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Uveal Melanoma: From Diagnosis to Therapy
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Uveal Melanoma: From Diagnosis to Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Causes, Screening and Diagnosis".

Deadline for manuscript submissions: closed (20 May 2022) | Viewed by 39249

Special Issue Editor

Dr. Emine Kilic

E-Mail Website
Guest Editor
Department of Ophthalmology, Erasmus MC Rotterdam, 3000 CA Rotterdam, The Netherlands
Interests: uveal melanoma; microRNA; genetics; prognostication; ctDNA; CTC
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Uveal melanoma incidence has not changed in the past few decades; however, knowledge on the genetic makeup of these tumors has grown tremendously. Progress has been made in the classification and and prognostication of uveal melanoma. With the developments in the field of mutation profiling and gene expression, the clinical classification of small tumors has also progressed. However, the effect on therapeutic processes has been dismal. Of course, the discovery of new mutations such as MDB4 will aid in the treatment of a small proportion of uveal melanoma patients in the case of metastatic disease. Further understanding of uveal melanoma biology is therefore vital to help us to understand how processes become dysfunctional in cancer development/progression, and may aid in the identification of new targets for treatment and/or biomarkers to improve our therapeutic strategy for cancer treatment, with the consequence of improving patient survival.

In this Special Issue, experts in the field will review the translation of genetic information in a clinical setting and the consequences for the management of uveal melanoma patients.

Dr. Emine Kilic
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • uveal melanoma
  • prognostication
  • metastases
  • genetics
  • epigenetics
  • mutation analysis

Published Papers (15 papers)

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18 pages, 2522 KiB  
Article
Novel Treatments of Uveal Melanoma Identified with a Synthetic Lethal CRISPR/Cas9 Screen
by Kseniya Glinkina, Arwin Groenewoud, Amina F. A. S. Teunisse, B. Ewa Snaar-Jagalska and Aart G. Jochemsen
Cancers 2022, 14(13), 3186; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133186 - 29 Jun 2022
Cited by 2 | Viewed by 1900
Abstract
Currently, no systemic treatment is approved as the standard of care for metastatic uveal melanoma (UM). mTOR has been evaluated as a drug target in UM. However, one of the main limitations is dose reduction due to adverse effects. The combination of everolimus [...] Read more.
Currently, no systemic treatment is approved as the standard of care for metastatic uveal melanoma (UM). mTOR has been evaluated as a drug target in UM. However, one of the main limitations is dose reduction due to adverse effects. The combination of everolimus with another targeted agent would allow the reduction of the dose of a single drug, thus widening the therapeutic window. In our study, we aimed to identify a synergistic combination with everolimus in order to develop a novel treatment option for metastatic UM. We exploited CRISPR-Cas9 synthetic lethality screening technology to search for an efficient combination. IGF1R and PRKDC and several other genes were identified as hits in the screen. We investigated the effect of the combination of everolimus with the inhibitors targeting IGF1R and DNA-PKcs on the survival of UM cell lines. These combinations synergistically slowed down cell growth but did not induce apoptosis in UM cell lines. These combinations were tested on PDX UM in an in vivo model, but we could not detect tumor regression. However, we could find significant activity of the dual DNA-PKcs/mTOR inhibitor CC-115 on PDX UM in the in vivo model. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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14 pages, 1946 KiB  
Article
Amelanotic Uveal Melanomas Evaluated by Indirect Ophthalmoscopy Reveal Better Long-Term Prognosis Than Pigmented Primary Tumours—A Single Centre Experience
by Anna Markiewicz, Piotr Donizy, Monika Nowak, Mateusz Krzyziński, Martyna Elas, Przemysław M. Płonka, Jolanta Orłowska-Heitzmann, Przemysław Biecek, Mai P. Hoang and Bożena Romanowska-Dixon
Cancers 2022, 14(11), 2753; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112753 - 01 Jun 2022
Cited by 6 | Viewed by 3665
Abstract
(1) Background: There is a constant search for new prognostic factors that would allow us to accurately determine the prognosis, select the type of treatment, and monitor the patient diagnosed with uveal melanoma in a minimally invasive and easily accessible way. Therefore, we [...] Read more.
