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Purpose Race-adjusted interpretation of data from Cirrus high-definition OCT (HD-OCT) devices is not standard practice. The aim of this study is to evaluate differences in peripapillary retinal nerve fiber layer (RNFL) thickness between healthy Black Americans and the Cirrus HD-OCT normative database. Design This is a cross-sectional observational study using control patients recruited from the greater Philadelphia, Pennsylvania, area. Participants A total of 466 eyes were included in this study. Subjects were retrospectively identified from the control cohort of the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. Methods Using an age-stratified or linear regression method, we reclassified white-green-yellow-red color probability codes for RNFL thicknesses by quadrant. Main Outcome Measures The distribution of reclassified color codes was compared with the expected 5%-90%-4%-1% percentiles and to the original color codes by the Cirrus machine. Results Average RNFL thickness in the POAAGG control cohort was thinner than in the Cirrus normative database in all except the nasal quadrant. The original color codes of the POAAGG cohort did not fall into the expected distributions, with more RNFL measurements assigned as white and red codes than expected (9.5% and 1.7%) and fewer measurements assigned as green and yellow codes than expected (85.3% and 3.5%) (P Conclusions Results further establish the presence of structural differences in the RNFL of Black American patients. Color code reclassification suggests that the existing Cirrus database may not be accurately evaluating glaucomatous nerves in patients of African descent. This study addresses an unmet need to assess Cirrus HD-OCT color probability codes in a Black American population.

Topic Visual impairment (VI) and cognitive impairment (CIM) are prevalent age-related conditions that impose substantial burden on the society. Findings on the hypothesized bidirectional association of VI and CIM remains equivocal. Hence, we conducted a systematic review and meta-analysis to examine this bidirectional relationship. Clinical Relevance Sixty percent risk of CIM has not been well elucidated in the literature. A bidirectional relationship between VI and CIM may support the development of strategies for early detection and management of risk factors for both conditions in older people. Methods PubMed, Embase, and Cochrane Central registers were searched systematically for observational studies, published from inception until April 6, 2020, in adults 40 years of age or older reporting objectively measured VI and CIM assessment using clinically validated cognitive screening tests or diagnostic evaluation. Meta-analyses on cross-sectional and longitudinal associations between VI and CIM outcomes (any CIM assessed using screening tests and clinically diagnosed dementia) were examined. Random effect models were used to generate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We also examined study quality, publication bias, and heterogeneity. Results Forty studies were included (n = 47 913 570). Meta-analyses confirmed that persons with VI were more likely to have CIM, with significantly higher odds of: (1) any CIM (cross-sectional: OR, 2.38 [95% CI, 1.84–3.07]; longitudinal: OR, 1.66 [95% CI, 1.46–1.89]) and (2) clinically diagnosed dementia (cross-sectional: OR, 2.43 [95% CI, 1.48–4.01]; longitudinal: OR, 2.09 [95% CI, 1.37–3.21]) compared with persons without VI. Significant heterogeneity was explained partially by differences in age, sex, and follow-up duration. Also, some evidence suggested that individuals with CIM, relative to cognitively intact persons, were more likely to have VI, with most articles (8/9 [89%]) reporting significantly positive associations; however, meta-analyses on this association could not be conducted because of insufficient data. Discussion Overall, our work suggests that VI is a risk factor of CIM, although further work is needed to confirm the association of CIM as a risk factor for VI. Strategies for early detection and management of both conditions in older people may minimize individual clinical and public health consequences.

Purpose: To investigate the association of quality of life (QoL) with ocular structure and function in glaucoma patients, and to identify which aspects of QoL are most closely tied to Visual Field (VF) and Visual Acuity (VA).Methods: We conducted a comprehensive review of studies on QoL in glaucoma patients using PubMed, Web of Science, and Google Scholar (from 1 January 1997 to 7 December 2019). A total of 21 studies in the United States that used the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ) or 51-item NEI VFQ were included. A descriptive analysis of data from the selected studies was conducted. The association between QoL scores and visual function and structure was investigated by ranking the strength of association on a scale from 1 (weakest) to 12 (strongest).Results: Studies reported correlations between QoL scores and Visual Structure. Associations were also reported between QoL and Visual Function both cross-sectionally and longitudinally, with a stronger association of VF and VA with distance activities (average ranking 9.1 and 9.6), vision-specific dependency (8.7 and 8.9), and driving (8.6 and 9.7). Vision-specific mental health (6.5 and 4.9), vision-specific social functioning (8.4 and 6.2), and vision-specific role difficulties (7.1 and 6.6) domains were more associated with VF than with VA.Conclusion: Our study was the first to quantify and rank the strength of association between visual function and QoL domains. Driving and psycho-social QoL domains tended to be most affected by glaucoma-related deterioration of visual function. QoL scores could be used for more patient-centered disease management.

Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects African Americans. Large-scale POAG genetic studies have focused on individuals of European and Asian ancestry, limiting our understanding of disease biology. Here we report genetic analysis of the largest-ever deeply phenotyped African American population (n=5950), identifying a novel POAG-associated SNP on chromosome 11 near the TRIM66 gene (rs112369934). POAG trait association also implicated SNPs in genes involved in trabecular meshwork homeostasis and retinal ganglion cell maintenance. These new loci deepen our understanding of the pathophysiology of POAG in African Americans.

We investigated the association of the single nucleotide polymorphism (SNP) rs112369934 near the TRIM66 gene with qualitative and quantitative phenotypes of primary open-angle glaucoma (POAG) in African Americans (AA). AA subjects over 35 years old were recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study in Philadelphia, PA. Glaucoma cases were evaluated for phenotypes associated with POAG pathogenesis, and the associations between rs112369934 and phenotypes were investigated by logistic regression analysis and in gender-stratified case cohorts: The SNP rs112369934 was found to have a suggestive association with retinal nerve fiber layer (RNFL) thickness and cup-to-disc ratio (CDR) in 1087 male AA POAG cases, individuals with the TC genotype having thinner RNFL (95% CI 0.85 to 6.61, p = 0.01) and larger CDR (95% CI −0.07 to −0.01, p = 0.02) than those with wildtype TT. No other significant associations were found. In conclusion SNP rs112369934 may play a role in POAG pathogenesis in male AA individuals. However, this SNP has been implicated in higher POAG risk in both male and female AA POAG cases.

