Non-synonymous, synonymous, and non-coding nucleotide variants contribute to recurrently altered biological processes during retinoblastoma progression.

Retinoblastomas form in response to biallelic RB1 mutations or MYCN amplification and progress to more aggressive and therapy-resistant phenotypes through accumulation of secondary genomic changes. Progression-related changes include recurrent somatic copy number alterations and typically non-recurrent nucleotide variants, including synonymous and non-coding variants, whose significance has been unclear. To determine if nucleotide variants recurrently affect specific biological processes, we identified altered genes and over-represented variant gene ontologies in 168 exome or whole-genome-sequenced retinoblastomas and 12 tumor-matched cell lines. In addition to RB1 mutations, MYCN amplification, and established retinoblastoma somatic copy number alterations, the analyses revealed enrichment of variant genes related to diverse biological processes including histone monoubiquitination, mRNA processing (P) body assembly, and mitotic sister chromatid segregation and cytokinesis. Importantly, non-coding and synonymous variants increased the enrichment significance of each over-represented biological process term. To assess the effects of such mutations, we examined the consequences of a 3' UTR variant of PCGF3 (a BCOR-binding component of Polycomb repressive complex I), dual 3' UTR variants of CDC14B (a regulator of sister chromatid segregation), and a synonymous variant of DYNC1H1 (a regulator of P-body assembly). One PCGF3 and one of two CDC14B 3' UTR variants impaired gene expression whereas a base-edited DYNC1H1 synonymous variant altered protease sensitivity and stability. Retinoblastoma cell lines retained only ~50% of variants detected in tumors and enriched for new variants affecting p53 signaling. These findings reveal potentially important differences in retinoblastoma cell lines and tumors and implicate synonymous and non-coding variants, along with non-synonymous variants, in retinoblastoma oncogenesis.

Response criteria for intraocular retinoblastoma: RB-RECIST.

Standardized guidelines for assessing tumor response to therapy are essential for designing and conducting clinical trials. The Response Evaluation Criteria In Solid Tumors (RECIST) provide radiological standards for assessment of solid tumors. However, no such guidelines exist for the evaluation of intraocular cancer, and ocular oncology clinical trials have largely relied on indirect measures of therapeutic response-such as progression-free survival-to evaluate the efficacy of treatment agents. Herein, we propose specific criteria for evaluating treatment response of retinoblastoma, the most common pediatric intraocular cancer, and emphasize a multimodal imaging approach for comprehensive assessment of retinoblastoma tumors in clinical trials.

A single-arm study of systemic and sub-Tenon chemotherapy for Groups C and D intraocular retinoblastoma: A Children's Oncology Group study (ARET 0231).

BACKGROUND: Eyes with Group D intraocular retinoblastoma have low salvage rates. A pilot study showed safety and efficacy of sub-Tenon's fascia carboplatin with systemic chemotherapy supporting further study. METHODS: Children with newly diagnosed bilateral intraocular retinoblastoma with at least one remaining Group C or D eye were treated with six courses of carboplatin/etoposide/vincristine (CEV) with sub-Tenon's fascia carboplatin for Group C/D eyes during courses 2-4. Local ophthalmic therapy started at course 3. The primary study objective was to determine the 1-year failure rate of Group D eyes. RESULTS: The study closed prematurely due to poor accrual and 22 of 30 patients were evaluable for failure rate, contributing 25 Group D and four Group C eyes. Among the 25 Group D eyes, there were 13 failures within the first year of study enrollment including eight needing external beam radiotherapy (EBR) and five needing enucleation, resulting in 1-year failure rate of 52%. The failure rate was significantly lower than the historical rate of 70% (P = .039). The 1-year eye preservation rate for Group D eyes was 80% (20/25). One-year failure rate for Group C eyes was 25% (1/4); 1-year preservation rate was 100% without need for EBR. Systemic toxicity included Grade 3 hearing loss in two subjects, infections, neutropenia, and thrombocytopenia. Ocular toxicities included periorbital fat atrophy (13/29 = 45% eyes), optic nerve atrophy (1/29 = 3% eyes), and restrictive fibrosis (1/29 = 3% eyes). CONCLUSIONS: Sub-Tenon's fascia carboplatin plus CEV was partially effective in Group D intraocular retinoblastoma but had unacceptable ocular toxicities.

