Narrative Review.
  48. Human iPS Cell-Derived Cell Aggregates Exhibited Dermal Papilla Cell Properties in in vitro Three-Dimensional Assemblage Mimicking Hair Follicle Structures.
  49. A systematic review of vitiligo onset and exacerbation in patients receiving biologic therapy.
  50. Skin of color in dermatology: analysis of representation in dermatologic journals.
  1. Nat Commun. 2021 Aug 20. 12(1): 5056
    Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4.
    Johanna Diener, Arianna Baggiolini, Mattias Pernebrink, Damian Dalcher, Luigi Lerra, Phil F Cheng, Sandra Varum, Jessica Häusel, Salome Stierli, Mathias Treier, Lorenz Studer, Konrad Basler, Mitchell P Levesque, Reinhard Dummer, Raffaella Santoro, Claudio Cantù, Lukas Sommer.
      Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::NrasQ61K; Cdkn2a-/- melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism.
    DOI:  https://doi.org/10.1038/s41467-021-25326-8
  2. J Cosmet Dermatol. 2021 Aug 20.
    Effect of estrogen in malignant melanoma.
    Neetu Bhari, Robert A Schwaertz, Zoe Apalla, Gabriel Salerni, Bengu Nisa Akay, Anant Patil, Stephan Grabbe, Mohamad Goldust.
      BACKGROUND: Melanoma is associated with poor prognosis in its advanced stages. Potential influence of estrogen and its metabolites on melanoma growth has been suggested.AIMS: The objective of this review was to provide an overview on the evidence related to estrogen in malignant melanoma.
    MATERIALS AND METHODS: Literature search using PubMed, Google Scholar and relevant cross-references of the retrieved articles was performed to review relevant published articles related to estrogen and its effects in malignant melanoma.
    RESULTS: Effect of estrogen signaling on a tissue largely depends on the relative expression of estrogen receptors (ER) α and β. Gender differences in melanoma may be explained by the difference in expression of these receptors. ERβ is the principal ER in melanoma.
    DISCUSSION: Although there is uncertainty about role of estrogen in pathogenensis and progression of melanoma, evidence suggests that its growth and metastasis are influenced by estrogen stimulation. Role ER on the proliferation of melanoma cells is well described.
    CONCLUSION: There is a need of safe and effective therapy for melanoma, especially for advanced cases. After the establishment of specific role of estrogen and its receptor, analysis of specific genetic mutation can be performed for proper utilization of targeted therapies.
    Keywords:  estrogen; melanocytes; melanoma
    DOI:  https://doi.org/10.1111/jocd.14391
  3. Br J Dermatol. 2021 Aug;185(2): 239-240
    Melanoma medicine in the new millennium.
    H Tsao.
      
    DOI:  https://doi.org/10.1111/bjd.20420
  4. Pigment Cell Melanoma Res. 2021 Aug 18.
    The Role of Ferroptosis in Melanoma.
    Ronan Talty, Marcus Bosenberg.
      Melanoma is the deadliest form of skin cancer. Although treatment with targeted therapies and immune checkpoint inhibitors has dramatically improved survival in advanced melanoma, many patients do not benefit from these therapies or relapse after an initial period of response. Thus, future outcomes in these categories of melanoma patients will depend on the identification of novel therapeutic targets and methods to enhance existing targeted therapy and immunotherapy regimens. Ferroptosis is a newly identified form of iron-dependent regulated cell death that is morphologically, biochemically, and genetically distinct from apoptosis, autophagy, pyroptosis, and necroptosis. Dysregulation of ferroptosis has been linked to the development of several forms of cancer. This review examines ferroptosis in the context of melanoma. It presents an overview of ferroptosis biology, summarizes and interprets the current literature, and poses several outstanding questions and areas of future direction.
    Keywords:  cell death; ferroptosis; immunotherapy; iron; melanoma; skin neoplasms
    DOI:  https://doi.org/10.1111/pcmr.13009
  5. Eur J Cancer. 2021 Aug 12. pii: S0959-8049(21)00427-5. [Epub ahead of print]155 268-280
    The concepts of rechallenge and retreatment with immune checkpoint blockade in melanoma patients.
    Anne Zaremba, Alexander M M Eggermont, Caroline Robert, Reinhardt Dummer, Selma Ugurel, Elisabeth Livingstone, Paolo A Ascierto, Georgina V Long, Dirk Schadendorf, Lisa Zimmer.
      Forty to 60% of patients with advanced or metastatic melanoma respond to first-line immune checkpoint inhibitors (ICI) and half of all patients in the metastatic setting eventually progress. This review evaluated the latest long-term data from clinical trials. It also considered data from recent retrospective studies, as these address important questions for clinical practice. 'Retreatment' defined as 'repeated treatment with the same therapeutic class following relapse after adjuvant treatment has ended' and showed activity in selected patients with recurrence after regular completion of adjuvant PD-1 treatment. In melanoma patients with adjuvant PD-1 monotherapy who recur during adjuvant treatment, further treatment with PD-1 monotherapy seems to have no clinical utility, indicating the need for a therapy switch or escalation in these patients. Targeted therapy with BRAF/MEK inhibitors and ipilimumab-based therapy (alone or combined with PD-1 blockade) show clinical activity in patients who recur during and after adjuvant treatment. 'Rechallenge', defined as 'repeated treatment with the same therapeutic class following disease progression in patients who had clinical benefit with prior treatment for unresectable or metastatic disease', with pembrolizumab at progression in the advanced setting achieving additional disease control. If possible, 'escalation' (PD-1 inhibitors combined with additional agents) should be preferred to PD-1 inhibitor monotherapy rechallenge as higher response rates were demonstrated. The combination of PD-1 plus CTLA-4 was found to be more effective but not more toxic than CTLA-4 alone. Promising antitumor activity was observed for escalation to lenvatinib plus pembrolizumab, entinostat plus pembrolizumab, and relatlimab plus nivolumab. Retreatment, rechallenge and escalation are available options for patients with melanoma who relapse in the adjuvant or advanced setting.
    Keywords:  Escalation; Immunotherapy; Melanoma; Rechallenge; Retreatment
    DOI:  https://doi.org/10.1016/j.ejca.2021.07.002
  6. Vestn Oftalmol. 2021 ;137(4): 5-17
    [Transformation of choroidal nevus into melanoma].
    A F Brovkina, A S Stoyukhina, I V Musatkina.
      The risk of choroidal melanoma developing from choroidal nevus (CN) varies in range of 0.78-7%. Absence of a common terminology and distinct diagnostic criteria characterizing small melanoma de novo and unusual CN often complicates treatment choice and patient prognosis.PURPOSE: To study the clinical features and the role of visualization methods in the diagnosis of CN transformation into melanoma.
    MATERIAL AND METHODS: The study analyzes the clinical picture and visualization results of 11 patients with initial diagnosis of «choroidal nevus» (n=3) and «suspicious choroidal nevus» (n=8).
    RESULTS AND DISCUSSION: Examination and continued observation revealed 7 patients to have melanoma that had developed from CN (2 of them confirmed with histological studies). The time before CN transformed into melanoma varied between 4 and 13 years, with median 5 [4; 12] years. Two patients were diagnosed with primary melanoma (melanoma de novo), two other patients - with suspicious CN. In progressive CN transforming into melanoma, visual impairments occurred between 6 months and 13 years in 6 out of 7 patients. Initial prominence of suspicious CN at the first visit was 1.9±0.68 mm (0.9 mm to 2.67 mm). The characteristic features of suspicious CN transforming into initial melanoma are: 1) asymmetric shape of the edges of expanded choroidal complex; 2) presence of areas of damaged choriocapillaris layer, direct and indirect signs of loss of integrity of the Bruch's membrane; 3) areas of accumulation of moderately hyperreflective subretinal exudate; 4) presence of intraretinal hyperreflective inclusions. The signs distinguishing primary choroidal melanoma from melanoma that had developed from CN are: 1) absence of areas with tomography pattern characteristic of nevi; 2) more pronounced asymmetry of the shape of edges, compared to melanoma developed from CN; 3) presence of cysts in larger tumors, compared to melanoma developed from CN.
    CONCLUSION: All patients with CN should be regularly followed up by an ophthalmologist.
    Keywords:  choroidal melanoma; choroidal nevus; choroidal nevus transformation to melanoma; optical coherence tomography; suspicious choroidal nevus
    DOI:  https://doi.org/10.17116/oftalma20211370415
  7. NPJ Genom Med. 2021 Aug 16. 6(1): 70
    Multiregional genetic evolution of metastatic uveal melanoma.
    Daniel A Rodriguez, Jessica Yang, Michael A Durante, Alexander N Shoushtari, Stergios J Moschos, Kazimierz O Wrzeszczynski, J William Harbour, Richard D Carvajal.
      Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and leads to deadly metastases for which there is no approved treatment. Genetic events driving early tumor development are well-described, but those occurring later during metastatic progression remain poorly understood. We performed multiregional genomic sequencing on 22 tumors collected from two patients with widely metastatic UM who underwent rapid autopsy. We observed multiple seeding events from the primary tumors, metastasis-to-metastasis seeding, polyclonal seeding, and late driver variants in ATM, KRAS, and other genes previously unreported in UM. These findings reveal previously unrecognized temporal and anatomic complexity in the genetic evolution of metastatic uveal melanoma, and they highlight the distinction between early and late phases of UM genetic evolution with implications for novel therapeutic approaches.