(1) Background: There is a constant search for new prognostic factors that would allow us to accurately determine the prognosis, select the type of treatment, and monitor the patient diagnosed with uveal melanoma in a minimally invasive and easily accessible way. Therefore, we decided to evaluate the prognostic role of its pigmentation in a clinical assessment. (2) Methods: The pigmentation of 154 uveal melanomas was assessed by indirect ophthalmoscopy. Two groups of tumours were identified: amelanotic and pigmented. The statistical relationships between these two groups and clinical, pathological parameters and the long-term survival rate were analyzed. (3) Results: There were 16.9% amelanotic tumours among all and they occurred in younger patients (p = 0.022). In pigmented melanomas, unfavourable prognostic features such as: epithelioid cells (p = 0.0013), extrascleral extension (p = 0.027), macronucleoli (p = 0.0065), and the absence of BAP1 expression (p = 0.029) were statistically more frequently observed. Kaplan–Meier analysis demonstrated significantly better overall (p = 0.017) and disease-free (p < 0.001) survival rates for patients with amelanotic tumours. However, this relationship was statistically significant for lower stage tumours (AJCC stage II), and was not present in larger and more advanced stages (AJCC stage III). (4) Conclusions: The results obtained suggested that the presence of pigmentation in uveal melanoma by indirect ophthalmoscopy was associated with a worse prognosis, compared to amelanotic lesions. These findings could be useful in the choice of therapeutic and follow-up options in the future. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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16 pages, 3009 KiB  
Article
Glycolysis Dependency as a Hallmark of SF3B1-Mutated Cells
by Raquel Vivet-Noguer, Malcy Tarin, Christine Canbezdi, Stephane Dayot, Lisseth Silva, Alexandre Houy, Sylvain Martineau, Virginie Mieulet, Géraldine Gentric, Damarys Loew, Bérangère Lombard, Fariba Nemati, Sophie Richon, Lea Guyonnet, Vincent Servois, Stephan Vagner, Marc-Henri Stern, Sergio Roman-Roman and Samar Alsafadi
Cancers 2022, 14(9), 2113; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092113 - 24 Apr 2022
Cited by 3 | Viewed by 2248
Abstract
SF3B1 mutations are recurrent in cancer and result in aberrant splicing of a previously defined set of genes. Here, we investigated the fate of aberrant transcripts induced by mutant SF3B1 and the related functional consequences. We first demonstrate that mutant SF3B1 does not [...] Read more.
SF3B1 mutations are recurrent in cancer and result in aberrant splicing of a previously defined set of genes. Here, we investigated the fate of aberrant transcripts induced by mutant SF3B1 and the related functional consequences. We first demonstrate that mutant SF3B1 does not alter global nascent protein synthesis, suggesting target-dependent consequences. Polysome profiling revealed that 35% of aberrantly spliced transcripts are more translated than their corresponding canonically spliced transcripts. This mostly occurs in genes with enriched metabolic functions. Furthermore, LC-MS/MS analysis showed that mutant SF3B1 impacts the abundance of proteins involved in metabolism. Functional metabolic characterization revealed that mutant SF3B1 decreases mitochondrial respiration and promotes glycolysis to compensate for defective mitochondrial metabolism. Hence, mutant SF3B1 induces glycolysis dependency, which sensitizes cells to glycolysis inhibition. Overall, we provide evidence of the oncogenic involvement of mutant SF3B1 in uveal melanoma through a metabolic switch to glycolysis, revealing vulnerability to glycolysis inhibitors as a promising therapeutic strategy. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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17 pages, 2991 KiB  
Article
Identification of Early-Onset Metastasis in SF3B1 Mutated Uveal Melanoma
by Wojtek Drabarek, Job van Riet, Josephine Q. N. Nguyen, Kyra N. Smit, Natasha M. van Poppelen, Rick Jansen, Eva Medico-Salsench, Jolanda Vaarwater, Frank J. Magielsen, Tom Brands, Bert Eussen, Thierry. P. P. van den Bosch, Robert M. Verdijk, Nicole C. Naus, Dion Paridaens, Annelies de Klein, Erwin Brosens, Harmen J. G. van de Werken, Emine Kilic and on behalf of the Rotterdam Ocular Melanoma Study Group
Cancers 2022, 14(3), 846; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030846 - 08 Feb 2022
Cited by 6 | Viewed by 3781
Abstract
Approximately 25% of all uveal melanoma (UM) contain driver mutations in the gene encoding the spliceosome factor SF3B1, and whilst patients with such SF3B1 mutations generally have an intermediate risk on developing metastatic disease, a third of these patients develop early metastasis [...] Read more.