The RB1 Story: Characterization and Cloning of the First Tumor Suppressor Gene.

The RB1 gene is the first described human tumor suppressor gene and plays an integral role in the development of retinoblastoma, a pediatric malignancy of the eye. Since its discovery, the stepwise characterization and cloning of RB1 have laid the foundation for numerous advances in the understanding of tumor suppressor genes, retinoblastoma tumorigenesis, and inheritance. Knowledge of RB1 led to a paradigm shift in the field of cancer genetics, including widespread acceptance of the concept of tumor suppressor genes, and has provided crucial diagnostic and prognostic information through genetic testing for patients affected by retinoblastoma. This article reviews the long history of RB1 gene research, characterization, and cloning, and also discusses recent advances in retinoblastoma genetics that have grown out of this foundational work.

Lens Dose-Response Prediction Modeling and Cataract Incidence in Patients With Retinoblastoma After Lens-Sparing or Whole-Eye Radiation Therapy.

PURPOSE: We retrospectively assessed the incidence of cataracts in patients with retinoblastoma (Rb) treated with either lens-sparing radiation therapy (LSRT) or whole-eye radiation therapy (WERT). A secondary aim of this study was to model the dose-response risk of cataract. METHODS AND MATERIALS: We reviewed 65 patients with Rb treated with radiation therapy (RT) at Children's Hospital, Los Angeles from 1997 to 2015. Eyes that were enucleated before RT or lacked follow-up eye examinations were excluded. All patients underwent computed tomography simulation, and mean lens dose data were collected. Follow-up ophthalmologic examinations and intraocular lens implant history were reviewed for cataracts. The primary event-free survival (EFS) outcome was cataract development. Eyes without cataracts were censored on the last date of eye examination or post-RT enucleation, if applicable. Kaplan-Meier estimates were used to compare EFS outcomes, and dose response was projected with Cox regression and logistic regression models. RESULTS: Sixty-one patients (94 eyes) were analyzed with a median follow-up of 51.8 months. For eyes treated with WERT, cataracts developed in 71.7% versus 35.3% for LSRT. Median EFS for WERT and LSRT were 20.8 and 67.9 months, respectively. Compared with WERT, a significant EFS benefit was demonstrated for LSRT (P < .001). Mean lens dose had a significant effect on cataracts in both Cox regression and logistic regression models (P < .01). The mean lens dose of 7 Gy was projected to have a 5-year cataract incidence of 20% and 25% with the logistic and Cox regression models, respectively. CONCLUSIONS: We report the first clinical data demonstrating significantly improved EFS in patients with Rb treated with LSRT. Through lens dose-response modeling, we validate a mean lens dose threshold of 7 Gy to keep cataract risk below 25%. Although RT is used less often for Rb owing to advances in chemotherapy delivery options, these findings are relevant for refining lens dose constraints, particularly in children who have received radiation dose near the orbit.

Genomic cfDNA Analysis of Aqueous Humor in Retinoblastoma Predicts Eye Salvage: The Surrogate Tumor Biopsy for Retinoblastoma.

Tumor-derived cell-free DNA (cfDNA) has biomarker potential; therefore, this study aimed to identify cfDNA in the aqueous humor (AH) of retinoblastoma eyes and correlate somatic chromosomal copy-number alterations (SCNA) with clinical outcomes, specifically eye salvage. AH was extracted via paracentesis during intravitreal injection of chemotherapy or enucleation. Shallow whole-genome sequencing was performed using isolated cfDNA to assess for highly recurrent SCNAs in retinoblastoma including gain of 1q, 2p, 6p, loss of 13q, 16q, and focal MYCN amplification. Sixty-three clinical specimens of AH from 29 eyes of 26 patients were evaluated; 13 eyes were enucleated and 16 were salvaged (e.g., saved). The presence of detectable SCNAs was 92% in enucleated eyes versus 38% in salvaged eyes (P = 0.006). Gain of chromosome 6p was the most common SCNA found in 77% of enucleated eyes, compared with 25% of salvaged eyes (P = 0.0092), and associated with a 10-fold increased odds of enucleation (OR, 10; 95% CI, 1.8-55.6). The median amplitude of 6p gain was 1.47 in enucleated versus 1.07 in salvaged eyes (P = 0.001). The presence of AH SCNAs was correlated retrospectively with eye salvage. The probability of ocular salvage was higher in eyes without detectable SCNAs in the AH (P = 0.0028), specifically 6p gain. This is the first study to correlate clinical outcomes with SCNAs in the AH from retinoblastoma eyes, as such these findings indicate that 6p gain in the aqueous humor is a potential prognostic biomarker for poor clinical response to therapy.Implications: The correlation of clinical outcomes and SCNAs in the AH identified in the current study requires prospective studies to validate these finding before SCNAs, like 6p gain, can be used to predict clinical outcomes at diagnosis. Mol Cancer Res; 16(11); 1701-12. ©2018 AACR.

