Prognostic Value of BAP1 and Preferentially Expressed Antigen in Melanoma (PRAME) Immunohistochemistry in Uveal Melanomas.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and despite excellent local control, more than 50% of patients develop and die from metastatic disease. Loss of BAP1 nuclear staining, a surrogate marker of BAP1 mutation, and preferentially expressed antigen in melanoma (PRAME) messenger RNA overexpression, as assessed using qPCR, have previously been shown to correlate with increased metastasis rate in UM. In this study, we demonstrated that UM could be successfully risk-stratified using a combination of BAP1 and PRAME immunohistochemical (IHC) stains. We retrospectively reviewed 318 UM cases with sufficient tissue and performed BAP1 and PRAME IHC to stratify them as BAP1+/PRAME- (group 1, n = 135), BAP1+/PRAME+ (group 2, n = 43), BAP1-/PRAME- (group 3, n = 94), and BAP1-/PRAME+ (group 4, n = 46). Increasing the study risk group on the basis of loss of BAP1 expression and positive PRAME staining was associated with a higher rate of metastasis and disease-specific death and lower metastasis-free survival (MFS) and disease-specific survival (DSS). Among tumors with loss of BAP1 staining, PRAME positivity was associated with shorter MFS (P = .018) and showed a trend toward shorter DSS (P = .061). Among tumors with retained BAP1 staining, PRAME positivity was associated with shorter MFS and DSS (P = .001 and P = .021, respectively). In summary, a combination of BAP1 and PRAME IHC can be used for risk stratification of UMs.

Complications of Acute Posterior Vitreous Detachment.

PURPOSE: To evaluate the risk factors for retinal tear (RT) or rhegmatogenous retinal detachment (RRD) associated with acute, symptomatic posterior vitreous detachment (PVD) in a large comprehensive eye care setting. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 8305 adult patients in the Kaiser Permanente Northern California Healthcare System (KPNC) during calendar year 2018 who met inclusion criteria. METHODS: The KPNC electronic medical record was queried to capture acute, symptomatic PVD events. Each chart was reviewed to confirm diagnoses and capture specific data elements from the patient history and ophthalmic examination. MAIN OUTCOME MEASURES: Presence of RT or RRD at initial presentation or within 1 year thereafter. RESULTS: Of 8305 patients who presented with acute PVD symptoms, 448 (5.4%) were diagnosed with RT and 335 (4.0%) were diagnosed with RRD. When considering variables available before examination, blurred vision (odds ratio [OR], 2.7; confidence interval [CI], 2.2-3.3), male sex (OR, 2.1; CI, 1.8-2.5), age < 60 years (OR, 1.8; CI, 1.5-2.1), prior keratorefractive surgery (OR, 1.6; CI, 1.3-2.0), and prior cataract surgery (OR, 1.4; CI, 1.2-1.8) were associated with higher risk of RT or RRD, whereas symptoms of flashes were mildly protective (OR, 0.8; CI, 0.7-0.9). Examination variables associated with a high risk of RT or RRD included vitreous pigment (OR, 57.0; CI, 39.7-81.7), vitreous hemorrhage (OR, 5.9; CI, 4.6-7.5), lattice degeneration (OR, 6.0; CI, 4.7-7.7), and visual acuity worse than 20/40 (OR, 3.0; CI, 2.5-3.7). Late RTs or RRDs occurred in 12.4% of patients who had vitreous hemorrhage, lattice degeneration, or a history of RT or RRD in the fellow eye at initial presentation but only 0.7% of patients without any of these 3 risk factors. Refractive error had an approximately linear relationship with age at presentation of PVD, with myopic patients presenting at a younger age (r = 0.4). CONCLUSIONS: This study, based in a comprehensive eye care setting, found the rate of RT and RRD associated with acute PVD to be lower than rates previously reported by retina subspecialty practices. Several patient features strongly predicted the presence of initial and late complications of acute PVD.

Multi-center analysis of intraocular biopsy technique and outcomes for uveal melanoma: Ocular Oncology Study Consortium report 4.