Approximately 25% of all uveal melanoma (UM) contain driver mutations in the gene encoding the spliceosome factor SF3B1, and whilst patients with such SF3B1 mutations generally have an intermediate risk on developing metastatic disease, a third of these patients develop early metastasis within 5 years after diagnosis. We therefore investigated whether clinical and/or genetic variables could be indicative of short progression-free survival (PFS < 60 months) or long PFS (PFS ≥ 60 months) for SF3B1-mutated (SF3B1mut) UM patients. We collected 146 SF3B1mut UM from our Rotterdam Ocular Melanoma Studygroup (ROMS) database and external published datasets. After stratification of all SF3B1mut UM using short PFS vs. long PFS, only largest tumor diameter (LTD) was significantly larger (mean: 17.7 mm (±2.8 SD) in the short PFS SF3B1mut group vs. the long PFS group (mean: 14.7 (±3.7 SD, p = 0.001). Combined ROMS and The Cancer Genome Atlas (TCGA) transcriptomic data were evaluated, and we identified SF3B1mut-specific canonical transcripts (e.g., a low expression of ABHD6 indicative for early-onset metastatic disease) or distinct expression of SF3B1mut UM aberrant transcripts, indicative of early- or late-onset or no metastatic SF3B1mut UM. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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11 pages, 712 KiB  
Article
Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Re-Induction following Resistance or Toxicity
by Elias A. T. Koch, Anne Petzold, Anja Wessely, Edgar Dippel, Anja Gesierich, Ralf Gutzmer, Jessica C. Hassel, Sebastian Haferkamp, Katharina C. Kähler, Harald Knorr, Nicole Kreuzberg, Ulrike Leiter, Carmen Loquai, Friedegund Meier, Markus Meissner, Peter Mohr, Claudia Pföhler, Farnaz Rahimi, Dirk Schadendorf, Beatrice Schell, Max Schlaak, Patrick Terheyden, Kai-Martin Thoms, Beatrice Schuler-Thurner, Selma Ugurel, Jens Ulrich, Jochen Utikal, Michael Weichenthal, Fabian Ziller, Carola Berking and Markus V. Hepptadd Show full author list remove Hide full author list
Cancers 2022, 14(3), 518; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030518 - 20 Jan 2022
Cited by 8 | Viewed by 2034
Abstract
Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM [...] Read more.
Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1–23.8) versus 9.4 months (cohort B, 95% CI: 6.1–14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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11 pages, 1127 KiB  
Article
Risk of New Primary Cancer in Patients with Posterior Uveal Melanoma: A National Cohort Study
by Mette Bagger, Vanna Albieri, Tine Gadegaard Hindso, Karin Wadt, Steffen Heegaard, Klaus Kaae Andersen and Jens Folke Kiilgaard
Cancers 2022, 14(2), 284; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020284 - 07 Jan 2022
Cited by 4 | Viewed by 1669
Abstract
Background: Studies on the risk of new primary cancer in patients with posterior uveal melanoma (UM) have produced conflicting results, and the role of socioeconomic status (SES) is unknown. The purpose of this population-based matched cohort study was to determine the risk of [...] Read more.