Porous orbital implant after enucleation in retinoblastoma patients: indications and complications.

This study aims to identify risk factors associated with complications in retinoblastoma patients following primary and secondary enucleations with porous implant placement. A retrospective case-control study was performed between 2010 and 2015. Data pertaining to subjects' demographics, medical history, clinical, and pathological findings, implant characteristics and complications were collected. The analysis included 103 eyes of 101 patients age 27.8 ± 21.9 months undergoing enucleation for retinoblastoma. Postoperatively, 19/103 (18%) eyes developed exposure, extrusion, or hematoma requiring subsequent surgery. Exposure was the most common postoperative complication (12/19, 63%). Age at enucleation 24 months or younger, Hispanic ethnicity, female gender, and intravenous chemotherapy prior to enucleation were associated with increased odds of implant complications. In contrast, patients who were given intravitreal melphalan (IM), subtenons carboplatin (SC), or external beam radiation therapy (EBRT) did not demonstrate an increased risk of complications. In this cohort of retinoblastoma patients undergoing primary or secondary enucleation with porous implants, implant exposure was the most common postoperative complication. Our findings suggest that female gender, Hispanic ethnicity, age at enucleation 24 months or younger, and intravenous chemotherapy prior to enucleation may increase the risk of complications.

Potential of Aqueous Humor as a Surrogate Tumor Biopsy for Retinoblastoma.

Importance: Retinoblastoma (Rb) is one of the first tumors to have a known genetic etiology. However, because biopsy of this tumor is contraindicated, it has not been possible to define the effects of secondary genetic changes on the disease course. Objective: To investigate whether the aqueous humor (AH) of Rb eyes has sufficient tumor-derived DNA to perform genetic analysis of the tumor, including DNA copy number alterations. Design, Setting, and Participants: This investigation was a case series study at a tertiary care hospital (Children's Hospital Los Angeles) with a large Rb treatment center. Cell-free DNA (cfDNA) was isolated from 6 AH samples from 3 children with Rb, including 2 after primary enucleation and 1 undergoing multiple intravitreous injections of melphalan for vitreous seeding. Samples were taken between December 2014 and September 2015. Main Outcomes and Measures: Measurable levels of nucleic acids in the AH and identification of tumor-derived DNA copy number variation in the AH. The AH was analyzed for DNA, RNA, and micro-RNA using Qubit high-sensitivity kits. Cell-free DNA was isolated from the AH, and sequencing library protocols were optimized. Shallow whole-genome sequencing was performed on an Illumina platform, followed by genome-wide chromosomal copy number variation profiling to assess the presence of tumor DNA fractions in the AH cfDNA of the 3 patients. One child's cfDNA from the AH and tumor DNA were subjected to Sanger sequencing to isolate the RB1 mutation. Results: Six AH samples were obtained from 3 Rb eyes in 3 children (2 male and 1 female; diagnosed at ages 7, 20, and 28 months). A corroborative pattern between the chromosomal copy number variation profiles of the AH cfDNA and tumor-derived DNA from the enucleated samples was identified. In addition, a nonsense RB1 mutation (Lys→STOP) from 1 child was also identified from the AH samples obtained during intravitreous injection of melphalan, which matched the tumor sample postsecondary enucleation. Sanger sequencing of the AH cfDNA and tumor DNA with polymerase chain reaction primers targeting RB1 gene c.1075A demonstrated this same RB1 mutation. Conclusions and Relevance: In this study evaluating nucleic acids in the AH from Rb eyes undergoing salvage therapy with intravitreous injection of melphalan, the results suggest that the AH can serve as a surrogate tumor biopsy when Rb tumor tissue is not available. This novel method will allow for analyses of tumor-derived DNA in Rb eyes undergoing salvage therapy that have not been enucleated.

