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.

Focal aggregates of normal or near normal uveal melanocytes (FANNUMs) in the choroid: a distinct clinical and histopathological entity?

PURPOSE: To define, describe, and illustrate a previously unreported category of discrete melanotic choroidal melanocytic lesion. METHODS: Prospective ophthalmoscopic study of the ocular fundi of 79 light-skinned persons 50 years of age or older not referred for any evident fundus lesion, with detection of all evident discrete melanotic choroidal lesions > 0.3 mm in largest basal diameter. RESULTS: One or more discrete dark-brown to gray choroidal lesions > 0.3 mm in largest basal diameter were detected in 27 of the 79 evaluated subjects (34.2%). All but four of the detected lesions were "flat" by both ophthalmoscopy and ultrasonography. A single flat lesion was present in one eye of 14 subjects whose fellow eye was normal, 2 or more flat lesions were evident in one eye of 5 subjects whose other eye was normal, and one or more lesions were evident in both eyes of 6 subjects. CONCLUSION: While some of the discrete small, flat melanocytic choroidal lesions detected in this study might have been choroidal nevi, the author hypothesizes that an indeterminate proportion of them may have been focal aggregates of normal or near normal uveal melanocytes (FANNUMs).

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.

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.

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.

Retinal Gliovascular Proliferation Secondary to Retinoblastoma Treated With Radiotherapy.

BACKGROUND AND OBJECTIVE: Retinal gliovascular proliferation (RGVP) is a benign lesion of the retina that can arise idiopathically or secondary to another disease entity. This study describes the clinical features, treatment, and outcomes of six patients with secondary RGVP associated with irradiated, regressed retinoblastoma, and distinguishes it from late local relapse of retinoblastoma. PATIENTS AND METHODS: In a retrospective review of available clinical records of 550 patients evaluated for retinoblastoma in a single ocular oncology practice between 1975 and 2022, seven eyes of six patients were identified as having secondary RGVP overlying a treated and regressed retinoblastoma. The clinical features, treatment, and outcomes are described. RESULTS: The median age at RGVP diagnosis was 20 years. All RGVPs were associated with a completely regressed retinoblastoma and in proximity to a calcific tumor residue or chorioretinal atrophy that remained after external beam radiotherapy (six eyes) or plaque brachytherapy (one eye). Lesions were measured between 2.8 to 12 mm in largest basal diameter and 1.3 to 4.4 mm in thickness and described as globular, raised areas with focal retinal telangiectasis often associated with overlying subretinal fluid or hemorrhage. Median time between initial retinoblastoma treatment and detection of RGVP was 20 years. Treatment was decided based on evidence of lesion growth and most often consisted of laser photocoagulation and intravitreal anti-VEGF injection. Through available follow-up of the treated lesions, all exhibited at least partial regression, while two untreated lesions remained stable, reassuring us against late local relapse of retinoblastoma. CONCLUSIONS: Secondary RGVP develops occasionally in association with regressed previously irradiated retinoblastoma. This lesion must be distinguished from late local relapse of active retinoblastoma. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Fundus autofluorescence findings of choroidal osteoma.

PURPOSE: To describe fundus autofluorescence (FAF) characteristics associated with choroidal osteomas and their secondary complications. METHODS: Retrospective descriptive case series of six eyes of five patients with choroidal osteomas. Findings of FAF correlated with visual acuity, clinical features, lesion characteristics, and findings from other imaging modalities. RESULTS: All 6 choroidal osteomas (100%) had totally or partially calcified, orange portions that were isoautofluorescent. Partial decalcification also produced areas of hyperautofluorescence and granular hypoautofluorescence corresponding to overlying retinal pigment epithelium mottling in 3 eyes (50%). Total decalcification with retinal pigment epithelial atrophy produced decreased FAF in 2 eyes (33%). Serous retinal detachment was present in 3 eyes (50%). When the overlying retinal pigment epithelium was viable, hyperautofluorescence as a result of elongation of the outer segments of photoreceptor was observed. In one eye where geographic atrophy of the retinal pigment epithelium was present, FAF was decreased even in the presence of serous retinal detachment. Portions of three partially or totally decalcified osteomas within the treatment field of photodynamic therapy for choroidal neovascularization were hypoautofluorescent. Four eyes (67%) had reduced foveal FAF and visual acuity <20/20, while both eyes with foveal isoautofluorescence had normal (20/20) visual acuity. CONCLUSION: Calcified portions of choroidal osteomas not previously treated with photodynamic therapy were isoautofluorescent. Decalcification and secondary complications of serous retinal detachment, choroidal neovascularization, and geographic atrophy altered foveal autofluorescence and were associated with reduced visual acuity.

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.

Malignant Transformation of a Choroidal Nevus after 19 Years of Observation Followed by Rapid Progression of the Choroidal Melanoma.

PURPOSE: To describe the case of a woman who developed rapid progression of a choroidal melanoma after 19 years of observation of a previously treated choroidal nevus. METHODS: A 71-year-old woman with a 22-year history of a choroidal nevus was observed for 19 years after undergoing transpupillary thermotherapy for a localized, macula-involving, exudative retinal detachment. Five months after her most recent stable examination, she presented for routine follow-up. RESULTS: The lesion was noted to have increased thickness with development of lipofuscin and subretinal fluid, suggestive of malignant transformation. In the 1 month between diagnosis and treatment with Iodine-125 plaque brachytherapy, the lesion continued to expand, requiring a radiation dose adjustment. CONCLUSION: Choroidal nevus transformation into melanoma has been well-documented, highlighting the need for routine follow-up. Treatment within 1 month is typically sufficient for appropriate management. Occasionally, melanomas may grow substantially between diagnosis and treatment, suggesting that repeat measurement may be necessary in rare instances to ensure appropriate radiation treatment.

Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.

PURPOSE: This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk). DESIGN: Prospective, multicenter study. PARTICIPANTS: A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers. TESTING: Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and chromosome 3 status. MAIN OUTCOME MEASURES: Patients were managed for their primary tumor and monitored for metastasis. RESULTS: The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status. CONCLUSIONS: The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.

Secondary intraocular uveal involvement by primary paranasal sinus lymphoma.

To report an unusual case of primary paranasal sinus lymphoma associated with intraocular secondary uveal involvement. Retrospective case report emphasizing the histopathologic diagnosis as well as imaging studies, and review of the pertinent literature. The diagnosis of ophthalmologic lymphoma can be difficult due to the infrequency of the disease, the diverse presentation, and the need for biopsy for definitive diagnosis. Prior clinical history and systemic testing may be important confirmations in diagnosing such cases.

Unilateral Multifocal Choroidal Melanoma with Underlying Isolated Choroidal Melanocytosis.

Isolated choroidal melanocytosis is a rare condition that appears to be a limited form of ocular melanocytosis. Ocular melanocytosis has been known to be associated with an increased risk of uveal melanoma, and more recently, a similar association has been suggested for isolated choroidal melanocytosis. We describe 3 cases of patients who developed unilateral, multifocal uveal melanoma in the setting of underlying isolated choroidal melanocytosis. All patients developed either two distinct tumors at presentation or a new discrete choroidal melanoma arising from the choroidal melanocytosis over 1 year following treatment of the original tumor by plaque brachytherapy. These cases provide additional evidence of the association between isolated choroidal melanocytosis and uveal melanoma and suggest increased risk of multifocal melanoma in patients with this condition.

Clinical and histopathological features and immunoreactivity of human choroidal and ciliary melanomas as prognostic factors for metastasis and death.

PURPOSES: To determine the relationship between immunohistochemical reactivity to osteopontin, vimentin, keratin 8/18, LZTS1, and beta-catenin and clinical and histopathological prognostic factors for metastasis and death in archival specimens of primary uveal melanomas, and the prognostic value of the evaluated study variables for death from metastasis. METHODS: Retrospective analysis of clinical records and formalin-fixed, paraffin-embedded slides of primary uveal melanomas treated by enucleation during May 1 1999, through June 30 2009. Immunofluorescent staining of each tumor was assessed on newly prepared histologic slides after the application of antibodies directed against five biomarkers associated with unfavorable prognosis in uveal melanoma. RESULTS: After exclusions, our study group consisted of 82 cases. Immunofluorescence was observed in 40.2% of specimens evaluated for keratin, 50.0% evaluated for osteopontin, 26.8% evaluated for ß-catenin, 65.9% evaluated for vimentin, and 70.7% evaluated for LZTS1. Through available follow-up, 27 patients (32.9%) were dead of confirmed or suspected metastatic uveal melanoma. None of the patients whose tumor exhibited strong immunoreactivity to ß-catenin died of metastasis. In contrast, patients whose tumor exhibited immunoreactivity of any intensity to LZTS1 were more likely to develop metastasis. In multivariate Cox proportional hazards modeling, a composite variable that took into account the immunostaining for both ß-catenin and LZTS1 had a statistically significant relationship with patient's survival time. CONCLUSIONS: Our study suggests that conventional clinical and histopathological prognostic factors, and immunoexpression of ß-catenin and LZTS1 combined may allow better prognostication of metastasis than clinical and histomorphological factors alone.

Pharmacokinetics and Toxicity Evaluation of a PLGA and Chitosan-Based Micro-Implant for Sustained Release of Methotrexate in Rabbit Vitreous.

The present research investigates the pharmacokinetics and toxicity of a chitosan (CS) and poly(lactic-co-glycolic) acid (PLGA)-based methotrexate (MTX) intravitreal micro-implant in normal rabbit eyes. PLGA and CS-based micro-implants containing 400 µg of MTX were surgically inserted in the vitreous of twenty-four New Zealand rabbits using minimally invasive procedures. The PLGA-coated CS-MTX micro-implant and the placebo micro-implant were inserted in the right eye and in the left eye, respectively, of each rabbit. The intravitreal MTX concentration was evaluated on Days 1, 3, 7, 14, 28 and 56. A therapeutic concentration of MTX (0.1-1.0 µM) in the rabbit vitreous was observed for 56 days. The release of MTX in the therapeutic release phase followed first-order kinetics. Histopathologic evaluation on Days 14, 28 and 56 of the enucleated eyes demonstrated no signs of toxicity or any anatomical irregularity in the vitreoretinal domain. Additionally, the micro-implants were stationary at the position of their implantation throughout the duration of the study. The PLGA-coated CS-MTX micro-implant can serve as a potential alternative to the current treatment modality of intravitreal MTX injections based on its performance, thereby avoiding associated complications and the treatment burden of multiple injections.

Successful salvage intravenous chemotherapy after tandem selective ophthalmic artery infusion chemotherapy in bilateral retinoblastoma.

We report the case of a 9-month-old girl with bilateral retinoblastoma who had incomplete tumor resolution after selective ophthalmic artery infusion chemotherapy (SOAIC). Systemic chemotherapy, rarely used as salvage therapy after SOAIC, with systemic carboplatin, etoposide, and vincristine achieved complete and sustained regression in both eyes.

Complete ring cyst of iris pigment epithelium documented by ultrasound biomicroscopy.

The authors report a complete ring cyst of the iris pigment epithelium confirmed by ultrasound biomicroscopy. In this case, ultrasound biomicroscopy effectively excluded the differential diagnoses of ring melanoma of the iris and multiple separate cysts of the iris pigment epithelium.