Treatment Of Retinoblastoma Research Articles

New approach of chemotherapy for the treatment of retinoblastoma: a review

Retinoblastoma is the most common primary intraocular malignancy of childhood. A potentially curable cancer, its treatment has improved significantly over the last few decades. In developed world current treatment options aim to preserve the globe as well as vision with minimum morbidity. High resolution imaging has improved tumor detection and is useful for prognosticating cases and monitoring response to treatment. Targeted chemotherapy has shown promising results and these routes are being increasingly employed world-wide for globe preservation. Chemotherapy is currently used as a first line approach for children with this malignancy and can be delivered by intravenous, intra-arterial, periocular, and intravitreal routes. The choice of route for chemotherapy administration depends upon the tumor laterality and tumor staging. This review aims to highlight newer advancements in the field of management of retinoblastoma that have been introduced in recent times, with a special emphasis on globe-preserving therapy.

Ретробульбарная инфузионная терапия интраокулярных осложнений локального лечения ретинобластомы

«Российская офтальмология онлайн» - электронное информационное издание, создается с 1 марта 2010 года под эгидой Российского общества офтальмологов. Основная задача проекта - научно-информационная поддержка специалистов в области офтальмологии.

Cataract surgery in treated retinoblastoma eyes: A study of 29 eyes.

To study the outcomes of cataract surgery in treated retinoblastoma (RB) eyes. Retrospective study of 29 eyes of 27 patients. Based on International Classification of Intraocular Retinoblastoma, tumors belonged to group B (n = 3, 10%), C (n = 1, 4%), D (n = 10, 34%), and E (n = 3, 10%). The remaining 12 eyes (41%) had regressed tumors on presentation due to prior treatment. The RB treatment details included intravenous chemotherapy (n = 24, 83%), external beam radiotherapy (n = 14, 48%), and others. The mean time interval between tumor regression and cataract surgery was 51 months (median, 26 months; range, 6-245 months). The post-operative visual acuity was 20/200 or better in 12 (41%) eyes. Overall, 16 (55%) eyes displayed improvement of vision post-cataract surgery, while 13 (45%) eyes had no improvement in vision. The complications of cataract surgery included visual axis opacification (n = 15, 52%), pupillary membrane (n = 4, 14%), hyphema (n = 1, 3%), and extraocular tumor extension (n = 1, 3%). Clearer fundus view post-surgery revealed underlying tumor edge recurrence in 1 (3%) eye, and two (7%) patients had tumor recurrence at a mean interval of 8 months (median, 8 months; range, 7-8 months) following cataract extraction. Globe salvage was achieved in 26 (90%) eyes over a mean follow-up period of 103 months (median, 91 months; range, 19-267 months). Cataract surgery in treated RB is safe with vision salvage in 55% eyes and globe salvage in 90% eyes. Though there is a risk of extraocular tumor extension, its occurrence is rare (3%).

CD24 blunts the sensitivity of retinoblastoma to vincristine by modulating autophagy.

Retinoblastoma (RB) is the most common childhood malignant intraocular tumor. The clinical efficacy of vincristine (VCR) in the treatment of RB is severely limited by drug resistance. Here, we found that CD24, a GPI‐anchored protein, was overexpressed in human RB tissues and RB cell lines, and was associated with the sensitivity of RB cells in response to VCR therapy. We demonstrated that CD24 plays a critical role in impairing RB sensitivity to VCR via regulating autophagy. Mechanistically, CD24 recruits PTEN to the lipid raft domain and regulates the PTEN/AKT/mTORC1 pathway to activate autophagy. Lipid raft localization was essential for CD24 recruitment function. Collectively, our findings revealed a novel role of CD24 in regulating RB sensitivity to VCR and showed that CD24 is a potential target for improving chemotherapeutic sensitivity and RB patient outcomes.

