Two-year results for ranibizumab for radiation retinopathy (RRR): a randomized, prospective trial.

PURPOSE: To assess the efficacy of a treat-and-extend strategy with intravitreal ranibizumab for radiation-related macular edema. METHODS: Forty eyes with radiation-induced macular edema and decreased visual acuity were enrolled in the phase IIb, prospective clinical trial and randomized into 3 cohorts: (A) monthly ranibizumab, (B) monthly ranibizumab with targeted retinal photocoagulation (TRP), or (C) as-needed ranibizumab and TRP. In year 2, all subjects entered a treat-and-extend protocol for ranibizumab. The primary outcome measure was mean change in early treatment diabetic retinopathy study (ETDRS) best-corrected visual acuity (BCVA) from baseline. RESULTS: Through year 1, the mean change in ETDRS BCVA was significantly different between the three cohorts (p < 0.001); cohort A saw the largest gain with + 4.0 letters. Significant anatomic improvements were also seen in all cohorts. Comparatively, through year 2, cohorts A, B, and C had a mean change in ETDRS BCVA of - 1.9, - 3.9, and + 1.3 letters, respectively; additionally, no significant differences were found in absolute ETDRS BCVA across time (ANOVA, p = 0.123). Overall, 90% of eyes maintained VA 20/200 or better and 33.3% of subjects gained at least one line of vision. There were no significant differences in mean central macular thickness for any cohort compared to baseline (p = 0.09). The presence of retinal hemorrhage and intraretinal exudates stayed consistent from year 1 to year 2 for all cohorts. CONCLUSIONS: Among eyes with radiation-related macular edema, a treat-and-extend regimen with ranibizumab may not result in as many visual and anatomic improvements as monthly injections. However, treat-and-extend still may prevent serious visual complications compared to historical controls. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02222610.

Recent advancements in the management of retinoblastoma and uveal melanoma.

Retinoblastoma in children and uveal melanoma in adults can pose a serious threat to both vision and life. For many decades, enucleation was often the only option to treat these intraocular malignancies. For retinoblastoma, intra-arterial chemotherapy is often utilized as the primary treatment at advanced academic centers and has dramatically improved local tumor control and eye salvage rates. For uveal melanoma, both plaque brachytherapy and proton beam irradiation have served as widely utilized therapies with a local failure rate of approximately 1-10%, depending on the series. Major recent advancements have allowed for a better understanding of the genomics of uveal melanoma and the impact of certain mutations on metastatic susceptibility. Gene expression profile stratifies uveal melanomas into two classes: low-risk (class 1) and high-risk (class 2). A loss-of-function mutation of BAP1 is associated with a class 2 gene expression profile and therefore confers worse prognosis due to elevated risk of metastasis. On the other hand, gain-of-function mutations of EIF1AX and SF3B1 correspond to a gene expression profile of class 1A and class 1B and confer a better prognosis. Preferentially expressed antigen in melanoma (PRAME) is an antigen that increases metastatic susceptibility when expressed in uveal melanoma cells. In addition to plaque brachytherapy and proton beam irradiation, both of which have demonstrated superb clinical outcomes, scientists are actively investigating newer therapeutic modalities as either primary therapy or adjuvant treatment, including a novel nanoparticle therapy and immunotherapy.

Randomized Trial of Monthly Versus As-Needed Intravitreal Ranibizumab for Radiation Retinopathy-Related Macular Edema: 1-Year Outcomes.

PURPOSE: To assess efficacy of intravitreal ranibizumab injections and targeted panretinal photocoagulation (TRP) for radiation retinopathy-related macular edema. DESIGN: Phase IIb, prospective, randomized clinical trial. METHODS: Setting: Multicenter. SUBJECTS: Forty eyes in 40 treatment-naïve patients with radiation-induced macular edema and a resulting decrease in visual acuity ranging between 20/25 and 20/400 (Snellen equivalent). INTERVENTION: Patients either received intravitreal 0.5 mg ranibizumab monthly, monthly ranibizumab with TRP, or 3 monthly ranibizumab (loading doses) followed by as-needed (PRN) injections and TRP. After week 52, all subjects entered a treat-and-extend protocol for ranibizumab. MainOutcomeMeasures: Mean Early Treatment Diabetic Maculopathy Study (ETDRS) BCVA change from baseline. RESULTS: Mean patient age was 57 years (range, 22-80 years), ETDRS BCVA was 56.7 letters (20/74 Snellen equivalent), and central macular thickness (CMT) was 423 µm (range, 183-826 µm). Thirty-seven patients completed the month 12 visit (92.5%), at which time the change in mean BCVA was +4.0 letters, -1.9 letters, and +0.9 letters in the monthly, monthly plus laser, and PRN plus laser cohorts, respectively. There was a significant difference in mean BCVA at 1 year among all 3 cohorts (P < .001), as well as between cohorts in pairwise comparisons, with the most significant gains in the monthly group. A total of 82.5% of the patients retained visual acuity of 20/200 or better, and 20.0% improved 10 or more ETDRS letters. CONCLUSIONS: Ranibizumab may improve vision and anatomy in patients with radiation retinopathy-related macular edema and prevent vision loss through 48 weeks of therapy. Monthly injections were more effective than as-needed approach, and the addition of TRP yielded no therapeutic benefits.