PURPOSE: To investigate the relationship between surgical approach for intraocular tumor biopsy of uveal melanoma and tumor morphologic features such as size and intraocular location and the effect of these variables on diagnostic yield and biopsy outcome. METHODS: Consecutive patients from nine Ocular Oncology centers with uveal melanoma (UM) undergoing tumor biopsy immediately preceding I125 plaque brachytherapy with tissue sent for gene expression profiling (GEP) testing were reviewed retrospectively. RESULTS: Three hundred sixty patients were included (50% men, mean age 60.2 years). Overall biopsy yield was 99% and 83% for GEP and cytopathology, respectively. Surgeon choice of biopsy approach (trans-vitreal vs. trans-scleral) was found to associate with both tumor location and tumor thickness. A trans-scleral rather than trans-vitreal approach was used more commonly for anteriorly located tumors (92% vs. 38% of posterior tumors, p < 0.001) and thicker tumors (86% vs. 55% of thin tumors, p < 0.001). When performing trans-vitreal biopsies, ocular oncologists with previous vitreoretinal surgery fellowship training were more likely to use wide-field surgical viewing systems, compared with indirect ophthalmoscopy (82.6% vs. 20.6%, p < 0.001). Surgical complications were rare and occurred more frequently with trans-vitreal biopsies (3.6% vs. 0.46%, p = 0.046). CONCLUSIONS: In this multi-center analysis of UM tumor biopsy, surgical yield was high for obtaining tumor tissue for GEP and cytopathology analysis with both trans-scleral and trans-vitreal techniques. Fellowship-trained ocular oncologists' preferred intraocular biopsy techniques associated strongly with tumor location, tumor thickness, and fellowship training of the surgeon. Short-term complication rates were low.

CORRELATION OF GENE EXPRESSION PROFILE STATUS AND AMERICAN JOINT COMMISSION ON CANCER STAGE IN UVEAL MELANOMA.

PURPOSE: To study the relationship between gene expression profile (GEP) subclass and American Joint Committee on Cancer (AJCC) stage in patients with uveal melanoma (UM). METHODS: A retrospective, multicenter study was undertaken with patients entered from nine major ocular oncology centers from across the United States. Three hundred sixty eligible patients had UM and underwent I-125 plaque brachytherapy with concurrent tumor biopsy with GEP testing between January 1, 2010, and October 28, 2014. Patient demographics and UM features were analyzed by both GEP and AJCC status. RESULTS: Gene expression profile class divided the cohort into three groups: Class 1a (n = 186), Class 1b (n = 77), and Class 2 (n = 113). When classified using AJCC staging criteria, we found the following: Stage I in 91 cases (25.3%), Stage IIA in 143 cases (39.7%), Stage IIB in 89 cases (24.7%), Stage IIIA in 36 cases (10%), and Stage IIIB in 1 case (0.3%). There were no Stage IV cases, as lymph node and metastatic data were not collected as a part of this study. Among Stage I tumors, both high tumor height and high largest basal diameter were associated with a higher frequency of Class 2 status (P < 0.05). As UMs progress to a larger AJCC tumor group (T1-T4), the odds ratio of having a worse prognosis based on GEP class was 1.75 (95% CI, 1.36-2.25; P < 0.001). Similarly, as UMs progress to a higher AJCC stage, the odds ratio of having a worse prognosis based on GEP class was 1.69 (95% CI, 1.36-2.10; P < 0.001). CONCLUSION: This report details the differences in clinical features between GEP subclasses and how they are distributed among the AJCC stages. When the tumors were grouped by AJCC staging criteria, both larger AJCC tumor (T) group and worsening AJCC stage were associated with worsening predicted prognosis, based on GEP subclass.

MOLECULAR PROGNOSTICS FOR UVEAL MELANOMA.

PURPOSE: To review laboratory methods, currently available commercial tests, caveats and clinical tips regarding prognostic analysis of uveal melanoma tissue. METHODS: A review of the literature was performed focused on the genetic abnormalities found in uveal melanoma cells, their correlation to the development of metastases, the validity of various laboratory approaches in their detection, and the existing commercially available tests for uveal melanoma prognostication. RESULTS: Numerous laboratory methods exist for analyzing genetic material obtained from uveal melanoma cells. Older tests have been gradually replaced with contemporary methods that are simpler with greater accuracy. Two commercially available assays exist which have not been directly compared-a gene expression profiling test has been validated directly through a large, prospective multicenter study and a DNA-based test which uses laboratory methods supported by extensive historical data. CONCLUSION: There are myriad laboratory methods for prognostic analysis of uveal melanoma tissue. These tests were historically only available to those with access to an outfitted laboratory. Newer commercially available assays have increased the accessibility of prognostic biopsy for uveal melanoma. The various caveats that exist when considering and performing prognostic biopsy of uveal melanoma are discussed.

