Carlos Bianciotto

Intra-arterial Chemotherapy for Retinoblastoma: Report No. 1, Control of Retinal Tumors, Subretinal Seeds, and Vitreous Seeds

OBJECTIVE To describe tumor control following intra-arterial chemotherapy (IAC) for retinoblastoma. METHODS A retrospective interventional series in which 17 patients were treated with ophthalmic artery injection of melphalan, 5 mg, was undertaken to determine retinoblastoma control. RESULTS Of 190 children with retinoblastoma, 17 (9%) were treated with IAC. Catheterization was successful in 37 of 38 attempts. The treatment was primary in 13 cases (1 failed catheterization) and secondary in 4. The median retinoblastoma base was 20 mm and the median retinoblastoma thickness was 9.0 mm. Iris neovascularization was present in 5 cases. Following IAC, complete response of the main tumor was found in 14 cases (88%) and partial response was found in 2 (12%). Eyes with complete response and followed up for a minimum of 1 year (n = 10) showed no solid tumor recurrence. Of 11 eyes with subretinal seeds, 9 (82%) had complete response, 1 (9%) had partial response, and 1 (9%) had recurrence. Of 9 eyes with vitreous seeds, 6 (67%) had complete response, 2 (22%) had partial response, and 1 (11%) had recurrence. Globe salvage was achieved in 8 of 12 eyes (67%) treated with primary IAC, including 2 of 2 group C eyes, 4 of 4 group D eyes, and 2 of 6 group E eyes according to the International Classification of Retinoblastoma. Globe salvage was achieved in 2 of 4 eyes (50%) treated secondarily after failure of other methods. CONCLUSIONS Of 12 eyes managed with IAC as primary treatment, globe salvage was achieved in 67%. Eyes classified as group C or D showed 100% globe salvage, whereas group E had 33% salvage. Of 4 eyes managed with IAC as secondary treatment, globe salvage was achieved in 50%.

Prognosis of Uveal Melanoma in 500 Cases Using Genetic Testing of Fine-Needle Aspiration Biopsy Specimens

PURPOSE To determine the relationship between monosomy 3 and incidence of metastasis after genetic testing of uveal melanoma using fine-needle aspiration biopsy (FNAB). DESIGN Noncomparative retrospective case series. PARTICIPANTS Five hundred patients. METHODS Fine-needle aspiration biopsy was performed intraoperatively immediately before plaque radiotherapy. The specimen underwent genetic analysis using DNA amplification and microsatellite assay. Systemic follow-up was obtained regarding melanoma-related metastasis. MAIN OUTCOME MEASURES Presence of chromosome 3 monosomy (loss of heterozygosity) and occurrence of melanoma metastasis. RESULTS Disomy 3 was found in 241 melanomas (48%), partial monosomy 3 was found in 133 melanomas (27%), and complete monosomy 3 was found in 126 melanomas (25%). The cumulative probability for metastasis by 3 years was 2.6% for disomy 3, 5.3% for partial monosomy 3 (equivocal monosomy 3), and 24.0% for complete monosomy 3. At 3 years, for tumors with disomy 3, the cumulative probability of metastasis was 0% for small (0-3 mm thickness), 1.4% for medium (3.1-8 mm thickness), and 23.1% for large (>8 mm thickness) melanomas. At 3 years, for tumors with partial monosomy 3, the cumulative probability of metastasis was 4.5% for small, 6.9% for medium, and [insufficient numbers] for large melanomas. At 3 years, for tumors with complete monosomy 3, the cumulative probability of metastasis was 0% for small, 24.4% for medium, and 57.5% for large melanomas. The most important factors predictive of partial or complete monosomy 3 included increasing tumor thickness (P = 0.001) and increasing distance to optic disc (P = 0.002). CONCLUSIONS According to FNAB results, patients with uveal melanoma demonstrating complete monosomy 3 have substantially poorer prognosis at 3 years than those with partial monosomy 3 or disomy 3. Patients with partial monosomy 3 do not significantly differ in outcome from those with disomy 3.

