Retinoblastoma Research Articles

The role of EZH2 as a potential therapeutic target in retinoblastoma

Enhancer of zeste homolog 2 (EZH2) has been reported selectively expressed in postnatal human retinoblastoma (RB). While, the contribution of EZH2 in progression of RB and its clinical importance has not been clarified. Here, immunohistochemistry (IHC) was performed on tumor specimens from 53 RB patients. UNC1999 and GSK503, inhibitors targeting EZH2, were incubated with human RB cell line WERI-Rb-1 and Y79 to assess the role and mechanism of EZH2 in RB proliferation, metastasis and tumor glycolysis. Administration of UNC1999 in subcutaneous tumor model of RB was conducted. The results showed that highly expressed EZH2 in RB tissues was significantly associated with the poor overall survival. UNC1999 and GSK503 inhibited proliferation, migration, invasion and tumor glycolysis of RB. Results in mouse xenograft model confirmed the inhibitory effect of UNC1999 on tumor growth of RB and the regulation effect of EZH2 to STAT3/FoxO1 signaling pathway. Therefore, EZH2 is rewarding to study as a potential target for anti-RB treatment.

Retinal microvasculature observations of fellow eyes after intra-arterial chemotherapy for unilateral retinoblastoma using optical coherence tomography angiography.

To investigate the characteristics of the retinal microvasculature of the fellow eyes in patients with unilateral retinoblastoma (RB) after intra-arterial chemotherapy (IAC) through optical coherence tomography angiography. This retrospective study enrolled 11 fellow eyes of patients with unilateral RB receiving IAC (group I), nine fellow eyes of patients with unilateral RB receiving IAC and intravenous chemotherapy (IVC) (group II), and 14 age-matched normal eyes (control group). Optical coherence tomography angiography was performed on all individuals. Vascular density of superficial capillary plexus and deep capillary plexus (DCP), foveal avascular zone related parameters, and retinal thickness were measured and compared among the three groups. There was no statistical difference in age and logMAR visual acuity among the three groups. Compared with the control group, the vascular density of the DCP was lower in group I and II. Decreased vascular density of FD-300 and thinner thickness of outer plexus layer to Bruch's membrane were detected in group II compared with the control group. The vascular density and retinal thickness showed no differences between group I and II. The decreased vascular density in the DCP without measurable visual impairment was observed in fellow eyes after IAC or IAC + IVC for unilateral RB. Further studies with a larger sample would be necessary to determine the clinical significance of these findings.

EZH2 Expression in Retinoblastoma: A Potential Therapeutic Target

Introduction: The enhancer of zeste homolog 2 (EZH2) is a member of the polycomb repressive complex 2 (PRC2) and is important in cell-cycle regulation. Increased expression of EZH2 has been reported in retinoblastoma (RB). The aim of the study was to determine EZH2 expression, compare this with clinicopathological parameters in RB, and assess its relationship with tumor cell proliferation. Methods: Ninety-nine retrospective cases of enucleated RB were included in the present study. Expression of EZH2 and the marker of cell proliferation, Ki67, were investigated by immunohistochemistry. Results: Among the 99 cases of RB in this study, EZH2 was found highly expressed (positive expression rate ≥70%) in 92 cases. EZH2 was expressed in tumor cells but absent in normal retinal tissues. The expression of EZH2 was positively linked to Ki67 expression (r = 0.65, p < 0.001). Conclusion: Elevated EZH2 expression was found in most RB cases, indicating that EZH2 could be a potential therapeutic target for RB.

