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Melanoma: HELP
Articles by Sarah Ellen Coupland
Based on 83 articles published since 2008
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Between 2008 and 2019, S. Coupland wrote the following 83 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline Uveal Melanoma UK National Guidelines. 2015

Nathan, P / Cohen, V / Coupland, S / Curtis, K / Damato, B / Evans, J / Fenwick, S / Kirkpatrick, L / Li, O / Marshall, E / McGuirk, K / Ottensmeier, C / Pearce, N / Salvi, S / Stedman, B / Szlosarek, P / Turnbull, N / Anonymous4090839. ·Mount Vernon Cancer Centre, Northwood, Middlesex, UK. Electronic address: nathan.pd@gmail.com. · Ocular Oncology Service, St Bartholomew's and Moorfields Eye Hospital, London, UK. · Department Molecular and Clinical Cancer Medicine, University of Liverpool, UK. · OcuMel UK, UK. · Royal Liverpool University Hospital, Liverpool, UK. · University Hospital Aintree, Liverpool, UK. · Patient Representative, UK. · Moorfields Eye Hospital, London, UK. · The Clatterbridge Cancer Centre, NHS Foundation Trust, Liverpool, UK. · Southampton University Hospitals and University of Southampton, UK. · University Hospital Southampton, Southampton, UK. · Royal Hallamshire Hospital, Sheffield, UK. · Southampton University Hospitals, NHS Trust, Southampton, UK. · St Bartholomew's Hospital, UK; Barts Cancer Institute, Queen Mary University of London, London, UK. · Project Manager, London, UK. ·Eur J Cancer · Pubmed #26278648.

ABSTRACT: The United Kingdom (UK) uveal melanoma guideline development group used an evidence based systematic approach (Scottish Intercollegiate Guidelines Network (SIGN)) to make recommendations in key areas of uncertainty in the field including: the use and effectiveness of new technologies for prognostication, the appropriate pathway for the surveillance of patients following treatment for primary uveal melanoma, the use and effectiveness of new technologies in the treatment of hepatic recurrence and the use of systemic treatments. The guidelines were sent for international peer review and have been accredited by NICE. A summary of key recommendations is presented. The full documents are available on the Melanoma Focus website.

2 Editorial Recent breakthroughs in metastatic uveal melanoma: a cause for optimism? 2018

Sacco, Joseph J / Kalirai, Helen / Kenyani, Jenna / Figueiredo, Carlos R / Coulson, Judy M / Coupland, Sarah E. ·Liverpool Ocular Oncology Research Group, Department of Molecular & Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, UK. · Department of Medical Oncology, Clatterbridge Cancer Centre, Bebington, UK. · Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, UK. · Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, UK. ·Future Oncol · Pubmed #29741103.

ABSTRACT: -- No abstract --

3 Editorial Managing patients with ocular melanoma: state of the art. 2008

Damato, Bertil / Coupland, Sarah E. · ·Clin Exp Ophthalmol · Pubmed #18983541.

ABSTRACT: -- No abstract --

4 Review Kinome-wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics. 2018

Bailey, Fiona P / Clarke, Kim / Kalirai, Helen / Kenyani, Jenna / Shahidipour, Haleh / Falciani, Francesco / Coulson, Judy M / Sacco, Joseph J / Coupland, Sarah E / Eyers, Patrick A. ·Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK. · Computational Biology Facility, Functional and Comparative Genomics, Institute of Integrative Biology, University of Liverpool, Liverpool, UK. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Research, University of Liverpool, Liverpool, UK. · Cellular and Molecular Physiology, Institute of Translational Research, University of Liverpool, Liverpool, UK. ·Pigment Cell Melanoma Res · Pubmed #28972303.

ABSTRACT: Metastatic uveal melanoma (UM) is invariably fatal, usually within a year of diagnosis. There are currently no effective therapies, and clinical studies employing kinase inhibitors have so far demonstrated limited success. This is despite common activating mutations in GNAQ/11 genes, which trigger signalling pathways that might predispose tumours to a variety of targeted drugs. In this study, we have profiled kinome expression network dynamics in various human ocular melanomas. We uncovered a shared transcriptional profile in human primary UM samples and across a variety of experimental cell-based models. The poor overall response of UM cells to FDA-approved kinase inhibitors contrasted with much higher sensitivity to the bromodomain inhibitor JQ1, a broad transcriptional repressor. Mechanistically, we identified a repressed FOXM1-dependent kinase subnetwork in JQ1-exposed cells that contained multiple cell cycle-regulated protein kinases. Consistently, we demonstrated vulnerability of UM cells to inhibitors of mitotic protein kinases within this network, including the investigational PLK1 inhibitor BI6727. We conclude that analysis of kinome-wide signalling network dynamics has the potential to reveal actionable drug targets and inhibitors of potential therapeutic benefit for UM patients.

5 Review [Ocular melanomas : An update]. 2017

Kalirai, H / Müller, P L / Jaehne, D / Coupland, S E. ·Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, Großbritannien. · Universitäts-Augenklinik Bonn, Bonn, Deutschland. · Institut für Gewebediagnostik Pathologie MVZ HELIOS Klinik Emil von Behring, Berlin, Deutschland. · Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, Großbritannien. s.e.coupland@liv.ac.uk. · Institute of Translational Medicine, 6th Floor Duncan Building, University of Liverpool, Daulby Street, L69 3GA, Liverpool, Großbritannien. s.e.coupland@liv.ac.uk. ·Pathologe · Pubmed #29038913.