Superselective intra-arterial chemotherapy treatment for retinoblastoma: clinical experience from a tertiary referral centre

ObjectiveTo evaluate the treatment outcomes of an alternative retrograde superselective ophthalmic artery catheterization (intra-arterial chemotherapy [IAC]), while treating retinoblastoma patients. MethodsA retrospective review of IAC for 21 treatment-naïve eyes (21 patients, primary group) and 10 eyes of previously treated 9 patients (secondary group). Statistical analysis was performed using Number Cruncher Statistical System 2007, Kaplan–Meier survival analysis, and Fisher’s exact test. ResultsTotal fluoroscopy time ranged from 3 to 12 minutes. Globe salvage was 71.4% (15/21 eyes) and 80% (8/10 eyes) in the primary and secondary groups, respectively. Globe salvage rates were recorded as 100%, 100%, 70%, and 0% for group B, C, D, and E patients, respectively. ConclusionsRetrograde IAC is effective in tumour control with shorter fluoroscopy time and acceptable complication rates both for naïve and treated patients. Furthermore, controlling retinoblastoma in advanced group D eyes was efficacious.

Benefit of Patching Therapy to Minimize Amblyopia After Retinoblastoma Treatment

Benefit of Patching Therapy to Minimize Amblyopia After Retinoblastoma Treatment

Optical coherence tomography in preclinical diagnosis of optic nerve disk changes after chemotherapy in children with retinoblastoma

Purpose . Using optical coherence tomography (OCT), determine the preclinical changes in optic nerve head (ONH) after chemotherapy in children with retinoblastoma (RB). Material and methods . 38 patients (76 eyes) were examined and treated: 15 girls, 23 boys with RB averagely aged 21.0 ± 1.5 months. Of these, 58 affected eyes before treatment belonged to groups А (3), В (16), С (33), D (3), and Е (3). All tumor nodes were located on the fundus outside the optic disk. The examination of these eyes was carried out on an optical coherent tomograph SOCT Copernicus 4.2 (Poland). The 58 eyes were first tested before treatment, then after 3 or 4 courses of systemic chemotherapy (CT), once again after 6 courses of systemic CT and 1–3 courses of superselective intraarterial CT and 4–9 courses of intravitreal CT. 15 healthy children (30 eyes) of the corresponding age were examined as a control. Results . After 3 courses of systemic CT, OCT determined optic neuropathy with edema in 46.6 %. Morphometric data included parapapillary retinal cystic cavities, elevation of the contour of the optic disc towards the vitreous, increased rim volume (to 0.87 ± 0.12 mm 3 ) and average thickness of the nerve fiber layer increased to 0.39 ± 0.06 mm (p < 0.01). After combined chemotherapy we revealed the thinning of the peripapillary choroid (to 80.0 ± 3.2 μm) with no retinal edema in 34.5 %, a reduction of rim volume to 0.34 ± 0.2 mm 3 and the layer of nerve fibers to 0.02 ± 0.01 mm (p < 0.01). These changes are evidences of optic nerve disc atrophy. Conclusion . OCT is an informative method of examining the optic disc in children with RB at different stages of treatment, which identifies signs of edema and symptoms of atrophy more often (respectively, by 15.6 % and 17.3 %). Preclinical diagnostics of optic disc pathology with the help of OCT allows predicting visual functions in children with RB at its early stages and developing a differentiated approach to the choice of RB treatment.

Innovations in retinoblastoma treatment and reflection to enucleation rate of 362 eyes of 262 CASES: Twenty years retrospective assessment at Ankara University.