Association between Tumor Regression Rate and Gene Expression Profile after Iodine 125 Plaque Radiotherapy for Uveal Melanoma.

PURPOSE: Gene expression profile (GEP) testing segregates uveal melanoma (UM) into 2 main prognostic classes. It is unknown if a greater tumor regression response after iodine 125 (I125) brachytherapy correlates with class 2 GEP status. The purpose of this study was to determine whether there is a significant relationship between the rate of UM height regression and GEP classification testing after I125 plaque brachytherapy. DESIGN: Multicenter, retrospective cohort study. PARTICIPANTS: Adult UM patients treated with I125 plaque brachytherapy who had concurrent tumor biopsy at the time of surgery with a GEP test result from January 1, 2010 through June 30, 2014. METHODS: Baseline clinical data and GEP class assignments were obtained. The ultrasonographic tumor height was recorded at baseline and at 3, 6, 9, and 12 months and at the most recent final follow-up visits. Subanalysis of paired cases based on pretreatment ultrasound height was performed. Statistical analysis was performed using Wilcoxon rank-sum tests, the Fisher exact test, and Kaplan-Meier analysis. MAIN OUTCOME MEASURES: Percentage change in tumor height from baseline. RESULTS: A total of 353 patients were included in the study. Median follow-up was 2.1 years (range, 0.5-5.3 years). Gene expression profile status was class 1 in 247 tumors (70%) and class 2 in 106 tumors (30%). Increased patient age, larger tumor dimensions, and greater tumor thickness were associated with class 2 GEP status (P = 0.006, P < 0.001, and P < 0.001, respectively). The percentage reduction in tumor height from baseline was significantly greater in class 1 than class 2 tumors at 3 months (17.5% vs. 11.8%; P = 0.007) and 6 months (26.8% vs. 17.1%; P = 0.007), respectively, but there was no significant difference in reduction between class 1 and 2 tumors at 9 months (P = 0.26) and 12 months (P = 0.57) after treatment. Class 1A and 1B tumors showed similar reduction compared with class 2 tumors (P < 0.05). CONCLUSIONS: Class 1 UM tumors tend to regress more rapidly than class 2 tumors in the first 6 months after plaque radiotherapy. Class 1A and 1B tumors regress at similar rates after plaque radiotherapy.

Cost of phacovitrectomy versus vitrectomy and sequential phacoemulsification.

PURPOSE: To evaluate and compare the cost of combined pars plana vitrectomy and phacoemulsification/intraocular lens implantation (phacovitrectomy) to a sequential approach to the surgical procedures for patients with an indication for vitrectomy and a visually significant cataract. METHODS: The total cost of both the combined and sequential approaches to surgery were calculated by combining the surgeon, ambulatory surgical center, and anesthesiology fees as reimbursed by Medicare. A univariate sensitivity analysis was also performed to examine the sensitivity of our estimations to changes in surgical duration. RESULTS: Phacovitrectomy afforded a 17% to 20% per-patient cost savings to Medicare (depending on the type of vitrectomy) compared with vitrectomy with sequential phacoemulsification. The conclusion that phacovitrectomy was less expensive than sequential surgery was robust in sensitivity analysis. CONCLUSION: Phacovitrectomy seems to be significantly less costly to Medicare than a sequential approach to surgery for patients with an indication for vitrectomy and a visually significant cataract.

The effect of procedure room temperature and humidity on LASIK outcomes.