Background: Studies on the risk of new primary cancer in patients with posterior uveal melanoma (UM) have produced conflicting results, and the role of socioeconomic status (SES) is unknown. The purpose of this population-based matched cohort study was to determine the risk of new primary cancer following the diagnosis of posterior UM. Methods: 2179 patients with posterior UM 1968–2016 and 22,717 matched controls without cancer were included. Incidence and time-dependent hazard ratio (HR) of new primary cancer were described, and the effect of SES was emphasized in a sub-cohort. Results: The incidence of new primary cancer was increased in patients with posterior UM, rate ratio (RR) 1.21 (95% CI: 1.08; 1.35), but the specific cancer types did not differ compared to the controls. The rate of new primary cancer following the diagnosis of posterior UM was significantly increased 2–5 years (HR 1.49 (95% CI: 1.23; 1.80)) and 11–15 years (HR: 1.49 (95% CI: 1.12; 1.99)), and adjusting for SES did not change the rate (HR 1.35 (95% CI:1.20; 1.55)). Conclusions: Patients with posterior UM have an increased risk of new primary cancer independent of SES. No difference in incidence of specific cancer type was observed compared to the control group. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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15 pages, 1794 KiB  
Article
Percutaneous Hepatic Perfusion (PHP) with Melphalan in Liver-Dominant Metastatic Uveal Melanoma: The German Experience
by Cornelia L. A. Dewald, Mia-Maria Warnke, Roland Brüning, Martin A. Schneider, Peter Wohlmuth, Jan B. Hinrichs, Anna Saborowski, Arndt Vogel and Frank K. Wacker
Cancers 2022, 14(1), 118; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010118 - 27 Dec 2021
Cited by 13 | Viewed by 3097
Abstract
Percutaneous hepatic perfusion (PHP) delivers high-dose melphalan to the liver while minimizing systemic toxicity via filtration of the venous hepatic blood. This two-center study aimed to examine the safety, response to therapy, and survival of patients with hepatic-dominant metastatic uveal melanoma (UM) treated [...] Read more.
Percutaneous hepatic perfusion (PHP) delivers high-dose melphalan to the liver while minimizing systemic toxicity via filtration of the venous hepatic blood. This two-center study aimed to examine the safety, response to therapy, and survival of patients with hepatic-dominant metastatic uveal melanoma (UM) treated with PHP. A total of 66 patients with liver-dominant metastasized uveal melanoma, treated with 145 PHP between April 2014 and May 2020, were retrospectively analyzed with regard to adverse events (AEs; CTCAE v5.0), response (overall response rate (ORR)), and disease control rate (DCR) according to RECIST1.1, as well as progression-free and overall survival (PFS and OS). With an ORR of 59% and a DCR of 93.4%, the response was encouraging. After initial PHP, median hepatic PFS was 12.4 (confidence interval (CI) 4–18.4) months and median OS was 18.4 (CI 7–24.6) months. Hematologic toxicity was the most frequent AE (grade 3 or 4 thrombocytopenia after 24.8% of the procedures); less frequent was grade 3 or 4 hepatic toxicity (increased aspartate transaminase (AST) and alanine transaminase (ALT) after 7.6% and 6.9% of the interventions, respectively). Cardiovascular events included four cases of ischemic stroke (2.8%) and one patient with central pulmonary embolism (0.7%). In conclusion, PHP is a safe and effective salvage treatment for liver-dominant metastatic uveal melanoma. Serious AEs—though rare—demand careful patient selection. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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18 pages, 3796 KiB  
Article
Analysis of Circulating Tumour Cells in Early-Stage Uveal Melanoma: Evaluation of Tumour Marker Expression to Increase Capture
by Aaron B. Beasley, Timothy W. Isaacs, Tersia Vermeulen, James Freeman, Jean-Louis DeSousa, Riyaz Bhikoo, Doireann Hennessy, Anna Reid, Fred K. Chen, Jacqueline Bentel, Daniel McKay, R. Max Conway, Michelle R. Pereira, Bob Mirzai, Leslie Calapre, Wendy N. Erber, Melanie R. Ziman and Elin S. Gray
Cancers 2021, 13(23), 5990; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13235990 - 28 Nov 2021
Cited by 4 | Viewed by 2502
Abstract
(1) Background: The stratification of uveal melanoma (UM) patients into prognostic groups is critical for patient management and for directing patients towards clinical trials. Current classification is based on clinicopathological and molecular features of the tumour. Analysis of circulating tumour cells (CTCs) has [...] Read more.
