bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021–09–26
67 papers selected by
Farah Jaber-Hijazi, University of the West of Scotland
  1. The mucin protein MUCL1 regulates melanogenesis and melanoma genes in a manner dependent on threonine content.
  2. SOX10 Knockdown Inhibits Melanoma Cell Proliferation via Notch Signaling Pathway.
  3. Melanoma and hypertension, is there an association? A U.S. population based study.
  4. L-Theanine inhibits melanoma cell growth and migration via regulating expression of the clock gene BMAL1.
  5. The Status of Adjuvant and Neoadjuvant Melanoma Therapy, New Developments and Upcoming Challenges.
  6. Design cytotoxicity: The effect of silver nanoparticles stabilized by selected antioxidants on melanoma cells.
  7. Inhibitory Effect of Dihydroartemisinin on the Proliferation and Migration of Melanoma Cells and Experimental Lung Metastasis From Melanoma in Mice.
  8. Biological effects of microRNA-320a/ STAT3 on cutaneous melanoma cells.
  9. Hinokitiol-induced decreases of tyrosinase and microphthalmia-associated transcription factor are mediated by the endoplasmic reticulum-associated degradation pathway in human melanoma cells.
  10. The Utility of Indocyanine Green Dye Fluorescence Lymphography and Angiography During Wide Excision of Cutaneous Melanoma.
  11. BRAF mutation correlates with worse local-regional control following radiation therapy in patients with stage III melanoma.
  12. The plasma exosomal miR-1180-3p serves as a novel potential diagnostic marker for cutaneous melanoma.
  13. Impact of the changes in the completion lymph node dissection criteria and approval of adjuvant therapies on the real-world outcomes of Japanese stage III melanoma patients.
  14. Tumor reactivity of CD8+ T cells favors acquisition of dysfunctional states in human melanoma.
  15. Malignant carcinoma and skin melanoma neoplasms concomitantly in the thyroid.
  16. Photodynamic Therapy of Melanoma B16 with Chlorin E6 Conjugated with a PSMA-Ligand.
  17. Descriptive epidemiology of cutaneous melanoma - A treasure for generating hypotheses.
  18. TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors.
  19. Changing epidemiology and age-specific incidence of cutaneous malignant melanoma in England: An analysis of the national cancer registration data by age, gender and anatomical site, 1981-2018.
  20. HSP70iQ435A to subdue autoimmunity and support anti-tumor responses.
  21. Comparative genomic characterization of melanoma of known and unknown primary.
  22. Comparison of Survival Outcomes With/Without Adjuvant Radiation Therapy in Desmoplastic Melanoma.
  23. Adjuvant Therapy for Stage III Melanoma Without Immediate Completion Lymph Node Dissection.
  24. Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease.
  25. Improving Dermal Delivery of Rose Bengal by Deformable Lipid Nanovesicles for Topical Treatment of Melanoma.
  26. Ortho- and Ectopic Zebrafish Xeno-Engraftment of Ocular Melanoma to Recapitulate Primary Tumor and Experimental Metastasis Development.
  27. Repigmentation of vitiligo-associated eyelash leukotrichia with topical tofacitinib.
  28. Survival of stage IV melanoma in Belgium and the Netherlands.
  29. Prognostic significance of platelet lymphocyte ratio in patients with melanoma: A meta-analysis.
  30. Paired comparisons of mutational profiles before and after brachytherapy in asian uveal melanoma patients.
  31. Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease.
  32. lncRNA TINCR attenuates the proliferation and invasion, and enhances the apoptosis of cutaneous malignant melanoma cells by regulating the miR‑424‑5p/LATS1 axis.
  33. The critical role of ROS in Ermanin-induced melanogenesis.
  34. UCHL3 plays an important role in the occurrence and development of melanoma.
  35. Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma.
  36. [Anti-PD-1 monoclonal antibody combined with HAIC in the treatment of malignant melanoma with liver metastasis: a case report].
  37. Multiparametric MRI of early tumor response to immune checkpoint blockade in metastatic melanoma.
  38. FDG PET biomarkers for prediction of survival in metastatic melanoma prior to anti-PD1 immunotherapy.
  39. Ginsenoside Rk1 protects human melanocytes from H2O2‑induced oxidative injury via regulation of the PI3K/AKT/Nrf2/HO‑1 pathway.
  40. Evaluation of a community education tool for detection of nail melanoma by nail salon technicians.
  41. Intragenic NF1 deletions in sinonasal mucosal malignant melanoma.
  42. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma.
  43. A Cloud Approach for Melanoma Detection based on Deep Learning Networks.
  44. Clinical Relevance of Serum Kyn/Trp Ratio and Basal and IFNγ-Upregulated IDO1 Expression in Peripheral Monocytes in Early Stage Melanoma.
  45. Polydopamine-based nanoplatform for photothermal ablation with long-term immune activation against melanoma and its recurrence.
  46. Metabolomic signature of amino acids in plasma of patients with non-segmental Vitiligo.
  47. Safety and Efficacy of High-Dose Fractional Erbium: Yttrium Aluminium Garnet Laser in Stable Vitiligo.
  48. Implementation of artificial intelligence algorithms for melanoma screening in a primary care setting.
  49. Magnetic lipid nanovehicles synergize the controlled thermal release of chemotherapeutics with magnetic ablation while enabling non-invasive monitoring by MRI for melanoma theranostics.
  50. Multiple oral erosions and ulcers in a patient with malignant melanoma.
  51. Tissue expression of glutathione S transferase isoenzymes in vitiligo.
  52. Adjuvant treatment in patients with melanoma: The planning of scanning.
  53. Vitiligo and pregnancy: How do each affect the other?
  54. Vulvar vitiligo and lichen sclerosus in children: A clinical challenge.
  55. Low-level laser treatment promotes skin wound healing by activating hair follicle stem cells in female mice.
  56. Clinico-epidemiological profile and long term follow up in Melasma.
  57. Outcomes of skin cancers in pediatric solid organ transplant patients: A systematic review.
  58. Ability of the Putative Decomposition Products of 2,3-dioxetanes of Indoles to Photosensitize Cyclobutane Pyrimidine Dimer (CPD) Formation and its Implications for the "Dark" (Chemisensitized) Pathway to CPDs in Melanocytes.
  59. Psychosocial Effects of Vitiligo: A Systematic Literature Review.
  60. Seq Your Destiny: Neural Crest Fate Determination in the Genomic Era.
  61. Molecular and cellular characterization of pyoderma gangrenosum: Implications for the use of gene expression.
  62. COVID vaccine-induced lichen planus on areas previously affected by vitiligo.
  63. Factors affecting gene expression associated with the skin color of black-bone chicken in Thailand.
  64. Clinical Findings of Melanoma-Associated Retinopathy with anti-TRPM1 Antibody.
  65. Melanosome Motility in Fish Retinal Pigment Epithelial (RPE) Cells.
  66. Locally advanced anorectal malignant melanoma in septuagenarian patient treated by laparoscopic abdominoperineal resection: A case report.
  67. Distinct genetic architectures underlie divergent thorax, leg, and wing pigmentation between Drosophila elegans and D. gunungcola.
  1. Br J Dermatol. 2021 Sep 21.
    The mucin protein MUCL1 regulates melanogenesis and melanoma genes in a manner dependent on threonine content.
    J Kim, H Choi.
       BACKGROUND: The regulation of melanogenesis has been investigated as a long-held aim for pharmaceutical manipulations with denotations for malignancy of melanoma. Mucins have protective function in epithelial organs however, the most outer organ, skin, the role of mucins has not studied enough.
    OBJECTIVES: Our initial hypothesis developed from the identification of correlations between pigmentation and expressions of skin mucins, particularly those exists in skin tissue. We try to investigate the action of mucins in human melanocytic cells.
    METHODS: The expression of mucin proteins in human skin was investigated using microarray data from Human Protein Atlas consortium and genome-based tissue expression consortium database. Mucin expression was measured at RNA and protein level in melanoma cells. Findings were further validated and confirmed by analysis of independent experiments.
    RESULTS: We found out that the several mucin proteins showed expressions in human skin cells and among these, mucin-like protein 1 (MUCL1) showed highest expression and also clear negative correlation with melanogenesis in epidermal melanocytes. We confirmed the correlations between melanogenesis and MUCL1 by revealing negative correlations in melanocytes with different melanin production, resulting from increased composition of threonine, mucin-conforming amino acid, and increased autophagy-related forkhead-box O signaling. Furthermore, threonine itself affects melanogenesis and metastatic activity in melanoma cells.
    CONCLUSIONS: We identified a significant association between MUCL1/Threonine with melanogenesis and metastasis-related genes in melanoma cells. Our results define a novel mechanism of mucin regulation, suggesting a diagnostic role and preventive actions of MUCL1 in cutaneous melanoma.
    DOI:  https://doi.org/10.1111/bjd.20761
  2. Cancer Manag Res. 2021 ;13 7225-7234
    SOX10 Knockdown Inhibits Melanoma Cell Proliferation via Notch Signaling Pathway.
    Youqun Tang, Yanming Cao.
       Purpose: Melanoma is a serious and malignant disease worldwide. Seeking diagnostic markers and potential therapeutic targets is urgent for melanoma treatment. SOX10, a member of the SoxE family of genes, is a transcription factor which can regulate the transcription of a wide variety of genes in multiple cellular processes.
    Methods: The mRNA level and protein expression of SOX10 is confirmed by bioinformatic analysis and IHC staining. MTT, clone formation and EdU analysis showed that SOX10 knockdown (KD) could significantly inhibit melanoma cell proliferation. FACS analysis showed that SOX10 KD could markedly enhance the level of cell apoptosis. The downstream target signaling pathway is predicted by RNA-seq based on the public GEO database. The activation of Notch signaling mediated by SOX10 is tested by qPCR and Western blot.
    Results: Ectopic upregulation of SOX10 was found in melanoma patient tissues compared to normal nevus tissues in mRNA and protein levels. Furthermore, both mRNA and protein level of SOX10 were negatively correlated with melanoma patient's prognosis. SOX10 knockdown could obviously suppress the proliferation ability of melanoma cells by inactivating Notch signaling pathway.
    Conclusion: Our study confirmed that SOX10 is an oncogene and activate Notch signaling pathway, which suggests the potential treatment for melanoma patients by target SOX10/Notch axis.
    Keywords:  SOX10; bioinformatics; biomarkers; melanoma; proliferation
    DOI:  https://doi.org/10.2147/CMAR.S329331
  3. Ital J Dermatol Venerol. 2021 Sep 21.
    Melanoma and hypertension, is there an association? A U.S. population based study.
    Amr E El-Qushayri, Amira Y Benmelouka, Samar Salman, Beatrice Nardone.
       BACKGROUND: Melanoma is one of the three major types of skin cancer. In this study we aimed to investigate the association between melanoma and hypertension comorbidity.
    METHODS: We performed a population based study using NHANES database during the period 1999-2004. Data were analyzed using SPSS version 24.
    RESULTS: Data for 12446 individuals of which 146 had a diagnosis for melanoma were extracted. Melanoma group were older than the no melanoma group as 51% of the melanoma group were 60 years or elder; however 53.6% of the no melanoma group falls below 30 years old. Melanoma group had higher frequency of hypertension (37%) compared to the no melanoma group (22.5%). Logistic regression revealed that melanoma patients had higher odds of hypertension prevalence using the unadjusted model (odds ratio (OR): 2.03, 95% confidence interval (CI): 1.45-2.84, p <0.001). However, after controlling of all potential confounding factors the significance was lost (OR: 0.89, 95% CI: 0.61-1.3, p = 0.54).
    CONCLUSIONS: There may be a possible association of melanoma with hypertension comorbidity. With the limitations we faced, we encourage further research to confirm the association of melanoma and hypertension comorbidity.
    DOI:  https://doi.org/10.23736/S2784-8671.21.07089-4
  4. Eur J Nutr. 2021 Sep 20.
    L-Theanine inhibits melanoma cell growth and migration via regulating expression of the clock gene BMAL1.
    Ruyi Zhang, Shuangning Zheng, Zhen Guo, Yanan Wang, Guocui Yang, Zhimin Yin, Lan Luo.
       PURPOSE: L-Theanine is a unique non-protein amino acid found in green tea, which has been identified as a safe dietary supplement. It has been reported that L-theanine exerts various biological activities. In this study, we explored the anti-cancer effects of L-theanine on melanoma cells.
    METHODS: A375, B16-F10, and PIG1 cell lines were used in the present study. EdU labeling, TUNEL and Annexin V/PI staining, wound-healing, and transwell migration assay were performed to detect the effects of L-theanine on melanoma cell proliferation, apoptosis, and migration. Brain and muscle Arnt-like protein 1 (BMAL1) was knocked down in melanoma cells to evaluate if L-theanine plays the anti-cancer role through regulating circadian rhythm of melanoma cells. The western blot, qRT-PCR, and dual luciferase assay were performed to explore the mechanism involved in the effects of L-theanine on melanoma cells.
    RESULTS: L-Theanine apparently reduced the viability of melanoma cells. Further experiments showed that L-theanine attenuated the proliferation and migration, and promoted apoptosis of melanoma cells. L-Theanine significantly enhanced the expression of BMAL1, a clock gene in melanoma cells. Down-regulation of BMAL1 suppressed the anti-cancer effects of L-theanine on melanoma cells. Further experiments indicated that the p53 transcriptional activity raised by L-theanine was dependent on BMAL1 expression in melanoma cells.
    CONCLUSION: L-Theanine exerts the anti-cancer effect on melanoma cells through attenuating the proliferation and migration, and promoting apoptosis of them, which is dependent on the regulation of the clock gene Bmal1 in melanoma cells.
    Keywords:  BMAL1; Clock gene; L-Theanine; Melanoma; p53
    DOI:  https://doi.org/10.1007/s00394-021-02677-y
  5. Target Oncol. 2021 Sep 23.
    The Status of Adjuvant and Neoadjuvant Melanoma Therapy, New Developments and Upcoming Challenges.
    Henner Stege, Maximilian Haist, Ulrike Nikfarjam, Michael Schultheis, Jaqueline Heinz, Saskia Pemler, Carmen Loquai, Stephan Grabbe.