ABSTRACT: Melanoma is the most common type of primary cancer to affect the adult eye. Approximately 95% of ocular melanomas are intraocular and arise from the uvea (i. e. iris, ciliary body, and choroid), while the remaining 5% are located in the conjunctiva. Although both uveal and conjunctival melanomas are thought to derive from malignantly transformed melanocytes, uveal melanoma is clinically and biologically distinct from conjunctival melanoma, and indeed from its more common cutaneous counterpart. Intense efforts have been recently made to understand the molecular biology involved in the development of ocular melanomas, and in their progression. Molecular advances, particularly for uveal melanoma, have enhanced prognostication and the identification of rational therapeutic targets for disseminated disease. In this review, recent advances in the molecular characterisation of both uveal and conjunctival melanomas are discussed, and how these may be used to develop personalised therapeutic strategies.

6 Review Intraocular collision tumour: case report and literature review. 2013

Coupland, Sarah E / Dodson, Andrew / Liu, Hongxiang / Du, Ming-Qing / Angi, Martina / Damato, Bertil E. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, 5th Floor Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. s.e.coupland@liverpool.ac.uk ·Graefes Arch Clin Exp Ophthalmol · Pubmed #23232651.

ABSTRACT: BACKGROUND: "Collision" tumours consist of different neoplasms coexisting within a single lesion. Whilst quite common in the skin, the gastrointestional tract, and the ovaries, intraocular collision tumours are exceedingly rare. We describe an exceptional case of a combined uveal melanoma and intraocular plasmacytoma. METHODS: Observational case report. A 61-year-old woman underwent enucleation for rubeotic glaucoma and cells in the anterior chamber after proton-beam radiotherapy of a cilio-choroidal melanoma of the right eye. Examination of the enucleated eye was performed with immunohistochemistry, multiplex ligation dependent probe amplification (MLPA), and polymerase chain reaction (PCR) for immunoglobulin heavy- and light-chain gene rearrangements. A review of the literature on ocular collision tumours and uveal involvement by plasma cell neoplasms was also performed. RESULTS: Morphological, immunophenotypical, and genotypical examination of the tumour revealed the co-existence of both a melanoma and a plasmacytoma within the choroid and ciliary body. The glaucoma was caused by extensive infiltration of the iris and trabecular meshwork by the plasmacytoma cells. Review of the literature revealed only four collision tumours involving the eyelid and three involving the choroid. All three intraocular collision tumours consisted of uveal melanoma and choroidal non-Hodgkin lymphoma. Uveal involvement by plasma cell neoplasms is also extremely rare, with only six reported cases. CONCLUSIONS: This is the first documented intraocular collision tumour consisting of a uveal melanoma and isolated plasmacytoma. If a patient presents with 'uveitis' after proton-beam radiotherapy of a cilio-choroidal melanoma, there may be scope for performing biopsies to determine whether the lymphoid infiltrate is reactive or neoplastic.

7 Review Conjunctival melanoma and melanocytic intra-epithelial neoplasia. 2013

Kenawy, N / Lake, S L / Coupland, S E / Damato, B E. ·St Paul's Eye Unit, Liverpool Ocular Oncology Service, Royal Liverpool University Hospital, Liverpool, UK. nkenawy@liv.ac.uk ·Eye (Lond) · Pubmed #23222568.

ABSTRACT: The rarity of conjunctival melanoma has impeded progress in the management of patients with this cancer; however, much progress has occurred in recent years. Primary acquired melanosis is now differentiated histologically into hypermelanosis and conjunctival melanocytic intra-epithelial neoplasia, for which an objective reproducible scoring system has been developed. Mapping and clinical staging of conjunctival disease has improved. Adjunctive radiotherapy and topical chemotherapy have made tumour control more successful, with reduced morbidity. Genetic analyses have identified BRAF and other mutations, which may predict responsiveness to new chemotherapeutic agents, for example Vemurafenib, should metastatic disease develop. Multicentre studies are under way to enhance survival prediction by integrating clinical stage of disease with histological grade of malignancy and genetic abnormalities. Such improved prognostication would not only be more relevant to individual patients, but would also provide greater opportunities for basic science research.

8 Review Molecular pathology of uveal melanoma. 2013

Coupland, S E / Lake, S L / Zeschnigk, M / Damato, B E. ·Pathology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. s.e.coupland@liverpool.ac.uk ·Eye (Lond) · Pubmed #23222563.

ABSTRACT: Like other cancers, uveal melanomas (UM) are characterised by an uncontrolled, clonal, cellular proliferation, occurring as a result of numerous genetic, and epigenetic aberrations. Signalling pathways known to be disrupted in UM include: (1) the retinoblastoma pathway, probably as a result of cyclin D1 overexpression; p53 signalling, possibly as a consequence of MDM2 overexpression; and the P13K/AKT and mitogen-activated protein kinase/extracellular signal-related kinase pathway pathways that are disturbed as a result of PTEN and GNAQ/11 mutations, respectively. Characteristic chromosomal abnormalities are common and include 6p gain, associated with a good prognosis, as well as 1p loss, 3 loss, and 8q gain, which correlate with high mortality. These are identified by techniques such as fluorescence in situ hybridisation, comparative genomic hybridisation, microsatellite analysis, multiplex ligation-dependent probe amplification, and single-nucleotide polymorphisms. UM can also be categorised by their gene expression profiles as class 1 or class 2, the latter correlating with poor survival, as do BRCA1-associated protein-1 (BAP1) inactivating mutations. Genetic testing of UM has enhanced prognostication, especially when results are integrated with histological and clinical data. The identification of abnormal signalling pathways, genes and proteins in UM opens the way for target-based therapies, improving prospects for conserving vision and prolonging life.

9 Review Estimating prognosis for survival after treatment of choroidal melanoma. 2011

Damato, Bertil / Eleuteri, Antonio / Taktak, Azzam F G / Coupland, Sarah E. ·Ocular Oncology Service, Royal Liverpool University Hospital, Prescot St, Liverpool L7 8XP, UK. Bertil@damato.co.uk ·Prog Retin Eye Res · Pubmed #21658465.