Risk of metastasis and orbital recurrence in advanced retinoblastoma eyes treated with systemic chemoreduction versus primary enucleation.

BACKGROUND: The purpose of this study was to evaluate the risk of metastatic disease and orbital recurrence in advanced retinoblastoma treated with systemic chemoreduction versus primary enucleation. METHODS: A retrospective review of patients with Group D/E retinoblastoma was conducted with data collection from 1995 to 2015. Overall, 345 eyes (294 patients) were included (165 Group D and 180 Group E). Primary outcome measures were orbital recurrence and metastatic disease. RESULTS: Of the 345 eyes, 139 were treated with systemic chemoreduction (102 Group D, 37 Group E) and 206 with primary enucleation (63 Group D, 143 Group E). In the chemoreduction group, one patient developed metastasis (0.7%) and one an orbital recurrence (0.7%). In the primary enucleation group, two patients developed metastases (0.9%) and one an orbital recurrence (0.5%). After systemic chemoreduction, 58 of the 139 eyes (30 Group D, 28 Group E) were secondarily enucleated for treatment failure (41.7%). The median time to secondary enucleation from diagnosis was 8.1 months. None of the eyes in the systemic chemoreduction group had high-risk pathologic features. In the primary enucleation group, 56 eyes had high-risk pathology. CONCLUSION: Over a 20-year period, 345 eyes were treated for advanced retinoblastoma at Children's Hospital Los Angeles. Incidence of orbital recurrence and metastatic disease was <1% and did not vary by treatment modality or group classification. None of the eyes enucleated for treatment failure had high-risk pathology, and none of these patients developed metastatic disease. Globe salvage therapy with systemic chemoreduction and subsequent enucleation for poor response does not increase the risk of metastatic disease or orbital recurrence.

Treatment Outcomes of Focal Laser Consolidation during Chemoreduction for Group B Retinoblastoma.

PURPOSE: To evaluate the ocular treatment outcomes of focal laser consolidation during systemic chemoreduction for Group B tumors in the posterior fundus. DESIGN: Single-institution retrospective chart review from 1995 to 2016. PARTICIPANTS: Patients with Group B retinoblastoma with at least 1 tumor in the posterior fundus. METHODS: Evaluation of tumor response to chemotherapy and laser consolidation. OUTCOME MEASURES: Change in the tumor size with treatment, and the association of timing of laser consolidation to the horizontal and vertical diameter of the final chorioretinal scar. RESULTS: Forty Group B eyes (22 right eyes and 18 left eyes) were included in the analysis. Mean age at diagnosis was 6.4 months (range 0-24 months). Of the 40 eyes, 35 were treated with both systemic chemotherapy and laser, 4 with chemotherapy only, and 1 eye with laser without chemotherapy. Mean age at initial laser treatment was 7.7 months (standard deviation 5.9 months) and mean number of laser sessions was 6 (standard deviation 5 sessions). The overall globe salvage rate was 95% (38/40 eyes). Mean horizontal and vertical diameters of the tumors in this group showed statistically significant decreases from diagnosis to all subsequent visits (P = 0.0024). The median percent reductions in the horizontal and vertical diameters of the tumors treated with both chemotherapy and laser from diagnosis to the final visit were 13% and 14%, respectively; the overall scar area showed a 13% decrease. For tumors receiving chemotherapy prior to laser therapy, the median reduction in tumor area was 18% from diagnosis to the final examination. Small tumors were found to have a 52% increase in final scar size from diagnosis, whereas larger tumors demonstrated a 37% decrease. CONCLUSIONS: The overall success in treating Group B tumors with chemotherapy and laser was very favorable when considering scar size and globe salvage rates. The size of the chorioretinal scar at the end of treatment was on average 13% smaller than the original tumor size, with greater reductions being noted when chemotherapy preceded laser treatment and when the tumor size at diagnosis was greater than 4.5 mm. A small subset of perifoveal lesions was treated successfully with chemotherapy, alone without laser consolidation.

