Vitreous Seeds Research Articles

Tridimensional Retinoblastoma Cultures as Vitreous Seeds Models for Live-Cell Imaging of Chemotherapy Penetration.

A preclinical model could aid in understanding retinoblastoma vitreous seeds behavior, drug penetration, and response to chemotherapy to optimize patient treatment. Our aim was to develop a tridimensional in vitro model of retinoblastoma vitreous seeds to assess chemotherapy penetration by means of live-cell imaging. Cell cultures from patients with retinoblastoma who underwent upfront enucleation were established and thoroughly characterized for authentication of human tumor origin. The correlation of the in vitro tridimensional structures resembling human spheres and dusts vitreous seeds was established. Confocal microscopy was used to quantify real-time fluorescence of topotecan as a measure of its penetration into different sizes of spheres. Cell viability was determined after chemotherapy penetration. The in vitro spheres and dusts models were able to recapitulate the morphology, phenotype, and genotype of patient vitreous seeds. The larger the size of the spheres, the longer the time required for the drug to fully penetrate into the core (p < 0.05). Importantly, topotecan penetration correlated with its cytotoxic activity. Therefore, the studied tridimensional cell model recapitulated several characteristics of vitreous seeds observed in patients with retinoblastoma and were successfully used to assess live-cell imaging of chemotherapy penetration for drug distribution studies.

The short-term outcome of intravitreal injection with topotecan for refractory vitreous seeding from retinoblastoma

Objective To observe and evaluate the short-term therapeutic effect of intravitreal injection with topotecan for refractory vitreous seeding from retinoblastoma (RB). Methods Eleven patients (11 eyes) of RB with refractory vitreous seeding (received intravenous chemotherapy, intra-arterial chemotherapy, intravitreal melphalan, laser, cryotherapy and subsequently developed refractory viable vitreous seeds) were enrolled in this study. There were 6 males (6 eyes) and 5 females (5 eyes). The aged from 9 to 44 months, with the mean age of 26 months. According to International Intraocular Retinoblastoma Classification, 11 eyes were initially classified as group E (3 eyes), D (6 eyes), B (1 eye) or A (1 eye). All patients were received intravitreal injection with topotecan. A total of 32 intravitreal topotecan injections were performed with a mean of 2.9 injections (median 3 injections; range 2−4 injections). The mean follow-up was 10 months. The safety and effectiveness of intravitreal injection with topotecan for refractory vitreous seeding from RB were observed. Results Complete regression of vitreous seeds was achieved in 11 of 11 eyes (100%), including complete disappearance in 9 eyes and fibrosis in 2 eyes. None of the patients needed enucleation and occured ocular or systemic complications in the follow-up period. Conclusion Intravitreal injection with topotecan for refractory vitreous seeds from RB is effective and safe. Key words: Retinoblastoma; Vitreous seeding; Topotecan/therapeutic use

Precision Intravitreal Chemotherapy for Localized Vitreous Seeding of Retinoblastoma

Purpose: To describe and evaluate the effectivity of a novel precision intravitreal injection technique for select cases of localized vitreous seeding in retinoblastoma. Methods: Patients with localized vitreous seeds from retinoblastoma received intravitreal chemotherapy via a precision injection technique (P-IVitC) intended to optimize local delivery of melphalan to target seeds. The needle was inserted trans-pars plana and chemotherapy deposited within 3 mm of the target seed(s) under indirect ophthalmoscopic guidance. Without subsequent globe manipulation, the head was then positioned to promote gravity-dependent settling of chemotherapy. Results: There were 8 eyes of 8 patients treated with P-IVitC for active vitreous seeds following adequate solid tumor control with intravenous chemotherapy (n = 3, 38%) or intra-arterial chemotherapy (n = 5, 63%). Viable vitreous seeds were primarily solitary spheres (n = 6, 75%) and measured an average of 2.7 mm in diameter. Vitreous seed resolution (n = 8, 100%) was noted after a mean of 2.6 injections (median 2; range 1–3) of 20 μg melphalan. There was no recurrence at a mean follow-up of 10.0 months. Only 1 eye had an associated complication (focal retinal pigment epithelial mottling, n = 1, 13%). Conclusions: With direct delivery of chemotherapy to within 3–4 mm of vitreous seed activity, P-IVitC provided complete control of localized vitreous seeds with minimal toxicity.

