Recurrence Of Uveal Melanoma Research Articles

Re-treatment of locally recurrent uveal melanoma with repeat eye plaque I-125 brachytherapy: A single institution experience

PurposeEye plaque brachytherapy (EPBT) is the most common treatment for uveal melanoma with high local control rates of 95-100%. When local recurrences occur following EPBT, salvage options include enucleation, transpupillary thermotherapy (TTT), external beam radiation, or re-irradiation with EPBT. The purpose of this study is to report our institution's experience with EPBT re-irradiation for locally recurrent uveal melanoma. Material and MethodsPatients were included if they were previously treated for uveal melanoma with EPBT, experienced local recurrence, and were subsequently treated at our institution with EPBT from 2016- 2020. ResultsA total of 5 patients with median age 68 years were included. All patients were initially treated at an outside institution (OSI) with Iodine-125 or Ruthenium-106 EPBT. Mean time between EPBT at the OSI and EPBT at our facility was 130 months (range 28 – 231 months). Patients were re-irradiated with Iodine-125 EPBT prescribed to 85Gy over 168 hours. Median follow up after re-treatment at our center was 24 months. Local control among this cohort was 100%. Metastasis occurred in two patients after re-treatment, at 8 months and 7 months. At last follow up, all treated lesions were decreased in size. Four patients experienced worsening visual acuity. Four patients developed cataracts, while two patients developed radiation retinopathy with cystoid macular edema requiring anti-VEGF injections. One patient developed radiation retinopathy but did not require injections. No patients required enucleation. ConclusionRe-treatment of locally recurrent uveal melanomas with EPBT is a feasible alternative to enucleation with a high local control rate. Ocular toxicities have not been significant enough to require enucleation.

Visual Outcomes after Proton Therapy for Recurrent Uveal Melanoma

Proton beam reirradiation remains an effective and globe-preserving alternative to enucleation in the treatment of local recurrence in uveal melanoma. The study aimed to assess visual outcomes and prognostic factors in visual acuity following proton beam salvage therapy. Retrospective study SUBJECTS: A retrospective study evaluated patients with recurrent uveal melanoma treated with proton beam irradiation (PBI) from 1984 through 2019 at a single academic tertiary center. Patient and tumor characteristics were collected from the medical record, as well as best visual acuity (BVA) and ocular outcomes following treatment of recurrent uveal melanoma with PBI. The primary outcome of the study was the visual acuity of patients following proton beam irradiation for recurrent uveal melanoma. Additional outcome measures included enucleation rate of patients following salvage PBI and analysis of tumor and patient characteristics in the prognostication of visual acuity. The study comprised 67 patients who received PBI for recurrent uveal melanoma. The median age at recurrence was 67.6 years (range 31.6-91.0 years) and median follow-up from the time of recurrence to last examination was 4.4 years (range 0.23-17.1 years). The median final BVA was hand motion (range 20/20-no light perception) and 6 (9.1%) patients maintained a Snellen VA 20/40 or better. The 5-year probability of visual acuity retention of 20/200 or better was 19%. In a multivariable Cox model, VA at tumor recurrence of less than 20/40 was found to be significantly associated with a VA of 20/200 or worse following retreatment with PBI. Twelve (18%) patients underwent enucleation following retreatment with PBI. PBI allows for ocular preservation and functional vision in the treatment of recurrent uveal melanoma in select patients.

Survival of patients with recurrent uveal melanoma after treatment with radiation therapy

Background/aimsWe evaluated a large cohort of patients treated for local recurrence of choroidal or ciliary body melanomas at the Massachusetts Eye and Ear (MEE) to quantify the risk of melanoma-related...

