bims-meladi 2021-06-27 papers

bims-meladi

Biomed News

on Melanocytes in development and disease

Issue of 2021‒06‒27
forty-seven papers selected by
Farah Jaber-Hijazi
University of the West of Scotland

Melanoma Engages Genetic and Nongenetic Drug Resistance Trajectories.
Tumor microenvironment immune-related lncRNA signature for patients with melanoma.
Pivotal factors associated with the immunosuppressive tumor microenvironment and melanoma metastasis.
RTP4 is a novel prognosis-related hub gene in cutaneous melanoma.
A Review of Epidemiology and Cancer Biology of Malignant Melanoma.
Photoacoustic detection of circulating melanoma cells in late stage patients.
ATR Inhibitors and Paclitaxel in Melanoma.
Bergamottin Induces DNA Damage and Inhibits Malignant Progression in Melanoma by Modulating miR-145/Cyclin D1 Axis.
[Treatment of melanoma with immune checkpoints inhibitors].
Identification of survival-related genes and a novel gene-based prognostic signature involving the tumor microenvironment of uveal melanoma.
Generating CAR T cells from tumor-infiltrating lymphocytes.
Eosinophilic gastroenteritis in a melanoma patient treated with nivolumab.
Circadian clock protein BMAL1 regulates melanogenesis through MITF in melanoma cells.
AMBRA1 has an impact on melanoma development beyond autophagy.
Retraction notice to "Long non-coding RNA UCA1 targets miR-185-5p and regulates cell mobility by affecting epithelial-mesenchymal transition in melanoma via Wnt/β-catenin signaling pathway" [Gene 676 (2018) 298-305].
Clinical application effect of Pembrolizumab in the treatment of advanced cutaneous malignant melanoma.
Diagnostic utility of PRAME in distinguishing proliferative nodules from melanoma in giant congenital melanocytic nevi.
Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy.
Changes in cytoarchitecture and mobility in B16F1 melanoma cells induced by 5-Br-2'-dU coincide with Rock2, miRNAs 138-5p and 455-3p reciprocal expressions.
[Metastatic melanoma and vitiligo-like depigmentation].
Advances in the discovery and development of melanoma drug therapies.
Microtubule destabilization is a critical checkpoint of chemotaxis and transendothelial migration in melanoma cells but not in T cells.
Pigmented lesion on the face: which is the chance of being melanoma using reflectance confocal microscopy features?
Melanoma reactive TCR-modified T cells generated without activation retain a less differentiated phenotype and mediate a superior in vivo response.
CD8 Positive T Lymphocyte Infiltration of Liver Metastases of Uveal Melanoma: A Case Report.
Phospho-β-catenin expression in primary and metastatic melanomas and in tumor-free visceral tissues, and associations with expression of PD-L1 and PD-L2.
Hindsight: Review of Preclinical Disease Models for the Development of New Treatments for Uveal Melanoma.
Multiscale anisotropy analysis of second-harmonic generation collagen imaging of mouse skin.
A Retrospective, Observational Analysis of Tumor Infiltrating Lymphocytes and Tumor Regression in Melanoma.
Psychological impact of BRAF mutational status in advanced melanoma patients.
SKAP2-BRAF fusion and response to an MEK inhibitor in a patient with metastatic melanoma resistant to immunotherapy.
Simultaneous silencing of Lysophosphatidylcholine Acyltransferases 1-4 by nucleic acid nanoparticles (NANPs) improves radiation response of melanoma cells.
Diagnosis of Melanoma by Imaging Mass Spectrometry: Development and Validation of a Melanoma Prediction Model.
Tumor-Penetrable Nitric Oxide-Releasing Nanoparticles Potentiate Local Antimelanoma Therapy.
A preclinical pipeline to evaluate migrastatics as therapeutic agents in metastatic melanoma.
SIRT2 promotes murine melanoma progression through natural killer cell inhibition.
The clinicopathologic spectrum and genomic landscape of de-/trans-differentiated melanoma.
Rejection of benign melanocytic nevi by nevus-resident CD4+ T cells.
A novel mouse model to evaluate neuropeptide Y-mediated melanocyte pathology.
Rate of Freeze Impacts the Survival and Immune Responses Post Cryoablation of Melanoma.
A melanoma patient with macrophage-cancer cell hybrids in the primary tumor, a lymph node metastasis and a brain metastasis.
Iris Melanocytoma in a Child: Clinical and Histopathological Findings.
Oral cyclosporine is effective in stabilizing active vitiligo: Results of a randomized controlled trial.
Cultured epidermal autografts for treatment of stable vitiligo: Quantitative analysis of color matching with surrounding normally pigmented skin.
Artificial Intelligence Image Recognition of Melanoma and Basal Cell Carcinoma in Racially Diverse Populations.
Hair-follicle mesenchymal stem-cell activity during homeostasis and wound healing.
Successful treatment with narrowband ultraviolet B phototherapy in prurigo pigmentosa.

Cancer Discov. 2021 Jun 25.

Melanoma Engages Genetic and Nongenetic Drug Resistance Trajectories.

Melanoma cells exploit both genetic and nongenetic mechanisms of resistance to MAPK inhibition.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2021-088
Ann Transl Med. 2021 May;9(10): 857

Tumor microenvironment immune-related lncRNA signature for patients with melanoma.

Jia-Hui Guo, Shan-Shan Yin, Hua Liu, Feng Liu, Feng-Hou Gao.

  Background: The incidence of malignant melanoma accounts for only approximately 5% of skin malignant tumors, however, it accounts for 75% of its mortality. Long-chain non-coding RNA (lncRNA) has a wide range of functional activities. Disorders of lncRNAs may lead to the occurrence and development of melanoma, and may also be related to immunotherapy.Methods: The transcriptomic data of primary and metastatic melanoma patients and 331 immune-related genes were downloaded from skin cutaneous melanoma (SKCM) in the The Cancer Genome Atlas (TCGA) database. On this basis, 460 immunologically relevant lncRNAs were identified by constructing a co-expression network of immunogenic genes and lncRNAs in primary and metastatic melanoma patients. Prognostic genes were screened using univariate Cox regression analysis. ROC analysis was performed to evaluate the robustness of the prognostic signature.
Results: Univariate correlation analysis showed that only 3 of the 23 immune-related lncRNAs were at high risk and the rest were at low risk. Signatures of 7 immune-related lncRNAs were identified by multivariate correlation analysis. The clinical correlation analysis showed that the 7 immune-related lncRNAs were associated with the clinical stage of primary and metastatic melanoma. Principal component analysis (PCA) showed that only 7 immune-related lncRNA signals divided tumor patients into high-risk and low-risk groups, while the low-risk group was enriched in the immune system process M13664 and immune response M19817 sets. PPI interaction network analysis showed that 11 G protein-coupled receptors and 6 corresponding ligands in the 2 gene sets affected the tumor microenvironment and were negatively related to the risk of the 7 immune-related lncRNAs. The tumor microenvironment immune cell infiltration analysis also supported the finding that anti-tumor immunity in the low-risk group was stronger than in the high-risk group.
Conclusions: These results indicate that characteristics of the 7 immune-related lncRNAs have prognostic value for melanoma patients and can be used as potential immunotherapy targets.

Keywords:  Long non-coding RNA; immune; melanoma; risk; signature

DOI:  https://doi.org/10.21037/atm-21-1794
Cancer Med. 2021 Jun 22.

Pivotal factors associated with the immunosuppressive tumor microenvironment and melanoma metastasis.

Chuan Zhang, Dan Dang, Lele Cong, Hongyan Sun, Xianling Cong.

  BACKGROUND: Considering melanoma is the deadliest malignancy among dermatoma and presently lacks effective therapies, there is an urgent need to investigate the potential mechanisms underlying melanoma metastasis and determine prospective therapeutic targets for precise treatment of melanoma.METHOD: Hub genes in melanoma metastasis were identified by analyzing RNA-seq data (mRNA, miRNA, and lncRNA) obtained from TCGA database. Then the identified hub genes were validated in human tissues with qRT-PCR, followed by survival analysis. Competing endogenous RNAs of the hub genes were defined to clarify potential molecular mechanism of melanoma progression. Then central gene-related signaling pathways were analyzed, followed by immune cell abundance analysis in tumor microenvironment with CYTERSORTx.
RESULT: A tetrad of IL2RA, IL2RG, IFNG, and IL7R genes were determined as hub genes and verified by qRT-PCR, which were significantly associated with unfavorable prognosis in melanoma. LINC02446, LINC01857, and LINC02384 may act as competing endogenous lncRNAs of IL2RA and IL7R through absorbing their shared miR.891a.5p and miR.203b.3p. JAK-STAT signaling pathway identified as the most relevant pathway in melanoma metastasis, as well as a wealthy of genes including TNFRSF 13B, TNFRSF17, TNFRSF9, TNFRSF8, TNFRSF13C, TNFRSF11B, LAG3, NRP1, ENTPD1, NT5E, CCL21, and CCR7, may induce tumor autoimmune suppression through enhancing regulatory T-cell abundance and performance in the tumor microenvironment. And regulatory T-cell proportion was indeed critically elevated in metastatic melanoma relative to primary melanoma, as well as in highly expressed IL2RA, IL2RG, IL7R, and IFNG group than their respective counterparts.
CONCLUSION: Elevated IL2RA, IL2RG, IL7R, and IFNG expression may play a central role in promoting melanoma metastasis through up regulation of intratumoral regulatory T-cell proportion mainly by activation of JAK-STAT signaling pathway. LINC02446, LINC01857, and LINC02384 may stimulate melanoma progression by reducing tumor-protecting miR.891a.5p and miR.203b.3p. A number of identified molecules including TNFRSF13B, LAG3, NRP1, ENTPD1, NT5E, CCL21, and CCR7 can serve as future therapeutic targets in melanoma treatment.