    DOI:  https://doi.org/10.1038/s41525-021-00233-5
  8. Biochem Biophys Res Commun. 2021 Aug 10. pii: S0006-291X(21)01176-1. [Epub ahead of print]573 93-99
    eIF4B enhances ATF4 expression and contributes to cellular adaptation to asparagine limitation in BRAF-mutated A375 melanoma.
    Yukie Iwao, Yuka Okamoto, Hitomi Shirahama, Satomi Tsukahara, Akihiro Tomida.
      ATF4 is a crucial transcription factor in the integrated stress response, a major adaptive signaling pathway activated by tumor microenvironment and therapeutic stresses. BRAF inhibitors, such as vemurafenib, induce ATF4 in BRAF-mutated melanoma cells, but the mechanisms of ATF4 induction are not fully elucidated. Here, we show that ATF4 expression can be upregulated by eukaryotic initiation factor 4B (eIF4B) in BRAF-mutated A375 cells. Indeed, eIF4B knockout (KO) prevented ATF4 induction and activation of the uORF-mediated ATF4 translation mechanism during vemurafenib treatment, which were effectively recovered by the rescue of eIF4B. Transcriptome analysis revealed that eIF4B KO selectively influenced ATF4-target gene expression among the overall gene expression changed by vemurafenib. Interestingly, eIF4B supported cellular proliferation under asparagine-limited conditions, possibly through the eIF4B-ATF4 pathway. Our findings indicate that eIF4B can regulate ATF4 expression, thereby contributing to cellular stress adaptation, which could be targeted as a therapeutic approach against malignancies, including melanoma.
    Keywords:  ATF4; Asparagine limitation; BRAF mutation; Melanoma; eIF4B; vemurafenib
    DOI:  https://doi.org/10.1016/j.bbrc.2021.08.022
  9. J Immunother. 2021 Aug 18.
    Long-term Overall Survival and Predictors in Anti-PD-1-naive Melanoma Patients With Brain Metastases Treated With Immune Checkpoint Inhibitors in the Real-world Setting: A Multicohort Study.
    Girish S Naik, Elizabeth I Buchbinder, Justine V Cohen, Michael P Manos, Alistair E W Johnson, Peter Bowling, Ayal A Aizer, Jonathan D Schoenfeld, Donald P Lawrence, Rizwan Haq, Frank Stephen Hodi, Ryan J Sullivan, Patrick A Ott.
      Long-term survival outcomes among melanoma patients with brain metastases treated with immune checkpoint inhibitors are limited. In this retrospective study at 2 centers, metastatic melanoma patients with radiographic evidence of brain metastases who received anti-programmed death-1 (PD-1) monotherapy or nivolumab in combination with ipilimumab between 2014 and 2017 were included. Overall survival (OS) was assessed in diagnosis-specific graded prognostic assessment (ds-GPA) and melanoma-molecular graded prognostic assessment (molGPA) prognostic risk groups. Baseline clinical covariates were used to identify predictors of OS in univariate/multivariable Cox proportional-hazards models. A total of 84 patients (58 monotherapy, 26 combination) were included with a median duration of follow-up of 43.4 months (maximum: 5.1 y). The median OS [95% confidence interval (CI)] was 3.1 months (1.8, 7) for ds-GPA 0-1, 22.1 months [5.4, not reached (NR)] for ds-GPA 2 and NR (24.9, NR) for ds-GPA 3-4 in the monotherapy cohort [hazard ratio (HR) for ds-GPA 3-4 vs. 0-1: 0.13 (95% CI: 0.052, 0.32); 0.29 (95% CI: 0.12, 0.63) for ds-GPA 2 vs. 0-1]. The median OS was 1.1 months (95% CI: 0.3, NR) for ds-GPA 0-1, 11.8 months (95% CI: 2.9, 23.3) for ds-GPA 2 and 24.4 months (95% CI: 3.4, NR) for ds-GPA 3-4 in the combination cohort [HR for 3-4 vs. 0-1: 0.013 (95% CI: 0.0012, 0.14); HR for ds-GPA 2 vs. 0-1: 0.033 (0.0035, 0.31)]. Predictors associated with longer survival included ds-GPA or molGPA>1 (among prognostic indices), neutrophil-to-lymphocyte ratio (<4 vs. ≥4), while high lactate dehydrogenase, neurological symptoms, and leptomeningeal metastases were associated with shorter survival. Baseline ds-GPA/molGPA>1 and neutrophil-to-lymphocyte ratio <4 were strong predictors of long-term survival to anti-PD-1-based immune checkpoint inhibitors in melanoma brain metastases patients previously naive to anti-PD-1 therapy in a real-world clinical setting treated at independent centers.
    DOI:  https://doi.org/10.1097/CJI.0000000000000385
  10. JAAD Int. 2020 Jul;1(1): 31-38
    Risk of skin cancer in patients with vitiligo in Denmark: A nationwide cohort study.
    Mads Gustaf Jørgensen, Navid Mohamadpour Toyserkani, Alexander Egeberg, Jens Ahm Sørensen.
      Background: Vitiligo is a depigmentation disorder associated with genetic loss of melanocytes and decreased melanin synthesis. The current literature is conflicting in regard to vitiligo patients' risk of cutaneous malignant melanoma and keratinocyte cancer.Objective: To investigate the risk of cutaneous malignant melanoma and keratinocyte cancer in vitiligo patients.
    Methods: We conducted a population-based study, including 2,339 subjects with a first-time vitiligo diagnosis between 1994 and 2017 and 23,293 age- and sex-matched (1:10) controls. To address surveillance bias, we included 12,380 subjects with a first-time diagnosis of lichen planus.
    Results: Age was the only significant factor for cutaneous malignant melanoma in comparison of vitiligo with controls and lichen planus (hazard ratio 1.04, 95% confidence interval [CI] 1.03-1.05; and hazard ratio 1.02, 95% CI 1.01-1.04, respectively). Similarly, age was a significant factor for keratinocyte cancer in comparison of vitiligo with controls and lichen planus (hazard ratio 1.07, 95% CI 1.06-1.07; and hazard ratio 1.06, 95% CI 1.05-1.07). Male sex was an additional factor for keratinocyte cancer in comparison of vitiligo with lichen planus (hazard ratio 1.38; 95% CI 1.09-1.75). Phototherapy did not increase the risk of receiving a diagnosis of cutaneous malignant melanoma or keratinocyte cancer in the vitiligo cohort.
    Conclusion: We observed no significant difference in cutaneous malignant melanoma or keratinocyte cancer risk among vitiligo subjects. Phototherapy use was not associated with a higher skin cancer risk in vitiligo compared with other skin diseases.
    Keywords:  CI, confidence interval; ICD-10, International Statistical Classification of Diseases and Related Health Problems, 10th Revision; ICD-8, International Classification of Diseases, Eighth Revision; basal cell; epidemiology; lichen planus; melanoma; squamous cell; vitiligo
    DOI:  https://doi.org/10.1016/j.jdin.2020.03.004
  11. JAMA Dermatol. 2021 Aug 18.
    Sentinel Lymph Node Biopsy in Cutaneous Melanoma-Where Do We Stand?
    Michael A Marchetti, Edmund K Bartlett.
      
    DOI:  https://doi.org/10.1001/jamadermatol.2021.3048
  12. Vestn Oftalmol. 2021 ;137(4): 31-37
    [The role of CXC and CC chemokines in patients with uveal melanoma].
    E B Myakoshina, I G Kulikova, N V Balatskaya, L A Katargina, S V Saakyan.
      Uveal melanoma is a malignant neoplasm with high metastatic potential; its pathogenesis is currently being studied. Chemokines play a key role not only in the inflammatory response, but also in enhancing angiogenesis, tumor invasiveness, increasing proliferative potential and metastasis.PURPOSE: To study the role of chemokines of classes CXC and CC in blood serum and tear fluid of patients with uveal melanoma.
    MATERIAL AND METHODS: The study included 118 people aged 53.7±12.2 years, among them 80 patients with uveal melanoma and 38 healthy donors. Group 1 included 32 patients with small tumors, group 2 (medium-sized tumors) - 26 patients; group 3 (large tumors) was comprised of 22 patients. Chemokines of classes CC (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES, CCL11/Eotaxin) and CXC (CXCL1/GRO-α, CXCL8/IL-8, CXCL10/IP-10, CXCL12/SDF-1α) were determined by multiplex analysis of the blood serum and tear fluid. Statistical processing: Student's t-test, Fisher criteria, and Pierson's chi-squared test (χ2), differences were considered significant at p<0.05.
    RESULTS: Significantly increased level of chemokines with pro-inflammatory (CCL5/RANTES), proliferative (CXCL10/IP-10) and pro-angiogenic (CXCL12/SDF-1α) effects was found in the blood serum of patients with small-sized uveal melanoma in comparison with healthy donors. Concentration of all studied pro-inflammatory, proliferative, and pro-angiogenic chemokines in the lacrimal fluid was found to be significantly elevated in both the affected and the paired "healthy" eyes in all 3 groups of patients, with the maximum content seen in the large tumor group.
