Prospective, Randomized Trial Comparing Simulator-based versus Traditional Teaching of Direct Ophthalmoscopy for Medical Students.

OBJECTIVE: To compare results of simulator-based vs traditional training of medical students in direct ophthalmoscopy. DESIGN: Randomized controlled trial. METHODS: First-year medical student volunteers completed 1 hour of didactic instruction regarding direct ophthalmoscopes, fundus anatomy, and signs of disease. Students were randomized to an additional hour of training on a direct ophthalmoscope simulator (n = 17) or supervised practice examining classmates (traditional method, n = 16). After 1 week of independent student practice using assigned training methods, masked ophthalmologist observers assessed student ophthalmoscopy skills (technique, efficiency, and global performance) during examination of 5 patient volunteers, using 5-point Likert scales. Students recorded findings and lesion location for each patient. Two masked ophthalmologists graded answer sheets independently using 3-point scales. Students completed surveys before randomization and after assessments. Training groups were compared for grades, observer- and patient-assigned scores, and survey responses. RESULTS: The simulator group reported longer practice times than the traditional group (P = .002). Observers assigned higher technique scores to the simulator group after adjustment for practice time (P = .034). Combined grades (maximum points = 20) were higher for the simulator group (median: 5.0, range: 0.0-11.0) than for the traditional group (median: 4.0, range: 0.0-9.0), although the difference was not significant. The simulator group was less likely to mistake the location of a macular scar in 1 patient (odds ratio: 0.28, 95% confidence interval: 0.056-1.35, P = .013). CONCLUSIONS: Direct ophthalmoscopy is difficult, regardless of training technique, but simulator-based training has apparent advantages, including improved technique, the ability to localize fundus lesions, and a fostering of interest in learning ophthalmoscopy, reflected by increased practice time.

Magrabi ICO Cameroon Eye Institute, Yaoundé, Cameroon: Ophthalmology Subspecialty Patient Care and Training Center in Central Africa.

PURPOSE: To report establishment of the Magrabi ICO Cameroon Eye Institute at Yaoundé, Cameroon, as an ophthalmology subspecialty patient care and training center in Central Africa. DESIGN: Perspective. METHODS: Assessment of unpublished and published material. RESULTS: To improve, preserve and restore eye health and vision in a region with world-high prevalence of functional vision impairment and blindness, the Africa Eye Foundation established the Magrabi ICO Cameroon Eye Institute as an ophthalmology subspecialty patient care center for all in need and a training center for ophthalmologists, ophthalmology subspecialists, and allied personnel. In 2017, the year of its inauguration and the first year of operation, the Magrabi ICO Cameroon Eye Institute provided ophthalmology subspecialty care to more than 25 000 patients and surgery for pediatric and adult cataract, glaucoma, retinal disease, oculoplastic disorders, and other vision-threatening conditions. Outreach programs extended care to an additional 2500 individuals in rural communities and 7 training courses were conducted for ophthalmologists and allied personnel. CONCLUSION: Through ophthalmology subspecialty patient care and the training of ophthalmologists and allied personnel, Magrabi ICO Cameroon Eye Institute is acting to enhance vision and the quality of life for individuals and families in all segments of society.

Bilateral Acquired Progressive Retinal Nerve Fiber Layer Myelination.

The authors present the multimodal imaging findings of an unusual case of bilateral acquired progressive myelination of the optic disc during a 10-year follow-up period in a hyperopic adolescent patient in the absence of an underlying ocular or systemic abnormality. Myelination of the left optic disc was noted at age 7 and of the right optic disc at age 13, but no other ocular or systemic abnormalities were identified. Cross-sectional optical coherence tomography (OCT) and en face OCT angiography confirmed the presence of myelination of the retinal nerve fiber layer and excluded other etiologic possibilities including an astrocytic hamartoma. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e147-e150.].

Mortality after deferral of treatment or no treatment for choroidal melanoma.