Diffuse preretinal vitreous seeding as a recurrence of uveal melanoma

Diffuse preretinal vitreous seeding as a recurrence of uveal melanoma

Gene Expression Profile Class Change in a Case of Aggressive, Recurrent Melanoma

Purpose: To report a novel case of a recurrent melanoma that had a change in its genetic expression profile (GEP) class over a 2-year period. Methods: This retrospective case study evaluated a patient with a recurrent uveal melanoma that changed classes from 1A to 1B. Results: A large melanoma was first treated with brachytherapy, and during that time genetic testing revealed a class 1A tumor. Two years later the tumor was noted to be enlarging, and the patient elected for enucleation. Subsequent GEP showed a class 1B tumor. Conclusions: An aggressive and large recurrent uveal melanoma that had changed from a class 1A to a class 1B tumor on subsequent GEP testing has never been reported before to our knowledge. It may imply that a recurrent or aggressive tumor has more mutations over time that could lead to a higher risk for metastasis. The natural course of a tumor’s GEP class should be explored further.

Diffuse Preretinal Vitreous Seeding as a Recurrence of Uveal Melanoma.

Diffuse Preretinal Vitreous Seeding as a Recurrence of Uveal Melanoma.

A 10-year fight for vision in a patient with recurrent uveal melanoma: a case report.

A 10-year fight for vision in a patient with recurrent uveal melanoma: a case report.

Adjuvant polypeptide vaccines for high-risk uveal melanoma.

e21509 Background: Due to biologic differences, uveal melanoma patients are often excluded from clinical trials for cutaneous melanoma; however, many antigens are shared between the two melanoma subtypes. Thus, our vaccine trials at the University of Virginia (UVA) have allowed enrollment of high-risk uveal melanoma patients, who have substantial risk of relapse without FDA-approved adjuvant therapy available. For the present study, we hypothesized that the vaccines would be well-tolerated and immunogenic in this population. We examined the clinical, immunogenicity and safety outcomes of subjects with uveal melanoma enrolled in our adjuvant vaccine clinical studies. Methods: Patients were identified through participation in an adjuvant vaccine study at UVA between 2012-2022. Ten patients received the 6-Melanoma-Helper Peptide (6-MHP) vaccine through Mel-65 and Mel-66 clinical trials (NCT03617328 and NCT04364230) and one patient received the 12-peptide MELITAC vaccine through the Mel-58 clinical trial (NCT01585350). Clinical outcomes included relapse-free (RFS) and overall survival (OS) and trial toxicity reporting. Immunogenicity was assessed by ex vivo interferon-gamma ELISpot assay of peripheral T cells. OS and RFS were reported by Kaplan-Meier survival analysis and compared by log rank test between groups. Results: Of the 11 identified patients, nine were male (82%) and two were female (18%), with a median age of 64 years. All patients were high risk by molecular testing, the majority by Castle Bioscience DecisionDx-UM. Five were PRAME positive, five PRAME negative, and one not reported. In the cohort, three patients had uveal melanoma recurrence and one subject died from metastatic disease during the evaluation period. The 5-year RFS and OS were 71% (95% CI 43-100) and 80% (95% CI 52-100), respectively. Two patients experienced dose-limiting, grade 3 toxicities to the vaccine, requiring early trial discontinuation, including one grade 3 injection-site reaction and one grade 3 uveitis. Nine patients experienced grade 1-2 toxicities, mostly injection-site reactions and constitutional symptoms. Of nine patients with available immunogenicity data, five (55%) had direct antigen-mediated immune response to vaccine. Two patients’ responses are pending. Patients with immunogenic response had a non-significant trend toward better RFS and OS (both p = 0.22). The 3-year RFS and OS were 100% for subjects with T cell response and the RFS and OS were 50% (95% CI 13-100) for patients without T cell response. Two of the relapsed patients did not have an immune response to vaccine, and response data were not available for the third. Conclusions: Melanoma polypeptide vaccines are immunogenic and safe in patients with uveal melanoma. Our early data suggests the possibility of early benefit with direct antigen response, though longer follow up and further study will be needed to investigate these findings.