Clinical Significance of Optic Nerve Enhancement on Magnetic Resonance Imaging in Enucleated Retinoblastoma Patients.

PURPOSE: The aim of this 8-year retrospective review was to determine the clinical significance of gadolinium-enhanced magnetic resonance imaging (MRI) findings in retinoblastoma patients after enucleation, particularly the presence of abnormal contrast enhancement of the transected optic nerve. DESIGN: Retrospective chart review. SUBJECTS: A review was done on 88 patients with retinoblastoma undergoing 90 enucleations between January 2008 and December 2015. METHODS: These patients underwent 233 MRI scans: 90 preoperative and 143 postoperative that were included for review. MAIN OUTCOME MEASURE: The primary outcome measure assessed was abnormal MRI findings in the preoperative and postoperative MRI scans, specifically enhancement of the optic nerve and correlations between abnormal MRI findings and clinical outcomes for the 88 patients. RESULTS: On the preoperative MRI, 4 optic nerves out of 90 scans showed positive enhancement. Fifty orbits had ≥1 postoperative MRI. Overall, 41 of 50 orbits (82%) of enucleated patients demonstrated postoperative contrast enhancement on MRI after enucleation, at a mean interval of 10 months after surgery. The percentage of MRI scans with optic nerve enhancement was 77% from 0 to 6 months after enucleation and 68% at >24 months after surgery. Postenucleation optic nerve enhancement did not correlate with preoperative optic nerve enhancement, chemotherapy administration, or the presence of optic nerve invasion on histopathology. No child required an orbital biopsy. None of the 88 patients were found to have subsequent orbital or metastatic disease at the last clinical follow-up visit (average, 29 months; range, 1-71). CONCLUSION: Optic nerve contrast enhancement on follow-up MRI after enucleation for retinoblastoma seems to be a common, benign radiographic finding; none of the patients in this series developed extraocular tumor relapse. The presence of postenucleation enhancement on MRI did not correlate with preoperative chemotherapy or the presence of optic nerve invasion on histopathology. Based on our findings, intervention for isolated optic nerve enhancement on MRI is not indicated in the absence of other abnormal clinical or radiographic signs. A prospective trial with a validated radiographic grading system would be helpful to clarify the MRI features to differentiate orbital recurrence from benign postoperative enhancement.

Optic Nerve Obscuration in Retinoblastoma: A Risk Factor for Optic Nerve Invasion?

BACKGROUND: The objective of this study is to evaluate the risk of optic nerve invasion associated with optic nerve obscuration at diagnosis or persisting during treatment. METHODS: Retrospective review from 2011-2016 of patients with advanced retinoblastoma (Group D/E) with complete obscuration of the nerve at diagnosis and a second group of patients with persistent, complete obscuration throughout treatment. RESULTS: Advanced retinoblastoma was diagnosed in 102 eyes of 86 patients. The optic nerve was obscured in 69 eyes (68%) at diagnosis. Of these, 30 (43%) underwent salvage therapy and 39 (57%) primary enucleation. Histopathologic analysis of primarily enucleated eyes showed 41% prelaminar and 15% postlaminar invasion. Four eyes in the salvage group demonstrated persistent nerve obscuration; 2 were subsequently enucleated without evidence of nerve invasion. Average follow-up was 23.5 months (range 1-62 months). CONCLUSIONS AND RELEVANCE: Optic nerve obscuration at diagnosis may be associated with postlaminar optic nerve invasion. While persistent, complete obscuration of the optic nerve by retinoblastoma during treatment is a poor prognostic sign for both globe salvage and vision, it does not appear, in this small cohort, to increase the risk of optic nerve invasion. With appropriate control of the intraocular tumor, these eyes can be salvaged.

Patterns of subretinal fluid resolution in Group D eyes treated with chemoreduction: Experience from the Children's Hospital Los Angeles/University of Southern California.

