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1
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Salzano S, Vecchio GM, Failla M, Russo A, Avitabile T, Longo A, Caltabiano R, Broggi G. Metastases from uveal melanoma may lack S100 expression: A clinico-pathologic and immunohistochemical study with emphasis on potential causes and diagnostic implications. Ann Diagn Pathol 2025; 76:152464. [PMID: 40056545 DOI: 10.1016/j.anndiagpath.2025.152464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/01/2025] [Accepted: 03/03/2025] [Indexed: 03/10/2025]
Abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with a high mortality rate due to metastasis, primarily to the liver. The differential diagnosis of metastatic UM, particularly in distinguishing it from cutaneous melanoma (CM), can be challenging due to overlapping histopathological features. This study investigates the immunohistochemical expression of S100 in a cohort of 41 cases, including 13 metastatic UMs, 18 metastatic CMs, and 10 primary UMs. Our results demonstrate a significant lack of S100 immunoreactivity in metastatic UM, with 84.6 % of cases showing negativity, in contrast to the diffuse positivity seen in both primary UM and metastatic CM. This finding suggests that the absence of S100 could serve as a useful marker to differentiate metastatic UM from CM, especially in cases where the primary tumor is unknown. Furthermore, the study highlights the potential diagnostic pitfall of relying solely on S100 expression on small biopsies. The absence of S100 in metastatic UM may reflect a shift in antigenic expression, possibly due to tumor dedifferentiation or clonal selection of S100-negative cells with a higher metastatic potential. Our findings emphasize the importance of employing a comprehensive immunohistochemical panel, including markers such as HMB45, SOX10, and Melan-A, in the accurate diagnosis of metastatic melanomas.
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Affiliation(s)
- Serena Salzano
- Department of Medical, Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Anatomic Pathology, University of Catania, 95123 Catania, Italy
| | - Giada Maria Vecchio
- Department of Medical, Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Anatomic Pathology, University of Catania, 95123 Catania, Italy
| | - Maria Failla
- Department of Medical, Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Anatomic Pathology, University of Catania, 95123 Catania, Italy
| | - Andrea Russo
- Department of Ophthalmology, University of Catania, Catania, Italy
| | | | - Antonio Longo
- Department of Ophthalmology, University of Catania, Catania, Italy
| | - Rosario Caltabiano
- Department of Medical, Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Anatomic Pathology, University of Catania, 95123 Catania, Italy
| | - Giuseppe Broggi
- Department of Medical, Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Anatomic Pathology, University of Catania, 95123 Catania, Italy.
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2
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Hanratty K, Finegan G, Rochfort KD, Kennedy S. Current Treatment of Uveal Melanoma. Cancers (Basel) 2025; 17:1403. [PMID: 40361330 PMCID: PMC12071000 DOI: 10.3390/cancers17091403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 04/15/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults worldwide [...].
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Affiliation(s)
- Katie Hanratty
- School of Biotechnology, Dublin City University, Collins Avenue, Glasnevin, Dublin 9, D09 V209 Dublin, Ireland; (K.H.); (G.F.); (K.D.R.)
- Research Foundation, Royal Victoria Eye and Ear Hospital, Adelaide Road, Dublin 2, D02 XK51 Dublin, Ireland
| | - Gráinne Finegan
- School of Biotechnology, Dublin City University, Collins Avenue, Glasnevin, Dublin 9, D09 V209 Dublin, Ireland; (K.H.); (G.F.); (K.D.R.)
- Research Foundation, Royal Victoria Eye and Ear Hospital, Adelaide Road, Dublin 2, D02 XK51 Dublin, Ireland
| | - Keith D. Rochfort
- School of Biotechnology, Dublin City University, Collins Avenue, Glasnevin, Dublin 9, D09 V209 Dublin, Ireland; (K.H.); (G.F.); (K.D.R.)
- Life Sciences Institute, Dublin City University, Collins Avenue, Glasnevin, Dublin 9, D09 V209 Dublin, Ireland
| | - Susan Kennedy
- Research Foundation, Royal Victoria Eye and Ear Hospital, Adelaide Road, Dublin 2, D02 XK51 Dublin, Ireland
- Life Sciences Institute, Dublin City University, Collins Avenue, Glasnevin, Dublin 9, D09 V209 Dublin, Ireland
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3
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Abdouh M, Chen Y, Goyeneche A, Burnier MN. Blue Light-Induced Mitochondrial Oxidative Damage Underlay Retinal Pigment Epithelial Cell Apoptosis. Int J Mol Sci 2024; 25:12619. [PMID: 39684332 DOI: 10.3390/ijms252312619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Reactive oxygen species (ROS) play a pivotal role in apoptosis. We reported that Blue Light (BL) induced oxidative stress in human retinal pigment epithelial (RPE) cells in vitro and increased drusen deposition and RPE cell apoptosis in human eyes. Here, we investigated the mechanisms underlying BL-induced damage to RPE cells. Cells were exposed to BL with or without the antioxidant N-acetylcysteine. Cells were analyzed for levels of ROS, proliferation, viability, and mitochondria membrane potential (ΔΨM) fluctuation. We performed proteomic analyses to search for differentially expressed proteins. ROS levels increased following RPE cell exposure to BL. While ROS production did not affect RPE cell proliferation, it was accompanied by decreased ΔΨM and increased cell apoptosis due to the caspase cascade activation in a ROS-dependent manner. Proteomic analyses revealed that BL decreased the levels of ROS detoxifying enzymes in exposed cells. We conclude that BL-induced oxidative stress is cytotoxic to RPE cells. These findings bring new insights into the involvement of BL on RPE cell damage and its role in the progression of age-related macular degeneration. The use of antioxidants is an avenue to block or delay BL-mediated RPE cell apoptosis to counteract the disease progression.