    CONCLUSION: The obtained data indicates that early local and systemic immune imbalance can be observed in uveal melanoma, and detection of chemokines can serve as a good reason for developing targeted therapy for small uveal melanoma.
    Keywords:  chemokines in blood serum and tear fluid; uveal melanoma
    DOI:  https://doi.org/10.17116/oftalma202113704131
  13. Sci Rep. 2021 Aug 17. 11(1): 17036
    Author Correction: Estimation of the timing of BAP1 mutation in uveal melanoma progression.
    Ogul E Uner, Thonnie Rose O See, Eszter Szalai, Hans E Grossniklaus, Gustav Stålhammar.
      
    DOI:  https://doi.org/10.1038/s41598-021-96113-0
  14. Int J Med Sci. 2021 ;18(14): 3299-3308
    Inhibition of melanogenesis by Aster yomena callus pellet extract in melanoma cells and patients with skin pigmentation.
    Jae-In Lee, Jeong Hun Seo, Eun-Sil Ko, Sang-Min Cho, Jea-Ran Kang, Jong-Hoon Jeong, Yu Jeong Jeong, Cha Young Kim, Jeong-Dan Cha, Woo Sik Kim, Young-Bae Ryu.
      Plant tissue culture holds immense potential for the production of secondary metabolites with various physiological functions. We recently established a plant tissue culture system capable of producing secondary metabolites from Aster yomena. This study aimed to uncover the mechanisms underlying the potential therapeutic effects of Aster yomena callus pellet extract (AYC-P-E) on photoaging-induced skin pigmentation. Excessive melanogenesis was induced in B16F10 melanoma cells using α-melanocyte stimulating hormone (α-MSH). The effects of AYC-P-E treatment on melanin biosynthesis inducers and melanin synthesis inhibition were assessed. Based on the results, a clinical study was conducted in subjects with skin pigmentation. AYC-P-E inhibited melanogenesis in α-MSH-treated B16F10 cells, accompanied by decreased mRNA and protein expression of melanin biosynthesis inducers, including cyclic AMP response element-binding protein (CREB), tyrosinase, microphthalmia-associated transcription factor (MITF), tyrosinase related protein-1 (TRP-1), and TRP-2. This anti-melanogenic effect was mediated by mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) phosphorylation. Treatment of subjects with skin pigmentation with AYC-P-E-containing cream formulations resulted in 3.33%, 7.06%, and 8.68% improvement in the melanin levels at 2, 4, and 8 weeks, respectively. Our findings suggest that AYC-P-E inhibits excessive melanogenesis by activating MEK/ERK and AKT signaling, potentiating its cosmetic applications in hyperpigmentation treatment.
    Keywords:  Aster yomena; callus; extract; melanogenesis; metabolite; skin pigmentation
    DOI:  https://doi.org/10.7150/ijms.62530
  15. Pathology. 2021 Aug 12. pii: S0031-3025(21)00419-0. [Epub ahead of print]
    Residual melanoma in wide local excision specimens after 'complete' excision of primary cutaneous in situ and invasive melanomas.
    Louise A Jackett, Laveniya Satgunaseelan, Edward Roper, Serigne N Lo, John F Thompson, Richard A Scolyer.
      Wide local excision (WLE) to achieve adequate clearance margins is the standard initial definitive treatment for patients with biopsy-proven primary cutaneous melanoma. Residual melanoma in WLE specimens after prior complete excision-biopsy (CEB) is reported in 0-6.3% of cases. However, studies evaluating the prevalence, clinicopathological features and relevance of persistent disease in WLE specimens are limited. This study sought to determine the frequency of and clinicopathological characteristics associated with residual melanoma in WLE specimens performed after a CEB of primary cutaneous or acral melanoma (in situ or invasive) with clinically and histologically tumour-free margins, and assess its relevance. A review of the research database and pathology archives of a large Australian tertiary referral melanoma treatment centre was performed. Eligible patients were those for whom a definitive WLE was performed after CEB of a primary melanoma (in situ or invasive) with negative clinical and histological margins, between May 2013 and May 2015. All partial biopsies were excluded. Of 640 eligible patients, 510 (79.7%) had invasive melanoma and 130 (20.3%) had melanoma in situ. Residual disease was identified in 20 cases (20/640, 3.1%), of which three (15%) were melanoma in situ on CEB and 17 (85%) were invasive melanoma. On univariate analysis, the presence of residual disease in WLE specimens was associated with lentigo maligna (LM)/LM melanoma (LMM) subtype [odds ratio (OR) 10.33; 95% confidence interval (CI) 2.84-37.54; p=0.004], nodular melanoma (NM) subtype (OR 4.92; 95% CI 1.53-15.85; p=0.0076) and, for invasive tumours, higher tumour mitotic rate (mean 7.7, SD 7.51 vs 3.4, SD 4.83; OR 1.11; 95% CI 1.04-1.18; p=0.0014). Breslow thickness >4 mm was associated with a higher risk of residual disease (OR 7.30; 95% CI 1.88, 28.26; p=0.004). Cases with residual disease had primary tumours with a significantly larger diameter (median 14 mm, range 4-25) than those without residual disease (median 9 mm, range 2-60), (OR 1.07; 95% CI 1.03-1.11; p≤0.001) and were also more likely to be amelanotic (38% vs 14%), (OR 3.69; 95% CI 1.17, 11.60; p=0.026). Residual disease was associated with assessment of >3 slides of tissue (OR 6.98; 95% CI 1.54-31.62; p=0.0118) and complete blocking of the scar (OR 31.69; 95% CI 3.98-252.21; p=0.0011). Residual melanoma in WLE specimens is an infrequent occurrence. Risk factors for residual disease are LM/LMM and NM melanoma subtypes, higher mitotic rate, larger lesion diameter and amelanosis. Tumours with these features warrant more extensive pathological sampling. WLE after CEB for melanoma remains an important procedure to reduce local recurrence; however, limited pathological sampling of the WLE scar is probably appropriate for cases lacking high risk features.
    Keywords:  Diagnosis; management; melanoma; pathology; recurrence; treatment
    DOI:  https://doi.org/10.1016/j.pathol.2021.05.094
  16. Clin Cancer Res. 2021 Aug 19.
    Impact of Prior Treatment on the Efficacy of Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma.
    Samantha J Seitter, Richard M Sherry, James C Yang, Paul F Robbins, Mackenzie L Shindorf, Amy R Copeland, Christine T McGowan, Monica Epstein, Thomas E Shelton, Michelle M Langhan, Zulmarie Franco, David N Danforth, Donald E White, Steven A Rosenberg, Stephanie L Goff.
      PURPOSE: Adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes (TIL) can mediate durable responses in patients with metastatic melanoma. This retrospective analysis provides long-term follow-up and describes the effect of prior therapy on outcomes after ACT-TIL.PATIENTS AND METHODS: Patients with metastatic melanoma underwent surgical resection of a tumor for generation of TILs and were treated with a lymphodepleting preparative regimen followed by adoptive transfer of TILs and intravenous IL2. Clinical characteristics of enrolled patients and treatment characteristics of TIL infusion products over two decades of ACT were analyzed to identify predictors of objective response.
    RESULTS: Adoptive transfer of TILs mediated an objective response rate of 56% (108/192) and median melanoma-specific survival of 28.5 months in patients naïve to anti-programmed cell death-1 (PD-1) therapy compared with 24% (8/34) and 11.6 months in patients refractory to anti-PD-1 (aPD-1). Among patients with BRAF V600E/K-mutated disease, prior treatment with targeted molecular therapy was also associated with a decreased response rate (21% vs. 60%) and decreased survival (9.3 vs. 50.7 months) when compared with those patients naïve to targeted therapy. With a median potential follow-up of 89 months, 46 of 48 complete responders in the aPD-1-naïve cohort have ongoing responses after a single treatment and 10-year melanoma-specific survival of 96%.
    CONCLUSIONS: Patients previously treated with PD-1 or MAPK inhibition are significantly less likely to develop durable objective responses to ACT-TIL. While ACT-TIL is currently being investigated for treatment-refractory patients, it should also be considered as an initial treatment option for eligible patients with metastatic melanoma.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-1171
  17. Radiol Clin North Am. 2021 Sep;pii: S0033-8389(21)00068-3. [Epub ahead of print]59(5): 755-772
    Precision Nuclear Medicine: The Evolving Role of PET in Melanoma.
    Chadwick L Wright, Eric D Miller, Carlo Contreras, Michael V Knopp.
