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What Is Metastatic Uveal Melanoma

Management And Surveillance For Metastatic Uveal Melanoma

Understanding metastatic uveal melanoma

In most cases of uveal melanoma, patients are diagnosed by an optometrist or ophthalmologist, with subsequent referral to a specialist ocular oncologist. Delays in treatment at this stage can have implications on preventable morbidity and overall patient outcomes. For example, a greater percentage of patients in the UK who experienced delays, or who reported their tumour as being misdiagnosed, ultimately required enucleation. Delays may arise from slow referral times, misdiagnosis or failed detection of tumours, delays in imaging and administrative delays.

Given the frequent development of metastases, consideration of active surveillance and management of patients following adjuvant therapy has been recommended within the UK Uveal Melanoma National Guidelines. Although no survival benefit as a result of the early detection of asymptomatic disease has been documented, surveillance allows for the identification of oligometastatic disease amenable to surgery or other local therapies, as well as patients eligible for clinical trials. Risk stratification by clinical criteria, cytogenetic studies and gene expression profiling can be used to identify patients at high risk of developing metastases and guide surveillance decisions accordingly.

Summary of key points relevant to multidisciplinary team management of uveal melanoma from the UK Uveal Melanoma National Guidelines.

Newer Methods On The Horizon

There are no currently approved targeted therapies for the treatment of early-stage ocular melanoma. One treatment currently in preclinical development is light-activated AU-011, a novel virus like particle drug conjugate as a targeted therapy for the treatment of primary uveal melanoma. The drug is administered through intravitreal injection and activation by laser to produce targeted, rapid, tumor necrosis while sparing healthy ocular tissue.

Promoting tumor cell death and preserving healthy cells and tissues are the twin, often conflicting, goals of cancer treatments. The key value of the mechanism of action of AU-011 relies on the combined principles of targeted cancer therapy and multivalency. The viral particle component of AU-011 offers a multivalent tumor binding capacity over traditional bivalent antibody treatments. The targeted delivery makes tumor tissue more susceptible to the cytotoxic effect of the light-activated dye component of the drug. Once the treated tumor is exposed to light at 689nm, excitation of the dye at the site of the tumor cell membrane leads to necrotic cell death without harming other ocular structures. Immunotherapy against uveal melanoma is also being studied with attempts to develop vaccine against uveal melanoma using autologous dendritic cells laden with tumor RNA.

Our Research On Uveal Melanoma

As a national centre of reference for the treatment of choroidal melanoma, a rare eye cancer, Institut Curie is continuing its commitment to better characterize this disease. Yhere has been close collaboration with researchers at Institut Curie for over 10 years regarding uveal melanoma. This has already enabled us to characterize the genetic anomalies of uveal melanoma, to correlate them to the risk of metastasis and to offer the patients concerned a clinical research protocol of adjuvant chemotherapy . Several clinical studies are also in progress for treating metastases, in particular early international trials testing new anticancer compounds. Scientific work is continuing in order to understand the disease better and find new, more active medicines for melanoma of the eye. In 2016 It starts a research program, a PIC3i, financed by its own funds and to a large extent by the generosity of the general public. The goal is to decode a new method of tumor dissemination.

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Uveal Melanoma Discovery Points To New Treatment Possibilities

    An illustration showing compact DNA bound to PRC1 . Loss of PRC1 leads to aberrant gene activity . Courtesy of Dr. Mathieu Bakhoum.

    A team co-led by scientists at Weill Cornell Medicine has revealed in detail how the most common primary eye cancer in adults, uveal melanoma , can progress from a slow-growing, indolent state to a lethal metastasizing state. The discovery is a significant advance in fundamental cancer research that also suggests new strategies for treatment.

    The scientists, whose study is published Sept. 13 in Nature Communications, examined thousands of individual UM cells from patients, using advanced methods to record and analyze gene activity in each cell. They showed that these melanomas move toward a metastatic state when they lose the function of a molecular machine in cells called Polycomb Repressive Complex 1 . This multi-protein machine normally works in the cell nucleus as an important epigenetic controller of DNA folding and gene activity. The scientists detailed how PRC1s loss leads to aberrant gene activity and errors in chromosome segregation during cell division, thereby enhancing the metastatic potential of tumors.

    Up to now it has seemed possible that the more indolent UM tumors and the metastatic ones are two different subtypes of uveal melanoma, with separate origins and fates. The new findings undercut that possibility.