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Affiliation(s)
- Mohamed Abdouh
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
- The MUHC-McGill University Ocular Pathology & Translational Research Laboratory, McGill University, Montreal, QC H4A 3J1, Canada
| | - Yunxi Chen
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Alicia Goyeneche
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
- The MUHC-McGill University Ocular Pathology & Translational Research Laboratory, McGill University, Montreal, QC H4A 3J1, Canada
| | - Miguel N Burnier
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
- The MUHC-McGill University Ocular Pathology & Translational Research Laboratory, McGill University, Montreal, QC H4A 3J1, Canada
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Liu B, Yao X, Shang Y, Dai J. The multiple roles of autophagy in uveal melanoma and the microenvironment. J Cancer Res Clin Oncol 2024; 150:121. [PMID: 38467935 PMCID: PMC10927889 DOI: 10.1007/s00432-023-05576-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 11/09/2023] [Indexed: 03/13/2024]
Abstract
PURPOSE Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults, and effective clinical treatment strategies are still lacking. Autophagy is a lysosome-dependent degradation system that can encapsulate abnormal proteins, damaged organelles. However, dysfunctional autophagy has multiple types and plays a complex role in tumorigenicity depending on many factors, such as tumor stage, microenvironment, signaling pathway activation, and application of autophagic drugs. METHODS A systematic review of the literature was conducted to analyze the role of autophagy in UM, as well as describing the development of autophagic drugs and the link between autophagy and the tumor microenvironment. RESULTS In this review, we summarize current research advances regarding the types of autophagy, the mechanisms of autophagy, the application of autophagy inhibitors or agonists, autophagy and the tumor microenvironment. Finally, we also discuss the relationship between autophagy and UM. CONCLUSION Understanding the molecular mechanisms of how autophagy differentially affects tumor progression may help to design better therapeutic regimens to prevent and treat UM.
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Affiliation(s)
- Bo Liu
- Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Xueting Yao
- Department of Laboratory Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Shang
- Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Jinhui Dai
- Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.
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5
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Orozco CA, Mejía-García A, Ramírez M, González J, Castro-Vega L, Kreider RB, Serrano S, Combita AL, Bonilla DA. Validation of an Ultraviolet Light Response Gene Signature for Predicting Prognosis in Patients with Uveal Melanoma. Biomolecules 2023; 13:1148. [PMID: 37509183 PMCID: PMC10377706 DOI: 10.3390/biom13071148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/10/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Uveal melanoma (UVM) is a highly aggressive ocular cancer with limited therapeutic options and poor prognosis particularly for patients with liver metastasis. As such, the identification of new prognostic biomarkers is critical for developing effective treatment strategies. In this study, we aimed to investigate the potential of an ultraviolet light response gene signature to predict the prognosis of UVM patients. Our approach involved the development of a prognostic model based on genes associated with the cellular response to UV light. By employing this model, we generated risk scores to stratify patients into high- and low-risk groups. Furthermore, we conducted differential expression analysis between these two groups and explored the estimation of immune infiltration. To validate our findings, we applied our methodology to an independent UVM cohort. Through our study, we introduced a novel survival prediction tool and shed light on the underlying cellular processes within UVM tumors, emphasizing the involvement of immune subsets in tumor progression.
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Affiliation(s)
- Carlos A Orozco
- Health and Sport Sciences Research Group, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá 111221, Colombia
- Professional Program in Surgical Instrumentation, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá 111221, Colombia
- Professional Program in Optometry, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá 111221, Colombia
- Technical Program in Radiology and Diagnostic Imaging, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá 111221, Colombia
| | - Alejandro Mejía-García
- Grupo de Investigación Genética Molecular (GENMOL), Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín 050010, Colombia
| | - Marcela Ramírez
- Health and Sport Sciences Research Group, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá 111221, Colombia
- Professional Program in Surgical Instrumentation, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá 111221, Colombia
| | - Johanna González
- Health and Sport Sciences Research Group, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá 111221, Colombia
- Professional Program in Optometry, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá 111221, Colombia
| | - Luis Castro-Vega
- Genetics and Development of Brain Tumors Team, Paris Brain Institute (ICM), Hôpital Pitié-Salpêtrière, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, 75013 Paris, France
| | - Richard B Kreider
- Exercise & Sport Nutrition Lab, Human Clinical Research Facility, Texas A&M University, College Station, TX 77843, USA
| | - Silvia Serrano
- Grupo de Investigación en Biología del Cáncer, Instituto Nacional de Cancerología de Colombia, Bogotá 111511, Colombia
| | - Alba Lucia Combita
- Grupo de Investigación Traslacional en Oncología, Instituto Nacional de Cancerología de Colombia, Bogotá 111511, Colombia
- School of Medicine, Microbiology Department, Universidad Nacional de Colombia, Bogotá 111321, Colombia
| | - Diego A Bonilla
- Research Division, Dynamical Business & Science Society-DBSS International SAS, Bogotá 110311, Colombia
- Research Group in Physical Activity, Sports and Health Sciences (GICAFS), Universidad de Córdoba, Montería 230002, Colombia
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6
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Barbagallo C, Stella M, Broggi G, Russo A, Caltabiano R, Ragusa M. Genetics and RNA Regulation of Uveal Melanoma. Cancers (Basel) 2023; 15:775. [PMID: 36765733 PMCID: PMC9913768 DOI: 10.3390/cancers15030775] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/20/2023] [Accepted: 01/23/2023] [Indexed: 01/28/2023] Open
Abstract
Uveal melanoma (UM) is the most common intraocular malignant tumor and the most frequent melanoma not affecting the skin. While the rate of UM occurrence is relatively low, about 50% of patients develop metastasis, primarily to the liver, with lethal outcome despite medical treatment. Notwithstanding that UM etiopathogenesis is still under investigation, a set of known mutations and chromosomal aberrations are associated with its pathogenesis and have a relevant prognostic value. The most frequently mutated genes are BAP1, EIF1AX, GNA11, GNAQ, and SF3B1, with mutually exclusive mutations occurring in GNAQ and GNA11, and almost mutually exclusive ones in BAP1 and SF3B1, and BAP1 and EIF1AX. Among chromosomal aberrations, monosomy of chromosome 3 is the most frequent, followed by gain of chromosome 8q, and full or partial loss of chromosomes 1 and 6. In addition, epigenetic mechanisms regulated by non-coding RNAs (ncRNA), namely microRNAs and long non-coding RNAs, have also been investigated. Several papers investigating the role of ncRNAs in UM have reported that their dysregulated expression affects cancer-related processes in both in vitro and in vivo models. This review will summarize current findings about genetic mutations, chromosomal aberrations, and ncRNA dysregulation establishing UM biology.
