Ocular survival after intra-arterial chemotherapy for retinoblastoma improves with accrual of experience and programmatic evolution.

BACKGROUND: Intra-arterial chemotherapy (IAC) for the treatment of intraocular retinoblastoma has gained recognition as a method to improve ocular salvage; however, there is a paucity of evidence supporting treatment factors prognosticating ocular survival. METHODS: All patients with retinoblastoma treated with IAC at a single institution between December 2008 and December 2019 were evaluated. Patient demographics, tumor classification, prior treatments, procedural data, other non-IAC therapies, adverse reactions, procedural complications, ocular outcomes, and overall survival were assessed via retrospective chart review. Factors suggestive of increased ocular survival were identified via univariate and multivariate analyses. The impact of accrued treatment experience was evaluated by grouping eyes by the respective year, IAC treatment was initiated. RESULTS: Forty-nine eyes of 43 patients were treated for retinoblastoma with IAC (256 total procedures). At least grade 3 neutropenia was observed following 19% of IAC procedures. The risk of neutropenia was not statistically different between single or multidrug IAC. Comparing those who received balloon-assisted intra-arterial chemotherapy (bIAC) in more than two-thirds of cycles to those who did not, the risk of arterial access site complications was not statistically different. Multivariate analysis revealed a significantly lower risk of enucleation associated with treatment era in years (hazard ratio [HR] = 0.52-1.00, p < .05) and laser therapies (HR = 0.02-0.60, p < .05). CONCLUSIONS: Ocular survival rates in patients treated with IAC for retinoblastoma at our institution have increased over time. Accrued treatment experience and programmatic changes have likely contributed. Larger, prospective series may lead to a better understanding of factors that consistently contribute to better ocular salvage.

Non-invasive evaluation of toxicity in vitreoretinal domain following insertion of sustained release methotrexate micro-implant.

PURPOSE: To evaluate the safety and toxicity profile of a chitosan (CS) and poly(lactic-co-glycolic) acid (PLGA)-based sustained release methotrexate (MTX) intravitreal micro-implant in normal rabbit eyes using non-invasive testing that included electroretinography (ERG), ultrasound biomicroscopy (US), slit-lamp biomicroscopy (SLB), funduscopy, and intraocular pressure (IOP). METHODS: PLGA-coated CS-based micro-implants containing 400 µg of MTX and placebo (without drug) micro-implants were surgically-implanted in the vitreous of the right and the left eyes, respectively, in each of the thirty New Zealand rabbits. ERG, US, SLB, funduscopy, and IOP were assessed in both eyes at pre-determined time points (days: 1, 3, 7, 14, 28 and 56). The safety of micro-implants was assessed by analyzing the ERG data using different statistical models, to quantify and compare the functional integrity of the retina. Further, US, funduscopy, SLB and IOP determined the condition of the retina, the micro-implant and associated intraocular features. RESULTS: Statistical analyses of the ERG data showed unchanged functional integrity of retina between eyes with the PLGA-coated CS-based MTX micro-implant and the placebo micro-implant. US analysis showed that micro-implants were stationary throughout the study. SLB, funduscopy and IOP further confirmed that there were no abnormalities in the intraocular physiology. CONCLUSION: The findings from ERG, US, SLB, funduscopy, and IOP showed no detectable adverse effects caused by our biodegradable micro-implants. These non-invasive techniques appeared to show lack of significant ocular toxicity over time in spite of degradation and changes in morphology of the micro-implants following intraocular implantation.

Isolated choroidal melanocytosis: clinical update on 37 cases.