ABSTRACT: Choroidal melanoma is fatal in about 50% of patients. This is because of metastatic disease, which usually involves the liver. Kaplan-Meier survival curves based only on tumor size and extent do not give a true indication of prognosis. This is because the survival prognosis of choroidal melanoma correlates not only with clinical stage but also with histologic grade, genetic type, and competing causes of death. We have developed an online tool that predicts survival using all these data also taking normal life-expectancy into account. The estimated prognosis is accurate enough to be relevant to individual patients. Such personalized prognostication improves the well-being of patients having an excellent survival probability, not least because it spares them from unnecessary screening tests. Such screening can be targeted at high-risk patients, so that metastases are detected sooner, thereby enhancing any opportunities for treatment. Concerns about psychological harm have proved exaggerated. At least in Britain, patients want to know their prognosis, even if this is poor. The ability to select patients with a high risk of metastasis improves prospects for randomised studies evaluating systemic adjuvant therapy aimed at preventing or delaying metastatic disease. Furthermore, categorization of tissue samples according to survival prognosis enables laboratory studies to be undertaken without waiting many years for survival to be measured. As a result of advances in histologic and genetic studies, biopsy techniques and statistics, prognostication has become established as a routine procedure in our clinical practice, thereby enhancing the care of patients with uveal melanoma.

10 Clinical Trial Concordant chromosome 3 results in paired choroidal melanoma biopsies and subsequent tumour resection specimens. 2015

Coupland, Sarah E / Kalirai, Helen / Ho, Vivian / Thornton, Sophie / Damato, Bertil E / Heimann, Heinrich. ·Department of Pathology, Royal Liverpool and Broadgreen University Hospital Trust (RLBUHT), University of Liverpool, Liverpool, UK. · Department of Ophthalmology, Royal Liverpool and Broadgreen University Hospital Trust (RLBUHT), Liverpool, UK. · Department of Ophthalmology, Royal Liverpool and Broadgreen University Hospital Trust (RLBUHT), Liverpool, UK Ocular Oncology Service, University of California, San Francisco, California, USA. ·Br J Ophthalmol · Pubmed #26206786.

ABSTRACT: BACKGROUND/AIM: The study's aim was to compare chromosome 3 aberrations of choroidal melanoma (CM) as determined by multiplex ligation dependent probe amplification (MLPA) or microsatellite analysis (MSA) in intraocular tumour biopsies with those results obtained from subsequent endoresection/enucleation of the same CM. METHODS: A retrospective cohort of 28 patients with CM seen between 2007 and 2014 at the Liverpool Ocular Oncology Centre was analysed. Prognostic genetic testing, for chromosome 3 status, was performed on all tumour specimens, either by MLPA or MSA, depending on DNA yield. In nine cases genetic testing was performed on a sample taken after radiotherapy; four of these had genetic information pre- and post-radiotherapy. RESULTS: Fourteen biopsy specimens were analysed by MLPA and 14 by MSA. Twenty-seven endoresection or enucleation specimens were analysed by MLPA, and a single enucleation specimen by MSA. Chromosome 3 data showed prognostic concordance for the patient-matched samples in all 28 cases including 4 cases where samples were taken pre pre- and post radiotherapy. Thirteen cases were classified as monosomy 3 and 12 as disomy 3. Two cases had a loss of chromosome arm 3q in both samples and a single case showed loss of 3p in the biopsy sample with complete monosomy 3 in the subsequent enucleation sample taken 5 months later. CONCLUSIONS: Intraocular biopsy of CM yields similar prognostic information to larger surgical specimens. Initial evidence, that genetic testing can be successfully conducted post radiotherapy, is also provided. TRIAL REGISTRATION NUMBER: NITRO trial, ISRCTN35236442.

11 Article Conjunctival melanoma and electrochemotherapy: preliminary results using 2D and 3D cell culture models in vitro. 2019

Fiorentzis, Miltiadis / Katopodis, Periklis / Kalirai, Helen / Seitz, Berthold / Viestenz, Arne / Coupland, Sarah E. ·Department of Ophthalmology, University Hospital Halle (Saale), Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany. · Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Department of Ophthalmology, Saarland University Medical Center, Homburg/Saar, Germany. ·Acta Ophthalmol · Pubmed #30548215.

ABSTRACT: PURPOSE: To investigate the cytotoxic effect of bleomycin, mitomycin C (MMC) and Fluorouracil (5-FU) in combination with electroporation (EP) on human conjunctival melanoma (CM) and normal conjunctival cell lines using 2D and 3D cell culture systems in vitro. METHODS: Two CM (CRMM1, CRMM2) and one normal conjunctival epithelial cell line (HCjE-Gi) were treated with various EP conditions and increasing concentrations of 5-FU, MMC and bleomycin. Cell survival was assessed by MTT viability assay. All cell lines were seeded to create spheroids and were treated with bleomycin on day 3 and day 8 combined with EP. Spheroids were collected, fixed in buffered formalin and subsequently paraffin embedded for histological assessment of the effects of the treatment on cell viability. RESULTS: CM cell lines were resistant to electroporation alone and showed a reduction in cell number only when treated with 1000 Volts/cm and 8 pulses. HCjE-Gi cells showed higher sensitivity to electric pulses over 750 Volts/cm. MMC and 5-FU demonstrated a higher cytotoxicity for the HCjE-Gi cell line. The CM cell lines were resistant to MMC and 5-FU. Bleomycin (1 μg/ml) alone had no significant effect on the HCjE-Gi even when combined with EP conditions ≥750 Volts/cm. In contrast, it significantly (p -, paired t-test) reduced cell viability in the CM cell lines. Spheroids treated with bleomycin and EP showed a reduction in tumour mass and proliferation rates after treatment. CONCLUSION: Our in vitro study using 2D and 3D models indicates that the application of EP may effectively enhance chemotherapy with bleomycin in CM. This may offer new viable perspectives for CM treatment.

