Faculty Bibliography

Radiation therapy has saved both sight and life for eye cancer patients. The most common methods include ophthalmic plaque brachytherapy and external beam techniques. However, subsequent dose-dependent radiation vasculopathy invariably occurs within and around the targeted zone. In 2006, Finger discovered that periodic intravitreal anti-vascular endothelial growth factor (anti-VEGF) bevacizumab could reverse and suppress intraocular radiation vasculopathy. At first, it was administered at the onset of radiation-related vision loss. Though bevacizumab induced regression of macular oedema, retinal haemorrhages and cotton-wool infarcts, most patients were left with residual retinal damage, manifest as metamorphopsia and loss of vision. These results led to earlier and earlier anti-VEGF interventions: first after signs of progressive radiation retinopathy, and then for signs of radiation maculopathy, and finally for high-risk eyes with no clinical signs of retinopathy. Earlier initiation of intravitreal anti-VEGF therapy typically resulted in greater restoration and preservation of macular anatomy, reductions of retinal haemorrhages, resolution of cotton-wool spots and vision preservation. Recent research on optical coherence tomography angiography (OCT-A) has revealed that radiation vasculopathy occurs prior to clinical ophthalmic signs or symptoms. Therefore, it seemed reasonable to consider treating high-risk patients (considered certain to eventually develop radiation maculopathy) to prevent or delay vision loss. Herein, we describe the evolution of treatment for radiation maculopathy as well as recent research supporting anti-VEGF treatment of high-risk patients immediately following radiation to maximize vision outcomes.

OBJECTIVE:To analyse ocular and systemic findings of patients presenting with systemic metastasis. METHODS AND ANALYSIS/UNASSIGNED:It is an international, multicentre, internet-enabled, registry-based retrospective data analysis. Patients were diagnosed between 2001 and 2011. Data included: primary tumour dimensions, extrascleral extension, ciliary body involvement, American Joint Committee on Cancer (AJCC)-tumour, node, metastasis staging, characteristics of metastases. RESULTS:Of 3610 patients with uveal melanoma, 69 (1.9%; 95% CI 1.5 to 2.4) presented with clinical metastasis (stage IV). These melanomas originated in the iris, ciliary body and choroid in 4%, 16% and 80% of eyes, respectively. Using eighth edition AJCC, 8 (11%), 20 (29%), 24 (35%), and 17 (25%) belonged to AJCC T-categories T1-T4. Risk of synchronous metastases increased from 0.7% (T1) to 1.5% (T2), 2.6% (T3) and 7.9% (T4). Regional lymph node metastases (N1a) were detected in 9 (13%) patients of whom 6 (67%) had extrascleral extension. Stage of systemic metastases (known for 40 (59%) stage IV patients) revealed 14 (35%), 25 (63%) and 1 (2%) had small (M1a), medium-sized (M1b) and large-sized (M1c) metastases, respectively. Location of metastases in stage IV patients were liver (91%), lung (16%), bone (9%), brain (6%), subcutaneous tissue (4%) and others (5%). Multiple sites of metastases were noted in 24%. Compared with the 98.1% of patients who did not present with metastases, those with synchronous metastases had larger intraocular tumours, more frequent extrascleral extension, ciliary body involvement and thus a higher AJCC T-category. CONCLUSIONS:Though higher AJCC T-stage was associated with risk for metastases at diagnosis, even small T1 tumours were stage IV at initial presentation. The liver was the most common site of metastases; however, frequent multiorgan involvement supports initial whole-body staging.