Abstract 1967: Potential of aqueous humor as a liquid biopsy for uveal melanoma

Abstract Introduction: Uveal melanoma (UM) is the most common primary intraocular tumor in adults and arises from the uvea (iris, ciliary body and choroid). Although there are prognostic biomarkers available, identifying them requires intraocular tumor biopsy. Blood biopsy has emerged as a significantly less invasive alternative that also offers the ability to longitudinally track disease. However, blood biopsy has been unsuccessful for clinical use in identifying prognostic biomarkers in UM due to low detection rates. Thus, eye-specific aqueous humor (AH) biopsy may be a better alternative. Methods: This case series includes 20 primary UM patients with 13 (65%) choroid and 7 (35%) ciliary body (CB) tumors. AH samples were collected prior to brachytherapy plaque placement (n = 17), after brachytherapy (n = 19) and at enucleation (n = 1). A tumor wash sample (n = 1) was collected after routine fine needle aspiration biopsy. Nucleic acids ([NA], dsDNA, RNA, ssDNA and miRNA) were quantitated by Qubit Assay Kits. All AH samples and cells from tumor washing underwent DNA isolation and was followed by shallow whole-genome sequencing for copy-number profiling. Results: Comparison of pre- and post-radiation samples revealed significantly higher concentration of ssDNA (n = 10 pairs, P = 0.039) and miRNA (n = 10 pairs, P = 0.008) in choroid post- samples and significantly higher concentration of dsDNA (n = 7 pairs, P = 0.031) and miRNA (n = 7 pairs, P = 0.016) in CB post- samples. Between choroid (n = 12) and CB (n = 7) post- samples, there was a significantly higher concentration of dsDNA (P = 0.022) and RNA (P = 0.009) in post- CB samples, suggesting NA content is released from the disturbance of tumor cells by radiation and due to the proximity of the tumor to the AH in CB. Highly recurrent UM somatic copy number alterations (SCNAs) of monosomy 3, 6p gain, 6q loss and 8q gain were identified in post- AH samples. There was a significant difference between altered SCNA profiles in CB and choroid (P= 0.038). Altered SCNA profiles were found in 1/12 (8.3%) and 4/7 (57.1%) post-radiation AH samples of choroid and CB, respectively. No SCNAs were found in the same eyes’ pre-radiation sample. A high concordance of DNA profiles between a tumor wash and post- AH sample was identified (r = 0.978) and UM mutations GNAQ and BAP1 were detected in 3/6 (50%) post- AH with 2/5 (40%) matching tumor samples, demonstrating AH dsDNA’s tumor-origin. Conclusions: The AH is a source of cfDNA, with a higher yield of NAs after radiation in UM. Given the significant increase in NA concentration after radiation and in CB compared to choroid tumors, we hypothesize that all detected NAs post-radiation are tumor-derived due to apoptosis of tumor cells and subsequent release of cfDNA and due to the proximity of the CB tumor to AH. These results represent the first time that UM SCNAs and mutations were identified in cfDNA isolated from the AH, and this suggests that the AH can serve as a liquid biopsy for UM, especially in CB tumors. Citation Format: Deborah H. Im, Chen-Ching Peng, Liya Xu, Mary E. Kim, Dejerianne Ostrow, Venkata Yellapantula, Moiz Bootwalla, Jaclyn A. Biegel, Xiaowu Gai, Peter Kuhn, James Hicks, Jesse L. Berry. Potential of aqueous humor as a liquid biopsy for uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1967.

Electrochemotherapy with Bleomycin Enhances Radiosensitivity of Uveal Melanomas: First In Vitro Results in 3D Cultures of Primary Uveal Melanoma Cell Lines