12 Article Detection of mutations in SF3B1, EIF1AX and GNAQ in primary orbital melanoma by candidate gene analysis. 2018

Rose, Anna M / Luo, Rong / Radia, Utsav K / Kalirai, Helen / Thornton, Sophie / Luthert, Philip J / Jayasena, Channa N / Verity, David H / Coupland, Sarah E / Rose, Geoffrey E. ·Orbital Service, Moorfields Eye Hospital, City Road, London, EC1V 2PD, UK. · UCL Institute of Ophthalmology, London, UK. · Department of Medicine, Imperial College, London, UK. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, UK. · Orbital Service, Moorfields Eye Hospital, City Road, London, EC1V 2PD, UK. geoff.rose@moorfields.nhs.uk. · UCL Institute of Ophthalmology, London, UK. geoff.rose@moorfields.nhs.uk. ·BMC Cancer · Pubmed #30558566.

ABSTRACT: BACKGROUND: Ocular melanoma is a rare but often deadly malignancy that arises in the uvea (commonest primary site), conjunctiva or the orbit. Primary orbital melanoma (POM) is exceedingly rare, with approximately 60 cases reported to date. Despite recent advances in our understanding of the genetics of primary uveal and conjunctival melanomas, this information is lacking for POM. METHODS: DNA was extracted from 12 POM tissues, with matched germline DNA (where available). MLPA was conducted to detect chromosomal alterations and Sanger sequencing used to identify point mutations in candidate melanoma driver genes (BRAF, NRAS, KRAS, GNA11, GNAQ), and other genes implicated in melanoma prognosis (EIF1AX, SF3B1). Immunohistochemistry was performed to analyse BAP1 nuclear expression. RESULTS: MLPA detected copy number alterations in chromosomes 1p, 3, 6 and 8. Sequencing of melanoma driver genes revealed GNAQ (p.Q209L) mutations in two samples; although it is possible that these samples represent extraocular spread of an occult uveal melanoma. A recurrent mutation in SF3B1 (p.R625H) was observed in indolent, but not aggressive, tumours; a mutation in EIF1AX (p.N4S) was detected in one patient with non-aggressive disease. CONCLUSIONS: EIF1AX and SF3B1 mutations appear have a role in determining the clinical course of POM and detection of these changes could have clinical significance. Further in depth analysis of this rare group using differing 'omic technologies will provide novel insights into tumour pathogenesis.

13 Article Altered Nuclear Expression of the Deubiquitylase BAP1 Cannot be Used as a Prognostic Marker for Canine Melanoma. 2018

Jama, N / Farquhar, N / Butt, Z / Coupland, S E / Sacco, J J / Scase, T / Fielding, A B / Coulson, J M / Kalirai, H / Killick, D R. ·Department of Small Animal Clinical Sciences, Institute of Veterinary Science, University of Liverpool, Liverpool, UK; Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Bridge Pathology Ltd., 637 Gloucester Road, Bristol, UK. · Department of Small Animal Clinical Sciences, Institute of Veterinary Science, University of Liverpool, Liverpool, UK. Electronic address: drk@liverpool.ac.uk. ·J Comp Pathol · Pubmed #30060843.

ABSTRACT: BRCA1-associated protein-1 (BAP1) is a nuclear localized deubiquitylating enzyme that belongs to the ubiquitin c-terminal hydrolase subfamily. The encoded protein is highly homologous between man and dogs, suggesting a functional significance preserved by evolution. BAP1 has multiple properties, including tumour suppressor activity. Loss of BAP1 function is implicated in the oncogenesis of several types of cancers including uveal, mucosal and some cutaneous melanomas in humans, as well as in mesothelioma. In this study we investigate the significance of BAP1 in canine melanoma. Nuclear BAP1 protein was detected in five canine oral melanoma cell lines using an antibody commonly used for analysis of human tissues. BAP1 loss of function mutations often lead to loss of nuclear BAP1 (nBAP1) expression in humans; this is associated with a poorer prognosis in uveal and mucosal melanoma. Therefore, as a prelude to a study evaluating the prognostic significance of nBAP1 expression in dogs, immunohistochemistry (IHC) was used to assess cases of canine melanoma for nBAP1 expression. In 89 cases where tumour cells were identified by melan-A labelling, 100% of tumour cells were positive for nBAP1 expression, including eight uveal tract and 29 oral mucosal melanomas. This finding indicates that BAP1 IHC cannot be used as a prognostic marker in canine uveal and mucosal melanoma. Moreover, this observation suggests that either BAP1 has a different functional significance in canine melanoma or that loss of BAP1 function is achieved by a different route. This is a novel finding that warrants further investigation to determine the comparative biological relevance.

14 Article Nestin expression in primary and metastatic uveal melanoma - possible biomarker for high-risk uveal melanoma. 2018

Djirackor, Luna / Shakir, Dilem / Kalirai, Helen / Petrovski, Goran / Coupland, Sarah E. ·Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Stem Cells and Eye Research Laboratory, Department of Ophthalmology, Faculty of Medicine, Albert Szent-Gyorgyi Clinical Center, University of Szeged, Szeged, Hungary. · Centre for Eye Research, Department of Ophthalmology, Oslo University Hospital and University of Oslo, Oslo, Norway. ·Acta Ophthalmol · Pubmed #29338117.