Purpose. To describe two ipsilateral, metachronous, ocular choroidal melanoma metastases. Material and methods. A 64-year-old choroidal melanoma patient was initially treated with palladium-103 ophthalmic plaque brachytherapy which induced local control of the primary cancer. Seven years later, ophthalmic findings of a second, ipsilateral, discrete choroidal melanoma prompted restaging which revealed new hepatic and nodal metastases. Systemic immunotherapy (ipilimumab 3 mg/kg with nivolumab 1 mg/kg IV every 3 weeks 4 doses) resulted in intraocular tumor regression and was followed by maintenance nivolumab 480 mg IV every 4 weeks with follow-up ophthalmic examinations. Results. Three years after initiation of systemic immunotherapy, the patient was found to have a second ipsilateral local recurrence of choroidal melanoma. It presented with retinal detachment, uveitis, and optic neuritis. Then, due to its anterior uveal location, extrascleral tumor extension was amenable to a diagnostic biopsy. Overall, 3 years after onset of metastatic uveal melanoma and 2 months after her second ocular metastasis, the patient died. This was 10 years after the initial diagnosis of choroidal melanoma. Conclusions. Metastatic choroidal melanoma can present twice in the same eye as the primary tumor. Ophthalmic and systemic examinations allowed for immunotherapy to affect initial systemic regression, vision sparing, and globe salvage.

Sebaceous carcinoma is characterized by its aggressive local tumor behavior and ability to metastasize. Small periocular sebaceous carcinoma are typically treated by excision with cryotherapy. Larger tumors often require adjuvant external beam radiotherapy (EBRT) and/or exenteration surgery. When used alone, EBRT techniques typically exceed the tolerance of critical normal ocular structures. The interstitial orbital brachytherapy-boost technique permits dose escalation to the tumor bed, while minimizing radiation dose to critical normal ocular structures. Here, we present a case of orbital sebaceous carcinoma treated with excision, cryotherapy, and super-thick amniotic membrane fornix reconstruction. Then, after 3 weeks of healing, adjuvant-combined electron interstitial high-dose rate brachytherapy-boost was added to electron-beam radiotherapy to optimize the orbital radiation dose distribution, increase dose to inferonasal orbit, and allow relative sparing of orbital tissues. At 1-year follow-up, there was no evidence of orbital tumor, no significant eye lash loss, normal ocular motility, no radiation retinopathy, optic neuropathy and a visual acuity of 20/20.

BACKGROUND:To relate conjunctival melanoma characteristics to local control. METHODS:Retrospective, registry-based interventional study with data gathered from 10 ophthalmic oncology centres from 9 countries on 4 continents. Conjunctival melanoma patients diagnosed between January 2001 and December 2013 were enrolled in the study. Primary treatments included local excision, excision with cryotherapy and exenteration. Adjuvant treatments included topical chemotherapy, brachytherapy, proton and external beam radiotherapy (EBRT). Cumulative 5-year and 10-year Kaplan-Meier local recurrence rates were related to clinical and pathological T-categories of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system. RESULTS:288 patients had a mean initial age of 59.7±16.8 years. Clinical T-categories (cT) were cT1 (n=218,75.7%), cT2 (n=34, 11.8%), cT3 (n=15, 5.2%), cTx (n=21,7.3%) with no cT4. Primary treatment included local excision (n=161/288, 55.9%) followed by excision biopsy with cryotherapy (n=108/288, 37.5%) and exenteration (n=5/288, 1.7%). Adjuvant therapies included topical mitomycin (n=107/288, 37.1%), plaque-brachytherapy (n=55/288, 19.1%), proton-beam (n=36/288, 13.5%), topical interferon (n=20/288, 6.9%) and EBRT (n=15/288, 5.2%). Secondary exenteration was performed (n=11/283, 3.9%). Local recurrence was noted in 19.1% (median=3.6 years). Cumulative local recurrence was 5.4% (3.2-8.9%), 19.3% (14.4-25.5%) and 36.9% (26.5-49.9%) at 1, 5 and 10 years, respectively. cT3 and cT2 tumors were twice as likely to recur than cT1 tumours, but only cT3 had statistically significantly greater risk of local recurrence than T1 (p=0.013). Factors such as tumour ulceration, plica or caruncle involvement and tumour thickness were not significantly associated with an increased risk of local recurrence. CONCLUSION/CONCLUSIONS:This multicentre international study showed that eighth edition of AJCC tumour staging was related to the risk of local recurrence of conjunctival melanoma after treatment. The 10-year cumulative local recurrence remains high despite current management.