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.

Primary Intra-Arterial Chemotherapy for Retinoblastoma in the Intravitreal Chemotherapy Era: Five Years of Experience

Purpose: To report our 5-year experience with intra-arterial chemotherapy (IAC) in the intravitreal chemotherapy (IvitC) era. Methods: Retrospective review of retinoblastoma treated with primary unilateral IAC in the IvitC era (2012–2017). Results: There were 34 eyes treated with IAC alone versus 20 eyes treated with IAC plus IvitC for vitreous seeds. IAC (IAC alone vs. IAC plus IvitC) consisted of melphalan (41 vs. 10%) or melphalan plus topotecan (59 vs. 90%, p = 0.03). IvitC consisted of melphalan (60%) or melphalan plus topotecan (40%). Tumor control and globe salvage were achieved in 100% of group B and C eyes without IvitC. Despite more extensive vitreous seeds in the IvitC group (p < 0.01), comparison of IAC alone versus IAC plus IvitC revealed no difference in tumor control for group D (88 vs. 69%, p = 0.36) or group E (67 vs. 100%, p = 0.25) and no difference in globe salvage for group D (88 vs. 69%, p = 0.36) or group E (58 vs. 57%, p = 0.39). Conclusions: IAC is effective as primary therapy for unilateral group B, C, D, and E retinoblastoma. IvitC is an important adjuvant therapy to achieve comparable globe salvage rates for group D and E eyes with persistent active vitreous seeds.

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.

Recent advancements in the management of retinoblastoma and uveal melanoma.

Retinoblastoma and uveal melanoma are the most common intraocular malignancies observed in pediatric and adult populations, respectively. For retinoblastoma, intra-arterial chemotherapy has dramatically improved treatment outcomes and eye salvage rates compared with traditional salvage rates of systemic chemotherapy and external beam radiation therapy. Intravitreal injections of chemotherapy have also demonstrated excellent efficacy for vitreous seeds. Uveal melanoma, on the other hand, is treated predominantly with iodine-125 plaque brachytherapy or with proton beam therapy. Major strides in uveal melanoma genomics have been made since the early 2000s, allowing ocular oncologists to better understand the metastatic risks of the tumor on the basis of specific genetic signatures. Loss-of-function mutations of the BAP1 gene are associated with the highest metastatic risk, whereas gain-of-function mutations of SF3B1 and EIF1AX often confer a better prognosis. Expression of a cancer-testis antigen called PRAME (preferentially expressed antigen in melanoma) has been shown to increase metastatic risks in both low-risk and high-risk melanomas. New therapeutic approaches, including molecular therapies and nanoparticle phototherapy, are currently being investigated as alternative treatment modalities for uveal melanoma.

Safety and efficacy of posterior sub-Tenon's carboplatin injection versus intravitreal melphalan therapy in the management of retinoblastoma with secondary vitreous seeds.