      The global incidence of malignant melanoma, the leading cause of skin cancer death, has steadily increased in recent years. Surgical excision is the treatment of choice for early-stage melanoma. However, 40-60% of patients with high-risk melanoma or with nodal involvement eventually experience loco-regional relapse or tumor progression. Adjuvant therapy aims to reduce the rate of recurrence in radically operated high-risk patients with melanoma and thus improves survival. Interferon-α has long been the only approved drug for adjuvant melanoma therapy, despite an unclear survival benefit. The landmark success of immune-checkpoint inhibitors and BRAF/MEK-directed targeted therapies in the treatment of patients with stage IV melanoma led to the initiation of clinical trials in the adjuvant setting. These trials demonstrated the efficacy of immune-checkpoint inhibitors and targeted therapies for the adjuvant treatment of high-risk patients with melanoma, as shown both by an increase in recurrence-free survival and the emergence of long-term survivors, finally resulting in the approval of the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab, PD1 inhibitors (nivolumab, pembrolizumab), and BRAF/MEK inhibitors for adjuvant melanoma therapy. This review aims to delineate the advances in adjuvant melanoma therapy, issuing particularly recent results from clinical trials. Moreover, we also discuss pending issues and future challenges, which comprise the adequate selection of adjuvant regimens for patient subgroups and the identification of markers likely to predict the individual response to adjuvant treatments. Last, we outline the role of emerging neoadjuvant approaches, which may complement adjuvant strategies and are currently investigated in clinical trials.
    DOI:  https://doi.org/10.1007/s11523-021-00840-3
  6. J Appl Toxicol. 2021 Sep 23.
    Design cytotoxicity: The effect of silver nanoparticles stabilized by selected antioxidants on melanoma cells.
    Anna Barbasz, Agnieszka Czyżowska, Natalia Piergies, Magdalena Oćwieja.
      Silver nanoparticles (AgNPs) prepared and stabilized by diverse biologically active substances seem to be especially useful in diverse biological and medical applications. The combination of AgNPs with bioactive substances, such as antioxidants, can lead to the development of new systems of desired anticancer properties. In this research, AgNPs were prepared with the use of diverse antioxidant combinations including gallic acid (GA), (-)-epicatechin-3-gallate (EGCG), and caffeine (CAF). The insightful physicochemical characteristic revealed that each type of AgNPs exhibited spherical shape, comparable size distribution and negative surface charge. Surface-enhanced Raman spectroscopy (SERS) delivered the information about the chemistry of AgNP stabilizing layers, which turned out to be a crucial factor tuning toxicity of AgNPs toward murine B16 melanoma cells (B16-F0) and human skin melanoma (COLO 679) cells. EGCGAgNPs were the most cytotoxic among all the investigated AgNPs. They strongly reduced the activity of mitochondria, damaged cell membrane integrity, and penetrated inside the cells causing DNA damage. In turn, the toxicity of GAAgNPs strongly manifested via the induction of oxidative stress in the cells. It was found that CAFGAAgNPs exhibited the lowest toxicity toward the melanoma cells, which proved that a proper combination of antioxidants enable to prepare AgNPs of differentiated toxicity. It was established that human skin melanoma cells were significantly more sensitive to AgNPs than the murine melanoma cells.
    Keywords:  antioxidants; cytotoxicity; melanoma; silver nanoparticles
    DOI:  https://doi.org/10.1002/jat.4240
  7. Front Pharmacol. 2021 ;12 727275
    Inhibitory Effect of Dihydroartemisinin on the Proliferation and Migration of Melanoma Cells and Experimental Lung Metastasis From Melanoma in Mice.
    Qi Zhang, Linbo Jin, Quanxin Jin, Qiang Wei, Mingyuan Sun, Qi Yue, Huan Liu, Fangfang Li, Honghua Li, Xiangshan Ren, Guihua Jin.
      Melanoma is aggressive and can metastasize in the early stage of tumor. It has been proved that dihydroartemisinin (DHA) positively affects the treatment of tumors and has no apparent toxic and side effects. Our previous research has shown that DHA can suppress the formation of melanoma. However, it remains poorly established how DHA impacts the invasion and metastasis of melanoma. In this study, B16F10 and A375 cell lines and metastatic tumor models will be used to investigate the effects of DHA. The present results demonstrated that DHA inhibited the proliferative capacity in A375 and B16F10 cells. As expected, the migration capacity of A375 and B16F10 cells was also reduced after DHA administration. DHA alleviated the severity and histopathological changes of melanoma in mice. DHA induced expansion of CD8+CTL in the tumor microenvironment. By contrast, DHA inhibited Treg cells infiltration into the tumor microenvironment. DHA enhanced apoptosis of melanoma by regulating FasL expression and Granzyme B secretion in CD8+CTLs. Moreover, DHA impacts STAT3-induced EMT and MMPS in tumor tissue. Furthermore, Metabolomics analysis indicated that PGD2 and EPA significantly increased after DHA administration. In conclusion, DHA inhibited the proliferation, migration and metastasis of melanoma in vitro and in vivo. These results have important implications for the potential use of DHA in the treatment of melanoma in humans.
    Keywords:  EMT; dihydroartemisinin; melanoma; metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2021.727275
  8. Minerva Med. 2021 Sep 20.
    Biological effects of microRNA-320a/ STAT3 on cutaneous melanoma cells.
    Shenjun Jiang, Yefeng Xu, Jiewen Yang, Qingying Yan, Zhen Wang.
      
    DOI:  https://doi.org/10.23736/S0026-4806.21.07714-4
  9. Biochimie. 2021 Sep 15. pii: S0300-9084(21)00219-4. [Epub ahead of print]
    Hinokitiol-induced decreases of tyrosinase and microphthalmia-associated transcription factor are mediated by the endoplasmic reticulum-associated degradation pathway in human melanoma cells.
    Takahiro Oyama, Haruka Ogawa, Yoko Shirai, Hideaki Abe, Takanori Kamiya, Takehiko Abe, Sei-Ichi Tanuma.
      Tyrosinase (TYR) is a key enzyme for melanin production. We previously showed that hinokitiol, a naturally occurring seven-membered ring terpenoid, potently inhibits human TYR activity. Interestingly, hinokitiol was recently reported to decrease expression of TYR and microphthalmia-associated transcription factor (MITF), which is a main transcription factor of the TYR gene, in murine melanoma cells. However, the mechanisms by which hinokitiol decreases the intracellular levels of TYR and MITF have not been fully elucidated. Here, we investigated the underlying mechanisms of the decreases using cultured human melanoma cells. As a result, hinokitiol treatment decreased TYR protein level in a time- and dose-dependent manner in G361 human melanoma cells, while MITF protein level was decreased only at higher concentrations after 3 days treatment. Notably, the mRNA levels of TYR and MITF were slightly increased by hinokitiol treatment. Therefore, we focused on the degradation of TYR and MITF in endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway. Importantly, co-treatment of ERAD inhibitor with hinokitiol restored the protein levels of TYR and MITF to approximately 30% and 20% of total those in untreated control cells, respectively. Hinokitiol affected the ER homeostasis as well as degradation of TYR and MITF in two human melanoma cell lines, G361 and HT-144, but the changes of ER-stress markers under the hinokitiol treatment were different in the two human melanoma cell lines. Taken together, these observations indicate that hinokitiol may induce ER stress and trigger the degradation of unfolded newly synthesizing TYR and MITF via the ERAD pathway.
    Keywords:  ER stress; ERAD pathway; Hinokitiol; MITF; Tyrosinase
    DOI:  https://doi.org/10.1016/j.biochi.2021.09.007
  10. Surg Innov. 2021 Sep 24. 15533506211020226
    The Utility of Indocyanine Green Dye Fluorescence Lymphography and Angiography During Wide Excision of Cutaneous Melanoma.
    Tzi-Shiang Chu, Yuan-Sheng Tzeng, Chi-Yu Wang, Yu-Jen Shih, Chun-Yu Chen, Chih-Hsin Wang.
      Background and Objectives. Lymph node status is the most important prognostic factor in cutaneous melanoma patients. Recent studies showed that indocyanine green (ICG) fluorescence lymphography helps locating sentinel nodes better. Sometimes, flap reconstruction is needed after wide excision of tumor. Indocyanine green fluorescence also simplifies the intraoperative design of flaps. This study investigates the use of ICG fluorescence in patients with cutaneous melanoma during operation. Methods. We performed a single-center, retrospective study of subjects with cutaneous melanoma using ICG lymphograhy and/or angiography during wide excision of tumor between 2015 and 2019. Patients received a dermal injection of ICG and patent blue (PB) dye. The positive node was excised. Indocyanine green angiography was utilized to visualize better skin paddle during flap reconstruction if needed. Results. A total of 37 sentinel lymph nodes (SLNs) were removed in 12 patients. Indocyanine green successful localization was found in 10 of the 12 patients (83%). Three patients were found with 6 metastatic nodes on final pathology. 100% of these 6 nodes were identified by ICG, while 83% (5/6) were positive PB. Three of the 12 patients received flap reconstruction after operation, and no major complications occurred. Conclusions. ICG dye lymphangiography is a good alternative for locating SLNs in patients with melanoma. It could also visualize well perfusion skin paddle during reconstruction. We reported a reproducible and simple method to utilize ICG fluorescence in cutaneous melanoma patients.
    Keywords:  angiography; flap reconstruction; fluorescence-guided; indocyanine green; lymphography; melanoma; sentinel lymph node biopsy
    DOI:  https://doi.org/10.1177/15533506211020226
  11. Radiat Oncol. 2021 Sep 18. 16(1): 181
    BRAF mutation correlates with worse local-regional control following radiation therapy in patients with stage III melanoma.
    Adam R Wolfe, Priyanka Chablani, Michael R Siedow, Eric D Miller, Steve Walston, Kari L Kendra, Evan Wuthrick, Terence M Williams.
       BACKGROUND: In patients with stage III melanoma, the use of adjuvant radiation therapy (RT) after lymph node dissection (LND) may be currently considered in selected high-risk patients to improve tumor control. Melanomas harbor BRAF mutations (BRAF+) in 40-50% of cases, the majority of which are on the V600E residue. This study sought to compare the clinical outcomes after RT between patients with BRAF+ and BRAF- melanoma.
    METHODS: This was a retrospective review of 105 Stage III melanoma patients treated at our institution with LND followed by adjuvant RT from 2006 to 2019. BRAF mutational status was determined on the primary skin or nodal tissue samples from all patients. We compared characteristics of the BRAF+ and BRAF- groups using Fisher's exact test and Wilcoxon rank sum test and performed univariate and multivariate analysis using Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards modeling with the clinical outcomes of local-regional lymph node control, distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS).
    RESULTS: Fifty-three (50%) patients harbored a BRAF mutation (92%, pV600E). BRAF+ patients were younger and had primary tumors more commonly found in the trunk vs head and neck compared to BRAF- patients (p < 0.05). The 5 year local-regional control in the BRAF + patients was 60% compared to 81% in the BRAF- patients (HR 4.5, 95% CI 1.3-15.5, p = 0.02). There were no significant differences in 5-year DMFS, RFS, and OS rates between the two BRAF patient groups. The presence of 4 or more positive LNs remained a significant prognostic factor for local-regional lymph node control, RFS, and OS in multivariate analysis.
    CONCLUSIONS: Stage III melanoma patients with BRAF mutation treated with adjuvant RT had > 4 times increased risk of local recurrence or regional lymph node recurrence. These results could be useful for adjuvant RT consideration in lymph node positive melanoma patients and supports other data that BRAF mutation confers radiation resistance.
    DOI:  https://doi.org/10.1186/s13014-021-01903-5
  12. Cancer Cell Int. 2021 Sep 20. 21(1): 487
    The plasma exosomal miR-1180-3p serves as a novel potential diagnostic marker for cutaneous melanoma.
    Yeye Guo, Xu Zhang, Linconghua Wang, Min Li, Minxue Shen, Zhe Zhou, Susi Zhu, Keke Li, Zhiqin Fang, Bei Yan, Shuang Zhao, Juan Su, Xiang Chen, Cong Peng.
       BACKGROUND: Exosomes are a promising tool in disease detection because they are noninvasive, cost-effective, sensitive and stable in body fluids. MicroRNAs (miRNAs) are the main exosomal component and participate in tumor development. However, the exosomal miRNA profile among Asian melanoma patients remains unclear.
    METHODS: Exosomal miRNAs from the plasma of melanoma patients (n = 20) and healthy individuals (n = 20) were isolated and subjected to small RNA sequencing. Real-time PCR was performed to identify the differential miRNAs and to determine the diagnostic efficiency. Proliferation, scratch and Transwell assays were performed to detect the biological behavior of melanoma cells.
    RESULTS: Exosomal miRNA profiling revealed decreased miR-1180-3p expression as a potential diagnostic marker of melanoma. The validation group of melanoma patients (n = 28) and controls (n = 28) confirmed the diagnostic efficiency of miR-1180-3p. The level of miR-1180-3p in melanoma cells was lower than that in melanocytes. Accordingly, the level of miR-1180-3p was negatively associated with the proliferation, migration and invasion of melanoma cells. Functional analysis and target gene prediction found that ST3GAL4 was a potential target and highly expressed in melanoma tissues and was negatively regulated by miR-1180-3p. Knockdown of ST3GAL4 hindered the malignant phenotype of melanoma cells.
    CONCLUSIONS: This study indicates that reduced exosomal miR-1180-3p in melanoma patient plasma is a promising diagnostic marker and provides novel insight into melanoma development.
    Keywords:  Diagnostic marker; Exosome; Melanoma; Plasma; ST3GAL4; miR-1180-3p
    DOI:  https://doi.org/10.1186/s12935-021-02164-8
  13. Int J Clin Oncol. 2021 Sep 21.
    Impact of the changes in the completion lymph node dissection criteria and approval of adjuvant therapies on the real-world outcomes of Japanese stage III melanoma patients.
    Dai Ogata, Keiji Tanese, Yoshio Nakamura, Masaki Otsuka, Kenjiro Namikawa, Takeru Funakoshi, Syusuke Yoshikawa, Keita Tsutsui, Kenta Nakama, Shunichi Jinnai, Yoshio Kiyohara, Akira Takahashi, Naoya Yamazaki.