Intra-arterial Chemotherapy for Retinoblastoma: Report No. 2, Treatment Complications

OBJECTIVE To describe treatment complications following intra-arterial chemotherapy (IAC) for retinoblastoma. METHODS A retrospective interventional series of ophthalmic artery cannulation for IAC injection (3 planned sessions at 1-month intervals) was undertaken. Thirty-eight catheterizations of 17 eyes of 17 patients were performed from September 2008 to September 2010. Fluoroscopy of the ophthalmic artery was performed before and immediately after treatment. Heparin was given during the procedure and aspirin (40 mg) was given orally for 1 week. The treatment complications were determined. RESULTS Only 17 of 190 children were selected for treatment with IAC during this period. Following successful ophthalmic artery cannulation in 16 cases, there was no evidence of metastasis, stroke, brain injury, or persistent systemic toxic effects. Fluoroscopy demonstrated patent ophthalmic artery immediately before and after IAC injection in each case. Following therapy, orbital and adnexal findings at 1 month included eyelid edema (n = 13), blepharoptosis (n = 10), cilia loss (n = 1), and orbital congestion with temporary dysmotility (n = 12). These findings resolved within 6 months in all cases. Following therapy, vascular findings included ophthalmic artery stenosis (permanent in 3 cases, temporary in 1 case), confirmed on fluoroscopy in 3 cases. Concomitant central or branch retinal artery occlusion was noted (permanent in 2 cases, temporary in 1 case). Subtle retinal pigment epithelial mottling in 9 cases that slowly evolved to later-onset underlying choroidal atrophy in 5 cases was noted. CONCLUSIONS Treatment with IAC for retinoblastoma can lead to mild and severe short-term ocular complications, including eyelid edema as well as potentially blinding vascular obstruction. This procedure should be used with caution.

Assessment of Anterior Segment Tumors with Ultrasound Biomicroscopy versus Anterior Segment Optical Coherence Tomography in 200 Cases

PURPOSE To compare ultrasound biomicroscopy (UBM) versus anterior segment optical coherence tomography (AS-OCT) for imaging of tumors of the anterior segment of the eye. DESIGN Retrospective, noninterventional case series. PARTICIPANTS We included 200 patients. METHODS Review of medical records of patients who underwent both UBM and AS-OCT for evaluation of anterior segment tumors. MAIN OUTCOME MEASURES Comparison of tumor surface and internal visualization. RESULTS There were 200 eyes with anterior segment tumors involving the iris stroma in 96 (48%), ciliary body in 14 (7%), combined iris and ciliary body in 32 (16%), iris pigment epithelium (IPE) in 44 (22%), conjunctiva in 6 (3%), sclera in 4 (2%), and others in 6 (1% each). The diagnoses included nevus in 75 eyes (38%), melanoma in 47 (24%), cyst in 48 (24%), epithelioma (adenoma) in 5 (3%), metastasis, melanocytosis and melanocytoma in 4 eyes each (2%), and others (1% each). Image analysis (UBM vs AS-OCT) revealed adequate visualization of all tumor margins (189 [95%] vs 80 [40%]), posterior tumor shadowing (9 [5%] vs 144 [72%]), and high overall image quality (159 [80%] vs 136 [68%]). Comparison for better image resolution (UBM vs AS-OCT) disclosed UBM provided better overall tumor visualization (138 [69%] vs 62 [31%]) and better resolution of the posterior margin (147 [74%] vs 53 [27%]), whereas AS-OCT provided better resolution of the anterior margin (40 [20%] vs 160 [80%]) as well as better overall resolution of anterior segment anatomy (41 [21%] vs 159 [80%]). Better resolution was found with UBM for pigmented tumors (n = 162; 107 [66%] vs 55 [34%]) as well as for nonpigmented tumors (n = 38; 23 [61%] vs 15 [39%]). Regarding location, iris tumor resolution was similar with each technique (49 [52%] vs 45 [48%]). CONCLUSIONS For anterior segment tumors, UBM offers better visualization of the posterior margin and provides overall better images for entire tumor configuration compared with AS-OCT.