(1) Background: The stratification of uveal melanoma (UM) patients into prognostic groups is critical for patient management and for directing patients towards clinical trials. Current classification is based on clinicopathological and molecular features of the tumour. Analysis of circulating tumour cells (CTCs) has been proposed as a tool to avoid invasive biopsy of the primary tumour. However, the clinical utility of such liquid biopsy depends on the detection rate of CTCs. (2) Methods: The expression of melanoma, melanocyte, and stem cell markers was tested in a primary tissue microarray (TMA) and UM cell lines. Markers found to be highly expressed in primary UM were used to either immunomagnetically isolate or immunostain UM CTCs prior to treatment of the primary lesion. (3) Results: TMA and cell lines had heterogeneous expression of common melanoma, melanocyte, and stem cell markers. A multi-marker panel of immunomagnetic beads enabled isolation of CTCs in 37/43 (86%) patients with UM. Detection of three or more CTCs using the multi-marker panel, but not MCSP alone, was a significant predictor of shorter progression free (p = 0.040) and overall (p = 0.022) survival. (4) Conclusions: The multi-marker immunomagnetic isolation protocol enabled the detection of CTCs in most primary UM patients. Overall, our results suggest that a multi-marker approach could be a powerful tool for CTC separation for non-invasive prognostication of UM. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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13 pages, 1176 KiB  
Article
The Effect of Intraocular Pressure-Lowering Medication on Metastatic Uveal Melanomas
by Jan Pals, Hanneke W. Mensink, Erwin Brosens, Robert M. Verdijk, Nicole C. Naus, Dion A. Paridaens, Emine Kilic and Wishal D. Ramdas
Cancers 2021, 13(22), 5657; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225657 - 12 Nov 2021
Viewed by 1375
Abstract
Background: There has been speculation that IOP-lowering medication, which increases aqueous humor outflow, increases the risk of metastatic uveal melanoma (UM). This hypothesis has not been studied previously but is relevant for UM patients who use IOP-lowering medication. The aim of the current [...] Read more.