To evaluate the safety and efficacy of posterior sub-Tenon's carboplatin injection compared to intravitreal melphalan injection in the management of retinoblastoma (RB) with secondary vitreous seeds. The outcome measures were vitreous seeds regression, need for other treatment modalities to achieve ocular salvage and treatment side effects. A prospective interventional comparative nonrandomized study included RB eyes developed secondary vitreous seeds during the period of follow up. They subdivided into two groups: study group I where posterior sub-Tenon's carboplatin (20 mg/2 mL) was injected and study group II where intravitreal melphalan (20 µg /0.1 mL) was injected. The injections repeated every 2-4wk. Thirty-three eyes were included in the study. Seventeen eyes (16 patients) in study group I and 16 eyes (16 patients) in study group II. Ten eyes (30.3%) were completely salvaged following local chemotherapies. Ocular salvage was 23.5% following posterior sub-Tenon's carboplatin injection versus 37.5% following intravitreal melphalan raised to 47.1% and 75% with addition of external beam radiotherapy (EBR) with no statistically significant difference between the study groups (P=0.16). A statistically significant correlation was found between ocular salvage rate and type of vitreous seeds either dust, spheres and clouds (r=0.42, P=0.015) and eyes harbor new solid tumor growth (r=0.35, P=0.045). The mean and median follow up periods following local chemotherapy injections were 2.0y in the study group I and 2.37y in the study group II. Few complications were reported: periorbital edema in all eyes and ocular motility disturbances in 13 eyes (76.5%) following posterior sub-Tenon's carboplatin injection. Vitreous hemorrhage developed in 2 eyes (12.5%) and localized retinopathy in 5 eyes (31.25%) following intravitreal melphalan. Local chemotherapy for treatment of RB with secondary vitreous seeds is safe and can salvage 30.3% of eyes without EBR. There is a superiority of intravitreal melphalan in ocular salvage however, no statistically significant difference between both groups.

Study of Management of Retinoblastoma with Vitreous Seeds (Retrospective Study)

AbstractBackground: The response of retinoblastoma with vitreous seeds to the different modalities of treatment as regards tumor regression, vitreous seeds regression and eye salvage.Aim of the Work: Study of the response of Rb with vitreous seeds to the different modalities of treatment as regards tumor regression, vitreous seeds regression and eye salvage.Patients and methods: This is a retrospective observational study in which we collected the data from medical records of cases of retinoblastoma with vitreous seeds who were managed over ten years at Ocular Oncology Unit, Ophthalmology Department, Ain Shams University Hospitals in the period from January 2004 to June 2015 and followed-up for at least 12 months after the completion of treatment. Our study included 37 patients. Fourty-two eyes affected with retino-blastoma with vitreous seeds were divided into four groups according to the modality of treatment: Group (1): 15 eyes treated with chemoreduction±focal therapy (diode laser ther-motherapy or cryotherapy), Group (2): 8 eyes treated with intravitreal chemotherapy, Group (3): 2 eyes treated with intra-arterial chemotherapy and Group (4): 17 eyes of treated with subTenon's Carboplatin. All eyes had received systemic chemotherapy as a primary treatment before these modalities of treatment.Results: Our study showed that the rate of ocular salvage was the highest in group 4 (52.9%) followed by group 1 (40%), group 2 (20%) and group 3 (0.0%). There was a statistically significant difference between group 1 and group 4 as regards tumor number, tumor location, tumor base diam-eter, number of thermotherapy sessions as primary treatment, mean duration of follow-up and event free interval from last treatment.Conclusion: Subtenon's Carboplatin, chemoreduction plus focal therapy, intravitreal chemotherapy and intra-arterial chemotherapy may be effective supplementary modalities of treatment that help in ocular salvage.

Commentary: Periocular topotecan for retinoblastoma.