Plakophilin 3 facilitates G1/S phase transition and enhances proliferation by capturing RB protein in the cytoplasm and promoting EGFR signaling

Plakophilin 3 (PKP3) is a component of desmosomes and is frequently overexpressed in cancer. Using keratinocytes either lacking or overexpressing PKP3, we identify a signaling axis from ERK to the retinoblastoma (RB) protein and the E2F1 transcription factor that is controlled by PKP3. RB and E2F1 are key components controlling G1/S transition in the cell cycle. We show that PKP3 stimulates the activity of ERK and its target RSK1. This inhibits expression of the transcription factor RUNX3, a positive regulator of the CDK inhibitor CDKN1A/p21, which is also downregulated by PKP3. Elevated CDKN1A prevents RB phosphorylation and E2F1 target gene expression, leading to delayed S phase entry and reduced proliferation in PKP3-depleted cells. Elevated PKP3 expression not only increases ERK activity but also captures phosphorylated RB (phospho-RB) in the cytoplasm to promote E2F1 activity and cell-cycle progression. These data identify a mechanism by which PKP3 promotes proliferation and acts as an oncogene.

Intra-arterial chemotherapy for retinoblastoma: Experience from the pediatric ophthalmology referral center in Malaysia with literature review.

We aimed to analyze our 4-year experience of intra-arterial chemotherapy (IAC) for retinoblastoma (RB) and to examine the tumor response, globe salvage, mortality, and safety profile of IAC in the Malaysian profile. This was a retrospective, interventional case series. A total of 22 eyes of 20 patients with RB who underwent IAC using melphalan and topotecan from January 2018 to December 2021 in Hospital Kuala Lumpur were retrospectively reviewed. Tumor response, globe salvage, mortality, and safety profile of IAC were compared based on the International Classification of Retinoblastoma. The mean patient age at IAC was 21.3 months. An overall globe salvage rate of 63.6% was observed: more specifically, 100% for Group A, 75% for Groups B and C, 66.7% for Group D, and 42.9% for Group E. Poor tumor response after IAC was significantly associated with a lesser chance of globe salvage (P = 0.045). The overall rate of good tumor response following IAC was 77.3%. Specifically, rates of good tumor response in each group were 100%, 75%, 75%, 83.3% and 71.4% in group A, B, C, D and E, respectively. The mortality rate was 5%. Complications (per-catheterization) included cerebral infarct (2.2%), oxygen desaturation (2.2%), vomiting (26.1%), periorbital edema (8.8%), ptosis (6.5%), fever, femoral hematoma, and hyperpigmentation over lid (4.4% each). Four-year experience showed that IAC is a safe and effective method for RB management. Patients with a poor response after IAC may have a lower chance of globe salvage. Careful patient selection is of utmost importance to achieve the best outcome in a setting of limited health-care resources.

Retinoblastoma: Current Management

Abstract Retinoblastoma (RB) is the most common intraocular malignancy in children. Unfortunately, survival in developing countries was found to be significantly worse (40%) compared with developed countries (79%). Early diagnosis and suspicion of RB in early intraocular stages is paramount for successful management and improved outcomes. The management of RB is in constant evolution for the sake of globe salvage. Treatment protocols are extremely diverse; varying from one case to another and are dependent on local resources, therefore, the success rates are variable. The introduction of chemotherapy in the early 1990s, especially intraarterial chemotherapy has led to remarkable success in treating eyes with more advanced diseases. Novel drugs, oncolytic viruses, and immunotherapy are promising approaches in the treatment of intraocular RB. This review navigates the landscape of RB management, delving into staging, diverse recent treatment modalities with their common side effects, and the ongoing challenges that necessitate a comprehensive approach.

Cavitary Retinoblastoma Imaged on Magnetic Resonance Imaging.

Cavitary retinoblastoma is a rare subtype, characterized by the presence of translucent cavities within the solid malignancy. A 2-year-old boy with bilateral retinoblastoma was found to have a unique cavitary retinoblastoma with seven cavities, more than previously reported, and large enough to be imaged on magnetic resonance imaging. [J Pediatric Ophthalmol Strabismus. 2023;60(1):e1-e4.].

A ROLE OF THE RB PROTEIN IN THE SUPPORT OF CELL STEMNESS

Summary. The present paper is a review on the literature data and our research, concerning a role of the retinoblastoma (RB) protein in pluripotent stem cells (SCs) proliferation and differentiation. The role of RB in the cell cycle, in development of pathological conditions, in the control on cell differentiation, and in epigenetic regulation of expression of the SC-specific genes is discussed, in the light of protein-protein interactions. The present review might be useful for the further studies and understanding of SC properties, as well as the effectiveness of use of SCs in medical practice.

