Ocular Survival Research Articles

Small choroidal melanoma: outcomes following apical height dose brachytherapy

AimTo assess the outcomes of small choroidal melanoma following iodine-125 episcleral brachytherapy (apical height dose of 85 Gy).MethodsPatients with small choroidal melanoma that underwent iodine-125 episcleral brachytherapy between January 2004...

Abstract 186: Gain of chromosome 6p is a molecular biomarker for prognostication of retinoblastoma ocular survival: The aqueous humor surrogate tumor biopsy

Abstract Purpose: Aqueous humor (AH) is a novel source of tumor-derived cell-free DNA (cfDNA) and can serve as a surrogate tumor biopsy, or liquid biopsy, for retinoblastoma (RB). We previously identified a somatic copy number alteration (SCNA) gain of chromosome 6p as associated with a 10-fold increased risk of enucleation. In this study, we provide a 2-year extended update to further explore 6p gain as a prognostic biomarker for ocular survival. Methods: Patients diagnosed with RB from 12/2014 - 7/2019 from whom AH was sampled were included. AH was extracted via clear corneal paracentesis at diagnosis, during intravitreal injection of chemotherapy or enucleation. CfDNA was extracted; shallow whole genome sequencing was performed to assess for cfDNA tumor fractions and highly recurrent RB SCNAs (gain of 1q, 2p, 6p, loss of 13q, 16q). Patient demographics, treatment regimen and globe salvage were recorded. Results: 50 eyes from 46 patients were included: 27 eyes were salvaged and 23 were enucleated. Most eyes (36/50,72%) were TNM stage cT2b. 116 samples of AH were analyzed. There were no cases of orbital relapse or metastatic spread. The median follow-up was 30 months (range 6-64 mos). After genomic evaluation, 33 / 50 eyes (66%) demonstrated one or more highly-recurrent RB SCNAs and 39/50 (78%) demonstrated any measurable SCNA. Gain of 6p was the most prevalent RB SCNA among all 50 eyes (50%), followed by 1q gain (38%), 16q loss (30%), 2p gain (including 3 focal MYCN gains; 18%), and 13q loss (16%). RB SCNAs were significantly more prevalent in enucleated eyes (21/23, 91.3%) than in salvaged eyes (12/27, 44.4%; Fisher's exact, P=0.0007). Of these, 6p gain was particularly more prevalent in enucleated eyes (17/23, 73.9%) than in salvaged eyes (8/27, 29.6%; Chi-squared, P=0.002) Of all the RB SCNAs, the presence of 6p gain in the cfDNA in the AH portended nearly 10 times greater odds of being enucleated (OR=9.87,95% CI=1.75-55.65, P=0.009). No single other SCNA had a statistically significant power to predict enucleation although there was a trend towards significance for 2p/focal MYCN gain (P=0.09) limited by the few number of eyes with this SCNA. Conclusions: Although we previously identified chromosomal gain of 6p as a potential indicator of an aggressive phenotype in RB, that study included a smaller cohort of patients and limited follow-up. With extended follow-up and nearly double the number of eyes and AH samples, the data continue to demonstrate that AH is a high-yield surrogate tumor biopsy, and the presence of RB-specific SCNAs–specifically gain of 6p–has the potential to serve as a prognostic biomarker for RB. Citation Format: Jesse L. Berry, Liya Xu, Ashley Polski, Rishvanth Prabakar, Mark Reid, Jonathan Kim, Peeter Kuhn, James Hicks. Gain of chromosome 6p is a molecular biomarker for prognostication of retinoblastoma ocular survival: The aqueous humor surrogate tumor biopsy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 186.

Chromosome 6p Amplification in Aqueous Humor Cell-Free DNA Is a Prognostic Biomarker for Retinoblastoma Ocular Survival.