Background/UNASSIGNED:Ciliary body tumors can remain undetected and achieve large dimensions. Pigmented ciliary body tumors include: melanoma, leiomyoma and melanocytoma, however correct diagnosis may require tissue diagnosis with immunohistochemical stains. Case presentation/UNASSIGNED:Two men presented with identical ciliochoroidal tumors. Both had darkly pigmented dome-shaped anterior uveal masses, exudative retinal detachments and transillumination shadowing. Ocular PET-CT imaging revealed that both were metabolically active consistent with a diagnosis of cancer. However, immunohistochemical examination revealed one a leiomyoma and the other melanoma. Conclusion/UNASSIGNED:Uveal leiomyoma can be an indistinguishable doppelgänger to ciliochoroidal melanoma, where the diagnosis can only be established by immunohistopathology.

PURPOSE/OBJECTIVE:To compare metastasis-related mortality, local treatment failure and globe salvage after retinoblastoma (RB) in countries with different national income levels. DESIGN/METHODS:International, multicenter, registry-based retrospective case series PARTICIPANTS: Two thousand one hundred and ninety patients, 18 ophthalmic oncology centers, 13 countries within 6 continents. METHODS:edition AJCC staging and analysis for the main outcome measures were available for 2085 patients. Each country was classified by national income level, as defined by the 2017 United Nations World Population Prospects and included high-income countries (HIC), upper middle-income countries (UMIC) and lower middle-income countries (LMIC). Patient survival was estimated with the Kaplan-Meier method. Logistic and Cox proportional hazards regression models were used to determine associations between national income and treatment outcomes. MAIN OUTCOME MEASURES/METHODS:Metastasis-related mortality and local treatment failure (defined as use of secondary enucleation or external beam radiation therapy). RESULTS:The majority (60%) of study patients resided in UMIC and LMIC. The global median age at diagnosis was 17.0 months [higher in UMIC (20.0 months) and LMIC (20.0 months) than HIC (14.0 months; p<0.001)]. Patients in UMIC and LMIC reported higher rates of disease-specific metastasis-related mortality and local treatment failure. As compared with HIC, metastasis-related mortality was 10.3-fold higher for UMIC and 9.3-fold higher for LMIC, and the risk for local treatment failure was 2.2-fold and 1.57-fold higher, respectively (all p<0.001). CONCLUSION/CONCLUSIONS:This international, multicenter, registry-based analysis of RB management revealed that lower national income levels were associated with significantly higher rates of metastasis-related mortality, local treatment failure and lower globe salvage.

OBJECTIVE:To perform micro-incision, trans-iridal, aspiration-cutter-assisted biopsy for ciliary body tumours. DESIGN/METHODS:Retrospective, nonrandomized, observational, interventional case series. METHODS:Five consecutive patients undergoing ciliary body tumour biopsy were clinically diagnosed using slit-lamp photography, gonioscopy, high-frequency ultrasound imaging, and systemic radiographic staging. A 1-2 mm clear cornea incision was placed opposite to the central clock hour of the ciliary body tumour. Viscoelastic was infused into the anterior chamber for stabilization and endothelial protection. Then, a 27-gauge aspiration cutter was used to make an iridotomy at the iris root and then extend through the iris into the tumour. Biopsy was performed using mechanical cutting starting at 300 cuts per minute and aspiration at 600 mm Hg. After withdrawal of the cutter from the eye, the effluent tube was flushed into a 3 cc syringe, inspected for specimen under the operating microscope and sent for pathology. Multiple biopsies were performed on each patient. Viscoelastic was removed and Seidel examination of the corneal wound performed. RESULTS:Five eyes were biopsied. A mean 3.6 passes were used to obtain tumour tissue. Tumour cells and tissue were obtained in all cases. Cytologic, histopathologic, and immuno-histochemical analysis were performed (100%, n = 5/5). Diagnoses included melanoma (60%, n = 3/5), melanocytoma (20%, n = 1/5), and leiomyoma (20%, n = 1/5). Transient postoperative hyphemas cleared within 1 week (80%, n = 4/5). No secondary glaucoma, infection, or cataracts were noted. CONCLUSION/CONCLUSIONS:Aspiration-cutter biopsy through the iris root provided a minimally invasive, safe method for obtaining ciliary body tissue for cytology, histopathology, and immunohistochemical analysis.

