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Radiology Jun 2023Background -amplified wild-type () retinoblastoma is a rare but clinically important subtype of retinoblastoma due to its aggressive character and relative resistance...
Background -amplified wild-type () retinoblastoma is a rare but clinically important subtype of retinoblastoma due to its aggressive character and relative resistance to typical therapeutic approaches. Because biopsy is not indicated in retinoblastoma, specific MRI features might be valuable to identify children with this genetic subtype. Purpose To define the MRI phenotype of retinoblastoma and evaluate the ability of qualitative MRI features to help identify this specific genetic subtype. Materials and Methods In this retrospective, multicenter, case-control study, MRI scans in children with retinoblastoma and age-matched children with subtype retinoblastoma were included (case-control ratio, 1:4; scans acquired from June 2001 to February 2021; scans collected from May 2018 to October 2021). Patients with histopathologically confirmed unilateral retinoblastoma, genetic testing ( status), and MRI scans were included. Associations between radiologist-scored imaging features and diagnosis were assessed with the Fisher exact test or Fisher-Freeman-Halton test, and Bonferroni-corrected values were calculated. Results A total of 110 patients from 10 retinoblastoma referral centers were included: 22 children with retinoblastoma and 88 control children with retinoblastoma. Children in the group had a median age of 7.0 months (IQR, 5.0-9.0 months) (13 boys), while children in the group had a median age of 9.0 months (IQR, 4.6-13.4 months) (46 boys). retinoblastomas were typically peripherally located (in 10 of 17 children; specificity, 97%; < .001) and exhibited plaque or pleomorphic shape (in 20 of 22 children; specificity, 51%; = .011) with irregular margins (in 16 of 22 children; specificity, 70%; = .008) and extensive retina folding with vitreous enclosure (specificity, 94%; < .001). retinoblastomas showed peritumoral hemorrhage (in 17 of 21 children; specificity, 88%; < .001), subretinal hemorrhage with a fluid-fluid level (in eight of 22 children; specificity, 95%; = .005), and strong anterior chamber enhancement (in 13 of 21 children; specificity, 80%; = .008). Conclusion retinoblastomas show distinct MRI features that could enable early identification of these tumors. This may improve patient selection for tailored treatment in the future. © RSNA, 2023 See also the editorial by Rollins in this issue.
Topics: Humans; Retinoblastoma; N-Myc Proto-Oncogene Protein; Retrospective Studies; Case-Control Studies; Retinal Neoplasms; Ubiquitin-Protein Ligases; Retinoblastoma Binding Proteins
PubMed: 37191489
DOI: 10.1148/radiol.222264 -
Nature Communications Sep 2021Retinoblastoma is the most frequent intraocular malignancy in children, originating from a maturing cone precursor in the developing retina. Little is known on the...
Retinoblastoma is the most frequent intraocular malignancy in children, originating from a maturing cone precursor in the developing retina. Little is known on the molecular basis underlying the biological and clinical behavior of this cancer. Here, using multi-omics data, we demonstrate the existence of two retinoblastoma subtypes. Subtype 1, of earlier onset, includes most of the heritable forms. It harbors few genetic alterations other than the initiating RB1 inactivation and corresponds to differentiated tumors expressing mature cone markers. By contrast, subtype 2 tumors harbor frequent recurrent genetic alterations including MYCN-amplification. They express markers of less differentiated cone together with neuronal/ganglion cell markers with marked inter- and intra-tumor heterogeneity. The cone dedifferentiation in subtype 2 is associated with stemness features including low immune and interferon response, E2F and MYC/MYCN activation and a higher propensity for metastasis. The recognition of these two subtypes, one maintaining a cone-differentiated state, and the other, more aggressive, associated with cone dedifferentiation and expression of neuronal markers, opens up important biological and clinical perspectives for retinoblastomas.
Topics: Biomarkers, Tumor; Cell Dedifferentiation; Child, Preschool; DNA Methylation; Female; Gene Expression; Genetic Heterogeneity; Humans; Infant; Male; Mutation; N-Myc Proto-Oncogene Protein; Neoplasm Metastasis; Retinal Cone Photoreceptor Cells; Retinal Ganglion Cells; Retinal Neoplasms; Retinoblastoma
PubMed: 34552068
DOI: 10.1038/s41467-021-25792-0 -
Eye (London, England) Jan 2022To determine the association between the parental age gap and the absolute parental age with the risk of retinoblastoma (RB) development in an offspring.
OBJECTIVE
To determine the association between the parental age gap and the absolute parental age with the risk of retinoblastoma (RB) development in an offspring.
METHODS
RB individuals diagnosed between March 2013 and December 2019 in a single tertiary eye care centre were included. We recorded the demographic data, parental age and RB1 gene mutation status in the patient's tumour, blood and the parental blood. We categorised RB1 mutation inheritance as sporadic RB with somatic mutations (only present in tumour), heritable RB with de novo (present in patient's blood) and familial (present in patient and parents' blood) germline mutations. The statistical significance was confirmed by Fisher's exact/Chi-square test.
