Retinoblastoma Vitreous Seeds Captured on OCT

BackgroundCurrent melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort.MethodsRabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction. Patients: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.ResultsIntravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90 across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%–79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 μV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged.ConclusionsTaken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.

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Is Combination Therapy for Resistant Vitreous Seeds Really Essential?—Reply

JAMA Ophthalmology ◽

10.1001/jamaophthalmol.2014.4657 ◽

2015 ◽

Vol 133 (2) ◽

pp. 232

Author(s):

Fariba Ghassemi ◽

Carol L. Shields ◽

Alireza Khodabande

Keyword(s):

Combination Therapy ◽

Vitreous Seeds

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

International Journal of Ophthalmology ◽

10.18240/ijo.2018.03.15 ◽

2018 ◽

Keyword(s):

Safety And Efficacy ◽

Vitreous Seeds

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

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2017-310641 ◽

2017 ◽

Vol 102 (4) ◽

pp. 490-495 ◽

Cited By ~ 20

Author(s):

Raksha Rao ◽

Santosh G Honavar ◽

Vishal Sharma ◽

Vijay Anand P Reddy

Keyword(s):

Visual Acuity ◽

Intravitreal Injection ◽

Primary Treatment ◽

Complete Regression ◽

Intravenous Chemotherapy ◽

Systemic Complications ◽

Group D ◽

Vitreous Seeds

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 enhanced technique.ResultsThe study included 17 consecutive patients with retinoblastoma with refractory or recurrent vitreous seeds. Five eyes (29%) belonged to International Classification of Retinoblastoma group C and 12 eyes (71%) belonged to group D. Primary treatment included triple drug intravenous chemotherapy for a mean of 10 cycles (median, 9 cycles; range, 6–18 cycles). Fifteen patients (88%) had undergone 56 periocular carboplatin injections with a mean of 4 injections (median, 3 injections; range, 1–8 injections), concurrent with intravenous chemotherapy. A total of 53 intravitreal topotecan injections were performed in 17 eyes of 17 consecutive patients with refractory or recurrent vitreous seeds with a mean of 3 injections (median, 3 injections; range, 2–6 injections). Complete regression of vitreous seeds was achieved in 17 of 17 eyes (100%). At a mean follow-up of 23.8 months (median, 24 months; range, 15.1–34.1 months), one eye (6%) with a recurrent retinal tumour needed enucleation, and the rest of the 16 eyes (94%) maintained complete regression. Final visual acuity could be reliably assessed in all 16 eyes (100%), of whom 12 eyes (75%) had visual acuity ≥20/200. None of the patients developed ocular or systemic complications.ConclusionThree-weekly intravitreal topotecan appears effective and safe in controlling focal or diffuse refractory or recurrent vitreous seeds in retinoblastoma.

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Artesunate induces mitochondria-mediated apoptosis of human retinoblastoma cells by upregulating Kruppel-like factor 6

Cell Death and Disease ◽

10.1038/s41419-019-2084-1 ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 1

Author(s):

Ying Yang ◽

Nandan Wu ◽

Yihui Wu ◽

Haoting Chen ◽

Jin Qiu ◽

...

Keyword(s):

Tumor Growth ◽

Cell Apoptosis ◽

Underlying Mechanism ◽

Dependent Manner ◽

Chemotherapeutic Drug ◽

Sprague Dawley ◽

Fundus Fluorescein Angiography ◽

Intravitreal Chemotherapy ◽

Vitreous Seeds

Abstract Retinoblastoma (RB) is the most common primary intraocular malignancy in children. Intravitreal chemotherapy achieves favorable clinical outcomes in controlling RB vitreous seeds, which are a common reason for treatment failure. Thus, a novel, effective and safe intravitreal chemotherapeutic drug is urgently required. The malaria drug artesunate (ART) recently demonstrated remarkable anticancer effects with mild side effects. The purpose of this study is to investigate the anti-RB efficacy, the underlying mechanism and the intraocular safety of ART. Herein, we verified that ART inhibits RB cell viability and induces cell apoptosis in a dose- and time-dependent manner. Microarray analysis revealed that Kruppel-like factor 6 (KLF6) was upregulated after ART treatment, and this was further confirmed by real-time PCR and western blot assays. Silencing of KLF6 expression significantly reversed ART-induced RB cell growth inhibition and apoptosis. Furthermore, ART activated mitochondria-mediated apoptosis of RB cells, while silencing KLF6 expression significantly inhibited this effect. In murine xenotransplantation models of RB, we further confirmed that ART inhibits RB tumor growth, induces tumor cell apoptosis and upregulates KLF6 expression. In addition, KLF6 silencing attenuates ART-mediated inhibition of tumor growth in vivo. Furthermore, we proved that intravitreal injection of ART in Sprague-Dawley (SD) rats is safe, with no obvious retinal function damage or structural disorders observed by electrophysiology (ERG), fundal photographs, fundus fluorescein angiography (FFA) or optical coherence tomography (OCT) examinations. Collectively, our study revealed that ART induces mitochondrial apoptosis of RB cells via upregulating KLF6, and our results may extend the application of ART to the clinic as an effective and safe intravitreal chemotherapeutic drug to treat RB, especially RB with vitreous seeds.