      The clinical management of melanoma patients has been rapidly evolving with the introduction of new targeted immuno-oncology (IO) therapeutics. The current diagnostic paradigms for melanoma patients begins with the histopathologic confirmation of melanoma, initial staging of disease burden with imaging and surgical approaches, treatment monitoring during systemic cytotoxic chemotherapy or IO therapeutics, restaging after completion of adjuvant systemic, surgical, and/or external radiation therapy, and the detection of recurrent malignancy/metastatic disease following therapy. New and evolving imaging approaches with positron-emission tomography (PET) imaging technologies, imaging methodologies, image reconstruction, and image analytics will likely continue to improve tumor detection, tumor characterization, and diagnostic confidence, enabling novel precision nuclear medicine practices for managing melanoma patients. This review will examine current concepts and challenges with existing PET imaging diagnostics for melanoma patients and introduce exciting new opportunities for PET in the current era of IO therapeutics.
    Keywords:  Computed tomography; Immuno-oncology; Immunotherapy; Melanoma; Positron emission tomography
    DOI:  https://doi.org/10.1016/j.rcl.2021.05.007
  18. Comb Chem High Throughput Screen. 2021 Aug 16.
    Integrated analysis of the expression, involved functions, and regulatory network of RUNX3 in melanoma.
    Yanxin Liu, Zhang Feng, Huaxia Chen.
      BACKGROUND: As a tumor suppressor or oncogenic gene, abnormal expression of RUNX family transcription factor 3 (RUNX3) has been reported in various cancers. <p> Introduction: This study aimed to investigate the role of RUNX3 in melanoma. <p> Methods: The expression level of RUNX3 in melanoma tissues was analyzed by immunohistochemistry and the Oncomine database. Based on microarray datasets GSE3189 and GSE7553, differentially expressed genes (DEGs) in melanoma samples were screened, followed by functional enrichment analysis. Gene Set Enrichment Analysis (GSEA) was performed for RUNX3. DEGs that co-expressed with RUNX3 were analyzed, and the transcription factors (TFs) of RUNX3 and its co-expressed genes were predicted. The protein-protein interactions (PPIs) for RUNX3 were analyzed utilizing the GeneMANIA database. MicroRNAs (miRNAs) that could target RUNX3 expression, were predicted. <p> Results: RUNX3 expression was significantly up-regulated in melanoma tissues. GSEA showed that RUNX3 expression was positively correlated with melanogenesis and melanoma pathways. Eleven DEGs showed significant co-expression with RUNX3 in melanoma, for example, TLE4 was negatively co-expressed with RUNX3. RUNX3 was identified as a TF that regulated the expression of both itself and its co-expressed genes. PPI analysis showed that 20 protein-encoding genes interacted with RUNX3, among which 9 genes were differentially expressed in melanoma, such as CBFB and SMAD3. These genes were significantly enriched in transcriptional regulation by RUNX3, RUNX3 regulates BCL2L11 (BIM) transcription, regulation of I-kappaB kinase/NF-kappaB signaling, and signaling by NOTCH. A total of 31 miRNAs could target RUNX3, such as miR-326, miR-330-5p, and miR-373-3p. <p> Conclusion: RUNX3 expression was up-regulated in melanoma and was implicated in the development of melanoma.
    Keywords:  Melanoma; RUNX family transcription factor 3; microRNAs
    DOI:  https://doi.org/10.2174/1386207324666210816121833
  19. Cancer Med. 2021 Aug 17.
    Cost-effectiveness of ipilimumab versus high-dose interferon as an adjuvant therapy in resected high-risk melanoma.
    Mia Salans, Patrick Travis Courtney, Anthony Yip, James D Murphy.
      BACKGROUND: Adjuvant ipilimumab was found to improve the overall survival and reduce toxicity compared to high-dose interferon (HDI) in patients with resected, high-risk melanoma. However, the cost of ipilimumab is substantially higher than HDI. This study evaluates the cost-effectiveness of ipilimumab as an adjuvant treatment in melanoma from a healthcare perspective.METHODS: We designed a Markov model simulating resected, high-risk melanoma patients receiving either ipilimumab or HDI. Transition probabilities, including risks of survival, disease progression, and toxicity, were ascertained from clinical trial data. Costs and quality of life measurements (health utilities) were extracted from the literature. Incremental cost-effectiveness ratios (ICERs), defined as incremental costs divided by incremental quality-adjusted life-years (QALYs), assessed cost-effectiveness. ICERs <$100,000/QALY were deemed cost-effective. We measured model uncertainty with one-way and probabilistic sensitivity analyses.
    RESULTS: In our base case model, ipilimumab increased costs by $107,100 and increased effectiveness by 0.43 QALY, yielding an ICER of $392,600/QALY. Our model was moderately sensitive to the costs of ipilimumab, though the cost of ipilimumab would need to decrease by 44% for ipilimumab to become cost-effective compared to HDI. The model was not sensitive to survival, toxicity, or other costs. Probabilistic sensitivity analysis showed that HDI would remain the cost-effective treatment option 96.2% of the time at a willingness-to-pay threshold of $100,000/QALY.
    CONCLUSIONS: Adjuvant ipilimumab increases the survival and decreases the toxicity compared to HDI in resected, high-risk melanoma patients, though this would not be considered cost-effective due to the high price of ipilimumab.
    Keywords:  cost-effectiveness; high-dose interferon; immunotherapy; ipilimumab; melanoma
    DOI:  https://doi.org/10.1002/cam4.4194
  20. Hua Xi Kou Qiang Yi Xue Za Zhi. 2021 Aug 01. pii: 1000-1182(2021)04-0413-06. [Epub ahead of print]39(4): 413-418
    Effect of piceatannol against malignant melanoma in vivo and in vitro.
    Bo Yu, Wei Liu, Min-Qi Hu, Xiu-Fa Tang, Chun-Jie Li, Lin Que.
      OBJECTIVES: To study the antitumor effect of piceatannol (PIC) on malignant melanoma in vitro and in vivo.METHODS: B16F10 cells were cultured in vitro and treated with gradient concentrations of PIC. Cell viability was detected with methyl thiazolyl tetrazolium (MTT) assay; matrix metalloproteinase (MMP)-2, MMP-9, vascular endothelial growth factor (VEGF), spleen tyrosine kinase (Syk), and p-Syk were detected with Western blot; migration ability was detected with wound healing assay; invasion ability was detected with Transwell assay. Syk expression was suppressed through RNA interference for the detection of the possible mechanism of PIC in melanoma. An in vivo study was established by creating B16F10-bearing mice with intraperitoneal injection of PIC.
    RESULTS: The cell viability of B16F10 decreased with increasing PIC concentration. The results of the Transwell assay showed that invasion ability decreased with increasing PIC concentration, and healing time was prolonged at increased PIC concentration in the wound healing assay. Western blot results showed that PIC mainly inhibited the phosphorylation of Syk and inhibited the expression of MMP-2, MMP-9, and VEGF. RNA interference pointed out that blocking the expression of Syk can reveal the same inhibition effect on B16F10 cells as PIC. In vivo study revealed that different concentrations of PIC cangreatly inhibit melanoma progression.
    CONCLUSIONS: PIC might block the progression of malignant melanoma by inhibiting spleen tyrosine kinase.
    Keywords:  malignant melanoma; piceatannol; spleen tyrosine kinase
    DOI:  https://doi.org/10.7518/hxkq.2021.04.006
  21. JAAD Int. 2021 Mar;2 19-21
    Cutaneous immune-related adverse events in patients with metastatic melanoma on antiprogrammed cell death protein 1 and anticytotoxic T-lymphocyte-associated protein 4 therapy: A retrospective cohort study.
    Sheida Naderi-Azad, Faisal Sickandar, Rossanna C Pezo.
      
    DOI:  https://doi.org/10.1016/j.jdin.2020.10.005
  22. Front Oncol. 2021 ;11 704543
    N6-Methyladenosine Regulators and Related LncRNAs Are Potential to be Prognostic Markers for Uveal Melanoma and Indicators of Tumor Microenvironment Remodeling.
    Zhicheng Liu, Shanshan Li, Shan Huang, Tao Wang, Zhicheng Liu.
      Uveal melanoma (UM) is one of the most common malignant intraocular tumors in adults. Few studies have investigated the effect of N6-methyladenosine (m6A) RNA methylation regulators and related long noncoding RNAs (lncRNAs) on the tumor microenvironment (TME) and survival time of patients with UM. Based on the transcriptome and clinical data from The Cancer Genome Atlas, we systematically identified m6A regulators. Then, we constructed an m6A regulators-based signature to predict the prognostic risk using univariate and LASSO Cox analyses. The signature was then validated by performing Kaplan-Meier, and receiver operating characteristic analyses. Through the correlation analysis, m6A regulators-related lncRNAs were identified, and they were divided into different clustering subtypes according to their expression. We further assessed differences in TME scores, the survival time of patients, and immune cell infiltration levels between different clustering subtypes. Finally, we screened out the common immune genes shared by m6A-related lncRNAs and determined their expression in different risk groups and clustering subtypes. For further validation, we used single-cell sequencing data from the GSE139829 dataset to explore the expression distribution of immune genes in the TME of UM. We constructed a prognostic risk signature representing an independent prognostic factor for UM using 3 m6A regulators. Patients in the low-risk group exhibited a more favorable prognosis and lower immune cell infiltration levels than patients in the high-risk group. Two subtypes (cluster 1/2) were identified based on m6A regulators-related lncRNAs. The TME scores, prognosis, and immune cell infiltration have a marked difference between cluster 1 and cluster 2. Additionally, 13 common immune genes shared by 5 lncRNAs were screened out. We found that these immune genes were differentially expressed in different risk groups and clustering subtypes and were widely distributed in 3 cell types of TME. In conclusion, our study demonstrated the important role of m6A regulators and related lncRNAs in TME remodeling. The signature developed using m6A regulators might serve as a promising parameter for the clinical prediction of UM.