    Standard Treatment Options For Small Choroidal Melanoma

    Insights into the evolution of metastatic uveal melanoma ...

    Standard treatment options for small choroidal melanoma include the following:

  • Observation. This strategy is important for patients with an uncertain diagnosis or in whom tumor growth has not been documented. It is also used for asymptomatic patients with stable lesions , and for patients with a tumor in their only useful eye.
  • Plaque radiation therapy. This treatment is used for small- or medium-sized uvealmelanomas, amelanotic tumors, or tumors that touch the optic disc for greater than 3 clock-hours of optic disk circumference.
  • External-beam, charged-particle radiation therapy. This approach is offered at specialized referral centers. It requires careful patient cooperation, with voluntary fixation of gaze.
  • Gamma-knife radiation surgery. This treatment may be a feasible option for small- to medium-sized melanomas.
  • Transpupillary thermotherapy. As noted above, this approach has very limited use, but it can be used as a primary treatment or as an adjunctive method to plaque radiation therapy.
  • Local tumor resection. This strategy is used mainly for selected ciliary body or anterior choroidal tumors with smaller basal dimensions and greater thickness.
  • Enucleation. This approach is used when severe intraocular pressure elevation is a factor. It may also be considered with small- and medium-sized melanomas that are invading the tissues of the optic nerve.
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    Residential Cells In The Liver

    Homeostatic immune microenvironment is tightly controlled by various residential non-immune cells and immune cells in the liver. There is a diverse population of residential cells in the liver, including the liver sinusoidal endothelial cells , Kupffer cells , HSCs, and hepatocytes .

    Figure 1. Cell population in the liver. The percentages indicate the estimated frequency of each population relative to the total number of parenchymal and non-parenchymal cells in the normal liver

    Eyeing New Therapies For Metastatic Uveal Melanoma

    – August 18, 2021

    Moffitt Cancer Center is leading a five-year research project taking a closer look at the mechanisms behind uveal melanoma, a rare type of eye cancer, including why the disease often spreads to the liver and ways to treat it. The project is in collaboration with the Sylvester Comprehensive Cancer Center at the University of Miami and the University of Florida Health Cancer Center.

    Uveal melanoma is rarer than melanomas of the skin. Approximately 7,000 people worldwide are diagnosed each year. It often goes undetected, as the most common place it develops is in tissue surrounding the back of the eye known as the choroid layer.

    Like skin melanomas, uveal melanoma starts in melanocytes, the pigment cells that give color to the eyes. However, its cause is unknown, as it is not closely linked to UV light exposure. Those with a fair complexion, blue or green eyes, and fair or red hair tend to be more at risk for developing this type of cancer. But having been diagnosed with a skin melanoma does not necessarily increase your risk.

    “Uveal melanoma is a highly aggressive disease. Even with treatment, nearly half of patients will develop metastatic disease, most commonly affecting the liver.”

    – Dr. Keiran Smalley, Director, Donald A. Adam Melanoma and Skin Cancer Center of Excellence

    We expect this work to lead to a future clinical trial and hopefully better outcomes for uveal melanoma patients, said Smalley.

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    The Expression Of Adhesion Molecules In The Sinusoid

    Vascular cell adhesion molecule-1 is expressed on sinusoidal endothelial cells and might trap tumor cells in slow blood flow. VCAM-1 is expressed on endothelial cells under inflammatory conditions, and mediate rolling and adhesion of various subsets of leukocytes as well as tumor cells for the recruitment and settlement of these cells from the blood stream. In animal models, partial-hepatectomy induced expression of inflammatory cytokines such as tumor necrosis factor -, interleukin -1 and IL-6 as well as the expression of VCAM-1 and facilitated liver metastasis. Endothelial cell expression of VCAM-1 showed adhesion of human malignant melanoma cells that expressed very late activation antigen-4 on their surface.

    Biology Of Uveal Melanoma

    Metastatic Uveal Melanoma Video

    Uveal melanoma is the most common primary intraocular malignancy in adults, representing 85% of ocular melanomas. Remaining ocular melanomas arise from the conjunctiva or other sites . Uveal melanoma is considered a rare cancer, representing 3%5% of recorded melanoma cases in the USA. Unlike cutaneous melanoma, the most common subtype, which arises from melanocytes located in the basal layer of the epidermis, uveal melanoma arises from melanocytes located anywhere in the uveal tract. Approximately 85%90% of cases involve the choroid, while those remaining are localised to the iris or ciliary body. Cutaneous and uveal melanomas are biologically distinct and differ in terms of incidence by gender, race and geographical area.