ZFPM2-AS1: An Oncogenic Long Non-coding RNA in Multiple Cancer Types.

Long non-coding RNA (lncRNA) is a novel kind of RNA transcript with lengths greater than 200 nucleotides. Functionally, lncRNAs lack the potential to encode peptides or proteins. Previous studies unveiled that lncRNA participated in numerous physiological and pathological processes, including cancer, aging, and immune responses. Newly discovered long noncoding RNA zinc finger protein, Friend of GATA (FOG) family member 2-antisense 1 (ZFPM2-AS1), located on the 8q23 chromosome, acts as a tumor stimulator in various cancer types, including Breast Cancer (BC), Colorectal Cancer (CRC), Esophageal Squamous Cell Carcinoma (ESCC), Gastric Cancer (GC), glioma, hepatocellular carcinoma (HCC), Lung Adenocarcinoma (LUAD), melanoma, non-small cell lung cancer (NSCLC), Retinoblastoma (RB), Small Cell Lung Cancer (SCLC) and thyroid cancer. Accumulative evidence also elucidated that ZFPM2-AS1 dysregulation was related to tumor proliferative, migratory, invasive, anti-apoptotic, and pro-epithelial-tomesenchymal Transition (EMT) effects, larger tumor volume, higher tumor weight, advanced tumor stage, high rates of lymphatic metastasis, distant metastasis, poor prognosis, histological differentiation, higher TNM (tumor, node, metastases) stage, depth of tumor invasion, reduced overall and disease- free survival, vein invasion, and shorter 5-year overall survival. Mechanistically, ZFPM2-AS1 acted as a ceRNA to play its oncogenic role. Thus, this study summarized the specific mechanisms of the lncRNA ZFPM2-AS1 in the aforementioned cancer types to reveal its novel application in cancer diagnosis, treatment, and prognosis.

Late and Distant Metastases of Retinoblastoma to Long Bones: A Purpose of a Case

The case of a 13-year-old male patient is presented, with a history of Bilateral Retinoblastoma since he was 2 years old, undergoing enucleation of the right eye in June 2007, and salvage of the left eye by chemotherapy and radiotherapy, said patient 11 years after This episode presented metastasis in the distal end of the right radius, performing neoadjuvant treatment and subsequent wide oncological resection with healthy margins of the distal end of the radius plus reconstruction with the proximal end of the ipsilateral fibula and arthrodesis of the wrist. . It is important to point out that distant bone involvement and that of long bones are very few cases reported in the literature, therefore this case was a challenge for diagnosis and treatment, since a retinoblastoma was obtained that metastasized 12 years later. of the enucleation of the eye with the primary tumor and in turn performed it in the long bone (radius), it is emphasized that said patient was followed up free of disease for 2 years after surgery (wrist fusion). Given the limitations of knowledge of the genetics of retinoblastoma metastasis to long bones, not all alterations are currently known. It is considered that a genetic study should be done in patients diagnosed on time.

Ultrawide-field imaging of bilateral retinoblastoma in an infant by “flying baby position”

Ultrawide-field imaging of bilateral retinoblastoma in an infant by “flying baby position”

Designing and implementation of a T-ARMS-PCR assay to genotype genetic variants associated with retinoblastoma in a cohort of Sri Lankan population