Background: There has been speculation that IOP-lowering medication, which increases aqueous humor outflow, increases the risk of metastatic uveal melanoma (UM). This hypothesis has not been studied previously but is relevant for UM patients who use IOP-lowering medication. The aim of the current study is to assess the association between the use of intraocular pressure (IOP)-lowering medication and the risk of metastatic UM, and mortality. Methods: A retrospective cohort study, in which patients from the Rotterdam Ocular Melanoma Study were included from 1986 onwards. Medical records were evaluated for use of IOP-lowering medication at baseline (i.e., before diagnosis). For each IOP-lowering medication, we divided patients into two groups for comparison (e.g., patients with alpha2-agonist use and patients without alpha2-agonist use). All patients underwent regular ophthalmic examinations and routine screening for metastasis. Survival analyses were initiated to compare groups in each IOP-lowering medication group. In addition, secondary analyses were performed to examine the association between IOP and the development of metastatic UM, and mortality. Results: A total of 707 patients were included of whom 13 patients used prostaglandin or pilocarpine at baseline. For alpha2-agonist, beta-blocker, carbonic anhydrase inhibitor, and oral IOP-lowering medication these were 4, 14, 11, and 12 patients, respectively. The risk of metastatic UM (choroid and ciliary body melanoma) among the prostaglandin/pilocarpine users was significantly higher than controls (HR [95% CI]: 4.840 [1.452–16.133]). Mortality did not differ significantly among the IOP-lowering medications groups, except for the prostaglandin or pilocarpine group (HR [95% CI]: 7.528 [1.836–30.867]). If we combined all IOP-lowering medication that increase aqueous humor outflow, the risk (HR [95% CI]) of metastatic UM and mortality was 6.344 (1.615–24.918) and 9.743 (2.475–38.353), respectively. There was an association between IOP and mortality, but not for the onset of metastatic UM. Conclusion: The use of topical prostaglandin or pilocarpine may increase the risk of metastatic UM and mortality compared to patients without prostaglandin or pilocarpine use. Therefore, use of IOP-lowering medication which increases aqueous humor outflow, should be avoided in patients with (presumed) UM. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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13 pages, 1212 KiB  
Article
Expression of HDACs 1, 3 and 8 Is Upregulated in the Presence of Infiltrating Lymphocytes in Uveal Melanoma
by Zahra Souri, Aart G. Jochemsen, Annemijn P. A. Wierenga, Wilma G. M. Kroes, Rob M. Verdijk, Pieter A. van der Velden, Gregorius P. M. Luyten and Martine J. Jager
Cancers 2021, 13(16), 4146; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164146 - 18 Aug 2021
Cited by 6 | Viewed by 1975
Abstract
In Uveal Melanoma (UM), an inflammatory phenotype is strongly associated with the development of metastases and with chromosome 3/BAP1 expression loss. As an increased expression of several Histone Deacetylases (HDACs) was associated with loss of chromosome 3, this suggested that HDAC expression might [...] Read more.
In Uveal Melanoma (UM), an inflammatory phenotype is strongly associated with the development of metastases and with chromosome 3/BAP1 expression loss. As an increased expression of several Histone Deacetylases (HDACs) was associated with loss of chromosome 3, this suggested that HDAC expression might also be related to inflammation. We analyzed HDAC expression and the presence of leukocytes by mRNA expression in two sets of UM (Leiden and TCGA) and determined the T lymphocyte fraction through ddPCR. Four UM cell lines were treated with IFNγ (50IU, 200IU). Quantitative PCR (qPCR) was used for mRNA measurement of HDACs in cultured cells. In both cohorts (Leiden and TCGA), a positive correlation occurred between expression of HDACs 1, 3 and 8 and the presence of a T-cell infiltrate, while expression of HDACs 2 and 11 was negatively correlated with the presence of tumor-infiltrating macrophages. Stimulation of UM cell lines with IFNγ induced an increase in HDACs 1, 4, 5, 7 and 8 in two out of four UM cell lines. We conclude that the observed positive correlations between HDAC expression and chromosome 3/BAP1 loss may be related to the presence of infiltrating T cells. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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17 pages, 1920 KiB  
Article
MiRNAs Correlate with HLA Expression in Uveal Melanoma: Both Up- and Downregulation Are Related to Monosomy 3
by Zahra Souri, Annemijn P. A. Wierenga, Emine Kiliç, Erwin Brosens, Stefan Böhringer, Wilma G. M. Kroes, Robert M. Verdijk, Pieter A. van der Velden, Gregorius P. M. Luyten and Martine J. Jager
Cancers 2021, 13(16), 4020; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164020 - 10 Aug 2021
Cited by 7 | Viewed by 2215
Abstract
MicroRNAs are known to play a role in the regulation of inflammation. As a high HLA Class I expression is associated with a bad prognosis in UM, we set out to determine whether any miRNAs were related to a high HLA Class I [...] Read more.
