Special Issue "Uveal Melanoma"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 31 May 2019

Special Issue Editor

Guest Editor
Dr. Ulrich Pfeffer

Molecular Pathology, Ospedale Policlinico San Martino, Genova, Italy
Website | E-Mail
Interests: cancer genomics; melanoma; uveal melanoma; gene editing

Special Issue Information

Dear Colleagues,

Uveal melanoma is among the best characterized solid tumors. It has become clear that there are mainly two subtypes that can eventually be subdivided into three or four, which are clearly distinct by their histopathological, cytogenetic, and molecular characteristics. The analysis of the subtypes allows to prognosticate the metastatic risk of each patient with an unmatched accuracy. While we essentially understand the molecular steps in uveal melanoma carcinogenesis, the mechanisms of metastasization and pronounced liver tropism are still poorly understood.

Unfortunately, the diagnostic and prognostic power is not matched by efficacy of therapy. The primary tumor is controlled by radiological and surgical interventions and local relapses are extremely rare. Nevertheless, approximately half of the patients develop metastases that rapidly progress to the fatal stage. Despite research, survival of patients with metastatic uveal melanoma has not changed over decades. The identification of the most frequent putative driver mutations, which occur in a mutually exclusive manner in two genes encoding alpha-subunits of G-proteins GNAQ and GNA11, has indicated G-protein signaling and the activation of MAP-kinases as potential targets, but MEK-inhibitors have failed to show major effects in clinical trials. More recently, the HIPPO independent activation of the YAP/TAZ signaling pathway by mutated GNAQ and GNA11 has been described, but, at present, no specific inhibitors have been tested in clinics. Recent reports on a specific inhibitor of the mutated form of GNAQ must be confirmed and translated into clinical applications. Immune checkpoint blockers that have met considerable success in the treatment of several cancers, including cutaneous melanoma, show very low response rates in uveal melanoma, likely due to the low number of neo-antigens, a consequence of a very low mutational burden.

Just like for other cancers, the identification of its Achilles’ heel will rely on a deep understanding of the molecular and cellular features of the cancer cell in its permissive microenvironment. This will likely be possible by the thorough molecular characterization of ever more tumors, the development of better cellular and animal models, such as three dimensional cultures, organoids, and patient derived xenografts, and the testing of new drugs, whether targeted at the molecular lesions typical of metastatic uveal melanoma or at the immune system.

In the present thematic issue, we try to summarize the current state of our understanding of uveal melanoma biology and recent advancements in uveal melanoma therapy and we discuss opportunities for therapeutic interventions that will hopefully soon improve the survival rates of metastatic uveal melanoma patients.

Dr. Ulrich Pfeffer
Guest Editor

Manuscript Submission Information

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Published Papers (3 papers)