Retinoblastoma (RB) is the most common intraocular malignancy, characterized by high mortality if not detected early and treated promptly. The rare childhood malignancy retinoblastoma serves one of the most important models in modern cancer genetics. Since the study of its familial and sporadic occurrence has led to the identification of the first tumor suppressor gene RB1. Mutations screening is important for risk assessment in future siblings and offspring of RB patients.The aim of this study was to design and implement a novel genetic assay to identify genetic variants associated with retinoblastoma in a cohort of Sri Lankan patients.Materials and methods: A prospective descriptive study was carried out with 59 patients referred to the Eye Unit of the Lady Ridgeway Hospital. Genomic DNA of 59 patients were genotyped using primers designed for Tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR).Results: The median age at diagnosis was 2 years and 7 months. Female to male ratio was 3:2. Out of which, 63% had unilateral retinoblastoma and 36% had bilateral retinoblastoma. Family history of RB was seen in 6.78% patients. Most cases were advanced group D at presentation. As the final result, all patients tested homozygous for the ancestral allele for both rs587776789 and rs121913305 variants of the RB1 gene.Discussion and conclusion: The discovery of germ-line mutations in unilateral patients is valuable since they can be segregated based on their mutational status and this would impact the genetic counselling given to them as they age. In conclusion, this assay can be introduced as a sensitive, specific and simple diagnostic technique for screening related genetic variants for retinoblastoma in the Sri Lankan population.

New phase therapeutic pursuits for targeted drug delivery in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is known as the most aggressive and prevalent brain tumor with a high mortality rate. It is reported in people who are as young as 10 years old to as old as over 70 years old, exhibiting inter and intra tumor heterogeneity. There are several genomic and proteomic investigations that have been performed to find the unexplored potential targets of the drug against GBM. Therefore, certain effective targets have been taken to further validate the studies embarking on the robustness in the field of medicinal chemistry followed by testing in clinical trials. Also, The Cancer Genome Atlas (TCGA) project has identified certain overexpressed targets involved in the pathogenesis of GBM in three major pathways, i.e., tumor protein 53 (p53), retinoblastoma (RB), and receptor tyrosine kinase (RTK)/rat sarcoma virus (Ras)/phosphoinositide 3-kinase (PI3K) pathways. This review focuses on the compilation of recent developments in the fight against GBM thus, directing future research into the elucidation of pathogenesis and potential cure for GBM. Also, it highlights the potential biomarkers that have undergone extensive research and have promising prognostic and predictive values. Additionally, this manuscript analyses the advent of gene therapy and immunotherapy, unlocking the way to consider treatment approaches other than, or in addition to, conventional chemo-radiation therapies. This review study encompasses all the relevant research studies associated with the pathophysiology, occurrence, diagnostic tools, and therapeutic intervention for GBM. It highlights the evolution of various therapeutic perspectives against GBM from the most conventional form of radiotherapy to the recent advancement of gene/cell/immune therapy. Further, the review focuses on various targeted therapies for GBM including chemotherapy sensitization, radiotherapy, nanoparticles based, immunotherapy, cell therapy, and gene therapy which would offer a comprehensive account for exploring several facets related to GBM prognostics.

Role of non-coding RNAs and exosomal non-coding RNAs in retinoblastoma progression.

Retinoblastoma (RB) is a rare aggressive intraocular malignancy of childhood that has the potential to affect vision, and can even be fatal in some children. While the tumor can be controlled efficiently at early stages, metastatic tumors lead to high mortality. Non-coding RNAs (ncRNAs) are implicated in a number of physiological cellular process, including differentiation, proliferation, migration, and invasion, The deregulation of ncRNAs is correlated with several diseases, particularly cancer. ncRNAs are categorized into two main groups based on their length, i.e. short and long ncRNAs. Moreover, ncRNA deregulation has been demonstrated to play a role in the pathogenesis and development of RB. Several ncRNAs, such as miR-491-3p, miR-613,and SUSD2 have been found to act as tumor suppressor genes in RB, but other ncRNAs, such as circ-E2F3, NEAT1, and TUG1 act as tumor promoter genes. Understanding the regulatory mechanisms of ncRNAs can provide new opportunities for RB therapy. In the present review, we discuss the functional roles of the most important ncRNAs in RB, their interaction with the genes responsible for RB initiation and progression, and possible future clinical applications as diagnostic and prognostic tools or as therapeutic targets.

Role of circular RNAs in retinoblastoma.