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Affiliation(s)
- Cristina Barbagallo
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy
| | - Michele Stella
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy
| | - Giuseppe Broggi
- Department of Medical, Surgical Sciences and Advanced Technologies G.F. Ingrassia—Section of Anatomic Pathology, University of Catania, 95123 Catania, Italy
| | - Andrea Russo
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy
| | - Rosario Caltabiano
- Department of Medical, Surgical Sciences and Advanced Technologies G.F. Ingrassia—Section of Anatomic Pathology, University of Catania, 95123 Catania, Italy
| | - Marco Ragusa
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy
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7
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Filtering blue light mitigates the deleterious effects induced by the oxidative stress in human retinal pigment epithelial cells. Exp Eye Res 2022; 217:108978. [DOI: 10.1016/j.exer.2022.108978] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/10/2022] [Accepted: 02/03/2022] [Indexed: 12/22/2022]
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8
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Barbagallo C, Platania CBM, Drago F, Barbagallo D, Di Pietro C, Purrello M, Bucolo C, Ragusa M. Do Extracellular RNAs Provide Insight into Uveal Melanoma Biology? Cancers (Basel) 2021; 13:5919. [PMID: 34885029 PMCID: PMC8657116 DOI: 10.3390/cancers13235919] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults, showing a high mortality due to metastasis. Although it is considered a rare disease, a growing number of papers have reported altered levels of RNAs (i.e., coding and non-coding RNAs) in cancerous tissues and biological fluids from UM patients. The presence of circulating RNAs, whose dysregulation is associated with UM, paved the way to the possibility of exploiting it for diagnostic and prognostic purposes. However, the biological meaning and the origin of such RNAs in blood and ocular fluids of UM patients remain unexplored. In this review, we report the state of the art of circulating RNAs in UM and debate whether the amount and types of RNAs measured in bodily fluids mirror the RNA alterations from source cancer cells. Based on literature data, extracellular RNAs in UM patients do not represent, with rare exceptions, a snapshot of RNA dysregulations occurring in cancerous tissues, but rather the complex and heterogeneous outcome of a systemic dysfunction, including immune system activity, that modifies the mechanisms of RNA delivery from several cell types.
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Affiliation(s)
- Cristina Barbagallo
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (D.B.); (C.D.P.); (M.P.); (M.R.)
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Chiara Bianca Maria Platania
- Department of Biomedical and Biotechnological Sciences—Section of Pharmacology, University of Catania, 95123 Catania, Italy; (C.B.M.P.); (F.D.)
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences—Section of Pharmacology, University of Catania, 95123 Catania, Italy; (C.B.M.P.); (F.D.)
- Center of Research in Ocular Pharmacology—CERFO, University of Catania, 95123 Catania, Italy
| | - Davide Barbagallo
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (D.B.); (C.D.P.); (M.P.); (M.R.)
| | - Cinzia Di Pietro
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (D.B.); (C.D.P.); (M.P.); (M.R.)
| | - Michele Purrello
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (D.B.); (C.D.P.); (M.P.); (M.R.)
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences—Section of Pharmacology, University of Catania, 95123 Catania, Italy; (C.B.M.P.); (F.D.)
- Center of Research in Ocular Pharmacology—CERFO, University of Catania, 95123 Catania, Italy
| | - Marco Ragusa
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (D.B.); (C.D.P.); (M.P.); (M.R.)
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9
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The Impact of Ultraviolet Radiation on the Aetiology and Development of Uveal Melanoma. Cancers (Basel) 2021; 13:cancers13071700. [PMID: 33916693 PMCID: PMC8038359 DOI: 10.3390/cancers13071700] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 03/29/2021] [Accepted: 04/01/2021] [Indexed: 12/13/2022] Open
Abstract
Uveal melanoma (UM) is currently classified by the World Health Organisation as a melanoma caused by risk factors other than cumulative solar damage. However, factors relating to ultraviolet radiation (UVR) susceptibility such as light-coloured skin and eyes, propensity to burn, and proximity to the equator, frequently correlate with higher risk of UM. These risk factors echo those of the far more common cutaneous melanoma (CM), which is widely accepted to be caused by excessive UVR exposure, suggesting a role of UVR in the development and progression of a proportion of UM. Indeed, this could mean that countries, such as Australia, with high UVR exposure and the highest incidences of CM would represent a similarly high incidence of UM if UVR exposure is truly involved. Most cases of UM lack the typical genetic mutations that are related to UVR damage, although recent evidence in a small minority of cases has shown otherwise. This review therefore reassesses statistical, environmental, anatomical, and physiological evidence for and against the role of UVR in the aetiology of UM.
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10
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Katopodis P, Khalifa MS, Anikin V. Molecular characteristics of uveal melanoma and intraocular tumors. Oncol Lett 2021; 21:9. [PMID: 33240415 PMCID: PMC7681201 DOI: 10.3892/ol.2020.12270] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 09/28/2020] [Indexed: 12/13/2022] Open
Abstract
Malignant melanomas within the eye present different types of metabolic and metastatic behavior. Uveal melanoma (UM) affects a quarter of a million individuals in the USA; however, the molecular pathogenesis is not well understood. Although UV radiation is a risk factor in cutaneous melanomas, it is not crucial for UM progression. Apart from chromosomal abnormalities, numerous major tumorigenic signaling pathways, including the PI3K/Akt, MAPK/ERK, Ras-association domain family 1 isoform A and Yes-associated protein/transcriptional co-activator with PDZ-binding motif signaling pathways, are associated with intraocular tumors. The present review describes the current insights regarding these signaling pathways that regulate the cell cycle and apoptosis, and could be used as potential targets for the treatment of UMs.