OBJECTIVE: To determine whether procedure room temperature or humidity during LASIK affect refractive outcomes in a large patient sample. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 202 394 eyes of 105 712 patients aged 18 to 75 years who underwent LASIK at an Optical Express, Inc., location in their United Kingdom and Ireland centers from January 1, 2008, to June 30, 2011, who met inclusion criteria. METHODS: Patient age, gender, flap creation technique, pre- and 1-month post-LASIK manifest refraction, and ambient temperature and humidity during LASIK were recorded. Effect size determination and univariate and multivariate analyses were performed to characterize the relationships between LASIK procedure room temperature and humidity and postoperative refractive outcome. MAIN OUTCOME MEASURES: One month post-LASIK manifest refraction. RESULTS: No clinically significant effect of procedure room temperature or humidity was found on LASIK refractive outcomes. When considering all eyes in our population, an increase of 1°C during LASIK was associated with a 0.003 diopter (D) more hyperopic refraction 1 month postoperatively, and an increase in 1% humidity was associated with a 0.0004 more myopic refraction. These effect sizes were the same or similar when considering only myopic eyes, only hyperopic eyes, and subgroups of eyes stratified by age and preoperative refractive error. CONCLUSIONS: Neither procedure room temperature nor humidity during LASIK were found to have a clinically significant relationship with postoperative manifest refraction in our population.

Glaucoma severity and medication adherence in a county hospital population.

OBJECTIVE: To assess the association between disease severity and adherence with glaucoma medications in a county hospital population. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 126 patients diagnosed with glaucoma receiving intraocular pressure (IOP)-lowering medication were recruited from the San Francisco General Hospital Ophthalmology Clinic. METHODS: Subjects completed an oral questionnaire to assess demographic information, knowledge of glaucoma, and perceptions of glaucoma medication adherence. Glaucoma disease severity was classified according to the American Academy of Ophthalmology's Preferred Practice Pattern guidelines. Medication adherence was measured for each patient by obtaining pharmacy refill data and calculating medication possession ratio (MPR), that is, the ratio of total days' supply of medication during a 365-day period. Adherence was measured retrospectively over the 18-month period before study entry. Subjects with an MPR >80% were considered adherent. MAIN OUTCOME MEASURE: Medication adherence. RESULTS: Subjects with mild or moderate glaucoma were more likely to be nonadherent to their prescribed glaucoma medications than those with severe disease (adjusted odds ratio [OR], 1.54; 95% confidence interval [CI], 1.03-2.31; P = 0.04). Age, gender, race, education level, years of glaucoma, number of medications, and glaucoma diagnosis were not found to be statistically significantly associated with adherence. CONCLUSION: Patients with severe glaucoma were more likely to adhere to their topical IOP-lowering medication regimen than those with milder glaucomatous disease. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Novel Guarded Needle Trans-Scleral Biopsy for Uveal Melanoma: A Pilot Study.

INTRODUCTION: Trans-scleral biopsy of uveal melanoma (UM) poses an inherent risk of tumor and possibly retinal perforation. We describe a novel technique for trans-scleral biopsy of UM and evaluate its safety and efficacy in an initial cohort of patients. METHODS: A retrospective, consecutive observational case series was conducted from October 14, 2019, to April 15, 2020, at Kaiser Permanente, San Francisco, CA among patients with UM of the ciliary body or anterior choroid undergoing trans-scleral fine-needle aspiration biopsy using a novel guarded needle technique. RESULTS: A total of 6 patients were included in the study, with a mean age of 64.3 (range 35-77) years (5 women 83%). Mean (±SD) tumor thickness and maximal basal diameter were 6.4 (±2.66) and 11.9 (±2.13) mm, respectively. Five out of 6 patients achieved a successful biopsy with reliable gene expression profiling (GEP) results. The only failure to obtain specimen occurred in the first attempted patient and, after a minor technique modification, all subsequent biopsies were successful. No intraoperative or short-term postoperative complications were observed in any patient. CONCLUSION: This novel trans-scleral biopsy technique appears to be safe and effective when obtaining UM tissue for GEP. This method may provide a more controlled biopsy depth thereby minimizing the risk of tumor perforation and its associated complications while still obtaining adequate biopsy yield.

Evaluation of a Series of Wrong Intravitreous Injections.