    Representation showing the mutations associated with the RAS/RAF/MEK/ERK pathway observed in melanoma. . GPCR, G-protein coupled receptor RTK, receptor tyrosine kinase.

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    Cellular Classification Of Intraocular Melanoma

    Primary intraocular melanomas originate from melanocytes in the uveal tract. The following four distinct cellular types are recognized in intraocular melanoma :

  • Spindle-A cells .
  • Spindle-B cells .
  • Epithelioid cells .
  • Intermediate cells .
  • Most primary intraocular melanomas contain variable proportions of epithelioid, spindle-A, and spindle-B cells . Pure epithelioid-cell primary melanomas are infrequent . In the Collaborative Ocular Melanoma Study, mixed-cell type melanomas predominated .

    References
  • Klintworth GK, Scroggs MW: The eye and ocular adnexa. In: Sternberg SS, ed.: Diagnostic Surgical Pathology. Lippincott Williams & Wilkins, 1999, pp 994-6.
  • Grossniklaus HE, Green WR: Uveal tumors. In: Garner A, Klintworth GK, eds.: Pathobiology of Ocular Disease: A Dynamic Approach. 2nd ed. M. Dekker, 1994, pp 1423-77.
  • Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. COMS report no. 6. Am J Ophthalmol 125 : 745-66, 1998.
  • How Are Uveal Melanomas Diagnosed

    Usually someone will notice something wrong with their vision. It doesnt typically cause pain. Depending exactly where the cancer is in the eye, people may describe a fluttering sensation or a feeling of drapes falling over their field of vision. Its diagnosed through a dilated eye exam by an ophthalmologist. Usually the diagnosis can be made without a biopsy, which would be difficult to obtain anyway.

    People with light-colored eyes seem to be at higher risk, as well as those who are Caucasian or of Western European ancestry. Even in this population, uveal melanoma is still very rare.

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    Human Leukocyte Antigen Expression

    Unlike the general rule of higher mortality with lower expression of HLA Class I determinants, uveal melanoma exhibits an opposite association. This could be related to natural killer cells playing an essential role in immune responses directed against uveal melanoma metastases rather than cytotoxic T-lymphocytes. Higher HLA Class I and II expression is associated with higher melanoma-related mortality. However, some studies have found no association between HLA expression and melanoma-related mortality.

    In a study by Ericsson et al., a significant correlation between the expression of HLA Class I antigens, 2-microglobulin, and HLA Class II antigens and the development of metastases was noted. Jager et al. demonstrated that the tumors expressing HLA-A exhibited higher melanoma-related mortality as compared to those not staining for HLA-A . HLA-A was found to be the strongest independent predictor of tumor-related mortality, whereas HLA-B expression was not an independent predictor of survival. Blom et al. have reported that a high expression of HLA-B significantly correlated with the presence of epitheloid cells, a cell type that carries a bad prognosis.

    Screening A Must For Patients At Risk

    A Potential Molecular Target for the Treatment of Uveal ...

    On average, liver metastasis occurred 27 months after uveal melanoma diagnosis . Overall median PFS was four months , and OS was 15 months . Upon multivariate analysis, patients who were diagnosed by symptoms had a much higher risk of mortality , with an OS of seven months compared with 16 months for patients who were asymptomatic at diagnosis .

    Treatment with checkpoint inhibitors did not improve average survival outcomes, although median follow-up was shorter in that group.

    This finding underscores the importance of screening patients at risk, says Cleveland Clinic Cancer Center medical oncologist Pauline Funchain, MD, lead investigator on the Gross Family Melanoma Registry and a co-author of the study. The best treatment for any cancer is early detection. Small uveal melanomas are known to have less metastatic potential. We are the only U.S. center with a familial melanoma registry that aims to identify individuals at high risk for developing melanoma with the goal of developing better surveillance and treatment strategies.

    Using data from this registry, Dr. Funchain and team have developed a clinical trial testing PARP inhibition combined with immunotherapy in the treatment of uveal and other metastatic melanomas.