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Affiliation(s)
- Periklis Katopodis
- College of Health, Medicine and Life Sciences, Brunel University, Uxbridge, London UB8 3PH, UK
- Division of Thoracic Surgery, The Royal Brompton and Harefield National Health Service Foundation Trust, Harefield Hospital, London UB9 6JH, UK
| | - Mohammad S. Khalifa
- College of Health, Medicine and Life Sciences, Brunel University, Uxbridge, London UB8 3PH, UK
| | - Vladimir Anikin
- College of Health, Medicine and Life Sciences, Brunel University, Uxbridge, London UB8 3PH, UK
- Division of Thoracic Surgery, The Royal Brompton and Harefield National Health Service Foundation Trust, Harefield Hospital, London UB9 6JH, UK
- Department of Oncology and Reconstructive Surgery, Sechenov First Moscow State Medical University, Moscow 119146, Russia
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Ortega MA, Fraile-Martínez O, García-Honduvilla N, Coca S, Álvarez-Mon M, Buján J, Teus MA. Update on uveal melanoma: Translational research from biology to clinical practice (Review). Int J Oncol 2020; 57:1262-1279. [PMID: 33173970 PMCID: PMC7646582 DOI: 10.3892/ijo.2020.5140] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 09/24/2020] [Indexed: 02/06/2023] Open
Abstract
Uveal melanoma is the most common type of intraocular cancer with a low mean annual incidence of 5‑10 cases per million. Tumours are located in the choroid (90%), ciliary body (6%) or iris (4%) and of 85% are primary tumours. As in cutaneous melanoma, tumours arise in melanocytes; however, the characteristics of uveal melanoma differ, accounting for 3‑5% of melanocytic cancers. Among the numerous risk factors are age, sex, genetic and phenotypic predisposition, the work environment and dermatological conditions. Management is usually multidisciplinary, including several specialists such as ophthalmologists, oncologists and maxillofacial surgeons, who participate in the diagnosis, treatment and complex follow‑up of these patients, without excluding the management of the immense emotional burden. Clinically, uveal melanoma generates symptoms that depend as much on the affected ocular globe site as on the tumour size. The anatomopathological study of uveal melanoma has recently benefited from developments in molecular biology. In effect, disease classification or staging according to molecular profile is proving useful for the assessment of this type of tumour. Further, the improved knowledge of tumour biology is giving rise to a more targeted approach to diagnosis, prognosis and treatment development; for example, epigenetics driven by microRNAs as a target for disease control. In the present study, the main epidemiological, clinical, physiopathological and molecular features of this disease are reviewed, and the associations among all these factors are discussed.
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Affiliation(s)
- Miguel A. Ortega
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid
- University Center for The Defense of Madrid (CUD-ACD), 28047 Madrid
| | - Oscar Fraile-Martínez
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid
- University Center for The Defense of Madrid (CUD-ACD), 28047 Madrid
| | - Santiago Coca
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid
- University Center for The Defense of Madrid (CUD-ACD), 28047 Madrid
| | - Melchor Álvarez-Mon
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid
- University Center for The Defense of Madrid (CUD-ACD), 28047 Madrid
- Internal and Oncology Service (CIBER-EHD), University Hospital Príncipe de Asturias, Alcalá de Henares, 28805 Madrid
| | - Julia Buján
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid
- University Center for The Defense of Madrid (CUD-ACD), 28047 Madrid
| | - Miguel A. Teus
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
- Ophthalmology Service, University Hospital Príncipe de Asturias, Alcalá de Henares, 28805 Madrid, Spain
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12
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Santos-Buitrago B, Santos-García G, Hernández-Galilea E. Artificial intelligence for modeling uveal melanoma. Artif Intell Cancer 2020; 1:51-65. [DOI: 10.35713/aic.v1.i4.51] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 11/05/2020] [Accepted: 11/21/2020] [Indexed: 02/06/2023] Open
Affiliation(s)
| | - Gustavo Santos-García
- IME, University of Salamanca, Salamanca 37007, Spain
- FADoSS Research Unit, Universidad Complutense de Madrid, Madrid 28040, Spain
| | - Emiliano Hernández-Galilea
- Department of Ophthalmology, Institute of Biomedicine Investigation of Salamanca (IBSAL), University Hospital of Salamanca, University of Salamanca, Salamanca 37007, Spain
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Broggi G, Ieni A, Russo D, Varricchio S, Puzzo L, Russo A, Reibaldi M, Longo A, Tuccari G, Staibano S, Caltabiano R. The Macro-Autophagy-Related Protein Beclin-1 Immunohistochemical Expression Correlates With Tumor Cell Type and Clinical Behavior of Uveal Melanoma. Front Oncol 2020; 10:589849. [PMID: 33330070 PMCID: PMC7714947 DOI: 10.3389/fonc.2020.589849] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/20/2020] [Indexed: 01/01/2023] Open
Abstract
Uveal melanoma, in spite of its rarity, represents the most common primitive intraocular malignant neoplasm of the adults; it affects choroid, ciliary bodied and iris and remains clinically silent for a long time, being accidentally discovered by routine ophthalmic exams. Prognosis of uveal melanoma is poor and frequently characterized by liver metastases, within 10-15 years from diagnosis. Autophagy is a multi-step catabolic process by which cells remove damaged organelles and proteins and recycle nutrients. It has been hypothesized that in early stages of tumorigenesis autophagy has a tumor suppressor role while, in more advanced stages, it may represent a survival mechanism of neoplastic cells in response to stress. Several proteins related to autophagy cascade have been investigated in numerous subtypes of human cancer, with overall controversal results. In this paper we studied the immunohistochemical expression of 3 autophagy related proteins (Beclin-1, p62 and ATG7) in a cohort of 85 primary uveal melanoma treated by primary enucleation (39 with metastasis and 46 non metastatic) and correlated their expression with clinico-pathological parameters and blood vascular microvessel density, in order to investigate the potential prognostic role of autophagy in this rare neoplasm. We found that high immunohistochemical levels of Beclin-1 correlated with a lower risk of metastasis and higher disease-free survival times, indicating a positive prognostic role for Beclin-1 in uveal melanoma. No statistically significative differences regarding the expression of ATG7 and p62 between metastatic and non metastatic patients was detected.