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide and has been associated with multiple genetic risk factors. The LMX1B gene is a genetic susceptibility factor for POAG, and several single-nucleotide polymorphisms (SNPs) were shown to be associated with POAG in our own prior Primary Open-Angle African American Glaucoma Genetics (POAAGG) study genome-wide association study (GWAS). This study evaluated the association of the LMX1B locus with baseline optic disc and clinical phenotypic characteristics of glaucoma patients from our African American cohort. Compared to the GG genotype in SNP rs187699205, the GC genotype in this SNP was found to be significantly associated with a smaller cup-to-disc ratio (CDR) and increased (better) visual field mean deviation (MD) in glaucoma cases. None of the glaucoma cases with the GC genotype had disc hemorrhages, disc notching, or beanpot disc appearance. In conclusion, glaucoma phenotypes differed significantly by LMX1B variant in African American patients with POAG, and a SNP variant was associated with certain disease features considered lower risk.

Objective: African Americans have been historically underrepresented in research studies. Our aim was to evaluate factors influencing enrollment in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. Design: Patients approached to enroll in the POAAGG study were asked to complete a 15-item survey addressing demographic characteristics, knowledge of genetics and glaucoma, and opinions on human research. Survey responses were compared between subjects who enrolled (Enrollers) and did not enroll (Decliners) in the POAAGG study. Results: Enrollers (N = 190) were 3.7 years younger (P = 0.007) and had similar gender, education, and income level to Decliners (N = 117). Knowledge about genetics and glaucoma was similar between groups. Enrollers were more comfortable providing DNA for research studies (93.1% vs 54.1%; P

Retinoblastoma (RB) is an inherited retinal disorder (IRD) caused by the mutation in the RB1 gene or, rarely, by alterations in the MYCN gene. In recent years, new treatment advances have increased ocular and visual preservation in the developed world. The management of RB has improved significantly in recent decades, from the use of external beam radiation to recently, more localized treatments. Determining the underlying genetic cause of RB is critical for timely management decisions. The advent of next-generation sequencing technologies have assisted in understanding the molecular pathology of RB. Liquid biopsy of the aqueous humor has also had significant potential implications for tumor management. Currently, patients’ genotypic information, along with RB phenotypic presentation, are considered carefully when making treatment decisions aimed at globe preservation. Advances in molecular testing that improve our understanding of the molecular pathology of RB, together with multiple directed treatment options, are critical for developing precision medicine strategies to treat this disease.

Background Eyes with Group D intraocular retinoblastoma have low salvage rates. A pilot study showed safety and efficacy of sub-Tenon's fascia carboplatin with systemic chemotherapy supporting further study. Methods Children with newly diagnosed bilateral intraocular retinoblastoma with at least one remaining Group C or D eye were treated with six courses of carboplatin/etoposide/vincristine (CEV) with sub-Tenon's fascia carboplatin for Group C/D eyes during courses 2-4. Local ophthalmic therapy started at course 3. The primary study objective was to determine the 1-year failure rate of Group D eyes. Results The study closed prematurely due to poor accrual and 22 of 30 patients were evaluable for failure rate, contributing 25 Group D and four Group C eyes. Among the 25 Group D eyes, there were 13 failures within the first year of study enrollment including eight needing external beam radiotherapy (EBR) and five needing enucleation, resulting in 1-year failure rate of 52%. The failure rate was significantly lower than the historical rate of 70% (P = .039). The 1-year eye preservation rate for Group D eyes was 80% (20/25). One-year failure rate for Group C eyes was 25% (1/4); 1-year preservation rate was 100% without need for EBR. Systemic toxicity included Grade 3 hearing loss in two subjects, infections, neutropenia, and thrombocytopenia. Ocular toxicities included periorbital fat atrophy (13/29 = 45% eyes), optic nerve atrophy (1/29 = 3% eyes), and restrictive fibrosis (1/29 = 3% eyes). Conclusions Sub-Tenon's fascia carboplatin plus CEV was partially effective in Group D intraocular retinoblastoma but had unacceptable ocular toxicities.

OBJECTIVE: To introduce a new method of grading optic nerve stereo disc photographs and evaluate reproducibility of assessments by non-physician graders in a reading center. METHODS: Three non-physician graders, experienced in grading features of the retina but not the optic nerve head (ONH), were trained by glaucoma specialists to assess digital stereo color images of the ONH. These graders assessed a total of 2554 digital stereo disc images from glaucoma cases and controls participating in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study by outlining the optic cup and disc. Inter-grader reproducibility of area, height, and width measurements was analyzed. RESULTS: Among all images, the intraclass correlation (95% confidence interval) was 0.90 (0.89, 0.90) for the cup area using only color cues; 0.92 (0.91, 0.92) for the cup area using contour and vascular cues; and 0.99 (0.99, 0.99) for the optic disc area. The intraclass correlation for cup-to-disc ratio (CDR) was 0.61 (0.58, 0.63), as determined by the ratio of optic cup area to optic disc area (using contour and vascular cues). The CDR difference by graders for area was ≤ 0.1 in 65% of images using color/vascular cues and ≤0.1 in 71% of images using color cues. CONCLUSIONS: After adequate training, non-physician graders were able to measure the optic nerve CDR with high inter-grader reliability.