Simple SummaryUveal melanoma (UM) is the most common primary intraocular tumor in adults. Treatment options for UM include radiotherapy, thermotherapy and tumor resection. Electrochemotherapy (ECT) is a new therapeutic modality for local tumor control in various cancer entities. The current study assesses the radiosensitizing effect of concomitant ECT with bleomycin and irradiation on 3D tumor spheroids with primary and radioresistant uveal melanoma cell lines. The evaluation of the radiosensitizing effect of ECT as a drug delivery system was based on the changes in the spheroid growth, the cell viability as well as the cytotoxic long-term effect of the combined treatment. The primary cell lines showed a higher radiosensitivity and required lower irradiation and bleomycin doses in comparison to cell lines originating from previously irratiated tumors. ECT should be further assessed for its applicability in clinical settings as a therapeutic radiosensitizing option for radioresistant tumors. Electrochemotherapy (ECT) is emerging as a complementary treatment modality for local tumor control in various cancer entities. Irradiation is an established therapeutic option for oncologic patients, which is commonly combined with chemotherapy due to its insufficient targeting ability. The efficiency of radiotherapy for tumors can be enhanced with different radiosensitizers. ECT can potentiate the radiosensitizing effect of chemotherapeutic agents such as bleomycin. The present study aims to evaluate the radiosensitizing effect of concomitant ECT with bleomycin on 3D tumor spheroids with primary and radioresistant uveal melanoma cell lines (UPMD2, UPMM3, UM92.1, Mel270) and irradiation. The changes in the spheroid growth and the cell viability as well the cytotoxic long-term effect of the combination treatment were evaluated with various combinations of electroporation settings and bleomycin concentrations as well as radiotherapy doses. A broad range of radiosensitivity was documented among the spheroids from different uveal melanoma cell lines. The primary cell lines showed a higher radiosensitivity and required lower irradiation and bleomycin doses. The maximal tumor control with a reduction of cell survival <10% was achieved with a 5 Gy irradiation only in the primary uveal melanoma cell lines and in combination with all tested ECT settings, whereas the same result could be obtained in UM92.1 spheroids only after ECT with 20 Gy irradiation. Based on the spheroid growth and the measurement of the cross-sectional area, the Mel270 spheroids, originating from a previously irradiated recurrent uveal melanoma, required higher doses of bleomycin and ECT settings after irradiation with 5 Gy in order to achieve a significant growth reduction. No significant difference could be demonstrated for the reduction of cell viability in the combination therapy with 20 Gy and 1000 V/cm between 1 and 2.5 µg/mL bleomycin even in Mel270 spheroids, underlying the importance of a drug delivery system to potentiate the radiosensitizing effect of agents in lower doses. ECT should be further assessed for its applicability in clinical settings as a therapeutic radiosensitizing option for radioresistant tumors and a sufficient local tumor control with lower chemotherapy and irradiation doses.

Local recurrence of uveal melanoma after proton beam therapy

Local recurrence of uveal melanoma after proton beam therapy

Quality of Life Concerns in Patients with Uveal Melanoma after Initial Diagnosis

Background: Patients with uveal melanoma (UM) are known to have quality of life (QOL) issues after treatment, but QOL concerns after initial diagnosis are ill-defined. Objectives: We studied the QOL concerns of patients with UM after initial diagnosis to identify factors associated with QOL. Method: Between September 2011 and May 2016, UM planning to undergo radiotherapy completed the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ)-C30, as well as the Ophthalmic Oncology module, QLQ-OPT30. Demographic, ophthalmic, and tumor related characteristics were recorded. The primary outcome was the QOL score and fraction of patients reporting any or severe symptoms. A multiple stepwise regression model investigated the association of demographic, ophthalmic, and tumor characteristics with QOL. Results: QOL concerns were assessed in 201 subjects. The majority (51/60) of QOL items had a high response rate (≥90%), and internal consistency on scales (median Cronbach α = 0.85) with the most common severe QOL concern being worry about disease recurrence (41%). The most common ophthalmic symptoms reported were vision impairment (81%) and ocular irritation (66%). Multivariable regression modeling demonstrated several significant associations. Conclusions: Severe worry about UM recurrence, ocular irritation, and vision impairment was reported by many patients. Clinicians should be aware of these concerns and implement management strategies.

Leptomeningeal disease in a case of recurrent uveal melanoma (P6.107)

Leptomeningeal disease in a case of recurrent uveal melanoma (P6.107)

Prognoses and Clinical Outcomes of Primary and Recurrent Uveal Melanoma.