We have long surpassed the era when enucleation or external beam radiotherapy (EBRT) was the only option for managing eyes with advanced retinoblastoma. Despite the groundbreaking advancements over the past few decades in the field of retinoblastoma management, persistant/recurrent vitreous seeds continue to remain the nemesis of ocular oncologists all over the world. Shield et al. reported that intravenous chemotherapy could salvage only 30% of eyes with diffuse vitreous seeds.[1] The relative resistance of vitreous seeds to systemic chemotherapy can be attributed to the avascularity of vitreous humor and has always been an impetus for exploring additional and alternate methods of more effective drug delivery into the vitreous. Wilson et al. found that cryotherapy increases the access of systemic chemotherapy into the vitreous.[2] Pascual Pasto et al. studied rabbit eyes and found that inhibition of blood–retinal barrier by systemic pantoprazole can lead to increased delivery of chemotherapy into vitreous.[3] The acceptance of intravitreal chemotherapy as a safe method of drug delivery was a quantam leap in the attempts to control the vitreous seeds.[4] Shields et al. achieved 100% vitreous seed control and 88% globe salvage over 3-year follow-up using intravitreal melphalan and/or topotecan. Employing enhanced safety techniques including choosing the correct site for injection in a region of least or no seeding, triple freeze–thaw cryotherapy at the needle site on withdrawal, and 1 min of constant ocular irrigation, they did not note any case of extraocular extension during 192 injections.[4] Combining intra-arterial chemotherapy with intravitreal chemotherapy has further improved globe salvage in eyes with advanced retinoblastoma.[5] Despite all the precautions, there is always a risk of extraocular tumor spread from intravitreal while injecting an eye with active tumor due to spillover, reflux, or tumor growth along the needle track.[6] Development of endophthalmitis after intravitreal injection in an eye with retinoblastoma, especially in developing countries, is, needless to say, a dreaded complication. Periocular chemotherapy is a relatively safer technique in this regard, as the chemotherapeutic drug is injected into the subtenon's space, thus avoiding any breach in the ocular integrity. Periocular carboplatin has been used in conjunction with systemic chemotherapy for retinoblastoma over two decades. Carcaboso et al. found considerable vitreous levels of topotecan in rabbit eyes after periocular delivery, as a consequence of a favored passage across the blood–retinal barrier.[7] Up to 2 mg periocular topotecan (POT) is considered safe and can be an effective alternative to intravitreal chemotherapy for controlling vitreous seeds.[8] Various modalities of periocular drug delivery have been explored by various authors including episcleral implants, fibrin sealants, and nanomolecular composition. Though periocular chemotherapy entails a risk of optic atrophy and muscle fibrosis, which can lead to strabismus and render enucleation rather difficult, these complications are seen mostly with periocular carboplatin. Periorbital topotecan is associated with mild and transient side effects such as eyelid edema and chemosis. The efficacy of POT in tumor regression has been reported previously. In an article in the current issue of IJO, Sthapit et al. have studied the efficacy of POT along with systemic chemotherapy in managing focal and diffuse vitreous seeds. The author could achieve remission of vitreous seeds (VS) in 63% of eyes and eye salvage in 95% of eyes with focal vitreous seeds and 68% of eyes with diffuse seeds.[9] The complications associated with POT were mild and transient and no metastasis was noted. In our opinion, POT is a safer alternative to intravitreal chemotherapy, especially in eyes with diffuse VS where finding a safe sight for injection is challenging. POT achieves good VS control with minimal complications. The results so far have been promising and there is a need for larger studies with longer follow-up to corroborate the results.

Retinal Toxicity of Intravitreal Melphalan in Albino Rabbits

Background: Intravitreal melphalan injections have been used for treating retinoblastoma with vitreous seeds. The aim of this study was to evaluate the safety margins for intravitreal melphalan, using clinical observations, electrophysiological testing and morphological observations. Methods: In this experimental study, 18 albino rabbits, were treated with intravitreal injection of 0.1 ml melphalan solution to the right, experimental eye, and were divided into 4 dose groups: 5 μg (N=4); 15 μg (N=4); 30 μg (N=5); 60 μg (N=5). The left, control eye, of each rabbit was injected with 0.1 ml saline. Clinical examination, electroretinography (ERG) and visual evoked potentials (VEP) were conducted at baseline and periodically throughout the 4-week follow-up. The eyes were then enucleated and the retinas were prepared for histology and glial fibrillary acidic protein (GFAP) immunocytochemistry. Results: No clinical, ERG, or histologic damage were found in rabbits treated with 5 μg melphalan. However, expression of glial fibrillary acidic protein was detected in retinal Muller cells of the experimental eyes and not in the control eyes. With all other doses of melphalan, dose-dependent funduscopic changes, ERG amplitude, histological damage and GFAP expression were found. VEP responses were similar between the experimental eyes and control eyes of all rabbits regardless of melphalan dose injected into the eye, indicating no change in retinal output. Conclusions: These findings indicate that intravitreal melphalan dose of 5 μg in rabbits, approximately equivalent to 10 μg in human, appears to be safe, but induce a mild stress to the retina. However, higher doses are toxic, and their utilization should be executed with caution, particularly if visual potential exists.