Aqueous humor contains tumor-derived cell-free DNA (cfDNA) and can serve as a liquid biopsy for retinoblastoma. We previously associated somatic copy-number alteration (SCNA) 6p gain with a 10-fold increased risk of enucleation. Here we provide a 2-year update to further explore 6p gain as a prognostic biomarker for ocular survival. Patients diagnosed with retinoblastoma from December 2014 to July 2019 from whom aqueous humor was sampled were included. cfDNA was extracted and shallow whole-genome sequencing performed to identify highly recurrent retinoblastoma SCNAs (gain of 1q, 2p, 6p, loss of 13q, 16q). 116 aqueous humor samples from 50 eyes of 46 patients were included: 27 eyes were salvaged, 23 were enucleated. Highly recurrent retinoblastoma SCNAs were found in 66% eyes. 6p gain was the most prevalent SCNA (50% eyes). It was particularly more prevalent in enucleated eyes (73.9%) than in salvaged eyes (29.6%; P = 0.004). 6p gain in aqueous humor cfDNA portended nearly 10-fold increased odds of enucleation (OR = 9.87; 95% confidence interval = 1.75-55.65; P = 0.009). In the enucleated eyes, 6p gain was associated with aggressive histopathologic features, including necrosis, higher degrees of anaplasia, and focal invasion of ocular structures. With extended follow-up and nearly double the aqueous humor samples, we continue to demonstrate 6p gain as a potential prognostic biomarker for retinoblastoma. IMPLICATIONS: Aqueous humor is a high-yield source of tumor-derived DNA in retinoblastoma eyes. Detection of 6p gain in the aqueous humor allows for targeted, patient-centered therapies based on this molecular prognostic marker. Prospective, multicenter studies with aqueous humor sampled from all eyes at diagnosis are warranted to validate these findings.

Surgical Management of Advanced Coats Disease in 32 Eyes: A 20-Year Study.

This work studies outcomes of external subretinal fluid (SRF) drainage in management of eyes with advanced Coats disease. Patients with advanced-stage Coats disease (≥stage 3B), who were younger than 12 years and underwent external SRF drainage from 1996 to 2016, were included in this retrospective study. Surgical intervention involved external drainage of SRF and cryotherapy. SRF drainage was performed by lamellar scleral dissection or by external needle drainage. Favorable anatomical outcome was defined as retinal reattachment with normal intraocular pressure (IOP). IOP greater than 24 mm Hg was considered raised. Univariate and multivariate analyses were performed to measure the association between preoperative or intraoperative factors and retinal status at final follow-up. Outcome measures evaluated included visual acuity, IOP, retinal status, globe status, and complications of surgery. Kaplan-Meier analysis was performed for globe salvage without pain. Thirty-two eyes of 32 patients were included in the study. Mean age at surgery was 3.8 ± 3 years. The mean duration of follow-up was 7 years (range, 6 months-15.7 years). Improvement in visual acuity was seen in 5 eyes. Retina was attached at final visit in 6 eyes. IOP in the range of 8 to 24 mm Hg was noted in 16 eyes. Favorable anatomical outcome was achieved in 3 (9%) eyes. Globe salvage was achieved in 84% of eyes. Complications included intraoperative vitreous hemorrhage (n = 1) and postoperative inflammation (n = 1). Kaplan-Meier ocular survival rate without pain at 10 years was 76%. SRF drainage and cryotherapy in eyes with advanced Coats disease favorably alter the natural history of the disease and prevent end-stage complications. Visual outcomes remain poor.

TOXICITY AND EFFICACY OF INTRAVITREAL MELPHALAN FOR RETINOBLASTOMA: 25 µg Versus 30 µg.

To compare retinal toxicity as measured by electroretinogram, ocular, and patient survival in retinoblastoma treated with intravitreal melphalan at two concentrations (25 vs. 30 µg). Single-center, retrospective analysis of retinoblastoma eyes receiving 25-µg or 30-µg intravitreal melphalan from September 2012 to January 2019. Ocular toxicity was measured by electroretinogram of evaluable injections in 449 injections in 136 eyes. A repeated-measures linear mixed model with a random intercept and slope was applied to account for repeated measures for each eye. Average decline in electroretinogram after each additional injection was -4.9 µV (95% confidence interval -6.3 to -3.4); electroretinogram declined by -4.6 µV (95% confidence interval -7.0 to -2.2) after 25-µg injections and -5.2 µV (95% confidence interval -6.6 to -3.8) after 30-µg injections (P = 0.66). Injection at a new clock site hour was associated with a -3.91-µV lower average (95% confidence interval -7.8 to -0.04). Electroretinogram-measured toxicity in retinoblastoma eyes treated with intravitreal injections was not found to be different across 25-µg and 30-µg injections. There were no cases of extraocular extension or metastatic deaths in our patient population.