The purpose of this study was to evaluate patterns of subretinal fluid (SRF) resolution in Group D retinoblastoma eyes. Fifty-three Group D eyes were evaluated for the presence of SRF at diagnosis. They were subsequently treated with systemic chemoreduction (CRD) and the duration of SRF was evaluated. Logistic regression analysis was used to assess the association between duration of SRF and enucleation. Among the 53 Group D eyes, 42 eyes exhibited SRF at diagnosis (79%). After the first cycle of CRD, 27/42 eyes showed SRF (64%); 8/42 eyes demonstrated SRF after three cycles of CRD (19%), and only 3/42 eyes had SRF after six cycles (7%). Ten eyes were enucleated (10/53 or 19%). Only 1 of 10 eyes demonstrated persistent SRF at the time of enucleation. This retrospective analysis of patterns of subretinal fluid in retinoblastoma eyes demonstrates that 80% of Group D eyes present with SRF. Of these eyes, approximately 60% have persistent fluid after one cycle of CRD and less than 10% have persistent fluid after six cycles. However, presence or persistence of SRF during chemoreduction was not found to be a risk factor for enucleation in Group D retinoblastoma eyes.

Outcomes of medium choroidal melanomas treated with ruthenium brachytherapy guided by three-dimensional pretreatment modeling.

PURPOSE: The Collaborative Ocular Melanoma Study (COMS) established iodine-125 (I-125) plaque brachytherapy for eye preserving treatment of medium-sized choroidal melanomas in the United States. Eye Physics I-125 plaque treatment modeled with Plaque Simulator (PS) software yields similar results to COMS. Herein, we report results from a series of 15 patients treated with ruthenium-106 (Ru-106) plaque brachytherapy using PS pretreatment modeling for plaque localization and dosimetry. METHODS AND MATERIALS: Fifteen patients with medium-sized choroidal melanomas (2.84-5.5 mm in apical height and a basal diameter of 7.8-12.6 mm) treated with ruthenium brachytherapy from 2003 to 2005 were evaluated retrospectively. Baseline and followup data were evaluated for tumor height, best corrected visual acuity, radiation retinopathy, radiation optic neuropathy, postradiation cataract formation, diplopia, and ptosis. Tumor response for both Ru-106 and I-125 plaques planned using the same PS pretreatment modeling was evaluated and compared. RESULTS: Isotope-specific radiation profiles were compared, and rates of local treatment failure (0%), optic neuropathy (6.7%), retinopathy (20%), and cataracts (33%) were evaluated. Five year-treated tumor heights were approximately 0.61 ± 0.29 (I-125, n = 16) and 0.53 ± 0.17 (Ru-106, n = 6) of their heights at diagnosis. CONCLUSIONS: This patient subset had background characteristics very similar to those of the COMS and patients treated at our institution with I-125 plaques. Treatment response was equivalent although radiation complications occurred slightly less frequently in the Ru-106 group compared with those treated with I-125. Image-guided three-dimensional pretreatment modeling for plaque localization and dosimetry seems to work equally as well for Ru as for I-125 plaques and justifies more extensive investigation.

Low-Dose Chemoreduction for Infants Diagnosed with Retinoblastoma before 6 Months of Age.

AIM: The purpose of this study was to evaluate the outcomes of infants diagnosed with retinoblastoma before 6 months of age, including the need for chemoreduction (CRD). In this age group, dosage of CRD was reduced due to its potential for toxicity. METHODS: This is a retrospective review from 2000 to 2009 that includes 126 eyes of 72 infants (18 unilateral, 54 bilateral). Systemic CRD was administered when local modalities failed or were considered inadequate. Primary outcome measures were the need for CRD and globe salvage. RESULTS: Of the 72 infants diagnosed before 6 months of age, 48 (67%) ultimately required CRD for globe salvage, 40 (56%) patients before 6 months of age. Globe salvage was achieved in 62% (78/126) of eyes overall and in 93% (68/73) of eyes with Group A-C disease. No patient was hospitalized for CRD-related illness; survival was 100%. The mean follow-up was 52.9 months (range 1-148 months). CONCLUSION: Utilizing a combination of focal modalities and reduced-dose CRD, children diagnosed with retinoblastoma before 6 months of age attain globe salvage rates comparable to those of older age groups. Two thirds of the infants ultimately required CRD for globe salvage. Bilateral disease as well as Group D and E classification in at least one eye at presentation increased the chance of requiring CRD (p < 0.0001 and p < 0.016, respectively).

Long-Term Outcomes of Group B Eyes in Patients with Retinoblastoma Treated with Short-Course Chemoreduction: Experience from Children's Hospital Los Angeles/University of Southern California.