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Affiliation(s)
- Giuseppe Broggi
- Section of Anatomic Pathology, Department Gian Filippo Ingrassia, University of Catania, Catania, Italy
| | - Antonio Ieni
- Section of Pathology, Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Messina, Italy
| | - Daniela Russo
- Pathology Unit, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
| | - Silvia Varricchio
- Pathology Unit, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
| | - Lidia Puzzo
- Section of Anatomic Pathology, Department Gian Filippo Ingrassia, University of Catania, Catania, Italy
| | - Andrea Russo
- Department of Ophthalmology, University of Catania, Catania, Italy
| | - Michele Reibaldi
- Department of Ophthalmology, University of Catania, Catania, Italy.,Department of Surgical Science, Eye Clinic, University of Torino, Torino, Italy
| | - Antonio Longo
- Department of Ophthalmology, University of Catania, Catania, Italy
| | - Giovanni Tuccari
- Section of Pathology, Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Messina, Italy
| | - Stefania Staibano
- Pathology Unit, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
| | - Rosario Caltabiano
- Section of Anatomic Pathology, Department Gian Filippo Ingrassia, University of Catania, Catania, Italy
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14
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Houtzagers LE, Wierenga APA, Ruys AAM, Luyten GPM, Jager MJ. Iris Colour and the Risk of Developing Uveal Melanoma. Int J Mol Sci 2020; 21:E7172. [PMID: 32998469 PMCID: PMC7583924 DOI: 10.3390/ijms21197172] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/15/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023] Open
Abstract
Uveal melanoma (UM) is a global disease which especially occurs in elderly people. Its incidence varies widely between populations, with the highest incidence among Caucasians, and a South-to-North increase in Europe. As northern Europeans often have blond hair and light eyes, we wondered whether iris colour may be a predisposing factor for UM and if so, why. We compared the distribution of iris colour between Dutch UM patients and healthy Dutch controls, using data from the Rotterdam Study (RS), and reviewed the literature regarding iris colour. We describe molecular mechanisms that might explain the observed associations. When comparing a group of Dutch UM patients with controls, we observed that individuals from Caucasian ancestry with a green/hazel iris colour (Odds Ratio (OR) = 3.64, 95% Confidence Interval (CI) 2.57-5.14) and individuals with a blue/grey iris colour (OR = 1.38, 95% CI 1.04-1.82) had a significantly higher crude risk of UM than those with brown eyes. According to the literature, this may be due to a difference in the function of pheomelanin (associated with a light iris colour) and eumelanin (associated with a brown iris colour). The combination of light-induced stress and aging may affect pheomelanin-carrying melanocytes in a different way than eumelanin-carrying melanocytes, increasing the risk of developing a malignancy.
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Affiliation(s)
| | | | | | | | - Martine J. Jager
- Department of Ophthalmology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; (A.P.A.W.); (A.A.M.R.); (G.P.M.L.)
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15
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Premi S. Role of Melanin Chemiexcitation in Melanoma Progression and Drug Resistance. Front Oncol 2020; 10:1305. [PMID: 32850409 PMCID: PMC7425655 DOI: 10.3389/fonc.2020.01305] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 06/23/2020] [Indexed: 01/26/2023] Open
Abstract
Melanoma is the deadliest type of skin cancer. Human melanomas often show hyperactivity of nitric oxide synthase (NOS) and NADPH oxidase (NOX), which, respectively, generate nitric oxide (NO · ) and superoxide (O2 ·- ). The NO · and O2 - react instantly with each other to generate peroxynitrite (ONOO-) which is the driver of melanin chemiexcitation. Melanoma precursors, the melanocytes, are specialized skin cells that synthesize melanin, a potent shield against sunlight's ultraviolet (UV) radiation. However, melanin chemiexcitation paradoxically demonstrates the melanomagenic properties of melanin. In a loop, the NOS activity regulates melanin synthesis, and melanin is utilized by the chemiexcitation pathway to generate carcinogenic melanin-carbonyls in an excited triplet state. These carbonyl compounds induce UV-specific DNA damage without UV. Additionally, the carbonyl compounds are highly reactive and can make melanomagenic adducts with proteins, DNA and other biomolecules. Here we review the role of the melanin chemiexcitation pathway in melanoma initiation, progression, and drug resistance. We conclude by hypothesizing a non-classical, positive loop in melanoma where melanin chemiexcitation generates carcinogenic reactive carbonyl species (RCS) and DNA damage in normal melanocytes. In parallel, NOS and NOX regulate melanin synthesis generating raw material for chemiexcitation, and the resulting RCS and reactive nitrogen species (RNS) regulate cellular proteome and transcriptome in favor of melanoma progression, metastasis, and resistance against targeted therapies.
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Affiliation(s)
- Sanjay Premi
- Department of Tumor Biology, Moffitt Cancer Center & Research Institute, Tampa, FL, United States
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16
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Sayan M, Mamidanna S, Oncel D, Jan I, Vergalasova I, Weiner J, Ohri N, Acikalin B, Chundury A. Clinical management of uveal melanoma: a comprehensive review with a treatment algorithm. Radiat Oncol J 2020; 38:162-169. [PMID: 33012143 PMCID: PMC7533402 DOI: 10.3857/roj.2020.00318] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 06/19/2020] [Indexed: 12/12/2022] Open
Abstract
Uveal melanoma (UM), the most frequently occurring non-cutaneous melanoma and most common primary intraocular malignancy in adults, arises from the melanocytes of the choroid in approximately 95% of cases. Prompt diagnosis and treatment is vital as primary tumor size is one of the key factors associated with survival. Despite recent advances in management, more than half of the patients develop metastatic disease which portends poor survival. Currently, treatment options for UM include local resection, enucleation, plaque brachytherapy, and/or particle beam radiotherapy (RT). Enucleation was initially the standard of care in the management of UM, but a shift towards eye-preserving therapeutic choices such as RT and local resection has been noted in recent decades. Plaque brachytherapy, a form of localized RT, is the most popular option and is now the preferred treatment modality for a majority of UM cases. In this review we discuss the etiopathogenesis, clinical presentation and diagnosis of UM and place a special emphasis on its therapeutic options. Furthermore, we review the current literature on UM management and propose a functional treatment algorithm for non-metastatic disease.
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Affiliation(s)
- Mutlay Sayan
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Swati Mamidanna
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Damla Oncel
- Department of Biochemistry, University of California, Los Angeles, CA, USA
| | - Imraan Jan
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Irina Vergalasova
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Joseph Weiner
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Nisha Ohri
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Banu Acikalin
- Department of Ophthalmology, Istanbul Fatih Sultan Mehmet Education and Research Hospital, Istanbul, Turkey
| | - Anupama Chundury
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
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17
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Bustamante P, Piquet L, Landreville S, Burnier JV. Uveal melanoma pathobiology: Metastasis to the liver. Semin Cancer Biol 2020; 71:65-85. [PMID: 32450140 DOI: 10.1016/j.semcancer.2020.05.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/04/2020] [Accepted: 05/05/2020] [Indexed: 12/12/2022]
Abstract
Uveal melanoma (UM) is a type of intraocular tumor with a propensity to disseminate to the liver. Despite the identification of the early driver mutations during the development of the pathology, the process of UM metastasis is still not fully comprehended. A better understanding of the genetic, molecular, and environmental factors participating to its spread and metastatic outgrowth could provide additional approaches for UM treatment. In this review, we will discuss the advances made towards the understanding of the pathogenesis of metastatic UM, summarize the current and prospective treatments, and introduce some of the ongoing research in this field.