Highlights • Campaigns can recruit African Americans to glaucoma screenings and studies. • Marketing with community partners successfully reached the target audience. • Radio commercials and postcards were most cost-effective in recruiting patients., Our objective was to determine which messaging approaches from a marketing campaign were most effective in recruiting African American individuals to a glaucoma screening and research study. We conducted a multimedia marketing campaign in Philadelphia from 01/31/2018 to 06/30/2018. Messaging approaches included radio advertisements and interviews (conducted in partnership with a local radio station with a large African American listener base), print materials, event tables, and online postings. Participants received free glaucoma screenings and the opportunity to enroll in our glaucoma genetics study. These screenings allowed individuals with glaucoma to receive a full examination and treatment plan with a glaucoma specialist, as well as to contribute to future efforts to identify genetic variants underlying this disease. We compared inquiry, enrollment, and cost yield for each messaging approach. Our campaign resulted in 154 unique inquiries, with 98 patients receiving glaucoma screenings (64%) and 60 patients enrolling in our study (39%). Commercials on WURD radio yielded the highest number of inquiries (62%) and enrollments (62%), but at relatively high cost ($814/enrolled patient). The most inexpensive approach that yielded more than five enrollments was postcards ($429/enrolled patient). Our campaign suggests that high-frequency commercials and postcards distributed at targeted healthcare locations are particularly effective and affordable options for connecting with the African American community. Our findings can help to inform recruitment efforts for other understudied diseases in minority populations.

The purpose of this study was to investigate the association between gender and primary open-angle glaucoma (POAG) among African Americans and to assess demographic, systemic, and behavioral factors that may contribute to differences between genders. The Primary Open-Angle African American Glaucoma Genetics (POAAGG) study had a case-control design and included African Americans 35 years and older, recruited from the greater Philadelphia, Pennsylvania. Diagnosis of POAG was based on evidence of both glaucomatous optic nerve damage and characteristic visual field loss. Demographic and behavioral information, history of systemic diseases and anthropometric measurements were obtained at study enrollment. Gender differences in risk of POAG were examined using multivariate logistic regression. A total of 2,290 POAG cases and 2,538 controls were included in the study. The percentage of men among cases was higher than among controls (38.6% vs 30.3%, P

The 2018 Ocular Oncogenesis and Oncology Conference was held through a partnership of the Association for Research in Vision and Ophthalmology (ARVO) and the Champalimaud Foundation. Twenty-one experts from international ocular oncology centers, from the Champalimaud Clinical Centre and the Champalimaud Foundation Cancer Research Program, and from patient advocacy organizations, delivered lectures on subjects that ranged from global ocular oncology, to basic research in mechanisms of ocular malignancy, to clinical research in ocular cancers, and to anticipated future developments in the area. The scientific program of the conference covered a broad range of ocular tumors-including uveal melanoma, retinoblastoma, ocular surface tumors, and adnexal and intraocular lymphomas-and pathogenesis and management were deliberated in the context of the broader systemic cancer discipline. In considering the latest basic and clinical research developments in ocular oncogenesis and oncology, and providing the opportunity for cross-talk between ocular cancer biologists, systemic cancer biologists, ocular oncologists, systemic oncologists, patients, and patient advocates, the forum generated new knowledge and novel insights for the field. This report summarizes the content of the invited talks at the 2018 ARVO-Champalimaud Foundation Ocular Oncogenesis and Oncology Conference.

To determine the relationship between positive family history (FH) and primary open-angle glaucoma (POAG) diagnosis and clinical presentation in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) cohort.FH of POAG in first-degree relatives was assessed in 2365 subjects in the POAAGG cohort. A standardized interview was used to assess FH of glaucoma, demographic characteristics, lifestyle choices, and medical and ocular comorbidities.Positive FH was associated with increased risk of POAG (age-adjusted odds ratio and 95% confidence interval 3.4 [2.8, 4.1]). In age-adjusted analysis among POAG cases, positive FH was associated with younger age (P.001), female sex (P.001), hypertension (P = .006), use of hypertension medication (P = .03), and prior glaucoma surgery (P = .02). Cases with positive FH also had thicker retinal nerve fiber layers (P = .03).The risk conferred by positive FH suggests strong genetic underpinnings for some patients with this disease, which will be investigated by genome-wide association studies and whole exome sequencing. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Purpose To describe the baseline characteristics of the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study cohort, the largest African American population with primary open-angle glaucoma (POAG) recruited at a single institution (University of Pennsylvania [UPenn], Department of Ophthalmology, Scheie Eye Institute) to date. Design Population-based, cross-sectional, case-control study. Participants A total of 2520 African American subjects aged 35 years or more who were recruited from the greater Philadelphia, Pennsylvania area. Methods Each subject underwent a detailed interview and eye examination. The interview assessed demographic, behavioral, medical, and ocular risk factors. Current ZIP codes surrounding UPenn were recorded and US census data were queried to infer socioeconomic status. The eye examination included measurement of visual acuity (VA) and intraocular pressure, and a detailed anterior and posterior segment examination, including gonioscopy, dilated fundus and optic disc examination, visual fields, stereo disc photography, optical coherence tomography, and measurement of central corneal thickness. Main Outcome Measures The baseline characteristics of gender, age, and glaucoma diagnosis were collected. Body mass index (BMI), hypertension, diabetes, alcohol and tobacco use, ocular conditions (including blindness, cataract, nonproliferative diabetic retinopathy, and age-related macular degeneration), and use of ocular medication and surgery were examined. Median population density, income, education level, and other socioeconomic measures were determined for the study cohort. Results Of the 2520 African Americans recruited to the POAAGG study to date, 2067 (82.0%), including 807 controls and 1260 POAG cases, met all inclusion criteria and completed the detailed clinical ocular examination. Cases were more likely to have a lower BMI ( P P P P = 0.02), and be female ( P Conclusions The POAAGG study has currently recruited more than 2000 African Americans eligible for a POAG genetics study. Blindness and low BMI were significantly associated with POAG. This population was predominantly recruited from neighborhoods whose population income exists at or near the federal poverty level.