PurposeUveal melanoma has a very poor prognosis despite successful local primary tumor treatment. In this study, we investigated prognostic factors that more accurately reflected the likelihood of recurrence and survival and delineated a prognostic model that could effectively identify different risk groups based on initial clinical parameters.Materials and MethodsPrognostic factors associated with distant recurrence, recurrence-free survival (RFS), progression-free survival, and overall survival from distant recurrence to death (OS2) were analyzed in 226 patients with stage I-III uveal melanoma who underwent primary local therapy.ResultsForty-nine patients (21.7%) had distant recurrences, which occurred most frequently in the liver (87.7%). In a multivariate analysis, local radiotherapy improved RFS among patients with multiple recurrence risk factors relative to excision (not reached vs. 19.0 months, p=0.004). Patients with BRCA1-associated protein-1 (BAP1)‒negative primary tumors showed a longer RFS duration after primary treatments, while those with BAP1-negative metastatic tissues had a shorter OS2 compared to those with BAP1-positive tumors, both not statistically insignificance (RFS: not reached vs. 82.0 months, p=0.258; OS2: 15.7 vs. 24.4 months, p=0.216). Male sex (hazard ratio [HR], 3.79; p=0.012), a short RFS (HR, 4.89; p=0.014), and a largest metastatic tumor linear diameter ≥ 45 mm (HR, 5.48; p=0.017) were found to correlate with worse post-recurrence survival.ConclusionRisk factors could be used to classify uveal melanoma cases and subsequently direct individual treatment strategies. Furthermore, metastasectomy appears to contribute to improved survival outcomes.

Co-expression modules construction by WGCNA and identify potential prognostic markers of uveal melanoma

Uveal melanoma is an aggressive cancer which has a high percentage recurrence and with a worse prognosis. Identify the potential prognostic markers of uveal melanoma may provide information for early detection of recurrence and treatment. RNA sequence data of uveal melanoma and patient clinic traits were obtained from The Cancer Genome Atlas (TCGA) database. Co-expression modules were built by weighted gene co -expression network analysis (WGCNA) and applied to investigate the relationship underlying modules and clinic traits. Besides, functional enrichment analysis was performed on these co-expression genes from interested modules. First, using WGCNA, identified 21 co-expression modules were constructed by the 10975 genes from the 80 human uveal melanoma samples. The number of genes in these modules ranged from 42 to 5091. Found four co -expression modules significantly correlated with three clinic traits (status, recurrence and recurrence Time). Module red, and purple positively correlated with patient's life status and recurrence Time. Module green positively correlates with recurrence. The result of functional enrichment analysis showed that the module magenta was mainly enriched genetic material assemble processes, the purple module was mainly enriched in tissue homeostasis and melanosome membrane and the module red was mainly enriched metastasis of cell, suggesting its critical role in the recurrence and development of the disease. Additionally, identified the hug gene (top connectivity with other genes) in each module. The hub gene SLC17A7, NTRK2, ABTB1 and ADPRHL1 might play a vital role in recurrence of uveal melanoma. Our findings provided the framework of co-expression gene modules of uveal melanoma and identified some prognostic markers might be detection of recurrence and treatment for uveal melanoma.

Recurrence of Uveal Melanoma

Recurrence of Uveal Melanoma

Orbital recurrence of uveal melanoma after 45 years from enucleation

PurposeA 52‐year‐old woman who had undergone enucleation of the left eye at the age of 7 years for posterior uveal melanoma, had no further problems until 45 years later, when she developed a multifocal malignancy of the ipsilateral orbit.MethodsCase report.ResultsMRI documented the presence of nodular multiple masses in the anophthalmic socket suggesting possible metastatic disease. Hepatic examination and ultrasound evaluation, CT scan of the thorax and bone scintigraphy excluded other sites of metastatic lesions.She underwent excissional of the 3 distinct tumors, 2 inferiorly and one superiorly in the anophthalmic socket. After surgery she received proton beem radiotherapy in the anopthalmic socket for a total of 4.600rads.Histopathology documented malignant melanoma of the orbit characterized by epitheliod cells.ConclusionsThe long interval between recognition of the primary tumor and enucleation and the appearance of clinically manifest metastatic disease in the ipsilateral orbit is the longest reported in the literature to date.A similar case of metastatic choroidal melanoma to the contralateral orbit 40 years after enucleation has been reported by Coupland (1996).