       BACKGROUND: Completion lymph node dissection (CLND) has long been the standard treatment for stage III melanomas identified as metastasis on the sentinel node (SN-positive). Two major changes occurred in 2017 and 2018, the change in the CLND criteria for SN-positive patients and the approval of several adjuvant therapies could revolutionize such management approach. However, their effects have not been fully investigated on the real-world outcomes of stage III melanoma patients. Therefore, we investigated the impact of these changes on the prognosis of Japanese stage III melanoma patients.
    METHODS: Totally, 119 stage III, SN-positive melanoma patients were included. They were categorized into those diagnosed as SN-positive between January 2015 and June 2017 (pre-June 2017 group) and between July 2017 and December 2019 (post-July 2017 group). Recurrence-free survival (RFS), overall survival, and prognostic factors were analyzed.
    RESULTS: The frequency of patients who received CLND was significantly higher in the pre-June 2017 group (p = 0.001), and those who received adjuvant therapy were significantly higher in the post-July 2017 group (p < 0.001). The 2-year RFS was 50.1% and 68.5% in the pre-June and post-July 2017 groups, respectively (p = 0.049). Cox proportional hazards model analysis for RFS showed that adjuvant therapies reduce the risk of recurrence (hazard ratio 0.37; 95% confidence interval 0.14-0.99; p = 0.047).
    CONCLUSION: Changes in the CLND criteria in SN-positive patients and the approval of adjuvant therapies for stage III melanomas have significantly impacted Japanese melanoma medicine. Adjuvant therapy tended to prolong patient's RFS while omitting immediate CLND had no significant negative influence on it.
    Keywords:  Adjuvant therapy; Lymph node dissection; Melanoma; Real-world outcome; Sentinel node
    DOI:  https://doi.org/10.1007/s10147-021-02029-0
  14. Immunol Cell Biol. 2021 Sep 20.
    Tumor reactivity of CD8+ T cells favors acquisition of dysfunctional states in human melanoma.
    Katharina Hochheiser, David E Gyorki, Thomas Gebhardt.
      A recent study by Oliveira et al. provides, in unprecedented detail, novel insights into the relationship between tumorreactivity and functional states of CD8 T cells in metastatic melanoma.
    DOI:  https://doi.org/10.1111/imcb.12498
  15. Clin Case Rep. 2021 Sep;9(9): e04790
    Malignant carcinoma and skin melanoma neoplasms concomitantly in the thyroid.
    Ali Al-Harake, Israa Dandache, Hiba Moukadem, Marwan Saliba, Jimmy Chahine, Hosni Yazbeck, Fadi Abdel-Sater, Hussein Karnib, Mahmoud H Younes.
      Malignant melanomas metastatic to the thyroid gland are uncommon. Based on microscopy and DNA methylation profile, we report a rare coexistence of neoplasms in the thyroid, presumably in our case, with relapse-free condition on adjuvant therapy.
    Keywords:  DNA methylation; malignant melanoma; medullary thyroid carcinoma; prognosis; thyroid
    DOI:  https://doi.org/10.1002/ccr3.4790
  16. Bull Exp Biol Med. 2021 Sep 20.
    Photodynamic Therapy of Melanoma B16 with Chlorin E6 Conjugated with a PSMA-Ligand.
    O B Abramova, M A Kaplan, M A Grin, V V Yuzhakov, N V Suvorov, A F Mironov, V V Drozhzhina, T P Churikova, E A Kozlovtseva, L N Bandurko, N D Yakovleva, S A Ivanov, A D Kaprin.
      The efficacy of a new photosensitizer of chlorin E6 conjugated with a prostate-specific membrane antigen (PSMA) in photodynamic therapy of murine melanoma B16 was studied in in vivo experiments. The dynamics of photosensitizer accumulation in the tumor and surrounding tissues was evaluated and antitumor efficacy of photodynamic therapy was assessed by parameters of regression and morphological characteristics of experimental transplanted melanoma B16. The inhibitory effect of photodynamic therapy on melanoma was evaluated by complete regression of the tumor, absolute tumor growth coefficient in animals with continuation of tumor growth, and the increase in life span in comparison with the control; the criterion of cure was the absence of signs of tumor recurrence in mice within 90 days after therapy. The therapeutic potential of photodynamic therapy was determined by devitalization of tumor cells (histological examination of the zones of laser exposure on day 21 after treatment). The photosensitizer with PSMA-ligand exhibited high antitumor activity in photodynamic therapy for melanoma B16. Photodynamic therapy carried out at the optimum time after photosensitizer injection with experimentally determined parameters of laser exposure allows achieving the maximum inhibitory effect on melanoma. Pathomorphological study in the zones of exposure detected no survived tumor cells.
    Keywords:  melanoma B16; pathomorphology; pharmacokinetics; photodynamic therapy; photosensitizer chlorin E6 with PSMAligand
    DOI:  https://doi.org/10.1007/s10517-021-05252-x
  17. Lancet Reg Health Eur. 2021 Mar;2 100040
    Descriptive epidemiology of cutaneous melanoma - A treasure for generating hypotheses.
    Andreas Stang, Axel Hauschild.
      
    DOI:  https://doi.org/10.1016/j.lanepe.2021.100040
  18. Pharmacol Res. 2021 Sep 21. pii: S1043-6618(21)00495-3. [Epub ahead of print] 105911
    TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors.
    Érica Aparecida de Oliveira, Jagat Chauhan, Julia Rezende da Silva, Larissa Anastacio da Costa Carvalho, Diogo Dias, Danielle Gonçalves de Carvalho, Luis Roberto Masao Watanabe, Vito W Rebecca, Gordon Mills, Yiling Lu, Aloisio Souza Felipe da Silva, Márcia Edilaine Lopes Consolaro, Meenhard Herlyn, Patricia A Possik, Colin R Goding, Silvya Stuchi Maria-Engler.
      In melanomas, therapy resistance can arise due to a combination of genetic, epigenetic and phenotypic mechanisms. Due to its crucial role in DNA supercoil relaxation, TOP1 is often considered an essential chemotherapeutic target in cancer. However, how TOP1 expression and activity might differ in therapy sensitive versus resistant cell types is unknown. Here we show that TOP1 expression is increased in metastatic melanoma and correlates with an invasive gene expression signature. More specifically, TOP1 expression is highest in cells with the lowest expression of MITF, a key regulator of melanoma biology. Notably, TOP1 and DNA Single-Strand Break Repair genes are downregulated in BRAFi- and BRAFi/MEKi-resistant cells and TOP1 inhibition decreases invasion markers only in BRAFi/MEKi-resistant cells. Thus, we show three different phenotypes related to TOP1 levels: i) non-malignant cells with low TOP1 levels; ii) metastatic cells with high TOP1 levels and high invasiveness; and iii) BRAFi- and BRAFi/MEKi-resistant cells with low TOP1 levels and high invasiveness. Together, these results highlight the potential role of TOP1 in melanoma progression and resistance.
    Keywords:  MITF; TOP1; Topotecan; melanoma; resistance
    DOI:  https://doi.org/10.1016/j.phrs.2021.105911
  19. Lancet Reg Health Eur. 2021 Mar;2 100024
    Changing epidemiology and age-specific incidence of cutaneous malignant melanoma in England: An analysis of the national cancer registration data by age, gender and anatomical site, 1981-2018.
    Anjum Memon, Peter Bannister, Imogen Rogers, Josefin Sundin, Bushra Al-Ayadhy, Peter W James, Richard J Q McNally.
       Background: The incidence of cutaneous malignant melanoma, which is mostly attributable (86%) to UV radiation exposure, has been steadily increasing over the past four decades in predominantly fair-skinned populations. Although public health campaigns are increasing sun-protective behaviour in England, their effect on melanoma incidence is largely unknown. We conducted a retrospective population-based cohort study to examine whether there have been changes in the epidemiology of melanoma in England during the past four decades.
    Methods: Individual level data for patients diagnosed with melanoma in England during 1981-2018 were obtained from the Office for National Statistics/Public Health England. Average annual incidence rates were calculated by three age categories (0-34, 35-64, 65+ years), gender and anatomical site during the seven five-year time periods (1981-85 to 2011-15) and the recent three-year period (2016-18). The percentage change in incidence was calculated as change in the average incidence rate from the first (1981-85) to the last time period (2016-18). The Average Annual Percentage Change (AAPC) was estimated using the slope of the linear trend line fitted to the incidence rates by year of diagnosis.
    Findings: During the 38-year period (1981-2018), a total of 265,302 cases of melanoma (45.7% males, 54.3% females) were registered in England. The average annual number of cases increased from 837/year in 1981-85 to 6963/year in 2016-18 in males (+732%), and from 1609/year in 1981-85 to 6952/year in 2016-18 in females (+332%). In the young age-group (0-34 years), the average annual incidence rates initially increased from 1981-85 to 2001-05 and then stabilised during the recent period (2006-18). In the middle age group (35-64 years), the rates increased by +332% (AAPC, 10.4%) in males (from 5.6/100,000 in 1981-85 to 24.2/100,000 in 2016-18) and +185% (AAPC, 5.7%) in females (from 10.2/100,000 in 1981-85 to 29.1/100,000 in 2016-18); and in the old age-group (65+ years) the rates increased by +842% (AAPC, 25.7%) in males (from 9.6/100,000 in 1981-85 to 90.4/100,000 in 2016-18) and +381% (AAPC, 11.2%) in females (from 12.5/100,000 in 1981-85 to 60.1/100,000 in 2016-18). The largest increase in incidence in both males and females was observed for melanoma of the trunk (+817%, AAPC, 24.8% in males and +613%, AAPC, 18.3% in females), followed by melanoma of upper limb (+750%, AAPC, 22.9% in males and 518%, AAPC, 15.5% in females).
    Interpretation: It appears that the incidence of melanoma among young people in England has stabilised (or levelled off) in recent decades, whereas it continues to increase substantially in older population. These findings suggest that public health campaigns targeted at children/adolescents/parents may be favourably influencing melanoma incidence. The steeper increase in incidence in males is consistent with their relatively greater sun exposure and poor sun-protective behaviour. All the available evidence suggests that the enormous increase in the melanoma of the trunk and upper limb, since the 1980s, is most likely due to increasing trend in intermittent high intensity recreational UV radiation exposure (e.g. sunbathing, holidaying in places with strong sunlight, indoor tanning).
    Funding: This work was supported by Brighton and Sussex Medical School (BSMS).
    Keywords:  Cutaneous melanoma; England; Incidence; Malignant melanoma; Skin cancer
    DOI:  https://doi.org/10.1016/j.lanepe.2021.100024
  20. Cell Stress Chaperones. 2021 Sep 20.
    HSP70iQ435A to subdue autoimmunity and support anti-tumor responses.
    Dinesh Jaishankar, Cormac Cosgrove, Prathyaya Ramesh, James Mahon, Rohan Shivde, Emilia R Dellacecca, Shiayin F Yang, Jeffrey Mosenson, José A Guevara-Patiño, I Caroline Le Poole.
      Developing immunosuppressive therapies for autoimmune diseases comes with a caveat that immunosuppression may promote the risk of developing other conditions or diseases. We have previously shown that biolistic delivery of an expression construct encoding inducible HSP70 (HSP70i) with one amino acid modification in the dendritic cell (DC) activating moiety 435-445 (HSP70iQ435A) to mouse skin resulted in significant immunosuppressive activity of autoimmune vitiligo, associated with fewer tissue infiltrating T cells. To prepare HSP70iQ435A as a potential therapeutic for autoimmune vitiligo, in this study we evaluated whether and how biolistic delivery of HSP70iQ435A in mice affects anti-tumor responses. We found that HSP70iQ435A in fact supports anti-tumor responses in melanoma-challenged C57BL/6 mice. Biolistic delivery of the HSP70iQ435A-encoding construct to mice elicited significant anti-HSP70 titers, and anti-HSP70 IgG and IgM antibodies recognize surface-expressed and cytoplasmic HSP70i in human and mouse melanoma cells. A peptide scan revealed that the anti-HSP70 antibodies recognize a specific C-terminal motif within the HSP70i protein. The antibodies elicited surface CD107A expression among mouse NK cells, representative of antibody-mediated cellular cytotoxicity (ADCC), supporting the concept, that HSP70iQ435A-encoding DNA elicits a humoral response to the stress protein expressed selectively on the surface of melanoma cells. Thus, besides limiting autoimmunity and inflammation, HSP70iQ435A elicits humoral responses that limit tumor growth and may be used in conjunction with immune checkpoint inhibitors to not only control tumor but to also limit adverse events following tumor immunotherapy.
    Keywords:  ADCC; Anti-tumor; Dendritic cell; Gene gun; Melanoma; Vitiligo
    DOI:  https://doi.org/10.1007/s12192-021-01229-x
  21. Clin Transl Oncol. 2021 Nov;23(11): 2302-2308
    Comparative genomic characterization of melanoma of known and unknown primary.
    E Rassy, S Boussios, A Chebly, C Farra, J Kattan, N Pavlidis.
       BACKGROUND: This study aims to genomically characterize melanoma of unknown primary (MUP) in comparison to melanomas of cutaneous primary (MCP).
    METHODS: Eligible cases were collected from the MSK-IMPACT™ Clinical Sequencing Cohort published in the cBioPortal database. Genomic analysis was performed using a hybridization-capture-based next-generation sequencing assay designed to detect mutations, small insertions and deletions, copy number alterations, and genomic rearrangements.
    RESULTS: Among 462 patients of whom 18.4% had MUP, brain metastasis was more common among patients with MUP (23% vs 7.1%). The differences in genomic profiling between MCP and MUP did not reach statistical significance. The 187 MCP and 44 MUP patients treated with immune checkpoint inhibitors had a median overall survival of 49 and 44 months, respectively (p = 0.705).
    CONCLUSIONS: The differences in somatic mutation patterns and survival outcomes were not statistically significant. These findings may allude to similar carcinogenic processes but should be considered exploratory and interpreted with caution.
    Keywords:  Genomics; Immunotherapy; Melanoma; Melanoma of unknown primary; Targeted therapies; Tumor mutational burden
    DOI:  https://doi.org/10.1007/s12094-021-02629-2
  22. Dermatol Surg. 2021 Oct 01. 47(10): 1333-1336
    Comparison of Survival Outcomes With/Without Adjuvant Radiation Therapy in Desmoplastic Melanoma.
    Gary D Lewis, Anthony K Guzman, Waqar Haque, Beth N McLellan, Bin S Teh.