The authors describe a case of presumed endogenous fungal endophthalmitis in an immunocompetent pediatric patient with acute lymphoblastic leukemia. A 15-year-old boy with a history of high-risk B-cell acute lymphoblastic leukemia status post-chemotherapy presented with acute changes in vision in his left eye. Fundus examination revealed a white bi-lobed chorioretinal lesion with overlying vitritis and associated subretinal fluid. Magnetic resonance imaging of the brain revealed small ring-enhancing lesions in the right parietal and left occipital lobes. Blood, cerebrospinal fluid, aqueous, and vitreous cultures were all negative. Bone marrow and vitreous cytology were negative for malignant cells. The patient was treated for presumed fungal endophthalmitis with systemic and intravitreal voriconazole, followed by pars plana vitrectomy with intravitreal voriconazole and amphotericin B injections. The chorioretinal lesion resolved and visual acuity recovered to 20/20. Chorioretinal infiltrates in a patient with leukemia may require treatment even in the absence of a definitive diagnostic test result. Intervention should be guided by risk analysis and clinical judgment. [ J Pediatr Ophthalmol Strabismus. 2017;54:e42–e46.]

Primary open-angle glaucoma (POAG) is a genetically, physiologically, and phenotypically complex neurodegenerative disorder. This study addressed the expanding collection of genes associated with POAG, referred to as the "POAGome." We used bioinformatics tools to perform an extensive, systematic literature search and compiled 542 genes with confirmed associations with POAG and its related phenotypes (normal tension glaucoma, ocular hypertension, juvenile open-angle glaucoma, and primary congenital glaucoma). The genes were classified according to their associated ocular tissues and phenotypes, and functional annotation and pathway analyses were subsequently performed. Our study reveals that no single molecular pathway can encompass the pathophysiology of POAG. The analyses suggested that inflammation and senescence may play pivotal roles in both the development and perpetuation of the retinal ganglion cell degeneration seen in POAG. The TGF-β signaling pathway was repeatedly implicated in our analyses, suggesting that it may be an important contributor to the manifestation of POAG in the anterior and posterior segments of the globe. We propose a molecular model of POAG revolving around TGF-β signaling, which incorporates the roles of inflammation and senescence in this disease. Finally, we highlight emerging molecular therapies that show promise for treating POAG.

Background African Americans have been historically under-represented in genetic studies. More research is needed on effective recruitment strategies for this population, especially on approaches that supplement traditional clinic enrollment. This study evaluates the cost and efficacy of four supplemental recruitment methods employed by the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. Methods After enrolling 2304 patients from University of Pennsylvania ophthalmology clinics, the POAAGG study implemented four new recruitment methods to supplement clinic enrollment. These methods included: 1) outreach in the local community, 2) in-house screening of community members (“in-reach”), 3) expansion to two external sites, and 4) sampling of the Penn Medicine Biobank. The cost per subject was calculated for each method and enrollment among cases, controls, and suspects was reported. Results The biobank offered the lowest cost ($5/subject) and highest enrollment yield (n = 2073) of the four methods, but provided very few glaucoma cases (n = 31). External sites provided 88% of cases recruited from the four methods (n = 388; $85/subject), but case enrollment at these sites declined over the next 9 months as the pool of eligible subjects was depleted. Outreach and in-reach screenings of community members were very high cost for low return on enrollment ($569/subject for 102 subjects and $606/subject for 45 subjects, respectively). Conclusions The biobank offered the most cost-effective method for control enrollment, while expansion to external sites was necessary to recruit richly phenotyped cases. These recruitment methods helped the POAAGG study to exceed enrollment of the discovery cohort (n = 5500) 6 months in advance of the predicated deadline and could be adopted by other large genetic studies seeking to supplement clinic enrollment.

Objective: No method of grading visual field (VF) defects has been widely accepted throughout the glaucoma community. The SCHEIE (Systematic Classification of Humphrey visual fields-Easy Interpretation and Evaluation) grading system for glaucomatous visual fields was created to convey qualitative and quantitative information regarding visual field defects in an objective, reproducible, and easily applicable manner for research purposes.Methods: The SCHEIE grading system is composed of a qualitative and quantitative score. The qualitative score consists of designation in one or more of the following categories: normal, central scotoma, paracentral scotoma, paracentral crescent, temporal quadrant, nasal quadrant, peripheral arcuate defect, expansive arcuate, or altitudinal defect. The quantitative component incorporates the Humphrey visual field index (VFI), location of visual defects for superior and inferior hemifields, and blind spot involvement. Accuracy and speed at grading using the qualitative and quantitative components was calculated for non-physician graders.Results: Graders had a median accuracy of 96.67% for their qualitative scores and a median accuracy of 98.75% for their quantitative scores. Graders took a mean of 56 seconds per visual field to assign a qualitative score and 20 seconds per visual field to assign a quantitative score.Conclusion: The SCHEIE grading system is a reproducible tool that combines qualitative and quantitative measurements to grade glaucomatous visual field defects. The system aims to standardize clinical staging and to make specific visual field defects more easily identifiable. Specific patterns of visual field loss may also be associated with genetic variants in future genetic analysis.

A man in his 60s with a history of hypertension, proliferative diabetic retinopathy, andprimaryopen-angleglaucomapresentedwith 6monthsof right-sidedbloodytearing.Examinationrevealeda7mm ×5mmpedunculatedmassextendingfromtheconjunctivaoftheright superolateral fornix (Figure).The lesionresembledapyogenicgranuloma; however, histopathological analysis was positive for markers characteristicofmelanoma—S100andMelan-A.Theconjunctivaoverlying the lesion showednoevidenceof aprecursor lesion suchasprimary acquiredmelanosis, so the possibility ofmetastasis to this site was explored. The patient underwent dermatological examination, whole-body positron emission tomography and computed tomography scans, colonoscopy, and orbital magnetic resonance imaging, fromwhichnootherprimarymucocutaneousmelanomalesionswere found. The patient was scheduled for additional excision with wide margins, cryotherapy for residual disease, and amniotic membrane grafting to prevent scar tissue formation.