Survival and ocular preservation in a long-term cohort of Japanese patients with retinoblastoma

BackgroundRetinoblastoma is an ocular tumor in infants with cancer predisposition. Treatment of the rare tumor needs to be optimized for ocular preserved survival without second primary malignancy (SPM).MethodsWe studied the outcomes of all patients with retinoblastoma at a tertiary center in 1984–2016, when preservation method changed from radiotherapy (1984–2001) to systemic chemotherapy (2002–2016).ResultsOne-hundred sixteen infants developed unilateral- (n = 77), bilateral- (n = 38), or trilateral-onset (n = 1) tumor. Ten (8.6%) had a positive family history, despite a few studies on RB1 gene. Contralateral disease occurred in one unilateral-onset case. One-hundred eight of 155 eyes (70%) were enucleated. Nine binocular survivors were from 5 bilateral- and 4 unilateral-onset cases. Two survivors received bilateral enucleation. Six deaths occurred; brain involvement (including 3 trilateral diseases) in 4 bilateral-onset, systemic invasion in a unilateral-onset, and SPM (osteosarcoma) in a bilateral-onset case(s). Two others survived SPM of osteosarcoma or lymphoma. The 10-year overall survival (OS: 98.5% vs. 91.3%, p = 0.068) and binocular survivors (13.2% vs. 5.2%, p = 0.154) between bilateral- and unilateral-onsets did not differ statistically. The 10-year OS and cancer (retinoblastoma/SPM)-free survival (CFS) rates of all patients were 94.9 and 88.5%, respectively. The proportion of preserved eyes did not differ between radiotherapy and chemotherapy eras. The CFS rate of bilateral-onset cases in systemic chemotherapy era was higher than that in radiotherapy era (p = 0.042). The CFS rates of bilateral-onset patients with neoadjuvant chemotherapy (upfront systemic therapy for preservation) was higher than those without it (p = 0.030).ConclusionsSystemic chemotherapy and local therapy raised OS and binocular survival rates of bilateral-onset patients similarly to those of unilateral-onset patients. All but one death was associated with a probable germline defect of the RB1 gene. Neoadjuvant stratified chemotherapy may support the long-term binocular life with minimized risk of SPM.

Intra-arterial chemotherapy as primary or secondary treatment for infants diagnosed with advanced retinoblastoma before 3\u2009months of age

BackgroundTo evaluate the safety and efficacy of intra-arterial chemotherapy (IAC) for the primary or secondary treatment of infants diagnosed with advanced retinoblastoma before 3 months of age.MethodsThis single-center retrospective study included 39 infants (42 eyes) aged ≤3 months who were diagnosed with unilateral or bilateral advanced intraocular retinoblastoma (group D and E eyes) and received IAC as primary or secondary treatment between June 2012 and February 2017. Based on each patient’s therapeutic history and response to chemotherapeutic drugs, melphalan, topotecan, and/or carboplatin were used for IAC. The main outcomes included the technical success rate for IAC, survival rates, and adverse events.ResultsIn total, 29 and 13 eyes received IAC as primary and secondary treatments, respectively. Catheterization was successful in 136 of 137 procedures. All eyes in the secondary IAC group had previously received intravenous chemotherapy. The mean number of IAC sessions for each eye was 3 (range, 2–6). The 2-year ocular survival rates were 80.7% (95% confidence interval [CI], 58.9–91.7) in the primary IAC group and 91.7% (95% CI, 53.9–98.8) in the secondary IAC group. During the follow-up period, 1 patient with unilateral disease (group E) developed extraocular disease and died. The 2-year recurrence-free survival rates in the primary and secondary IAC groups were 71.9% (95% CI, 49.4–85.7) and 75.0% (95% CI, 40.8–91.2), respectively. During each catheterization procedure, the main complications included eyelid erythema (2.4%), fundus hemorrhage (11.9%), myelosuppression (7.7%), transient vomiting and hair loss (2.6%), and transient pancytopenia (2.6%). Prolonged complications included phthisis bulbi (19.0%), vision loss (19.0%), poor vision (9.5%), and cataract (2.4%). There was no case of stroke, neurological impairment, secondary malignant tumor, or metastasis.ConclusionsOur findings suggest that IAC, whether primary or secondary, is effective and fairly safe for the management of advanced retinoblastoma in infants aged < 3 months. However, adverse events related to intra-arterial injection and the visual outcomes cannot be neglected and require further investigation.