RESULTS
Out of 259 RB patients, 247 were included in our study. Heritable RB with de novo germline mutations was significantly less common (p value: 0.0387; 95% CI: 0.2676-0.9329) and sporadic RB with somatic mutations was more common (p value: 0.0545; 95% CI: 1.025-3.39), if the parental age gap was <10 years. There were increased odds of a heritable RB with de novo germline mutation with an increase in paternal age and this was more intensified when combined with parental age gap of more than ≥10 years. The heritable RB with de novo germline mutations significantly increased as maternal age progressed, only when it was adjusted to ≥10 years parental age gap (p value: 0.0262; 95% CI: 1.26-17.91).
CONCLUSIONS
An increased parental age gap and increased paternal age are independent risk factors for the development of heritable RB with de novo germline mutation.
Topics: Child; Demography; Humans; Mutation; Parents; Retinal Neoplasms; Retinoblastoma; Retrospective Studies
PubMed: 34799705
DOI: 10.1038/s41433-021-01771-z -
International Journal of Public Health 2023To study the prevalence and the association of HPV infection in retinoblastoma and to determine the most common genotype presented in RB. Following the PRIMSA... (Meta-Analysis)
Meta-Analysis Review
To study the prevalence and the association of HPV infection in retinoblastoma and to determine the most common genotype presented in RB. Following the PRIMSA guideline, 14 studies reporting HPV infection in RB acquired from six databases were included. The prevalence of HPV from 941 RB samples was 15.6% [95% confidence interval (CI): 7.3-30]. Mexico followed by India and Brazil had the highest HPV prevalence in RB samples, 61.7% (95% CI: 17-93), 22.5% (95% CI: 9-47), and 12.1% (95% CI: 2-52), in order. HPV 16 was the most common genotype presented in RB samples 23% (95% CI: 9-47), followed by HPV 18 10% (95% CI: 3-30) and the combined HPV 16-18 6% (95% CI: 0-50). We did not find a significant association between HPV and RB [odds ratio (OR): 12.2; 95% CI: 0.65-232; = 0.09]. However, after removing the largest-weighted study, a significant association between HPV and RB was observed (OR: 45.9; 95% CI; 8.6-245; < 0.001). HPV prevalence in RB samples was 15% and HPV 16 was the most presented genotype in RB samples. There may be an association between HPV and RB that is needed to be confirmed by high quality future studies. Preventive and treatment measures against HPV infection are essential for the prevention of any possible consequences, in particular, RB.
Topics: Humans; Retinoblastoma; Papillomavirus Infections; Human Papillomavirus Viruses; Cross-Sectional Studies; Human papillomavirus 16; Prevalence; Retinal Neoplasms
PubMed: 37497122
DOI: 10.3389/ijph.2023.1605284 -
Molecules and Cells Oct 2022Carboplatin-based chemotherapy is the primary treatment option for the management of retinoblastoma, an intraocular malignant tumor observed in children. The aim of the...
Carboplatin-based chemotherapy is the primary treatment option for the management of retinoblastoma, an intraocular malignant tumor observed in children. The aim of the present study was to establish carboplatin-resistant retinoblastoma cell lines to facilitate future research into the treatment of chemoresistant retinoblastoma. In total, two retinoblastoma cell lines, Y79 and SNUOT-Rb1, were treated with increasing concentrations of carboplatin to develop the carboplatin-resistant retinoblastoma cell lines (termed Y79/CBP and SNUOT-Rb1/CBP, respectively). To verify resistance to carboplatin, the degree of DNA fragmentation and the expression level of cleaved caspase-3 were evaluated in the cells, following carboplatin treatment. In addition, the newly developed carboplatin-resistant retinoblastoma cells formed intraocular tumors more effectively than their parental cells, even after the intravitreal injection of carboplatin. Interestingly, the proportion of cells in the G0/G1 phase was higher in Y79/CBP and SNUOT-Rb1/CBP cells than in their respective parental cells. In line with these data, the expression levels of cyclin D1 and cyclin D3 were decreased, whereas p18 and p27 expression was increased in the carboplatin-resistant cells. In addition, the expression levels of genes associated with multidrug resistance were increased. Thus, these carboplatin-resistant cell lines may serve as a useful tool in the study of chemoresistance in retinoblastoma and for the development potential therapeutics.
Topics: Antineoplastic Agents; Carboplatin; Caspase 3; Cell Line, Tumor; Child; Cyclin D1; Cyclin D3; Humans; Retinal Neoplasms; Retinoblastoma
PubMed: 36047446
DOI: 10.14348/molcells.2022.2014 -
Ophthalmic Epidemiology Oct 2023To determine the seasonal variation in the diagnosis of retinoblastoma in a global sample of children and to investigate predictors of seasonal trends.