Clinical Survey of 3680 Iris Tumors Based on Patient Age at Presentation

OBJECTIVE To report the spectrum of iris lesions based on patient age at presentation. DESIGN Retrospective, nonrandomized, single-center case series. PARTICIPANTS We included 3680 iris tumors in 3451 patients. METHODS Chart review. MAIN OUTCOME MEASURES Diagnostic category based on age. RESULTS The mean age at presentation was 48 years and there were 449 (12%) tumors in children (≤20 years), 788 (21%) in young adults (21-40 years), 1308 (36%) in mid adults (41-60 years), and 1135 (31%) in senior adults (>60 years). Of 3680 tumors, the diagnostic category was cystic (n = 768; 21%) or solid (n = 2912; 79%). The cystic tumors originated from iris pigment epithelium (IPE; n = 672; 18%) or iris stroma (n = 96; 3%). The solid tumors included melanocytic (n = 2510; 68%) and nonmelanocytic (n = 402; 11%). The melanocytic tumors comprised nevus (n = 1503; 60%), melanocytoma (n = 68; 3%), melanoma (n = 645; 26%), and melanocytosis (n = 64; 3%). Of 2510 melanocytic tumors, the first and second most common diagnoses by age (children, young adult, mid adult, senior adult) were nevus (53%, 57%, 63%, and 63%, respectively) and melanoma (17%, 27%, 26%, and 27%, respectively). The nonmelanocytic tumors included categories of choristomatous (n = 4; <1%), vascular (n = 57; 2%), fibrous (n = 2; <1%), neural (n = 3; <1%), myogenic (n = 2;, <1%), epithelial (n = 35; 1%), xanthomatous (n = 8; <1%), metastasis (n = 67; 2%), lymphoid (n = 12; <1%), leukemic (n = 2; <1%), secondary (n = 12; <1%), and nonneoplastic simulators (n = 198; 5%). The median age (in years) at diagnosis included cystic (39), melanocytic (52), choristomatous (0.7), vascular (56), fibrous (53), neural (8), myogenic (42), epithelial (63), xanthomatous (1.9), metastasis (60), lymphoid (57), leukemic (25.5), secondary (59), and nonneoplastic simulators (49). Overall, the 3 most common specific diagnoses (children, young adult, mid adult, senior adult) were nevus (25%, 36%, 47%, and 47%, respectively), IPE cyst (28%, 30%, 15%, and 14%, respectively), and melanoma (8%, 16%, 20%, and 19%, respectively). CONCLUSIONS In an ocular oncology practice, the spectrum of iris tumors includes cystic (21%) and solid (79%) tumors. The solid tumors were melanocytic (68%) or nonmelanocytic (11%). At all ages, the most common specific diagnoses were nevus (42%), IPE cyst (19%), and melanoma (17%).

Histopathologic Observations After Intra-arterial Chemotherapy for Retinoblastoma

OBJECTIVE To describe histopathologic observations in eyes enucleated after intra-arterial chemotherapy (IAC) for retinoblastoma (Rb). METHODS Retrospective histopathologic analysis of 8 eyes. RESULTS The eyes were enucleated for tumor viability (n = 4), neovascular glaucoma (n = 2), anaphylactic reaction from IAC (n = 1), and persistent retinal detachment with poor visualization of the tumor (n = 1). Of the 2 eyes judged clinically with complete tumor regression and the 5 with viable tumor, the findings were confirmed on histopathology. The Rb response ranged from minimal (n = 1) to moderate (n = 1) to extensive (n = 4) to complete regression (n = 2). Viable vitreous seeds (n = 4 eyes), invasion into the optic nerve (n = 3), reaching the lamina cribrosa in 2 cases, and invasion into the choroid (n = 1) were observed. Histopathologic evidence of ischemic atrophy involving the outer retina and choroid was found in 4 eyes. One eye treated at another center with IAC and enucleated by our team for recurrence was observed to have extensive choroidal and outer retinal atrophy. This case showed orbital vascular occlusion and subendothelial smooth muscle hyperplasia. Intravascular birefringent foreign material was observed in 5 cases within occluded vessels, stimulating a granulomatous inflammatory response. The foreign material comprised cellulose fibers (n = 3), synthetic fabric fibers (n = 1), or unknown composition (n = 2). Thrombosed blood vessels were identified in 5 eyes and involved ciliary arteries in the retrobulbar orbit (n = 5), scleral emissarial canals (n = 1), small choroidal vessels (n = 1), and central retinal artery (n = 1). CONCLUSION Retinoblastoma can be controlled with IAC, but histopathology of enucleated eyes reveals that ocular complications including thromboembolic events can occur.