To compare the diagnostic value of magnetic resonance (MR) imaging and ophthalmoscopy for staging of retinoblastoma. MR and ophthalmoscopic images of 36 patients who underwent enucleation were evaluated retrospectively following institutional review board approval. Histopathology being the standard of reference, the sensitivity and specificity of both diagnostic modalities were compared regarding growth pattern, iris neoangiogenesis, retinal detachment, vitreous seeds and optic nerve invasion. Data were analysed via McNemar’s test. Both investigations showed no significant difference in accuracy for the detection of different tumour growth patterns (P = 0.80). Vitreous seeding detection was superior by ophthalmoscopy (P

Purpose We investigate the function of the V83I polymorphism (m.6150G>A, rs879053914) in the mitochondrial cytochrome c oxidase subunit 1 (MT-CO1) gene and its role in African American (AA) primary open-angle glaucoma (POAG). Methods This study used Sanger sequencing (1339 cases, 850 controls), phenotypic characterization of Primary Open-Angle African American Glaucoma Genetics study (POAAGG) cases, a masked chart review of CO1 missense cases (V83I plus M117T, n = 29) versus wild type cases (n = 29), a yeast 2-hybrid (Y2H) cDNA library screen, and quantification of protein–protein interactions by Y2H and ELISA. Results The association of V83I with POAG in AA was highly significant for men (odds ratio [OR] 6.5; 95% confidence interval [CI] 2.0–21.3, P = 0.0001), but not for women (OR 1.1; 95% CI, 0.62–2.00, P = 0.78). POAG cases having CO1 double missense mutation (V83I + M117T, L1c2 haplogroup) had a higher cup-to-disc ratio (0.77 vs. 0.71, P = 0.04) and significantly worse visual function (average pattern standard deviation, 6.5 vs. 4.3, P = 0.009; average mean deviation −10.4 vs. −4.5, P = 0.006) when compared to matched wild type cases (L1b haplogroup). Interaction of the V83I region of CO1 with amyloid beta peptide (Aβ) was confirmed by ELISA assay, and this interaction was abrogated by V83I. A Y2H screen of an adult human brain cDNA library with the V83 region of CO1 as bait retrieved the UBQLN1 gene. Conclusions The V83I polymorphism was associated strongly with POAG in AA men and disrupts Aβ-binding to CO1. This region also interacts with a neuroprotective protein, UBQLN1.

BACKGROUND Uveal melanoma is the most common intraocular cancer. There are no effective therapies for metastatic disease. Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas. METHODS We sequenced exon 5 of GNAQ and GNA11, a paralogue of GNAQ, in 713 melanocytic neoplasms of different types (186 uveal melanomas, 139 blue nevi, 106 other nevi, and 282 other melanomas). We sequenced exon 4 of GNAQ and GNA11 in 453 of these samples and in all coding exons of GNAQ and GNA11 in 97 uveal melanomas and 45 blue nevi. RESULTS We found somatic mutations in exon 5 (affecting Q209) and in exon 4 (affecting R183) in both GNA11 and GNAQ, in a mutually exclusive pattern. Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. In contrast, we observed Q209 mutations in GNAQ in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases. Mutations affecting R183 in either GNAQ or GNA11 were less prevalent (2% of blue nevi and 6% of uveal melanomas) than the Q209 mutations. Mutations in GNA11 induced spontaneously metastasizing tumors in a mouse model and activated the mitogen-activated protein kinase pathway. CONCLUSIONS Of the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11. Constitutive activation of the pathway involving these two genes appears to be a major contributor to the development of uveal melanoma. (Funded by the National Institutes of Health and others.).

Background Trilateral retinoblastoma has been lethal in virtually all cases previously reported. We describe a series of 13 patients treated with intensive chemotherapy, defined as the intention to include high-dose chemotherapy with autologous hematopoietic stem cell rescue. Procedure Induction chemotherapy generally included vincristine, cisplatin or carboplatin, cyclophosphamide, and etoposide. Hematopoietic stem cells typically were harvested after the first or second cycle of induction chemotherapy, usually from peripheral blood. High-dose chemotherapy regimens were thiotepa-based (n = 7) or melphalan and cyclophosphamide (n = 3). Results Trilateral sites were pineal (n = 11) and suprasellar (n = 2); 7 patients had localized (M-0) disease and six had leptomeningeal dissemination (M-1+). Five patients had trilateral retinoblastoma at original diagnosis of intra-ocular retinoblastoma; eight later developed trilateral disease at a median of 35 months (range 3–60 months) following diagnosis of intra-ocular retinoblastoma. One patient died of toxicity (septicemia and multi-organ system failure) during induction and three developed disease progression prior to high-dose chemotherapy. Nine patients received high-dose chemotherapy at a median of 5 months (range 4–9) post-diagnosis of trilateral disease. Five patients survive event-free at a median of 77 months (range 36–104 months) and never received external beam radiation therapy. Four of seven patients with M-0 disease survive event-free versus only one of six patients with M-1+ disease. Conclusions Intensive chemotherapy is potentially curative for some patients with trilateral retinoblastoma, especially those with M-0 disease Pediatr Blood Cancer 2010;54:384–387. © 2009 Wiley-Liss, Inc.

Retinoblastoma is curable when diagnosed early and treated appropriately; however, the prognosis is dismal when the basic elements of diagnosis and treatment are lacking. In developing countries, poor education, lower socioeconomic conditions, and inefficient health care systems result in delayed diagnosis and suboptimal care. Furthermore, the complexity of multidisciplinary care required is seldom possible. Whereas ocular salvage is a priority in the Western world, death from retinoblastoma is still a major problem in developing countries. To bring the 2 ends of this spectrum together and provide a forum for discussion, the “One World, One Vision” symposium was organized, at which clinicians and researchers from various cultural, geographic, and socioeconomic backgrounds converged to discuss their experiences. Strategies for early diagnosis in developing countries were discussed. Elements of the development of retinoblastoma centers in developing countries were discussed, and examples of successful programs were highlighted. An important component in this process is twinning between centers in developing countries and mentor institutions in high-income countries. Global initiatives by nongovernmental organizations such as the International Network for Cancer Treatment and Research, Orbis International, and the International Agency for Prevention of Blindness were presented. Treatment of retinoblastoma in developing countries remains a challenge; however, it is possible to coordinate efforts at multiple levels, including public administrations and nonprofit organizations, to improve the diagnosis and treatment of retinoblastoma and to improve the outcome for these children.