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    Role Of Radiation Therapy

    Episcleral brachytherapy using plaques containing small radioactive seeds is the most common form of radiation used in the management of intraocular melanoma. Iodine I 125 , cobalt Co 60 , palladium Pd 103 , iridium Ir 192 , and ruthenium Ru 106 are examples of radioactive isotopes used in the brachytherapy plaques. Isotopes with relatively low photon and electron emissions are more easily shielded to reduce the exposure to adjacent normal tissues, and 125I is probably the most commonly used radioisotope. Although plaque radiation therapy allows preservation of the eye, visual acuity is frequently lost over time.

    In a case series of 1,106 patients who were treated with plaque radiation therapy for uveal melanoma and who had an initial acuity of at least 20/100, 68% developed poor acuity within 10 years.

    Factors associated with worse acuity outcomes included the following:

    • Age older than 60 years.
    • Diminished baseline acuity.
    • Increased tumor size and thickness.
    • Location near the fovea or optic disc.
    • Isotope .

    In a single-center, single-surgeon study, 184 patients with uveal melanomas smaller than 15 mm in diameter and smaller than 10 mm in thickness were randomly assigned to receive 125I brachytherapy versus helium ion radiation . The local tumor regrowth rate by 4 years was 13.3% in the brachytherapy arm compared with 0% in the helium ion arm . However, the rates of metastasis, death from metastasis, and overall mortality were very similar in both arms.

    Uveal Melanoma: What Is It

    Uveal melanoma is a term with which many people may be unfamiliar. In part, that’s because it’s a relatively rare type of cancer, but also because it’s been called different names by different sources.Essentially, uveal melanoma is a cancer, or melanoma, of the eye. While it’s not seen as often as cutaneous melanoma, which accounts for the vast majority of melanoma cases, it’s the second most common type of primary malignant melanoma in the body. It represents an estimated 5% to 6% of all melanoma diagnoses.Uveal melanoma involves one of the three parts of the eye that comprise the uvea: the iris, the ciliary body and the choroid. The National Cancer Institute provides useful information on uveal melanoma under the heading of intraocular melanoma, defined as a disease in which malignant cells form in the tissues of the eye.Intraocular disease starts in the middle layer — the uvea — of the wall of the eye. The uvea is located behind the sclera and the cornea, the window at the front of the eye. Of the three main components of the uvea, the iris is the colored area of the eye.Behind the iris is the ciliary body, a ring of tissue with muscle fibers that alter the size of the pupil and the shape of the lens. The choroid is a layer of blood vessels that bring oxygen and nutrients to the eye this is where most intraocular melanomas develop.Risks and symptomsAccording to the NCI, risk factors for intraocular melanoma are:

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    The Tumor Immune Contexture Is Associated With Overall Survival In Immunotherapy

    In the study cohort, 13 patients were treated with checkpoint inhibitors immunotherapy, while 8 patients with other targeted/systematic therapies . No difference in the OS was observed between the two groups , although immunotherapy-treated patients displayed a significantly lower density of CD4+FoxP3+ Treg lymphocytes both in the intra-tumoral and stromal regions, as compared to individuals receiving other treatments . Moreover, within the tumor region, they had a lower density of total CD4+ cells and a lower CD4+FoxP3+/CD8+Granzyme B+ cell ratio . Whether considering only the proportion of patients treated with immunotherapies, we additionally observed that those still alive at the end of the follow-up had a lower percentage of Treg cells both in the total area and in the intra-tumoral region only , and a lower CD4+FoxP3+/CD8+Granzyme B+ cell ratio . Finally, in immunotherapy-treated patients the low density of stromal Treg cells , the low stromal Treg/CD8+ cell ratio , and the low percentage of Treg cells among total CD4+ T lymphocytes both at stromal and intra-tumoral level , are all features associated with a prolonged OS. Collectively, these observations suggest that CD4+FoxP3+ Treg cells appear a crucial population for response to immunotherapy.

    Fig. 5

    Understanding What Is Metastatic Melanoma

    Ocular Melanoma Patient Retreat 2013 – Dr. Richard Carvajal – Mgmt of Metastatic Uveal Melanoma

    Melanoma is the most severe and aggressive form of skin cancer. If you are wondering what is metastatic melanoma? It is when cancer has spread to other parts of the body such as the brain, bones, liver, or become lung cancer. They classify melanoma in stages that give you an idea of the survival outcome. Stage four is the worst form.

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