Keywords:  IL2RA; IL7R; INFG; TNFRSF; lncRNA; melanoma; miRNA; regulatory T cell

DOI:  https://doi.org/10.1002/cam4.3963
Hereditas. 2021 Jun 21. 158(1): 22

RTP4 is a novel prognosis-related hub gene in cutaneous melanoma.

Yiqi Li, Jue Qi, Jiankang Yang.

  OBJECTIVE: Melanoma accounts for 80% of skin cancer deaths. The pathogenesis of melanoma is regulated by gene networks. Thus, we aimed here to identify gene networks and hub genes associated with melanoma and to further identify their underlying mechanisms.METHODS: GTEx (normal skin) and TCGA (melanoma tumor) RNA-seq datasets were employed for this purpose. We conducted weighted gene co-expression network analysis (WGCNA) to identify key modules and hub genes associated with melanoma. Log-rank analysis and multivariate Cox model analysis were performed to identify prognosis genes, which were validated using two independent melanoma datasets. We also evaluated the correlation between prognostic gene and immune cell infiltration.
RESULTS: The blue module was the most relevant for melanoma and was thus considered the key module. Intersecting genes were identified between this module and differentially expressed genes (DEGs). Finally, 72 genes were identified and verified as hub genes using the Oncomine database. Log-rank analysis and multivariate Cox model analysis identified 13 genes that were associated with the prognosis of the metastatic melanoma group, and RTP4 was validated as a prognostic gene using two independent melanoma datasets. RTP4 was not previously associated with melanoma. When we evaluated the correlation between prognostic gene and immune cell infiltration, we discovered that RTP4 was associated with immune cell infiltration. Further, RTP4 was significantly associated with genes encoding components of immune checkpoints (PDCD1, TIM-3, and LAG3).
CONCLUSIONS: RTP4 is a novel prognosis-related hub gene in cutaneous melanoma. The novel gene RTP4 identified here will facilitate the exploration of the molecular mechanism of the pathogenesis and progression of melanoma and the discovery of potential new target for drug therapy.

Keywords:  Melanoma; Prognostic gene; RTP4

DOI:  https://doi.org/10.1186/s41065-021-00183-z
Cureus. 2021 May 18. 13(5): e15087

A Review of Epidemiology and Cancer Biology of Malignant Melanoma.

Matthew G Davey, Nicola Miller, Niall M McInerney.

  Malignant melanoma is a neoplasm originating in the melanocytes in the skin. Although malignant melanoma is the third most common cutaneous cancer, it is recognized as the main cause of skin cancer-related mortality, and its incidence is rising. The natural history of malignant melanoma involves an inconsistent and insidious skin cancer with great metastatic potential. Increased ultra-violet (UV) skin exposure is undoubtedly the greatest risk factor for developing cutaneous melanoma; however, a plethora of risk factors are now recognized as causative. Moreover, modern oncology now considers melanoma proliferation a complex, multifactorial process with a combination of genetic, epigenetic, and environmental factors all known to be contributory to tumorgenesis. Herein, we wish to outline the epidemiological, molecular, and biological processes responsible for driving malignant melanoma proliferation.

Keywords:  biology; epidemiology; melanoma; oncology; skin cancer

DOI:  https://doi.org/10.7759/cureus.15087
J Innov Opt Health Sci. 2020 Nov;pii: 2050023. [Epub ahead of print]13(6):

Photoacoustic detection of circulating melanoma cells in late stage patients.

John A Viator, Marc Hazur, Andrea Sajewski, Ahmad Tarhini, Martin E Sanders, Robert H Edgar.

  Melanoma is the deadliest skin cancer and is responsible for over 7000 deaths in the US annually. The spread of cancer, or metastasis, is responsible for these deaths, as secondary tumors interrupt normal organ function. Circulating tumor cells, or those cells that spread throughout the body from the primary tumor, are thought to be responsible for metastasis. We developed an optical method, photoacoustic flow cytometry, in order to detect and enumerate circulating melanoma cells (CMCs) from blood samples of patients. We tested the blood of Stage IV melanoma patients to show the ability of the photoacoustic flow cytometer to detect these rare cells in blood. We then tested the system on archived blood samples from Stage III melanoma patients with known outcomes to determine if detection of CMCs can predict future metastasis. We detected between 0 and 66 CMCs in Stage IV patients. For the Stage III study, we found that of those samples with CMCs, 2 remained disease free and 5 developed metastasis. Of those without CMCs, 6 remained disease free and 1 developed metastasis. We believe that photoacoustic detection of CMCs provides valuable information for the prediction of metastasis and we postulate a system for more accurate prognosis.

Keywords:  diagnosis; metastasis; optoacoustics

DOI:  https://doi.org/10.1142/s1793545820500236
Clin Cancer Res. 2021 Jun 25. pii: clincanres.1778.2021. [Epub ahead of print]

ATR Inhibitors and Paclitaxel in Melanoma.

Alan Ashworth.

A Phase 1 study defined a tolerable combination of the ATR inhibitor ceralasertib with paclitaxel and responses were seen in melanoma patients who had progressed on an immune checkpoint inhibitor. This combination warrants further exploration to determine the extent and molecular determinants of clinical activity.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-1778
Onco Targets Ther. 2021 ;14 3769-3781

Bergamottin Induces DNA Damage and Inhibits Malignant Progression in Melanoma by Modulating miR-145/Cyclin D1 Axis.

Zhongfang Zhao, Nong Liao.

  Background: Melanoma is a prevalent skin cancer with the high rate of metastasis and mortality, affecting the increasing number of people worldwide. Bergamottin (BGM) is a natural furanocoumarin derived from grapefruits and presents the potential anti-cancer activity in several tumor models. However, the role of BGM in the development of melanoma remains unclear. Here, we aimed to explore the effect of BGM on the DNA damage and progression of melanoma.Methods: The effect of BGM on the melanoma progression was analyzed by CCK-8 assays, colony formation assays, transwell assays, Annexin V-FITC Apoptosis Detection Kit, cell-cycle analysis, in vivo tumorigenicity analysis. The mechanism investigation was performed using luciferase reporter gene assays, qPCR assays, and Western blot analysis.
Results: We identified that BGM repressed cell proliferation, migration, and invasion of melanoma cells. BGM induced cell cycle arrest at the G0/G1 phase and enhanced apoptosis of melanoma cells. The DNA damage in the melanoma cells was stimulated by the BGM treatment. Meanwhile, BGM was able to up-regulate the expression of miR-145 and miR-145 targeted Cyclin D1 in the melanoma cells. Furthermore, BGM inhibited the progression of melanoma by targeting miR-145/Cyclin D1 axis in vitro. BGM attenuated the tumor growth of melanoma in vivo.
Conclusion: Thus, we conclude that BGM induces DNA damage and inhibits tumor progression in melanoma by modulating the miR-145/Cyclin D1 axis. Our finding provides new insights into the mechanism by which BGM modulates the development of melanoma. BGM may be applied as a potential anti-tumor candidate for the clinical treatment of melanoma.

Keywords:  Cyclin D1; DNA damage; bergamottin; melanoma; miR-145; progression

DOI:  https://doi.org/10.2147/OTT.S275322
Rev Prat. 2021 Apr;71(4): 380-383

[Treatment of melanoma with immune checkpoints inhibitors].

Jeremy Lupu, Pierre Hamann, Émilie Routier, Caroline Robert.

Treatment of melanoma with immune checkpoints inhibitors .Immunotherapy with checkpoints inhibitors stimulates the anti-tumor response. It has dramatically changed the prognosis of advanced melanoma and other cancers. Anti-PD1, alone or in combination with anti-CTLA4, has demonstrated significantly better response and overall survival rates than chemotherapy. The immuno-mediated toxicity is more frequent and more serious with the combination of anti-PD1 and anti-CTLA4, which also appears as the most effective treatment for metastatic melanoma. Adjuvant anti-PD1 therapy is also effective in preventing recurrence in patients with resected stage III or IV melanoma. Studies are underway to evaluate this treatment in a neo-adjuvant situation and in localized melanomas with high risk of recurrence (stage II) with promising results.

Keywords: Immunotherapy; Melanoma
Int Immunopharmacol. 2021 Jul;pii: S1567-5769(21)00452-5. [Epub ahead of print]96 107816

Identification of survival-related genes and a novel gene-based prognostic signature involving the tumor microenvironment of uveal melanoma.

Shizhen Lei, Yi Zhang.

  Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults and almost fifty percent of patients subsequently develop systemic metastases usually involving the liver. The tumor microenvironment (TME) is crucial to the initiation and progression of tumors. In the present study, we comprehensively evaluated the TME of primary UM samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database by using several bioinformatic algorithms. The prognostic value of immune score and infiltrating immune cells in the TME were evaluated. Differentially expressed genes between the low- and high-immune score groups were also identified. The majority of tumor-infiltrating lymphocytes in UM have been determined to be activated CD8 + T cells. Therefore, weighted gene co-expression network analysis (WGCNA) was performed to identify the co-expression modules and genes significantly associated with the level of infiltrating CD8 + T cells in UM. Survival-related genes involved in the TME were identified by univariate Cox regression analysis. Furthermore, an eight-gene-based prognostic signature was established in the training dataset TCGA-UM via Lasso-penalized and multivariate Cox regression analyses. The predictive value of this signature was validated in two testing datasets. Besides, a nomogram was established to serve clinical practice. Moreover, hub genes involved in the infiltrating CD8 + T cells were identified and a potential targeted therapy for preventing metastasis of UM was proposed based on the results. In summary, our results provided a robust gene-based prognostic signature for predicting prognosis of UM patients and proposed a potential targeted therapy for preventing UM metastasis.

Keywords:  Immune infiltration; Prognosis; Tumor microenvironment (TME); Uveal melanoma; WGCNA

DOI:  https://doi.org/10.1016/j.intimp.2021.107816
Ther Adv Vaccines Immunother. 2021 ;9 25151355211017119

Generating CAR T cells from tumor-infiltrating lymphocytes.

Jane K Mills, Melissa A Henderson, Lauren Giuffrida, Pasquale Petrone, Jennifer A Westwood, Phillip K Darcy, Paul J Neeson, Michael H Kershaw, David E Gyorki.

  Background: Tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapies have demonstrated promising, though limited, efficacy against melanoma. Methods: We designed a model system to explore the efficacy of dual specific T cells derived from melanoma patient TILs by transduction with a Her2-specific CAR. Results: Metastatic melanoma cells in our biobank constitutively expressed Her2 antigen. CAR-TIL produced greater amounts of IFN compared with parental TIL, when co-cultured with Her2 expressing tumor lines, including autologous melanoma tumor lines, although no consistent increase in cytotoxicity by TIL was afforded by expression of a CAR. Results of an in vivo study in NSG mice demonstrated tumor shrinkage when CAR-TILs were used in an adoptive cell therapy protocol. Conclusion: Potential limitations of transduced TIL in our study included limited proliferative potential and a terminally differentiated phenotype, which would need addressing in further work before consideration of clinical translation.

Keywords:  Her2; autologous tumor; chimeric antigen receptor; immunotherapy; melanoma

DOI:  https://doi.org/10.1177/25151355211017119
J Dermatol. 2021 Jun 20.

Eosinophilic gastroenteritis in a melanoma patient treated with nivolumab.

Hiroka Tomiyasu, Takaya Komori, Yoshihiro Ishida, Atsushi Otsuka, Kenji Kabashima.

DOI: https://doi.org/10.1111/1346-8138.16036
Pigment Cell Melanoma Res. 2021 Jun 23.

Circadian clock protein BMAL1 regulates melanogenesis through MITF in melanoma cells.

Soumyadeep Sarkar, Kenneth I Porter, Panshak P Dakup, Rajendra P Gajula, Bala S C Koritala, Ryan Hylton, Michael G Kemp, Kazumasa Wakamatsu, Shobhan Gaddameedhi.

  Solar ultraviolet B radiation (UVB) is one of the leading causes of various skin conditions, including photoaging, sunburn erythema and melanoma. As a protective response, the skin has inbuilt defense mechanisms, including DNA repair, cell cycle checkpoint, apoptosis, and melanin synthesis, of which DNA repair, cell cycle and apoptosis have been shown to be under control of the circadian clock. However, the mechanism by which the circadian clock regulates melanin synthesis is not well understood. Using human melanocytes and melanoma cells under circadian synchronized conditions, we report that the microphthalmia-associated transcription factor (MITF), a rate-limiting protein in melanin synthesis, is expressed rhythmically with 24-hour periodicity in the presence of BMAL1, a canonical clock protein. We further demonstrate that BMAL1 binds to the promoter region of MITF and transcriptionally regulates its expression, which positively influences melanin synthesis. Finally, we report that an increase in melanin levels due to BMAL1 overexpression protects human melanoma cells from UVB. In conclusion, our studies provide novel insights to the mechanistic role of the circadian clock in melanin synthesis and protection against UVB mediated DNA damage and genomic instability.

Keywords:   MITF ; BMAL1; Melanin; Melanogenesis; Ultraviolet radiation

DOI:  https://doi.org/10.1111/pcmr.12998
Autophagy. 2021 Jun 22. 1-2

AMBRA1 has an impact on melanoma development beyond autophagy.

Luca Di Leo, Daniela De Zio.

  AMBRA1 (autophagy/beclin 1 regulator 1) is a multifunctional scaffold protein involved in several cellular processes spanning from cell proliferation to apoptosis and to regulation of macroautophagy/autophagy. Our recent publication revealed that Ambra1 has an antitumorigenic role in melanoma, the most aggressive and deadly skin cancer. We have indeed collected data indicating that the increased proliferative and invasive/metastatic features that we observed in ambra1-ablated melanomas are related to a remarkable regulation by Ambra1 on cellular processes which are beyond autophagy. Our study therefore sheds light on intriguing processes affected by Ambra1 which can be exploited as therapeutic targets in AMBRA1 low-expressing melanoma.

Keywords:  AMBRA1; FAK1; GEMMs; cyclin D1; melanoma; metastasis; proliferation

DOI:  https://doi.org/10.1080/15548627.2021.1940608
Gene. 2021 Jun 17. pii: S0378-1119(21)00373-5. [Epub ahead of print] 145778

Retraction notice to "Long non-coding RNA UCA1 targets miR-185-5p and regulates cell mobility by affecting epithelial-mesenchymal transition in melanoma via Wnt/β-catenin signaling pathway" [Gene 676 (2018) 298-305].

Xige Chen, Juan Gao, Yanhua Yu, Zhengjuan Zhao, Yingli Pan.

DOI: https://doi.org/10.1016/j.gene.2021.145778
Am J Transl Res. 2021 ;13(5): 5380-5385

Clinical application effect of Pembrolizumab in the treatment of advanced cutaneous malignant melanoma.

Lei Fu, Hui Zhang, Jingwen Jiang, Xuewu Chen, Lang Chen, Hui Gong.

OBJECTIVE: To investigate the clinical application value of Pembrolizumab (PEM) in the treatment of advanced cutaneous malignant melanoma (ACMM).METHODS: The data of 56 patients with ACMM were retrospectively analyzed. According to the treatment methods, they were divided into a control group (30 cases) and an observation group (26 cases). Patients in the control group were given chemotherapy with Temozolomide (TEM), and patients in the observation group were treated with PEM on the basis of the treatment provided to the control group. The short-term therapeutic efficacy, long-term survival rate and the incidence of adverse reactions were compared between the two groups.
RESULTS: After treatment, the short-term clinical effective rate was higher in the observation group than that in the control group (P<0.05). In addition, the survival time in the observation group was longer than that in the control group (P<0.001); and the one-year survival rate was higher in the observation group (53.85% vs. 40.00%, P>0.05). No statistical difference was found in the incidence of adverse reactions between the two groups (P>0.05).
CONCLUSION: PEM can improve the short-term clinical effective recovery rate, long-term survival time and prognosis survival rate of patients with cutaneous malignant melanoma, with no increased incidence of drug-related adverse reactions. It is relatively safe and worthy of front-line clinical promotion and application.

Keywords: Advanced cutaneous malignant melanoma; Pembrolizumab; adverse reaction; chemotherapy; clinical efficacy
J Cutan Pathol. 2021 Jun 23.

Diagnostic utility of PRAME in distinguishing proliferative nodules from melanoma in giant congenital melanocytic nevi.

Pavandeep Gill, Victor G Prieto, Mary T Austin, Alessio Giubellino, Carlos A Torres-Cabala.

  We describe a case of a melanocytic proliferation arising in a giant congenital melanocytic nevus (CMN) and outline the potential utility of an immunohistochemical study with PReferentially expressed Antigen in MElanoma (PRAME) in distinguishing benign proliferative nodules (PN) from melanoma in this context. A 15-day-old girl presented with a fibrotic nodule clinically suspicious for melanoma within a giant CMN. Histopathologic examination showed a predominantly intradermal melanocytic nevus with congenital features intermixing with an ill-defined proliferation of larger melanocytes demonstrating mild to moderate cytologic atypia and increased mitotic activity. Anti-PRAME was diffusely positive within the congenital nevus while negative within the larger proliferating cells. Chromosomal microarray analysis revealed whole chromosomal gains and losses only, consistent with a PN arising in a giant CMN. To our knowledge, PRAME expression in giant CMN, PN, and pediatric melanomas has not been previously described. Based on our experience with this case, we propose that differential patterns of PRAME expression may be present in these three lesions, allowing PRAME immunohistochemistry to potentially serve as a helpful adjunct diagnostic tool for laboratories that do not readily have access to molecular testing in rendering a diagnosis for atypical melanocytic proliferations arising in giant CMN. This article is protected by copyright. All rights reserved.

Keywords:  Melanoma; PRAME; giant congenital melanocytic nevus; immunohistochemistry; proliferative nodule

DOI:  https://doi.org/10.1111/cup.14091
Oncogene. 2021 Jun 21.

Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy.