ABSTRACT: PURPOSE: Nestin, a member of the intermediate filament protein family, has been described as a putative cancer stem cell marker (CSC) in uveal melanoma and poor prognostic factor in a variety of tumours, including cutaneous melanoma. In this study, we examined the expression of nestin in primary (PUM) and metastatic uveal melanoma (MUM) samples, and correlated the findings with histological, clinical and survival data. METHODS: Nestin expression was assessed by immunohistochemistry in 141 PUM and 26 MUM samples; 11 PUM cases were matched with their corresponding metastases. The percentage of tumour cells expressing nestin was scored by three independent observers. Statistical analysis of all data was performed with SPSS. RESULTS: Nestin expression was identified in both the cytoplasm and membrane of UM cells. Increased expression of nestin in PUM samples was associated with known poor prognostic parameters, including epithelioid cell morphology (p < 0.001), closed loops (p = 0.001), higher mitotic count (p < 0.001), monosomy 3 (p = 0.007) and chromosome 8q gain (p < 0.001). Primary uveal melanoma (PUM) with nestin expression levels above a cut-off value of 10% [as determined by receiver operating characteristic (ROC) analysis] was associated with a significantly reduced survival time (Log-rank, p = 0.002). In MUM, a higher percentage of nestin-positive tumour cells combined with poor prognostic markers in the PUM led to a shorter survival time following the development of metastases. CONCLUSION: In conclusion, increased nestin expression in PUM is a predictor of a tumour phenotype associated with metastatic progression and reduced survival time at onset of metastasis.

15 Article Combined mutation and copy-number variation detection by targeted next-generation sequencing in uveal melanoma. 2018

Smit, Kyra N / van Poppelen, Natasha M / Vaarwater, Jolanda / Verdijk, Robert / van Marion, Ronald / Kalirai, Helen / Coupland, Sarah E / Thornton, Sophie / Farquhar, Neil / Dubbink, Hendrikus-Jan / Paridaens, Dion / de Klein, Annelies / Kiliç, Emine. ·Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · The Rotterdam Eye Hospital, Rotterdam, The Netherlands. ·Mod Pathol · Pubmed #29327717.

ABSTRACT: Uveal melanoma is a highly aggressive cancer of the eye, in which nearly 50% of the patients die from metastasis. It is the most common type of primary eye cancer in adults. Chromosome and mutation status have been shown to correlate with the disease-free survival. Loss of chromosome 3 and inactivating mutations in BAP1, which is located on chromosome 3, are strongly associated with 'high-risk' tumors that metastasize early. Other genes often involved in uveal melanoma are SF3B1 and EIF1AX, which are found to be mutated in intermediate- and low-risk tumors, respectively. To obtain genetic information of all genes in one test, we developed a targeted sequencing method that can detect mutations in uveal melanoma genes and chromosomal anomalies in chromosome 1, 3, and 8. With as little as 10 ng DNA, we obtained enough coverage on all genes to detect mutations, such as substitutions, deletions, and insertions. These results were validated with Sanger sequencing in 28 samples. In >90% of the cases, the BAP1 mutation status corresponded to the BAP1 immunohistochemistry. The results obtained in the Ion Torrent single-nucleotide polymorphism assay were confirmed with several other techniques, such as fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and Illumina SNP array. By validating our assay in 27 formalin-fixed paraffin-embedded and 43 fresh uveal melanomas, we show that mutations and chromosome status can reliably be obtained using targeted next-generation sequencing. Implementing this technique as a diagnostic pathology application for uveal melanoma will allow prediction of the patients' metastatic risk and potentially assess eligibility for new therapies.

16 Article Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. 2017

Robertson, A Gordon / Shih, Juliann / Yau, Christina / Gibb, Ewan A / Oba, Junna / Mungall, Karen L / Hess, Julian M / Uzunangelov, Vladislav / Walter, Vonn / Danilova, Ludmila / Lichtenberg, Tara M / Kucherlapati, Melanie / Kimes, Patrick K / Tang, Ming / Penson, Alexander / Babur, Ozgun / Akbani, Rehan / Bristow, Christopher A / Hoadley, Katherine A / Iype, Lisa / Chang, Matthew T / Anonymous1031111 / Cherniack, Andrew D / Benz, Christopher / Mills, Gordon B / Verhaak, Roel G W / Griewank, Klaus G / Felau, Ina / Zenklusen, Jean C / Gershenwald, Jeffrey E / Schoenfield, Lynn / Lazar, Alexander J / Abdel-Rahman, Mohamed H / Roman-Roman, Sergio / Stern, Marc-Henri / Cebulla, Colleen M / Williams, Michelle D / Jager, Martine J / Coupland, Sarah E / Esmaeli, Bita / Kandoth, Cyriac / Woodman, Scott E. ·Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Buck Institute for Research on Aging, Novato, CA 94945, USA. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. · Department of Biomolecular Engineering, Center for Biomolecular Sciences and Engineering, University of California, Santa Cruz, CA 95064, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Public Health Sciences, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA. · The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA. · Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Human Oncology and Pathogenesis Program, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. · Molecular and Medical Genetics, Computational Biology, Oregon Health and Science University, Portland, OR 97239, USA. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Institute for Applied Cancer Science, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Institute for Systems Biology, Seattle, WA 98109, USA. · Human Oncology and Pathogenesis Program, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Departments of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94122, USA. · Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Dermatology, University Hospital Essen, 45157 Essen, Germany. · Center for Cancer Genomics, National Cancer Institute, Bethesda, MD 20892, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Pathology, The Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA. · Department of Pathology, Dermatology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Departments of Ophthalmology and Internal Medicine, Division of Human Genetics, The Ohio State University, Columbus, OH 43210, USA. · Department of Translational Research, Institut Curie, PSL Research University, Paris 75248, France. · Havener Eye Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43212, USA. · Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands. · Department of Molecular & Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool L7 8TX, UK; Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, L69 3GA, UK. · Orbital Oncology & Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: besmaeli@mdanderson.org. · Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. Electronic address: kandothc@mskcc.org. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: swoodman@mdanderson.org. ·Cancer Cell · Pubmed #28810145.

ABSTRACT: Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

17 Article Inflammatory cell infiltrates in advanced metastatic uveal melanoma. 2017

Krishna, Yamini / McCarthy, Conni / Kalirai, Helen / Coupland, Sarah E. ·Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, L7 8XP, UK. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, L7 8TX, UK. · Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, L7 8XP, UK; Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, L7 8TX, UK. Electronic address: s.e.coupland@liverpool.ac.uk. ·Hum Pathol · Pubmed #28655639.

