Number, frequency and time interval of examinations under anesthesia in bilateral retinoblastoma.

PURPOSE: Current practice in retinoblastoma (Rb) has transformed this malignancy into a curable disease. More attention should therefore be given to quality of life considerations, including measures related to examinations under anesthesia (EUAs). We aimed to investigate EUA measures in bilateral Rb patients and compare the findings to EUAs in unilateral Rb. METHODS: A retrospective analysis of bilateral Rb patients that presented to the London Rb service from 2006 to 2013, were treated and had long-term follow-up. RESULTS: A total of 62 Rb patients, 15 (24.2%) of which had International Intraocular Retinoblastoma Classification (IIRC) group A/B/no Rb at presentation, 26 (41.9%) C/D, and 21 (33.9%) were E in at least one eye. The mean number of EUAs was 35.8 ± 21.5, mean time from first to last EUA was 50.6 ± 19.9 months, and mean EUA frequency was 0.715 ± 0.293 EUAs/month. IIRC group was found not to correlate with any of the EUA measures. Age at presentation inversely correlated with time interval from first to last EUA and to EUA frequency (p ≤ 0.029). Rb family history correlated with the latter measure (p = 0.005) and intraophthalmic artery chemotherapy and brachytherapy correlated with all EUA measures (p ≤ 0.029). Mean follow-up time was 80.1 ± 24.3 months. When compared with a previously reported cohort of unilateral Rb, the present group underwent 3× more EUAs (p < 0.001) over nearly double the time (p < 0.001). CONCLUSIONS: Families should be counselled on anticipated EUA burden associated with bilateral Rb. In this respect, age at presentation and family history were found to have a predictive role, whereas IIRC group did not.

Contemporary management of retinoblastoma in the context of a low-resource country.

Retinoblastoma (RB) is the most common ocular cancer, and it typically presents before the age of 5 years in over 90% of cases. In high resource countries, RB patients tend to survive and retain their sight. This is not the case in low-resource countries because of late presentation and delayed intervention arising mostly from sociocultural and socioeconomic challenges. RB has no gender or racial predilection; the incidence is estimated as 1:16,000-1:18,000 live-births or 11/1 million children under 5 years. Most of the world's RB cases are found in Asia and Africa while most RB treatment centres are in America and Europe. RB is easy to detect by caregivers as a glowing white 'cat eye reflex' at night or when captured on camera. Health workers at primary care level can detect RB in early life if red reflex test and/or squint (Hirschberg) tests are deployed as part of wellness checks done especially during routine immunisation and well-baby clinics in the first 24 months of life. In most cases of RB, biopsies for histological confirmation are not required for diagnosis and treatment decisions to be made. Clinical information, ophthalmic evaluation and imaging modalities are typically used. There have been significant changes in the management of RB using various treatment modalities such as enucleation with orbital implant, use of chemotherapy delivered through intravenous, intravitreal, periocular and intra-arterial routes and targeted treatment with laser, cryotherapy and brachytherapy. Algorithm for management and development of the national RB program within the context of a low-resource country is presented from review of data extracted from Mendeley library, PubMed library, Google Scholar and One Network; full-text articles were mostly retrieved through the American Academy of Ophthalmology.

THE RECOGNITION OF CAVITARY RETINOBLASTOMA TUMORS: Implications for Management and Genetic Analysis.

PURPOSE: To assess the role of consolidating adjuvant therapy for cavitary retinoblastoma and to understand if there is any phenotype-genotype correlation. METHODS: Patients with retinoblastomas having ophthalmoscopically visible cavities between 2004 and 2014 in whom 4 to 6 cycles of systemic chemotherapy were given. RESULTS: Eighteen eyes of 17 patients displayed cavitary retinoblastomas. This represented 6.8% of 250 patients. Mean age at diagnosis was 13 months; 5 unilateral (29%) and 12 bilateral (71%). The mean (median, range) number of retinoblastoma tumors per eye was 2 (2; 1-6). The number of cavities per tumor was 3 (2, 1-6). Intratumoral cavities were seen in the superficial portion of the tumor in 10 eyes (55%). The cavities became visible in eight eyes (44%) and collapsed in eight eyes (44%). Two eyes required enucleation because of relapse in noncavitary tumors. Germline mutations were detected in 14 patients (82%) of whom four demonstrated mosaicism (29%); only one had a low penetrant mutation. The mean follow-up period was 40 (35, 6-120) months. CONCLUSION: Cavitary retinoblastomas can be detected after systemic chemotherapy with cavities becoming visible after mean two cycles of chemotherapy (secondary cavitary retinoblastoma). The etiology is uncertain. They remain stable and do not require aggressive adjuvant therapy. There was no evident phenotype-genotype correlation with mosaicism noted in 29%.