    Keywords:  immune cell infiltration; long noncoding RNAs; m6A RNA methylation regulators; tumor microenvironment; uveal melanoma
    DOI:  https://doi.org/10.3389/fonc.2021.704543
  23. Clin Cancer Res. 2021 Aug 19.
    TIL in Melanoma-Similar Approaches, Different Results, Unanswered Questions.
    Mario Sznol.
      Prior treatment with anti-PD-1 and/or BRAF-targeted therapies was associated with limited activity of tumor infiltrating lymphocytes (TIL) in metastatic melanoma. Recent insights into mechanisms of action for TIL and anti-PD-1 provide the foundation for understanding differences in outcomes in different trials or populations, and a roadmap for developing improved products.See related article by Seitter et al. p. XXXX.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-2450
  24. Int J Surg Case Rep. 2021 Aug 16. pii: S2210-2612(21)00813-0. [Epub ahead of print]86 106311
    Metastatic malignant melanoma of unknown primary site to the brain: A case report.
    Alex Mremi, Gregory Goodluck, Adnan Sadiq, Jay Lodhia.
      INTRODUCTION AND IMPORTANCE: The natural history of metastatic melanoma in the absence of a known primary site has been poorly defined. The disease usually presents a significant cause of morbidity and mortality. Around 90% of melanomas have cutaneous origin, but still there are melanomas that could be found in visceral organs or lymph nodes with unknown primary site. Spontaneous regression of the primary site could be an explanation. The disease is frequently diagnosed after treatment for known extracranial metastases and has a poor outcome despite various local and systemic therapeutic approaches.CASE PRESENTATION: Herein, we present a case of a 43-year old female presented with history of headaches and enlarged a left inguinal lymph node. Notably, no cutaneous lesions could be identified by history or on physical examination. CT-scan of the brain revealed a space occupying lesion and the inguinal lymph node biopsy confirmed the diagnosis of metastatic malignant melanoma. The patient succumbed shortly after establishment of diagnosis.
    CLINICAL DISCUSSION: Most patients with brain metastases from malignant melanoma are diagnosed after treatment for known extracranial metastases and have a poor outcome despite various local and systemic therapeutic approaches.
    CONCLUSION: Metastatic melanomas of brain with unknown primary present a significant morbidity and mortality and confer a poor prognosis. Delay in diagnosis and treatment is of serious concern when it comes to improve the prognosis of patients with this disease. The optimal treatment depends on the objective situation, often surgery, radiosurgery, whole brain radiotherapy and chemotherapy can be used in combination to obtain longer remissions and optimal symptom relieve.
    Keywords:  Brain; Inguinal lymph node; Malignant melanoma; Metastasis; Unknown primary
    DOI:  https://doi.org/10.1016/j.ijscr.2021.106311
  25. Int J Ophthalmol. 2021 ;14(8): 1151-1159
    Identification and validation of tumor microenvironment-related lncRNA prognostic signature for uveal melanoma.
    Chen-Lu Liao, Nan Hu, Xing-Yu Sun, Qi Zhou, Min Tian, Yang Cao, Hong-Bin Lyu.
      AIM: To investigate the role of tumor microenvironment (TME)-related long non-coding RNA (lncRNA) in uveal melanoma (UM), probable prognostic signature and potential small molecule drugs using bioinformatics analysis.METHODS: UM expression profile data were downloaded from the Cancer Genome Atlas (TCGA) and bioinformatics methods were used to find prognostic lncRNAs related to UM immune cell infiltration. The gene expression profile data of 80 TCGA specimens were analyzed using the single sample Gene Set Enrichment Analysis (ssGSEA) method, and the immune cell infiltration of a single specimen was evaluated. Finally, the specimens were divided into high and low infiltration groups. The differential expression between the two groups was analyzed using the R package 'edgeR'. Univariate, multivariate and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analyses were performed to explore the prognostic value of TME-related lncRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses were also performed. The Connectivity Map (CMap) data set was used to screen molecular drugs that may treat UM.
    RESULTS: A total of 2393 differentially expressed genes were identified and met the criteria for the low and high immune cell infiltration groups. Univariate Cox analysis of lncRNA genes with differential expression identified 186 genes associated with prognosis. Eight prognostic markers of TME-included lncRNA genes were established as potentially independent prognostic elements. Among 269 differentially expressed lncRNAs, 69 were up-regulated and 200 were down-regulated. Univariate Cox regression analysis of the risk indicators and clinical characteristics of the 8 lncRNA gene constructs showed that age, TNM stage, tumor base diameter, and low and high risk indices had significant prognostic value. We screened the potential small-molecule drugs for UM, including W-13, AH-6809 and Imatinib.
    CONCLUSION: The prognostic markers identified in this study are reliable biomarkers of UM. This study expands our current understanding of the role of TME-related lncRNAs in UM genesis, which may lay the foundations for future treatment of this disease.
    Keywords:  bioinformatics; connectivity map; lncRNA; prognosis; tumor microenvironment; uveal melanoma
    DOI:  https://doi.org/10.18240/ijo.2021.08.03
  26. Melanoma Res. 2021 Aug 17.
    Combination of radiotherapy and targeted therapy for melanoma brain metastases: a systematic review.
    Yi Ge, Xuanlin Che, Xin Gao, Shuang Zhao, Juan Su.
      Radiotherapy is a mainstay of efficient treatment of brain metastases from solid tumors. Immunotherapy has improved the survival of metastatic cancer patients across many tumor types. However, targeted therapy is a feasible alternative for patients unable to continue immunotherapy or with poor outcomes of immunotherapy. The combination of radiotherapy and targeted therapy for the treatment of brain metastases has a strong theoretical underpinning, but data on the efficacy and safety of this combination is still limited. A systematic search of PubMed, Embase, Web of Science and the Cochrane library database was conducted. Eleven studies were included for a total of 316 patients. Median OS was about 6.2-17.8 months from radiotherapy. Weighted survival and local control at 1 and 2 years were correlated (50.1 and 17.8%, 90.7 and 14.7% at 1 and 2 year, respectively). Radiotherapy given before or concurrently to targeted therapy provided the best effect on the outcome. For patients with brain metastases from cutaneous melanoma, the addition of concurrent targeted therapy to brain radiotherapy can increase survival and provide long-term control.
    DOI:  https://doi.org/10.1097/CMR.0000000000000761
  27. Dermatol Pract Concept. 2021 Jul;11(3): e2021037
    Collision Cutaneous Neoplasms Consisting of Melanoma and Basal Cell Carcinoma.
    Maryam Aghighi, David Chercover, Maral Rahvar.
      
    Keywords:  Basal Cell carcinoma; Collision tumor; Lentigo Maligna Melanoma
    DOI:  https://doi.org/10.5826/dpc.1103a37
  28. J Cutan Med Surg. 2021 Aug 15. 12034754211038509
    Risk of Developing Melanoma With Systemic Agents Used to Treat Psoriasis: A Review of the Literature.
    Amy Semaka, Thomas G Salopek.
      BACKGROUND: Psoriasis is a chronic inflammatory skin disease induced by autoimmune-like dysregulation of the immune system. Treatment options have drastically evolved in recent years, and treatment advances that target specific cytokines and other molecules involved in dysregulation have had a profound effect in controlling the disease.OBJECTIVE: We reviewed the literature to assess the risk of developing melanoma with conventional therapies and newer agents used to treat psoriasis.
    METHODS: A comprehensive literature search using Medline (via Ovid) and Embase was conducted.
    RESULTS: The majority of studies reviewed reported insignificant results. Potential risk for melanoma was identified for only 3 out of 15 anti-psoriatic treatments analyzed: adalimumab (relative risk 1.8, 95% CI 1.06-3.00), etanercept (relative risk 2.35, 95% CI 1.46-3.77) and infliximab (Empirical Bayes Geometric Mean 7.90, 95% CI 7.13-8.60). The confidence intervals provided are from prior studies. There are not enough collective data on newer agents to make any conclusions on risk.
    CONCLUSIONS: We were unable to identify any substantial risk for developing melanoma due to the use of anti-psoriatic treatments. Until additional long-term registry data become available, it would be prudent to continue screening patients with psoriasis at baseline and periodically for melanoma when these agents are used.
    Keywords:  biologics; immunosuppressives; melanoma; psoriasis; skin cancer
    DOI:  https://doi.org/10.1177/12034754211038509
  29. PLoS One. 2021 ;16(8): e0256238
    The calcium-binding protein S100B reduces IL6 production in malignant melanoma via inhibition of RSK cellular signaling.
    Milad J Alasady, Alexander R Terry, Adam D Pierce, Michael C Cavalier, Catherine S Blaha, Kaylin A Adipietro, Paul T Wilder, David J Weber, Nissim Hay.