PURPOSE: To report mortality of patients who were eligible for enrollment in the Collaborative Ocular Melanoma Study (COMS) clinical trials of medium-sized choroidal melanoma or large-sized choroidal melanoma but chose to defer treatment or receive no melanoma treatment. DESIGN: Prospective nonrandomized multicenter cohort study as an adjunct to COMS randomized clinical trials. METHODS: Patient follow-up procedures included examinations, correspondence, telephone contacts, and National Death Index searches. Primary outcome was patient death measured by all-cause mortality. Secondary outcomes were melanoma treatment and melanoma metastasis. RESULTS: Of 77 patients eligible for COMS clinical trials who chose to defer or receive no melanoma treatment, 61 were appropriate candidates and 45 (74%) enrolled in the natural history study (NHS). In all, 42 patients (42 eyes) had medium melanoma, and the median follow-up was 5.3 years (range, 4-10.7 years). In all, 22 patients (52%) had subsequent melanoma treatment, and 20 (48%) had no melanoma treatment. For the 42 patients, Kaplan-Meier estimate of 5-year mortality was approximately 30% [95% confidence interval (CI), 18%-47%]. For COMS medium melanoma trial, 5-year mortality was 18% (95% CI, 16%-20%), not statistically significantly different from the NHS patients. After adjusting for differences in age and longest basal diameter, the 5-year risk of death for NHS patients versus COMS trial patients was 1.54 (95% CI, 0.93-2.56). Three patients had large melanoma. Melanoma metastasis was confirmed or suspected in 8 (42%) of 19 deaths. CONCLUSION: Greater mortality and higher risk of death for NHS patients are probative but not conclusive evidence of a beneficial, life-extending effect of medium melanoma treatment.

Outcomes of cataract surgery in eyes with ocular melanoma treated with iodine-125 brachytherapy.

PURPOSE: To evaluate visual and surgical outcomes of cataract surgery in eyes with a history of iodine-125 (I125) brachytherapy for ocular melanoma. SETTING: Department of Ophthalmology, David Geffen School of Medicine at UCLA and the Stein Eye Institute, Los Angeles, California, USA. DESIGN: Retrospective case series. METHODS: Patients with ocular melanoma treated by I125 brachytherapy who subsequently had cataract surgery were evaluated. The recorded data included tumor size, location, preoperative ocular comorbidities, corrected distance visual acuity (CDVA), operative complications, and brachytherapy-related maculopathy before and after surgery. RESULTS: Thirty-two eyes of 32 patients were included. The mean age at the time of cataract surgery was 66.1 years. The median follow-up was 53.5 months. There were no intraoperative complications. Eighteen eyes (56.3%) had a history of preoperative radiation retinopathy, 10 involving the macula. Between 2 weeks and 4 weeks postoperatively, 22 eyes (68.8%) had an improvement in CDVA (≥2 lines). Seven of 10 eyes that failed to improve had radiation maculopathy. By the last follow-up examination, 13 eyes (40.6%) had improved CDVA, 9 eyes (28.1%) were worse (≥2 lines), and 10 eyes (31.3%) were unchanged (within ±1 line). Of 15 eyes that lost CDVA gains achieved between 2 weeks and 4 weeks postoperatively, 9 eyes had new-onset or worsening maculopathy. Cataract surgery had no effect on local tumor control or distant metastasis. CONCLUSIONS: Cataract surgery after I125 brachytherapy for ocular melanoma improved CDVA in most eyes during the immediate postoperative period. Gains were often lost with further follow-up. Progression of radiation maculopathy was primarily responsible for subsequent visual decline.

Jules Stein, MD: Ophthalmologist, Entertainment Magnate, and Advocate for Vision.

PURPOSE: To report the lifetime activities and accomplishments of Jules Stein, MD. DESIGN: Retrospective review. METHODS: Assessment of published and unpublished biographical material. RESULTS: Jules Stein combined his love of music and medicine with organizational skills to achieve successive careers as a musician, an ophthalmologist, an entertainment magnate, and an advocate for vision. To preserve vision, he founded Research to Prevent Blindness, founded the Jules Stein Eye Institute at the University of California, Los Angeles, and led a multiyear campaign to establish the National Eye Institute. CONCLUSIONS: With successive careers and extraordinary achievements, Jules Stein created an enduring legacy of benefits to ophthalmology, vision research, and the prevention of blindness.

Visual Acuity, Contrast Sensitivity and Color Vision Three Years After Iodine-125 Brachytherapy for Choroidal and Ciliary Body Melanoma.

PURPOSE: To report visual acuity, contrast sensitivity and color vision prior to, 1 year after, 2 years after and 3 years after iodine-125 brachytherapy for choroidal and ciliary body melanoma (CCM). DESIGN: Prospective interventional case series. PARTICIPANTS: Thirty-seven patients (37 eyes) with CCM. METHODS: Patients had best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, Pelli-Robson contrast sensitivity and Hardy-Rand-Rittler color vision measurement; comprehensive ophthalmology examination; optical coherence tomography; and ultrasonography at baseline prior to, 1 year after, 2 years after and 3 years after I-125 brachytherapy. MAIN OUTCOME MEASURES: Visual acuity, contrast sensitivity and color vision prior to, 1 year after, 2 years after and 3 years after brachytherapy. RESULTS: Nineteen (19) men and 18 women with mean age of 58 years (SD 13, range 30-78) prior to, 1 year after, 2 years after and 3 years after brachytherapy had mean best-corrected visual acuity of 77 letters (20/32), 65 letters (20/50), 56 letters (20/80) and 47 letters (20/125); contrast sensitivity of 30, 26, 22 and 19 letters; color vision of 26, 20, 17 and 14 test figures, respectively. Decrease in visual acuity, contrast sensitivity and color vision was statistically significant from baseline at 1 year, 2 years, and 3 years after brachytherapy. Decreased acuity at 3 years was associated with mid-choroid and macula melanoma location, ≥ 4.1 mm melanoma height, radiation maculopathy and radiation optic neuropathy. CONCLUSION: 1, 2 and 3 years after brachytherapy, eyes with CCM had significantly decreased visual acuity, contrast sensitivity and color vision.