Purpose/UNASSIGNED:To provide real-world data on the world-wide-web for patient and doctor awareness. Methods/UNASSIGNED:From December 2017 to January 2020, consecutive patients with choroidal melanoma (CM), iris ciliary body melanoma (ICM), and ocular surface squamous carcinoma (OSSC) had specific outcomes recorded at each return visit. Each result was anonymized, entered in an online portal, and sent to a unique software program where it was used to create real-world data of number of patients, mean vision, local tumor control, eye salvage, systemic metastases, and length of follow-up for our eye cancer center. Results/UNASSIGNED:A HIPAA compliant, internet-based software program was developed and linked to public access web page to collect and analyze near-real-time data pertaining to the treatment, vision, life, and follow-up time of patients. During this period, CM radiation plaque tumor control was 99.7%, median vision 20/25 (mean 20/50) and eye salvage 95.8%. ICM tumor control was 99.1% and the median vision 20/20 (mean 20/20). OSSC tumor control was 100% and the most common vision was 20/20 (mean 20/25). Rates of primary enucleation as treatment were 4.2% for CM, 2.8% for ICM, and 0% for OSSC. All patient results were updated by the ophthalmic oncology fellow at each patient visit as to reflect near-real-time outcomes at our center. Conclusion/UNASSIGNED:Prospective data collection of returning patients was found to be a simple method to reflect patient care outcomes. This method of reporting doctor outcomes offers a measure of transparency for patients and an opportunity to compare results with other clinical practices.

PURPOSE/OBJECTIVE:edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual to estimate metastatic and mortality rates for children with retinoblastoma(RB). DESIGN/METHODS:International, multicenter, registry-based retrospective case series PARTICIPANTS: 2190 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents. METHODS:Patient-specific data fields for RB were designed by participating eye cancer specialists. All RB patients with adequate records to allow tumor staging by the AJCC criteria and follow-up for metastatic disease were studied. MAIN OUTCOME MEASURES/METHODS:Metastasis-related 5- and 10-year survival data after initial tumor staging were estimated with the Kaplan-Meier method depending on AJCC clinical (cTNM) and pathological (pTNM) tumor, node, metastasis category and age, tumor laterality, and presence of heritable trait. RESULTS:Of the 2190 patients, the records of 2085 patients(95.2%) with 2905 eyes were complete. The median age at diagnosis was 17.0 months. 1260 (65.4%) had unilateral RB. Amongst the 2085 patients, tumor categories were cT1a in 55 (2.6%), cT1b 168 (8.1%), cT2a 197 (9.4%), cT2b 812 (38.9%), cT3 835 (40.0%) and cT4 in 18 (0.9%) patients. Of these, 1397 eyes in 1353 patients(48.1%) were treated with enucleation. One hundred and nine patients (5.2%) developed metastases and died. The median time(n=92) from diagnosis to metastasis was 9.50 months. The 5- year Kaplan-Meier cumulative survival estimates by clinical tumor categories were 100% for category cT1a, 98% (95% confidence interval[CI], 97-99) for cT1b and cT2a, 96% (95% CI, 95-97) for cT2b, 89%(95% CI, 88-90) for cT3 tumors, and 45%(95% CI, 31-59) for cT4 tumors, respectively. Risk of metastasis increased with increasing cT (and pT) category(p < .001). Cox proportional hazards regression analysis confirmed a higher risk of metastasis in category cT3 (hazard rate [HR], 8.09; 95% CI, 2.55-25.70; p<0.001) and cT4 (HR, 48.55; 95% CI, 12.86-183.27; p< 0.001) compared to category cT1. Age, tumor laterality and presence of heritable trait did not influence the incidence of metastatic disease. CONCLUSION/CONCLUSIONS:edition AJCC RB Staging System for metastasis-related mortality and offered a proof of concept yielding quantitative, predictive estimates per category in a large, real life, heterogenous RB patient population.