PURPOSE: Isolated choroidal melanocytosis is a congenital melanocytic hyperpigmentation involving the choroid that is not associated with iridic or scleral features of ocular melanocytosis. The purpose of this work was to describe the clinical features and course of a relatively large series of patients with this disorder. METHODS: A retrospective clinical study of 37 patients with isolated choroidal melanocytosis encountered in a single practice 1986-2018 was done. All lesions were 5 mm or larger in the largest basal diameter, homogeneously melanotic, and completely flat by conventional ocular ultrasonography. RESULTS: The 37 patients ranged in age from 2 weeks to 87 years (mean 31.5 years, median 18 years) at initial diagnosis of the melanotic choroidal lesion. Arc length largest basal diameter of the melanotic choroidal lesion ranged from 5.5 to 37 mm (mean 14.6 mm, median 13 mm). The lesion extended beneath the fovea in 18 eyes and to the optic disc margin in 6 eyes. Ten of the lesions straddled the ocular equator, but the center point of all of the lesions was posterior to the equator. The retina was fully attached and appeared normal over the melanotic choroidal lesion in each of these eyes. None of the melanotic choroidal lesions exhibited clumps of orange pigment or drusen on its surface. The lesion was unilateral and unifocal in 36 of the 37 patients. One patient had bilateral choroidal melanocytosis that was isolated in one eye but associated with partial iris melanocytosis in the fellow eye. Three adult patients had a choroidal melanoma localized to the patch of choroidal melanocytosis at baseline. One other adult patient had a choroidal melanoma in the fellow eye at baseline. One pediatric patient had viable unilateral non-familial retinoblastoma in the fellow eye and two adult patients had a classic choroidal nevus in the fellow eye. None of the flat patches of choroidal melanocytosis that were monitored periodically after initial diagnosis expanded appreciably during follow-up ranging from 4.9 months to 15.2 years (mean 5.0 years, median 2.3 years). CONCLUSIONS: Isolated choroidal melanocytosis is a distinct clinical entity that must be distinguished from broad-based choroidal nevus, choroidal melanocytoma, small choroidal malignant melanoma, acquired bilateral patchy-streaky choroidal melanocytic fundopathy associated with disorders such as cutaneous vitiligo and Waardenburg syndrome, acquired bilateral zonal choroidal melanocytic fundopathy, and diffuse uveal melanocytic proliferation associated with systemic cancer. This disorder appears to predispose affected eyes to development of choroidal melanoma arising from the hypermelanotic patch.

Relationship between clinical features, GEP class, and PRAME expression in uveal melanoma.

BACKGROUND: Metastatic risk for uveal melanoma (UM) patients can be characterized by gene expression profiling (GEP) (Castle Biosciences, Friendswood, TX). Class 1A tumors carry low metastatic risk; class 1B tumors have intermediate risk; and class 2 tumors have high risk. Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated antigen which is expressed in various neoplasms including UM. Recently, PRAME expression in uveal melanoma was first recognized to confer an additional metastatic risk beyond GEP status. METHODS: This was a retrospective, consecutive, multicenter chart review study. All patients diagnosed with UM at two major ocular oncology centers from August 2016 to February 2018 who underwent both GEP and PRAME mRNA expression testing were included. Patient age at diagnosis, gender, and tumor variables such as thickness, largest basal diameter (LBD), tumor volume, TNM stage, and GEP class and PRAME status were extracted from the medical records. Statistical analysis was performed to analyze the association of PRAME +/- status with all clinical and molecular variables. RESULTS: One hundred forty-eight UM patients were identified. TNM was stage I in 51 (34.5%), stage IIA in 33 (22.3%), stage IIB in 34 (23%), stage IIIA in 20 (13.5%), and stage IIIB in 10 (6.8%) patients. Fifty-five patients (37%) were PRAME-positive, a significant fraction. There was no association between higher TNM stage and positive PRAME status (p = 0.129). PRAME expression was found to be independent of gender, patient age, and tumor thickness. PRAME expression was statistically associated with LBD and tumor volume. Higher GEP class was associated with higher TNM staging (p < 0.001). Worsening GEP class was associated with PRAME+ status with 28% of GEP class 1A tumors having PRAME+ status, 29% of GEP class 1B tumors having PRAME+ status, and 56% of GEP class 2 tumors having PRAME+ status. CONCLUSIONS: In this study cohort, PRAME+ status was significantly associated with LBD and tumor volume as well as worsening GEP class. Nearly a third of GEP class 1A tumors expressed PRAME. Given the recent published data on increased metastatic risk among patients with tumors expressing PRAME, this study suggests that a significant fraction of 1A patients may harbor an increased metastatic risk. Future large, multicenter studies with long-term follow-up will clarify this finding.

Unilateral retinoblastoma with contralateral isolated choroidal Melanocytosis: case report of an unexpected presentation.