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Affiliation(s)
- Prisca Bustamante
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Canada; Experimental Pathology Unit, Department of Pathology, McGill University, Montréal, Canada
| | - Léo Piquet
- Département d'ophtalmologie et d'ORL-CCF, Faculté de médecine, Université Laval, Quebec City, Canada; CUO-Recherche and Axe médecine régénératrice, Centre de recherche du CHU de Québec-Université Laval, Quebec City, Canada; Centre de recherche sur le cancer de l'Université Laval, Quebec City, Canada; Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Quebec City, Canada
| | - Solange Landreville
- Département d'ophtalmologie et d'ORL-CCF, Faculté de médecine, Université Laval, Quebec City, Canada; CUO-Recherche and Axe médecine régénératrice, Centre de recherche du CHU de Québec-Université Laval, Quebec City, Canada; Centre de recherche sur le cancer de l'Université Laval, Quebec City, Canada; Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Quebec City, Canada
| | - Julia V Burnier
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Canada; Experimental Pathology Unit, Department of Pathology, McGill University, Montréal, Canada; Gerald Bronfman Department Of Oncology, McGill University, Montréal, Canada.
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18
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Wessely A, Steeb T, Erdmann M, Heinzerling L, Vera J, Schlaak M, Berking C, Heppt MV. The Role of Immune Checkpoint Blockade in Uveal Melanoma. Int J Mol Sci 2020; 21:ijms21030879. [PMID: 32013269 PMCID: PMC7037664 DOI: 10.3390/ijms21030879] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/27/2020] [Accepted: 01/27/2020] [Indexed: 12/25/2022] Open
Abstract
Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies.
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Affiliation(s)
- Anja Wessely
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
| | - Theresa Steeb
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
| | - Michael Erdmann
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
| | - Lucie Heinzerling
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
| | - Julio Vera
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
| | - Max Schlaak
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Frauenlobstr. 9-11, 80337 Munich, Germany;
| | - Carola Berking
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
| | - Markus Vincent Heppt
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
- Correspondence: ; Tel.: +49-9131-85-35747
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19
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El Zaoui I, Bucher M, Rimoldi D, Nicolas M, Kaya G, Pescini Gobert R, Bedoni N, Schalenbourg A, Sakina E, Zografos L, Leyvraz S, Riggi N, Rivolta C, Moulin AP. Conjunctival Melanoma Targeted Therapy: MAPK and PI3K/mTOR Pathways Inhibition. ACTA ACUST UNITED AC 2019; 60:2764-2772. [DOI: 10.1167/iovs.18-26508] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Ikram El Zaoui
- Department of Computational Biology, Unit of Medical Genetics, Lausanne University, Lausanne, Switzerland
| | - Maya Bucher
- Dermatology Unit, CHUV, Lausanne University, Lausanne, Switzerland
| | - Donata Rimoldi
- Ludwig Institute for Cancer Research, Epalinges, Switzerland
| | - Michael Nicolas
- Jules-Gonin Eye Hospital, Lausanne University, FAA, Lausanne, Switzerland
| | - Gurkan Kaya
- Dermatology and Venerology Division, Dermatopathology Laboratory, Geneva University Hospital, Geneva, Switzerland
| | | | - Nicola Bedoni
- Department of Computational Biology, Unit of Medical Genetics, Lausanne University, Lausanne, Switzerland
| | - Ann Schalenbourg
- Jules-Gonin Eye Hospital, Lausanne University, FAA, Lausanne, Switzerland
| | - Ezziat Sakina
- Jules-Gonin Eye Hospital, Lausanne University, FAA, Lausanne, Switzerland
| | - Leonidas Zografos
- Jules-Gonin Eye Hospital, Lausanne University, FAA, Lausanne, Switzerland
| | - Serge Leyvraz
- Charité Cancer Comprehensive Center, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Nicolo Riggi
- Experimental Pathology, Lausanne University Pathology Institute, Lausanne, Switzerland
| | - Carlo Rivolta
- Department of Computational Biology, Unit of Medical Genetics, Lausanne University, Lausanne, Switzerland
- Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom
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20
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Weis E, Vrouwe SQ, LeBaron DB, Parliament MB, Shields J, Shields CL. Changes in Ultraviolet Radiation Exposure to the Ocular Region: A Population-Based Study. Cancers (Basel) 2019; 11:cancers11050719. [PMID: 31137687 PMCID: PMC6562648 DOI: 10.3390/cancers11050719] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/06/2019] [Accepted: 05/15/2019] [Indexed: 11/17/2022] Open
Abstract
In contrast to the well-established association between ultraviolet radiation (UVR) exposure and skin cancers, the relationship between UVR and uveal malignant melanoma (UM) remains controversial. To address this controversy, we evaluated the incidence rates of cutaneous malignancies in the eyelids as a proxy for UVR exposure in the ocular region using a population-based cancer registry. Overall, 74,053 cases of eyelid basal cell carcinoma (BCC) and 7890 cases of melanoma over a 26-year period (1982–2007) were analyzed. The incidence of eyelid basal cell carcinoma and uveal melanoma remained stable, whereas other cutaneous areas demonstrated an increase in the rates. A comparability test demonstrated that BCC incidence trends were significantly different between the eyelid versus both chronically exposed (males p = 0.001; females p = 0.01) and intermittently exposed skin (males and females, p = 0.0002), as well as the skin of the face (males p = 0.002; females p = 0.02). Similarly, melanoma trends were significantly different between the UM group versus both chronically exposed cutaneous melanoma (CM) (males p = 0.001; females p = 0.04) and intermittently exposed CM (males p = 0.005), as well as facial skin CM (males and females p = 0.0002). The discrepancy of cancer incidence between tumors in the peri-ocular region versus the rest of the body suggests that the peri-ocular region might have a different or unique exposure pattern to ultraviolet radiation.
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Affiliation(s)
- Ezekiel Weis
- Department of Ophthalmology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T5H 3V9, Canada.