e22509 Background: Enucleation used as the first-line tx option for RB, dx in advanced stages. Methods: To evaluate the enucleation rates of RB cases in 20 years period, to emphasize the recent developments in the tx of RB that contribute to the improvement of tx outcomes. Results: 262 patients, with the dx of RB between June 1998 &December 2018 in Ankara University Departmant of Pediatric Oncology were evaluated retrospectively. The M / F ratio was 1.2, mean age at dx 19.39 mos; 22.7 mos for unilateral &14.1 mos for bilateral dx. 61.8% of the patients had unilateral, 38.2% bilateral RB. 362 eyes were evaluated, 12.5% of the patients had a family history of RB bilateral dx was more frequent. The initial findings were leucocori in 58%& strabismus in 27.9%, similar to the literature. According to ICRB, 6% of the patients were diagnosed in Group A, 22% in Group B, 19% in Group C, 22% in Group D and 31% in Group E. Patients with bilateral dx were diagnosed at an earlier stage. Enucleation, in 50.5% of 362 eyes analyzed. There was no enucleated eye in Group A. In group B,10.1% of the eyes were enucleated, as of recurrence. 32.3% of eyes in Group C, 60.7% of eyes in Group D and 92.9% of eyes in Group E were enucleated. Enucleation was performed in 25.4% of the eyes within the first month after dx as of the advanced stage. 33.7% of of the eyes who did not have enucleation at the time of dx required enucleation at FU. The most common causes of enucleation were tumor recurrence, total retinal detachment & vitreous hemorrhage. The tx methods other than enucleation are systemic CT, RT & local treatments; cryotherapy, thermotherapy, episcleral brachytherapy, intravitreal CT & intraarterial CT. Systemic CT applied to 77% of the patients.CT protocol were VEC and ICE.RT was applied to 17% of the patients. After 2012, radiotherapy was used only in 2 patients with systemic involvement. Cryotherapy was performed in 48.3% of the eyes, thermotherapy in 38.6%, episcleral brachytherapy in 3.8% of the eyes included.Intraarterial CT to be used after 2004 was applied to 16.6% of eyes dx & intravitreal CT was used after 2009 was applied to13.2% of eyes. Enucleation was avoided in 84.6% of eyes in which these two tx modalities were applied together. Enucleation rates of 56.3% &61.2% between 1998-2004 and 2004-2009, respectively; with active use of intraarterial and intravitreal CT, decreased to 40.2% between 2009-2018. Conclusions: It was observed that enucleation rates &RT gradually decreased with using systemic CT and local treatment methods.

MicroRNA -378a-3p Restrains the Proliferation of Retinoblastoma Cells but Promotes Apoptosis of Retinoblastoma Cells via Inhibition of FOXG1.

PurposeMore recently, literature has emerged providing findings about the novelty of microRNAs (miR)-targeted therapeutics in the treatment of retinoblastoma (RB). The prime objective of this study was to identify the potential role of miR-378a-3p and its regulation in RB cells via forkhead box G1 (FOXG1).MethodsThe expression of miR-378a-3p and FOXG1 in the clinical RB tissues was determined using RNA quantitation and Western blot assays. The interaction between miR-378a-3p and FOXG1 was identified using dual luciferase reporter gene assay. The potential effects of miR-378a-3p on the RB cell biological processes were evaluated by conducting gain- and loss-of-function studies of miR-378a-3p and FOXG1, followed by cell viability, cell cycle progression, and apoptosis measurements. Furthermore, experiments were performed in nude mice to assess its effects on tumor formation.ResultsmiR-378a-3p was poorly expressed, whereas FOXG1 was highly expressed in RB tissues and cells. miR-378a-3p bound to the FOXG1 3′ untranslated region and negatively modulated its expression. The overexpression of miR-378a-3p was found to decrease RB cell viability and to promote cell apoptosis in vitro, whereas overexpressed FOXG1 reversed the regulatory effects of miR-378a-3p on RB cellular behaviors. In nude mice, the restoration of miR-378a-3p by miR-378a-3p agomir was shown to play a role in the reduction of tumor volume and size relative to nude mice injected with negative control-agomir.ConclusionsOur findings identified that increased miR-378a-3p exerted an inhibitory effect on RB cell proliferation by targeting FOXG1, suggesting the role of miR-378a-3p as a novel therapeutic target for RB.

Screening and identification of key biomarkers for retinoblastoma: Evidence from bioinformatics analysis.

