Anthony B. Daniels

Regression of Some High-risk Features of Age-related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment

Importance Age-related macular degeneration (AMD) remains the leading cause of blindness in developed countries, and affects more than 150 million worldwide. Despite effective anti-angiogenic therapies for the less prevalent neovascular form of AMD, treatments are lacking for the more prevalent dry form. Similarities in risk factors and pathogenesis between AMD and atherosclerosis have led investigators to study the effects of statins on AMD incidence and progression with mixed results. A limitation of these studies has been the heterogeneity of AMD disease and the lack of standardization in statin dosage. Objective We were interested in studying the effects of high-dose statins, similar to those showing regression of atherosclerotic plaques, in AMD. Design Pilot multicenter open-label prospective clinical study of 26 patients with diagnosis of AMD and the presence of many large, soft drusenoid deposits. Patients received 80 mg of atorvastatin daily and were monitored at baseline and every 3 months with complete ophthalmologic exam, best corrected visual acuity (VA), fundus photographs, optical coherence tomography (OCT), and blood work (AST, ALT, CPK, total cholesterol, TSH, creatinine, as well as a pregnancy test for premenopausal women). Results Twenty-three subjects completed a minimum follow-up of 12 months. High-dose atorvastatin resulted in regression of drusen deposits associated with vision gain (+ 3.3 letters, p = 0.06) in 10 patients. No subjects progressed to advanced neovascular AMD. Conclusions High-dose statins may result in resolution of drusenoid pigment epithelial detachments (PEDs) and improvement in VA, without atrophy or neovascularization in a high-risk subgroup of AMD patients. Confirmation from larger studies is warranted.

High Throughput Mass Spectrometry-Based Mutation Profiling of Primary Uveal Melanoma

PURPOSE We assessed for mutations in a large number of oncogenes and tumor suppressor genes in primary uveal melanomas using a high-throughput profiling system. METHODS DNA was extracted and purified from 134 tissue samples from fresh-frozen tissues (n = 87) or formalin-fixed, paraffin-embedded tissues (n = 47) from 124 large uveal melanomas that underwent primary treatment by enucleation. DNA was subjected to whole genome amplification and MALDI-TOF mass spectrometry-based mutation profiling (>1000 mutations tested across 120 oncogenes and tumor suppressor genes) using the OncoMap3 platform. All candidate mutations, as well as commonly occurring mutations in GNAQ and GNA11, were validated using homogeneous mass extension (hME) technology. RESULTS Of 123 samples, 97 (79%, representing 89 unique tumors) were amplified successfully, passed all quality control steps, and were assayed with the OncoMap platform. A total of 58 mutation calls was made for 49 different mutations across 26 different genes in 34/98 (35%) samples. Of 91 tumors that underwent hME validation, 83 (91%) harbored mutations in the GNAQ (47%) or GNA11 (44%) genes, while hME validation revealed two tumors with mutations in EGFR. These additional mutations occurred in tumors that also had mutations in GNAQ or GNA11. CONCLUSIONS The vast majority of primary large uveal melanomas harbor mutually-exclusive mutations in GNAQ or GNA11, but very rarely have the oncogenic mutations that are reported commonly in other cancers. When present, these other mutations were found in conjunction with GNAQ/GNA11 mutations, suggesting that these other mutations likely are not the primary drivers of oncogenesis in uveal melanoma.

Intra-Arterial Chemotherapy (Ophthalmic Artery Chemosurgery) for Group D Retinoblastoma.