MicroRNAs are known to play a role in the regulation of inflammation. As a high HLA Class I expression is associated with a bad prognosis in UM, we set out to determine whether any miRNAs were related to a high HLA Class I expression and inflammation. We also determined whether such miRNAs were related to the UM’s genetic status. The expression of 125 miRNAs was determined in 64 primary UM from Leiden. Similarly, the mRNA expression of HLA-A, HLA-B, TAP1, BAP1, and immune cell markers was obtained. Expression levels of 24 of the 125 miRNAs correlated with expression of at least three out of four HLA Class I probes. Four miRNAs showed a positive correlation with HLA expression and infiltration with leukocytes, 20 a negative pattern. In the first group, high miRNA levels correlated with chromosome 3 loss/reduced BAP1 mRNA expression, in the second group low miRNA levels. The positive associations between miRNA-22 and miRNA-155 with HLA Class I were confirmed in the TCGA study and Rotterdam cohort, and with TAP1 in the Rotterdam data set; the negative associations between miRNA-125b2 and miRNA-211 and HLA-A, TAP1, and CD4 were confirmed in the Rotterdam set. We demonstrate two patterns: miRNAs can either be related to a high or a low HLA Class I/TAP1 expression and the presence of infiltrating lymphocytes and macrophages. However, both patterns were associated with chromosome 3/BAP1 status, which suggests a role for BAP1 loss in the regulation of HLA expression and inflammation in UM through miRNAs. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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16 pages, 2219 KiB  
Article
Evaluation of a Three-Marker Panel for the Detection of Uveal Melanoma Metastases: A Single-Center Retrospective Analysis
by Zenan Lin and Daniela Süsskind
Cancers 2021, 13(10), 2464; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102464 - 18 May 2021
Cited by 3 | Viewed by 1782
Abstract
Blood-based B-cell activating factor (BAFF), growth differentiation factor-15 (GDF-15) and osteopontin (OPN) have been identified to be promising biomarkers for the metastases of uveal melanoma (UM). This study intended to assess their kinetics and to evaluate their significance as a three-marker panel. A [...] Read more.
Blood-based B-cell activating factor (BAFF), growth differentiation factor-15 (GDF-15) and osteopontin (OPN) have been identified to be promising biomarkers for the metastases of uveal melanoma (UM). This study intended to assess their kinetics and to evaluate their significance as a three-marker panel. A group of 36 UM patients with and 137 patients without metastases were included in the study. Their plasma OPN levels were measured by ELISA; serum BAFF and GDF-15 levels were determined with a Luminex MAGPIX system. Receiver operating characteristic (ROC) analysis was performed to calculate the cutoff values of the three markers for identifying the patients with metastases. The ability to identify patients with metastases was compared between the single markers and the combination as a three-marker panel. By using the Student’s t-test, we also investigated the kinetic changes of the levels of BAFF, GDF-15 and OPN across six periods (i.e., 0–6 months, 6–12 months, 12–18 months, 18–24 months, >24 months and post-metastasis) before the imaging diagnosis of metastases. By maximizing the Youden’s index, the serum GDF-15 level of 1209 pg/mL and the plasma OPN level of 92 ng/mL were identified to have the best performance for distinguishing the metastatic patients from non-metastatic patients. The three-marker panel offered a better performance in distinguishing patients with metastases, with an area under the curve of 0.802, than any single biomarker. Increasing trends of the levels of three biomarkers were observed in the two-year period before the imaging diagnosis of metastases. The combined panel of BAFF, GDF-15 and OPN might be a utilizable implementation for the detection of UM metastases. In the bioinformatics study with two external datasets, the high expression of gene BAFF and GDF-15 in primary UM tissues was identified to be associated with poor overall survival rates. As the current work is a single-center retrospective study, more well-designed prospective investigations employing larger cohorts are urgently needed to validate our findings. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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30 pages, 2212 KiB  
Review
Imaging of Uveal Melanoma—Current Standard and Methods in Development
by Małgorzata Solnik, Natalia Paduszyńska, Anna M. Czarnecka, Kamil J. Synoradzki, Yacoub A. Yousef, Tomasz Chorągiewicz, Robert Rejdak, Mario Damiano Toro, Sandrine Zweifel, Katarzyna Dyndor and Michał Fiedorowicz
Cancers 2022, 14(13), 3147; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133147 - 27 Jun 2022
Cited by 19 | Viewed by 3408
Abstract
Uveal melanoma is the most common primary intraocular malignancy in adults, characterized by an insidious onset and poor prognosis strongly associated with tumor size and the presence of distant metastases, most commonly in the liver. Contrary to most tumor identification, a biopsy followed [...] Read more.