Background:Retinoblastoma (RB) is one of the most common malignant tumors in pediatrics; to clarify the cause of RB, a lot of manpower and material resources have been invested but have not been well explained.Methods:To identify the candidate genes in the occurrence and development of the disease, we downloaded the microarray datasets GSE97508, GSE92987, and GSE24673 from the gene expression database (GEO). The differentially expressed gene (DEG) was identified and functional enrichment analysis was performed. The protein–protein interaction network was constructed and analyzed by String and Cytoscape.Results:A total of 74 DEGs were identified, including 40 up-regulated genes and 34 down-regulated genes. The rich functions and pathways of DEG include regulating mitosis, cell cycle, DNA transcription process, promoting protein phosphorylation, regulating energy metabolism in vivo, promoting the binding of some macromolecular complexes, and regulating the cell cycle. Twenty-four HUB genes were identified. Biological process analysis showed that these genes were mainly enriched in regulating energy metabolism in vivo, promoting the binding of some small molecules and regulating the cell cycle. Survival analysis showed that DGPDC1, NDC80, SHCBP, TOP2A, and DLGAP5 may be involved in the occurrence, invasion, or recurrence of RB.Conclusion:In conclusion, screening DEGs and HUB genes in RB can help us to better understand the mechanism of the occurrence and development of RB at the molecular level, and provide candidate targets for the diagnosis and treatment of RB.

High levels of global genome methylation in patients with retinoblastoma.

Retinoblastoma is a tumor of the embryonic neural retina in young children. The DNA methyltransferase 1 (DNMT1) gene has been demonstrated to be transcriptionally activated in cells lacking retinoblastoma 1 (RB1). Thus, there is a direct interaction between DNMT1 and RB1 in vivo. The present study hypothesized that uncontrolled DNMT1, DNMT2 and DNMT3 expression may lead to a high level of global genome methylation causing a second hit or where both alleles are altered, in RB1 and/or inactivation of other genes in retinal cells. To test this, the global genome methylation levels were analyzed in 69 patients with retinoblastoma, as well as 26 healthy siblings and 18 healthy unrelated children as the control groups. Peripheral blood and tumor tissue samples were obtained from 32 patients. The expression levels of DNMT genes were also determined in cell lines. Based on the median levels of global genome methylation in patients, higher genome-wide methylation levels in peripheral blood were associated with a 3.33-fold increased risk for retinoblastoma in patients compared with all healthy controls (95% confidence interval, 0.98–11.35; P<0.0001). The level of global genome methylation and the expression of DNMT genes were increased in the WERI-RB-1 cell line, which has a mutated RB1 gene, compared with a wild-type RB1-expressing cell line. These results supported the hypothesis that epigenetic alterations, as well as mutations in RB1, may be associated with the oncogenesis and inheritance of retinoblastoma. The repression of genes that interact with RB1, such as the DNMT gene family, may be important in patients with retinoblastoma with alterations in RB1, and may serve a role in the treatment and regression of retinoblastoma.

The long non-coding RNA ILF3-AS1 increases the proliferation and invasion of retinoblastoma through the miR-132–3p/SMAD2 axis

A great deal of evidence suggests that long non-coding RNAs (lncRNAs) function in the tumorigenesis of retinoblastoma (RB). However, the roles of lncRNA ILF3-AS1 in RB are still unclear. In the present study, our work revealed that the lncRNA ILF3-AS1 was increased in both RB tissues and cell lines. Repression of ILF3-AS1 suppressed both RB cell proliferation and invasion in vitro. ILF3-AS1 also promoted tumor growth in vivo. While exploring the mechanisms behind ILF3-AS1 in RB, we identified that ILF3-AS1 sponges with miR-132–3p that is expressed at low levels in RB tissues as well as attenuates RB progression. Furthermore, SMAD2 was confirmed to be a miR-132–3p target. Finally, we found that SMAD2 overexpression or miR-132–3p inhibitors recover the inhibitory effects of ILF3-AS1 suppression on RB progression. Collectively, these data indicate that ILF3-AS1 is involved in RB progression through the miR-132–3p/SMAD2 axis, providing a novel and promising biomarker that can be used for the treatment of RB.