Proliferative Radiation Retinopathy after Plaque Radiotherapy for Uveal Melanoma

PURPOSE To determine risk factors, occurrence rate, management, and outcome of proliferative radiation retinopathy (PRR) after plaque radiotherapy for uveal melanoma. DESIGN Case-control study. PARTICIPANTS Three thousand eight hundred forty-one patients who underwent plaque radiotherapy for uveal melanoma were entered into the study. METHODS Retrospective review of medical records. MAIN OUTCOME MEASURES Proliferative radiation retinopathy after plaque radiotherapy for uveal melanoma. RESULTS Of 3841 eyes treated with plaque radiotherapy for uveal melanoma, PRR developed in 5.8% at 5 years and in 7% at 10 and 15 years using Kaplan-Meier analysis. The mean time to onset of PRR was 32 months (median, 30 months; range, 4-88 months). On univariate analysis, baseline factors predictive of PRR (P<0.05) included young age, diabetes, hypertension, Hispanic race, shorter tumor distance to the optic disc and to the foveola, Bruchs membrane rupture, choroidal location of the tumor, subretinal fluid, higher radiation dose to the optic nerve and to the foveola, higher radiation rate to the tumor apex and to the tumor base, additional transpupillary thermotherapy, and notched plaque. In the multivariate model, young age (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.25-1.67, per decade decrease), diabetes mellitus (OR, 2.73; 95% CI, 1.69-4.40), and shorter tumor distance to the optic disc (OR, 1.10; 95% CI, 1.04-1.17) were related to the occurrence of PRR. The most common forms of management included panretinal photocoagulation (70%), vitrectomy (21%), and observation (17%). Resolution of the neovascularization was obtained in 63% of eyes after treatment. CONCLUSIONS Proliferative radiation retinopathy developed in 7% of eyes by 10 years after plaque radiotherapy for uveal melanoma. The main factors for development of PRR included young age, preexistent diabetes mellitus, and shorter tumor distance to the optic disc.

Minimal Exposure (One or Two Cycles) of Intra-arterial Chemotherapy in the Management of Retinoblastoma

PURPOSE To assess the efficacy of less than 3 cycles of intra-arterial chemotherapy (IAC) for retinoblastoma. DESIGN Retrospective, nonrandomized, interventional case series. PARTICIPANTS Eight patients. INTERVENTION Intra-arterial chemotherapy. MAIN OUTCOME MEASURES Tumor control and globe salvage. RESULTS Eight patients received fewer than 3 cycles of IAC for retinoblastoma because there was complete tumor control with no residual viable tumor (n = 7) or poor response (n = 1) with little hope that further therapy would benefit the patient. In 3 cases, additional vascular compromise precluded further IAC. The treatment was primary in 6 cases and secondary after failure of other treatment in 2 cases. The 8 eyes were classified (International Classification of Retinoblastoma) as group C (n = 2), group D (n = 3), group E (n = 1), and secondary treatment (n = 2). At initial examination, the main tumor showed a mean basal diameter of 16 mm, a thickness of 8.6 mm, vitreous seeds (n = 2), subretinal seeds (n = 6), and iris neovascularization (n = 1). Three patients were treated with a single cycle of IAC, and 5 patients were treated with 2 cycles of IAC. After IAC, complete tumor response was found in 7 eyes (88%) and partial response was found in 1 eye (13%). Over a mean of 13 months follow-up, there was intraretinal tumor recurrence (n = 1), subretinal seed recurrence (n = 1), and no case of vitreous seed recurrence. Globe salvage was achieved in 2 of 2 group C eyes (100%), 3 of 3 group D eyes (100%), 0 of 1 group E eye (0%), and 1 of 2 secondary treatment eyes (50%). Globe salvage was achieved in 6 of 8 eyes (75%), and 2 of 8 eyes (25%) required enucleation. CONCLUSIONS One or 2 cycles of IAC can be sufficient for selected eyes with group C or D retinoblastoma, with remarkable tumor control. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Intravenous and intra-arterial chemotherapy for retinoblastoma: what have we learned?