- Division of Ophthalmology, Department of Surgery, University of Calgary, Calgary, AB T2V 4R6, Canada.
| | - Sebastian Q Vrouwe
- Department of Ophthalmology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T5H 3V9, Canada.
| | - David B LeBaron
- Department of Ophthalmology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T5H 3V9, Canada.
| | - Matthew B Parliament
- Division of Radiation Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 1Z2, Canada.
| | - Jerry Shields
- Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA 19107, USA.
| | - Carol L Shields
- Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA 19107, USA.
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21
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Vorbeugung gesundheitlicher Schäden durch die Sonne – Verhältnisprävention in der Stadt und auf dem Land: Grundsatzpapier des UV-Schutz-Bündnisses. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2017; 60:1153-1160. [PMID: 28932865 DOI: 10.1007/s00103-017-2619-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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22
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Spontaneous regression of malignant melanoma - is it based on the interplay between host immune system and melanoma antigens? Anticancer Drugs 2017; 28:819-830. [DOI: 10.1097/cad.0000000000000526] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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23
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Malignant melanoma of sun-protected sites: a review of clinical, histological, and molecular features. J Transl Med 2017; 97:630-635. [PMID: 28092366 DOI: 10.1038/labinvest.2016.147] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 11/22/2016] [Accepted: 12/06/2016] [Indexed: 01/16/2023] Open
Abstract
In most cases of cutaneous melanoma, ultraviolet (UV) radiation is recognized as a prominent risk factor. Less is known regarding the mechanisms of mutagenesis for melanoma arising in sun-protected sites, such as acral and mucosal melanoma. Acral and mucosal melanoma share many common features, including a late age of onset, a broad radial growth phase with prominent lentiginous growth, the presence of field cancerization cells, and, in most cases, lack of a precursor nevus. In addition to early chromosomal instability, many of the same genes are also involved in these two distinct melanoma subtypes. To better understand non-UV-mediated pathogenesis in melanoma, we conducted a joint literature review of clinical, histological, and molecular features in acral and mucosal melanoma. We also reviewed the current literature regarding aberrations in KIT, PDGFRA, TERT, and other commonly involved genes. By comparing common features of these two subtypes, we suggest potential mechanisms underlying acral and/or mucosal melanoma and offer direction for future investigations.
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24
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Abstract
Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11. Cytogenetic alterations, in particular monosomy of chromosome 3 and amplification of the long arm of chromosome 8, and mutation of the BRCA1-associated protein 1, BAP1, a tumor suppressor gene, or the splicing factor SF3B1 determine UM metastasis. Cytogenetic and molecular profiling allow for a very precise prognostication that is still not matched by efficacious adjuvant therapies. G protein signaling has been shown to activate the YAP/TAZ pathway independent of HIPPO, and conventional signaling via the mitogen-activated kinase pathway probably also contributes to UM development and progression. Several lines of evidence indicate that inflammation and macrophages play a pro-tumor role in UM and in its hepatic metastases. UM cells benefit from the immune privilege in the eye and may adopt several mechanisms involved in this privilege for tumor escape that act even after leaving the niche. Here, we review the current knowledge of the biology of UM and discuss recent approaches to UM treatment.
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Affiliation(s)
- Adriana Amaro
- Laboratory of Molecular Pathology, Department of Integrated Oncology Therapies, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, L.go Rosanna Benzi 10, 16132, Genoa, Italy
| | - Rosaria Gangemi
- Laboratory of Biotherapies, Department of Integrated Oncology Therapies, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
| | - Francesca Piaggio
- Laboratory of Molecular Pathology, Department of Integrated Oncology Therapies, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, L.go Rosanna Benzi 10, 16132, Genoa, Italy
| | - Giovanna Angelini
- Laboratory of Molecular Pathology, Department of Integrated Oncology Therapies, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, L.go Rosanna Benzi 10, 16132, Genoa, Italy
| | - Gaia Barisione
- Laboratory of Biotherapies, Department of Integrated Oncology Therapies, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
| | - Silvano Ferrini
- Laboratory of Biotherapies, Department of Integrated Oncology Therapies, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
| | - Ulrich Pfeffer
- Laboratory of Molecular Pathology, Department of Integrated Oncology Therapies, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, L.go Rosanna Benzi 10, 16132, Genoa, Italy.
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25
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Csoma RZ, Tóth-Molnár E, Varga A, Szabó H, Orvos H, Kemény L, Oláh J. Risk Factors and Relationship of Cutaneous and Uveal Melanocytic Lesions in Monozygotic and Dizygotic Twin Pairs. PLoS One 2016; 11:e0160146. [PMID: 27486750 PMCID: PMC4972429 DOI: 10.1371/journal.pone.0160146] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 07/14/2016] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND The similar genetic background of a pair of twins, and the similar environmental impacts to which they are exposed allow an exact and objective investigation of various constitutional and environmental factors in naevus development. As far as we are aware, this is the first published survey that simultaneously examines cutaneous and ocular pigmented lesions in an appreciable sample of identical and non-identical twins. METHODS 172 pairs of twins of Caucasian origin were included in this study. A whole-body skin examination and a detailed ophthalmological examination were performed to determine the density of melanocytic lesions. A standardized questionnaire was used to assess the data relating to constitutional, sun exposure and other variables. RESULTS A notably high proportion of the subjects (36.78%) manifested one or more clinically atypical melanocytic naevi (CAMNs), and approximately one-third (31.4%) of them at least one benign uveal pigmented lesion (BUPL). The incidence of iris freckles (IFs), iris naevi (INs) and choroidal naevi (CHNs) proved to be 25.35%, 5.98% and 3.52%, respectively. The interclass correlation coefficients for common melanocytic naevi (CMNs), CAMNs, and INs were 0.77, 0.76 and 0.86 in monozygotic twins, as compared with 0.5, 0.27 and 0.25 in dizygotic twin pairs, respectively. A statistically significant correlation was found between the prevalence of CAMNs and that of INs. CONCLUSIONS This significant correlation suggests the existence of a subgroup of Caucasian people with an increased susceptibility to both cutaneous and ocular naevus formation. There is accumulating evidence that, besides the presence of cutaneous atypical naevi, INs can serve as a marker of a predisposed phenotype at risk of uveal melanoma. The correlation between cutaneous and ocular pigmented lesions underlines the need for the adequate ophthalmological screening of subjects with CAMNs and INs.