Assessment of retinoblastoma RNA reflux after intravitreal injection of melphalan

BackgroundIntravitreal injection of chemotherapy in retinoblastoma eyes with vitreous seeds may lead to a risk of extraocular tumour dissemination that has not been assessed so far.AimsTo develop a sensitive and...

Alternated intra‐arterial and intravitreal chemotherapy: successes and failures of advanced intraocular retinoblastoma treated without systemic chemotherapy

PurposeTo report the efficacy of combined intravitreal chemotherapy (IViC) and intra‐arterial chemotherapy (IAC) for the treatment of advanced stage retinoblastoma.MethodsThe medical records of twenty patients affected by unilateral advanced retinoblastoma (Reese‐Ellsworth stage Vb/D of ABC classification). After clinical and ophthalmoscopic evaluation, they underwent MRI to exclude local and CNS dissemination. The IAC was given to treat retinal masses and intravitreal injections to treat vitreous seeding. Patients had received two cycles (six infusions) of IAC, and from six up to ten melphalan injections into the vitreous, with an interval of 7–10 days between them.ResultsAll patients underwent to bimonthly MRI examination, during treatment and every 3 months for 1 year after last injection, to exclude orbital dissemination. Successful control (57.8%) of tumor masses and vitreous seeds was achieved in all cases at 12 up to 60 months follow‐up. No permanent complications have been reported. Transient omplications disappeared throughout the months. No intraocular or orbital tumor recurrence or retinoblastoma metastases were observed.ConclusionsSequential IAC and intravitreal melphalan for advanced retinoblastoma is a good tool to provide retinal and vitreous seed control.

Usefulness of Ret‐Cam imaging in diagnosis, treatment and monitoring of retinoblastoma

PurposeTo present a group of children with retinoblastoma whose diagnostic, therapeutic and monitoring decisions were made using Ret‐CamMethodsChildren treated in the Department of Ophthalmology and Ophthalmic Oncology for retinoblastoma in the 1900s. Diagnosis was made after ophthalmic examination under general anesthesia with Ret‐Cam and ultrasonography. Treatment was performed with VEC chemoreduction, iodine and ruthenium brachytherapy, cryotherapy, and transpupillary thermotherapy.ResultsThe results of treatment and control were documented on a Ret‐Cam camera. Photographs of intraocular tumors have been made prior to treatment, after chemoreduction, after local treatment and during the follow‐up. Tumors regression, vitreous seeds and possible radiation retinopathy were monitored.ConclusionsPhotographic documentation using the Ret‐Cam is very useful in treating retinoblastoma. The biggest advantage is the objective possibility to compare and evaluate the results of treatment and control

Intravitreal topotecan in the management of refractory and recurrent vitreous seeds in retinoblastoma

Background/aimTo evaluate the efficacy of intravitreal topotecan for refractory or recurrent vitreous seeds in retinoblastoma.MethodsIntravitreal injection of topotecan hydrochloride (30 µg/0.15 mL) was provided every 3 weeks by the safety...