Retinoblastoma (RB), the most common malignant retinal tumor among children under 3years old, is lethal if left untreated. Early diagnosis, together with timely and effective treatment, is important to improve retinoblastoma-related outcomes. Circular RNAs (circRNAs), a new class of non-coding RNAs with the capacity to regulate cellular activities, have great potential in retinoblastoma diagnosis and treatment. Recent studies have identified circular RNAs that regulate multiple cellular processes involved in retinoblastoma, including cell viability, proliferation, apoptosis, autophagy, migration, and invasion. Six circular RNAs (circ-FAM158A, circ-DHDDS, circ-E2F3, circ-TRHDE, circ-E2F5, and circ-RNF20) promote disease progression and metastasis in retinoblastoma and function as oncogenic factors. Other circular RNAs, such as circ-TET1, circ-SHPRH, circ-MKLN1, and circ-CUL2, play tumor suppressive roles in retinoblastoma. At present, the studies on the regulatory mechanism of circular RNAs in retinoblastoma are not very clear. The purpose of this review is to summarize recent studies on the functional roles and molecular mechanisms of circular RNAs in retinoblastoma and highlight novel strategies for retinoblastoma diagnosis, prognosis, and treatment.

Vision-related quality of life compared to generic measures in retinoblastoma survivors

PurposeTo (1) Compare vision-related quality of life (VRQOL) in adolescent and young adult (AYA) unilateral versus bilateral retinoblastoma (RB) survivors using a vision-targeted measure and a generic health-related quality of life (HRQOL) measure and (2) Assess associations among VRQOL and generic HRQOL domains and overall QOL and estimate associations of the VRQOL and HRQOL domains with overall QOL.MethodsThe National Institute for Health (NIH) Toolbox® VRQOL instrument, PROMIS®-29 Profile v 2.1, and a single-item QOL measure were administered in a cross-sectional study of 101 RB survivors. Reliability for multi-item scales was estimated. Product-moment and Spearman rank correlation coefficients and stepwise ordinary least squares were used to measure associations of other variables with overall QOL.ResultsSignificantly worse VRQOL was reported by bilateral than unilateral RB survivors. Cronbach’s alpha coefficients for all VRQOL scales ranged from 0.83 to 0.95. Medium to large correlations were found between all NIH Toolbox® VRQOL scales and the PROMIS®-29 measures. Depression and ability to participate in social roles and activities from the PROMIS®-29 Profile accounted for 38% of the variance in overall QOL with the psychosocial domain of the NIH Toolbox® VRQOL explaining 16% of the variance.ConclusionVRQOL is impaired in bilateral RB survivors. VRQOL is associated substantially with the PROMIS-29 generic HRQOL measure but has significant unique associations with overall QOL. The NIH Toolbox® VRQOL measure provides important information about the vision-related effects on daily life of AYA RB survivors.

Survival trends for patients with retinoblastoma between 2000 and 2018: What has changed?

Retinoblastoma (RB) is the most common primary intraocular cancer of childhood. Over the last few decades, a variety of techniques and treatment modalities emerged that improved the survival and ocular salvage rate of patients with RB. We investigated the relative survival trends of patients with RB from 2000 to 2018 by using the Surveillance, Epidemiology, and End Results (SEER) database. Retrospective database review. We extracted data from SEER 18 from 2000 to 2018. All patients with clinically diagnosed RB during the study period were included. We utilized SEER*Stat 8.3.9 and JPSurv software to estimate relative 5- and 10-year survival rates and trends and generated descriptive analyses with IBM SPSS. Patient survival rates at 5- and 10-year after RB diagnosis. RB was diagnosed in 1479 patients within the SEER 18 Program during our study period. The cohort comprised 776 (52.5%) males, 615 (41.6%) non-Hispanic whites, 487(32.9%) Hispanics, 1030 (69.6%) patients with unilateral disease, and 1087 (73.5%) patients with localized disease. Relative survival trends at 5- and 10-year significantly declined over the study periods (-0.42%, and -0.50% annually, respectively) but the decline was not significant in unilateral and bilateral RB cases separately. Five- and ten-year relative survival trends declined from 2000 to 2018 and were significantly decreasing. Further studies that include more patients are needed to identify the factors contributing to reduced survival of patients with RB over time.