Pilot study using mobile health to coordinate the diabetic patient, diabetologist, and ophthalmologist.

In the United States, more than 25 million adults have diabetes, 40% of diabetics have diabetic retinopathy, and diabetes is the leading cause of blindness in people 20 to 74 years of age. Clinical trials have shown that strict control of blood glucose level and other risk factors delays diabetic retinopathy onset, progression, and vision loss. Patients with Type 1 or Type 2 diabetes mellitus, access to an Apple iPhone or iPad, and no psychological or medical condition that would interfere with the study participated in a nonrandomized clinical trial using SightBook™, a free mobile app that enables self-measurement of visual function and creates a password-protected web account for each patient. Sixty patients enrolled in the clinical trial over a 6 month period. Twenty-six participants were men and 34 were women, with ages from 23 to 72 years (mean 45 ± 15) and diabetes duration of 1.5 to 50 years (mean 15.5 ± 11.5). Thirty-nine (65%) patients reported Type 1 diabetes and 21 (35%) patients reported Type 2 diabetes. Every patient established a personal web account on SightBook and invited participation of treating physicians; 51 (85%) patients completed the validated self-reported outcome assessments. Diabetologist examinations of 49 (82%) patients demonstrated systolic hypertension (≥140 mgHg) in 20% and hemoglobin A1c ≥ 7.0% in 56%. Ophthalmology examinations of 45 patients showed visual acuity in the worse-seeing eye of < 20/40 in 18% and diabetic retinopathy in 42% of patients. This clinical trial used a mobile health app to incorporate diabetic patient self-measurement of vision and coordinate the diabetic patient, diabetologist, and ophthalmologist for control of diabetes and diabetic retinopathy risk factors.

Radiation-related cancer risk associated with surveillance imaging for metastasis from choroidal melanoma.

OBJECTIVE: To estimate the lifetime attributable risk of cancer associated with whole-body positron emission tomography (PET)/computed tomography (CT) and with CT of the chest, abdomen, and pelvis if performed at various frequencies and for different durations for surveillance of patients with primary choroidal or ciliary body melanoma for distant metastasis. METHODS: Effective radiation doses for whole-body CT and for CT of the chest, abdomen, and pelvis were calculated using Monte Carlo simulation studies. The effective dose of the PET scan was estimated by multiplying fludeoxyglucose F18 radioactivity with dose coefficients. Lifetime attributable risks of cancer were calculated using the approach described in the Biological Effects of Ionizing Radiation VII report. RESULTS: For a 50-year-old patient, an annual CT of the chest, abdomen, and pelvis for 10 years carries an estimated lifetime attributable risk of cancer of 0.9% for male patients and 1.3% for female patients, whereas an annual PET/CT each year for 10 years carries an estimated lifetime attributable risk of cancer of 1.6% for male patients and 1.9% for female patients. Lifetime risk was found to be higher in younger, female patients. The lifetime attributable risk of cancer was estimated to be as high as 7.9% for a 20-year-old female patient receiving a PET/CT scan every 6 months for 10 years. CONCLUSIONS: Aggressive surveillance protocols incorporating CT scanning or PET/CT scanning for detection of metastasis from primary choroidal or ciliary body melanoma appear to confer a significant substantial risk of a secondary malignant tumor in patients who do not succumb to metastatic melanoma within the first few posttreatment years.

Ocular response of choroidal melanoma with monosomy 3 versus disomy 3 after iodine-125 brachytherapy.