ABSTRACT: Current treatments for metastatic uveal melanoma (mUM) are limited and rarely prolong patient survival. Immunotherapy trials for mUM are few and to date have demonstrated only marginal success. High densities of tumor-associated macrophages (TAMs) and infiltrating T lymphocytes (TILs) in primary UM are associated with poor prognosis. Little is known about the immune microenvironment of mUM. Our aim was to examine the presence and distribution of TAMs and TILs in mUM within the liver. Whole-tissue sections of liver mUM (n=35) were examined by immunohistochemistry. For TAMs, monoclonal antibodies against CD68 and CD163 were used. Macrophage density and morphology were scored using previous established systems. Density and spatial distribution of TILs were highlighted using antibodies against CD3 (pan-lymphocyte marker), CD4 (T-helper cells), and CD8 (T-cytotoxic cells). CD68+ and CD163+ TAMs were seen within the tumor in all 35 specimens; their density was "moderate" in 50% of cases and "few" in 43%, and the majority showed an "indeterminate" phenotype. CD3+ TILs were noted both within mUMs and surrounding the tumor. Of these, CD8+ TILs were "few" in number within mUM but were predominantly seen peritumorally at the tumor/normal liver interface, whereas CD4+ TILs showed a high perivascular density within mUM. CD68+ and CD163+ TAMs of "indeterminate" morphology were observed in mUM, suggesting a tendency toward the protumorigenic M2 phenotype. CD4+ TILs were seen within the mUM, whereas CD8+ TILs tended to be peritumoral. The biological and functional roles of inflammatory cells in mUM require further investigation to determine if they represent potential targets for future therapies in mUM.

18 Article Fucoidan Does Not Exert Anti-Tumorigenic Effects on Uveal Melanoma Cell Lines. 2017

Dithmer, Michaela / Kirsch, Anna-Maria / Richert, Elisabeth / Fuchs, Sabine / Wang, Fanlu / Schmidt, Harald / Coupland, Sarah E / Roider, Johann / Klettner, Alexa. ·Department of Ophthalmology, University of Kiel, University Medical Center, Arnold-Heller-Str. 3, 24105 Kiel, Germany. michaela_dithmer@web.de. · Department of Ophthalmology, University of Kiel, University Medical Center, Arnold-Heller-Str. 3, 24105 Kiel, Germany. anna.maria.kirsch@gmx.de. · Department of Ophthalmology, University of Kiel, University Medical Center, Arnold-Heller-Str. 3, 24105 Kiel, Germany. elisabeth.richert@uksh.de. · Experimental Trauma Surgery, University of Kiel, University Medical Center, Arnold-Heller-Str. 3, 24105 Kiel, Germany. sabine.fuchs@uksh.de. · Experimental Trauma Surgery, University of Kiel, University Medical Center, Arnold-Heller-Str. 3, 24105 Kiel, Germany. fanlu.wang@uksh.de. · MetaPhysiol, Am Römerberg, 55270 Essenheim, Germany. schmidt@metaphysiol.de. · Department of Molecular and Clinical Cancer Medicine, Liverpool Ocular Oncology Research Group, Pathology, University of Liverpool, Liverpool L69 3BX, UK. s.e.coupland@liverpool.ac.uk. · Department of Ophthalmology, University of Kiel, University Medical Center, Arnold-Heller-Str. 3, 24105 Kiel, Germany. johann.roider@uksh.de. · Department of Ophthalmology, University of Kiel, University Medical Center, Arnold-Heller-Str. 3, 24105 Kiel, Germany. aklettner@auge.uni-kiel.de. ·Mar Drugs · Pubmed #28640204.

ABSTRACT: BACKGROUND: The polysaccharide fucoidan is widely investigated as an anti-cancer agent. Here, we tested the effect of fucoidan on uveal melanoma cell lines. METHODS: The effect of 100 µM fucoidan was investigated on five cell lines (92.1, Mel270 OMM1, OMM2.3, OMM2.5) and of 1 µg/mL-1 mg/mL fucoidan in two cell lines (OMM1, OMM2.3). Cell proliferation and viability were investigated with a WST-1 assay, migration in a wound healing (scratch) assay. Vascular Endothelial Growth Factor (VEGF) was measured in ELISA. Angiogenesis was evaluated in co-cultures with endothelial cells. Cell toxicity was induced by hydrogen-peroxide. Protein expression (Akt, ERK1/2, Bcl-2, Bax) was investigated in Western blot. RESULTS: Fucoidan increased proliferation in two and reduced it in one cell line. Migration was reduced in three cell lines. The effect of fucoidan on VEGF was cell type and concentration dependent. In endothelial co-culture with 92.1, fucoidan significantly increased tubular structures. Moreover, fucoidan significantly protected all tested uveal melanoma cell lines from hydrogen-peroxide induced cell death. Under oxidative stress, fucoidan did not alter the expression of Bcl-2, Bax or ERK1/2, while inducing Akt expression in 92.1 cells but not in any other cell line. CONCLUSION: Fucoidan did not show anti-tumorigenic effects but displayed protective and pro-angiogenic properties, rendering fucoidan unsuitable as a potential new drug for the treatment of uveal melanoma.

19 Article Prognostic biopsy of choroidal melanoma: an optimised surgical and laboratory approach. 2017

Angi, Martina / Kalirai, Helen / Taktak, Azzam / Hussain, Rumana / Groenewald, Carl / Damato, Bertil E / Heimann, Heinrich / Coupland, Sarah E. ·Department of Clinical and Molecular Cancer Medicine, Liverpool Ocular Oncology Research Group, University of Liverpool, Liverpool, UK. · Liverpool Ocular Oncology Centre, St Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, UK. · Department of Medical Physics & Clinical Engineering, Royal Liverpool University Hospital, Liverpool, UK. · Department of Ophthalmology and Radiation Oncology, Ocular Oncology Service, University of California, San Francisco, California, USA. · Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, UK. ·Br J Ophthalmol · Pubmed #28596284.