PurposeWe previously determined that intravenous administration of rituximab results in limited penetration of this agent into the leptomeningeal space. Systemic rituximab does not reduce the risk of CNS relapse or dissemination in patients with large cell lymphoma. We therefore conducted a phase I dose-escalation study of intrathecal rituximab monotherapy in patients with recurrent CNS non-Hodgkin's lymphoma (NHL).Patients and MethodsThe protocol planned nine injections of rituximab (10 mg, 25 mg, or 50 mg dose levels) through an Ommaya reservoir over 5 weeks. The safety profile of intraventricular rituximab was defined in 10 patients.ResultsThe maximum tolerated dose was determined to be 25 mg and rapid craniospinal axis distribution was demonstrated. Cytologic responses were detected in six patients; four patients exhibited complete response. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. High RNA levels of Pim-2 and FoxP1 in meningeal lymphoma cells were associated with disease refractory to rituximab monotherapy.ConclusionThese results suggest that intrathecal rituximab (10 to 25 mg) is feasible and effective in NHL involving the CNS.

Purpose To evaluate a chemoreduction regimen using systemic vincristine and carboplatin (VC) and local ophthalmic therapies to avoid external-beam radiotherapy (EBRT) or enucleation in patients with Group B intraocular retinoblastoma. Patients and methods Twenty-one patients (25 eyes) were treated with six cycles of VC, accompanied by local ophthalmic therapies after cycle 1. The primary study objective was to determine the 2-year event-free survival (EFS) where an event was defined as the use of systemic chemotherapy in addition to vincristine or carboplatin, EBRT, and/or enucleation. Results All patients had tumor regression after the first cycle of VC and only two patients had progression during therapy. There were seven treatment failures within 2 years of study enrollment, resulting in 2-year EFS of 65% and early study closure in accordance with the statistical design. The 2-year cumulative incidence of enucleation was 15%; for external beam radiation therapy, it was 10%; and for chemotherapy to control progressive disease, it was 10%. All patients sustaining a treatment failure were salvaged with additional therapy. Conclusions For the majority of patients with Group B intraocular retinoblastoma, chemoreduction with VC, without etoposide, in conjunction with local therapy provides excellent opportunity for ocular salvage. Local therapy given with every chemotherapy cycle and incorporation of etoposide may provide improved ocular salvage rates. Central review of group at diagnosis is critical in assigning appropriate therapies.

Objective: To identify the major risk factors for primary open-angle glaucoma (POAG) in individuals of African descent. Methods: We searched PubMed for relevant articles, with results spanning April 1947 to present. All abstracts were reviewed and, where relevant to POAG and race, articles were catalogued and analyzed. Additional sources were identified through citations in articles returned by our search. Results: Numerous potential POAG risk factors were identified and organized into categories by demographics (age, sex, and skin color), lifestyle choices (smoking, alcohol), comorbidities (hypertension, diabetes, and obesity), ophthalmic findings (eye structure, central corneal thickness, corneal hysteresis, elevated intraocular pressure, myopia, cataract, and vascular abnormalities), family history, socioeconomic status, and adherence. Older age, male sex, lower central corneal thickness, decreased corneal hysteresis, elevated intraocular pressure, myopia, vascular abnormalities, and positive family history were definitively associated with increased risk of POAG. Conclusions: Individuals at greatest risk for POAG should be screened by an ophthalmologist to allow earlier detection and to slow disease progression. Further studies on the genetics of the disease will provide more insight into underlying pathologic mechanisms and could lead to improved therapeutic interventions. Continued research in urban areas with large populations of blacks is especially needed.

An 80-year-old monocular patient presented with progressively worsening vision in his right eye. He was noted to have choroidal metastasis in this eye and was subsequently admitted for a thorough work-up per oncology to find a primary tumor. After whole body imaging was completed, he was found to have hepatocellular carcinoma proven histopathologically from liver biopsy. He was treated with external beam radiation therapy and his visual acuity and imaging at one-month follow-up showed no improvement. This case highlights the interesting relation between two highly vascular organs – the liver and the choroid - and the diagnostic challenge that exists with choroidal metastases from an unknown primary tumor. It also underscores the need for additional studies to determine whether primary tumor type affects therapeutic management and prognosis.

This letter is in response to the case published last month in your journal: “A Case of Choroidal Metastasis Determined to be Hepatocellular Carcinoma” for which I was the primary author. As it was noted in this publication, hepatocellular carcinoma (HCC).

The aim of this study is to (1) compare the delineation of the tumor volume for ocular melanoma on high-resolution three-dimensional (3D) T2-weighted fast spin echo magnetic resonance imaging (MRI) images with conventional techniques of A- and B-scan ultrasound, transcleral illumination, and placement of tantalum markers around tumor base and (2) to evaluate whether the surgically placed marker ring tumor delineation can be replaced by 3D MRI based tumor delineation. High-resolution 3D T2-weighted fast spin echo (3D FSE) MRI scans were obtained for 60 consecutive ocular melanoma patients using a 1.5 T MRI (GE Medical Systems, Milwaukee, WI), in a standard head coil. These patients were subsequently treated with proton beam therapy at the UC Davis Cyclotron, Davis, CA. The tumor was delineated by placement of tantalum rings (radio-opaque markers) around the tumor periphery as defined by pupillary transillumination during surgery. A point light source, placed against the sclera, was also used to confirm ring agreement with indirect ophthalmoscopy. When necessary, intraoperative ultrasound was also performed. The patients were planned using EYEPLAN software and the tumor volumes were obtained. For analysis, the tumors were divided into four categories based on tumor height and basal diameter. In order to assess the impact of high-resolution 3D T2 FSE MRI, the tumor volumes were outlined on the MRI scans by two independent observers and the tumor volumes calculated for each patient. Six (10%) of 60 patients had tumors, which were not visible on 3D MRI images. These six patients had tumors with tumor heights < or = 3 mm. A small intraobserver variation with a mean of (-0.22 +/- 4)% was seen in tumor volumes delineated by 3D T2 FSE MR images. The ratio of tumor volumes measured on MRI to EYEPLAN for the largest to the smallest tumor volumes varied between 0.993 and 1.02 for 54 patients. The tumor volumes measured directly on 3D T2 FSE MRI ranged from 4.03 to 0.075 cm3. with a mean of 0.87 +/- 0.84 cm3. The tumor shapes obtained from 3D T2 FSE MR images were comparable to the tumor shapes obtained using EYEPLAN software. The demonstration of intraocular tumor volumes with the high-resolution 3D fast spin echo T2 weighted MRI is excellent and provides additional information on tumor shape. We found a high degree of accuracy for tumor volumes with direct MRI volumetric measurements in uveal melanoma patients. In some patients with extra large tumors, the tumor base and shape was modified, because of the additional information obtained from 3D T2 FSE MR images.