BACKGROUND: Congenital ocular melanocytosis has been shown to be extremely uncommon in studies of numerous infants and children with retinoblastoma and disorders such as retinopathy of prematurity. CASE PRESENTATION: A 33-month-old Caucasian boy presented with a solid white predominantly endophytic retinoblastoma filling most of the nasal aspect of the fundus and extensive vitreous seeding. Fundus exam of the contralateral eye showed a broad-based flat melanotic area of the choroid extending from the subfoveal region to the ora serrata temporally. The child was treated by enucleation of the retinoblastoma-containing eye (homozygous non-germline RB1 mutation) and is being monitored annually. The patient has been followed for 4 years. CONCLUSIONS: This rare presentation of advanced unilateral retinoblastoma and contralateral isolated choroidal melanocytosis in a young child emphasizes the importance of detailed fundus mapping of the non-affected eye and has potential implications due to the increased incidence of uveal melanoma later in life.

Ultrasonographical assessment of implanted biodegradable device for long-term slow release of methotrexate into the vitreous.

Our group has developed a biodegradable drug delivery device (micro-implant) for long-term slow intraocular release of methotrexate (MTX) that can be implanted in the peripheral vitreous. The purpose of this study was to assess the position of the implanted devices and the status of the adjacent vitreous and peripheral retina over time using B-scan ocular ultrasonography (US). In each of the eight New Zealand rabbits used in this study, a chitosan (CS) and poly-lactic acid (PLA)-based micro-implant containing approximately 400 µg of MTX and a placebo micro-implant without MTX were inserted into the peripheral vitreous of the right and left eyes, respective, employing minimally invasive surgery. B-scan US imaging was performed on all of the rabbits immediately after implant insertion and on two rabbits at each of several pre-determined time points post-insertion (post-insertion days 5, 12, 19, and 33) to evaluate the position of the micro-implants and identify any evident morphological changes in the micro-implants and in the peripheral retina and vitreous during treatment. US imaging revealed stable positioning of the PLA-coated CS-based MTX micro-implant and the placebo micro-implant in the respective eyes throughout the study and lack of any changes in size, shape or sonoreflectivity of the micro-implants or abnormalities of the peripheral vitreous or retina in any of the study eyes. In summary, US did not show any evident morphological changes in the micro-implants, shifts in post-insertion position of the micro-implants, or identifiable changes in the micro-implants or peripheral vitreous and retina of the study eyes.

Assessing Prognosis in Uveal Melanoma.

BACKGROUND: Because uveal melanoma is the most common primary malignant intraocular tumor in adults and carries a significant risk of metastases, which are mostly unresponsive to available systemic therapy, researchers have been searching for prognostic indicators to identify patients at increased risk for developing such metastasis. METHODS: The purpose of this study is to describe recent advances in prognostic testing of patients with uveal melanoma and the impact of these advances on the management of uveal melanoma. The relevant, peerreviewed literature as extracted and then further reviewed for scientific content. RESULTS: Demographic characteristics, clinical, and histopathological features alone are inadequate for predicting metastatic risk in individual patients with uveal melanoma. Some research has shown that cytogenetic abnormalities and principally transcriptomic features of tumor cells can independently predict high risk for uveal melanoma metastatic spread. Gene expression profiling of uveal melanoma cells may be accurate and biologically informative for molecular prognostication. Methods for detecting chromosomal gains and losses have predictive value but require additional clinical and cytological information. The latest step in the evolution of molecular testing has been the discovery of major driver mutations for possible use in targeted therapy. CONCLUSIONS: Assay validation, quality control, and interpretation of results are essential for the reliability and reproducibility of these tests. Although these prognostic tests have improved the ability to identify patients at increased risk for developing metastasis, their use has not changed the management of uveal melanoma. However, genomic, analytical, and sequencing technologies will provide a critical step toward useful targeted therapies for patients with high-risk uveal melanoma.

Selective Ophthalmic Artery Infusion Chemotherapy for Advanced Intraocular Retinoblastoma: CCHMC Early Experience.