Abstract 2877: Genomic cfDNA analysis of aqueous humor in retinoblastoma (RB) predicts eye salvage

Abstract Background: Retinoblastoma (RB) was one of the first tumors to demonstrate a genetic basis to the development of cancer. However, unlike other cancers, RB cannot be directly biopsied due to the high risk of extraocular cancer spread. Therefore, unless the eye is enucleated, tumor tissue is not evaluated for genetic and genomic changes and these alterations are not used to inform diagnosis or prognosis for this disease. However, in a 2017 publication in JAMA Ophthalmology, we demonstrated that tumor-derived cell-free DNA can be extracted from the aqueous humor (AH) of RB eyes, which is safe to remove even with active intraocular disease. The purpose of this current study (Berry JL, Xu L et al. Molec Canc Res 2018) was to identify somatic chromosomal copy number alterations (SCNA) in tumor-derived cell-free DNA in the AH of RB eyes and to correlate with clinical outcomes particularly tumor relapse requiring enucleation. Methods: AH was extracted via paracentesis from RB eyes during intravitreal injection of chemotherapy or post enucleation. Shallow whole genome sequencing was performed to assess for cell-free tumor DNA fractions and highly-recurrent SCNAs in RB which include gain of 1q, 2p, 6p and loss of 13q and 16q. Globe salvage was recorded. Results: 26 patients were included; 3 patients had both eyes included for 29 eyes. From these, 63 samples of AH were analyzed; 5 post-enucleations and 58 during intravitreal chemotherapy injection. Ultimately 13 eyes required enucleation and 16 eyes were salvaged. Follow-up ranged from 8-43 months (median 17 months). The presence of any detectable SCNA was 92% in enucleated eyes versus 38% in salvaged eyes (p=0.006). 6p gain was the most common SCNA found in 77% of enucleated eyes versus 25% of salvaged eyes (p=0.0092). 6p gain was associated with a ten-fold increased odds of enucleation (OR=10, 95% CI:1.8-55.6). The mean amplitude of 6p gain was 1.47 in enucleated eyes versus 1.07 in salvaged eyes (p=0.001). The probability of ocular survival was higher in eyes without detectable SCNAs in the AH (p=0.0028). Serum testing was positive for a germline mutation in 17 eyes of 14 patients with the following incidence of RB SCNAs 1q (35%); 2p (18%); 6p (47%); 13q (18%) and 16q (35%) versus 12 eyes of 12 patients without germline disease with 1q (33%); 2p (8%); 6p (50%); 13q (17%) and 16q (33%) (p=0.71). Conclusions: This is the first study to show that clinical outcomes correlate with highly-recurrent SCNAs in the AH from RB eyes. This study suggests that the AH can reliably serve as a surrogate to tumor biopsy and improves upon current clinical staging to predict tumor response to therapy and the ability to salvage the eye. Unlike previous studies that suggest a greater incidence of RB SCNAs in patients with non-germline disease, this was not seen in this evaluation which may be because all previous work was done on tumor from enucleated eyes instead of salvaged eyes. Citation Format: Liya Xu, Jesse L. Berry, Irsan Kooi, A Linn Murphree, Rishvanth K. Prabakar, Mark W. Reid, Kevin Stachelek, Bao Han A. Le, Lisa Welter, Rima Jubran, Thomas C. Lee, Jonathan W. Kim, Peter Kuhn, David Cobrinik, James B. Hicks. Genomic cfDNA analysis of aqueous humor in retinoblastoma (RB) predicts eye salvage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2877.