Ongoing studies based on gene expression profile analysis using microarrays have provided preliminary evidence for significant molecular distinctions between primary central nervous system lymphoma (PCNSL) and nodal lymphomas of the large B-cell type. The application of array-based comparative genomic hybridization techniques attempts to identify genomic distinctions between PCNSL and nodal lymphomas and to identify the molecular markers that relate to prognosis. It is possible that insights gained from these studies will facilitate the development of targeted therapies, which address the fundamental genetic mutations that drive PCNSL and intraocular lymphoma growth.

To report a rare case of a patient with two germline mutations arising de novo resulting in bilateral retinoblastoma and hypochondroplasia.A brief review about retinoblastoma and hypochondroplasia; a case report with genetic mutational analysis results.We report a patient manifesting the clinical features of both bilateral retinoblastoma and hypochondroplasia. Genetic analysis revealed two germline mutations, a seven base-pair deletion in exon 12 (G70313-703129del) in one allele of the retinoblastoma gene (RB1) and the N540K (C1620CA) mutation in one allele of the fibroblast growth factor 3 (FGFR3) gene, a frequent mutation in hypochondroplasia. Neither parent has a personal or family history of cancer or ocular tumors. Only the patient's mother is short in stature, and her genetic analysis revealed no FGFR3 mutations.Although the probability of both germline mutations occurring in a single individual is exceedingly low, the etiology and mechanism are unknown in this patient. To the best of our knowledge, this is the first report of two clinically distinct heritable germline mutations arising de novo in an individual.

This chapter focuses on the diagnosis and management of choroidal melanoma in light of recent findings from the COMS. Retinoblastoma is emphasized to describe recent trends in primary treatment away from EBRT and toward chemoreduction with local therapy. In addition, vascular and glial tumors of the retina and tumors of the retinal pigment epithelium are described because of the association between these lesions and systemic disease. Recent advances in treatment and genetic testing for these diseases are discussed. Finally, ocular metastasis, intraocular lymphoid tumors, and intraocular leukemia are included because of their importance in determining systemic treatment and prognosis. The chapter gives an overview of important posterior pole tumors and highlights recent developments in the management of each intraocular disease process.

Purpose: To describe the effects of collagen vascular diseases on the eyelids and periorbital tissues. Methods: Retrospective review of dermatologic pathology slides at Massachusetts General Hospital and eye pathology slides at Massachusetts Eye and Ear Infirmary, Boston, Massachusetts. Results: A spectrum of dermatologic manifestations of collagen vascular diseases was observed, affecting the eyelids and periorbital region. Conclusions: Collagen vascular diseases may present complicated diagnostic and clinical challenges for the practicing ophthalmologist. Familiarity with the cutaneous periocular manifestations of these diseases may facilitate early recognition, diagnosis, and ophthalmologic intervention where necessary.

Retinoblastoma is the most frequently occurring malignant intraocular tumor of childhood, presenting in 1 in 20,000 live births, with an overall survival rate of 84% to 95%. 64,67,77 Management of retinoblastoma has changed significantly in recent years. The major goals of treatment are primarily to save the patient's life, and secondarily to salvage the eye and vision if possible. Current treatment modalities include enucleation, external beam radiotherapy, plaque radiotherapy, laser photoablation, thermotherapy, cryotherapy, chemotherapy, and combinations of these. The choice of treatment depends on the size, location, and extent of the tumor; whether the disease is unilateral or bilateral; the visual potential of the involved eyes; and whether evidence exists for extraocular or metastatic disease. These treatment options are discussed in detail with an emphasis on newer approaches.

Uveal melanoma is the most common primary intraocular malignancy in adults,50 with an estimated incidence in the United States of six cases per one million population.21,36,62,88,94,119 White patients are 7 to 10 times more likely to develop choroidal melanoma than African-American patients42,65,78,90 and 3 times more likely than certain Asian populations.49,55,57,88 Several epidemiologic studies suggest that the risk of developing uveal melanoma may be elevated in persons with light irides35,51,116 or light skin pigmentation.91 The median age at diagnosis is about 60 years.40,53,62,83,119 Very few cases have been reported in persons under the age of 15 years.97,109 This article provides a brief review of the differential diagnosis and options for management of choroidal melanoma, and discusses the controversy regarding management of small choroidal melanocytic lesions.

Purpose To report choroidal detachment following tamsulosin (Flomax, an α 1A -adrenoceptor antagonist) treatment of benign prostatic hyperplasia (BPH). Design Case report. Methods Chart review, serial examination. Results A 65-year-old man underwent uncomplicated cataract extraction and placement of a posterior chamber intraocular lens. The patient subsequently developed three separate episodes of choroidal detachments in the operated eye. Each episode was preceded by treatment with an α 1 -adrenoceptor antagonist. Conclusions Tamsulosin may cause adverse ocular effects including recurrent choroidal detachments. α 1A is the dominant α-adrenoceptor in the rabbit choroid, and the mechanism for choroidal detachment in this patient could include some effect of antagonists like tamsulosin on these receptors.