Overview of Bilateral Retinoblastoma at Dr. M. Djamil General Hospital, Padang, Indonesia

Background: Retinoblastoma is the most common intraocular primary malignant tumor in children. In the United States, cases of retinoblastoma are estimated to be found in 1 in 18,000 children under 5 years. The incidence of retinoblastoma ranges from 1:14.00 to 1:34.000 live births. The highest incidence occurs in developing countries. This study aimed to provide a clinical picture of bilateral retinoblastoma at Dr. M. Djamil General Hospital, Padang, Indonesia, as basic data for further policy-making in order to optimize services related to the management of bilateral retinoblastoma.&#x0D; Methods: This study was a descriptive observational study with 29 study subjects. Sociodemographic, clinical, and management data are presented descriptively. Data analysis was performed with the help of SPSS software version 25.&#x0D; Results: Based on the age group, the majority of bilateral retinoblastoma cases were less than 5 years old, with the most age range being 3-4 years. The majority of therapeutic management for cases of bilateral retinoblastoma is exenteration in combination with chemotherapy.&#x0D; Conclusion: A combination of surgery and chemotherapy is the most frequently used treatment for bilateral retinoblastoma at Dr. M. Djamil General Hospital, Padang, Indonesia.

LncRNA MEG3 attenuates the malignancy of retinoblastoma cells through inactivating PI3K /Akt/mTOR signaling pathway

Retinoblastoma (RB) is the most common neoplasm found in the eye of children. There are increasing interests to develop targeted gene therapy for this disease. This study was performed to investigate the impact of long non-coding RNA (lncRNA) MEG3 on the biological features of RB cells. Vector overexpressing MEG3 was constructed and introduced into two RB cell lines. Transfected RB cells were assessed for proliferation, apoptosis, migration ability, expression levels of important genes in the PI3K/Akt/mTOR signaling pathway using qRT-PCR and Western blot analysis. Xenograft mouse models were constructed to determine the tumorigenicity of RB cells overexpressing MEG3. MEG3 mRNA level was significantly lower in RB cells than in non-cancer cells (p < 0.01). Overexpressing MEG3 resulted in significant reduction in cell proliferation (p < 0.05), migration (p < 0.01) and significant increase in apoptosis (p < 0.01). After overexpressing MEG3, p-PI3K, p-Akt and p-mTOR levels were significantly downregulated (p < 0.01). Furthermore, in the xenograft model, RB cells overexpressing MEG3 generated significantly smaller tumors as compared to RB cells that did not overexpress MEG3 (p < 0.05). Our data suggest that MEG3 increases apoptosis and reduces tumorigenicity of RB cells through inactivating the PI3K/Akt/mTOR pathway. Therefore, MEG3 could be further investigated as a potential new therapeutic agent and target for RB therapy.

LATE CHOROIDAL NEOVASCULAR COMPLICATIONS IN A PATIENT TREATED FOR RETINOBLASTOMA. A CASE REPORT.

Case report of choroidal neovascularization (CNV) detection in patient who was treated for bilateral retinoblastoma in early childhood. Patient at 1.5 years of age treated for endophytic retinoblastoma stage 4 (according to the Reese-Ellsworth classification) bilaterally, with a positive mutation in the Rb1 gene. After undergoing bilateral retinal laser treatment and 6 cycles of systemic chemotherapy, the tumor remained inactive without other complications. At the age of 14, the boy developed visual impairment in his left eye with metamorphosis. Based on a local finding and other auxiliary examinations, he was diagnosed with CNV in the macular area at the interface of the tumor scar and the healthy retina of the left eye. After three applications of anti-VEGF (antibodies blocking vascular endothelial growth factor) substance intravitreally (bevacizumab 1.2 mg), there was a reduction in CNV and also an improvement in visual function.