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Affiliation(s)
- Renáta Zsanett Csoma
- Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
| | - Edit Tóth-Molnár
- Department of Ophthalmology, University of Szeged, Szeged, Hungary
| | - Anita Varga
- Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
| | - Hajnalka Szabó
- Department of Paediatrics, University of Szeged, Szeged, Hungary
| | - Hajnalka Orvos
- Department of Obstetrics and Gynaecology, University of Szeged, Szeged, Hungary
| | - Lajos Kemény
- Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Dermatological Research Group of the Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary
| | - Judit Oláh
- Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
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Abstract
Uveal melanoma is the most common intraocular malignancy in adults. Despite excellent rates of local control, half of all patients with uveal melanoma ultimately go on to develop fatal metastatic disease. This review focuses on disparities and differences in the underlying characteristics of the patients, and how these patient characteristics impact the development of metastasis and subsequent patient survival. Specifically, we detail disparities in epidemiology and risk factors as they relate to the development of primary uveal melanoma, to the development of metastasis, and to patient survival following metastasis.
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Affiliation(s)
- Erin E Nichols
- a Department of Ophthalmology and Visual Sciences , Vanderbilt University Medical Center , Nashville , TN , USA
| | - Ann Richmond
- b Tennessee Valley Healthcare System , Department of Veterans Affairs , Nashville , TN , USA.,c Department of Cancer Biology , Vanderbilt University , Nashville , TN , USA.,d Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center , Nashville , TN , USA
| | - Anthony B Daniels
- a Department of Ophthalmology and Visual Sciences , Vanderbilt University Medical Center , Nashville , TN , USA.,c Department of Cancer Biology , Vanderbilt University , Nashville , TN , USA.,d Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center , Nashville , TN , USA.,e Department of Radiation Oncology , Vanderbilt University Medical Center , Nashville , TN , USA
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27
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Ultraviolet or blue-filtering intraocular lenses: what is the evidence? Eye (Lond) 2016; 30:215-21. [PMID: 26742866 DOI: 10.1038/eye.2015.267] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 11/25/2015] [Indexed: 11/08/2022] Open
Abstract
Cataract surgery was revolutionised by the introduction of modern intraocular lenses in the late 1940's. By the late 1960's to 1970's evidence had emerged that short-wavelength light caused phototoxicity at the retina and retinal pigment epithelium. By the early 1980's ultraviolet filters had been incorporated into intraocular lenses. This caused intense controversy, as there was concern that the UV-filtering chromophore might leach out into the eye causing toxicity. With the arrival of blue-filtering intraocular lenses (BFIOLs) in 1990's, a further debate was ignited as to their safety and potential disadvantages. Selecting the optimal performing intraocular lens to obtain the best visual performance with the fewest potential drawbacks has become complex and challenging for cataract surgeons and their patients with the wide choice of lenses available. Choosing a personalised lens to address astigmatism, presbyopia, spherical aberration, chromatic aberration, and potentially to shield the retina from short-wavelength light is now possible. The potential benefits and possible side effects of these different innovations emphasise the importance of assessing the evidence for their clinical utility, allowing the surgeon and the patient to weigh-up the risk benefit ratio and make an informed decision. The BFIOLs were developed to reduce cyanopsia, address chromatic aberration, and improve contrast sensitivity in different lighting conditions, as well as to prevent short-wavelength light reaching the retina thus potentially reducing the risk of developing age-related macular degeneration. Further design development of the BFIOLs was to mimic the natural crystalline lens absorption and transmittance properties in adulthood. Multiple publications have reported on the potential benefits and pitfalls of implanting a blue-filtering lens. The potential disadvantages raised in the literature over the last 25 years since their introduction, regarding compromise of visual function and disruption of the circadian system, have been largely dispelled. The clear benefits of protecting the retina from short-wavelength light make a BFIOLs a sensible choice. The purpose of this article presented at the Cambridge symposium 2015 is to review the literature on this subject.
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28
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Mitochondrial DNA copy number in peripheral blood and melanoma risk. PLoS One 2015; 10:e0131649. [PMID: 26110424 PMCID: PMC4482392 DOI: 10.1371/journal.pone.0131649] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 06/05/2015] [Indexed: 02/07/2023] Open
Abstract
Mitochondrial DNA (mtDNA) copy number in peripheral blood has been suggested as risk modifier in various types of cancer. However, its influence on melanoma risk is unclear. We evaluated the association between mtDNA copy number in peripheral blood and melanoma risk in 500 melanoma cases and 500 healthy controls from an ongoing melanoma study. The mtDNA copy number was measured using real-time polymerase chain reaction. Overall, mean mtDNA copy number was significantly higher in cases than in controls (1.15 vs 0.99, P<0.001). Increased mtDNA copy number was associated with a 1.45-fold increased risk of melanoma (95% confidence interval: 1.12-1.97). Significant joint effects between mtDNA copy number and variables related to pigmentation and history of sunlight exposure were observed. This study supports an association between increased mtDNA copy number and melanoma risk that is independent on the known melanoma risk factors (pigmentation and history of sunlight exposure).
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Lucas RM, Norval M, Neale RE, Young AR, de Gruijl FR, Takizawa Y, van der Leun JC. The consequences for human health of stratospheric ozone depletion in association with other environmental factors. Photochem Photobiol Sci 2015; 14:53-87. [DOI: 10.1039/c4pp90033b] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Ozone depletion, climate and human health.
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Affiliation(s)
- R. M. Lucas
- National Centre for Epidemiology and Population Health
- The Australian National University
- Canberra 2601
- Australia
- Telethon Kids Institute
| | - M. Norval
- Biomedical Sciences
- University of Edinburgh Medical School
- Edinburgh EH8 9AG
- UK
| | - R. E. Neale
- QIMR Berghofer Medical Research Institute
- Brisbane 4029
- Australia
| | - A. R. Young
- King's College London (KCL)
- St John's Institute of Dermatology
- London SE1 9RT
- UK
| | - F. R. de Gruijl
- Department of Dermatology
- Leiden University Medical Centre
- NL-2300 RC Leiden
- The Netherlands
| | - Y. Takizawa
- Akita University Graduate School of Medicine
- Akita Prefecture
- Japan
- National Institute for Minamata Diseases
- Kumamoto Prefecture
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