A 20-year audit of retinoblastoma treatment outcomes.

ObjectivesTo evaluate the long-term treatment outcomes in intraocular retinoblastoma (RB) including the associated factors for eventual treatment with external beam radiotherapy (EBRT) and enucleation as well as to analyse the risk factors for metastasis and death in extraocular RB.MethodsRetrospective analysis of 390 eyes from 256 (89.8%) intraocular RB and 29 (10.2%) extraocular RB cases diagnosed and treated between October 1998 and May 2018 at one of the largest tertiary care centers in Turkey.ResultsOf 351 intraocular RB eyes, 53.3% had group D/E disease at presentation. 75 (21.4%) of 351 eyes underwent primary enucleation. Of the remaining 276 eyes undergoing eye-conserving treatments, 201 (72.8%) were salvaged. Most of these eyes were treated using intravenous chemotherapy and/or focal treatments [transpupillary thermotherapy (TTT) and cryotherapy] initially. EBRT was eventually required in 48 (17.4%) eyes and secondary enucleation in 75 (27.2%) eyes. At mean follow-ups of 76.7 and 39.7 months for intraocular and extraocular RB cohorts, respectively, 180 (46.2%) eyes underwent primary/secondary enucleation and exenteration. Overall, 13 cases developed metastasis and 9 died. Two patients with trilateral RB also expired. Multivariable risk factors for enucleation were the presence of vitreous seeds (p < 0.001), absence of EBRT administration (p = 0.033), 5–9 TTT applications compared with no TTT (p = 0.031), and each 1 mm increase in tumour base diameter (p < 0.001). Univariate factors predictive of metastasis were the presence of extraocular RB detected by imaging methods (p < 0.001) and extrascleral/optic nerve cut end involvement at histopathological examination (p < 0.001).ConclusionsIn our series, 72.8% of the intraocular RB eyes undergoing eye-conserving treatments were saved. The globe salvage rate for all intraocular and extraocular RB eyes was 53.8% and the overall survival rate was 96.1%.

Retinoblastoma presentation, treatment and outcome in a large referral centre in Tehran: a 10-year retrospective analysis.

Early diagnosis, care and treatment of retinoblastoma is a challengeable issue for Iranian health system. This study was designed and conducted in a referral multidisciplinary centre in the capital city of Iran to evaluate management, care, prognosis and survival rates of paediatric patients with retinoblastoma. In this retrospective study, a total number of 309 patients younger than 15 years, diagnosed with retinoblastoma, who referred for diagnosis and treatment to MAHAK's Pediatric Cancer Treatment and Research Center (MPCTRC) from 2007 to 2017 were evaluated. All data were analyzed via SPSS version 22 software in regard of parametric and non-parametric data. Survival rates were analyzed using the Kaplan-Meyer method. The mean age of patients was 20 months and the majority of patients (77%) had leukocoria as a common clinical symptom at the time of diagnosis. Primary treatment methods were systemic chemotherapy (94%), laser (35%) and primary enucleation (28%). Relapses occurred in nearly 42% of cases, and the median time from diagnosis to the first relapse was 9 months. At the time analyzing the data, 11% of patients died. Patients' 5-year OS and RFS rates were 79.6% and 41.5%, respectively. Comparing results with other conducted studies identifies that the recurrence rate was high in our considered patients. Also, OS and RFS rates in our study were not as considerable as other reports. Screening methods, updating protocols and follow-up of patients may lead to improvements in survival rates of patients with retinoblastoma.

Cancer Stem Cells with Overexpression of Neuronal Markers Enhance Chemoresistance and Invasion in Retinoblastoma.