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”

Retinoblastoma is lethal by metastasis if left untreated, so the primary goal of therapy is to preserve life, with ocular survival, visual preservation and quality of life as secondary aims. Historically, enucleation was the first successful therapeutic approach to decrease mortality, followed over 100 years ago by the first eye salvage attempts with radiotherapy. This led to the empiric delineation of a window for conservative management subject to a "state of metastatic grace" never to be violated. Over the last two decades, conservative management of retinoblastoma witnessed an impressive acceleration of improvements, culminating in two major paradigm shifts in therapeutic strategy. Firstly, the introduction of systemic chemotherapy and focal treatments in the late 1990s enabled radiotherapy to be progressively abandoned. Around 10 years later, the advent of chemotherapy in situ, with the capitalization of new routes of targeted drug delivery, namely intra-arterial, intravitreal and now intracameral injections, allowed significant increase in eye preservation rate, definitive eradication of radiotherapy and reduction of systemic chemotherapy. Here we intend to review the relevant knowledge susceptible to improve the conservative management of retinoblastoma in compliance with the "state of metastatic grace", with particular attention to (i) reviewing how new imaging modalities impact the frontiers of conservative management, (ii) dissecting retinoblastoma genesis, growth patterns, and intraocular routes of tumor propagation, (iii) assessing major therapeutic changes and trends, (iv) proposing a classification of relapsing retinoblastoma, (v) examining treatable/preventable disease-related or treatment-induced complications, and (vi) appraising new therapeutic targets and concepts, as well as liquid biopsy potentiality.

Episcleral brachytherapy for retinoblastoma

Background/AimsTo report visual outcomes, survival outcomes and complications following episcleral brachytherapy (EB) for retinoblastoma.MethodsRetrospective review of retinoblastoma cases treated with EB in a single institution. Survival outcomes were analysed using...

Ruthenium-106 versus iodine-125 plaque brachytherapy of 571 choroidal melanomas with a thickness of ≥5.5 mm

BackgroundEpiscleral brachytherapy is the most common eye-preserving treatment for medium-sized choroidal melanomas. γ-emitting iodine-125 (125I) and β-emitting ruthenium-106 (106Ru) are widely used. The latter is however generally reserved for thinner...

No Gender Differences in Long-Term Survival after Brachytherapy of 1,541 Patients with Uveal Melanoma

Background: In several malignancies, gender-based survival differences after specific therapeutic interventions have been demonstrated. It is not known whether such differences exist after plaque brachytherapy of uveal melanoma. Methods: All patients who received brachytherapy for uveal melanoma at St. Erik Eye Hospital from November 1, 1979 through November 20, 2017 were included (n = 1,541). Retrospective data were retrieved including baseline patient and tumor characteristics, brachytherapy nuclide (ruthenium-106 or iodine-125), radiation dose, treatment duration, tumor relapses, date of metastasis, and cause of death. Results: A total of 775 men and 766 women were treated with plaque brachytherapy. There were no significant differences between the genders in baseline characteristics, treatment, or follow-up. Men and women had similar rates of tumor relapses, hazard for repeated brachytherapy (men vs. women 0.8, p = 0.47), enucleation-free survival, and survival after detection of metastasis. Five-, 10-, and 15-year melanoma-related mortality was 14, 24, and 27% for men and 15, 26, and 32% for women, respectively. There were no significant differences in hazard for melanoma-related mortality (men vs. women 0.9, p = 0.32), median Kaplan-Meier disease-specific survival (men 18.2 years, women 15.5 years, p = 0.22), or median overall survival (men 13.5 years, women 12.6 years, p = 0.60). Conclusion: There are no relevant differences between men and women in ocular or patient survival after brachytherapy for uveal melanoma.