A Review of Management Strategies for Nociceptive and Neuropathic Ocular Surface Pain.

Despite being a common presenting symptom to eye-care clinics, many ophthalmologists have difficulty diagnosing and managing ocular surface pain. The purpose of this review is to discuss potential causes of ocular surface pain, focusing on both nociceptive and neuropathic aetiologies. Specifically, we outline an approach to the diagnosis of ocular surface pain and focus on various management strategies, providing supporting evidence on the efficacy of various treatments.

The envelope of active hip motion in different sporting, recreational, and daily-living activities: A systematic review.

BACKGROUND: In treating patients with limitations of hip motion, it is generally assumed that correction of bony morphology will provide the patient with the joint motion required to resume their activities. However, the positions of impingement and the specific excursions of joint motion required by each sport may vary. This systematic review aimed to define the envelope of active hip joint motion for participation in different sporting, recreational, and daily-living activities. METHODS: The EMBASE, PubMed, Google Scholar, and Cochrane databases were searched to identify studies that reported kinematics of the hip in sporting, recreational, and daily-living activities. Inclusion criteria were (1) peer-reviewed articles reporting hip kinematics in a certain type of activity, and (2) presented in English. To synthesize the kinematic data, the peak values of kinematic components (i.e. flexion/extension, abduction/adduction, and internal/external rotation) during an activity, as well as the concurrent values in a certain phase of the activity were collected from each study. RESULTS: A total of 67 studies met the inclusion criteria, involving 32 different types of activities. Seventeen activities required at least one component of supra-physiologic hip motion, however, there were eight different combinations of flexion/extension, abduction/adduction, and internal/external rotation observed. Specifically, three activities (sex, sitting cross-legged, and grand ecart lateral of ballet dancing) required simultaneous extreme degrees of all three components, five activities (arabesque, developpe devant right, and developpe a la seconde right of ballet dancing, picking up something, and taekwondo) required high degrees of two components, most commonly hip abduction combined with flexion or internal rotation. SIGNIFICANCE: This review highlighted that many activities place supraphysiologic demands on hip joint motion, however, the kinematic components affected differ dramatically with the specific activity. This suggests that the demands of each patient's individual activities must be assessed before recommending or planning treatment rather than assuming that a fixed value of "normal" hip motion is applicable to all.

Elevated Choroidal Thickness and Central Serous Chorioretinopathy in the Fellow Eyes of Patients with Circumscribed Choroidal Hemangioma.

OBJECTIVE: To determine whether increased choroidal thickness (CT) is associated with circumscribed choroidal hemangioma (CCH) and whether patients with CCH are predisposed to central serous chorioretinopathy (CSCR). METHODS: We performed a retrospective consecutive observational study of 15 fellow eyes of 15 patients who had CCH. A- and B-scan ultrasonography, fluorescein angiography (FA), and optical coherence tomography (OCT) findings were reviewed to confirm the diagnosis of CCH. Fellow eye CT was measured using enhanced depth imaging OCT. FA, indocyanine green angiography, and OCT images of fellow eyes were reviewed for signs of CSCR. RESULTS: Mean subfoveal CT was significantly greater in the fellow eyes of patients with CCH than in age-matched normal eyes (p = 0.004). Three of 15 (20.0%) fellow eyes of CCH patients had retinal pigment epithelium disruptions and/or pigment epithelial detachments indicative of previous asymptomatic CSCR. CONCLUSION: In this pilot study, elevated CT was associated with a risk of developing CCH as well as CSCR in patients of varying ages. Patients diagnosed with CCH should be screened for CSCR in the fellow eye. Further exploration of this association may reveal useful clues about the biology of abnormally elevated choroidal hyperpermeability and its various clinical manifestations.

Recent advancements in the management of retinoblastoma and uveal melanoma.