      S100B is frequently elevated in malignant melanoma. A regulatory mechanism was uncovered here in which elevated S100B lowers mRNA and secreted protein levels of interleukin-6 (IL6) and inhibits an autocrine loop whereby IL6 activates STAT3 signaling. Our results showed that S100B affects IL6 expression transcriptionally. S100B was shown to form a calcium-dependent protein complex with the p90 ribosomal S6 kinase (RSK), which in turn sequesters RSK into the cytoplasm. Consistently, S100B inhibition was found to restore phosphorylation of a nuclear located RSK substrate, CREB, which is a potent transcription factor for IL6 expression. Thus, elevated S100B reduces IL6-STAT3 signaling via RSK signaling pathway in malignant melanoma. Indeed, the elevated S100B levels in malignant melanoma cell lines correspond to low levels of IL6 and p-STAT3.
    DOI:  https://doi.org/10.1371/journal.pone.0256238
  30. Dermatol Pract Concept. 2021 Jul;11(3): e2021058
    The Bork-Baykal Phenomenon in Congenital Melanocytic Nevus.
    Tugba Kevser Uzuncakmak, Defne Özkoca, Server Serdaroğlu.
      
    Keywords:  Baykal Phenomenon; congenital nevus; melanocytic nevus
    DOI:  https://doi.org/10.5826/dpc.1103a58
  31. Exp Dermatol. 2021 Aug 16.
    Is Fas-mediated apoptosis of melanocytes indispensable in vitiligo?
    Julia Schmitz, Markus Böhm.
      
    DOI:  https://doi.org/10.1111/exd.14448
  32. Chem Biodivers. 2021 Aug 18.
    Chemical composition of Miscanthus sinensis var. purpurascens flower absolute and its beneficial effects on skin wound healing and melanogenesis-related cell activities.
    Hye Min Kang, Kyung Jong Won, Do Yoon Kim, Su Yeon Lee, Mi Jung Kim, Yu Rim Won, Bokyung Kim, Hwan Myung Lee.
      Miscanthus sinensis var. purpurascens (MSP, flame grass) is found in Korea, Japan, and China, and its biological activities include anti-cancer, detoxifying, vasodilatory, antipyretic, and diuretic effects. However, no study has investigated the effects of MSP on skin-related biological activities. In this study, we explored the effects of the absolute extracted from the MSP flowers (MSPFAb) on skin wound healing- and whitening-related responses in keratinocytes or melanocytes. MSPFAb contained 6 components and induced the proliferation, migration, and syntheses of type I and IV collagens in keratinocytes. MSPFAb also increased the phosphorylations of serine/threonine-specific protein kinase, p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase1/2 in keratinocytes. In addition, treatment with MSPFAb decreased serum-induced melanoma cell proliferation and inhibited tyrosinase activity and melanin contents in α-MSH-stimulated melanoma cells. Taken together, this study indicates MSPFAb may promote wound healing- and whitening-associated activities in dermal cells, and suggests that it has potential use as a wound healing and skin whitening agent.
    Keywords:  Absolute; Dermal cells; Melanin biosynthesis; Miscanthus sinensis var. purpurascens; Wound healing
    DOI:  https://doi.org/10.1002/cbdv.202100383
  33. In Vivo. 2021 Sep-Oct;35(5):35(5): 2589-2597
    Scoparone Induces Expression of Pluripotency Transcription Factors SOX2 and NANOG in Dermal Papilla Cells.
    Nattha Suwanprakorn, Pithi Chanvorachote, Thitiporn Tongyen, Boonchoo Sritularak, Pichit Suvanprakorn.
      BACKGROUND/AIM: Dermal papilla cells (DPCs) regulate hair follicle development. We aimed to investigate the effect of scoparone from Dendrobium densiflorum on DPCs in the induction of stem cell properties and pluripotency-related proteins.MATERIALS AND METHODS: DPC viability was evaluated by the MTT assay. Apoptosis or necrosis of DPCs was determined by Hoecsht33342/PI nuclear staining analysis. Expression of OCT4, NANOG and SOX2 genes was determined using Real-Time Polymerase Chain Reaction (PCR). Immunocytochemistry and western blot analysis were performed to determine pluripotency related proteins.
    RESULTS: Scoparone increased the expression of pluripotency related transcription factors SOX2 and NANOG, while it had minimal effects on OCT4 levels. Scoparone exerted its stemness-enhancing activity through the up-regulation of Akt-dependent inhibition of GSK3β, resulting in increased cellular levels of β-catenin.
    CONCLUSION: Our results show a potential novel activity and mechanism of action of scoparone on human DPCs that could facilitate the development of hair enrichment approaches.
    Keywords:  NANOG; SOX2; Scoparone; dermal papilla; pluripotency; stemness
    DOI:  https://doi.org/10.21873/invivo.12541
  34. Dermatol Pract Concept. 2021 Jul;11(3): e2021028
    Congenital Melanocytic Nevus Regression Lacking the Halo Phenomenon: The Influence of the Body Site.
    Maristela Garcia Bassotto de Andrade, Giuseppe Argenziano, Vincenzo Piccolo, Eugenia Veronica Di Brizzi, Elvira Moscarella.
      
    Keywords:  Congenital melanocytic nevus; children; dermoscopy; involution of nevus; pediatric dermatology; spontaneous regression
    DOI:  https://doi.org/10.5826/dpc.1103a28
  35. Postepy Dermatol Alergol. 2021 Feb;38(2): 156-158
    Is vitiligo associated with systemic aquaporin-3 deficiency?
    Laxmisha Chandrashekar, Medha Rajappa, Kalai Selvi Rajendiran, Malathi Munisamy.
      Introduction: Recent studies on pathomechanisms of vitiligo have focused on the abnormality of keratinocytes that affect the melanocytes. Aquaporin-3 (AQP3) was implicated as a mechanism for keratinocyte apoptosis owing to the relationship between the PI3K/AKT pathway and the E-cadherin-catenin complex.Aim: Based on this evidence, we undertook a cross-sectional study to assess the skin and blood AQP-3 levels in patients with non-segmental vitiligo in comparison to controls and to correlate these levels with malondialdehyde (MDA) levels and total antioxidant status (TAS) in the skin and blood of patients with non-segmental vitiligo and also with their disease activity.
    Material and methods: Thirty-six patients with non-segmental vitiligo and 36 controls were included in this study. AQP3, TAS and MDA levels were assayed both in skin as well as in circulation.
    Results: We observed that skin and plasma aquaporin and TAS were lowered and MDA levels were increased in patients with non-segmental vitiligo as compared to controls. There was a significant negative correlation of skin and plasma aquaporin levels with disease activity. We also observed the local and systemic AQP3 deficiency to correlate with the local and systemic oxidative stress in vitiligo.
    Conclusions: Our results demonstrate a systemic and local AQP3 deficiency in vitiligo correlating with the disease severity and oxidative stress which might have therapeutic implications.
    Keywords:  aquaporin-3; oxidative stress; vitiligo
    DOI:  https://doi.org/10.5114/ada.2021.104291
  36. Dermatol Ther. 2021 Aug 20. e15103
    Tranexamic acid versus fractional carbon dioxide laser in post-acne hyperpigmentation.
    Shereen Osama Tawfic, Rania Abel Hay, Hadeel Salim, Maha Fathy Elmasry.
      Post-acne hyperpigmentation is a common undesirable sequela of acne vulgaris that causes distress for many patients. This study's objective was to compare the efficacy of both low-power/low-density fractional carbon-dioxide (CO2) laser and tranexamic acid (TXA) microinjection on post-acne hyperpigmentation. Twenty-five post-acne hyperpigmentation patients (resistant to regular treatment for more than six months) were enrolled in this randomized split-face study. One side of the face was randomly assigned to low-power fractional CO2 laser every four weeks and the other side was assigned to TXA intradermal-microinjection every two weeks for three months. Efficacy was evaluated using digital photography, dermoscopy, post-acne hyperpigmentation index (PAHPI), melanin index (MI), and erythema index (EI) at baseline and four weeks after the last session. Both fractional CO2 laser and TXA microinjection treatment sides showed a significant reduction in the PAHPI and MI (P < 0.001). There was statistically significant difference with better percentage of improvement regarding total dermoscopic score on the fractional CO2 laser side than the TXA microinjections side (P < 0.009). Both fractional CO2 laser and TXA microinjection are effective and safe treatment options for post-acne hyperpigmentation with potential superiority of fractional CO2 laser. We also believe that dermoscopy could be helpful tool for assessment of pigmentation depth in patients on treatment by analyzing the color pattern. ClinicalTrials.govID NCT03765021. This article is protected by copyright. All rights reserved.
    Keywords:  Dermoscopy; Fractional CO2 laser; Post-acne hyperpigmentation; Tranexamic acid (TXA)
    DOI:  https://doi.org/10.1111/dth.15103
  37. J Drugs Dermatol. 2021 Aug 01. 20(8): 865-867
    Clinical Evidence of Cell-Targeted Topical Therapy for Treating Skin Dyspigmentation.
    Zoe Diana Draelos, Frederick W Woodin.