Purpose of review To review the recent literature on two methods of chemotherapy for retinoblastoma using intravenous versus intra-arterial route. Recent findings In 1996, the era of intravenous chemotherapy (chemoreduction) for retinoblastoma was introduced with major centers providing published information on impressive tumor control, without the need for external beam radiotherapy or enucleation. Later reports heralded continued impressive long-term control, minimal systemic toxicities, likely prevention of pinealoblastoma (trilateral retinoblastoma), and reduction in numbers of germline mutation second cancers. There is no reported ophthalmic toxicity and no evidence of reduction in fertility with chemoreduction. In 2011, the era of intra-arterial chemotherapy was announced with several studies and three conflicting editorials in the literature. This technique requires a catheterization through the arterial tree from the femoral artery into the ophthalmic artery. Outstanding tumor control is achieved with only three cycles, but more-than-expected ocular ischemic events have been noted. Further improvements in this technique could minimize complications. Summary Both intravenous and intra-arterial chemotherapy are powerful methods for retinoblastoma control. In addition to tumor control, intravenous chemotherapy protects from systemic metastasis and pinealoblastoma, minimizes long-term second cancers, and has few systemic and no ocular toxicities. Intra-arterial chemotherapy provides excellent tumor control for slightly more advanced eyes with retinoblastoma and, in addition, can be used to treat eyes that fail other methods. However, local ocular toxicities can be vision-threatening and long-term systemic toxicities are not yet understood.

Genomic profile of 320 uveal melanoma cases: chromosome 8p-loss and metastatic outcome.

PURPOSE Uveal melanoma (UM) was a fatal malignancy in 40% to 50% of cases. The aim of this study is to evaluate the independent contributions of chromosome 1, 3, 6, and 8 abnormalities for prognostication of metastasis, and to define multichromosome copy number aberration (CNA) signatures that can be used to evaluate risk. METHODS A series of 320 UM were analyzed for chromosome 1, 3, 6, and 8 abnormalities using whole genome single-nucleotide polymorphism arrays. Results for changes in six chromosomal regions were analyzed using univariate and multivariate Cox proportional hazard modeling to identify significant predictors of metastasis and CNA signatures. RESULTS Univariate Cox analysis indicated that losses of chromosome 3, 1p, 6q, and 8p and gain of 8q, as well as sex, source of tumor tissue (fine-needle aspiration biopsy [FNAB] compared with tumor from an enucleated eye), tumor basal diameter and height, and ciliary body involvement were all significant predictors of poor metastatic outcome. In the multivariate analysis, loss of chromosome 3 and 8p remained significant after adjusting for the effects of all other variables, as did sex, tissue source, and basal diameter. Multivariate analysis of the joint effects of changes in the six chromosomal regions showed that six signatures, including chromosome 3-loss, 1p-loss, 8p-loss, and/or 8q-gain had hazard ratios (HR) ranging from 7.90 to 37.25. CONCLUSIONS In UM, tumor size and location, tissue source, and sex were all significantly associated with increased metastasis. In addition, chromosome 3-loss and 8p-loss were found to be independent predictors of poor metastatic outcome and CNA signatures were identified that can add a specific HR value for classification of risk categories.