PURPOSE
To determine the seasonal variation in the diagnosis of retinoblastoma in a global sample of children and to investigate predictors of seasonal trends.
METHODS
Data were collected through a global, multicenter, 1-year cross-sectional analysis that included all treatment- naïve retinoblastoma patients presenting to participating centers between January 1, 2017, and December 31, 2017. Due to variations in days per month, data were normalized to a 30-day/month calendar. Observed data were compared to a simulation study of expected results using a uniform distribution.
RESULTS
Patient-level data were available for 4,351 children from 276 centers in 153 countries, of which 3,966 had a month of presentation recorded. There were relative peaks in disease presentation in January and July, with lower counts in November and December (p = .0015). No covariates were found to be significantly associated with the seasonal trend. Two covariates, patient age at presentation and extraocular tumor spread, showed a moderate association with month of presentation.
CONCLUSION
Our findings suggest seasonal trends in the presentation of retinoblastoma across the world. However, these trends do not appear to be related to income level of a country, climate, or other covariates. Any connection between seasonal variation of retinoblastoma presentation and retinoblastoma outcomes remains unclear or not present.
Topics: Child; Humans; Seasons; Retinoblastoma; Cross-Sectional Studies; Retinal Neoplasms
PubMed: 36503408
DOI: 10.1080/09286586.2022.2153872 -
Eye (London, England) Apr 2020A retrospective case series describing the clinical features and treatment outcomes in eye with cavitary retinoblastoma.
AIM
A retrospective case series describing the clinical features and treatment outcomes in eye with cavitary retinoblastoma.
METHODS
Case records of patients diagnosed with cavitary retinoblastoma from 2013 to 2017 were reviewed and their demographic details, clinical presentation, and treatment outcomes were analysed.
RESULTS
Thirteen tumours from ten eyes of ten patients were included. Mean age at diagnosis was 36 months (median = 30, range = 2-60 months). Mean number of cavities per tumour were two (median 1, range 1-5). Sixty-two percent of tumours had primary cavities, 23% had secondary cavities, while 15% had both types. Mean basal tumour diameter at presentation was 10.9 mm, and at final follow-up was 10.4 mm. Mean tumour thickness at presentation was 7.7 mm, and at final follow-up was 6.5 mm. Majority of tumours (46%) showed type 2 regression pattern. Tumour recurrence was noted in 1(8%) eye. Cavity rupture with release of vitreous seeds was observed in one eye. Two (20%) eyes with vitreous seeds were treated with intravitreal chemotherapy. Two eyes were advised enucleation, one due to tumour recurrence and the other due to persistent vitreous seeds. No patients had metastasis or death. Mean follow-up was 54 months (median 20, SD 66.82, range 3-183).
CONCLUSION
Cavitary tumours have variable presentations, are often associated with vitreous seeds, and in some cases the latter emanates from them as well. Cavitary tumours tend to maintain stable tumour dimensions.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Humans; Infant; Neoplasm Recurrence, Local; Retinal Neoplasms; Retinoblastoma; Retrospective Studies
PubMed: 31534184
DOI: 10.1038/s41433-019-0581-1 -
Ophthalmology Feb 2022This study attempted to estimate the impact of eye-preserving therapies for the long-term prognosis of patients with advanced retinoblastoma with regard to overall...
PURPOSE
This study attempted to estimate the impact of eye-preserving therapies for the long-term prognosis of patients with advanced retinoblastoma with regard to overall survival and ocular salvage.
DESIGN
Retrospective cohort study covering all 31 provinces (38 retinoblastoma treating centers) of mainland China.
PARTICIPANTS
One thousand six hundred seventy-eight patients diagnosed with group D or E retinoblastoma from January 2006 through May 2016.
METHODS
Chart review was performed. The patients were divided into primary enucleation and eye-preserving groups, and they were followed up for survival status. The impact of initial treatment on survival was evaluated by Cox analyses.
MAIN OUTCOME MEASURES
Overall survival and final eye preservation.
RESULTS
After a median follow-up of 43.9 months, 196 patients (12%) died, and the 5-year overall survival was 86%. In total, the eyeball preservation rate was 48%. In this cohort, 1172 patients (70%) had unilateral retinoblastoma, whereas 506 patients (30%) had bilateral disease. For patients with unilateral disease, 570 eyes (49%) underwent primary enucleation, and 602 patients (51%) received eye-preserving therapies initially. During the follow-up (median, 45.6 months), 59 patients (10%) from the primary enucleation group and 56 patients (9.3%) from the eye-preserving group died. Multivariate Cox analyses indicated no significant difference in overall survival between the 2 groups (hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.85-1.84; P = 0.250). For patients with bilateral disease, 95 eyes (19%) underwent primary enucleation, and 411 patients (81%) received eye-preserving therapies initially. During the follow-up (median, 40.1 months), 12 patients (13%) from the primary enucleation group and 69 patients (17%) from the eye-preserving group died. For bilateral retinoblastoma with the worse eye classified as group E, patients undergoing primary enucleation exhibited better overall survival (HR, 2.35; 95% CI, 1.10-5.01; P = 0.027); however, this survival advantage was not evident until passing 22.6 months after initial diagnosis.