      BACKGROUND: New development of cell-targeted therapies to enable site-specific skin tissue drug delivery may reduce off-target effects, decrease unwanted toxicities, and enhance drug efficacy. These efforts have led to several targeting strategies that modulate active product delivery to include small molecule-, nucleic acid-, peptide-, antibody-, and cell-based strategies. Tissue specific cell-targeting strategies such as these may be useful in cosmetic dermatologic applications.OBJECTIVE: The aim of this 16-week clinical trial of a skin brightening composition containing melanocyte cell-targeted biodelivery was to assess its effectiveness in restoring the skin complexion evenness by modulating melanocyte activity in a cohort of 50 Fitzpatrick type I&ndash;VI subjects with moderate to severe dyspigmentation.
    RESULTS: Data from expert grading, skin surface colorimetry, and subject self-assessments reflected significant improvement in facial skin tone as early as 2 weeks after treatment initiation, with continual improvement through week 16. The most dramatic pigmentation improvement, based on investigator assessments, was a statistically significant improvement in skin brightness at week 2 that progressed to week 8 with significant improvement in skin evenness and brightness. By weeks 12 and 16, progressive levels of significant improvement in skin evenness and brightening became apparent. Colorimetry demonstrated progressive improvement in skin dyspigmentation starting at 2 weeks and continuing to week 16. Subject self-assessment data supported similar improvements in skin dyspigmentation.
    CONCLUSION: These results demonstrate the ability of a cell-targeted topical therapy to achieve improvements in skin pigmentation through site-specific suppression of melanocyte activity. J Drugs Dermatol. 2021;20(8):865-867. oi:10.36849/JDD.6037 THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL fTEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.
    DOI:  https://doi.org/10.36849/JDD.6037
  38. J Am Acad Dermatol. 2021 Aug 11. pii: S0190-9622(21)02293-3. [Epub ahead of print]
    Polypodium leucotomos as an adjunct to the treatment of vitiligo.
    Tamara Searle, Firas Al-Niaimi, Faisal R Ali.
      
    Keywords:  Diet; NB-UVB; PUVA; Polypodium leucotomos; Vitiligo
    DOI:  https://doi.org/10.1016/j.jaad.2021.05.073
  39. Aging (Albany NY). 2021 Aug 17. 13(undefined):
    TGF-β2 and collagen play pivotal roles in the spheroid formation and anti-aging of human dermal papilla cells.
    Hyunju Kim, Nahyun Choi, Doo Yeong Kim, So Yoon Kim, Seung Yong Song, Jong-Hyuk Sung.
      Dermal papilla cells (DPCs) tend to aggregate both in vitro and in vivo, which increases the hair inductivity of DPCs. However, the underlying mechanism of spheroid formation is unknown. We investigated whether collagen expression in human DPCs (hDPCs) is involved in the spheroid formation and hair inductivity of hDPCs and further examined the underlying molecular mechanism of collagen upregulation. The expression of diverse collagens, such as COL13A1 and COL15A1, was upregulated in three dimensional (3D)-cultured or intact DPCs, compared to 2D-cultured hDPCs. This collagen expression was a downregulated in aged hair follicle, and aged DPCs were difficult to aggregate. Blocking of COL13A1 and COL15A1 by small interfering RNA reduced aggregation, while induced senescence of hDPCs in vitro. Further, transforming growth factor-β2 (TGF-β2) expression decreases with aging, and is involved in regulating the expression of COL13A1 and COL15A1. Addition of recombinant TGF-β2 delayed cellular senescence, and recovered spheroid formation in aged hDPCs by upregulating collagen levels. On the contrary, knock-out of TGF-β2 induced the aging of DPCs, and inhibited spheroid formation. These results suggested that COL13A1 and COL15A1 expression is downregulated with aging in DPCs, and upregulation of collagen by TGF-β2 induces the spheroid formation of DPCs. Therefore, TGF-β2 supplement in DPC culture medium could enhance the maintenance and hair inductivity of DPCs.
    Keywords:  TGF-beta2; aggregation; anti-aging; collagen; human dermal papilla cells
    DOI:  https://doi.org/10.18632/aging.203419
  40. Cancer Cell. 2021 Aug 18. pii: S1535-6108(21)00402-5. [Epub ahead of print]
    Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy.
    Yujue Wang, Sixue Liu, Zhentao Yang, Alain P Algazi, Shirley H Lomeli, Yan Wang, Megan Othus, Aayoung Hong, Xiaoyan Wang, Chris E Randolph, Alexis M Jones, Marcus W Bosenberg, Stephanie D Byrum, Alan J Tackett, Henry Lopez, Clayton Yates, David B Solit, Antoni Ribas, Marco Piva, Gatien Moriceau, Roger S Lo.
      Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.
    Keywords:  BRAF/NRAS/KRAS/NF1; MAPK/BRAF/MEK inhibitor resistance; anti-CTLA-4; anti-PD-1/L1; brain metastasis; colorectal carcinoma; melanoma; pancreatic ductal adenocarcinoma; sequential-combination therapy; tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2021.07.023
  41. Dermatol Surg. 2021 Aug 18.
    Immunological Overkilling Followed by Cellular Replenishment: A Novel 2-Step Treatment for Halo Congenital Melanocytic Nevus.
    Vishal Gupta, Rashi Pangti, Somesh Gupta.
      
    DOI:  https://doi.org/10.1097/DSS.0000000000003156
  42. Biochem Biophys Res Commun. 2021 Aug 12. pii: S0006-291X(21)01174-8. [Epub ahead of print]573 151-157
    Human embryonic stem cell-derived melanocytes exhibit limited immunogenicity.
    Jinqi Wang, Xuanhao Zeng, Yating Liu, Weiling Lian, Haozhen Lv, Kelu Wei, Qi Zhang, Jinhua Xu.
      Although surgical interventions have become optional for refractory vitiligo, grafting related injuries is inevitable. Embryonic stem cell (ESC) derivatives can be used in transplantation to address this issue, but the immune rejection due to allogeneic transplantation is of great concern. To investigate the immunogenicity of ESC derived melanocytes (ES-MC), we established a co-culture system of ES-MC and allogeneic PBMC. The results showed that ES-MC were similar to human primary melanocytes, with low expression of immune related molecules, and limited capability of stimulating allogeneic lymphocytes in vitro. Taken together, our findings confirm that ES-MC are of limited immunogenicity, providing new insights into the application of ES-MC in the regenerative medicine such as treating vitiligo.
    Keywords:  Embryonic stem cells; Immunogenicity; Melanocyte; Regenerative medicine; Vitiligo
    DOI:  https://doi.org/10.1016/j.bbrc.2021.07.103
  43. J Cosmet Laser Ther. 2021 Aug 18. 1-7
    Evaluation of the of the efficacy of Fractional Erbium-Doped Yttrium Aluminum Garnet Laser-Assisted Drug Delivery of Kojic Acid in the Treatment of Melasma; A split face, comparative clinical study.
    Muhsin A Al-Dhalimi, Raya Hamid Yasser.
      Melasma is a common, difficult to treat hyperpigmentary disorder. Recently, ablative fractional lasers were utilized to enhance topical agents delivery to treat different skin conditions. This work was designed to evaluate the efficacy of fractional Er:YAG laser in enhancing the effect of topical kojic acid in patients with facial melasma. The patients were randomly treated in a split-face mode, by simple randomization, either with kojic acid alone on one side or combined with fractional Er:YAG laser on the other side. Twenty five patients completed six laser sessions at 2 week interval. The severity of melasma was assessed before and after treatment in addition to 3 months follow up after the last treatment session. The response to the treatment was evaluated by Melasma Area and Severity Index Score, physician global assessment of photographs and patient satisfaction. The side treated with fractional Er:YAG laser and kojic acid cream was found to have a statistically significant better improvement than the side treated with kojic acid alone. The patients were reported mild tingling sensation and mild erythema on both sides. Using combination of fractional Er:YAG laser and topical kojic acid was effective in the treatment of melasma.
    Keywords:  Laser treatment; kojic acid; melasma
    DOI:  https://doi.org/10.1080/14764172.2021.1964536
  44. Oncologist. 2021 Aug 18.
    Knowledge about risks, benefits, and curative potential of immunotherapy among patients with advanced cancer.
    Laura A Petrillo, Ashley Z Zhou, Ryan Sullivan, Angelo Volandes, Joseph A Greer, Jennifer S Temel, Areej El-Jawahri.
      BACKGROUND: Immunotherapy is first-line treatment for melanoma and lung cancer and brings new risks of immune-related adverse events. We aimed to describe patients' knowledge about risks, benefits and goals of immunotherapy.MATERIALS AND METHODS: Cross-sectional study of patients with advanced melanoma or non-small cell lung cancer using a 9-item knowledge survey and questions from the Perceptions of Prognosis and Treatment Questionnaire.
    RESULTS: We surveyed 105 participants (57 with melanoma, 48 with lung cancer) with median age 69 years (range 36-89). Participants' responses revealed knowledge deficits about immunotherapy mechanism of action and lack of awareness about the timing and severity of side effects. One third (34%; 36/105) of participants reported that the primary goal of their treatment is to cure their cancer.