Short-term efficacy of intravitreal injection of melphalan for refractory vitreous seeding from retinoblastoma

Objective: To evaluate the efficacy and safety of intravitreal chemotherapy for refractory vitreous seeding from retinoblastoma. Methods: Retrospective series of case studies. Nine patients (13 eyes) with the diagnosis of refractory vitreous seeding were enrolled in Department of Ophthalmology of Eye& ENT Hospital of Fudan University from March 2014 to October 2015.There were 6 males and 3 females. Children aged 8 to 40 months, median age of 18 months. In the 13 eyes, 3 eyes were E period, 9 eyes were D period, and 1 eyes were C period. The fundus was examined by indirect ophthalmoscope and recorded by RetcamIII. Systemic chemotherapy was performed using the VEC protocol, that is vincristine, etoposide, and carboplatin. Local treatment also involves cryotherapy and/or thermotherapy. All patients were treated with intravitreal injection of melphalan. They underwent intravitreal melphalan, once every 4 weeks, with an average of 3 times of injections. The treatment dose of melphalan is 20 to 40 μg per dose. Observe the vitreous seed control and complications of therapy. Results: Vitreous seeds control was attained in all cases. There was no case of orbital extension or remote metastasis. Complications included retinal pigment epithelial and choroidal atrophy in 7 eyes, pupillary synechia and iris atrophy in 2 eyes,retinal vasculitis and vascular occlusion in 2 eyes, optic atrophy in 2 eyes, vitreous hemorrhage in 1 eye, and temporary hypotony in 3 eyes. Conclusions: Intravitreal melphalan is an effective treatment for refractory vitreous seeding from retinoblastoma. High dose may lead to local adverse reactions. (Chin J Ophthalmol, 2017, 53: 570-574).

Not All Seeds Are Created Equal: Seed Classification Is Predictive of Outcomes in Retinoblastoma

Intravitreal chemotherapy has emerged as an important modality for treating vitreous seeding in retinoblastoma. A classification system has been described as predictive of response to intravitreal melphalan (IVM) in patients treated predominantly with primary intra-arterial chemotherapy. The objective of this study is to evaluate the outcomes of retinoblastoma treated with intravenous chemotherapy and IVM as salvage for vitreous seeding, and further to determine whether vitreous seed classification (dust, spheres, cloud) is predictive of the total number and dose of IVM injections required for treatment in this cohort. A nonrandomized retrospective review. Retinoblastoma patients treated at a single center with intravenous chemotherapy and IVM. Retrospective review of patients with vitreous seeding from retinoblastoma treated with intravenous chemotherapy and IVM from 2012 to2016. Primary outcome measure was eradication of seeds and globe salvage. Secondary measures included IVM-associated toxicity and complications. Overall, 28 eyes of 25 patients were included, with a total of 110 IVM injections. By seed classification, eyes with dust (n= 15) required a median of 3 injections, spheres (n= 8) required 4 injections, and clouds (n= 5) required 6 injections. Spherical seeds were only seen in recurrent vitreous seeding. Of the 28 treated eyes, 9 were enucleated, 6 for recurrent retinal disease, resulting in an overall globe salvage rate of 68%. The salvage rate secondary to active retinoblastoma was 79%. Dust classification was the most prevalent seeding type of the 9 enucleated eyes. There was 100% regression of vitreous seeds after intravitreal injection and no eye was treated with radiation or enucleated for seeding. Twelve eyes demonstrated grade 3 or greater IVM-associated retinal or anterior segment toxicity post injection. Mean follow-up was 33 months (range, 9-51 months). IVM is an effective treatment for vitreous seeding after intravenous chemotherapy for retinoblastoma. As with eyes treated with intra-arterial chemotherapy, seed classification is predictive of the total number and dose of IVM injections in eyes treated with intravenous chemotherapy. Eyes with clouds required significantly more injections than eyes with dust or spheres.

Long-term outcomes of Group D retinoblastoma eyes during the intravitreal melphalan era.

