A Proposal for Future Modifications on Clinical TNM Staging System of Retinoblastoma Based on the American Joint Committee on Cancer Staging Manual, 7th and 8th Editions.

Importance: The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual incorporated new changes from its 7th edition for classifying retinoblastoma (RB). Objective: We assessed the comparative prognostic values of the 7th and 8th editions of the AJCC clinical (cTNM) staging manuals for RB and suggested modifications for future edition accordingly. Design: A retrospective, observational study. Setting: King Hussein Cancer Centre. Participants: A cohort of 478 patients and 565 eyes with RB. Main Outcomes and Measures: Main outcome measures included demographics; tumor features, AJCC cTNM stage, and eye salvage rates. The prognostic performance of the different staging systems was assessed with the concordance index (C-index) and likelihood ratio χ2 tests. Results: The overall eye salvage rate was 65%. Stage migration occurred for 330 (48%) eyes with the AJCC Staging Manual, 8th edition. Based on the 7th edition AJCC staging, the eye salvage rate was 94% (n=177) for T1 tumors (98% for T1a, 93%for T1b, and 90%for T1c), 69% (n=204) for T2 tumors (73% for T2a and 62%for T2b), and 51% (n=40) for T3 tumors. Based on the 8th edition AJCC staging, the eye salvage rate was 95% (n=139) for T1 tumors (98% for T1a and 93% for T1b), 68% (n=281) for T2 tumors (90%for T2a and 66%for T2b), and 12% (n=1) for T3 tumors. With our proposed cTNM modifications, the eye salvage rate was 94% (n=177) for T1 tumors (98%for T1a, 93%for T1b, and 90% for T1c), 66% (n=243) for T2 tumors (73% for T2a, 62% for T2b, and 55% for T2c), and 12% (n=1) for T3 tumors. As estimated by odds ratios, more advanced cTNM stage (regardless of the cTNM staging system) was significantly associated with an increased chance of treatment failure (P < .0001). The C-index for both the 8th edition and the proposed modifications were approximately equal, and both were higher than that of the 7th edition. However, the proposed modifications had the highest likelihood ratio χ2 value and the best bootstrap 95% confidence interval. Conclusions and Relevance: Our proposed modifications on the clinical TNM Staging System for RB harbor more detailed subgroup classification criteria that provides better prognostic value for eye globe salvage than the published similar (but not identical) AJCC Staging Manual, 7th and 8th editions, furthermore these modifications may resolve the discrepancies in the previously published different classification systems for RB.

Ultrasound Biomicroscopy Measurements of the Normal Thickness for the Ciliary Body and the Iris in a Middle East Population.

PURPOSE: Ciliary body (CB) and iris thicknesses may change with certain eye diseases as well as between different populations. Here, we report Ultrasound Biomicroscopy Measurements (UBM) of the normal thickness for the CB and the iris from a homogenous population in the Middle East. PATIENTS AND METHODS: Sonomed 35-MHz (SONOMED, INC. New York, USA) images were obtained at 4 radial meridians, and the thickness was measured at 3 locations along the radial length of the iris and at the thickest part of the CB. Parameters included mean thickness, median thickness, range, and standard deviation. RESULTS: Of 46 adult patients, 83 normal eyes were included in this analysis. The overall mean, median iris thicknesses at the iris root, midway along the radial length of the iris, and at the juxtapupillary margin in mm were 0.42, 0.41 ± 0.08, 0.52, 0.51± 0.08, and 0.72, 0.71± 0.1, respectively. The overall mean, median thicknesses of the CB and CB + ciliary processes in mm were 0.72, 0.71 ± 0.1, and 1.42, 1.37 ± 0.2 respectively. Gender, age, side, and height had no impact on iris and/or CB thickness (p>0.05). However, the iris thickness was significantly thicker in the superior quadrant than inferiorly, and in the nasal quadrant than the temporal quadrant (p=0.04), and the CB thickness and the CB + ciliary processes thickness were significantly thicker in the superior quadrant than inferiorly (P = 0.04 and 0.02 consecutively). CONCLUSION: We measured in this study the normal thickness of the CB and the iris in normal eyes from homogenous population in the Middle East using ultrasound biomicroscopy. Our findings are essential for the ophthalmic community worldwide and in the Middle East region and can be used as a normative thickness data for the iris and CB in healthy eyes.