Reduction of Ocular Surface Damage and Bacterial Survival Using 0.05% Povidone-Iodine Ocular Surface Irrigation before Cataract Surgery

Background: To investigate the effects of 0.05% povidone-iodine (PI) irrigation on the ocular surface structure and bacterial survival rate in patients with cataract. Methods: Ninety eyes of 90 patients with cataract were included. Before surgery, the operative field was irrigated with 0.05% PI and divided into 30-s, 1-, and 2-min groups. Anterior chamber fluid was cultured bacteriologically. Tear film breakup time (BUT), corneal fluorescein staining (CFS), lacrimal river height (LRH), and Schirmer test I (STI) were conducted to assess ocular surface. Results: In all groups, the patients had significantly shorter postoperative BUT at 1 day, 3 days, and 1 week postoperatively than preoperatively. In addition, there was still lower BUT at 1 month postoperatively in the 1- and 2-min groups. STI and LRH were all decreased postoperatively at different time points (1 day, 3 days, 1 week), while CFS was increased. With the extension of time preoperatively (1 and 3 months), the ocular surface indicators returned to the preoperative level. The bacterial cultures after eye irrigating were negative in all groups. Conclusion: 0.05% PI irrigating the conjunctival sac for 30 s can achieve a low bacterial contamination rate. Importantly, it reduced the damage of ocular surface, which is beneficial to the recovery of ocular surface function.

Intravenous Chemotherapy Plus Intra-Arterial Chemotherapy Versus Intra-Arterial Chemotherapy in Patients with Advanced Retinoblastoma Cancer: A Retrospective, Multicentre-Based Study

Background: Intra-arterial chemotherapy (IAC) was found to be effective for the management of advanced retinoblastoma. However, the value of the addition of intravenous chemotherapy (IVC) to IAC in advanced retinoblastoma is unclear. Methods: Kaplan-Meier analyses were performed to compare 2-year rates of ocular survival, overall survival and event-free survival between the groups. Cox proportional hazards model was used to test the independent significance of different factors. Details of enucleated eyes and their histopathological results were recorded. Findings: Between July 2008 and December 2016, 213 patients at five institutions in China with advanced retinoblastoma (group D and E eyes) were included for analysis. They were treated with IVC plus IAC (n=103) or IAC (n=110). The proportion of patients with ocular survival at 2 years was 68% (95%CI 57-76) in the IVC plus IAC group and 72% (95%CI 60-80) in the IAC group (hazard ratio [HR] 0.88 [95%CI 0.55-1.43], P=0.61).The proportion of patients with overall survival at 2 years was 97% (95%CI 92-99) in the IVC plus IAC group and 96% (95%CI 90-99) in the IAC group (HR 1.56 [95%CI 0.41-5.90], P=0.51). The proportion of patients with event-free survival at 2 years was 76% (95%CI 67-83) in the IVC plus IAC group and 79% (95%CI 69-86) in the IAC group (HR 0.96 [95%CI 0.56-1.65], P=0.89). Multivariate analyses showed eye staging and local therapy were significant prognostic factors of ocular survival. High-risk histopathologic features were identified in 10.5% (4/38) of the IVC plus IAC group and 16.7% (5/30) of the IAC group, with no statistical difference (P=0.46). Interpretation: Addition of IVC to IAC did not significantly improve survival outcomes and lower the risk of metastasis in patients with advanced retinoblastoma cancer. Longer follow-up is needed to determine long-term efficacy, but at present, additional IVC is not recommended for using outside the scope of clinical research. Funding Statement: The National Natural Science Foundation of China; the National Natural Science Foundation of Guangdong Province; the Science and Technology Planning Project of Guangdong Province; the Scientific Research General Project of Guangzhou Science Technology and Innovation Commission; and the China Postdoctoral Science Foundation. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Targeting the Platelet-Derived Growth Factor-beta Stimulatory Circuitry to Control Retinoblastoma Seeds.