Audrey Lequeux, Muhammad Zaeem Noman, Malina Xiao, Kris Van Moer, Meriem Hasmim, Alice Benoit, Manon Bosseler, Elodie Viry, Tsolere Arakelian, Guy Berchem, Salem Chouaib, Bassam Janji.

Hypoxia is a key factor responsible for the failure of therapeutic response in most solid tumors and promotes the acquisition of tumor resistance to various antitumor immune effectors. Reshaping the hypoxic immune suppressive tumor microenvironment to improve cancer immunotherapy is still a relevant challenge. We investigated the impact of inhibiting HIF-1α transcriptional activity on cytotoxic immune cell infiltration into B16-F10 melanoma. We showed that tumors expressing a deleted form of HIF-1α displayed increased levels of NK and CD8+ effector T cells in the tumor microenvironment, which was associated with high levels of CCL2 and CCL5 chemokines. We showed that combining acriflavine, reported as a pharmacological agent preventing HIF-1α/HIF-1β dimerization, dramatically improved the benefit of cancer immunotherapy based on TRP-2 peptide vaccination and anti-PD-1 blocking antibody. In melanoma patients, we revealed that tumors exhibiting high CCL5 are less hypoxic, and displayed high NK, CD3+, CD4+ and CD8+ T cell markers than those having low CCL5. In addition, melanoma patients with high CCL5 in their tumors survive better than those having low CCL5. This study provides the pre-clinical proof of concept for a novel triple combination strategy including blocking HIF-1α transcription activity along vaccination and PD-1 blocking immunotherapy.

DOI: https://doi.org/10.1038/s41388-021-01846-x
Biochem Biophys Rep. 2021 Sep;27 101027

Changes in cytoarchitecture and mobility in B16F1 melanoma cells induced by 5-Br-2'-dU coincide with Rock2, miRNAs 138-5p and 455-3p reciprocal expressions.

Esther Natalia Muñoz, Hernán Mauricio Rivera, Luis Alberto Gómez.

  ROCK2 is a protein involved in the restructuring of the cytoskeleton in cell adhesion and contractibility processes. miR-138-5p and miR-455-3p regulate Rock2 expression, cell proliferation, migration, and invasion in different experimental cell models. However, their participation in the cytoarchitecture and mobility of B16F1 melanoma cells exposed to 5-Br-2'-dU is partially known. This work aimed to analyze ROCK2 and miRs 138-5p and 455-3p expression associated with morphological and mobility changes of B16F1 mouse melanoma cells exposed to the thymidine analog 5-Bromo-2'-deoxyuridine (5-Br-2'-dU). We observed an increase (2.2X n = 3, p < 0.05) in the cell area, coinciding with an increase in cell diameter (1.27X n = 3, p < 0.05), as well as greater cell granularity, capacity for circularization, adhesion, which was associated with more significant polymerization of F-actin, collapsed in the intermediate filaments of vimentin (VIM), and coinciding with a decrease in migration (87%). Changes coincided with a decrease in Rock2 mRNA expression (2.88X n = 3, p < 0.05), increased vimentin and a reciprocal decrease in miR-138-5p (1.8X), and an increase in miR-455-3p (2.39X). The Rock2 kinase inhibitor Y27632 partially rescued these changes. These results suggest ROCK2 and VIM regulate the morphological and mobility changes of B16 melanoma cells after exposure to 5-Br-2'-dU, and its expression may be reciprocally regulated, at least in part, by miR-138-5p and miR-455-3p.

Keywords:  5-Bromo-2'-deoxyuridine; Invasion; Melanoma; Migration; miRNAs

DOI:  https://doi.org/10.1016/j.bbrep.2021.101027
Rev Prat. 2021 Feb;71(2): 169

[Metastatic melanoma and vitiligo-like depigmentation].

Loubab Omahsan, Afaf Khouna, Siham Dikhaye, Nada Zizi.

Keywords: Melanoma; Neoplasm Metastasis
Expert Opin Drug Discov. 2021 Jun 23.

Advances in the discovery and development of melanoma drug therapies.

Monica Chanda, Mark S Cohen.

INTRODUCTION: Therapeutic strategies for melanoma have evolved significantly over the last decade shifting from cytotoxic chemotherapies like dacarbazine to targeted therapies and immunotherapies including immune checkpoint inhibitors. These new drug therapies have improved overall as well as progression-free survival, lowering the mortality of this cancer for melanoma patients with advanced disease. Newer strategies incorporate combination therapies that harness synergies between mechanisms of anticancer efficacy as well as help overcome resistance issues of monotherapies, which remain a challenge.AREAS COVERED: This review looks at each class of drug therapy for melanoma and provides an overview of the preclinical mechanism of action, the clinical efficacy data, and their applications in combination therapy regimens. NCCN treatment guidelines, safety, toxicity, and immune related adverse events are also described as well as a note on cost.
EXPERT OPINION: Numerous ongoing trials continue to evaluate the role of novel therapies and combinations for this challenging disease and understanding their mechanism of action, risks, benefits, and treatment guidelines can help care providers and patients have a more comprehensive and tailored discussion of treatment options and expectations.

DOI: https://doi.org/10.1080/17460441.2021.1942834
Cell Adh Migr. 2021 Dec;15(1): 166-179

Microtubule destabilization is a critical checkpoint of chemotaxis and transendothelial migration in melanoma cells but not in T cells.

Francesco Roncato, Ofer Regev, Sandeep Kumar Yadav, Ronen Alon.

  Microtubules (MTs) control cell shape and intracellular cargo transport. The role of MT turnover in the migration of slow-moving cells through endothelial barriers remains unclear. To irreversibly interfere with MT disassembly, we have used the MT-stabilizing agent zampanolide (ZMP) in Β16F10 melanoma as amodel of slow-moving cells. ZMP-treated B16 cells failed to follow chemotactic gradients across rigid confinements and could not generate stable sub-endothelial pseudopodia under endothelial monolayers. In vivo, ZMP-treated Β16 cells failed to extravasate though lung capillaries. In contrast to melanoma cells, the chemotaxis and transendothelial migration of ZMP-treated Tcells were largely conserved. This is afirst demonstration that MT disassembly is akey checkpoint in the directional migration of cancer cells but not of lymphocytes.

Keywords:  Cytoskeleton; cancer; metastasis; motility; taxol

DOI:  https://doi.org/10.1080/19336918.2021.1934958
Arch Dermatol Res. 2021 Jun 21.

Pigmented lesion on the face: which is the chance of being melanoma using reflectance confocal microscopy features?

Fernanda Berti Rocha Mendes, Juliana Casagrande Tavoloni Braga, Clóvis Antônio Lopes Pinto, Mariana Petaccia de Macedo, Harold Habinovitz, Gisele Gargantini Rezze.

  Facial melanoma presents itself as a brownish macula, being difficult to differentiate it from benign pigmented lesions of the face on clinical examination. Reflectance confocal microscopy (RCM) assists in diagnosing facial lesions in which dermoscopy has limitations, allowing to increase the diagnostic accuracy. The study aimed to analyze the RCM features of pigmented isolated lesions of the face for diagnosing melanoma. Also, we sought to establish the chance of a pigmented lesion on the face being a melanoma using RCM criteria. In this retrospective and prospective study, 105 clinical pigmented lesions on the face underwent RCM, and cytoarchitectural features in the epidermis, the dermo-epidermal junction (DEJ), and dermis were described. For statistical analysis, the exact chi-square test was applied to the RCM criteria. The odds ratio was estimated using univariate logistic regression. Finally, we used the multiple logistic regression method for creating a nomogram to predict the chance of a lesion being a melanoma. After univariate and multivariate logistic regression, atypical round nucleated cells within the epidermis, pagetoid spread, and follicular dendritic cells presented as statistically significant features. Then, a complex nomogram was created to give the chance of a pigmented lesion on the face being a melanoma. The presence of these three features resulted in a 98% probability for melanoma. This study allowed to estimate the diagnosis of melanoma on the face, using RCM, practicable and feasible in the daily routine, through the presence of some RCM nomogram criteria.

Keywords:  Facial melanoma; Immunohistochemistry; Lentigo maligna; Melanoma; Reflectance confocal microscopy

DOI:  https://doi.org/10.1007/s00403-021-02263-6
Sci Rep. 2021 Jun 25. 11(1): 13327

Melanoma reactive TCR-modified T cells generated without activation retain a less differentiated phenotype and mediate a superior in vivo response.

Siao-Yi Wang, Tamson V Moore, Annika V Dalheim, Gina M Scurti, Michael I Nishimura.

Adoptive T cell therapy with T cell receptor (TCR)-modified T cells has shown promise in treating metastatic melanoma and other malignancies. However, studies are needed to improve the efficacy and durability of responses of TCR-modified T cells. Standard protocols for generating TCR-modified T cells involve activating T cells through CD3 stimulation to allow for the efficient transfer of tumor-reactive receptors with viral vectors. T cell activation results in terminal differentiation and shortening of telomeres, which are likely suboptimal for therapy. In these studies, we demonstrate efficient T cell transduction with the melanoma-reactive TIL1383I TCR through culturing with interleukin 7 (IL-7) in the absence of CD3 activation. The TIL1383I TCR-modified T cells generated following IL-7 culture were enriched with naïve (TN) and memory stem cell populations (TSCM) while maintaining longer telomere lengths. Furthermore, we demonstrated melanoma-reactivity of TIL1383I TCR-modified cells generated following IL-7 culture using in vitro assays and a superior response in an in vivo melanoma model. These results suggest that utilizing IL-7 to generate TCR-modified T cells in the absence of activation is a feasible strategy to improve adoptive T cell therapies for melanoma and other malignancies.