New Therapeutic Perspectives in the Treatment of Uveal Melanoma: A Systematic Review.

Uveal melanoma (UM) is a rare disease, but the most common primary intraocular cancer, mostly localized in the choroid. Currently, the first-line treatment options for UM are radiation therapy, resection, and enucleation. However, although these treatments could potentially be curative, half of all patients will develop metastatic disease, whose prognosis is still poor. Indeed, effective therapeutic options for patients with advanced or metastatic disease are still lacking. Recently, the development of new treatment modalities with a lower incidence of adverse events, a better disease control rate, and new therapeutic approaches, have merged as new potential and promising therapeutic strategies. Additionally, several clinical trials are ongoing to find new therapeutic options, mainly for those with metastatic disease. Many interventions are still in the preliminary phases of clinical development, being investigated in phase I trial or phase I/II. The success of these trials could be crucial for changing the prognosis of patients with advanced/metastatic UM. In this systematic review, we analyzed all emerging and available literature on the new perspectives in the treatment of UM and patient outcomes; furthermore, their current limitations and more common adverse events are summarized.

Safety and Efficacy of Intravitreal Chemotherapy (Melphalan) to Treat Vitreous Seeds in Retinoblastoma.

Background: Active vitreous seeds in eyes with retinoblastoma (Rb) adversely affects the treatment outcome. This study aimed to investigate the safety and efficacy of intravitreal melphalan chemotherapy (IViC) as a treatment for recurrent and refractory vitreous seeds in patients with Rb. Methods: We used a retrospective non-comparative study of patients with intraocular Rb who had vitreous seeds and were treated by IViC (20-30 µg of melphalan) using the safety-enhanced anti-reflux technique. Tumor response, ocular toxicity, demographics, clinical features, and survival were analyzed. Results: In total, 27 eyes were treated with 108 injections for recurrent (16 eyes) or refractory (11 eyes) vitreous seeds after failed systemic chemotherapy. A total of 15 (56%) were males, and 20 (74%) had bilateral disease. At diagnosis, the majority (n = 21) of the injected eyes were group D, and n = 6 were group C. Vitreous seeds showed complete regression in 21 (78%) eyes; 100% (n = 10) for eyes with focal seeds; 65% (n = 11/17 eyes) for eyes with diffuse seeds (p = 0.04); 7 (64%) eyes with refractory seeds; and 14 (87%) eyes with recurrent seeds showed complete response (p = 0.37). In total, 16 (59%) eyes developed side effects: retinal toxicity (48%), pupillary synechiae (15%), cataracts (30%), iris atrophy (7%), and retinal and optic atrophy (4%). Only one child was lost to follow-up whose family refused enucleation and none developed orbital tumor recurrence or distant metastasis. Conclusion: IViC with melphalan is effective (more for focal than diffuse seeding) and a relatively safe treatment modality for Rb that can improve the outcomes of eye salvage procedures. However, unexpected toxicity can occur even with the standard dose of 20-30 µg.

Delayed Intravitreal Anti-VEGF Therapy for Patients During the COVID-19 Lockdown: An Ethical Endeavor.