Selective ophthalmic artery infusion chemotherapy (SOAIC) is increasingly used to treat retinoblastoma. We report the toxicities and outcome of 19 eyes in 17 patients with retinoblastoma receiving SOAIC treatment between 2008 and 2013. From the 87 treatments, mild local reactions were common. Myelosuppression was more common after triple-agent SOAIC (melphalan, carboplatin, and topotecan) than single-agent melphalan. Ocular salvage was achieved in 11 of 19 eyes and associated with triple-agent therapy. SOAIC is a effective therapy for some retinoblastoma with manageable toxicity; however, systemic toxicity increases with increasing therapeutic intensity of SOAIC.

Biodegradable chitosan and polylactic acid-based intraocular micro-implant for sustained release of methotrexate into vitreous: analysis of pharmacokinetics and toxicity in rabbit eyes.

PURPOSE: The purpose of this study was to evaluate the pharmacokinetics and toxicity of a chitosan (CS) and polylactic acid (PLA) based methotrexate (MTX) intravitreal micro-implant in an animal model using rabbit eyes. METHODS: CS- and PLA-based micro-implants containing 400 µg of MTX were fabricated using lyophilization and dip-coating techniques. The micro-implants were surgically implanted in the vitreous of eight New Zealand rabbits employing minimally invasive technique. The PLA-coated CS-MTX micro-implant was inserted in the right eye and the placebo micro-implant in the left eye of each rabbit. Two rabbits were euthanized at each pre-determined time point post-implantation (days 5, 12, 19, and 33) for pharmacokinetics and histopathology evaluation. RESULTS: A therapeutic concentration of MTX (0.1-1.0 µM) in the vitreous was detected in the rabbit eyes studied for 33 days. The MTX release from the coated micro-implants followed a first order kinetics (R (2) ~ 0.88), implying that MTX release depends on the concentration of MTX in the micro-implant. Histopathological analysis of the enucleated eyes failed to show any signs of infection or tissue toxicity in any of the specimens. CONCLUSION: The PLA-coated CS-MTX micro-implants were able to deliver therapeutic release of MTX for a period of more than 1 month without detectable toxicity in a rabbit model. The micro-implants can be further investigated as a prospective alternative to current treatment protocols of repeated intravitreal MTX injections in intraocular disorders such as primary intraocular lymphoma, and selected cases of non-microbial intraocular inflammation.

Sufficiency of FNAB aspirates of posterior uveal melanoma for cytologic versus GEP classification in 159 patients, and relative prognostic significance of these classifications.

OBJECTIVE: To determine the relative sufficiency of paired aspirates of posterior uveal melanomas obtained by FNAB for cytopathology and GEP, and their prognostic significance for predicting death from metastasis. METHODS: Prospective non-randomized IRB-approved single-center longitudinal clinical study of 159 patients with posterior uveal melanoma sampled by FNAB in at least two tumor sites between 09/2007 and 12/2010. Cases were analyzed with regard to sufficiency of the obtained aspirates for cytopathologic classification and GEP classification. Statistical strength of associations between variables and GEP class was computed using Chi-square test. Cumulative actuarial survival curves of subgroups of these patients based on their cytopathologic versus GEP-assigned categories were computed by the Kaplan-Meier method. The endpoint for this survival analysis was death from metastatic uveal melanoma. RESULTS: FNAB aspirates were insufficient for cytopathologic classification in 34 of 159 cases (21.9 %). In contrast, FNAB aspirates were insufficient for GEP classification in only one of 159 cases (0.6 %). This difference is statistically significant (P < 0.001). Six of 34 tumors (17.6 %) that yielded an insufficient aspirate for cytopathologic diagnosis were categorized as GEP class 2, while 43 of 125 tumors (34.7 %) that yielded a sufficient aspirate for cytopathologic diagnosis were categorized as GEP class 2. To date, 14 of the 49 patients with a GEP class 2 tumor (28.6 %) but only five of the 109 patients with a GEP class 1 tumor (5.6 %) have developed metastasis. Fifteen of 125 patients (12 %) whose tumors yielded sufficient aspirates for cytopathologic classification but only four of 34 patients (11.8 %) whose tumors yielded insufficient aspirates for cytopathologic classification developed metastasis. The median post-biopsy follow-up time for surviving patients in this series was 32.5 months. Cumulative actuarial 5-year probability of death from metastasis 14.1 % for those with an insufficient aspirate for cytopathologic classification versus 22.4 % for those with a sufficient aspirate for cytopathologic classification (log rank P = 0.68). In contrast, the cumulative actuarial 5-year probability of metastatic death was 8.0 % for those with an insufficient/unsatisfactory aspirate for GEP classification or GEP class 1 tumor, versus 45.0 % for those with a GEP class 2 tumor (log rank P = 0.005). CONCLUSION: This study confirmed that GEP classification of posterior uveal melanoma cells obtained by FNAB is feasible in almost all cases, including most in which FNAB yields an insufficient aspirate for cytodiagnosis. The study also confirmed that GEP classification is substantially better than cytologic classification for predicting subsequent metastasis and metastatic death.