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Research

Open AccessArticle MRI of Uveal Melanoma
Cancers 2019, 11(3), 377; https://doi.org/10.3390/cancers11030377
Received: 8 February 2019 / Revised: 8 March 2019 / Accepted: 12 March 2019 / Published: 17 March 2019
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Abstract
Uveal Melanoma (UM) is the most common primary malignant ocular tumor. The high soft tissue contrast and spatial resolution, and the possibility of generating 3D volumetric and functional images, make Magnetic Resonance Imaging (MRI) a valuable diagnostic imaging technique in UM. Current clinical [...] Read more.
Uveal Melanoma (UM) is the most common primary malignant ocular tumor. The high soft tissue contrast and spatial resolution, and the possibility of generating 3D volumetric and functional images, make Magnetic Resonance Imaging (MRI) a valuable diagnostic imaging technique in UM. Current clinical MRI protocols, however, are not optimized for UM and therefore lack the quality for accurate assessments. We therefore developed a dedicated protocol at a 3 Tesla MRI, using an eye coil, consisting of multi-slice 2D sequences, different isotropic sequences and diffusion and perfusion-weighted images. This protocol was prospectively evaluated in 9 uveal melanoma patients. The multi-slice 2D sequences had the highest in-plane resolution, being the most suited for lesion characterization and local extension evaluation. The isotropic 3D Turbo-Spin Echo (TSE) sequences were the most suitable for accurate geometric measurements of the tumor and are therefore important for therapy planning. Diffusion and perfusion-weighted images aid in differentiating benign from malignant lesions and provide quantitative measures on tumor hemodynamics and cellularity, which have been reported to be effective in predicting and assessing treatment outcome. Overall, this dedicated MRI protocol provides high-quality imaging of UM, which can be used to improve its diagnosis, treatment planning, and follow-up. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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Open AccessArticle Absence of Intraocular Lymphatic Vessels in Uveal Melanomas with Extrascleral Growth
Cancers 2019, 11(2), 228; https://doi.org/10.3390/cancers11020228
Received: 20 January 2019 / Revised: 10 February 2019 / Accepted: 12 February 2019 / Published: 15 February 2019
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Abstract
The aim of this study was to investigate the presence of intraocular lymphatic vessels in patients with uveal melanomas and extrascleral extension using a panel of lymphatic markers. The following immunohistochemical markers were analyzed: lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE-1), podoplanin (D2-40), [...] Read more.
The aim of this study was to investigate the presence of intraocular lymphatic vessels in patients with uveal melanomas and extrascleral extension using a panel of lymphatic markers. The following immunohistochemical markers were analyzed: lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE-1), podoplanin (D2-40), prospero-related homeobox gene-1 (Prox-1), pan-endothelial marker cluster of differentiation 31 (CD31), and blood vessel endothelium-specific CD34. Lymphatic vessels were defined as a combination of staining of the following positive markers: LYVE-1, D2-40, Prox-1, and CD31; and no staining of the negative marker CD34. In total, 456 patients were enucleated; 16 of the 46 uveal melanomas with extrascleral extension were contained in stored paraffin tissue. Two samples of the 16 uveal melanomas showed focal positive intraocular vascular staining for LYVE-1 and co-expression of CD31 and CD34. Due to the lack of Prox-1 and D2-40, and positive expression of CD34, these cannot be classified as lymphatic vessels. In one case recruitment of an extraocular, intratumoral lymphatic vascular structure was observed in the periphery of the subconjunctival extrascleral extension. Intraocular lymphatic vessels are absent in uveal melanomas with extrascleral extension; however, we provide proof for recruitment of intratumoral lymphatics by uveal melanomas with extraocular extension from subconjunctival lymphatics that may explain the rare cases of regional lymphatic spread. A panel of antibodies is necessary to detect lymphatic vessels with high specificity. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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Open AccessArticle Adjuvant Ipilimumab in High-Risk Uveal Melanoma
Cancers 2019, 11(2), 152; https://doi.org/10.3390/cancers11020152
Received: 29 November 2018 / Revised: 14 January 2019 / Accepted: 21 January 2019 / Published: 29 January 2019
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Abstract
Uveal melanoma is a common intraocular malignant tumor that is uniformly fatal once metastatic. No effective adjuvant therapy currently exists to reduce the risk of distant metastasis after definitive treatment of the primary lesion. Immunotherapy has been used effectively in the adjuvant setting [...] Read more.
Uveal melanoma is a common intraocular malignant tumor that is uniformly fatal once metastatic. No effective adjuvant therapy currently exists to reduce the risk of distant metastasis after definitive treatment of the primary lesion. Immunotherapy has been used effectively in the adjuvant setting in locally advanced cutaneous melanoma. We performed a Phase I/II clinical trial of adjuvant ipilimumab in high-risk primary uveal melanoma with distant metastasis-free survival (DMFS) as the primary objective. A total of 10 patients with genomically high-risk disease were treated: three at a dose of 3 mg/kg and seven at 10 mg/kg. Two of the seven patients at the higher dose had to discontinue therapy secondary to grade 3 toxicity. At 36 months follow-up, 80% of patients had no evidence of distant disease (95% CI, 58.7–100). With recent advancements in CTLA-4 inhibition, PD-1 inhibition, and combined checkpoint blockade, immunotherapy is a promising avenue of treatment in uveal melanoma. Further clinical trials are needed to elucidate the role of immunotherapy in the adjuvant setting. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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