Retinoblastoma and uveal melanoma are the most common intraocular malignancies observed in pediatric and adult populations, respectively. For retinoblastoma, intra-arterial chemotherapy has dramatically improved treatment outcomes and eye salvage rates compared with traditional salvage rates of systemic chemotherapy and external beam radiation therapy. Intravitreal injections of chemotherapy have also demonstrated excellent efficacy for vitreous seeds. Uveal melanoma, on the other hand, is treated predominantly with iodine-125 plaque brachytherapy or with proton beam therapy. Major strides in uveal melanoma genomics have been made since the early 2000s, allowing ocular oncologists to better understand the metastatic risks of the tumor on the basis of specific genetic signatures. Loss-of-function mutations of the BAP1 gene are associated with the highest metastatic risk, whereas gain-of-function mutations of SF3B1 and EIF1AX often confer a better prognosis. Expression of a cancer-testis antigen called PRAME (preferentially expressed antigen in melanoma) has been shown to increase metastatic risks in both low-risk and high-risk melanomas. New therapeutic approaches, including molecular therapies and nanoparticle phototherapy, are currently being investigated as alternative treatment modalities for uveal melanoma.

Association between traditional clinical high-risk features and gene expression profile classification in uveal melanoma.

PURPOSE: To evaluate the association between traditional clinical high-risk features of uveal melanoma patients and gene expression profile (GEP). METHODS: This was a retrospective, single-center, case series of patients with uveal melanoma. Eighty-three patients met inclusion criteria for the study. Patients were examined for the following clinical risk factors: drusen/retinal pigment epithelium (RPE) changes, vascularity on B-scan, internal reflectivity on A-scan, subretinal fluid (SRF), orange pigment, apical tumor height/thickness, and largest basal dimensions (LBD). A novel point system was created to grade the high-risk clinical features of each tumor. Further analyses were performed to assess the degree of association between GEP and each individual risk factor, total clinical risk score, vascularity, internal reflectivity, American Joint Committee on Cancer (AJCC) tumor stage classification, apical tumor height/thickness, and LBD. RESULTS: Of the 83 total patients, 41 were classified as GEP class 1A, 17 as class 1B, and 25 as class 2. The presence of orange pigment, SRF, low internal reflectivity and vascularity on ultrasound, and apical tumor height/thickness ≥ 2 mm were not statistically significantly associated with GEP class. Lack of drusen/RPE changes demonstrated a trend toward statistical association with GEP class 2 compared to class 1A/1B. LBD and advancing AJCC stage was statistically associated with higher GEP class. CONCLUSIONS: In this cohort, AJCC stage classification and LBD were the only clinical features statistically associated with GEP class. Clinicians should use caution when inferring the growth potential of melanocytic lesions solely from traditional funduscopic and ultrasonographic risk factors without GEP data.

USE OF FEMORAL ARTERY ULTRASOUND DURING INTRAARTERIAL CHEMOTHERAPY FOR CHILDREN UNDER 10 KG WITH RETINOBLASTOMA.

PURPOSE: To demonstrate the safety and efficacy of intraarterial chemotherapy (IAC) in small infants (<10 kg) with retinoblastoma. METHODS: Retrospective, consecutive, observational case series of patients treated with IAC. Femoral arterial access was obtained using a micropuncture kit and ultrasound guidance, which enabled direct visualization. Melphalan (1.5-5.0 mg), topotecan (0.3-2.0 mg), and/or carboplatin (30-40 mg) were used. Patients underwent adjuvant therapies including laser, cryotherapy, and intravitreal melphalan if persistent disease or recurrence was observed. RESULTS: Fifty-nine injections were administered to 11 eyes of 6 patients. All eyes but one were classified as International Classification Groups C or D. Median patient weight at first IAC cycle was 9.2 kg (mean, 8.9 kg). Median diameter of the femoral artery at the catheterization site was 3.74 mm, measured by two independent observers. Median follow-up was 21.4 months (range 13.1-34.5 months). All eyes were salvaged. CONCLUSION: This study confirmed the safety and efficacy of IAC in infants under 10 kg. Ultrasound guidance enabled successful catheterization of femoral arteries as small as 2.7 mm in diameter. Patients in this study appeared to require fewer injections and lower total doses of chemotherapy compared with previously reported series of comparably advanced disease in larger infants.

Early outcomes of uveal melanoma treated with intraoperative ultrasound guided brachytherapy using custom built plaques.

PURPOSE: To report early outcomes of patients with uveal melanoma treated with Eye Physics iodine-125 episcleral plaque therapy using modern biopsy techniques and intraoperative ultrasound guidance at our institution. METHODS AND MATERIALS: A retrospective chart review was conducted for 48 consecutive patients with uveal melanoma who were treated with Eye Physics plaque brachytherapy performed by 1 ocular oncologist. All patients underwent intraoperative ultrasound for image guidance of plaque placement. A dose of 85 Gy was prescribed to the apical height of the tumor or 5 mm from the inner sclera, whichever was greater. Forty-five patients underwent biopsy. Visual acuity, complication data, and recurrence rates were recorded. RESULTS: Median age at presentation was 63.0 years (range, 19-86 years). Median follow-up was 21.6 months. Median tumor apical height was 3.3 mm (range, 1.8-11.5 mm). Median dose at apex for tumor height >5 mm was 85.0 Gy and 142.5 Gy for tumor height ≤5 mm. Mean percent decrease in tumor height from baseline at 12, 24, and 36 months was 39.6%, 51.8%, and 53.8%, respectively. At 24 months, 19/23 (82.6%) patients maintained vision within 3 lines of baseline visual acuity. Twelve patients developed radiation retinopathy, 6 of whom were treated with anti-vascular endothelial growth factor therapy in the context of a clinical trial. No patients to date have local failure. Three patients are alive with confirmed hepatic metastases. CONCLUSIONS: We reported 0% early local failure rate and steady reduction in tumor height in 48 patients with uveal melanoma, ranging from small to large size, who were treated with Eye Physics iodine-125 episcleral plaque therapy using intraoperative ultrasound guidance. This promising result emphasizes the importance of image guided brachytherapy with intraoperative ultrasound at the time of plaque placement.