Scleral Necrosis Simulating Recurrent Uveal Melanoma after Plaque Brachytherapy

Scleral Necrosis Simulating Recurrent Uveal Melanoma after Plaque Brachytherapy

Local Recurrence Significantly Increases the Risk of Metastatic Uveal Melanoma

To assess of the effect of local recurrence of uveal melanoma on metastasis using a multicenter international tumor registry. Retrospective study using an online tumor registry. Patients with uveal melanoma diagnosed between 2001 and2011. A committee was formed to create uveal melanoma patient-specific data fields. Ten subspecialty ophthalmic oncology centers from 4 continents shared data. Patient selection criteria included diagnosis of uveal melanoma and adequate records to allow tumor staging by American Joint Committee on Cancer (AJCC) criteria and follow-up for metastatic melanoma. Local tumor recurrence and metastatic uveal melanoma. Of 3809 total entries, 3217 patients with ciliary body and choroidal (CBC) melanoma and 160 with iris melanoma were evaluated. There was a median follow-up of 3.7 years (95% confidence interval [CI], 3.5-3.8). One hundred fifty-two patients (4.7%) with CBC melanoma experienced local recurrence, with a cumulative incidence of 11%. Kaplan-Meier point estimates for remaining free of local recurrence were 99% (95% CI, 99-99) at 1 year, 93% (95% CI, 92-94) at 5 years, and 89% (95% CI, 86-91) at 10 years. Five- and 10-year metastasis-free Kaplan-Meier estimates for the recurrence-free group were 87% (95% CI, 86-89) and 82% (95% CI, 79-84), and those for the local recurrence group were 71% (95% CI, 62-78) and 62% (95% CI, 49-72). The difference between these 2 groups was statistically significant (P < 0.001). Furthermore, local tumor recurrence increased the risk of metastasis by a hazard ratio (HR) of 6.28 (95% CI, 4.4-8.9; P < 0.001). Local recurrence was detected up to 9.8 years after treatment. Extrascleral extension also was associated with local recurrence (HR, 3.2; 95% CI, 1.5-6.7; P= 0.003), but higher AJCC T-size category was not (P= 0.63). Five patients (n= 5/161 [3.1%]) with iris melanoma demonstrated local recurrence and 1 metastasized. International multicenter data sharing was used to evaluate the effect of local tumor recurrence on metastatic rate. In that local tumor recurrence was associated with a significantly higher risk of systemic metastasis, effective initial treatment and long-term surveillance of treated uveal melanoma patients is necessary.

Salvage Proton Beam Therapy in Local Recurrent Uveal Melanoma

To evaluate survival and ocular outcome in recurrent uveal melanoma treated with proton beam therapy as salvage therapy. Retrospective, interventional case series. We evaluated 48 patients with local recurrence of uveal melanoma after primary treatment with brachytherapy, transpupillary thermotherapy, proton beam therapy, laser photocoagulation, CyberKnife radiation, or photodynamic therapy. All patients received proton beam therapy as a salvage therapy at the Helmholtz Zentrum Berlin between July 2000 and December 2010. Kaplan-Meier analysis was used to obtain survival rates. The Kaplan-Meier estimator for local tumor control was 92.1% at 10 years after secondary treatment with proton beam therapy. Local recurrence developed in 3 patients; 1 of them underwent enucleation. During follow-up, 20.8% of the patients died (16.7% of metastasis, 4.1% of other causes or not specified). The most frequent surgical interventions were phacoemulsification (20.8%) and pars plana vitrectomy (10.4%). The Kaplan-Meier estimators were 77.4% for survival and 70.1% for the absence of metastasis 10 years after the primary treatment. Proton beam therapy as a salvage treatment resulted in high local tumor control rates in recurrent uveal melanoma, especially if the primary therapy was transpupillary thermotherapy or plaque brachytherapy. Preservation of the globe was possible in most patients. Enucleations were indicated only in case of re-recurrences of uveal melanoma, but not because of secondary complications like intractable pain or secondary glaucoma. Retreatment was associated with vision deterioration, but loss of vision remained exceptional. Further larger prospective studies are needed to confirm the presented results of our retrospective analysis.