Development of chitosan and polylactic acid based methotrexate intravitreal micro-implants to treat primary intraocular lymphoma: an in vitro study.

Primary intraocular lymphoma (PIOL) is an uncommon but clinically and pathologically distinct form of non-Hodgkin's lymphoma. It provides a therapeutic challenge because of its diverse clinical presentations and variable clinical course. Currently available treatments for PIOL include intravenous multiple drug chemotherapy, external beam radiation therapy, and intravitreal methotrexate (MTX) injection. Each intravitreal injection of MTX is associated with potentially toxic peaks and subtherapeutic troughs of intraocular MTX concentration. Repetitive injections are required to maintain therapeutic levels of MTX in the eye. A sustained release drug delivery system is desired for optimized therapeutic release (0.2-2.0 µg/day) of MTX for over a period of 1 month to achieve effective treatment of PIOL. This study reports development of a unique intravitreal micro-implant, which administers therapeutic release of MTX over a period of 1 month. Chitosan (CS) and polylactic acid (PLA) based micro-implants are fabricated for different MTX loadings (10%, 25%, and 40% w/w). First, CS and MTX mixtures are prepared for different drug loadings, and lyophilized in Tygon® tubing to obtain CS-MTX fibers. The fibers are then cut into desired micro-implant lengths and dip coated in PLA for a hydrophobic surface coating. The micro-implant is characterized using optical microscopy, scanning electron microscopy (SEM), time of flight-secondary ion mass spectroscopy (ToF-SIMS), and differential scanning calorimetry (DSC) techniques. The release rate studies are carried out using a UV-visible spectrophotometer. The total release durations for 10%, 25%, and 40% w/w uncoated CS-MTX micro-implants are only 19, 29, and 32 h, respectively. However, the therapeutic release durations for 10%, 25%, and 40% w/w PLA coated CS-MTX micro-implants significantly improved to 58, 74, and 66 days, respectively. Thus, the PLA coated CS-MTX micro-implants are able to administer therapeutic release of MTX for more than 50 days. The release kinetics of MTX from the coated micro-implants is explained by (a) the Korsmeyer-Peppas and zero order model fit (R2 ∼ 0.9) of the first 60% of the drug release, which indicates the swelling of polymer and initial burst release of the drug; and (b) the first order and Higuchi model fit (R2 ∼ 0.9) from the tenth day to the end of drug release, implying MTX release in the therapeutic window depends on its concentration and follows diffusion kinetics. The PLA coated CS-MTX micro-implants are able to administer therapeutic release of MTX for a period of more than 1 month. The proposed methodology could be used for improved treatment of PIOL.

PRAME induces genomic instability in uveal melanoma.

PRAME is a CUL2 ubiquitin ligase subunit that is normally expressed in the testis but becomes aberrantly overexpressed in many cancer types in association with aneuploidy and metastasis. Here, we show that PRAME is expressed predominantly in spermatogonia around the time of meiotic crossing-over in coordination with genes mediating DNA double strand break repair. Expression of PRAME in somatic cells upregulates pathways involved in meiosis, chromosome segregation and DNA repair, and it leads to increased DNA double strand breaks, telomere dysfunction and aneuploidy in neoplastic and non-neoplastic cells. This effect is mediated at least in part by ubiquitination of SMC1A and altered cohesin function. PRAME expression renders cells susceptible to inhibition of PARP1/2, suggesting increased dependence on alternative base excision repair pathways. These findings reveal a distinct oncogenic function of PRAME that can be targeted therapeutically in cancer.

Comparative Metastatic Rates in GEP Class 1A versus 1B Posterior Uveal Melanoma: Results Contrary to Expectations.