Histopathologic Analysis of Transvitreal Fine Needle Aspiration Biopsy Needle Tracts for Uveal Melanoma.

PURPOSE: Perform the first in vivo examination of fine needle aspiration biopsy (FNAB) scleral tracts to determine the incidence of iatrogenic extension of tumor cells. DESIGN: A prospective, consecutive, observational case series. METHODS: This study was performed in a clinical/surgical setting at Retina Consultants of Houston and Houston Methodist Hospital, Houston, Texas, and included 10 patients who were scheduled for enucleation as primary treatment for uveal melanoma. Treatment included FNAB, enucleation, and histopathologic analysis. The primary outcomes were tumor location and dimension as identified by B-scans and histopathologic analysis. Tumor type was classified by gene expression profile and American Joint Committee on Cancer staging. Twenty-five- or 27-gauge needles were used for FNAB under direct visualization. Cell blocks of acquired specimens were examined using hematoxylin-eosin stain and double immunostain using HMB45 with red chromogen and Ki67 with brown 3,3'-diaminobenzidine chromogen. RESULTS: Mean follow-up after enucleation was 20.4 months (range 9.9-31.7). All biopsy specimens had adequate yields for genomic analysis. No enucleation specimen contained tumor cells within sclera, pars plana, or pars plicata. One specimen contained a small collection of tumor cells within the anterior vitreous in the quadrant of the biopsy site. No patient developed an orbital recurrence. Four patients developed nonorbital metastatic uveal melanoma during the study period. Three of them died, and 1 is alive with hepatic metastasis. CONCLUSIONS: No iatrogenic extension of tumor was reported. FNAB is a safe procedure that produces a high cellular yield for cytologic and genomic analyses with minimal risk of extraocular dissemination.

Osteochondral Allograft Donor-Host Matching by the Femoral Condyle Radius of Curvature.

BACKGROUND: Conventional osteochondral allograft (OCA) matching, requiring orthotopic, size-matched condyles, and narrow surgical time windows often prohibit timely transplantation. HYPOTHESIS: The femoral condyle radius of curvature (RoC) is an appropriate, isolated criterion for donor-host matching in fresh OCAs, potentially enhancing matching efficiency when compared with conventional matching techniques. STUDY DESIGN: Descriptive laboratory study. METHODS: In part 1 of this study, 3-dimensional digital reconstructions of 14 randomly selected, cadaveric distal femoral hemicondyles were performed. Each condyle was divided into anterior, middle, and posterior zones. A virtual best-fit grid was applied to each, and each zone's sagittal- and coronal-plane RoCs were determined. Seven nonorthotopic OCA transplantations were performed based on RoC matching with 1-mm tolerance, and the preoperative and postoperative surface geometry were quantified to assess the accuracy of articular surface restoration. Of note, each donor-host pair did not match by the conventional method. In part 2 of this study, 12 cadaveric distal femora were categorized by size and digitized in the aforementioned manner. Simulated circular defects measuring 20, 25, and 30 mm in diameter were introduced into each zone. OCA matches were determined based on donor and host RoCs, and the total number of potential matches (of 71 total comparisons) was recorded as a percentage for each simulated defect. Finally, the results of RoC matching were compared with the conventional method for simulated defects in all zones of both the medial and lateral femoral condyles. RESULTS: Part 1: The mean surface deviation after OCA transplantation was -0.09 mm, with a mean maximum protrusion at any point of 0.59 mm. Part 2: Using the RoC, 20-mm defects had a 100% chance of being matched. Defects of 25 and 30 mm had a 91% and 64% chance of being matched, respectively. Compared with the conventional method, the RoC method yielded a 3.2-fold greater match rate for lesions of the medial and lateral femoral condyles ( P = .02). CONCLUSION: This investigation shows that femoral condyle RoCs in the sagittal and coronal planes may be useful, alternative matching criteria, expanding on current standards. CLINICAL RELEVANCE: These matching criteria may increase the number of available matches, reduce wait times for patients, and reduce the number of wasted grafts.