CONCLUSIONS
Eye-preserving therapies have been used widely for advanced retinoblastoma in China. Patients with bilateral disease whose worse eye was classified as group E and who initially underwent eye-preserving therapies exhibited a worse overall survival. The choice of primary treatment for advanced retinoblastoma should be weighed carefully.
Topics: Antineoplastic Agents; Brachytherapy; Child, Preschool; China; Combined Modality Therapy; Cryotherapy; Eye Enucleation; Female; Follow-Up Studies; Humans; Infant; Laser Coagulation; Male; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Salvage Therapy; Survival Rate
PubMed: 34536465
DOI: 10.1016/j.ophtha.2021.09.002 -
Eye (London, England) Apr 2023In this review we discuss several recent concepts regarding retinoblastoma control and its impact. In a cohort of 482 patients with solitary unilateral retinoblastoma... (Review)
Review
In this review we discuss several recent concepts regarding retinoblastoma control and its impact. In a cohort of 482 patients with solitary unilateral retinoblastoma revealed germline mutation in 16% and the likelihood of germline retinoblastoma was greater for younger children (≤1 year versus (vs.) >1 year at presentation) with odds ratio (OR) 2.96 (p = 0.001), and greatest for the youngest infants (≤3 months vs. >3-12 months) (OR 5.52) (p = 0.002). Retinocytoma/retinoma, a benign variant of retinoblastoma, was studied in 78 tumours and demonstrated transformation into retinoblastoma in 9.2% by 5 years and 15.3% by 10 years and 20 years. An international global study on retinoblastoma over 1.5 years revealed 4351 new patients and 85% from low- and middle-income countries, notably with older age at detection and greater risk for metastasis. Management of retinoblastoma in 964 eyes using intravenous chemotherapy showed 20-year globe salvage at 96% in group A, 90% in group B, 90% in group C, 68% in group D, and 32% in group E eyes. The 5-year globe salvage with intra-arterial chemotherapy for 160 eyes (655 infusions) with retinoblastoma showed success in 100% for group B, 80% for group C, 78% for group D, and 55% for group E. The psychological impact of retinoblastoma on the parents revealed depression (73%), anxiety (64%), and/or stress (100%), and on the patient revealed deficits in quality of life issues. Retinoblastoma is a challenging disease and chemotherapy provides reliable tumour control and globe salvage. Continuing efforts to improve quality of life issues is important.
Topics: Child; Infant; Humans; Retinoblastoma; Retinal Neoplasms; Global Burden of Disease; Quality of Life; Antineoplastic Combined Chemotherapy Protocols; Infusions, Intra-Arterial; Eye Neoplasms; Retrospective Studies; Treatment Outcome
PubMed: 35217824
DOI: 10.1038/s41433-022-01980-0 -
The Kaohsiung Journal of Medical... Mar 2022Retinoblastoma, also known as ocular cancer, usually affects children under the age of five. The standard of care for managing early-stage retinoblastoma is a...
Retinoblastoma, also known as ocular cancer, usually affects children under the age of five. The standard of care for managing early-stage retinoblastoma is a combination of vincristine, carboplatin, and etoposide. However, this combination-based modality has limited applications owing to its side and late effects. Moreover, in advanced tumor stages, nearly 50% of patients would suffer a partial or full loss of vision. Therefore, therapies that preserve vision and reduce side effects are urgently required. Here, we focused mainly on the common loss-of-function (LOF) mutation of retinoblastoma gene 1 (RB1) in advanced retinoblastoma and investigated the synthetic lethality between RB1-LOF and Aurora kinase inhibition. We showed that Aurora kinase A inhibition could lead to cell mitotic abnormality and apoptosis, and demonstrated in vivo efficacy in a mouse model xenografted with RB1-deficient retinoblastoma. Our findings provide a promising druggable molecular target and potential clinical strategy for tackling retinoblastoma disease.
Topics: Animals; Antineoplastic Agents; Apoptosis; Aurora Kinase A; Cell Line, Tumor; Disease Models, Animal; Female; Genes, Retinoblastoma; Humans; Loss of Function Mutation; Mice, Inbred BALB C; Mice, Nude; Mitosis; Retinal Neoplasms; Retinoblastoma; Mice
PubMed: 34741392
DOI: 10.1002/kjm2.12469