ABSTRACT: BACKGROUND: Accurate survival prognostication for patients with uveal melanoma (UM) enables effective patient counselling and permits personalised systemic surveillance for the early detection of metastases and, in high-risk patients, enrolment in any trials of systemic adjuvant therapy. The aim of this work is to determine the success of prognostic UM tumour biopsy using an improved surgical approach and optimised sample handling workflow. METHODS: Patients with UM treated by primary radiotherapy between 2011 and 2013 and who underwent a prognostic biopsy with cytology, multiplex ligation-dependent probe amplification and/or microsatellite analysis were included. The main outcomes and measures were success of cytology and genetic studies, and surgical complications. RESULTS: The cohort comprised 232 patients with UM having a median age of 59 years (range, 25-82) at treatment. The median largest basal diameter was 11.4 mm (range, 4.1-20.8) and tumour height was 3.4 mm (range, 0.7-10.3). Ciliary body involvement was noted in 42 cases. Treatment consisted of Ru-106 brachytherapy in 151 cases (65%) and proton beam radiotherapy in 81 cases (35%). With improvements in surgical techniques and laboratory methods over time, cytology success increased from 92% (131/142) to 99% (89/90) and the numbers of samples with sufficient DNA for genetic testing increased from 79% (104/131) to 93% (83/89). Overall, chromosome 3 loss was noted in 64/187 (34%) cases. Surgical complications, including transient localised bleeding, vitreous haemorrhage and retinal perforation, decreased over time. Eight patients required additional surgery. CONCLUSIONS: Improved surgical techniques and laboratory methods yielded successful cytology and genetic information in the majority of cases. PRECIS: Analysis of data from 232 patients with uveal melanoma undergoing prognostic tumour biopsy demonstrated that improved surgical techniques and laboratory methods yielded successful cytology and genetic information in 99% and 89% of cases, respectively.

20 Article Incorporating Clinical, Histological, and Genetic Parameters for Choroidal Melanoma Prognostication. 2017

Coupland, Sarah E / Taktak, Azzam / Damato, Bertil. ·Department of Cellular and Molecular Pathology, University of Liverpool, Liverpool, England. · Royal Liverpool University Hospital, Liverpool, England. · Ocular Oncology Service, University of California-San Francisco, San Francisco. ·JAMA Ophthalmol · Pubmed #28542696.

ABSTRACT: -- No abstract --

21 Article RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma. 2017

Chen, Xu / Wu, Qiuxia / Depeille, Philippe / Chen, Peirong / Thornton, Sophie / Kalirai, Helen / Coupland, Sarah E / Roose, Jeroen P / Bastian, Boris C. ·Departments of Dermatology and Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: xu.chen@ucsf.edu. · Departments of Dermatology and Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. · Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Mewdicine, University of Liverpool, Liverpool L7 8TX, UK. · Departments of Dermatology and Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: boris.bastian@ucsf.edu. ·Cancer Cell · Pubmed #28486107.

ABSTRACT: Constitutive activation of Gαq signaling by mutations in GNAQ or GNA11 occurs in over 80% of uveal melanomas (UMs) and activates MAPK. Protein kinase C (PKC) has been implicated as a link, but the mechanistic details remained unclear. We identified PKC δ and ɛ as required and sufficient to activate MAPK in GNAQ mutant melanomas. MAPK activation depends on Ras and is caused by RasGRP3, which is significantly and selectively overexpressed in response to GNAQ/11 mutation in UM. RasGRP3 activation occurs via PKC δ- and ɛ-dependent phosphorylation and PKC-independent, DAG-mediated membrane recruitment, possibly explaining the limited effect of PKC inhibitors to durably suppress MAPK in UM. The findings nominate RasGRP3 as a therapeutic target for cancers driven by oncogenic GNAQ/11.

22 Article External Validation of the Liverpool Uveal Melanoma Prognosticator Online. 2016

DeParis, Sarah W / Taktak, Azzam / Eleuteri, Antonio / Enanoria, Wayne / Heimann, Heinrich / Coupland, Sarah E / Damato, Bertil. ·Department of Ophthalmology, University of California-San Francisco, San Francisco, California, United States. · Department of Medical Physics and Clinical Engineering, Royal Liverpool University Hospital, Liverpool, United Kingdom. · Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, California, United States. · Liverpool Ocular Oncology Service, Royal Liverpool University Hospital, Liverpool, United Kingdom. · Pathology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Department of Ophthalmology, University of California-San Francisco, San Francisco, California, United States 4Liverpool Ocular Oncology Service, Royal Liverpool University Hospital, Liverpool, United Kingdom. ·Invest Ophthalmol Vis Sci · Pubmed #27835710.

ABSTRACT: Purpose: To validate the Liverpool Uveal Melanoma Prognosticator Online (LUMPO) in a cohort of patients treated at the University of California-San Francisco (UCSF). Methods: A retrospective chart review was performed of 390 patients treated between 2002 and 2007 for choroidal melanoma at UCSF. Similar patients (n = 1175) treated at the Liverpool Ocular Oncology Centre (LOOC) were included in the study. The data were analyzed using the model previously developed for LUMPO, an online prognostication tool combining multiple prognostic factors. Main outcome measures included all-cause mortality and melanoma-specific mortality. Reliability of the survival estimates in each group of patients was indicated by the C-indices of discrimination and Hosmer-Lemeshow test. Results: Patients treated at UCSF tended to be younger with thicker tumors, and were more likely to receive proton beam radiotherapy as primary treatment compared to patients at LOOC. There were no significance differences with respect to ciliary body involvement, melanoma cytomorphology, and mitotic counts between the two groups. Death occurred in 140/390 (35%) patients from UCSF and 409/1175 (34%) patients from LOOC, with no difference in overall mortality by Kaplan-Meier analysis (log rank test, P = 0.503). For all-cause mortality and melanoma-specific mortality, the C-index of discrimination and Hosmer-Lemeshow test at 5 years after treatment indicated good discrimination performance of the model, with no statistically significant difference between observed and predicted survival. Conclusions: Despite differences between the two cohorts, external validation in patients treated at UCSF indicates that LUMPO estimated the all-cause and melanoma-specific mortality well.