Purpose To report globe salvage rates, patient survival and adverse events of ophthalmic artery chemosurgery (OAC) for International Classification of Retinoblastoma (ICRB) group D retinoblastoma (naive and after prior failures). Methods Single institution retrospective review of all Group D eyes treated with OAC from 5/2006-12/2012. Patients were treated according to our previously-published techniques. Primary outcome was globe retention without need for external beam radiotherapy (EBRT). Demographics, prior treatments, OAC agents used, and adverse events were also recorded. Results 112 group D eyes (103 patients) that underwent OAC were included (average follow-up was 34 months, range: 2–110 months). 47 eyes were treatment-naïve, 58 eyes received prior treatments elsewhere, and 7 young infants (7 eyes) underwent our published “bridge therapy” (single agent intravenous carboplatin) until old enough to undergo OAC. Median number of OAC sessions/eye was 3 (range 1–9). 110/112 eyes received intra-arterial melphalan, but only 31 eyes received melphalan alone. 43 eyes received carboplatin, and 78 eyes received topotecan (never as a single agent). 80/112 eyes received >1 drug over their treatment course, and 39 eyes received all three agents. 24 eyes (16 pretreated, 7 treatment-naïve, 1 bridge) failed treatment and required enucleation during the study period. Enucleation and EBRT were avoided in 88/112 eyes (78.6%; including 40/47 [85.1%] treatment-naïve eyes, 42/58 [72.4%] previously-treated eyes, and 6/7 eyes [85.7%] among bridge patients). By Kaplan-Meier survival analysis, globe salvage rate was 74% at 110 months among all patients, and 85% at 110 months in the treatment-naïve subgroup. Transient grade 3/4 neutropenia was more common in patients receiving OAC bilaterally. No child died of metastatic disease. Conclusions OAC is effective for curing group D retinoblastoma, achieving rates of globe salvage many times higher than systemic chemotherapy (10–47%), even in eyes that previously failed other treatments. OAC can be performed multiple times, using multiple agents, on one or both eyes of patients.

Tumor Characteristics, Genetics, Management, and the Risk of Metastasis in Uveal Melanoma

ABSTRACT Uveal melanoma is the most common intraocular malignancy in adults. Although rates of local control for uveal melanoma exceed 95% with radiotherapy or enucleation, as many as 50% of patients develop hematogenous metastases, which manifest in the decades following initial diagnosis and are uniformly and rapidly fatal. Recent compelling evidence suggests that not all uveal melanomas are themselves equivalent with respect to metastatic potential and patient survival. This review focuses on the mounting evidence of survival disparities based on intrinsic tumor clinical and histopathologic characteristics and based on tumor genetics and gene expression profiles.

An international survey of classification and treatment choices for group D retinoblastoma

AIM To determine which IIRC scheme was used by retinoblastoma centers worldwide and the percentage of D eyes treated primarily with enucleation versus globe salvaging therapies as well as to correlate trends in treatment choice to IIRC version used and geographic region. METHODS An anonymized electronic survey was offered to 115 physicians at 39 retinoblastoma centers worldwide asking about IIRC classification schemes and treatment patterns used between 2008 and 2012. Participants were asked to record which version of the IIRC was used for classification, how many group D eyes were diagnosed, and how many eyes were treated with enucleation versus globe salvaging therapies. Averages of eyes per treatment modality were calculated and stratified by both IIRC version and geographic region. Statistical significance was determined by Chi-square, ANOVA and Kruskal-Wallis tests using Prism. RESULTS The survey was completed by 29% of physicians invited to participate. Totally 1807 D eyes were diagnosed. Regarding IIRC system, 27% of centers used the Childrens Hospital of Los Angeles (CHLA) version, 33% used the Childrens Oncology Group (COG) version, 23% used the Philadelphia version, and 17% were unsure. The rate for primary enucleation varied between 0 and 100% and the mean was 29%. By IIRC version, primary enucleation rates were: Philadelphia, 8%; COG, 34%; and CHLA, 37%. By geographic region, primary enucleation rates were: Latin America, 57%; Asia, 40%; Europe, 36%; Africa, 10%, US, 8%; and Middle East, 8%. However, systemic chemoreduction was used more often than enucleation in all regions except Latin America with a mean of 57% per center (P<0.0001). CONCLUSION Worldwide there is no consensus on which IIRC version is used, systemic chemoreduction was the most frequently used initial treatment during the study period followed by enucleation and primary treatment modality, especially enucleation, varied greatly with regards to IIRC version used and geographic region.

Local treatment of Kaposi sarcoma of the conjunctiva.

In 1872, Kaposi, a Hungarian dermatologist, first reported 5 cases of elderly men in Vienna with a ‘‘sarcoma idiopathicum multiple hemorrhagicum.’’ The disease that now bears his name is a vascular, multicentric tumor with mucocutaneous and sometimes lymphatic and visceral organ involvement. There are 4 different but related variants of Kaposi sarcoma (KS). Before the acquired immunodeficiency syndrome (AIDS) epidemic, ‘‘classic’’ KS was predominately an indolent disease of immunocompetent elderly men from Eastern Europe (especially Ashkenazi Jews), the Mediterranean, and from equatorial Africa. Another variant of KS, now known as ‘‘endemic’’ KS affects both children and adult men in Africa and follows a more aggressive course with early and widespread visceral involvement leading to significant morbidity and mortality. The ‘‘iatrogenic’’ or drug-induced variant of KS affects patients undergoing immunosuppressive therapy, and has been reported in organ transplant patients, or patients undergoing treatment for lymphoma, giant cell arteritis, pemphigus, and lupus. After the AIDS was first described in 1981, a new AIDS-related or ‘‘epidemic’’ form of KS was recognized. In the pre-HAART (highly active antiretroviral therapy) era, this form of KS became one of the most aggressive and fatal AIDS-related cancers.