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Intravitreal melphalan therapy for vitreous seeds in retinoblastoma: Implementation and outcomes of a new chemotherapy protocol

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155220904410 ◽

2020 ◽

Vol 26 (8) ◽

pp. 1829-1835 ◽

Cited By ~ 1

Author(s):

Antonio Solana-Altabella ◽

Silvia Valero ◽

Julia Balaguer ◽

Paloma Escobar-Cava ◽

Honorio Barranco ◽

...

Keyword(s):

Overall Survival ◽

Adverse Effects ◽

Health Outcomes ◽

Chemotherapeutic Agent ◽

Treatment Protocol ◽

Treatment Team ◽

Intravitreal Chemotherapy ◽

Chemotherapy Protocol ◽

Salt And Pepper ◽

Vitreous Seeds

Retinoblastoma is the most common paediatric ocular tumour, which appears in the retina. Without treatment, retinoblastoma grows and destroys the internal ocular globe architecture, even leading to metastasis. When treated, overall survival is close to 97%, the alkylating drug melphalan being the most extensively used chemotherapeutic agent in localised treatment. The aim of this study is to describe the implementation of a new intravitreal chemotherapy retinoblastoma treatment protocol for children implanting vitreous seeds through intravitreal melphalan injections and to evaluate the patients’ health outcomes treated with it. Between December 2014 and July 2018, seven patients were treated with this protocol. They received a mean of 3.3 cycles of intravitreal melphalan with standard doses of 30 mcg per cycle. In the seven eyes treated in our hospital, the response was as expected; three eyes with vitreous seedings (43%) were successfully treated. The main adverse effects presented by all patients were scars at cryogenisation points. In two patients, the appearance of ‘salt and pepper’ retinopathy was reported. Oncology pharmacists, as part of the treatment team, can provide information about recommended doses, expected adverse effects, stability of preparations, most appropriate method of processing, packaging, and methods of drug administration, to ensure efficacy and especially safety in the administration of these drugs.

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Assessment of retinoblastoma RNA reflux after intravitreal injection of melphalan

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2017-310574 ◽

2017 ◽

Vol 102 (3) ◽

pp. 415-418 ◽

Cited By ~ 5

Author(s):

Ursula Winter ◽

Michael Nicolas ◽

Mariana Sgroi ◽

Claudia Sampor ◽

Ana Torbidoni ◽

...

Keyword(s):

Intravitreal Injection ◽

Tumour Cell ◽

Limit Of Detection ◽

Local Treatment ◽

Homeobox Gene ◽

Simple Method ◽

Retinoblastoma Cell ◽

Filter Papers ◽

Cell Dissemination ◽

Vitreous Seeds

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 clinically feasible technique to assess for potential retinoblastoma cell reflux after intravitreal injection of melphalan.MethodsFilter papers were cut in 6 mm diameter circles and sterilised before use. Eyes with retinoblastoma vitreous seeds (group D, International Classification) received weekly intravitreal melphalan injections (20 µg or 30 µg/dose) followed by cryotherapy as part of local treatment. Immediately after finishing the injection and cryotherapy, filter papers were placed on the injection site and on the cryoprobe tip to assess for the expression of the cone-rod homeobox gene (CRX) by real-time qPCR as a surrogate of retinoblastoma RNA. The assay was developed and validated to determine sensitivity, linearity, recovery, repeatability and reproducibility.ResultsThe assay for quantitation of CRX expression was linear in the range of 1 to 1000 cells. The lowest limit of detection was one retinoblastoma cell and allowed to recover 100% of the cell load in external supplementation. A total of 14 eyes received 22 cycles of intravitreal melphalan and were evaluated for potential extraocular tumour cell dissemination using the developed technique. None of the cycles were positive for CRX in samples from the scar or from the cryoprobe tip.ConclusionsA sensitive and simple method of tumour cell assessment has been developed that can be used in the clinics to assess for potential extraocular dissemination after intravitreal injections to assure its performance.

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