Retinoblastoma is a sight and life-threatening embryonal tumor in children. Though chemotherapy is the main mode of therapy, evolving resistance remains a major obstacle in treatment success. The presence of cancer stem cells (CSC) is frequently reported to be responsible for chemoresistance in multiple tumors. Our study aims to identify the molecular factors that facilitate the chemoresistance through cancer stem cells in retinoblastoma. We developed etoposide and carboplatin resistant retinoblastoma (Y79) cell lines by stepwise drug increment treatment, validated with MTT and TUNEL assays. Colony forming and invasive ability were studied by soft-agar colony forming and transwell assays, respectively. Similar analysis in non-responsive retinoblastoma tumors were carried out by histopathology. Finally, expression of CSC/neuronal markers and ABC transporters were examined by quantitative PCR and protein expression of neuronal stem cell markers was confirmed by Western blot. Larger colony size of resistant cells in soft-agar assay provided evidence for increased selfrenewability. Histopathology in non-responsive tumors showed poorly differentiated cells predominantly. Besides, both resistant cell lines and non-responsive tumors showed increased invasion with higher expression of neuronal stem cell markers - SOX2, NANOG, OCT4 and ABC transporters - ABCB1 and ABCC3. Increased self-renewal ability and invasion along with overexpression of stemness markers in resistant cells and tumors provide evidence for stemness driving chemoresistance and invasion in retinoblastoma. We have demonstrated Neuronal stem cell/CSC markers that facilitate the maintenance of cancer stem cells. Developing therapies targeting these factors will help in overcoming resistance and improving retinoblastoma treatment.

Intra-arterial chemotherapy for retinoblastoma: Our first three-and-a-half years' experience in Malaysia.

AimTo report our first three-and-a-half years’ experience with intra-arterial chemotherapy (IAC) in managing retinoblastoma (RB).MethodsSingle institution, retrospective, interventional case series of 14 retinoblastoma patients managed with IAC from December 2014 to June 2018. Demographics were described. Outcomes measures were tumor response, treatment complications and globe salvage.ResultsSubjects’ mean age at the first administration of IAC was 31.4 months. 57.1% of the eyes were Group D and E retinoblastoma, while 79% were bilateral disease. 93% of the eyes were as secondary treatment. Of 32 IAC cannulations performed, 23 (71.8%) were successful and received chemotherapy drug melphalan. Each eye received a mean of 1.8 (range 1–4) IAC injections. 53% of the eyes showed regression post treatment. After a mean follow up period of 19 months, globe salvage rate was 38%. Most of the adverse effects experienced were localized and transient.ConclusionIAC has provided an added recourse in the armamentarium of retinoblastoma treatment in our center. IAC treatment is a viable alternative in the treatment of retinoblastoma to salvage globe, for eyes that would conventionally require enucleation especially in bilateral disease.

LncRNA CANT1 suppresses retinoblastoma progression by repellinghistone methyltransferase in PI3K\u03b3 promoter

Retinoblastoma (RB) is the most common malignant intraocular tumor of childhood. Recent studies have shown that long noncoding RNAs (lncRNAs), which are longer than 200 bp and without protein-coding ability, are key regulators of tumorigenesis. However, the role of lncRNAs in retinoblastoma remains to be elucidated. In this study, we found that the expression of lncRNA CASC15-New-Transcript 1 (CANT1) was significantly downregulated in RB. Notably, overexpression of CANT1 significantly inhibited RB growth both in vitro and in vivo. Furthermore, lncRNA CANT1, which was mainly located in the nucleus, occupied the promoter of phosphoinositide 3-kinase gamma (PI3Kγ) and blocked histone methyltransferase hSET1 from binding to the PI3Kγ promoter, thus abolishing hSET1-mediated histone H3K4 trimethylation of the PI3Kγ promoter and inhibiting PI3Kγ expression. Furthermore, we found that silencing PI3Kγ either by lncRNA CANT1 overexpression or by PI3Kγ siRNA, reduced the activity of PI3K/Akt signaling and suppressed RB tumorigenesis. In summary, lncRNA CANT1 acts as a suppressor of RB progression by blocking gene-specific histone methyltransferase recruitment. These findings outline a new CANT1 modulation mechanism and provide an alternative option for the RB treatment.