       BACKGROUND: Desmoplastic melanoma (DM) is a rare variant of cutaneous melanoma with a high rate of local recurrence. Recent studies have indicated a potential benefit in local control with the addition of adjuvant radiotherapy (RT).
    OBJECTIVE: This study sought to evaluate the outcomes of adjuvant RT for patients with DM.
    MATERIALS AND METHODS: The National Cancer Database was queried (2004-2015) for patients with newly diagnosed, nonmetastatic DM. Patients were divided into 2 groups based on the adjuvant therapy they received: RT or observation. Statistics included multivariable logistic regression to determine factors predictive of receiving adjuvant RT, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS.
    RESULTS: There was no difference in median OS between patients treated with RT when compared with patients observed (111.4 months vs 133.9 months, p = .1312). On multivariable analysis, older age, T stage ≥2, N stage ≥1, and no receipt of immunotherapy were associated with worse OS.
    CONCLUSION: In this large study evaluating efficacy of adjuvant RT in DM, no overall survival benefit was observed among patients receiving adjuvant RT.
    DOI:  https://doi.org/10.1097/DSS.0000000000003177
  23. Ann Surg Oncol. 2021 Sep 19.
    Adjuvant Therapy for Stage III Melanoma Without Immediate Completion Lymph Node Dissection.
    Robert J Torphy, Chloe Friedman, Felix Ho, Laura D Leonard, Daniel Thieu, Karl D Lewis, Theresa M Medina, William A Robinson, Rene C Gonzalez, Camille L Stewart, Nicole Kounalakis, Martin D McCarter, Ana Gleisner.
       INTRODUCTION: For patients with stage III melanoma with occult lymph node metastasis, the use of adjuvant therapy is increasing, and completion lymph node dissection (CLND) is decreasing. We sought to evaluate the use of modern adjuvant therapy and outcomes for patients with stage III melanoma who did not undergo CLND.
    METHODS: Patients with a positive SLNB from 2015 to 2020 who did not undergo CLND were evaluated retrospectively. Nodal recurrence, recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and melanoma-specific survival were evaluated.
    RESULTS: Among 90 patients, 56 (62%) received adjuvant therapy and 34 (38%) underwent observation alone. Patients who received adjuvant therapy were younger (mean age: 53 vs. 65, p < 0.001) and had higher overall stage (Stage IIIb/c 75% vs. 54%, p = 0.041). Disease recurred in 12 of 34 patients (35%) in the observation group and 11 of 56 patients (20%) in the adjuvant therapy group. The most common first site of recurrence was distant recurrence alone (5/34 patients) in the observation group and nodal recurrence alone (8/90 patients) in the adjuvant therapy group. Despite more adverse nodal features in the adjuvant therapy group, 24-month nodal recurrence rate and RFS were not significantly different between the adjuvant and observation cohorts (nodal recurrence rate: 26% vs. 20%, p = 0.68; RFS: 75% vs. 61%, p = 0.39). Among patients with stage IIIb/c disease, adjuvant therapy was associated with a significantly improved 24-month DMFS (86% vs. 59%, p = 0.04).
    CONCLUSIONS: In this early report, modern adjuvant therapy in patients who forego CLND is associated with longer DMFS among patients with stage IIIb/c disease.
    DOI:  https://doi.org/10.1245/s10434-021-10775-8
  24. Ann Intern Med. 2021 Sep;174(9): 1345
    Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease.
    Xi Yang, Lilit Karapetyan, John M Kirkwood.
      
    DOI:  https://doi.org/10.7326/L21-0441
  25. Mol Pharm. 2021 Sep 23.
    Improving Dermal Delivery of Rose Bengal by Deformable Lipid Nanovesicles for Topical Treatment of Melanoma.
    Sara Demartis, Giovanna Rassu, Sergio Murgia, Luca Casula, Paolo Giunchedi, Elisabetta Gavini.
      Cutaneous melanoma is one of the most aggressive and metastatic forms of skin cancer. However, current therapeutic options present several limitations, and the annual death rate due to melanoma increases every year. Dermal delivery of nanomedicines can effectively eradicate primary melanoma lesions, avoid the metastatic process, and improve survival. Rose Bengal (RB) is a sono-photosensitizer drug with intrinsic cytotoxicity toward melanoma without external stimuli but the biopharmaceutical profile limits its clinical use. Here, we propose deformable lipid nanovesicles, also known as transfersomes (TF), for the targeted dermal delivery of RB to melanoma lesions to eradicate them in the absence of external stimuli. Considering RB's poor ability to cross the stratum corneum and its photosensitizer nature, transfersomal carriers were selected simultaneously to enhance RB penetration to the deepest skin layers and protect RB from undesired photodegradation. RB-loaded TF dispersion (RB-TF), prepared by a modified reverse-phase evaporation method, were nanosized with a ζ-potential value below -30 mV. The spectrophotometric and fluorimetric analysis revealed that RB efficiently interacted with the lipid phase. The morphological investigations (transmission electron microscopy and small-angle X-ray scattering) proved that RB intercalated within the phospholipid bilayer of TF originating unilamellar and deformable vesicles, in contrast to the rigid multilamellar unloaded ones. Such outcomes agree with the results of the in vitro permeation study, where the lack of a burst RB permeation peak for RB-TF, observed instead for the free drug, suggests that a significant amount of RB interacted with lipid nanovesicles. Also, RB-TF proved to protect RB from undesired photodegradation over 24 h of direct light exposure. The ex vivo epidermis permeation study proved that RB-TF significantly increased RB's amount permeating the epidermis compared to the free drug (78.31 vs 38.31%). Finally, the antiproliferative assays on melanoma cells suggested that RB-TF effectively reduced cell growth compared to free RB at the concentrations tested (25 and 50 μM). RB-TF could potentially increase selectivity toward cancer cells. Considering the outcomes of the characterization and cytotoxicity studies performed on RB-TF, we conclude that RB-TF represents a valid potential alternative tool to fight against primary melanoma lesions via dermal delivery in the absence of light.
    Keywords:  dermal delivery; liposome; melanoma; nanoparticle; rose bengal; skin cancer
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.1c00468
  26. J Vis Exp. 2021 Sep 04.
    Ortho- and Ectopic Zebrafish Xeno-Engraftment of Ocular Melanoma to Recapitulate Primary Tumor and Experimental Metastasis Development.
    Arwin Groenewoud, Jie Yin, B Ewa Snaar-Jagalska.
      There are currently no animal models for metastatic ocular melanoma. The lack of metastatic disease models has greatly hampered the research and development of novel strategies for the treatment of metastatic ocular melanoma. In this protocol we delineate a quick and efficient way to generate embryonic zebrafish models for both the primary and disseminated stage of ocular melanoma, using retro-orbital orthotopic and intravascular ectopic cell engraftment, respectively. Combining these two different engraftment strategies we can recapitulate the etiology of cancer in its totality, progressing from primary, localized tumor growth under the eye to a peri-vascular metastasis formation in the tail. These models allow us to quickly and easily modify the cancer cells prior to implantation with specific labeling, genetic or chemical interference; and to treat the engrafted hosts with (small molecular) inhibitors to attenuate tumor development. Here, we describe the generation and quantification of both orthotopic and ectopic engraftment of ocular melanomas (conjunctival and uveal melanoma) using fluorescently labelled stable cell lines. This protocol is also applicable for engraftment of primary cells derived from patient biopsy and patient/PDX derived material (manuscript in preparation). Within hours post engraftment cell migration and proliferation can be visualized and quantified. Both tumor foci are readily available for imaging with both epifluorescence microscopy and confocal microscopy. Using these models, we can confirm or refute the activity of either chemical or genetic inhibition strategies within as little as 8 days after the onset of the experiment, allowing not only highly efficient screening on stable cell lines, but also enables patient directed screening for precision medicine approaches.
    DOI:  https://doi.org/10.3791/62356
  27. JAAD Case Rep. 2021 Oct;16 90-91
    Repigmentation of vitiligo-associated eyelash leukotrichia with topical tofacitinib.
    Sa Rang Kim, Brittany G Craiglow.
      
    Keywords:  JAK inhibitor; JAK, Janus kinase; Janus kinase; leukotrichia; pediatric; therapy; tofacitinib; topical; treatment; vitiligo
    DOI:  https://doi.org/10.1016/j.jdcr.2021.07.021
  28. J Eur Acad Dermatol Venereol. 2021 Sep 18.
    Survival of stage IV melanoma in Belgium and the Netherlands.
    K P M Suijkerbuijk, J B A G Haanen, M J Boers-Sonderen, G A P Hospers, C U Blank, F W P J van den Berkmortel, J W B de Groot, D Piersma, M J B Aarts, R S van Rijn, G Vreugdenhil, H M Westgeest, E Kapiteijn, A A M van der Veldt, A J M van den Eertwegh.
      With interest we read the paper by Reyn et al. [1] in which the authors describe striking differences in melanoma incidence and survival between Belgium and The Netherlands.
    Keywords:  DMTR; The Netherlands; advanced melanoma; survival
    DOI:  https://doi.org/10.1111/jdv.17668
  29. Medicine (Baltimore). 2021 Sep 24. 100(38): e27223
    Prognostic significance of platelet lymphocyte ratio in patients with melanoma: A meta-analysis.
    Enwen Wang, Hui Huang, Long Tang, Ling Tian, Liejun Yang, Sixiong Wang, Huiwen Ma.
       BACKGROUND: The aim of this study was to systematically evaluate the prognostic role of platelet lymphocyte ratio (PLR) in patients with melanoma through performing a meta-analysis.
    METHODS: PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure were searched for potential studies. The basic characteristics and relevant data were extracted. Hazard ratios with 95% confidence intervals (CIs) were pooled to evaluate the prognostic role of PLR in patients with melanoma.
    RESULTS: Ten studies enrolling 2422 patients were included. The pooled hazard ratios of higher PLR for overall survival and progression-free survival in melanoma were 1.70 (95% CI, 1.22-2.37) and 1.65 (95% CI, 1.10-2.47), respectively. Sensitivity analysis and subgroup analyses were also performed. No significant publication bias was observed.
    CONCLUSION: Our results showed that higher PLR was associated with poorer overall survival and progression-free survival in patients with melanoma. These findings may help to determine the prognosis and explore future novel therapies based on modulating inflammation and immune responses in melanoma.
    DOI:  https://doi.org/10.1097/MD.0000000000027223
  30. Sci Rep. 2021 Sep 20. 11(1): 18594
    Paired comparisons of mutational profiles before and after brachytherapy in asian uveal melanoma patients.
    Woo Seung Lee, Junwon Lee, Jun Jeong Choi, Hyun Goo Kang, Sung Chul Lee, Ju Han Kim.
      Uveal melanoma(UM) is the most common primary intraocular malignancy in adults. However, the incidence of UM in Asia is 10 to 20 times less than in Western populations. Therefore, for the first time, we report our whole exome sequencing (WES) data analysis to discover differences in the molecular features of Asian and Western UM, and to determine the disparities between the primary tumor before brachytherapy and enucleated samples after brachytherapy. WES of 19 samples (13 primary tumors, 5 enucleation samples after brachytherapy, and 1 liver metastasis) from 13 patients diagnosed with UM and treated between 2007 and 2019 at the Yonsei University Health System (YUHS) were analyzed using bioinformatics pipelines. We identified significantly altered genes in Asian UM and changes in mutational profiles before and after brachytherapy using various algorithms. GNAQ, BAP1, GNA11, SF3B1 and CYSLTR2 were significantly mutated in Asian UM, which is similar that reported frequently in previous Western-based UM studies. There were also similar copy number alterations (M3, 1p loss, 6p gain, 8q gain) in both groups. In paired comparisons of the same patients, DICER1 and LRP1B were distinctly mutated only in tumor samples obtained after brachytherapy using rare-variant association tests (P = 0.01, 0.01, respectively). The mutational profiles of Asian UM were generally similar to the data from previous Western-based studies. DICER1 and LRP1B were newly mutated genes with statistical significance in the regrowth samples after brachytherapy compared to the primary tumors, which may be related to resistance to brachytherapy.
    DOI:  https://doi.org/10.1038/s41598-021-98084-8
  31. Ann Intern Med. 2021 Sep;174(9): 1345-1346
    Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease.
    Monique K van der Kooij, Karijn P M Suijkerbuijk, Olaf M Dekkers, Ellen Kapiteijn.
      
    DOI:  https://doi.org/10.7326/L21-0442
  32. Oncol Rep. 2021 Nov;pii: 238. [Epub ahead of print]46(5):
    lncRNA TINCR attenuates the proliferation and invasion, and enhances the apoptosis of cutaneous malignant melanoma cells by regulating the miR‑424‑5p/LATS1 axis.
    Xuemei Han, Yuxi Jia, Xiangru Chen, Chengkuan Sun, Jing Sun.
      Cutaneous malignant melanoma (CMM) is responsible for ≥1/2 of skin cancer‑related mortalities. The aberrant expression of long non‑coding RNAs (lncRNAs) has been associated with the development of CMM. However, to the best of our knowledge, the role of the lncRNA TINCR ubiquitin domain containing (TINCR) in CMM has not been previously investigated, and thus, the current study aimed to evaluate this in vitro and in vivo. Reverse transcription‑quantitative PCR (RT‑qPCR) was used to analyze microRNA (miR)‑424‑5p expression, and RT‑qPCR and western blotting were used to measure TINCR, large tumor suppressor kinase 1 (LATS1), cellular communication network factor 2 (CTGF), cellular communication network factor 1 (CCN1) and AXL receptor tyrosine kinase (AXL) mRNA and protein expression levels, respectively. Cell Counting Kit‑8, flow cytometry and Transwell assays were used to detect the proliferation, apoptosis and invasion of CMM cell lines, respectively. The binding sites between TINCR and miR‑424‑5p were predicted using the miRDB database. A dual luciferase reporter assay and RT‑qPCR were used to identify the relationship between TINCR and miR‑424‑5p in CMM cell lines. The bioinformatics analysis revealed that TINCR was one of the most significantly downregulated lncRNAs in CMM, and advanced stage CMM tissues showed the greatest decrease in TINCR expression. Moreover, in the collected CMM tissues and tested cell lines of the current study, TINCR expression was found to be downregulated compared with the respective controls. Notably, TINCR overexpression inhibited the expression levels of CTGF, CCN1 and AXL, decreased the proliferation and invasion, and induced the apoptosis of CMM cell lines. In addition, a mutual binding association was identified between miR‑424‑5p and TINCR in CMM cells. LATS1, a target of miR‑424‑5p, was found to be positively regulated by TINCR. TINCR activated Hippo signaling and repressed the activity of Yes 1 associated transcriptional regulator by regulating LATS1 expression, while LATS1 knockdown reversed the effect of TINCR overexpression on CMM cells. Collectively, the findings of the present study suggested that TINCR may attenuate the progression of CMM by regulating the miR‑424‑5p/LATS1 signaling axis. These results indicated that TINCR may play a tumor suppressive role in CMM.