Thin Silastic sheet alloplasts (Dow Corning, Midland, MI, U.S.A) are commonly used to reconstruct posttraumatic orbital floor defects. Complications associated with orbital Silastic implantation include infection, migration, and extrusion. The authors report an unusual case of an intraorbital, squamous, epithelial-lined cyst appearing as progressive vertical globe dystopia and proptosis occurring after Silastic reconstruction of a traumatic orbital floor defect.

We present an unusual case of metastatic choriocarcinoma in a patient whose visual symptoms led to diagnosis and treatment of his underlying malignancy. He presented with vision loss and a visual field defect in his left eye, representing a choroidal mass and large exudative retinal detachment. In addition, metastatic investigation revealed abdominal, chest, and brain metastases. Metastatic choriocarcinoma was suspected because of an elevated β-human chorionic gonadotrophin (HCG), and the diagnosis was confirmed by fine needle aspiration of one pulmonary mass. A retroperitoneal mass was identified as the primary site, which is the first reported case of metastatic choriocarcinoma from the retroperitoneum. A 34 year old man presented initially to his physician with complaints of back pain and pain with coughing for 2 years. Abdominal computed tomograph (CT) scan revealed a retroperitoneal mass with an elevated β-HCG level to 137 420. …

This review discusses the epidemiology, clinical manifestations, differential diagnosis, genetics, management, and prognosis for retinoblastoma. Genetic counseling, information provided by various techniques of genetic screening, and management strategies for retinoblastoma are emphasized.

Retinoblastoma was the first tumor suppressor gene to be discovered and has defined the paradigm of the two-hit model of tumorigenesis. Because heritable retinoblastoma is associated with the RB1 cancer syndrome and puts offspring at risk of retinoblastoma development, it is important for patients to receive genetic counseling. Testing can be performed on blood or fresh frozen tumor. Common presenting signs in the developed world include leukocoria (white pupil) and strabismus (misalignment of the eyes). Most patients in the US are cured using surgery and/or chemotherapy.

We review the genetics of retinoblastoma and the most recent molecular detection methods. Retinoblastoma, the most common intraocular tumor in children, occurs in either a heritable or non-heritable form. The heritable form, which is highly penetrant and predisposes individuals to a considerably greater second tumor risk, can be distinguished most definitively through the use of genetic testing. Genetic testing for individuals and families suspected of carrying the heritable mutations can help ensure that more comprehensive treatment plans and accurate genetic counseling for affected individuals and their families are provided.

In recent months, many authors have described distinct surgical approaches to orbital decompression in thyroid ophthalmopathy. Comparison of outcomes data should allow the surgeon to decide on the best approach to orbital decompression in an individual patient. Patients with thyroid-associated lid retraction may also benefit from approaches that allow for postoperative suture adjustment, because alignment of the lids can be particularly challenging in these patients. The clinical evaluation of patients with thyroid disease has evolved with the recognition that magnetic resonance T2 relaxation time prolongation may correlate with an inflammatory disease phase and, perhaps, with improved response to medical management. Medical management of orbital inflammation and infection should be tailored to the specific disease process and, in many cases of infection, to the age of the patient.

Purpose: To evaluate the use of spiral/helical computed tomography (CT) in the preoperative evaluation of pediatric leukocoria. Methods: A total of 34 patient charts and imaging studies were reviewed from a consecutive series of children referred with the diagnosis of presumed retinoblastoma. Of these patients, 31 had a confirmed diagnosis of retinoblastoma. Three patients had simulating lesions, including one patient with persistent hyperplastic primary vitreous and two with Coats disease. Results: In all patients, a diagnosis of intraocular retinoblastoma could be established or excluded at the same clinical level by spiral CT as by conventional CT. Spiral CT of the eye, orbit, and midline structures was performed without a requirement for patient anesthesia. This technique resulted in a reduced volume of contrast material required for evaluation of the central nervous system and a small decrease in total radiation exposure. There was an attendant reduction in the amount of monitoring equipment required and the necessity for attending anesthesia staff. Conclusions: The primary advantage of spiral CT is reduced anesthesia risk in small children. In addition, this technique provides necessary clinical information with a reduction in image acquisition time, monitoring equipment, and monitoring staff.

Retinoblastoma is the most common intraocular childhood malignancy, with a prevalence of one in 18,000 children younger than 5 years old in the United States. In 80% of patients, retinoblastoma is diagnosed before the age of three, and in 95% of patients, retinoblastoma is diagnosed before the age of five. Although reports exist of retinoblastoma in adults, onset beyond 6 years of age is rare. Broadly, retinoblastoma may be classified into two groups: sporadic and heritable. In either case, the origin of the tumor is a biallelic mutation in primitive neuroepithelial cells. Although their details vary, several staging schemes are used to describe the extent of retinoblastoma according to the following four general criteria: intraocular location, extraocular (extraorbital) location, central nervous system disease, and systemic metastases. In the past decade, substantial changes have taken place in terms of staging and monitoring treatment in patients with retinoblastoma. Diagnosis and treatment of retinoblastoma involve a multidisciplinary approach, for which imaging is a vital component. Increasing awareness and concerns about the effects of radiation in patients with retinoblastoma have led to a shift away from external-beam radiation therapy and toward chemotherapy and locoregional treatment, as well as the establishment of magnetic resonance imaging as the most important imaging modality for diagnosis, staging, and treatment monitoring.

Retinoblastoma is a pediatric retinal tumor initiated by biallelic inactivation of the retinoblastoma gene (RB1). RB1 was the first identified tumor suppressor gene and has defined roles in the regulation of cell cycle progression, DNA replication, and terminal differentiation. However, despite the abundance of work demonstrating the molecular function and identifying binding partners of pRb, the challenge facing molecular biologists and clinical oncologists is how to integrate this vast body of molecular knowledge into the development of targeted therapies for treatment of retinoblastoma. We propose that a more thorough genetic understanding of retinoblastoma would inform targeted treatment decisions and could improve outcomes and quality of life in children affected by this disease.