BACKGROUND/AIMS: Chemoreduction protocols for retinoblastoma vary widely across institutions. Herein, we compare a 3- versus 6-cycle chemotherapy approach for group B retinoblastoma. METHODS: A nonrandomized, retrospective review of patients diagnosed with group B retinoblastoma from 1991-2011 at Children's Hospital Los Angeles was performed. A total of 72 eyes of 63 patients were analyzed. Mean follow-up time was 82 months (range 6-272 months). Main outcome measures were globe salvage and need for external beam radiation. RESULTS: Forty-six patients (55 eyes) were treated upfront with 3 cycles of carboplatin, etoposide, and vincristine; 17 patients (17 eyes) received 6 cycles. Thirty-seven eyes (67%) in the 3-cycle group were cured with initial chemoreduction alone. An additional 10 eyes with persistent or recurrent tumors were rescued with 3 more cycles for a total salvage rate of 85% (47/55 eyes). In the 6-cycle group, 16 of 17 eyes (94%) avoided radiation and enucleation. CONCLUSION: The initial recurrence rate was higher for the 3-cycle group (p = 0.03). However, eyes failing short-course chemoreduction were rescued with 3 additional cycles and achieved a similar overall event-free survival rate (p = 0.16). In our cohort, this short-course approach spared 63% (29/46) of patients with group B retinoblastoma the extra 3 cycles of systemic chemotherapy.

Retcam fluorescein angiography findings in eyes with advanced retinoblastoma.

PURPOSE: To characterise the fluorescein angiogram (FA) findings of eyes with advanced retinoblastoma evaluated with the Retcam contact fundus camera. METHODS: A retrospective case series was performed on all new retinoblastoma patients evaluated with Retcam FA between 2000 and 2012. Inclusion criteria included (1) patients with advanced retinoblastoma (group D or E), (2) eyes studied with early, mid-phase and late-phase Retcam FA photographs and (3) no prior treatment. RESULTS: A total of 100 eyes fulfilling the inclusion criteria were identified. For the 47 group D eyes, FA findings included iris neovascularisation (10/47), large retinal vessel dilatation (46/47), small retinal vessel changes (35/47) and retinal venous leakage (20/47). Among the 53 group E eyes, FA findings included iris neovascularisation (45/53), large retinal vessel dilatation (43/53), small retinal vessel changes (37/53) and vascular abnormalities at multiple levels (11/53). CONCLUSIONS: Advanced intraocular retinoblastoma is associated with multiple retinal vascular abnormalities on Retcam FA. These findings may be helpful in defining the extent of disease and distinguishing this tumour from other paediatric ocular conditions. Key clinical findings were subclinical iris neovascularisation, a variety of small vessel changes, intrinsic tumour vessels and retinal venous leakage. Retcam FA was not found to be clinically useful after 3 min.

Factors predictive of long-term visual outcomes of Group D eyes treated with chemoreduction and low-dose IMRT salvage: the Children's Hospital Los Angeles experience.

AIM: To evaluate clinical factors predictive of visual outcomes in Group D retinoblastoma eyes. METHODS: Retrospective chart review of patients with Group D retinoblastoma from January 2000 to December 2009. All patients were treated with systemic chemoreduction and external beam radiation as salvage therapy when indicated. Primary outcome measure was visual acuity. Clinical factors evaluated include quadrants of subretinal fluid, extent of vitreous seeding, involvement of more/less than 50% of the macula, endophytic/exophytic tumour classification, and presence of tumour behind the lens at diagnosis. RESULTS: Fifty-two Group D eyes of 41 patients were included; 10 eyes with visual acuity better than 20/80, 32 eyes with vision worse than 20/100 and 10 eyes with indeterminate vision (fix and follow). Complete retinal detachment (p=0.002), involvement of >50% of the macula (p=0.01), and seeding >3 quadrants (p=0.05) were associated with worse visual outcome. Average follow-up was 50.0 months (range: 10-118 months). CONCLUSIONS: At presentation, it is difficult to predict which Group D eyes will be salvaged with useful vision following systemic chemotherapy. The presence of complete retinal detachment, macular involvement and extensive seeding on presentation were factors associated with a worse visual prognosis in this study. These findings can guide the ophthalmologist in clinical decision making, as well as in counselling parents.