    Keywords:  cell apoptosis; cell proliferation; cutaneous malignant melanoma; long non‑coding RNA TINCR ubiquitin domain containing; microRNA‑424‑5p/large tumor suppressor kinase 1 axis
    DOI:  https://doi.org/10.3892/or.2021.8189
  33. Free Radic Biol Med. 2021 Sep 21. pii: S0891-5849(21)00737-1. [Epub ahead of print]
    The critical role of ROS in Ermanin-induced melanogenesis.
    Qiong Ding, Lin Luo, Lan Yu, Si-Lu Huang, Xiao-Qin Wang, Bo Zhang.
      Vitiligo is a depigmented disease featured as diagnosis simplicity and cure difficulty. Its occurrence and development are associated with a variety of factors, including oxidative stress, heredity and immunity, etc. Existing drugs for the treatment of vitiligo are to reduce the death of melanocytes and induce pigment accumulation as the main treatment strategy. Ermanin, a member of the flavonoids, is extracted from bee glue which is wildly used to treat vitiligo in Traditional Chinese medicine. Therefore, this article discusses the relationship between melanogenesis and ROS production by ermanin via biochemical and free radical approaches in vivo and in vitro. In this study, we found that ermanin effectively increased the melanin content at the in vivo model (zebrafish). Moreover, the melanin levels at the in vitro models (B16F10 cells and primary melanocytes) were also increased significantly accompanied with an increase in ROS levels. Ermanin also significantly enhanced the activity of tyrosinase. Meanwhile, ermanin increased the expression levels of TYR, TRP-1, and DCT genes, while ROS mediated the accumulation of pigments caused by ermanin, which increased the production of pigments and regulated the expression mRNA levels of TYR and DCT genes. From the perspective of pigment production regulation pathways, western blot showed that the pigment accumulation caused by ermanin was closely related to the CREB-MITF pathways, it activated CREB, TYR, TRP-1, and DCT proteins. The use of CREB specific inhibitor 666-15 and MITF inhibitor ML329 confirmed that the pigment accumulation caused by ermanin was positively correlated with CREB and MITF proteins. Our findings revealed the potential mechanisms by which ermanin promoted the production of melanin through activated CREB-MITF signaling pathway and ROS function as signaling messengers are beneficial to melanin production and thereby will help develop novel therapeutic approaches for vitiligo.
    Keywords:  CREB-MITF pathway; Ermanin; Melanogenesis; ROS; Redox homeostasis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.09.017
  34. Oncol Lett. 2021 Nov;22(5): 756
    UCHL3 plays an important role in the occurrence and development of melanoma.
    Runzhi He, Yajing Zhou, Jianmin Liu, Xiaochong Zhang, Xiaoling Zhao, Lihui An, Zihan Li, Fang Cheng.
      It has been reported that ubiquitin C-terminal hydrolase-L3 (UCHL3) plays an important role in cancer development; however, the role of UCHL3 in melanoma remains unclear. The present study aimed to investigate the role of ubiquitin C-terminal hydrolase-L3 (UCHL3) and determine its underlying molecular mechanisms in melanoma occurrence and development using in vitro studies. Reverse transcription-quantitative PCR analysis was performed to detect UCHL3 mRNA expression. The MTT assay was performed to assess cell proliferation. Cell apoptosis was analyzed via flow cytometry and the TUNEL assay. Cell ultrastructure was observed via transmission electron microscopy. LC3B protein expression was detected via cellular immunofluorescence, while neural precursor cell-expressed developmentally downregulated protein 8 (NEDD8) and LC3 protein expression levels, and NEDD8 ubiquitination were detected via western blot analysis. The results demonstrated that transfection with small interfering (si)RNA-UCHL3 significantly suppressed cell proliferation, whereas apoptosis was significantly enhanced, as well as autophagy, autophagosome formation and LC3B protein expression. In addition, NEDD8 protein expression and autophagosome numbers significantly decreased, while the LC3II/LC3I ratio significantly increased. NEDD8 knockdown via transfection with si-NEDD8 had similar effects to si-UCHL3, as well as si-UCHL3+ si-NEDD8. Taken together, the results of the present study suggest that UCHL3 knockdown decreases melanoma cell proliferation by increasing cell autophagy through regulating NEDD8 expression and autophagosome numbers.
    Keywords:  autophagosome; autophagy; melanoma; neural precursor cell-expressed developmentally downregulated protein 8; ubiquitin C-terminal hydrolase-L3
    DOI:  https://doi.org/10.3892/ol.2021.13017
  35. Front Cell Dev Biol. 2021 ;9 710558
    Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma.
    Chufeng Gu, Xin Gu, Yujie Wang, Zhixian Yao, Chuandi Zhou.
       Objectives: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and immune infiltration plays a crucial role in the prognosis of UM. This study aimed to generate an immunological marker-based predictive signature for the overall survival (OS) of UM patients.
    Methods: Single-sample gene-set enrichment analysis (ssGSEA) was used to profile immune cell infiltration in 79 patients with UM from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate least absolute shrinkage and selection operator (LASSO) Cox regressions were used to determine the prognostic factors for UM and construct the predictive immunosignature. Receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves were performed to evaluate the clinical ability and accuracy of the model. In addition, the predictive accuracy was compared between the immunosignature and the Tumor, Node, Metastasis (TNM) staging system of American Joint Committee on Cancer (AJCC). We further analyzed the differences in clinical characteristics, immune infiltrates, immune checkpoints, and therapy sensitivity between high- and low-risk groups characterized by the prognostic model.
    Results: Higher levels of immune cell infiltration in UM were related to a lower survival rate. Matrix metallopeptidase 12 (MMP12), TCDD inducible poly (ADP-ribose) polymerase (TIPARP), and leucine rich repeat neuronal 3 (LRRN3) were identified as prognostic signatures, and an immunological marker-based prognostic signature was constructed with good clinical ability and accuracy. The immunosignature was developed with a concordance index (C-index) of 0.881, which is significantly better than that of the TNM staging system (p < 0.001). We further identified 1,762 genes with upregulated expression and 798 genes with downregulated expression in the high-risk group, and the differences between the high- and low-risk groups were mainly in immune-related processes. In addition, the expression of most of the immune checkpoint-relevant and immune activity-relevant genes was significantly higher in the high-risk group, which was more sensitive to therapy.
    Conclusion: We developed a novel immunosignature constructed by MMP12, TIPARP, and LRRN3 that could effectively predict the OS of UM.
    Keywords:  immune microenvironment; immunological marker; overall survival; prognostic signatures; uveal melanoma
    DOI:  https://doi.org/10.3389/fcell.2021.710558
  36. Zhonghua Nei Ke Za Zhi. 2021 Oct 01. 60(10): 918-920
    [Anti-PD-1 monoclonal antibody combined with HAIC in the treatment of malignant melanoma with liver metastasis: a case report].
    C L Wang, H P Yu, Y Xu, W Gao, X Y Guo, X L Yang, Z Guo.
      
    DOI:  https://doi.org/10.3760/cma.j.cn112138-20201008-00853
  37. J Immunother Cancer. 2021 Sep;pii: e003125. [Epub ahead of print]9(9):
    Multiparametric MRI of early tumor response to immune checkpoint blockade in metastatic melanoma.
    Doreen Lau, Mary A McLean, Andrew N Priest, Andrew B Gill, Francis Scott, Ilse Patterson, Bruno Carmo, Frank Riemer, Joshua D Kaggie, Amy Frary, Doreen Milne, Catherine Booth, Arthur Lewis, Michal Sulikowski, Lee Brown, Jean-Martin Lapointe, Luigi Aloj, Martin J Graves, Kevin M Brindle, Pippa G Corrie, Ferdia A Gallagher.
       BACKGROUND: Immune checkpoint inhibitors are now standard of care treatment for many cancers. Treatment failure in metastatic melanoma is often due to tumor heterogeneity, which is not easily captured by conventional CT or tumor biopsy. The aim of this prospective study was to investigate early microstructural and functional changes within melanoma metastases following immune checkpoint blockade using multiparametric MRI.
    METHODS: Fifteen treatment-naïve metastatic melanoma patients (total 27 measurable target lesions) were imaged at baseline and following 3 and 12 weeks of treatment on immune checkpoint inhibitors using: T2-weighted imaging, diffusion kurtosis imaging, and dynamic contrast-enhanced MRI. Treatment timepoint changes in tumor cellularity, vascularity, and heterogeneity within individual metastases were evaluated and correlated to the clinical outcome in each patient based on Response Evaluation Criteria in Solid Tumors V.1.1 at 1 year.
    RESULTS: Differential tumor growth kinetics in response to immune checkpoint blockade were measured in individual metastases within the same patient, demonstrating significant intertumoral heterogeneity in some patients. Early detection of tumor cell death or cell loss measured by a significant increase in the apparent diffusivity (Dapp) (p<0.05) was observed in both responding and pseudoprogressive lesions after 3 weeks of treatment. Tumor heterogeneity, as measured by apparent diffusional kurtosis (Kapp), was consistently higher in the pseudoprogressive and true progressive lesions, compared with the responding lesions throughout the first 12 weeks of treatment. These preceded tumor regression and significant tumor vascularity changes (Ktrans, ve, and vp) detected after 12 weeks of immunotherapy (p<0.05).
    CONCLUSIONS: Multiparametric MRI demonstrated potential for early detection of successful response to immune checkpoint inhibitors in metastatic melanoma.
    Keywords:  CTLA-4 antigen; biomarkers; immunotherapy; melanoma; translational medical research; tumor
    DOI:  https://doi.org/10.1136/jitc-2021-003125
  38. Sci Rep. 2021 Sep 22. 11(1): 18795
    FDG PET biomarkers for prediction of survival in metastatic melanoma prior to anti-PD1 immunotherapy.
    A Flaus, V Habouzit, N De Leiris, J P Vuillez, M T Leccia, J L Perrot, N Prevot, F Cachin.
      Our aim was to analyse whether biomarkers extracted from baseline 18F-FDG PET before anti-PD1 treatment contribute to prognostic survival information for early risk stratification in metastatic melanoma. Fifty-six patients, without prior systemic treatment, BRAF wild type, explored using 18F-FDG PET were included retrospectively. Our primary endpoint was overall survival (OS). Total metabolic tumoral volume (MTV) and forty-one IBSI compliant parameters were extracted from PET. Parameters associated with outcome were evaluated by a cox regression model and when significant helped build a prognostic score. Median follow-up was 22.1 months and 21 patients died. Total MTV and long zone emphasis (LZE) correlated with shorter OS and served to define three risk categories for the prognostic score. For low, intermediate and high risk groups, survival rates were respectively 91.1% (IC 95 80-1), 56.1% (IC 95 37.1-85) and 19% (IC 95 0.06-60.2) and hazard ratios were respectively 0.11 (IC 95 0.025-0.46), P = 0.0028, 1.2 (IC 95 0.48-2.8), P = 0.74 and 5.9 (IC 95 2.5-14), P < 0.0001. To conclude, a prognostic score based on total MTV and LZE separated metastatic melanoma patients in 3 categories with dramatically different outcomes. Innovative therapies should be tested in the group with the lowest prognosis score for future clinical trials.
    DOI:  https://doi.org/10.1038/s41598-021-98310-3
  39. Mol Med Rep. 2021 Nov;pii: 821. [Epub ahead of print]24(5):
    Ginsenoside Rk1 protects human melanocytes from H2O2‑induced oxidative injury via regulation of the PI3K/AKT/Nrf2/HO‑1 pathway.
    Jian Xiong, Jianing Yang, Kai Yan, Jing Guo.
      Vitiligo is a cutaneous depigmentation disorder caused by melanocyte injury or aberrant functioning. Oxidative stress (OS) is considered to be a major cause of the onset and progression of vitiligo. Ginsenoside Rk1 (RK1), a major compound isolated from ginseng, has antioxidant activity. However, whether RK1 can protect melanocytes against oxidative injury remains unknown. The aim of the present study was to investigate the potential protective effect of RK1 against OS in the human PIG1 melanocyte cell line induced with hydrogen peroxide (H2O2), and to explore its underlying mechanism. PIG1 cells were pretreated with RK1 (0, 0.1, 0.2 and 0.4 mM) for 2 h followed by exposure to 1.0 mM H2O2 for 24 h. Cell viability and apoptosis were determined with Cell Counting Kit‑8 and flow cytometry assays, respectively. The activity levels of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH‑Px) were analyzed using ELISA kits. Protein expression levels, including Bax, caspase‑3, Bcl‑2, phosphorylated‑AKT, AKT, nuclear factor erythroid 2‑related factor 2 (Nrf2), heme oxygenase‑1 (HO‑1), cytosolic Nrf2 and nuclear Nrf2, were analyzed using western blot analysis. In addition, the expression and localization of Nrf2 were detected by immunofluorescence. RK1 treatment significantly improved cell viability, reduced the apoptotic rate and increased the activity levels of SOD, CAT and GSH‑Px in the PIG1 cell line exposed to H2O2. In addition, RK1 treatment notably induced Nrf2 nuclear translocation, increased the protein expression levels of Nrf2 and HO‑1, and the ratio of phosphorylated‑AKT to AKT in the PIG1 cells exposed to H2O2. Furthermore, LY294002 could reverse the protective effect of RK1 in melanocytes against oxidative injury. These data demonstrated that RK1 protected melanocytes from H2O2‑induced OS by regulating Nrf2/HO‑1 protein expression, which may provide evidence for the application of RK1 for the treatment of vitiligo.
    Keywords:  PI3K/AKT/Nrf2/HO‑1; ginsenoside Rk1; oxidative stress; vitiligo
    DOI:  https://doi.org/10.3892/mmr.2021.12462
  40. J Am Acad Dermatol. 2021 Sep 21. pii: S0190-9622(21)02503-2. [Epub ahead of print]
    Evaluation of a community education tool for detection of nail melanoma by nail salon technicians.