DOI: https://doi.org/10.1038/s41598-021-92808-6
Front Oncol. 2021 ;11 672660

CD8 Positive T Lymphocyte Infiltration of Liver Metastases of Uveal Melanoma: A Case Report.

Naoki Takahashi, Kazuto Tajiri, Ko Kagoyana, Shinichi Tanaka, Ichiro Yasuda.

  A 78-year-old Japanese man was referred for examination of multiple small nodules on his liver detected by magnetic resonance imaging (MRI). These small nodules were hyperintense on T1-weighted MRI, and were in hepatobiliary phase on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid enhanced MRI. Five years earlier, he had undergone curative enucleation of his left eye for uveal melanoma. US-guided biopsy revealed that the liver nodules were metastases of melanoma. Pathological examination also showed infiltration of CD8 positive T lymphocytes. The metastatic nodules remained unchanged for more than 2 years and he was not further treated. This pathology and clinical course suggest that the systemic immune response of the host could suppress hepatic metastases of uveal melanoma.

Keywords:  CD8 positive T lymphocyte; host immune response; liver metastasis; malignant melanoma; uveal melanoma

DOI:  https://doi.org/10.3389/fonc.2021.672660
Pathol Res Pract. 2021 Jun 17. pii: S0344-0338(21)00188-6. [Epub ahead of print]224 153527

Phospho-β-catenin expression in primary and metastatic melanomas and in tumor-free visceral tissues, and associations with expression of PD-L1 and PD-L2.

Joel Pinczewski, Rebecca C Obeng, Craig L Slingluff, Victor H Engelhard.

  β-catenin (βcat) is an important downstream effector in the Wnt signaling pathway and plays important roles in the development and progression of many cancers including melanoma. βcat expression is regulated by GSK-3β-mediated phosphorylation at positions 33, 37 and 41. In normal cells, phosphorylation at these sites triggers proteasomal degradation, which prevents accumulation of free cytoplasmic βcat. In cancer cells, stabilized β-catenin translocates into the nucleus, where it associates with TCF/Lef proteins to activate transcription of genes that promote tumorigenesis and metastasis, including PD-L1. It has been suggested that nuclear phospho-βcat (pβcat) staining may be diagnostically useful in differentiating primary from metastatic melanoma. Also, a pβcat peptide (residues 30-39, with only S33 phosphorylated) is naturally presented by melanoma cells as a T-cell target. We evaluated expression of pS33-βcat in primary and metastatic melanomas by immunohistochemistry and found its expression varied widely but was most commonly cytoplasmic. Nuclear staining was identified in only 18% of metastatic melanomas. Staining with antibodies to pS33-βcat and pS33/37/T41-βcat was most intense in mitotic melanoma cells; however, pS33-βcat intensity was not significantly associated with AJCC stage, tumor location, BRAF mutation status, or immune infiltrates. Yet, PD-L1 and PD-L2 expression by tumor cells were significantly higher in tumors with high pS33-βcat expression. The low rate of nuclear pS33-βcat expression suggests that pS33-βcat may have limited utility for identifying metastatic melanomas. However, high expression in dividing cells and strong associations with PD-L1 and PD-L2 expression may inform future personalized therapies for tumors with high pS33-βcat expression.

Keywords:  Beta-catenin; Human; Immunohistochemistry; Melanoma; Metastasis

DOI:  https://doi.org/10.1016/j.prp.2021.153527
J Cancer. 2021 ;12(15): 4672-4685

Hindsight: Review of Preclinical Disease Models for the Development of New Treatments for Uveal Melanoma.

Caoimhe Goldrick, Letizia Palanga, Bobby Tang, Grace Mealy, John Crown, Noel Horgan, Susan Kennedy, Naomi Walsh.

  The molecular, histopathological, genomic and transcriptomic characteristics of uveal melanoma (UM) have identified four molecular subgroups with different clinical outcomes. Despite the improvements in UM classification and biological pathology, current treatments do not reduce the occurrence of metastasis. The development of effective adjuvant and metastatic therapies for UM has been slow and extremely limited. Preclinical models that closely resemble the molecular and genetic UM subgroups are essential for translating molecular findings into improved clinical treatment. In this review, we provide a retrospective view of the existing preclinical models used to study UM, and give an overview of their strengths and limitations. We review targeted therapy clinical trial data to evaluate the gap in the translation of preclinical findings to human studies. Reflecting on the current high attrition rates of clinical trials for UM, preclinical models that effectively recapitulate the human in vivo situation and/or accurately reflect the subtype classifications would enhance the translational impact of experimental data and have crucial implications for the advancement of personalised medicine.

Keywords:  GEMM; PDX; cell lines; personalised medicine; preclinical disease models; uveal melanoma; zebrafish models

DOI:  https://doi.org/10.7150/jca.53954
J Biomed Opt. 2021 Jun;26(6):

Multiscale anisotropy analysis of second-harmonic generation collagen imaging of mouse skin.

Karissa Tilbury, XiangHua Han, Peter Brooks, Andre Khalil.

  SIGNIFICANCE: Morphological collagen signatures are important for tissue function, particularly in the tumor microenvironment. A single algorithmic framework with quantitative, multiscale morphological collagen feature extraction may further the use of collagen signatures in understanding fundamental tumor progression.AIM: A modification of the 2D wavelet transform modulus maxima (WTMM) anisotropy method was applied to both digitally simulated collagen fibers and second-harmonic-generation imaged collagen fibers of mouse skin to calculate a multiscale anisotropy factor to detect collagen fiber organization.
APPROACH: The modified 2D WTMM anisotropy method was initially validated on synthetic calibration images to establish the robustness and sensitivity of the multiscale fiber organization tool. Upon validation, the algorithm was applied to collagen fiber organization in normal wild-type skin, melanoma stimulated skin, and integrin α10KO skin.
RESULTS: Normal wild-type skin collagen fibers have an increased anisotropy factor at all sizes scales. Interestingly, the multiscale anisotropy differences highlight important dissimilarities between collagen fiber organization in normal wild-type skin, melanoma stimulated, and integrin α10KO skin. At small scales (∼2 to 3 μm), the integrin α10KO skin was vastly different than normal skin (p-value ∼ 10 - 8), whereas the melanoma stimulated skin was vastly different than normal at large scales (∼30 to 40 μm, p-value ∼ 10 - 15).
CONCLUSIONS: This objective computational collagen fiber organization algorithm is sensitive to collagen fiber organization across multiple scales for effective exploration of collagen morphological alterations associated with melanoma and the lack of α10 integrin binding.

Keywords:  anisotropy; cryptic epitope; melanoma; second-harmonic generation; wavelets

DOI:  https://doi.org/10.1117/1.JBO.26.6.065002
J Surg Res. 2021 Jun 18. pii: S0022-4804(21)00315-2. [Epub ahead of print]267 203-208

A Retrospective, Observational Analysis of Tumor Infiltrating Lymphocytes and Tumor Regression in Melanoma.

Angela Zaladonis, Jeffrey Farma, Maureen Hill, Meghan Hotz, Karli Meller, Tamsin Board, Mengying Deng, Hong Wu, Sanjay Reddy, Eileen O'Halloran.

  BACKGROUND: Tumor infiltrating lymphocytes (TILs) and regression are thought to be distinct markers of the immune response to melanoma.OBJECTIVE: This study sought to analyze the relationship of TIL grade and presence of regression to each other and to other prognostic histopathologic and clinical values in melanoma.
MATERIALS AND METHODS: A retrospective analysis was conducted using patients diagnosed with melanoma between 2013 and 2019 whose complete histopathologic reports were available.
RESULTS: Regression was seen in 48.9%, 30.1% and 37.9% of patients with brisk, non-brisk, and absent TILs respectively (P=0.019). Melanoma tumors with brisk TILs were found to have a lower Breslow thickness than those with non-brisk or absent (P= 0.001). Tumors with regression were also found to have lower Breslow thickness (P<0.001). Neither TIL grade nor regression were protective of nodal metastasis or associated with improved survival.
CONCLUSION: Brisk TILs have a positive association with thinner tumors and the presence of tumor regression relative to non-brisk or absent TILs. This may suggest a more robust immune response in tumors with brisk TILs. Further exploration of the interplay between TIL grade, lymphocyte cell subtype and lymphocyte density may help explain this finding.

Keywords:  Brisk; Melanoma; Regression; Tumor Infiltrating Lymphocytes

DOI:  https://doi.org/10.1016/j.jss.2021.05.008
Ital J Dermatol Venerol. 2021 Jun 23.

Psychological impact of BRAF mutational status in advanced melanoma patients.

Bernardo Carli, Eleonora Campolmi, Isabella Ciardetti, Raffaella Grifoni, Serena Sestini, Maria Simona Pino, Lucia Caligiani, Lorenzo Borgognoni, Nicola Pimpinelli.