Uveal melanoma is the most common primary intraocular malignancy in adults, characterized by an insidious onset and poor prognosis strongly associated with tumor size and the presence of distant metastases, most commonly in the liver. Contrary to most tumor identification, a biopsy followed by a pathological exam is used only in certain cases. Therefore, an early and noninvasive diagnosis is essential to enhance patients’ chances for early treatment. We reviewed imaging modalities currently used in the diagnostics of uveal melanoma, including fundus imaging, ultrasonography (US), optical coherence tomography (OCT), single-photon emission computed tomography (SPECT), fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), fundus autofluorescence (FAF), as well as positron emission tomography/computed tomography (PET/CT) or magnetic resonance imaging (MRI). The principle of imaging techniques is briefly explained, along with their role in the diagnostic process and a summary of their advantages and limitations. Further, the experimental data and the advancements in imaging modalities are explained. We describe UM imaging innovations, show their current usage and development, and explain the possibilities of utilizing such modalities to diagnose uveal melanoma in the future. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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20 pages, 624 KiB  
Review
Poor Response to Checkpoint Immunotherapy in Uveal Melanoma Highlights the Persistent Need for Innovative Regional Therapy Approaches to Manage Liver Metastases
by Brett M. Szeligo, Abby D. Ivey and Brian A. Boone
Cancers 2021, 13(14), 3426; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143426 - 08 Jul 2021
Cited by 10 | Viewed by 2503
Abstract
Uveal melanoma is a cancer that develops from melanocytes in the posterior uveal tract. Metastatic uveal melanoma is an extremely rare disease that has a poor long-term prognosis, limited treatment options and a strong predilection for liver metastasis. Median overall survival has been [...] Read more.
Uveal melanoma is a cancer that develops from melanocytes in the posterior uveal tract. Metastatic uveal melanoma is an extremely rare disease that has a poor long-term prognosis, limited treatment options and a strong predilection for liver metastasis. Median overall survival has been reported to be 6 months and 1 year mortality of 80%. Traditional chemotherapy used in cutaneous melanoma is ineffective in uveal cases. Surgical resection and ablation is the preferred therapy for liver metastasis but is often not feasible due to extent of disease. In this review, we will explore treatment options for liver metastases from uveal melanoma, with a focus on isolated hepatic perfusion (IHP). IHP offers an aggressive regional therapy approach that can be used in bulky unresectable disease and allows high-dose chemotherapy with melphalan to be delivered directly to the liver without systemic effects. Long-term median overall survival has been reported to be as high as 27 months. We will also highlight the poor responses associated with checkpoint inhibitors, including an overview of the biological rationale driving this lack of immunotherapy effect for this disease. The persistent failure of traditional treatments and immunotherapy suggest an ongoing need for regional surgical approaches such as IHP in this disease. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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17 pages, 759 KiB  
Review
The Impact of Ultraviolet Radiation on the Aetiology and Development of Uveal Melanoma
by Melissa Chalada, Charmaine A. Ramlogan-Steel, Bijay P. Dhungel, Christopher J. Layton and Jason C. Steel
Cancers 2021, 13(7), 1700; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071700 - 03 Apr 2021
Cited by 13 | Viewed by 3442
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Uveal Melanoma: From Diagnosis to Therapy)
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