    CONCLUSION: Given the widespread use of immunotherapy, patients would benefit from educational tools so that they know what to expect regarding side effects and prognosis.
    Keywords:  Immunotherapy; carcinoma; melanoma; non-small cell lung; prognosis
    DOI:  https://doi.org/10.1002/onco.13945
  45. J Adv Vet Anim Res. 2021 Jun;8(2): 266-273
    Specific mutations in the genes of MC1R and TYR have an important influence on the determination of pheomelanin pigmentation in Korean native chickens.
    In Sik Nam, Min Gee Oh, Myoung Soo Nam, Woan Sub Kim.
      Objective: The TYR (Tyrosinase) and MC1R (Melanocortin 1 receptor) genes are recognized as important genes involved in plumage pigmentation in Korean native chickens. Specifically, most color patterns in chicken result from differential expression of the TYR gene. In this study, the co-segregation of the pigmentation and sequence of the TYR and MC1R genes was investigated through intercrosses between red (R1q1), red with black and black plumage color types of native Korean chickens.Materials and Methods: Using DNA, RNA, and tissue by plumage color of each Korean native chickens, the role of major genes in pigmentation of pheomelanin was evaluated. Reverse transcription polymerase chain reaction, sequencing, western blot, and immunohistochemical were performed to determine the effect of TYR and MC1R genes on plumage pigmentation in Korean native chickens.
    Results: The KCO line (Korean chicken Ogol: Black-line) with an EEC _ genotype exhibited black feathers, whereas red and red mixed with black chicken with EeC genotype exhibited white feathers. There were notable differences between the base sequences of MC1R and TYR in three Korean chicken breeds, with the highest variation in TYR. Perhaps this is the key characteristics of Korean chicken. Further, we analyzed the expression patterns of MC1R and TYR genes in each type of Korea native chicken and observed that TYR expression was high in feather follicle (R1q2) of KCO tissue. However, native red (Korean chicken red) and native red with black (Korean chicken red dark) chickens have increased TYR expression in the tissue. However, the expression of MC1R was much different from that of TYR.
    Conclusion: In this study, our results suggest that the differences in position and TYR expression levels exert more influence on plumage pigmentation in native Korean chicken breeds than changes in MC1R expression levels.
    Keywords:  MC1R; TYR; chicken; melanin; plumage pigmentation
    DOI:  https://doi.org/10.5455/javar.2021.h511
  46. J Cosmet Dermatol. 2021 Aug 20.
    Repigmentation of nipple-areola complex after ReCell® treatment on breast vitiligo.
    Nanze Yu, Runzhu Liu, Panxi Yu, Ruijia Dong, Cheng Chen, Ang Zeng, Fei Long, Zenan Xia, Ping Ma, Yong Tao, Zhifei Liu.
      BACKGROUND: Nipple-areola complex is a naturally hyperpigmented skin area which can be involved in vitiligo. But limited study focused on the treatment of nipple-areola complex vitiligo, and few methods were proven to be effective. In this study, we aimed to explore the feasibility and efficacy of ReCell® on vitiligo in the nipple-areola complex area.METHODS: Medical records of patients with vitiligo involving nipple-areola complex and underwent ReCell® treatment from October 2016 to April 2020 were retrospectively reviewed. The repigmentation rate of the nipple-areola complex and other breast area were calculated under the Wood's light at each follow-up. The grade of repigmentation and patient-reported satisfaction rate were also evaluated to prove the effect of ReCell® on vitiligo of breast and especially in the nipple-areola complex area.
    RESULTS: A total of 18 patients were included in this study. No surgical complications were reported. The mean postoperative repigmentation rate in the nipple-areola complex area (3rd-month, 78.7 ± 5.8%; 6th-month, 87.6 ± 5.1%; and 12th-month, 96.1 ± 3.5%) was significantly higher than that in the other breast treatment area (3rd-month, 70.4 ± 6.9%; 6th-month, 84.2 ± 5.7%, and 12th-month, 93.2 ± 3.6%). All patients showed good or excellent grades at the last follow-up, and 94.4% of them considered the overall treatment results satisfactory.
    CONCLUSIONS: ReCell® is a feasible and efficient treatment strategy in the nipple-areola complex vitiligo.
    Keywords:  ReCell®; nipple-areola complex; repigmentation; vitiligo
    DOI:  https://doi.org/10.1111/jocd.14399
  47. Case Rep Dermatol. 2021 May-Aug;13(2):13(2): 372-378
    Psoriasis, Vitiligo, and Biologic Therapy: Case Report and Narrative Review.
    Martina Burlando, Andrea Muracchioli, Emanuele Cozzani, Aurora Parodi.
      Psoriasis and vitiligo are 2 multifactorial immune-mediated diseases, partially sharing pathogenetic underpinnings. Their coexistence in the same patient, although uncommon, is documented in the literature. Further, several cases of vitiligo induced by biological drugs in psoriatic patients are reported. However, improvements in psoriasis and pre-existing vitiligo after the introduction of biological therapy are also described. To date, anti-TNF-alpha is the most cited group of biological drugs that induce new-onset vitiligo or progression of pre-existence vitiligo in psoriatic patients. Even anti-IL-12/23 class would seem to induce vitiligo (as in our case) or even worse it. Anti-IL-17 drugs induce a progression of pre-existing vitiligo while, to date, no cases are reported in literature considering anti-IL-23 class.
    Keywords:  Biologic therapy; Narrative review; Psoriasis; Vitiligo
    DOI:  https://doi.org/10.1159/000514198
  48. Front Cell Dev Biol. 2021 ;9 590333
    Human iPS Cell-Derived Cell Aggregates Exhibited Dermal Papilla Cell Properties in in vitro Three-Dimensional Assemblage Mimicking Hair Follicle Structures.
    Masahiro Fukuyama, Aki Tsukashima, Momoko Kimishima, Yoshimi Yamazaki, Hideyuki Okano, Manabu Ohyama.
      Current approaches for human hair follicle (HF) regeneration mostly adopt cell-autonomous tissue reassembly in a permissive murine intracorporeal environment. This, together with the limitation in human-derived trichogenic starting materials, potentially hinders the bioengineering of human HF structures, especially for the drug discovery and treatment of hair loss disorders. In this study, we attempted to reproduce the anatomical relationship between an epithelial main body and the dermal papilla (DP) within HF in vitro by three-dimensionally assembling columnarly molded human keratinocytes (KCs) and the aggregates of DP cells and evaluated how HF characteristics were reproduced in the constructs. The replaceability of human-induced pluripotent stem cell (hiPSC)-derived DP substitutes was assessed using the aforementioned reconstruction assay. Human DP cell aggregates were embedded into Matrigel as a cluster. Subsequently, highly condensed human KCs were cylindrically injected onto DP spheroids. After 2-week culture, the structures visually mimicking HFs were obtained. KC-DP constructs partially reproduced HF microanatomy and demonstrated differential keratin (KRT) expression pattern in HFs: KRT14 in the outermost part and KRT13, KRT17, and KRT40, respectively, in the inner portion of the main body. KC-DP constructs tended to upregulate HF-related genes, KRT25, KRT33A, KRT82, WNT5A, and LEF1. Next, DP substitutes were prepared by exposing hiPSC-derived mesenchymal cells to retinoic acid and subsequently to WNT, BMP, and FGF signal activators, followed by cell aggregation. The resultant hiPSC-derived DP substitutes (iDPs) were combined with KCs in the invented assay. KC-iDP constructs morphologically resemble KC-DP constructs and analogously mimicked KRT expression pattern in HF. iDP in the constructs expressed DP-related markers, such as vimentin and versican. Intriguingly, KC-iDP constructs more intensely expressed KRT33A, KRT82, and LEF1, which were stepwisely upregulated by the addition of WNT ligand and the mixture of WNT, SHH, and EDA signaling activators, supporting the idea that iDP exhibited biological properties analogous to DP cell aggregates in the constructs in vitro. These preliminary findings suggested the possibility of regenerating DP equivalents with in vitro hair-inductive capacity using hiPSC-derived cell composites, which potentially reduce the necessity of human tissue-derived trichogenic cell subset and eventually allow xeno-free bioengineering of human HFs.
    Keywords:  WNT signaling; dermal papilla; epithelial–mesenchymal interactions; hair follicle; human induced pluripotent stem cells; regeneration
    DOI:  https://doi.org/10.3389/fcell.2021.590333
  49. JAAD Int. 2021 Mar;2 37-39
    A systematic review of vitiligo onset and exacerbation in patients receiving biologic therapy.
    Muskaan Sachdeva, Asfandyar Mufti, Nadia Kashetsky, Jorge R Georgakopoulos, Sheida Naderi-Azad, Jennifer Salsberg, Jensen Yeung.
      
    DOI:  https://doi.org/10.1016/j.jdin.2020.10.007
  50. Int J Dermatol. 2021 Aug 19.
    Skin of color in dermatology: analysis of representation in dermatologic journals.
    Kelsey B Nusbaum, Stephanie Adame, Desmond Shipp, John C Trinidad.
      
    DOI:  https://doi.org/10.1111/ijd.15828
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