BACKGROUND: The aim of the study is to highlight the psychological aspects involved in patients with advanced melanoma and to describe the differences between subjects who are positive and negative for the BRAFv600e genetic mutation, a variable that leads to a different medical approach to cancer therapy. The hypothesis is that following knowledge of the genetic mutation and the therapeutic possibilities inherent to it, mutation positive patients (BRAF+) exhibit fewer negative psychological reactions than negative patients (BRAF-) at the time of diagnosis.METHODS: The tests used (SF-12, MHQ) were administered at the time of diagnosis and after three months.
RESULTS: The main findings suggest a greater impairment of quality of life at T1 than at T0, regardless of the mutation; BRAF mutated patients show more favourable scores at diagnosis and a reversal of the trend at three months after diagnosis.
CONCLUSIONS: The results obtained, in line with the literature under review, show a significant general psychological distress in the present oncological sample, suggesting the importance of a psychological, as well as medical, care of the patient and the family.

DOI: https://doi.org/10.23736/S2784-8671.21.07023-7
BMJ Case Rep. 2021 Jun 24. pii: e238494. [Epub ahead of print]14(6):

SKAP2-BRAF fusion and response to an MEK inhibitor in a patient with metastatic melanoma resistant to immunotherapy.

Sonya Minmin Chew, Mairi Lucas, Michelle Brady, Catherine Margaret Kelly.

  A woman in her 40s presented to the emergency department with headache and unintentional weight loss in September 2018. Investigations revealed a widely metastatic pan-negative melanoma of unknown primary. She had multiple lines of treatment including combination immunotherapy and chemotherapy. Next-generation sequencing identified an SKAP2-BRAF fusion protein, and she was commenced on an MEK inhibitor in September 2019 with a partial response seen on restaging scans after 6 weeks and a dramatic fall in her lactate dehydrogenase from 2248 IU/L to 576 IU/L. Unfortunately, the response was not maintained and she died from progression of her cancer in January 2020. SKAP2-BRAF fusions have a dimerisation domain that paradoxically activates the mitogen-activated protein kinase pathway, resulting in hyperproliferation if first-generation or second-generation BRAF inhibitors are used. Our knowledge is limited regarding the complex effects of targeted therapy in rare BRAF fusion proteins.

Keywords:  immunological products and vaccines; malignant disease and immunosuppression; skin cancer

DOI:  https://doi.org/10.1136/bcr-2020-238494
Nanomedicine. 2021 Jun 22. pii: S1549-9634(21)00061-7. [Epub ahead of print] 102418

Simultaneous silencing of Lysophosphatidylcholine Acyltransferases 1-4 by nucleic acid nanoparticles (NANPs) improves radiation response of melanoma cells.

Renata F Saito, Maria Cristina Rangel, Justin R Halman, Morgan Chandler, Luciana Nogueira de Sousa Andrade, Silvina Odete-Bustos, Tatiane Katsue Furuya, Alexis Germán Murillo Carrasco, Adriano B Chaves-Filho, Marcos Y Yoshinaga, Sayuri Miyamoto, Kirill A Afonin, Roger Chammas.

  Radiation induces the generation of Platelet-activating factor receptor (PAF-R) ligands, including PAF and oxidized phospholipids. Alternatively, PAF is also synthesized by the biosynthetic enzymes lysophosphatidylcholine acyltransferases (LPCATs) which are expressed by tumor cells including melanoma. The activation of PAF-R by PAF and oxidized lipids triggers a survival response protecting tumor cells from radiation-induced cell death, suggesting the involvement of the PAF/PAF-R axis in radioresistance. Here, we investigated the role of LPCATs in the melanoma cell radiotherapy response. LPCAT is a family of four enzymes, LPCAT1-4, and modular nucleic acid nanoparticles (NANPs) allowed for the simultaneous silencing of all four LPCATs. We found that the in vitro simultaneous silencing of all four LPCAT transcripts by NANPs enhanced the therapeutic effects of radiation in melanoma cells by increasing cell death, reducing long-term cell survival, and activating apoptosis. Thus, we propose that NANPs are an effective strategy for improving radiotherapy efficacy in melanomas.

Keywords:  Lysophosphatidylcholine acyltransferase; Nucleic acid nanoparticles (NANPs); Platelet-activating factor; RNA nanotechnology; Radiotherapy

DOI:  https://doi.org/10.1016/j.nano.2021.102418
J Cutan Pathol. 2021 Jun 21.

Diagnosis of Melanoma by Imaging Mass Spectrometry: Development and Validation of a Melanoma Prediction Model.

Rami N Al-Rohil, Jessica L Moore, Nathan Heath Patterson, Sarah Nicholson, Nico Verbeeck, Marc Claesen, Jameelah Z Muhammad, Richard M Caprioli, Jeremy L Norris, Sara Kantrow, Margaret Compton, Jason Robbins, Ahmed K Alomari.

  BACKGROUND: The definitive diagnosis of melanocytic neoplasia using solely histopathologic evaluation can be challenging. Novel techniques that objectively confirm diagnoses are needed. This study details the development and validation of a melanoma prediction model from spatially resolved multivariate protein expression profiles generated by Imaging Mass Spectrometry (IMS).METHODS: Three board-certified dermatopathologists blindly evaluated 333 samples. Samples with triply concordant diagnoses were included in this study, divided into a training set (n = 241) and a test set (n = 92). Both the training and test sets included various representative subclasses of unambiguous nevi and melanomas. A prediction model was developed from the training set using a linear support vector machine (SVM) classification model.
RESULTS: We validated the prediction model on the independent test set of 92 specimens (75 classified correctly, two misclassified, and 15 indeterminate). IMS detects melanoma with a sensitivity of 97.6% and a specificity of 96.4% when evaluating each unique spot. IMS predicts melanoma at the sample level with a sensitivity of 97.3% and a specificity of 97.5%. Indeterminate results were excluded from sensitivity and specificity calculations.
CONCLUSION: This study provides evidence that IMS-based proteomics results are highly concordant to diagnostic results obtained by careful histopathologic evaluation from a panel of expert dermatopathologists. This article is protected by copyright. All rights reserved.

Keywords:  Diagnostic Test; Imaging Mass Spectrometry; MALDI-IMS; Melanoma; Proteomics

DOI:  https://doi.org/10.1111/cup.14083
ACS Appl Mater Interfaces. 2021 Jun 23.

Tumor-Penetrable Nitric Oxide-Releasing Nanoparticles Potentiate Local Antimelanoma Therapy.

Juho Lee, Shwe Phyu Hlaing, Nurhasni Hasan, Dongmin Kwak, Hyunwoo Kim, Jiafu Cao, In-Soo Yoon, Hwayoung Yun, Yunjin Jung, Jin-Wook Yoo.

  Although nitric oxide (NO) has been emerging as a novel local anticancer agent because of its potent cytotoxic effects and lack of off-target side effects, its clinical applications remain a challenge because of the short effective diffusion distance of NO that limits its anticancer activity. In this study, we synthesized albumin-coated poly(lactic-co-glycolic acid) (PLGA)-conjugated linear polyethylenimine diazeniumdiolate (LP/NO) nanoparticles (Alb-PLP/NO NPs) that possess tumor-penetrating and NO-releasing properties for an effective local treatment of melanoma. Sufficient NO-loading and prolonged NO-releasing characteristics of Alb-PLP/NO NPs were acquired through PLGA-conjugated LP/NO copolymer (PLP/NO) synthesis, followed by nanoparticle fabrication. In addition, tumor penetration ability was rendered by the electrostatic adsorption of the albumin on the surface of the nanoparticles. The Alb-PLP/NO NPs showed enhanced intracellular NO delivery efficiency and cytotoxicity to B16F10 murine melanoma cells. In B16F10-tumor-bearing mice, the Alb-PLP/NO NPs showed improved extracellular matrix penetration and spatial distribution in the tumor tissue after intratumoral injection, resulting in enhanced antitumor activity. Taken together, the results suggest that Alb-PLP/NO NPs represent a promising new modality for the local treatment of melanoma.

Keywords:  intratumoral injection; local anticancer therapy; melanoma; nitric oxide; nitric oxide releasing nanoparticles; tumor penetration

DOI:  https://doi.org/10.1021/acsami.1c07407
Br J Cancer. 2021 Jun 25.

A preclinical pipeline to evaluate migrastatics as therapeutic agents in metastatic melanoma.

Oscar Maiques, Bruce Fanshawe, Eva Crosas-Molist, Irene Rodriguez-Hernandez, Alessia Volpe, Gaia Cantelli, Lena Boehme, Jose L Orgaz, Faraz K Mardakheh, Victoria Sanz-Moreno, Gilbert O Fruhwirth.

BACKGROUND: Metastasis is a hallmark of cancer and responsible for most cancer deaths. Migrastatics were defined as drugs interfering with all modes of cancer cell invasion and thus cancers' ability to metastasise. First anti-metastatic treatments have recently been approved.METHODS: We used bioinformatic analyses of publicly available melanoma databases. Experimentally, we performed in vitro target validation (including 2.5D cell morphology analysis and mass spectrometric analysis of RhoA binding partners), developed a new traceable spontaneously metastasising murine melanoma model for in vivo validation, and employed histology (haematoxylin/eosin and phospho-myosin II staining) to confirm drug action in harvested tumour tissues.
RESULTS: Unbiased and targeted bioinformatic analyses identified the Rho kinase (ROCK)-myosin II pathway and its various components as potentially relevant targets in melanoma. In vitro validation demonstrated redundancy of several RhoGEFs upstream of RhoA and confirmed ROCK as a druggable target downstream of RhoA. The anti-metastatic effects of two ROCK inhibitors were demonstrated through in vivo melanoma metastasis tracking and inhibitor effects also confirmed ex vivo by digital pathology.
CONCLUSIONS: We proposed a migrastatic drug development pipeline. As part of the pipeline, we provide a new traceable spontaneous melanoma metastasis model for in vivo quantification of metastasis and anti-metastatic effects by non-invasive imaging.