Ophthalmic artery catheterization for retinoblastoma treatment: does reflux affect tumor response?

BackgroundIntra-arterial chemotherapy (IAC) for retinoblastoma (Rb) has been established as a primary treatment for the disease. To determine whether the presence of reflux into the ICA is associated with tumor...

Silencing of lncRNA XIST suppresses proliferation and autophagy and enhances vincristine sensitivity in retinoblastoma cells by sponging miR-204-5p.

Retinoblastoma (RB) is the most prevalent intraocular malignancy in childhood. Long non-coding RNAs (lncRNAs) have been found as critical oncogenic drivers and tumor suppressor in RB. The aim of the present work was to investigate the impact and mechanism of XIST on RB cell autophagy and vincristine (VCR) sensitivity. The levels of XIST and miR-204-5p were assessed by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Western blot analysis was used for the determination of related protein levels. Cell proliferation and IC50 value of VCR were detected using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Flow cytometry was performed to evaluate cell apoptosis. The activities of caspase-3 and caspase-9 were identified using a corresponding assay kit. The direct interaction between XIST and miR-204-5p was confirmed using Dual-Luciferase reporter assay. Xenograft model was established to observe the effect of XIST on RB in vivo. Our data indicated that XIST was highly expressed in RB tissues and cell lines. XIST knockdown weakened the proliferation and autophagy and enhanced VCR sensitivity in RB cells. XIST acted as a molecular sponge of miR-204-5p. Moreover, the regulatory effects of XIST silencing on RB cell proliferation, autophagy and VCR sensitivity were mediated by miR-204-5p. Additionally, XIST silencing weakened tumor growth and enhanced VCR sensitivity in vivo through up-regulating miR-204-5p. Our current study suggested that XIST silencing suppressed RB progression and promoted VCR sensitivity in vitro and in vivo at least partially by acting as a miR-204-5p sponge, highlighting a powerful therapeutic strategy for RB treatment.

Severe Periocular Edema after Intraarterial Carboplatin Chemotherapy for Retinoblastoma in a Rabbit (Oryctolagus cuniculus) Model

Endovascular microcatheter-based intraarterial (ophthalmic artery) chemotherapy is becoming widely used for the clinical treatment of intraocular retinoblastoma due to its apparent increased efficacy compared with traditional intravenous chemotherapy; however local ocular complications are not uncommon. Carboplatin is a chemotherapeutic agent used in both intravenous and intraarterial chemotherapy. We used rabbits to assess pharmacokinetics and ocular and systemic toxicity after intraarterial carboplatin infusion. Subsequent to unilateral intraarterial administration of carboplatin, severe unilateral or bilateral periocular edema occurred in 6 adult male New Zealand white rabbits. Time to onset varied from less than 4 h after administration (n = 3, 50 mg) to approximately 24 h afterward (n = 3, 25 mg). After becoming symptomatic, 5 of the 6 animals were promptly euthanized, and the remaining animal (25 mg treatment) was medically managed for 4 d before being euthanized due to intractable edema-related lagophthalmos. Globes and orbits from all 6 euthanized rabbits were harvested en bloc; whole-mount sections were prepared for histologic evaluation, which revealed drug-induced vasogenic edema in confined spaces as the main underlying pathogenesis. Transient and self-limiting periocular edema is a common side effect of intraarterial chemotherapy but is thought to occur predominantly with melphalan monotherapy or combination therapy using melphalan, carboplatin, and topotecan. The severity of this adverse consequence in rabbits was unexpected, and its use in the study was subsequently discontinued. Although the definitive cause for this vasotoxicity and striking clinical presentation is unknown, we suspect species-specific anatomic features and sensitivity might have contributed to amplified complications after intraarterial carboplatin chemotherapy of the eye. Due to the adverse effects of intraarterial carboplatin chemotherapy that we observed in 2 experimental cohorts of rabbits, we recommend caution regarding its use in this species.