PurposeVitreous seeding remains the primary reason for treatment failure in eyes with retinoblastoma (Rb). Systemic and intra-arterial chemotherapy, each with its own inherent set of complications, have improved salvage rates for eyes with advanced disease, but the location and biology of vitreous seeds present a fundamental challenge in developing treatments with minimal toxicity and risk. The aim of this study was to target the platelet-derived growth factor (PDGF)– PDGF-receptor β (PDGFRβ) signaling pathway and investigate its role in the growth of Rb seeds, apoptotic activity, and invasive potential.MethodsWe performed ex vivo analyses on vitreous samples from Rb patients that underwent enucleation and from patient-derived xenografts. These samples were evaluated by quantitative PCR, immunohistochemistry, and ELISA. The effects of disruption of the PDGF-PDGFRβ signaling pathway, both by pharmacologic and genomic knockdown approaches, were evaluated in vitro by cell proliferation and apoptotic assays, quantitative PCR analyses, Western blotting, flow cytometry, and imaging flow cytometry. A three-dimensional cell culture system was generated for in-depth study of Rb seeds.ResultsOur results demonstrated that PDGFRβ signaling is active in the vitreous of Rb patients and patient-derived xenografts, sustaining growth and survival in an AKT-, MDM2-, and NF-κB-dependent manner. The novel three-dimensional cell culture system mimics Rb seeds, as the in vitro generated spheroids have similar morphologic features to Rb seeds and mimicked their natural physiology.ConclusionsTargeting the PDGFRβ pathway in vitro reduces Rb cell growth, survival, and invasiveness and could augment current therapies. This represents a novel signaling pathway for potential targeted therapy to further improve ocular survival in advanced Rb.

Associated features of strabismus in the presentation of retinoblastoma

The common presenting features of intraocular retinoblastoma (RB) include leukocoria (L), strabismus (S), and inflammation (I). Leukocoria has been associated with poorer ocular survival. Exotropia has been shown to be more common than expected in infantile strabismus. The impact of the combination of L and S presenting together has not been assessed. The need for enucleation at presentation and the use of adjuvant chemotherapy post-enucleation are recognised indicators of advanced disease.

Prior non-irradiative focal therapies do not compromise the efficacy of delayed episcleral plaque brachytherapy in retinoblastoma

Background/aims Non-irradiative local therapies have shown promise in delaying or supplanting external beam radiotherapy (EBRT) and enucleation in patients with retinoblastoma. We hypothesised that prior focal therapy does not compromise...

Current Treatment of Bilateral Retinoblastoma: The Impact of Intraarterial and Intravitreous Chemotherapy

PURPOSE: To evaluate the management and outcomes of naïve bilateral retinoblastoma treated at a single-center over a 5-year period during the era of ophthalmic artery chemosurgery (OAC) and intravitreous chemotherapy. METHODS: Retrospective cohort study of 46 patients (92 eyes) with naïve bilateral retinoblastoma treated at Memorial Sloan Kettering Cancer Center between January 2012 and February 2017. Indirect ophthalmoscopy, fundus photography, ultrasonography, and ultrasonic biomicroscopy were used to evaluate clinical response. Patient, ocular, ocular progression-free, ocular recurrent event–free, and second ocular survivals were assessed by Kaplan-Meier estimates. Retinal toxicity was evaluated by electroretinography. Snellen visual acuity and complete blood count metrics were recorded. RESULTS: Sixty-four eyes (70%) in 41 patients (89%) received ophthalmic artery chemosurgery as part of their treatment. Twenty-six patients (56%) received tandem OAC (bilateral simultaneous infusions). Seven eyes were primarily enucleated. No eye receiving initial OAC was enucleated. There was a single secondary enucleation in an eye initially treated with focal therapy with anterior chamber recurrence. The 3-year Kaplan-Meier estimates for overall ocular, secondary ocular (survival after treatment for recurrence), progression-free, and recurrent event–free survival were 91.3% [95% confidence interval (CI) 83.4-95.5], 98.7% (95% CI 91.3-99.8), 91.5% (95% CI 83.0-95.8), and 78.9% (95% CI 68.2-86.3), respectively. Overall and secondary ocular survivals were 100% for International Classification of Retinoblastoma (ICRB) groups A-C. Overall ocular survival was 91.5% (95% CI 70-97.8) for ICRB group D and 71.4% (95% CI 47.1-79.4) for group E. Secondary ocular survival was 95.4% (95% CI 71.8-99.3) for ICRB group D and 100% for group E. There were no treatment-related deaths, three patients developed trilateral retinoblastoma (one died), and one patient (who did not receive OAC) developed metastatic disease and is in remission at 32-month follow-up. CONCLUSION: The majority (89%) of bilateral retinoblastoma patients in the current era and at this center were treated with OAC. This has resulted in saving a historic number of eyes. A quarter of eyes developed recurrent disease (defined as recurrent disease requiring any treatment including focal), the majority of which occurred in the first year after treatment, and all but one was saved. There has been no compromise in patient survival.