    Lindsey J Gaghan, Helen Bui, Shari R Lipner, Nathaniel J Jellinek, Julie E Mervak.
      
    Keywords:  Hutchinson sign; Melanoma; cancer screening; educational intervention; melanonychia; nail salon; nail technician
    DOI:  https://doi.org/10.1016/j.jaad.2021.09.025
  41. Pigment Cell Melanoma Res. 2021 Sep 21.
    Intragenic NF1 deletions in sinonasal mucosal malignant melanoma.
    Cristina Riobello, Rodrigo Casanueva Muruais, Laura Suárez-Fernández, Rocío García-Marín, Virginia N Cabal, Verónica Blanco-Lorenzo, Alessandro Franchi, Jan Laco, Fernando López, José Luis Llorente, Mario A Hermsen.
      Mucosal malignant melanoma (MMM) is a rare and aggressive tumor. Despite effective local therapies, tumor recurrence and metastasis remain frequent. The genetics of MMM remain incompletely understood. This study is aimed to identify actionable genetic alterations by next generation sequencing. Fifteen MMM samples were analyzed by next-generation and Sanger sequencing. Gene copy number alterations were analyzed by MLPA. Mutation status was correlated with pERK, pAKT and Ki-67 expression and follow-up data. Inactivating mutations and intragenic deletions in NF1 were identified in 3 and 2 cases, respectively (in total 5/15, 33%) and activating mutations in NRAS and KRAS (3/15, 20%) cases. Other mutated genes included CDKN2A, APC, ATM, MITF, FGFR1 and FGFR2. BRAF and KIT mutations were not observed. Cases with NF1 alterations tended to have worse overall survival. The mutational status was not associated with pERK, pAKT or Ki-67 immunostaining. MMM carry frequent gene mutations activating the MAPK pathway, similar to cutaneous melanoma. In contrast, NF1 is the most frequently affected gene. Intragenic NF1 deletions have not been described before and may go undetected by sequencing studies. This finding is clinically relevant as NF1 mutated melanomas have worse survival and could benefit from therapy with immune checkpoint and MEK inhibitors.
    Keywords:  NF1; intragenic deletion; mucosal melanoma; mutation; next-generation sequencing; sinonasal cancer
    DOI:  https://doi.org/10.1111/pcmr.13015
  42. N Engl J Med. 2021 Sep 23. 385(13): 1196-1206
    Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma.
    IMCgp100-202 Investigators
       BACKGROUND: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells.
    METHODS: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival.
    RESULTS: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported.
    CONCLUSIONS: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
    DOI:  https://doi.org/10.1056/NEJMoa2103485
  43. IEEE J Biomed Health Inform. 2021 Sep 20. PP
    A Cloud Approach for Melanoma Detection based on Deep Learning Networks.
    Luigi Dibiasi, Michele Risi, Genoveffa Tortora, Alessia Auriemma Citarella.
      In the era of digitized images, the goal is to be able to extract information from them and create new knowledge thanks to the use of Computer Vision techniques, Machine Learning and Deep Learning. This allows their use for early diagnosis and subsequent determination of the treatment of many pathologies. In the specific case treated here, deep neural networks are used in the dermatological field to distinguish between melanoma and non-melanoma images. In this work we have underlined two essential points of melanoma detection research. The first aspect taken into consideration is how even a simple modification of the parameters in the dataset determines a change of the accuracy of the classifiers, while working on the same original dataset. The second point is the need to have a system architecture that can be more flexible in updating the training datasets for the classification of this pathology. In this context, the proposed architecture reserves the goal of developing and implementing a hybrid architecture based on Cloud, Fog and Edge Computing in order to provide a Melanoma Detection service based on clinical and/or dermoscopic images. At the same time, this architecture must be able to interface with the amount of data to be analyzed by reducing the running time of the necessary computational operations. This has been highlighted with experiments carried out on a single machine and on different distribution systems, highlighting how a distributed approach guarantees the achievement of an output in a much more acceptable time without the need to fully rely on data scientists skills.
    DOI:  https://doi.org/10.1109/JBHI.2021.3113609
  44. Front Immunol. 2021 ;12 736498
    Clinical Relevance of Serum Kyn/Trp Ratio and Basal and IFNγ-Upregulated IDO1 Expression in Peripheral Monocytes in Early Stage Melanoma.
    Annabel Meireson, Liesbeth Ferdinande, Marc Haspeslagh, Benjamin Hennart, Delphine Allorge, Piet Ost, Nora Sundahl, Mathieu Spaas, Annelies Demeyer, Lieve Brochez.
      Immune escape is an early phenomenon in cancer development/progression. Indoleamine 2,3-dioxygenase 1 (IDO1) is a normal endogenous mechanism of acquired peripheral immune tolerance and may therefore be tumor-promoting. This study investigated the clinical relevance of IDO1 expression by immune cells in the lymph nodes and blood and of the serum kynurenine/tryptophan (Kyn/Trp) ratio in 65 systemic treatment naïve stage I-III melanoma patients. Blood samples were collected within the first year of diagnosis. Patients had a median follow-up of 61 months. High basal IDO1 expression in peripheral monocytes and low IFNγ-induced IDO1 upregulation correlated with worse outcome independent from disease stage. Interestingly studied factors were not interrelated. During follow-up, the risk of relapse was 9% (2/22) in the subgroup with high IFNγ-induced IDO1 upregulation in monocytes. In contrast, if IDO1 upregulation was low, relapse occurred in 30% (3/10) of patients with low basal IDO1 expression in monocytes and in 61.5% (8/13) in the subgroup with high basal IDO1 expression in monocytes (Log-Rank test, p=0.008). This study reveals some immune features in the blood of early stage melanoma that may be of relevance for disease outcome. These may offer a target for sub-stratification and early intervention.
    Keywords:  IDO1; Kyn/Trp; biomarker; early stage melanoma; immune cells; liquid biopsy; monocytes; tryptophan metabolism
    DOI:  https://doi.org/10.3389/fimmu.2021.736498
  45. Acta Biomater. 2021 Sep 15. pii: S1742-7061(21)00602-4. [Epub ahead of print]
    Polydopamine-based nanoplatform for photothermal ablation with long-term immune activation against melanoma and its recurrence.
    Mengmeng Li, Rong Guo, Jiaojie Wei, Miao Deng, Jiaxin Li, Yuan Tao, Man Li, Qin He.
      The high risk of tumor recurrence presents a big challenge in melanoma therapy. Photothermal therapy (PTT) has merged as a powerful weapon against tumor in recent years, which produces tumor-associated antigens (TAA) and recruits dendritic cells (DCs) to tumor sites through immunogenic cell death (ICD) for immune activation. However, due to the lack of activation signals of DCs, the immune effect induced by PTT is not sufficient to inhibit the recurrence and proliferation of tumor. To efficiently cooperate PTT and immunotherapy to circumvent tumor recurrence, here we constructed a polydopamine (PDA) based core-shell nanoplatform loading CpG ODNs to elicit robust photothermal ablation and antitumor immune responses. Cationized polydopamine coated with hyaluronic acid (HA) shell was proven an efficient photothermal agent that increased the surface temperature of tumor by 16°C and induced ICD. CpG ODNs effectively induced maturation of DCs by elevating the expression of co-stimulating markers. PTT combined with CpG ODNs achieved a remarkable synergistic treatment effect in the maturation of DCs and activation of T cells in melanoma-bearing mice model compared with PTT or CpG ODNs alone. Furthermore, in a tumor recurrence model, photothermal-immune combination therapy increased the infiltration of CTLs in distant tumor compared with PTT or CpG ODNs alone. The combination therapy overcame insufficient immunity at distant tumor caused by PTT alone and relieved immunosuppression microenvironment of the tumor. Hence, the PDA based core-shell nanoplatform presents a potent photo-immunotherapy against proliferation and recurrence of melanoma. STATEMENT OF SIGNIFICANCE: In order to solve the insufficient immunity induced by photothermal therapy (PTT), CpG ODNs were utilized to enhance the weak immune response mediated by PTT through inducing DCs maturation. Hence, we designed a polydopamine (PDA) based core-shell nanoplatform loading CpG ODNs followed by hyaluronic acid named PPP/CpG/HA to elicit robust photothermal ablation and antitumor immune responses. CpG ODNs were delivered to the tumor site through the targeting effect of the HA shell. The core-shell nanoplatform achieved a remarkable synergistic treatment effect in the maturation of DCs and activation of T cells, thereby overcoming insufficient immunity at distant tumor caused by PTT alone. The core-shell nanoplatform presents a potent photo-immunotherapy against proliferation and recurrence of melanoma.
    Keywords:  CpG ODNs; anti-tumor immune response; immunogenic cell death (ICD); matured DC cells; photothermal-immunotherapy; polydopamine (PDA)
    DOI:  https://doi.org/10.1016/j.actbio.2021.09.014
  46. Metabolomics. 2021 Sep 25. 17(10): 92
    Metabolomic signature of amino acids in plasma of patients with non-segmental Vitiligo.
    Rezvan Marzabani, Hassan Rezadoost, Peyman Choopanian, Sima Kolahdooz, Nikoo Mozafari, Mehdi Mirzaie, Mehrdad Karimi, Anni I Nieminen, Mohieddin Jafari.
       INTRODUCTION: Vitiligo pathogenesis is complicated, and several possibilities were suggested. However, it is well-known that the metabolism of pigments plays a significant role in the pathogenicity of the disease.
    OBJECTIVES: We explored the role of amino acids in vitiligo using targeted metabolomics.
    METHODS: The amino acid profile was studied in plasma using liquid chromatography. First, 22 amino acids were derivatized and precisely determined. Next, the concentrations of the amino acids and the molar ratios were calculated in 31 patients and 34 healthy individuals.
    RESULTS: The differential concentrations of amino acids were analyzed and eight amino acids, i.e., cysteine, arginine, lysine, ornithine, proline, glutamic acid, histidine, and glycine were observed differentially. The ratios of cysteine, glutamic acid, and proline increased significantly in Vitiligo patients, whereas arginine, lysine, ornithine, glycine, and histidine decreased significantly compared to healthy individuals. Considering the percentage of skin area, we also showed that glutamic acid significantly has a higher amount in patients with less than 25% involvement compared to others. Finally, cysteine and lysine are considered promising candidates for diagnosing and developing the disorder with high accuracy (0.96).
    CONCLUSION: The findings are consistent with the previously illustrated mechanism of Vitiligo, such as production deficiency in melanin and an increase in immune activity and oxidative stress. Furthermore, new evidence was provided by using amino acids profile toward the pathogenicity of the disorder.
    Keywords:  Amino acids; Liquid chromatography; Metabolomics; Plasma; Vitiligo
    DOI:  https://doi.org/10.1007/s11306-021-01843-x
  47. Photobiomodul Photomed Laser Surg. 2021 Sep;39(9): 600-606
    Safety and Efficacy of High-Dose Fractional Erbium: Yttrium Aluminium Garnet Laser in Stable Vitiligo.
    Aysenur Botsali, Ercan Caliskan.
      Objective: Evaluate the treatment outcome of vitiligo patients receiving a standard regimen of high-dose biweekly fractional 2940 nm erbium:yttrium aluminium garnet (YAG) laser applications as an add-on to various treatment modalities. Materials and methods: The authors extracted the study population's clinical images before treatment and 3rd-month control from their clinical archive and used the medical records. The primary outcome measure was 50% repigmentation at 3rd-month follow-up. Institutional ethical committee approved the study. Results: Of the evaluated 28 patients, 18 were eligible with 31 treatment regions. All patients received at least one topical agent [steroids, calcineurin inhibitors, or 5-fluorouracil (5-FU)] and 11 patients received either targeted ultraviolet B (UVB) or narrow-band UVB. Of the 31 study regions, 88.8% (8/9) of facial; 77.7% (7/9) of dorsal hand; 75% (3/4) of limb; and 25% (2/8) of finger lesions achieved 50% repigmentation at 3rd-month control. The facial and dorsal hand lesions' treatment responses were higher than finger lesions (p = 0.008 and 0.03, respectively). Upon evaluating adjuvant treatment modalities, all of the treatment regions receiving targeted UVB (n = 4) or topical 5-FU (n = 5) achieved the primary endpoint, whereas severe irritation limited the topical use of 5-FU. The most common adverse effects were mild oozing and crusting related to laser treatments. Conclusions: Even with high-energy settings, fractional erbium: YAG laser does not induce the Koebner phenomenon. Although controlled trials are required to make firm conclusions, fractional erbium: YAG laser was an effective and safe adjunctive option for stable vitiligo in a real-life setting.
    Keywords:  erbium:YAG laser; laser-assisted transdermal delivery; vitiligo
    DOI:  https://doi.org/10.1089/photob.2021.0016
  48. PLoS One. 2021 ;16(9): e0257006
    Implementation of artificial intelligence algorithms for melanoma screening in a primary care setting.
    Mara Giavina-Bianchi, Raquel Machado de Sousa, Vitor Zago de Almeida Paciello, William Gois Vitor, Aline Lissa Okita, Renata Prôa, Gian Lucca Dos Santos Severino, Anderson Alves Schinaid, Rafael Espírito Santo, Birajara Soares Machado.
      Skin cancer is currently the most common type of cancer among Caucasians. The increase in life expectancy, along with new diagnostic tools and treatments for skin cancer, has resulted in unprecedented changes in patient care and has generated a great burden on healthcare systems. Early detection of skin tumors is expected to reduce this burden. Artificial intelligence (AI) algorithms that support skin cancer diagnoses have been shown to perform at least as well as dermatologists' diagnoses. Recognizing the need for clinically and economically efficient means of diagnosing skin cancers at early stages in the primary care attention, we developed an efficient computer-aided diagnosis (CAD) system to be used by primary care physicians (PCP). Additionally, we developed a smartphone application with a protocol for data acquisition (i.e., photographs, demographic data and short clinical histories) and AI algorithms for clinical and dermoscopic image classification. For each lesion analyzed, a report is generated, showing the image of the suspected lesion and its respective Heat Map; the predicted probability of the suspected lesion being melanoma or malignant; the probable diagnosis based on that probability; and a suggestion on how the lesion should be managed. The accuracy of the dermoscopy model for melanoma was 89.3%, and for the clinical model, 84.7% with 0.91 and 0.89 sensitivity and 0.89 and 0.83 specificity, respectively. Both models achieved an area under the curve (AUC) above 0.9. Our CAD system can screen skin cancers to guide lesion management by PCPs, especially in the contexts where the access to the dermatologist can be difficult or time consuming. Its use can enable risk stratification of lesions and/or patients and dramatically improve timely access to specialist care for those requiring urgent attention.