IMPORTANCE: This case series describes events associated with errors in intravitreous injections. Given the volume of injections performed worldwide, it is important to identify the factors associated with these wrong events to try to reduce their occurrences. OBJECTIVE: To evaluate a series of errors in intravitreous injections within Kaiser Permanente Northern California (KPNC). DESIGN, SETTING, AND PARTICIPANTS: In this retrospective small case series of a convenience sample at KPNC between January 1, 2019, and December 30, 2020, cases of errors in intravitreous injection were identified either as part of a formal institutional quality review or by self-report of the involved surgeon during quality improvement discussions. MAIN OUTCOMES AND MEASURES: Description of the medical errors and the circumstances surrounding these errors. RESULTS: During the 2 years of this evaluation, there were more than 147 000 injections performed within KPNC. Four cases of errors in intravitreous injection were identified. Mistakes were associated with inaccurate review of the electronic medical record, poor surgeon and staff focus, and inconsistent use of surgical checklists and timeouts. No long-term ocular morbidity occurred following any of these errors. CONCLUSIONS AND RELEVANCE: Medical errors related to intravitreous injections have occurred within KPNC. We trust these events are not unique to our practice. A standardized teams-based approach that incorporates rigorous safety protocols will likely be needed to reduce the risk of future wrong intravitreous injections.

Crystalline Lens Resorption Caused by Ciliary Body Melanoma.

We report a case of a 51-year-old Caucasian female who presented with a ciliary body melanoma of the right eye leading to focal resorption of the crystalline lens and inducing posterior subcapsular cataract. She underwent successful enucleation, and histopathology demonstrated a ciliary body melanoma with a predominance of epithelioid cells and focal scleral extension. Genetic testing revealed a heterozygous, pathogenic mutation of BAP1 (c.1717delC, p.Leu573fs). Crystalline lens resorption is a rare but potentially important finding in ciliary body melanoma, as early detection of malignancy can be lifesaving.

Comparison of Smartphone Photography, Single-Lens Reflex Photography, and Field-Grading for Trachoma.

Conjunctival examination for trachomatous inflammation-follicular (TF) guides public health decisions for trachoma. Smartphone cameras may allow remote conjunctival grading, but previous studies have found low sensitivity. A random sample of 412 children aged 1-9 years received an in-person conjunctival examination and then had conjunctival photographs taken with 1) a single-lens reflex (SLR) camera and 2) a smartphone coupled to a 3D-printed magnifying attachment. Three masked graders assessed the conjunctival photographs for TF. Latent class analysis was used to determine the sensitivity and specificity of each grading method for TF. Single-lens reflex photo-grading was 95.0% sensitive and 93.6% specific, and smartphone photo-grading was 84.1% sensitive and 97.6% specific. The sensitivity of the smartphone-CellScope device was considerably higher than that of a previous study using the native smartphone camera, without attachment. Magnification of smartphone images with a simple attachment improved the grading sensitivity while maintaining high specificity in a region with hyperendemic trachoma.

Practice Patterns for the Treatment of Uveal Melanoma with Iodine-125 Plaque Brachytherapy: Ocular Oncology Study Consortium Report 5.

BACKGROUND: Treatment planning for I-125 plaque therapy for uveal melanoma has advanced significantly since the Collaborative Ocular Melanoma Study trial, with more widely available image-guided planning and improved dosimetry. OBJECTIVE: We evaluated real-world practice patterns for I-125 plaque brachytherapy in the United States by studying practice patterns at centers that comprise the Ocular Oncology Study Consortium (OOSC). METHODS: The OOSC database and responses to a treatment practice survey were evaluated. The database contains treatment information from 9 institutions. Patients included in the database were treated between 2010 and 2014. The survey was conducted in 2018 and current treatment planning methods and prescriptions were queried. RESULTS: Examination of the OOSC database revealed that average doses to critical structures were highly consistent, with the exception of one institution. Survey responses indicated that most centers followed published guidelines regarding dose and prescription point. Dose rate ranged from 51 to 118 cGy/h. As of 2018, most institutions use pre-loaded plaques and fundus photographs and/or computed tomography or magnetic resonance imaging in planning. CONCLUSIONS: While there were differences in dosimetric practices, overall agreement in plaque brachytherapy practices was high among OOSC institutions. Clinical margins and planning systems were similar among institutions, while prescription dose, dose rates, and dosimetry varied.