Uveal metastasis from nonsmall cell lung carcinoma with dramatic response to erlotinib.

PURPOSE To report the case of a never-smoker patient whose initial presentation of metastatic nonsmall cell lung carcinoma was with uveal metastasis, which had a dramatic response to targeted biologic therapy with erlotinib (Tarceva) after failing conventional chemotherapy. METHODS Case report. A 43-year-old man with uveal metastasis from nonsmall cell lung adenocarcinoma. RESULTS After failing conventional chemotherapy with carboplatin and taxol, with continued documented rapid growth of the uveal metastasis, treatment was initiated with the targeted biologic agent, erlotinib, which is a protein tyrosine kinase inhibitor of the epidermal growth factor receptor(EGFR). Within 3 days of starting erlotinib, shrinkage of the choroidal lesion was noted, and over the course of the next 3 months, the tumor completely and durably disappeared, with vision improving from hand motion to 20/25. The patient is still alive and well after 3 years, on continued daily oral erlotinib treatment. CONCLUSION Erlotinib is a well-tolerated newly available Food and Drug Administration-approved oral targeted biologic agent, which may be beneficial in some patients with uveal metastasis from nonsmall cell lung carcinoma, in which an underlying epidermal growth factor receptor mutation is suspected.

Disparities in Retinoblastoma Presentation, Treatment, and Outcomes in Developed and Less-Developed Countries

ABSTRACT Retinoblastoma (RB) is the most common intraocular malignancy in children. In the past century, RB survival rates in developed countries (DCs) have improved from <5% to as high as 99%. In contrast, in less developed countries (LDCs) where the tumor burden is greatest, survival rates remain poor, with some countries reporting survival rates as low as 0–5%. In addition, there are disparities between DCs and LDCs in RB presentation, treatment modalities, and prognosis. These disparities are due to many underlying causes, including delays in diagnosis, access to medical care, patient and physician familiarity with the disease, availability and cost of treatment, and patient acceptance of enucleation. It is our belief that attempts to extend the improvements in prognosis achieved in DCs to various LDCs must be culturally sensitive and tailored to each country’s specific challenges, and thus, a “one-size-fits-all” approach to improving patient outcomes in LDCs is unlikely to work well. We discuss several culturally sensitive approaches that have been successfully implemented in various LDCs, including those that make use of telemedicine and “twinning” with centers of excellence around the world.

Intraorbital metastasis from solitary fibrous tumor.

Solitary fibrous tumor (SFT) is a rare spindle cell tumor of mesenchymal origin that usually arises from pleura or pericardium but can also arise from many extraserosal sites. Although more than 50 cases of primary SFT of the orbit have been reported, there are no reports to date of a malignant nonophthalmic SFT metastasizing in the orbital soft tissues (although sphenoid wing bony involvement has been reported). The authors report here the first case of a patient with intraorbital metastasis of a CD34-positive malignant SFT. The patient was a 57-year-old man with a history of malignant pleural SFT and a prior kidney metastasis. He presented with the rapid appearance of proptosis and massive conjunctival chemosis preventing eyelid closure, and he was found to have a well-circumscribed metastasis to his lateral rectus muscle. Surgical excision cured his ocular symptoms, although he died 3 months later from brain and widespread metastases.

Utility of Ocular Ultrasonography in Diagnosing Infectious Endophthalmitis in Patients with Media Opacities

Assessment of patients with infectious endophthalmitis is frequently limited by media opacities, and ocular ultrasonography is routinely performed in this setting. We examined the literature to assess the level of evidence for the utility of ocular ultrasonography in these patients. Common ultrasonographic findings reported include low amplitude mobile echoes, vitreous membranes, and thickening of the retina and choroid. Based on the available evidence, we conclude that ocular ultrasound may be a useful adjunct in guiding treatment and minimizing complications. While positive findings may be confirmatory in cases in which the clinical suspicion is high, ocular ultrasound alone cannot be used to prove or to exclude the diagnosis of infectious endophthalmitis.