    DOI:  https://doi.org/10.1371/journal.pone.0257006
  49. Bioact Mater. 2022 Feb;8 153-164
    Magnetic lipid nanovehicles synergize the controlled thermal release of chemotherapeutics with magnetic ablation while enabling non-invasive monitoring by MRI for melanoma theranostics.
    Lorena García-Hevia, Íñigo Casafont, Jessica Oliveira, Nuria Terán, Mónica L Fanarraga, Juan Gallo, Manuel Bañobre-López.
      Nowadays, a number of promising strategies are being developed that aim at combining diagnostic and therapeutic capabilities into clinically effective formulations. Thus, the combination of a modified release provided by an organic encapsulation and the intrinsic physico-chemical properties from an inorganic counterpart opens new perspectives in biomedical applications. Herein, a biocompatible magnetic lipid nanocomposite vehicle was developed through an efficient, green and simple method to simultaneously incorporate magnetic nanoparticles and an anticancer drug (doxorubicin) into a natural nano-matrix. The theranostic performance of the final magnetic formulation was validated in vitro and in vivo, in melanoma tumors. The systemic administration of the proposed magnetic hybrid nanocomposite carrier enhanced anti-tumoral activity through a synergistic combination of magnetic hyperthermia effects and antimitotic therapy, together with MRI reporting capability. The application of an alternating magnetic field was found to play a dual role, (i) acting as an extra layer of control (remote, on-demand) over the chemotherapy release and (ii) inducing a local thermal ablation of tumor cells. This combination of chemotherapy with thermotherapy establishes a synergistic platform for the treatment of solid malignant tumors under lower drug dosing schemes, which may realize the dual goal of reduced systemic toxicity and enhanced anti-tumoral efficacy.
    Keywords:  Drug delivery systems; Magnetic hyperthermia; Magnetic resonance imaging; Melanoma; Theranosis
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.06.009
  50. BMJ. 2021 Sep 23. 374 n1967
    Multiple oral erosions and ulcers in a patient with malignant melanoma.
    Hsi Yen, John Wen-Cheng Chang, Wen-Hung Chung, Chun-Bing Chen.
      
    DOI:  https://doi.org/10.1136/bmj.n1967
  51. Biotech Histochem. 2021 Sep 22. 1-5
    Tissue expression of glutathione S transferase isoenzymes in vitiligo.
    Tugba Kevser Uzuncakmak, Seyma Ozkanli, Arzu Kaya Kocdogan, Serpil Oguztuzun, Ayse Serap Karadag, Emin Ozlu, Necmettin Akdeniz.
      The association of glutathione S-transferase (GST) enzymes with vitiligo is inconclusive. To evaluate tissue expressions of GST isoenzymes in vitiligo patients and to compare these expressions with healthy controls, we used 26 active depigmented patches on the trunk of vitiligo patients and 20 healthy sex and age matched controls. Punch biopsies were taken from the lesioned or normal skin. Tissue expression of GST isoenzymes were analyzed immunohistochemically. Tissue expression of GSTT1, GSTA1 and GSTP1 was significantly higher in the patient group than controls. Tissue expression of GSTM1 was not significantly different between the two groups. The increased tissue expression of GSTT1, GSTA1 and GSTP1 may represent a response to excess free radical formation in vitiligo and may support the role of oxidative stress in the pathogenesis of vitiligo.
    Keywords:  Antioxidants; dermatology; glutathione S transferase; human; oxidative stress; pathology; vitiligo
    DOI:  https://doi.org/10.1080/10520295.2021.1977998
  52. Eur J Cancer. 2021 Sep 20. pii: S0959-8049(21)00572-4. [Epub ahead of print]157 306-307
    Adjuvant treatment in patients with melanoma: The planning of scanning.
    Evalyn E A P Mulder, Dirk J Grünhagen, Stefan Sleijfer, Carin A Uyl-de Groot, Astrid A M van der Veldt.
      
    DOI:  https://doi.org/10.1016/j.ejca.2021.08.041
  53. Ann Med Surg (Lond). 2021 Oct;70 102833
    Vitiligo and pregnancy: How do each affect the other?
    Mohsen M A Abdelhafez, Karim A M Ahmed, Nicholas Tze Ping Pang, Dg Marshita Pg Baharuddin, Win Win Than, Fairrul Kadir, Mohammad Saffree Jeffree, Firdaus Hayati.
      Vitiligo is one of the dermatomes affecting the melanocytes resulting in their destruction and subsequent patchy depigmentation of the skin. It is postulated to occur due to an autoimmune problem. Despite being a disease with limited systemic involvement and lack of mortality, it has a severe psychological impact. It may have a powerfully negative effect on a patient's quality of life. The relationship between vitiligo and pregnancy is not widely acknowledged. It may be associated with adverse pregnancy outcomes such as recurrent miscarriage, prematurity, intrauterine growth retardation and pre-eclampsia. Herein, this review describes the disease's adverse effects on pregnancy outcomes and the influence of pregnancy itself on the clinical evolution and prognosis of vitiligo.
    Keywords:  Adverse outcomes; Autoimmune; Pregnancy; Vitiligo
    DOI:  https://doi.org/10.1016/j.amsu.2021.102833
  54. Pediatr Dermatol. 2021 Sep 24.
    Vulvar vitiligo and lichen sclerosus in children: A clinical challenge.
    Giulia Veronesi, Annalucia Virdi, Miriam Leuzzi, Carlotta Gurioli, Marco Adriano Chessa, Alba Guglielmo, Iria Neri.
      Vulvar vitiligo (VV) and vulvar lichen sclerosus (VLS), both feature skin and mucosal hypo-/depigmentation. The aim of this study was to describe the clinical and dermoscopic features of VV and VLS in the pediatric population, providing diagnostic clues, and to define their association. We performed a systematic literature review of the clinical and dermoscopic features of pediatric VV and VLS. An observational study was conducted on children affected by VLS associated with VV, referred to the Dermatology Unit of the Sant'Orsola Polyclinic in Bologna, Italy. Medical history, age at diagnosis, ethnicity, clinical and dermoscopic features, and symptoms were recorded for all patients. 124 cases of VLS and 10 cases of VV were reviewed. Clinical manifestations included hypo-/depigmented patches in both conditions, while ecchymosis/purpura and fissures/erosion were observed in VLS. Symptoms including pruritus, pain, or burning were reported only by VLS patients. In our study five patients with VLS associated with VV were retrieved. Clinical features included well-demarcated depigmented patches in VV and translucent areas, erythema, ecchymoses/purpura, and labial fusion in VLS. Dermoscopy showed white structureless areas with a whipped cream-like appearance, linear or dotted vessels, white chrysalis-like structures, erosion and red-purpuric blotches in VLS and reduced pigment network or pigment absence, intralesional spots of residual pigmentation and telangiectasias in VV. Symptoms were present in all patients. Both VV and VLS show hypo-/depigmented patches. In the presence of associated symptoms, possible VLS should be investigated with clinical and dermoscopic examination to achieve a prompt diagnosis.
    Keywords:  child; children; dermoscopy; vulvar lichen sclerosus; vulvar vitiligo
    DOI:  https://doi.org/10.1111/pde.14771
  55. Lasers Med Sci. 2021 Sep 21.
    Low-level laser treatment promotes skin wound healing by activating hair follicle stem cells in female mice.
    Yihua Chen, Liqiang Liu, Jincai Fan, Tiran Zhang, Yan Zeng, Zhiguo Su.
      The aim of the study was to explore the effect and mechanism of a low-level laser on hair follicle stem cells in full-thickness skin wound healing in mice. Full-thickness skin defects were generated by a 5-mm punch biopsy tool on the backs of depilated C57/BL6N mice, which were randomly divided thereafter into a low-dose laser treatment group (LLLT-Low), a high-dose laser treatment group (LLLT-High), and a control group (control). From the day of modeling to the day before the skin samples were taken, the wound area and wound edge of the mice in the LLLT-Low and LLLT-High groups were irradiated with a laser comb every 24 h, and the energy density was 1 J/cm2 and 10 J/cm2, respectively. The control group was irradiated with an ordinary fluorescent lamp. At 0, 3, 5, 10, and 14 days after modeling, pictures of each wound were taken, and the percent wound closure was analyzed. At 3, 5, 10, and 14 days after modeling, the samples were observed by hematoxylin and eosin (HE) and immunofluorescence (IF) staining. Whole transcriptome sequencing (RNA-Seq) was performed on the samples on day 10. Gene Ontology (GO) analysis was performed, and the results were validated by Western blot analysis and enzyme-linked immunosorbent assay (ELISA). The analysis of the percent of wound closure showed that healing was accelerated (significantly from 5 to 10 days) in the LLLT-Low group, but there was no clear change in the LLLT-High group. HE staining showed that the LLLT-Low group had an increasing number of hair follicles and a tendency to migrate to the center of the wound. There was no significant increase in the number of hair follicles and no obvious migration in the LLLT-High group. Immunofluorescence staining showed that the total number of CK15 + hair follicle stem cells in the LLLT-Low group was higher than that in the control group and LLLT-High group at all time points. The number and farthest migration distance of CK15 + hair follicle stem cells increased significantly with time, and after 5 days, they were significantly higher than those in the control group and LLLT-High group. RNA-Seq and Western blot analysis showed that the expression of related genes in hair follicle stem cells, including CK15, in the LLLT-Low group was upregulated. GO analysis and ELISA showed that the expression of many cytokines, represented by IL34, in the LLLT-Low group was upregulated. Low-level laser treatment can promote the proliferation, differentiation, and migration of CK15 + hair follicle stem cells by upregulating the cytokine IL34, thereby promoting skin wound healing in mice.
    Keywords:  Hair follicle stem cells; IL34; Low-level laser treatment; Wound healing
    DOI:  https://doi.org/10.1007/s10103-021-03419-6
  56. Dermatol Ther. 2021 Sep 21. e15143
    Clinico-epidemiological profile and long term follow up in Melasma.
    Muthu Sendhil Kumaran, R Vignesh Narayan, Akanksha Kaushik, Anuradha Bishnoi, Keshavamurthy Vinay, Davinder Parsad.
      Melasma is a disorder of hyperpigmentation that is frustratingly resistant to therapy with high recurrence rate on treatment discontinuation. With scarcity of melasma epidemiological studies from India, we conducted this study to see clinico-epidemiological trends and therapeutic response. Totally 957 melasma patients were studied during 5-year period between October 2014 to September 2019. A female preponderance was seen. Patients were classified as early, moderate and late responders if they had more than 80% clinical improvement within 8 weeks, 8-12 weeks, and 12-16 weeks rest classified as non-responders. 648 patients with mMASI of ≤ 5 had been prescribed non-hydroquinone-based therapies who had over all response rate of 40.9% by end of 16 weeks, 309 with mMASI > 5 received hydroquinone based triple combination with a response rate of 33.6% at end of 16 weeks. A total of 33.65% responded to triple combination compared to 40.1% in the non-hydroquinone group. All non-responders received oral tranexamic acid 250mg twice daily. Most patients on oral tranexamic acid group developed recurrence by 6 weeks post discontinuation, compared to triple combination therapy group who had relapse by second month post discontinuation and four months to relapse with non-hydroquinone-based therapies. Side effects experienced was 0.83 % in hydroquinone group reporting erythema and burning. 0.57 % in non-hydroquinone group perceived stinging sensation and none from tranexamic acid group. The longest follow up available in our study was for 18 months. The emergent need of the hour is a long, safe and effective therapy for melasma.
    Keywords:  melasma; tranexamic acid
    DOI:  https://doi.org/10.1111/dth.15143
  57. Pediatr Transplant. 2021 Sep 25. e14146
    Outcomes of skin cancers in pediatric solid organ transplant patients: A systematic review.
    Muskaan Sachdeva, Irene Lara-Corrales, Elena Pope, An-Wen Chan, Rulan S Parekh, Abhijat Kitchlu, Cathryn Sibbald.
       BACKGROUND: The most frequently reported malignancies after solid organ transplant are cutaneous, but data on the risk in pediatric populations varies across studies.
    OBJECTIVES: To perform a systematic review including reported features and outcomes of skin cancers in pediatric solid organ transplant recipients.
    METHODS: EMBASE and MEDLINE were systematically searched (Prospero CRD42020201659).
    RESULTS: The review summarizes data from 20 studies on 337 patients, with a median age ranging from 15.0 to 19.5 years as reported in 4 studies, who developed skin malignancies after pediatric solid organ transplantation. Median ages at transplant and skin cancer diagnosis ranged from 1.5 to 17.0 years and 15.3 to 33.5 years, respectively. Squamous cell carcinoma (SCC) was most commonly reported (218 cases), followed by basal cell carcinoma (BCC) (91 cases), melanoma (18 cases), and unspecified keratinocyte carcinomas (2 cases). The median latency period between transplantation and cancer diagnosis ranged from 2.2 to 21.0 years. Overall, 4 studies reported 17 cases of metastasis in total, and recurrence was reported in one case. Six deaths were reported in one study related to SCC and melanoma metastases. The incidence rate of skin cancer after pediatric transplantation per 100 person-years of follow-up was 2.1 based on 5 studies.
    CONCLUSION: The most frequent post-transplant malignancy in pediatric organ transplant recipients was SCC.
    Keywords:  keratinocyte carcinoma; melanoma; pediatric; skin cancer; transplant
    DOI:  https://doi.org/10.1111/petr.14146
  58. Photochem Photobiol. 2021 Sep 24.
    Ability of the Putative Decomposition Products of 2,3-dioxetanes of Indoles to Photosensitize Cyclobutane Pyrimidine Dimer (CPD) Formation and its Implications for the "Dark" (Chemisensitized) Pathway to CPDs in Melanocytes.
    Yanjing Wang, Elena M Cacchillo, Dariusz M Niedzwiedzki, John-Stephen Taylor.