Intravitreal chemotherapy in retinoblastoma: expanded use beyond intravitreal seeds.

Ophthalmic artery chemosurgery (OAC) has changed the face of retinoblastoma treatment and led to a higher rate of globe salvage. The introduction of intravitreal chemotherapy (IVitC) has further enhanced globe salvage with increased success in treatment of intravitreal seeds. Our group has seen success at treating non-vitreous disease that is refractory to OAC using IVitC. This study was undertaken to quantify and report on this success. A retrospective review was used to identify patients treated with IVitC for indications other than vitreous seeds from two centres. The indication, prior and concurrent treatment, response time and duration of treatment were documented. Kaplan-Meier estimates were used to evaluate ocular and recurrence-free survival. Ocular toxicity was evaluated using the 30 Hz flicker electroretinogram (ERG). Continuous and categorical variables were compared with Student's t-test and χ2test, respectively. Fifty-six eyes from 52 retinoblastoma patients were identified. There were no disease-related or treatment-related deaths. One patient developed a second primary malignancy (pinealoblastoma) and subsequent leptomeningeal spread. Ninety-eight percent of the eyes showed clinical regression. Recurrence was seen in 14.3%. Of the recurrences, five occurred in retinal tumours and three in subretinal seeds.The Kaplan-Meier estimated risk of recurrence in all patients treated was 83.5% (95%CI7.9to14.1) at 10 months. The mean change in ERG over treatment course was -17.7μV. Intravitreal chemotherapy is successful for thetreatment of subretinal seeds and recurrent retinal tumours and could be considered as adjunctive therapy in globe-sparing treatment of retinoblastoma.

Ten-year experience with ophthalmic artery chemosurgery: Ocular and recurrence-free survival.

PurposeTo report associations between disease- and treatment-related variables and rates of recurrence-free survival and ocular survival in eyes treated with ophthalmic artery chemosurgery (OAC) for retinoblastoma.DesignPre-post study.SubjectsAll eyes treated with OAC for retinoblastoma at Memorial Sloan Kettering Cancer Center between May 2006 and February 2017.MethodsThis retrospective review included 452 retinoblastoma eyes treated with OAC. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS), progression-free survival (PFS) and ocular survival (OcS), and Cox regression was used to estimate hazard ratios. Eyes treated in the pre-intravitreous chemotherapy era were analyzed separately from eyes treated in the intravitreal era.Main outcome measuresRecurrence-free survival, ocular survival, associations with risk of recurrenceResultsDisease and treatment characteristics were recorded over a median 23.6 month follow-up. One-year OcS, PFS and RFS were 96% (95% CI 93–99%), 88% (95% CI 88–94%) and 74% (95% CI 67–81%) in the pre-intravitreal era and 96% (95% CI 94–99%), 93% (95% CI 89–96%) and 78% (95% CI 72–83%) in the intravitreal era, respectively. Presence of vitreous seeds was associated with increased risk of recurrence in the pre-intravitreal era but not in the intravitreal era. Longer time interval between OAC sessions was associated with increased risk of recurrence and majority OAC access via the ophthalmic artery was associated with decreased risk of recurrence in both eras.ConclusionsApproximately a quarter of eyes initially treated with ophthalmic artery chemosurgery develop recurrent disease, with the majority of recurrences within the first year following completion of OAC. Despite this, these eyes have a very good chance of salvage. In eyes with vitreous seeds at presentation, intravitreal injections are useful in minimizing future vitreous recurrence. Eyes that receive the majority of drug infusions via non-ophthalmic artery routes or greater interval between OAC are more likely to recur and might warrant closer monitoring.