23 Article MicroRNA Expression Profile in Conjunctival Melanoma. 2016

Larsen, Ann-Cathrine / Mikkelsen, Lauge H / Borup, Rehannah / Kiss, Katalin / Toft, Peter B / von Buchwald, Christian / Coupland, Sarah E / Prause, Jan U / Heegaard, Steffen. ·Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark. · Microarray Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. · Department of Pathology, Rigshospitalet, Copenhagen, Denmark. · Department of Ophthalmology, Rigshospitalet-Glostrup, Copenhagen, Denmark. · Department of Otorhinolaryngology, Head & Neck Surgery, and Audiology, Copenhagen University Hospital, Rigshospitalet, and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Division of Pathology, Department of Molecular and Clinical Medicine, Royal Liverpool University Hospital, Liverpool, England. · Department of Pathology, Rigshospitalet, Copenhagen, Denmark 4Department of Ophthalmology, Rigshospitalet-Glostrup, Copenhagen, Denmark. ·Invest Ophthalmol Vis Sci · Pubmed #27548891.

ABSTRACT: PURPOSE: Conjunctival melanoma (CM) is a rare disease associated with considerable mortality. As opposed to cutaneous melanoma, the epigenetic mechanisms involved in the development of CM and other mucosal melanomas (MMs) are unclear. The purpose of this study was to identify tumor-specific and prognostic microRNA (miRNA) in CM and to compare the miRNA profile with that of MM. METHODS: Using microarray analysis (Affymetrix) we determined the miRNA expression profile in 40 CMs compared with 7 normal conjunctival samples. Changes in miRNA expression were associated with T stage, local recurrence, metastasis, and mortality. Furthermore, the expression of six fresh frozen tissue samples of CM was compared with that of four laryngeal and sinonasal MM. RESULTS: Our analysis revealed 24 upregulated and 1 downregulated miRNA in CM; several of these miRNAs have key functions in the pathogenesis and progression of cutaneous melanoma. Additionally, we identified seven upregulated miRNAs specific for stage-T1 and stage-T2 CM, whose expression was associated with increased tumor thickness (P = 0.007), and two upregulated miRNAs (miR-3687 and miR-3916) associated with an increased risk of local recurrence. No stage T3-specific miRNAs were identified. CONCLUSIONS: We identified differentially expressed and potentially prognostic miRNAs in CM. Furthermore, the miRNA expression pattern of CM resembled that in MM. The identification of these differentially expressed miRNAs provides an entry point for future functional studies of miRNAs as prognostic or therapeutic targets in CM and highlights the resemblance between CM, MM, and cutaneous melanoma.

24 Article Genetic Variants of the BTNL2 Gene in Uveal Melanoma. 2016

Coupland, Sarah E / Krishna, Yamini. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. ·JAMA Ophthalmol · Pubmed #27533527.

ABSTRACT: -- No abstract --

25 Article Metastatic ocular melanoma to the liver exhibits infiltrative and nodular growth patterns. 2016

Grossniklaus, Hans E / Zhang, Qing / You, Shuo / McCarthy, Conni / Heegaard, Steffen / Coupland, Sarah E. ·Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA 30322; Winship Cancer Institute, Emory University, Atlanta, GA, USA 30322. Electronic address: ophtheg@emory.edu. · Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA 30322. · Winship Cancer Institute, Emory University, Atlanta, GA, USA 30322. · Molecular and Clinical Cancer Medicine, Royal Liverpool and Broadgreen University Hospital NHS Trust, University of Liverpool, Liverpool, L69 3GA UK. · Department of Pathology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; Department of Ophthalmology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark. ·Hum Pathol · Pubmed #27476775.

ABSTRACT: We examined liver specimens from 15 patients with uveal melanoma (UM) who had died of their disseminated disease. We found 2 distinct growth patterns of UM metastasis: infiltrative (n = 12) and nodular (n = 3). In the infiltrative pattern, individual UM cells with a CD133+ cancer stem cell-like phenotype were present and formed aggregates of stage I <50-μm-diameter micrometastases in the sinusoidal spaces. These micrometastases appeared to expand, destroy adjacent hepatocytes, and form stage II 51- to 500-μm-diameter and then stage III >500μm-diameter metastases, which were encapsulated by collagenized fibrous septae. In the nodular growth pattern, CD133+ melanoma cells aggregated adjacent to portal venules and subsequently appeared to grow and efface the adjacent hepatocytes to form stage II 51- to 500-μm-diameter nodules that surrounded the portal venule. These avascular nodules appeared to further expand to form stage III >500-μm-diameter nodules that exhibited vascularization with minimal fibrosis. The tumor stem cell-like phenotype seen in individual UM cells was lost as the tumors progressed. There were CD56+ natural killer cells in sinusoidal spaces and CD3+ lymphocytes in periportal areas. The nodular growth pattern showed UM cells expressing MMP9 and VEGF. UM cells in both above-described growth patterns exhibited variable BAP1 expression. We propose that changes in the liver microenvironment are related to metastatic UM growth. We hypothesize that these changes include immune regulation within the sinusoidal space for the infiltrative pattern and changes in the VEGF/PEDF ratio for the nodular pattern.

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