DOI: https://doi.org/10.1038/s41416-021-01442-6
Sci Rep. 2021 Jun 21. 11(1): 12988

SIRT2 promotes murine melanoma progression through natural killer cell inhibition.

Manchao Zhang, Scarlett Acklin, John Gillenwater, Wuying Du, Mousumi Patra, Hao Yu, Bo Xu, Jianhua Yu, Fen Xia.

SIRT2, an NAD+-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and function in various malignancies. Using murine allograft melanoma models, our results suggest increased systemic expression of SIRT2 promotes tumor progression. In this study, SIRT2-overexpressing mice exhibited enhanced tumor growth and larger tumor volumes compared to their wild-type littermates. Mechanistically, systemic overexpression of SIRT2 reduces the number of tumor-infiltrating natural killer (NK) cells and suppresses NK cell function and proliferation within the tumor microenvironment (TME). Furthermore, despite the enhancing effect of NK cell depletion on tumor volume and growth rate in wild-type littermate mice, this effect was diminished in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increases NK cell tumor infiltration and suppresses allograft melanoma tumor growth. The findings of this study identify a dynamic functional interaction between systemic SIRT2 and NK cell activity, which controls melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could present a new opportunity to mediate immunotherapy response and resistance.

DOI: https://doi.org/10.1038/s41598-021-92445-z
Mod Pathol. 2021 Jun 21.

The clinicopathologic spectrum and genomic landscape of de-/trans-differentiated melanoma.

Ingrid Ferreira, Alastair Droop, Olivia Edwards, Kim Wong, Victoria Harle, Omar Habeeb, Deepa Gharpuray-Pandit, Joseph Houghton, Katharina Wiedemeyer, Thomas Mentzel, Steven D Billings, Jennifer S Ko, Laszlo Füzesi, Kathleen Mulholland, Ivana Kuzmic Prusac, Bernadette Liegl-Atzwanger, Nicolas de Saint Aubain, Helen Caldwell, Laura Riva, Louise van der Weyden, Mark J Arends, Thomas Brenn, David J Adams.

Dedifferentiation and transdifferentiation are rare and only poorly understood phenomena in cutaneous melanoma. To study this disease more comprehensively we have retrieved 11 primary cutaneous melanomas from our pathology archives showing biphasic features characterized by a conventional melanoma and additional areas of de-/trans-differentiation as defined by a lack of immunohistochemical expression of all conventional melanocytic markers (S-100 protein, SOX10, Melan-A, and HMB-45). The clinical, histologic, and immunohistochemical findings were recorded and follow-up was obtained. The patients were mostly elderly (median: 81 years; range: 42-86 years) without significant gender predilection, and the sun-exposed skin of the head and neck area was most commonly affected. The tumors were deeply invasive with a mean depth of 7 mm (range: 4-80 mm). The dedifferentiated component showed atypical fibroxanthoma-like features in the majority of cases (7), while additional rhabdomyosarcomatous and epithelial transdifferentiation was noted histologically and/or immunohistochemically in two tumors each. The background conventional melanoma component was of desmoplastic (4), superficial spreading (3), nodular (2), lentigo maligna (1), or spindle cell (1) types. For the seven patients with available follow-up data (median follow-up period of 25 months; range: 8-36 months), two died from their disease, and three developed metastases. Next-generation sequencing of the cohort revealed somatic mutations of established melanoma drivers including mainly NF1 mutations (5) in the conventional component, which was also detected in the corresponding de-/trans-differentiated component. In summary, the diagnosis of primary cutaneous de-/trans-differentiated melanoma is challenging and depends on the morphologic identification of conventional melanoma. Molecular analysis is diagnostically helpful as the mutated gene profile is shared between the conventional and de-/trans-differentiated components. Importantly, de-/trans-differentiation does not appear to confer a more aggressive behavior.

DOI: https://doi.org/10.1038/s41379-021-00857-z
Sci Adv. 2021 Jun;pii: eabg4498. [Epub ahead of print]7(26):

Rejection of benign melanocytic nevi by nevus-resident CD4+ T cells.

Erik B Schiferle, Se Yun Cheon, Seokjin Ham, Heehwa G Son, Jonathan L Messerschmidt, Donald P Lawrence, Justine V Cohen, Keith T Flaherty, James J Moon, Christine G Lian, Ryan J Sullivan, Shadmehr Demehri.

Melanoma and melanocytic nevi harbor shared lineage-specific antigens and oncogenic mutations. Yet, the relationship between the immune system and melanocytic nevi is unclear. Using a patient-derived xenograft (PDX) model, we found that 81.8% of the transplanted nevi underwent spontaneous regression, while peripheral skin remained intact. Nevus-resident CD4+ T helper 1 cells, which exhibited a massive clonal expansion to melanocyte-specific antigens, were responsible for nevus rejection. Boosting regulatory T cell suppressive function with low-dose exogenous human interleukin-2 injection or treatment with a human leukocyte antigen (HLA) class II-blocking antibody prevented nevus rejection. Notably, mice with rejected nevus PDXs were protected from melanoma tumor growth. We detected a parallel CD4+ T cell-dominant immunity in clinically regressing melanocytic nevi. These findings reveal a mechanistic explanation for spontaneous nevus regression in humans and posit the activation of nevus-resident CD4+ effector T cells as a novel strategy for melanoma immunoprevention and treatment.

DOI: https://doi.org/10.1126/sciadv.abg4498
Exp Dermatol. 2021 Jun 11.

A novel mouse model to evaluate neuropeptide Y-mediated melanocyte pathology.

Zoya T Anderson, Julian Mehl, Katelynn M Corder, Lynn E Dobrunz, Melissa L Harris.

  Vitiligo is an autoimmune disease characterized by depigmented patches of skin due to loss of the pigment-producing melanocytes. No cure exists for vitiligo. The available treatments are inefficient for many patients, suggesting that universal treatment approaches may be inappropriate. Deeper understanding of the mechanistic basis for variability in vitiligo aetiologies is necessary. Genetic mutations in neuropeptide Y (NPY), a widely distributed protein, are associated with increased NPY expression and increased susceptibility for vitiligo. NPY is also upregulated in the circulation and lesional skin of some vitiligo patients. However, the contributions of NPY to melanocyte pathology are not understood, and presently there are no models with which to investigate this possibility. In this study, we employed NPY-overexpressing mice to explore the role of NPY in melanocyte dysfunction. Our results show that NPY overexpression induces progressive hair greying (depigmentation) due to premature depletion of follicular melanocyte stem cells. Additionally, NPY transcripts and protein are elevated in the skin and melanocytes of these mice, respectively, suggesting that these effects may be mediated locally. Together, these results suggest that supraphysiological levels of NPY in the skin can induce melanocyte dysfunction, thus identifying this mouse line as a novel model to study NPY-mediated melanocyte pathology.

Keywords:  melanocyte; melanocyte stem cell; mouse model; neuropeptide Y; pigmentation; vitiligo

DOI:  https://doi.org/10.1111/exd.14406
Front Immunol. 2021 ;12 695150

Rate of Freeze Impacts the Survival and Immune Responses Post Cryoablation of Melanoma.

Chakradhar Yakkala, Julien Dagher, Christine Sempoux, Cheryl Lai-Lai Chiang, Alban Denys, Lana E Kandalaft, Bhanu Koppolu, Rafael Duran.

  The emergence of ablative therapies has revolutionized the treatment of inoperable solid tumors. Cryoablation stands out for its uniqueness of operation based on hypothermia, and for its ability to unleash the native tumor antigens, resulting in the generation of anti-tumor immune responses. It is not clearly understood how alterations in the rate of freeze impact the immune response outcomes. In this study, we tested fast freeze and slow freeze rates for their locoregional effectiveness and their ability to elicit immune responses in a B16F10 mouse model of melanoma. Tumor bearing mice treated with fast freeze protocol survived better than the ones treated with slow freeze protocol. Fast freeze resulted in a higher magnitude of CD4+ and CD8+ T-cell responses, and a significantly extended survival post re-challenge. Thus, fast freeze rate should be applied in any future studies employing cryoablation as an in vivo vaccination tool in conjunction with targeted immunotherapies.

Keywords:  cryoablation; immune response; immunotherapy; melanoma; tumors

DOI:  https://doi.org/10.3389/fimmu.2021.695150
Cancer Genet. 2021 May 28. pii: S2210-7762(21)00115-0. [Epub ahead of print]256-257 162-164

A melanoma patient with macrophage-cancer cell hybrids in the primary tumor, a lymph node metastasis and a brain metastasis.

Greggory LaBerge, Eric Duvall, Zachary Grasmick, Kay Haedicke, Anjela Galan, John Pawelek.