      The formation of cyclobutane pyrimidine dimers (CPDs) by a "dark" pathway in melanocytes has been attributed to chemisensitization by dioxetanes produced from peroxynitrite oxidation of melanin or melanin precursors. These dioxetanes are proposed to decompose to triplet state compounds which sensitize CPD formation by triplet-triplet energy transfer. To determine whether such compounds are capable of sensitizing CPD formation, the putative decomposition products of 2,3-dioxetanes of variously substituted indoles were synthesized and their triplet state energies determined at 77 K. Their ability to photosensitize CPD formation was determined by an enzyme-coupled gel electrophoresis assay in comparison to norfloxacin (NFX) which has the lowest triplet energy known to sensitize CPD formation. The decomposition products of 2,3-dioxetanes of 5-hydroxy and 5,6-dimethoxy indoles used as models for melanin precursors had lower triplet energies and were incapable of photosensitizing CPD formation. Theoretical calculations suggest that the decomposition products of the 2,3-dioxetanes of melanin precursors DHI and DHICA will have similarly low triplet energies. Decomposition products of the 2,3-dioxetanes of indoles lacking oxygen substituents had higher triplet energies than NFX and were capable of photosensitizing CPD formation, suggesting that peroxynitrite oxidation of tryptophan could play a hitherto unrecognized role in the dark pathway to CPDs.
    DOI:  https://doi.org/10.1111/php.13529
  59. Am J Clin Dermatol. 2021 Sep 23.
    Psychosocial Effects of Vitiligo: A Systematic Literature Review.
    Khaled Ezzedine, Viktoria Eleftheriadou, Heather Jones, Kristen Bibeau, Fiona I Kuo, Daniel Sturm, Amit G Pandya.
       BACKGROUND: Patients with vitiligo experience reduced quality of life.
    OBJECTIVE: To comprehensively describe the available evidence for psychosocial burden in vitiligo.
    METHODS: A systematic review of observational studies and clinical trials identified using PubMed, EMBASE, Scopus, and the Cochrane databases was performed through 1 March, 2021, to assess psychosocial comorbidities in vitiligo. Two independent reviewers performed an assessment of articles and extracted data for qualitative synthesis.
    RESULTS: Included studies (N = 168) were published between 1979 and 1 March, 2021; 72.6% were published since 2010. Disorders including or related to depression (41 studies, 0.1-62.3%) and anxiety (20 studies, 1.9-67.9%) were the most commonly reported. The most prevalent psychosocial comorbidities were feelings of stigmatization (eight studies, 17.3-100%), adjustment disorders (12 studies, 4-93.9%), sleep disturbance (seven studies, 4.6-89.0%), relationship difficulties including sexual dysfunction (ten studies, 2.0-81.8%), and avoidance or restriction behavior (12.5-76%). The prevalence of most psychosocial comorbidities was significantly higher vs healthy individuals. Factors associated with a significantly higher burden included female sex, visible or genital lesions, age < 30 years (particularly adolescents), and greater body surface area involvement, among others. The most commonly reported patient coping strategy was lesion concealment.
    LIMITATIONS: Available studies were heterogeneous and often had limited details; additionally, publication bias is possible.
    CONCLUSIONS: The results of this systematic review show that vitiligo greatly affects psychosocial well-being. The extent of psychosocial comorbidities supports the use of multidisciplinary treatment strategies and education to address the vitiligo-associated burden of disease.
    PROTOCOL REGISTRATION: PROSPERO (CRD42020162223).
    DOI:  https://doi.org/10.1007/s40257-021-00631-6
  60. Annu Rev Genet. 2021 Sep 21.
    Seq Your Destiny: Neural Crest Fate Determination in the Genomic Era.
    Shashank Gandhi, Marianne E Bronner.
      Neural crest stem/progenitor cells arise early during vertebrate embryogenesis at the border of the forming central nervous system. They subsequently migrate throughout the body, eventually differentiating into diverse cell types ranging from neurons and glia of the peripheral nervous system to bones of the face, portions of the heart, and pigmentation of the skin. Along the body axis, the neural crest is heterogeneous, with different subpopulations arising in the head, neck, trunk, and tail regions, each characterized by distinct migratory patterns and developmental potential. Modern genomic approaches like single-cell RNA- and ATAC-sequencing (seq) have greatly enhanced our understanding of cell lineage trajectories and gene regulatory circuitry underlying the developmental progression of neural crest cells. Here, we discuss how genomic approaches have provided new insights into old questions in neural crest biology by elucidating transcriptional and posttranscriptional mechanisms that govern neural crest formation and the establishment of axial level identity. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-genet-071719-020954
  61. J Invest Dermatol. 2021 Sep 15. pii: S0022-202X(21)02211-9. [Epub ahead of print]
    Molecular and cellular characterization of pyoderma gangrenosum: Implications for the use of gene expression.
    Alex G Ortega-Loayza, Marcia A Friedman, Ashley M Reese, Yuangang Liu, Teri M Greiling, Pamela B Cassidy, Angelo V Marzano, Lina Gao, Suzanne S Fei, James T Rosenbaum.
      
    DOI:  https://doi.org/10.1016/j.jid.2021.08.431
  62. J Eur Acad Dermatol Venereol. 2021 Sep 21.
    COVID vaccine-induced lichen planus on areas previously affected by vitiligo.
    Vincenzo Piccolo, Carlo Mazzatenta, Andrea Bassi, Giuseppe Argenziano, Mario Cutrone, Ramon Grimalt, Teresa Russo.
      We recently came across a 64-year-old woman who developed pruritic papules on both hands previously affected by vitiligo since 30 years earlier. The lesion firstly appeared 5 days after the first dose of BNT162b2 mRNA COVID-19 Vaccine, then faded away, thus recurring 24 hours soon after the second dose with a more extensive and symptomatic eruption. The patient noticed and referred a worsening of skin condition after sun exposure.
    Keywords:  covid; cutaneous; lichen planus; reaction; sars-cov-2; skin; vaccine; vitiligo
    DOI:  https://doi.org/10.1111/jdv.17687
  63. Poult Sci. 2021 Aug 19. pii: S0032-5791(21)00463-6. [Epub ahead of print]100(11): 101440
    Factors affecting gene expression associated with the skin color of black-bone chicken in Thailand.
    Panuwat Khumpeerawat, Monchai Duangjinda, Yupin Phasuk.
      The objective of this study was to investigate the effect of breed, sex, and age on the gene expression level of melanocortin 1 receptor (MC1R), DOPA chrome tautomerase (DCT), tyrosinase-related protein 1 (TYRP1), tyrosinase (TYR), and agouti signaling protein (ASIP) genes in Thai commercial chicken lines. All chicken have received Newscastle vaccination, and no antibiotics or any drugs were used in this study. Four chicken breeds including Black-Chinese, KU-Phuparn, Sri Mok, and Pradu Hang Dam were used in this study. These breeds can be classified by their skin color into 3 group including black (Black Chinese and KU-Phuparn), light black (Sri Mok), and yellowish white (Pradu Hang Dam). One hundred chickens per breed were used in this study. Breast skin tissue was randomly collected from 8 chickens (4 males, 4 females) per breed at 4, 8, 12, and 16 wk of age. The mRNA expression was analyzed using qRT-PCR and the gene expression level was calculated as 2-ΔΔCT. From the results, breed significantly (P < 0.01) affected the expression level for the 5 genes evaluated. Birds with the black skin color had greater TYRP1 and TYR gene expression when compared to chickens with light black and yellowish-white skin color, respectively. Whereas, chickens with yellowish-white skin color had greater ASIP gene expression when compared to chickens having the other skin colors. Sex significantly affected DCT, TYRP1, and TYR gene expression where the gene expression in males was greater when compared to females (P < 0.05). Age affected all gene expression levels (P < 0.01). At 4 wk of age, MC1R, DCT, TYRP1, and TYR gene expression was the highest and decreased as bird age increased (P < 0.05); however, ASIP gene expression was greatest at 8 wk of age. After 8 wk of age all gene expression for the genes evaluated in this study decreased as age increased. In addition, an interaction between breed and sex (P < 0.05) impacted DCT and ASIP gene expression. The results from this study showed that all genes evaluated can be used as candidate markers to further improve the blackness of the chicken's skin because the most desired skin color is black in the Thai black-bone chicken population.
    Keywords:  black-bone chicken; factor; gene expression; skin color
    DOI:  https://doi.org/10.1016/j.psj.2021.101440
  64. Case Rep Ophthalmol Med. 2021 ;2021 6607441
    Clinical Findings of Melanoma-Associated Retinopathy with anti-TRPM1 Antibody.
    Yoichiro Shinohara, Ryo Mukai, Shinji Ueno, Hideo Akiyama.
       Introduction: We report the clinical features and clinical course of melanoma-associated retinopathy (MAR), in which autoantibodies against the transient receptor potential cation channel subfamily M member 1 (TRPM1) were detected. Case Presentation. A 74-year-old man was referred to our hospital for treatment of bilateral vision loss. The best-corrected visual acuity was 20/100 in the right eye and 20/200 in the left eye. His electroretinogram (ERG) showed a reduced b-wave and a normal dark-adapted a-wave in both eyes. Optical coherence tomography (OCT) revealed loss of the interdigitation zone in both eyes. We strongly suspected MAR based on the markedly reduced b-wave in the ERG and a history of intranasal melanoma. The diagnosis was confirmed after autoantibodies against TRPM1 were detected in his blood serum. Fifteen months later, his ERG remained unchanged, and OCT showed bilateral cystic changes in the internal nuclear layer. The visual acuity in both eyes also remained unchanged.
    Conclusions: Anti-TRPM1 autoantibodies were detected in a patient diagnosed with MAR who had negative flash ERG and retinal microstructural abnormalities, and the impairment did not recover during the follow-up period. Identification of anti-TRPM1 antibodies was helpful in confirming the diagnosis of MAR.
    DOI:  https://doi.org/10.1155/2021/6607441
  65. Methods Mol Biol. 2022 ;2364 319-326
    Melanosome Motility in Fish Retinal Pigment Epithelial (RPE) Cells.
    Christina King-Smith.
      Several model systems have been developed to investigate mechanisms and regulation of intracellular organelle motility. The fish retinal pigment epithelial (RPE) cell represents an unusual but simple system for the study of actin-dependent organelle motility. Primary cultures of RPE dissociated from the eye are amenable to motility studies using a simple perfusion chamber and conventional phase contrast microscopy. In vivo, melanin-containing pigment granules (melanosomes) within fish RPE migrate distances up to 100 μm in response to light flux. When sheets of RPE are removed from the eye and dissociated, they attach to the substrate with apical projections extending radially from the central cell body. Melanosomes can be chemically triggered to aggregate or disperse throughout the projections. Melanosome migration in RPE apical projections is dependent on actin filaments and thus renders this model system useful for investigations of actin-dependent organelle motility.
    Keywords:  Actin; Melanosomes; Microtubules; Motor proteins; Organelle transport; Pigment granules; RPE
    DOI:  https://doi.org/10.1007/978-1-0716-1661-1_15
  66. Int J Surg Case Rep. 2021 Sep 06. pii: S2210-2612(21)00880-4. [Epub ahead of print]87 106378
    Locally advanced anorectal malignant melanoma in septuagenarian patient treated by laparoscopic abdominoperineal resection: A case report.
    Takuya Futori, Tsuyoshi Enomoto, Yohei Owada, Yusuke Ohara, Hideki Matsumura, Tatsuya Oda.
       INTRODUCTION: Anorectal malignant melanoma (ARMM) is a rare disease with a poor prognosis. In cases involving locally advanced disease, the treatment strategy is difficult, especially in octogenarian patients, because the prognosis is poor, despite the corresponding decrease or loss of the anal function.
    PRESENTATION OF CASE: A 78-year-old woman was admitted to a local hospital with chief complaints of severe anal discomfort due to an egg-sized tumor that was protruding out of the anus and melena. A diagnosis of ARMM was confirmed based on the examination of biopsy specimens and imaging study showed swollen lymph nodes on the dorsal side of the middle rectum and left internal iliac lymph nodes. Laparoscopic abdominoperineal resection with left lateral lymph node dissection was performed. The examination of the resected specimen revealed two polypoid tumors with a maximum diameter of 38 mm and 14 mm with a metastatic lymph node of 62 mm in the mesorectum. The postoperative course was uneventful. Relapse and local recurrence free survival without any complaints was obtained for more than 12 months.
    DISCUSSION: With respect to locoregional disease control, it has been reported that abdominoperineal resection can obtain better control of local disease in comparison to local resection. Laparoscopic surgery is advantageous in its facilitation of an early postoperative recovery for elderly patient.
    CONCLUSION: Laparoscopic abdominoperineal resection may control locoregional disease and improve the patient's QOL with early postoperative recovery. -even in septuagenarian patients-may become a treatment strategy for advanced ARMM.
    Keywords:  Anorectal malignant melanoma; Case report; Laparoscopic abdominoperineal resection; Septuagenarian
    DOI:  https://doi.org/10.1016/j.ijscr.2021.106378
  67. Heredity (Edinb). 2021 Sep 18.
    Distinct genetic architectures underlie divergent thorax, leg, and wing pigmentation between Drosophila elegans and D. gunungcola.
    Jonathan H Massey, Jun Li, David L Stern, Patricia J Wittkopp.
      Pigmentation divergence between Drosophila species has emerged as a model trait for studying the genetic basis of phenotypic evolution, with genetic changes contributing to pigmentation differences often mapping to genes in the pigment synthesis pathway and their regulators. These studies of Drosophila pigmentation have tended to focus on pigmentation changes in one body part for a particular pair of species, but changes in pigmentation are often observed in multiple body parts between the same pair of species. The similarities and differences of genetic changes responsible for divergent pigmentation in different body parts of the same species thus remain largely unknown. Here we compare the genetic basis of pigmentation divergence between Drosophila elegans and D. gunungcola in the wing, legs, and thorax. Prior work has shown that regions of the genome containing the pigmentation genes yellow and ebony influence the size of divergent male-specific wing spots between these two species. We find that these same two regions of the genome underlie differences in leg and thorax pigmentation; however, divergent alleles in these regions show differences in allelic dominance and epistasis among the three body parts. These complex patterns of inheritance can be explained by a model of evolution involving tissue-specific changes in the expression of Yellow and Ebony between D. elegans and D. gunungcola.
    DOI:  https://doi.org/10.1038/s41437-021-00467-0
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