PURPOSE: To assess the impact of Jordanian's Corona Virus Disease (COVID-19) lockdown on visual acuity and macular thickness in patients with macular edema receiving intravitreal injections, and to assess the ethical endeavor of lockdown among serious sight threatening conditions. PATIENTS AND METHODS: This retrospective observational study included patients planned for intravitreal injections who did not complete the planned course before the lockdown (ie, before 20th of March 2020). Data included demographics, indication for the intravitreal injection, corrected distance visual acuity (CDVA), and central macular thickness on Optical Coherence Tomography (OCT) before and after the lockdown. RESULTS: One-hundred and sixty-six eyes of 125 patients were studied, 68 (54.4%) patients were males, and the mean (± standard deviation, SD) age was 64.79 (±9.41) years. Mean (±SD) duration of delay in the planned injection was 60.97 (±24.35) days. The change in visual acuity was statistically significant for patients with diabetic macular edema (p= 0.045 improvement), patients with central retinal vein thrombosis (CRVO) (p= 0.05 deterioration), and patients with age-related macular degeneration (AMD) (p= 0.005 deterioration). Of interest, delay of more than 2 months and the previous need for 3 or more injections were significant poor prognostic factors for visual outcome for patients with diabetic macular edema (p=0.027 and 0.045). CONCLUSION: The impact of delay in the scheduled intravitreal injections resulted in variable outcomes depending on the indication. Triaging the urgency of patients should be based on the indication to support the equity principle of bioethics, where those in need are prioritized against others, depending on potential adverse outcome.

Management and Outcomes of Unilateral Group D Tumors in Retinoblastoma.

PURPOSE: Retinoblastoma presents most commonly as advanced unilateral disease, particularly in developing countries for which primary enucleation has been the preferred method of treatment. However, with the evolution of newer treatment modalities including intravitreal chemotherapy, intra-arterial chemotherapy and newer chemotherapeutic combinations, a trend towards more conservative approaches is being observed. Our aim is to evaluate outcomes of group D eyes following conservative and non-conservative treatment options. PATIENTS AND METHODS: The ocular oncology database was used to identify eyes with unilateral retinoblastoma that fulfilled the International Intraocular Retinoblastoma Classification (IIRC) group D criteria from August 2010 to August 2018 and these were retrospectively reviewed. Overall, 39 eyes were identified. RESULTS: Nineteen (49%) eyes underwent primary enucleation and 20 (51%) received eye-conserving treatment. Eye salvage was possible in 15 (75%) eyes in the attempted salvage group. None of the patient revealed signs of metastasis. All eyes received conventional chemotherapy (carboplatin, vincristine, etoposide) and focal laser therapy. Additional treatment modalities offered included intravitreal chemotherapy, intra-arterial chemotherapy and topotecan. Three (11%) eyes in the primary enucleation group showed high-risk features on histopathology and none developed metastasis. CONCLUSION: The results of the study seem promising and conservative measures can be adopted in selected unilateral group D eyes.

Coats' disease: characteristics, management, outcome, and scleral external drainage with anterior chamber maintainer for stage 3b disease.

To report on the characteristics and outcome of management of Coats' disease, and to describe a novel surgical technique for management of stage 3B with total retinal detachment (RD) by scleral external drainage with anterior chamber (AC-maintainer) placement before the drainage without pars plana vitrectomy.A retrospective study of 26 eyes from 25 Coats' patients. Outcome measures included: demographics, presentation, laterality, stage, treatment, and outcome.The median age at diagnosis was 3.5 years. Twenty patients (80%) were males, and all except 1 girl had unilateral disease. The presenting complaint was impaired vision in 13 (50%) eyes, leukocoria in 6 (23%) eyes, and strabismus in 7 (27%) eyes. Based on the Shields classification; 3(12%) eyes were stage 1, 9 (35%) eyes were stage 2, 10 (38%) eyes were stage 3, 2 (8%) eyes were stag e4, and 2 (8%) eyes were stage 5. Primary management included cryotherapy (54%), laser photocoagulation (27%), intravitreal anti-vascular endothelial growth factor (23%), intravitreal steroids (23%), and surgical drainage (12%). The 3 eyes in stage 3B (with total exudative RD) underwent subretinal fluid drainage with AC maintainer, and all had the retina reattached completely for 6 months follow up after the surgery. At mean follow up 21 months, 4 (15%) eyes were enucleated, 19 (73%) eyes had improvement or stabilization in visual acuity.Coats' disease usually presents at advanced stage with poor visual prognosis, individualized management with close follow up are mandatory to save the eye. Subretinal fluid drainage with AC maintainer is a safe and useful technique for repairing total RD in eyes with stage 3B Coats' disease.