Ocular oncology: advances in retinoblastoma, uveal melanoma and conjunctival melanoma.

Background: Retinoblastoma, uveal and conjunctival melanomas are important malignancies within the remit of ocular oncology. Outlined are the diagnostic features and management principles, as well as advancements in the field and current challenges. Sources of data: Original papers, reviews and guidelines. Areas of agreement: Most eyes with retinoblastoma (International Intraocular Retinoblastoma Classification (IIRC) Group A-D) are salvaged, whereas advanced cases (Group E) remain a challenge. Despite a high rate of local tumour control in uveal melanoma, metastatic spread commonly occurs. Conjunctival melanoma is treated by complete resection, but high rates of local recurrence occur, with the possibility of systemic relapse and death. Areas of controversy: Use of the IIRC in retinoblastoma, and systemic screening in melanomas. Growing points: Utilization of novel treatment modalities in retinoblastoma and an increasing understanding of the genetic basis of melanomas. Areas timely for developing research: Improvements in chemotherapy delivery in retinoblastoma and prognostic tests in melanomas.

High-Risk Histopathology Features in Primary and Secondary Enucleated International Intraocular Retinoblastoma Classification Group D Eyes.

PURPOSE: To evaluate the rate and identify the risk factors for high-risk histopathologic features in group D retinoblastoma eyes enucleated as primary or secondary treatment. DESIGN: Retrospective analysis. PARTICIPANTS: A total of 64 enucleated group D eyes (62 patients), of which 40 (40 patients) were primary and 24 (22 patients) were secondary to other treatments. METHODS: Clinicopathologic correlation of consecutive group D eyes enucleated from 2002 to 2014. High-risk histopathologic features were defined as the presence of anterior chamber seeds, iris infiltration, ciliary body/muscle infiltration, massive (≥3 mm) choroidal invasion, retrolaminar optic nerve invasion, or combined non-massive choroidal and prelaminar/laminar optic nerve invasion. MAIN OUTCOME MEASURES: High-risk histopathologic features, metastasis, and death. RESULTS: Of the 64 group D eyes, 37 (58%) were classified as cT2bN0M0H0, 24 (38%) were classified as cT2bN0M0H1, and 3 (5%) were classified as cT2aN0M0H1, according to the 8th edition cTNMH Retinoblastoma Staging. High-risk histopathologic features were detected in 10 eyes (16%) in the entire cohort, 5 eyes (13%) of the primary enucleated group (pT3aNxM0, n = 2 and pT3bNxM0, n = 3, 8th edition pTNM), and 5 eyes (21%) of the secondary enucleated group (pT2bNxM0, n = 2, pT3aNxM0, n = 2 and pT3cNxM0, n = 1). Absence of vitreous seeds at presentation was the only predictive factor found for high-risk histopathologic features in the primary enucleation group (P = 0.042), whereas none were found in the secondary group (P ≥ 0.179). Invasion of the anterior structures (anterior chamber, iris, ciliary body/muscle) was detected significantly more after secondary enucleation (P = 0.048). All patients with high-risk histopathologic features were treated with adjuvant chemotherapy, and no metastases were recorded in a median follow-up time of 73.2 months (mean, 71.5; range, 13.7-153.0). CONCLUSIONS: The choice of primary treatment for group D retinoblastoma should be carefully weighed, because according to this study, 13% of eyes harbor high-risk histopathologic features at presentation, with the absence of vitreous seeds being a potential risk factor. It is of special importance in group D eyes being considered for nonsystemic treatment, such as primary intraophthalmic artery chemotherapy. Secondary enucleated group D eyes with high-risk histopathologic features more commonly involved anterior structures, warranting meticulous clinical and histologic examinations for this subset of patients.

Spectrum of RB1 mutations identified in 403 retinoblastoma patients.

BACKGROUND: Retinoblastoma (RB) is a malignant, childhood tumour of the developing retina that occurs with an estimated frequency of 1 in 20 000. Identification of oncogenic mutations in the RB1 gene aids in the clinical management of families with a heritable predisposition to RB. Here we present the spectrum of genetic and epigenetic changes identified in 194 tumours and 209 blood samples, from 403 unrelated RB patients. METHODS: Mutation screening was carried out across all 27 RB1 exons and their associated splice sites. Small coding sequence changes were detected using fluorescent conformation analysis followed by sequencing. Large exonic deletions were detected by quantitative fluorescent PCR. Methylation specific PCR of the RB1 promoter was performed to detect epigenetic alterations. Polymorphism analysis was used to determine loss of heterozygosity in tumour samples. RESULTS: 95% of the expected mutations were identified in the tumour samples, with 16 samples exhibiting only one mutation, while two samples had no detectable RB1 mutation. 96% of bilateral/familial RB blood samples and 9.5% of unilateral sporadic blood samples, yielded mutations. 111 were novel mutations. CONCLUSIONS: The full range of screening techniques is required to achieve a high screening sensitivity in RB patients.