Purpose: The purpose of this study was to determine whether the metastatic rates in patients with gene expression profile (GEP) class 1A versus 1B posterior uveal malignant melanoma supported or contradicted predictions of very low metastatic rate in GEP 1A cases and moderate rate in GEP 1B cases. Patients/Methods: 164 patients with a cytopathologically confirmed primary posterior uveal malignant melanoma classified by GEP testing as class 1 (100 GEP 1A, 64 GEP 1B) were evaluated. Kaplan-Meier rates of metastasis were computed and plotted for the GEP class 1 subgroups. Median follow-up of patients who were still alive without metastasis on the date of data analysis was 100.5 months for the GEP 1A patients and 97.2 months for the GEP 1B patients. Results: The actuarial 5-year rate of uveal melanoma metastasis was 10.8% (std. error = 3.2%) in the GEP 1A patients versus 0% in the GEP 1B patients, and the actuarial 10-year rate of metastasis was 12.2% (std. error = 3.5%) in the GEP 1A patients versus 2.1% (std. error 2.1%) in the GEP 1B patients. Conclusion: The results of this retrospective single-center study cast doubt on the validity of the prognostic stratification of GEP class 1 posterior uveal malignant melanomas into very low risk (GEP 1A) versus intermediate risk (GEP 1B) of metastasis subgroups provided by the commercially available GEP test.

Early treatment and toxicity outcomes for small posterior uveal melanomas treated using custom loaded eye plaques.

Introduction: Iodine-125 loaded Collaborative Ocular Melanoma Study plaques can achieve excellent tumor control for patients diagnosed with uveal melanomas. Our ocular cancer team hypothesized that use of novel, partially loaded COMS plaques could ease and improve accurate plaque placement during treatment of small, posterior tumors while providing equivalent tumor control. Materials/methods: Records of 25 patients treated with custom plaques were compared to 20 patients treated with fully loaded plaques, who had received treatment prior to our institution's adopting the use of these partial plaques. Tumors were matched with regards to location and dimensions as measured by the ophthalmologist. Retrospective analysis of dosing parameters, tumor control and toxicity outcomes were performed. Results: There were no cancer related deaths, local recurrences or metastases in either cohort at an average follow up of 24 months for patients treated with custom plaques and 60.7 months for patients treated with fully loaded plaques. No statistically significant difference was found in regards to post-operative development of cataracts (χ2 = 0.76) or radiation retinopathy (χ2 = 0.22). Patients treated with custom loaded plaques noted significantly less clinical visual loss (χ2 = 0.006) and were more likely to have vision preserved at ≥20/200 (χ2 = 0.006). Conclusion: Treatment of small, posterior uveal melanomas with partially loaded COMS plaques results in equivalent survival and recurrence outcomes as treatment with fully loaded plaques, while exposing the patient to less radiation. Additionally, treatment with partially loaded plaques reduces the incidence of clinically significant visual loss. These promising early results support the use of partially loaded plaques in well-selected patients.

IRIS METASTASIS FROM BREAST CANCER SUCCESSFULLY TREATED WITH ABEMACICLIB AND LETROZOLE.

PURPOSE: To describe a patient with an unusual presentation of iris metastasis from breast cancer and her response to systemic therapy. METHODS: Retrospective chart review of one patient. RESULTS: A 57-year-old woman presented with a superonasal translucent vascularized iris stromal mass with fish egg-like structures budding from the surface. High-frequency anterior segment ultrasonography demonstrated a solid iris stromal mass measuring 6.0 mm × 3.3 mm × 1.9 mm. On optical coherence tomography, the egglike structures appeared as hyperreflective spheres, some of which were detached from the main iris stromal tumor. Oncologic evaluation revealed metastatic breast cancer involving the brain and lung. She was treated with oral abemaciclib and letrozole, as well as external beam radiotherapy to the brain. The iris mass had completely regressed within 4 months and remained undetectable through the 8-month follow-up. The other metastatic lesions responded well to therapy. CONCLUSION: A case of iris metastasis was reported as the presenting sign of cancer dissemination that was successfully treated with targeted systemic therapy without ocular radiotherapy.

Direct Gene Expression Profile Prediction for Uveal Melanoma from Digital Cytopathology Images via Deep Learning and Salient Image Region Identification.