PURPOSE: To report the ocular response of choroidal melanoma with monosomy 3 vs. disomy 3 after (125)I brachytherapy. METHODS AND MATERIALS: We evaluated patients with ciliochoroidal melanoma managed with fine needle aspiration biopsy immediately before plaque application for (125)I brachytherapy between January 1, 2005 and December 31, 2008. Patients with (1) cytopathologic diagnosis of melanoma, (2) melanoma chromosome 3 status identified by fluorescence in situ hybridization, and (3) 6 or more months of follow-up after brachytherapy were sorted by monosomy 3 vs. disomy 3 and compared by Kruskal-Wallis test. RESULTS: Among 40 ciliochoroidal melanomas (40 patients), 15 had monosomy 3 and 25 had disomy 3. Monosomy 3 melanomas had a median greatest basal diameter of 12.00 mm and a median tumor thickness of 6.69 mm before brachytherapy; at a median of 1.75 years after brachytherapy, median thickness was 3.10 mm. Median percentage decrease in tumor thickness was 48.3%. Disomy 3 melanomas had a median greatest basal diameter of 10.00 mm and median tumor thickness of 3.19 mm before brachytherapy; at a median of 2.00 years after brachytherapy, median tumor thickness was 2.37 mm. The median percentage decrease in tumor thickness was 22.7%. Monosomy 3 melanomas were statistically greater in size than disomy 3 melanomas (p < 0.001) and showed a greater decrease in tumor thickness after brachytherapy (p = 0.006). CONCLUSION: In this study, ciliochoroidal melanomas with monosomy 3 were significantly greater in size than disomy 3 melanoma and showed a significantly greater decrease in thickness at a median of 1.75 years after brachytherapy. The greater decrease in monosomy 3 melanoma thickness after brachytherapy is consistent with other malignancies in which more aggressive pathology has been shown to be associated with a greater initial response to radiotherapy.

Genomic identification of significant targets in ciliochoroidal melanoma.

PURPOSE: To identify genomic targets for ciliochoroidal melanoma diagnosis, prognosis, and therapy. METHODS: Fifty-eight ciliochoroidal melanomas were analyzed by high-resolution, genome-wide, single nucleotide polymorphism (SNP) mapping arrays. The 58 SNP arrays were compared to 48 HapMap normals representing both sexes and assessed with a systematic statistical method, Genomic Identification of Significant Targets in Cancer (GISTIC), to identify significant ciliochoroidal chromosomal abnormalities including chromosome-arm-sized as well as focal events of amplification and deletion. The 58 SNP arrays were also analyzed to assess copy number. RESULTS: The 58 ciliochoroidal melanomas analyzed by GISTIC showed large regions of chromosome amplification on 6p and 8q in addition to focal amplification peaks on 1q31.3, 4p16.2, 9p23, and 9q33.1. The melanomas also showed large regions of deletion on 1p and all of 3, 6q, 8p, and 16q, as well as focal deletion peaks on 2p12, 2q14.3, 4q26, 5q21.1, 7q21.11, 8p21.3, 9p21.1, 13q21.31, 13q31.3, and 16q23.3. For each large region and focal peak, the statistical significance was computed, and known genes were specified. CONCLUSIONS: High-resolution analysis of ciliochoroidal melanoma cytogenetic aberration patterns supports the utility of systematic characterization of the cancer genome by corroborating known melanoma-related genomic aberrations and identifying additional melanoma-related genomic abnormalities that can be used to identify potential targets for diagnosis, prognosis and therapy.

Identification of candidate tumor oncogenes by integrative molecular analysis of choroidal melanoma fine-needle aspiration biopsy specimens.

OBJECTIVE: To report integrative molecular analysis of choroidal melanoma fine-needle aspiration biopsy specimens to identify candidate tumor oncogenes. METHODS: Thirty-one choroidal melanoma fine-needle aspiration biopsy specimens were analyzed using cytopathologic diagnosis of melanoma, fluorescence in situ hybridization for chromosome 3, cytogenetic characterization (GeneChip Human 250K NSPI Mapping Arrays; Affymetrix, Santa Clara, California), and gene expression profiles (GeneChip Human Genome U133 Plus 2.0 Arrays, Affymetrix). These analyses were performed by clustering of cytogenetic aberrations, sorting by chromosome 3 loss and chromosome 6p gain, and comparing gene expression profiles in chromosome 3 loss- and chromosome 6p-gain tumors to identify genes with differential expression based on cytogenetic characteristics. RESULTS: Of 31 choroidal melanoma biopsy specimens included in this study, 19 tumors had chromosome 3 loss, and 12 tumors without chromosome 3 loss had chromosome 6p gain. Comparative RNA analysis for these 2 groups revealed 49 genes with greater than 4-fold higher expression and 31 genes with greater than 4-fold lower expression in chromosome 3-loss tumors relative to chromosome 6p-gain tumors. CONCLUSIONS: Molecular analysis of choroidal melanoma fine-needle aspiration biopsy specimens demonstrated 2 cytogenetically distinct groups characterized by chromosome 3 loss or chromosome 6p gain. In chromosome 3-loss melanomas relative to chromosome 6p-gain melanomas, integrative RNA analysis revealed genes with higher expression and lower expression and identified several genes that have not been reported in previous studies. CLINICAL RELEVANCE: Genes differentially expressed between chromosome 3-loss and chromosome 6p-gain melanomas may provide new knowledge about the biologic nature of choroidal melanoma and may contribute to the development of targeted therapies.