To evaluate outcomes of Group D retinoblastoma (Rb) eyes during the intravitreal melphalan era. Retrospective chart review of patients diagnosed with Group D Rb from 2011 to 2016 was done. Overall, 76 Group D eyes of 68 patients were included; salvage therapy included systemic chemoreduction with vincristine, etoposide, and carboplatin with local consolidation, followed by intravitreal injection of melphalan for recurrent or persistent seeding. External beam radiation was not used as a treatment modality. Primary outcome measurement was globe salvage. Of 76 Group D eyes, 24 were enucleated primarily and 52 were treated with intent to salvage the globe. Systemic chemoreduction salvaged 25 of 52 eyes (48%). Tumor recurrences were diagnosed in 27 eyes (52%); five with massive retinal recurrences underwent enucleation and 22 were treated with intravitreal melphalan injection. Of the 22 injected eyes, 14 (64%) were salvaged and eight required enucleation primarily for retinal recurrences. Success in eradicating vitreous seeds was 100%. The Kaplan-Meier 3-year survival estimate for treated eyes is 76.5% (95% CI: 61.4-86.3). Median follow-up for the group of 76 Group D eyes was 29.5 months (SD 17.9 months). During a 6-year period that included the initiation of intravitreal melphalan at our institution, the salvage rate of treated Group D eyes was 75% (39/52 eyes). Intravitreal melphalan was utilized for ocular salvage in 42% (22/52 eyes). Systemic chemoreduction combined with intravitreal melphalan for seeding demonstrated a high overall salvage rate for Group D eyes in this cohort.

Retinoblastoma Vitreous Seed Clouds (Class 3): A Comparison of Treatment with Ophthalmic Artery Chemosurgery with or without Intravitreous and Periocular Chemotherapy

To compare the efficacy and toxicity of treating class 3 retinoblastoma vitreous seeds with ophthalmic artery chemosurgery (OAC) alone versus OAC with intravitreous chemotherapy. Retrospective cohort study. Forty eyes containing clouds (class 3 vitreous seeds) of 40 retinoblastoma patients (19 treated with OAC alone and 21 treated with OAC plus intravitreous and periocular chemotherapy). Ocular survival, disease-free survival and time to regression of seeds were estimated with Kaplan-Meier estimates. Ocular toxicity was evaluated by clinical findings and electroretinography: 30-Hz flicker responses were compared at baseline and last follow-up visit. Continuous variables were compared with Student t test, and categorical variables were compared with the Fisher exact test. Ocular survival, disease-free survival, and time to regression of seeds. There were no disease- or treatment-related deaths and no patient demonstrated externalization of tumor or metastatic disease. There was no significant difference in the age, laterality, disease, or disease status (treatment naïve vs. previously treated) between the 2 groups. The time to regression of seeds was significantly shorter for eyes treated with OAC plus intravitreous chemotherapy (5.7 months) compared with eyes treated with OAC alone (14.6 months; P < 0.001). The 18-month Kaplan-Meier estimates of disease-free survival were significantly worse for the OAC alone group: 67.1% (95% confidence interval, 40.9%-83.6%) versus 94.1% (95% confidence interval, 65%-99.1%) for the OAC plus intravitreous chemotherapy group (P= 0.05). The 36-month Kaplan-Meier estimates of ocular survival were 83.3% (95% confidence interval, 56.7%-94.3%) for the OAC alone group and 100% for the OAC plus intravitreous chemotherapy group (P= 0.16). The mean change in electroretinography responses was not significantly different between groups, decreasing by 11 μV for the OAC alone group and 22 μV for the OAC plus intravitreous chemotherapy group (P= 0.4). Treating vitreous seed clouds with OAC and intravitreous and periocular chemotherapy, compared with OAC alone, resulted in a shorter time to regression and was associated with fewer recurrences requiring additional treatment and fewer enucleations. The toxicity to the retina does not seem to be significantly worse in the OAC plus intravitreous chemotherapy group.