Objective: To demonstrate that deep learning (DL) methods can produce robust prediction of gene expression profile (GEP) in uveal melanoma (UM) based on digital cytopathology images. Design: Evaluation of a diagnostic test or technology. Subjects Participants and Controls: Deidentified smeared cytology slides stained with hematoxylin and eosin obtained from a fine needle aspirated from UM. Methods: Digital whole-slide images were generated by fine-needle aspiration biopsies of UM tumors that underwent GEP testing. A multistage DL system was developed with automatic region-of-interest (ROI) extraction from digital cytopathology images, an attention-based neural network, ROI feature aggregation, and slide-level data augmentation. Main Outcome Measures: The ability of our DL system in predicting GEP on a slide (patient) level. Data were partitioned at the patient level (73% training; 27% testing). Results: In total, our study included 89 whole-slide images from 82 patients and 121 388 unique ROIs. The testing set included 24 slides from 24 patients (12 class 1 tumors; 12 class 2 tumors; 1 slide per patient). Our DL system for GEP prediction achieved an area under the receiver operating characteristic curve of 0.944, an accuracy of 91.7%, a sensitivity of 91.7%, and a specificity of 91.7% on a slide-level analysis. The incorporation of slide-level feature aggregation and data augmentation produced a more predictive DL model (P = 0.0031). Conclusions: Our current work established a complete pipeline for GEP prediction in UM tumors: from automatic ROI extraction from digital cytopathology whole-slide images to slide-level predictions. Our DL system demonstrated robust performance and, if validated prospectively, could serve as an image-based alternative to GEP testing.

Acute serous and hemorrhagic choroidal effusion associated with topical dorzolamide therapy.

Purpose: To report a case of acute onset unilateral hemorrhagic and serous choroidal effusion associated with dorzolamide administration and antiplatelet use that recurred in a patient who experienced a dorzolamide-induced choroidal effusion ten years prior to presentation. Observations: A 78-year-old male with a history of POAG in both eyes presented with sudden onset decreased vision and flashes of light in the left eye two days after escalating from timolol maleate 0.5% twice daily in both eyes to fixed combination dorzolamide-timolol 22.3-6.8 mg/mL twice daily in both eyes. Systemic medication included daily aspirin 81 mg for primary prevention of cardiovascular disease. Dilated fundus examination and B-scan ultrasound of the left eye revealed a hemorrhagic choroidal effusion in the nasal retinal periphery and low lying serous choroidal effusion in the temporal periphery. Complete resolution of the choroidal detachment was achieved in four days following prompt cessation of dorzolamide, and treatment with topical prednisolone acetate 1% four times daily and atropine 1% two times daily. Conclusions and importance: Topical dorzolamide may induce an idiosyncratic reaction leading to serous and hemorrhagic choroidal effusion, which can be exacerbated by antiplatelet use. Prompt recognition and management of drug-induced choroidal effusion can lead to improved visual outcomes and prevent long-term sequelae.

A slow-release dexamethasone implant for cancer-associated retinopathy.

This case report aims to show the anatomical and functional results of a patient diagnosed as having cancer-associated retinopathy treated with a controlled-release dexamethasone implant (Ozurdex). Anatomical outcomes were assessed using spectral domain optical coherence tomography; and functional outcomes, by measuring visual acuity, microperimetry, and mutifocal electroretinography. The follow-up period was 1 year.

PRAME induces genomic instability in uveal melanoma.

PRAME is a CUL2 ubiquitin ligase subunit that is normally expressed in the testis but becomes aberrantly overexpressed in many cancer types in association with aneuploidy and metastasis. Here, we show that PRAME is expressed predominantly in spermatogonia around the time of meiotic crossing-over in coordination with genes mediating DNA double strand break repair. Expression of PRAME in somatic cells upregulates pathways involved in meiosis, chromosome segregation and DNA repair, and it leads to increased DNA double strand breaks, telomere dysfunction and aneuploidy in neoplastic and non-neoplastic cells. This effect is mediated at least in part by ubiquitination of SMC1A and altered cohesin function. PRAME expression renders cells susceptible to inhibition of PARP1/2, suggesting increased dependence on alternative base excision repair pathways. These findings reveal a distinct oncogenic function of PRAME than can be targeted therapeutically in cancer.