Rosai-Dorfman disease masquerading as Uveal Melanoma: Case report and review of literature.

OBJECTIVE/BACKGROUND: Intra ocular Rosai-Dorfman disease (RDD) is an extremely rare disease. We are reporting the first case of RDD presenting as ciliary body mass mimicking ciliary body melanoma, and we are reviewing the English literature reporting on cases of RDD presented with intraocular disease. METHODS: An 18-year-old lady presented with loss of vision in the right eye, and was found to have intraocular mass lesion. She was diagnosed clinically and radiologically as a case of ciliary body melanoma associated with total retinal detachment. RESULTS: Histopathological sections and stains proved to be intraocular RDD. Review of the literature revealed three cases of intraocular RDD; two of them had choroid thickening associated with serous retinal detachment, and one presented with intraocular mass mimicking choroid melanoma. Two of the three cases were enucleated. Our case is the first case in English literature of intraocular ciliary body RDD, mimicking ciliary body melanoma. CONCLUSION: RDD can present as an intraocular mass that mimics ciliary body melanoma. This case emphasizes the importance of diagnostic biopsy before considering the final therapy in unclear cases, mainly when associated with unusual systemic features like lymphadenopathy.

Management outcome(s) in eyes with retinoblastoma previously inadequately treated with systemic chemotherapy alone without focal therapy.

OBJECTIVE: The objective of this study was to evaluate the outcome of management in eyes with intraocular retinoblastoma (RB) that had received inadequate initial therapy (chemotherapy without focal therapy) before eventually receiving necessary consolidation therapy at a tertiary referral center. METHODS: A retrospective observational case series of 30 eyes from 26 RB patients who had initially received systemic chemotherapy as a sole therapy. The main outcome measures were demographics, laterality, International Classification of RB (ICRB), treatments, tumor control, and survival. RESULTS: The median age at diagnosis was 24 months and the median delay between time at diagnosis and time at referral to a tertiary center that has adequate focal therapy for RB was 9.5 months (range 5-20 months). Sixteen (62%) patients were monocular from enucleation of the contralateral eye. Features of ICRB Group A tumors were seen in 3 (10%) eyes, Group B in 7 (23%) eyes, Group C in 2 (7%) eyes, Group D in 16 (53%) eyes, and Group E in 2 (7%) eyes. Eighteen (69%) patients required more systemic chemotherapy (median, 4.4 cycles; range, 2-8 cycles), and 8 (26%) eyes received local chemotherapy (subtenon, intravitreal, or intra-arterial). All treated eyes received consolidation therapy as transpupillary thermotherapy and/or cryotherapy. Radioactive plaque therapy was used in 1 (3%) eye and external beam radiation therapy in 3 (10%) eyes. At a mean follow-up of 13 months (median, 11.5 months; range, 9-27 months), enucleation was avoided in 25 (83%) eyes. Two (7%) eyes were enucleated initially, and 3 (10%) were enucleated after failure of additional therapy. Twenty-three (77%) eyes did not show any viable tumor after a median of 11.5 months of follow-up after the last treatment, and 2 (7%) eyes still have residual tumor recurrences that need more consolidation focal therapy. CONCLUSION: Chemotherapy alone cannot eradicate RB cells in effected eyes without combination with consolidation therapy by a multidisciplinary team to salvage the affected eye as well as its vision. Nonetheless, chemotherapy can be initiated (to keep the tumor at a less invasive stage) for patients from centers or countries where combination therapy is not available until they gain access to adequate management of RB.