Novel KRIT1/CCM1 mutation in a patient with retinal cavernous hemangioma and cerebral cavernous malformation.

BACKGROUND: Retinal cavernous hemangiomas are rare vascular anomalies, and can be associated with cerebral cavernous malformations (CCM). Distinct mutations have been reported in patients who have both CCMs and retinal cavernous hemangiomas. METHODS: Fluorescein angiography, spectral domain optical coherence tomography, and genetic testing were performed on a patient with a retinal cavernous hemangioma and a CCM. RESULTS: Our patient was heterozygous in the KRIT1/CCM1 gene for a frameshift mutation, c.1088delC. This would be predicted to result in premature protein termination. DISCUSSION: We have identified a novel mutation in the KRIT1/CCM1 gene in a patient with both CCM and retinal cavernous hemangioma. We hypothesize that the occurrence of retinal cavernous hemangiomas and CCMs is underlaid by a common mechanism present in the KRIT1/CCM1 gene.

Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma.

PURPOSE: Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. EXPERIMENTAL DESIGN: Autologous DC were pulsed with MART-1(26-35) peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. RESULTS: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. CONCLUSION: The combination of MART-1 peptide-pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.

Reactions to and desire for prognostic testing in choroidal melanoma patients.

To determine if choroidal melanoma patients want cytogenetic prognostic information. Ninety-nine choroidal melanoma patients completed a questionnaire regarding their opinions about receiving prognostic information. The perceived usefulness of prognostic information was evaluated in patients who had undergone cytogenetic testing. Depressive symptoms, quality of life, and interest in supportive counseling during test receipt were assessed. Ninety-seven percent of respondents reported that they would have wanted prognostic information at the time of their treatment and 98% of respondents reported that supportive counseling should be offered when prognostic information is given. Patients who had received a more favorable prognostic result were more likely to endorse the usefulness of cytogenetic testing than were patients who had received a less favorable prognostic result. Psychological status did not vary significantly as a function of cytogenetic test result. Prognostic information was important to patients with choroidal melanoma, even in the absence of prophylactic measures which might improve prognosis.

Assessment of central vision and macular structure in patients undergoing iodine-125 brachytherapy for ciliochoroidal melanoma.

OBJECTIVES: To prospectively report standardized visual function and macular structural assessment in patients undergoing iodine-125 brachytherapy for choroidal and ciliary body melanoma. MATERIALS AND METHODS: Patients were enrolled for pretreatment and annual posttreatment assessment. Evaluations included ophthalmic history; standardized refraction; visual acuity, contrast sensitivity, and color vision measurement; comprehensive ophthalmic examination; fundus photography; fluorescein angiography; optical coherence tomography; and ultrasonography. Radiation doses to the foveola and optic disc margin were calculated. RESULTS: Forty-two patients were enrolled. Melanoma location included 3 in the ciliary body, 7 anterior, 11 equatorial, 13 posterior, and 8 macular tumors. Mean apical tumor height was 4.45 mm (range 1.79-9.83 mm) and mean longitudinal tumor diameter was 9.41 mm (range 4.52-4.73 mm). Pretreatment mean best-corrected Ferris-Bailey early treatment diabetic retinopathy study visual acuity was 50 (standard deviation +/- 15) letters (Snellen equivalent 20/32, range 20/15 to hand motions). The mean Pelli-Robson contrast threshold percentage was 4.1% (+/- 2.5%). The mean Hardy-Rand-Rittler color vision score was 13/14 (+/- 2.7). Mean distances from the posterior edge of the tumor to the foveola and the optic disc margin were 6.99 mm (+/- 6.22 mm) and 7.28 mm (+/- 5.98 mm), respectively. At the foveola, median total radiation dose was 36.2 Gy (+/-50.6 Gy) and median dose rate was 31.6 cGy/h (+/- 39.8 cGy/h). At the optic nerve, median total radiation dose was 42.8 Gy (+/- 30.8 Gy) and median dose rate was 36.2 cGy/h (+/- 21.4 cGy/h). CONCLUSION: This prospective assessment of macular structure and function will provide more complete understanding of the ocular effects of radiation therapy for ocular melanoma.