  In 1911 it was proposed that cancer might result from fusion and hybridization between macrophages and cancer cells. Using immunohistochemistry it was determined that essentially all solid tumors expressed macrophage-like molecules on their cell surface. More recently we have used forensic (STR) genetics that allows one to detect DNA from more than one individual in the same sample. By studying biopsies from individuals receiving allogeneic stem cell transplants and later developed solid tumor metastases, we were able to detect both donor and patient DNA sequences suggesting that hybrids were present. Previously we found hybrids in biopsies of a renal cell carcinoma, a melanoma in a brain metastasis and a melanoma in a primary tumor with lymph node metastases. Here we have traced hybrids from a primary melanoma to an axillary lymph node to a brain metastasis. This is the first time that the entire metastatic process has been documented.

Keywords:  Leukocyte–cancer cell fusion; Metastasis; New therapeutic targets

DOI:  https://doi.org/10.1016/j.cancergen.2021.05.009
Am J Case Rep. 2021 Jun 21. 22 e931385

Iris Melanocytoma in a Child: Clinical and Histopathological Findings.

Abdulkarim Al-Kharashi, Wael A Alsakran, Abdulaziz A Alshamrani, Abdulrahman AlZaid, Azza M Y Maktabi, Yahya A Alzahrani.

BACKGROUND Melanocytoma is rare and can affect any part of the uveal tract. In rare cases, iris melanocytoma shows signs of growth, with extrascleral extension that mimics melanoma. This phenomenon makes clinical differentiation between the 2 pathologies particularly challenging. CASE REPORT A 3-year-old boy presented with recurrent ocular inflammation. Examination revealed a large, solid, homogenous mass in the inferior quadrants of the iris, with secondary localized corneal edema. The lesion did not extend to the ciliary body and fundus examination showed no lesions in the posterior segment, including the head of the optic nerve. The patient underwent a sectoral iridocyclectomy and excisional biopsy of the lesion in the iris. Histopathology of the lesion confirmed the diagnosis of iris melanocytoma. CONCLUSIONS The differential diagnosis for a mass in the iris is broad, ranging from benign cysts to melanoma, which is a life-threatening ocular condition. An iris melanocytoma always should be considered in the differential of these masses, despite their exceedingly low incidence. Although iris melanocytoma mainly manifests in patients who are middle-aged or older, it should be suspected in young children, as underscored by the present report.

DOI: https://doi.org/10.12659/AJCR.931385
Dermatol Ther. 2021 Jun 20. e15033

Oral cyclosporine is effective in stabilizing active vitiligo: Results of a randomized controlled trial.

Hitaishi Mehta, Sheetanshu Kumar, Davinder Parsad, Anuradha Bishnoi, Keshavamurthy Vinay, Muthu Sendhil Kumaran.

  Oral dexamethasone mini pulse (OMP) is an established treatment modality for active vitiligo. Cyclosporine may have therapeutic role in active vitiligo but current evidence supporting its role is scarce. The objective of study was to compare the efficacy and safety of oral cyclosporine with OMP in patients of active vitiligo. Fifty patients with active vitiligo were randomized into two groups of 25 patients. Group 1 was treated with OMP (2.5 mg dexamethasone) on two consecutive days/week for 4 months while group 2 was treated with cyclosporine (3 mg/kg/day) for 4 months. Laboratory monitoring was performed as per the prevalent protocol. The patients were followed up for another 2 months after stopping treatment. Arrest of disease progression (ADP) was defined as change of vitiligo disease activity score from 4+ to 3+ (time elapsed since last disease activity being more than 6 weeks upto 3 months) during the study period (6 months). ADP was attained in 21 patients in group 1 and 22 patients in group 2 (84% vs. 88%, p = 1.00) at the end of 6 months. However, mean time to achieve ADP was significantly lower in group 2 as compared to group 1 (10.92 [4.12] weeks vs. 13.90 [3.92] weeks, p = 0.01). Extent of repigmentation, improvement in patient assessment score, vitiligo quality of life and clinical markers of disease activity were marginal and comparable in both groups. Cyclosporine leads to earlier disease stabilization in active vitiligo as compared to OMP. Although considered a rescue drug in dermatology, low dose cyclosporine can be an effective therapeutic alternative in vitiligo patients.

Keywords:  cyclosporine; disease stabilization; oral minipulseunstable; vitiligo

DOI:  https://doi.org/10.1111/dth.15033
J Dermatol. 2021 Jun 25.

Cultured epidermal autografts for treatment of stable vitiligo: Quantitative analysis of color matching with surrounding normally pigmented skin.

Kazuhiro Toriyama, Hiroshi Kato, Hideyoshi Sato, Tomoyo Tanaka, Masukazu Inoie, Akimichi Morita.

  Cultured epidermal autografts (CEA) are surgical therapeutic alternatives for patients with stable vitiligo resistant to conventional medical treatments. In the present study, we assessed color matching before and at 12 months after CEA treatment. Eleven patients with 16 vitiligo lesions were included in this prospective study. The recipient sites were prepared by CO2 laser superficial ablation and subjected to CEA application. We clinically evaluated and categorized the color matching of the repigmented skin as well as the percentage of repigmentation. We also obtained three color values (L*a*b*) for the vitiligo lesions and surrounding normally pigmented skin. We then calculated the color differences between the two regions and compared them before and at 12 months after treatment. The mean percentage of repigmentation was 63.3% at 12 months. Six of the 16 lesions were categorized as "same as" and had color difference values of ≤5 at 12 months after treatment. Clinical evaluation of the color matching coincided well with the calculated color difference values. CEA application after CO2 laser superficial ablation was useful for treating vitiligo assessed by the percentage of repigmentation and color matching. Quantification of color differences may be a useful parameter for evaluating color matching in vitiligo.

Keywords:  color difference; color matching; cultured epidermal autograft; repigmentation; vitiligo

DOI:  https://doi.org/10.1111/1346-8138.16028
J Dermatolog Treat. 2021 Jun 22. 1-17

Artificial Intelligence Image Recognition of Melanoma and Basal Cell Carcinoma in Racially Diverse Populations.

St Lt Pushkar Aggarwal, Francis A Papay.

  BACKGROUND: Artificial intelligence (AI) image recognition models have been relatively successful in diagnosing cutaneous manifestations in individuals with light skin tone. However, when these models are tested on the same cutaneous manifestations in individuals with darker or brown skin tone, the performance of the model drops due to a paucity of such images available for model training.OBJECTIVE: The objective of this study was to improve the performance of AI models in recognizing cutaneous diseases in individuals with darker skin tone.
METHODS: Unsupervised computer darkening of skin color with preservation of the dermatological disease/lesion characteristics in images of light skinned individuals with basal cell carcinoma (BCC) and melanoma was performed.
RESULTS: Training an AI model on these artificially "darkened" images as compared to training on the original light skinned images resulted in a higher sensitivity, specificity, positive predictive value, negative predictive value, F1 score and area under the receiver operating characteristic curve of the AI model in differentiating between BCC and melanoma in individuals with brown skin tone.
CONCLUSION: Use of unsupervised image to image translation in medical AI image recognition models has the potential to significantly improve their accuracy in diagnosing diseases in individuals with racially diverse skin tone.

Keywords:  Cutaneous Manifestations; Machine Learning; Skin of Color

DOI:  https://doi.org/10.1080/09546634.2021.1944970
J Invest Dermatol. 2021 Jun 21. pii: S0022-202X(21)01350-6. [Epub ahead of print]

Hair-follicle mesenchymal stem-cell activity during homeostasis and wound healing.

Emil Aamar, Efrat Avigad Laron, Wisal Asaad, Sarina Harshuk-Shabso, David Enshell-Seijffers.

  The mesenchymal components of the hair follicle, the dermal papilla (DP) and dermal sheath (DS), are maintained by hair-follicle dermal stem cells (hfDSCs), but the position of this stem cell population throughout the hair cycle, its contribution to the maintenance of the dermis and the existence of a migratory axis from the DP to the dermis remain unclear. Here we show that during homeostasis DP and DS cells are confined to their compartments, and during the regression phase of the hair cycle, some undergo apoptosis and subsequently are internalized by nearby adipocytes. In contrast, during wound healing, DP/DS cells move towards the wound, but do not directly participate in follicle neogenesis. Furthermore, hfDSCs, driving the cyclic renewal of the DS during the hair cycle, are heterogeneous and housed during the growth phase within the most proximal part of the DS. Our analysis provides insight into the mechanisms of tissue maintenance and unravels a previously-unknown potential function of adipocytes in phagocytosis.

Keywords:  Hair follicle; mesenchymal stem cells

DOI:  https://doi.org/10.1016/j.jid.2021.05.023
J Eur Acad Dermatol Venereol. 2021 Jun 24.

Successful treatment with narrowband ultraviolet B phototherapy in prurigo pigmentosa.

M S Jang, K S Suh, D I Kwon, J H Jung, S H Seong, K H Lee, J H Kang, J B Park.

  Prurigo pigmentosa (PP) is a recurrent severe pruritic inflammatory dermatosis characterized by the sudden appearance of erythematous papules on the chest, back, or neck.1,2 The treatment options include minocycline, doxycycline, and dapsone.3 However, these treatments have limitations in that they are restricted during pregnancy and patients who cannot take oral medications. We experienced the first dramatic improvement of PP in a pregnant woman after narrowband ultraviolet B phototherapy (NB-UVB).4.

Keywords:  NBUVB; NBUVB phototherapy; Narrowband ultraviolet B; Phototherapy; Prurigo pigmentosa

DOI:  https://doi.org/10.1111/jdv.17477