Genetic Diagnosis of Retinoblastoma Using Aqueous Humour-Findings from an Extended Cohort.

The identification of somatic RB1 variation is crucial to confirm the heritability of retinoblastoma. We and others have previously shown that, when tumour DNA is unavailable, cell-free DNA (cfDNA) derived from aqueous humour (AH) can be used to identify somatic RB1 pathogenic variation. Here we report RB1 pathogenic variant detection, as well as cfDNA concentration in an extended cohort of 75 AH samples from 68 patients. We show cfDNA concentration is highly variable and significantly correlated with the collection point of the AH. Cell-free DNA concentrations above 5 pg/µL enabled the detection of 93% of known or expected RB1 pathogenic variants. In AH samples collected during intravitreal chemotherapy treatment (Tx), the yield of cfDNA above 5 pg/µL and subsequent variant detection was low (≤46%). However, AH collected by an anterior chamber tap after one to three cycles of primary chemotherapy (Dx1+) enabled the detection of 75% of expected pathogenic variants. Further limiting our analysis to Dx1+ samples taken after ≤2 cycles (Dx ≤ 2) provided measurable levels of cfDNA in all cases, and a subsequent variant detection rate of 95%. Early AH sampling is therefore likely to be important in maximising cfDNA concentration and the subsequent detection of somatic RB1 pathogenic variants in retinoblastoma patients undergoing conservative treatment.

Differences in Childhood Growth Parameters Between Patients With Somatic and Heritable Retinoblastoma.

Purpose: Little is known regarding differences in childhood growth between somatic and heritable retinoblastoma (Rb) populations. We aimed to compare childhood growth parameters between somatic and heritable Rb cohorts at birth and at time of diagnosis with Rb. Methods: A multinational, longitudinal cohort study was conducted with patients from 11 centers in 10 countries who presented with treatment naïve Rb from January to December 2019. Variables of interest included age, sex, and size characteristics at birth and at time of presentation, as well as germline mutation status. After Bonferroni correction, results were statistically significant if the P value was less than 0.005. Results: We enrolled 696 patients, with 253 analyzed after exclusion criteria applied. Between somatic (n = 39) and heritable (n = 214) Rb cohorts, with males and females analyzed separately, there was no significant difference in birth weight percentile, weight percentile at time of diagnosis, length percentile at time of diagnosis, weight-for-length percentile at time of diagnosis, or change of weight percentile from birth to time of diagnosis. Patients with heritable Rb had a smaller mean weight percentile at birth and smaller mean weight and length percentiles at time of diagnosis with Rb, although this difference was not statistically significant. All cohorts experienced a slight negative change of weight percentile from birth to time of diagnosis. No cohort mean percentiles met criteria for failure to thrive, defined as less than the 5th percentile. Conclusions: Children with Rb seem to have normal birth and childhood growth patterns. There is no definitive evidence that somatic or heritable Rb has a biological or environmental impact on childhood growth parameters.

Relationships between maternal ethnicity, gestational age, birth weight, weight gain, and severe retinopathy of prematurity.

OBJECTIVE: To develop an algorithm that allows advanced identification of infants requiring treatment for retinopathy of prematurity (ROP). STUDY DESIGN: A retrospective observational study was performed at 2 tertiary neonatal units serving a multiethnic population in the UK, using data on 929 infants eligible for ROP screening. The relationships between study variables and the risk of developing ROP requiring treatment were analyzed using multiple logistic regression. RESULTS: After applying exclusion criteria, data from 589 infants were analyzed; of these, 57 required laser treatment. The proportion of treated infants was 5.9% of those born to black mothers, 9.39% of those born to white mothers, and 12.8% of those born to Asian mothers (P = .047). Multiple logistic regression showed that gestational age, birth weight, maternal ethnicity, and early weight gain were predictors for the development of ROP requiring treatment, with maternal ethnicity having greater predictive power compared with early weight gain. We developed an algorithm for predicting the development of ROP requiring treatment with sensitivity, specificity, and positive and negative predictive values of 100%, 65.7%, 23.8%, and 100%, respectively. CONCLUSION: Gestational age, birth weight, early weight gain, and maternal ethnicity are important predictors for the development of ROP requiring treatment. In a multiethnic population, an algorithm to predict development of ROP requiring treatment should include maternal ethnicity. If confirmed through prospective studies, this algorithm could reduce the number of opthalmologic examinations performed for ROP screening.

An overview of RB1 transcript alterations detected during retinoblastoma genetic screening.

Identification of pathogenic RB1 variants aids in the clinical management of families with retinoblastoma. We routinely screen DNA for RB1 variants, but transcript analysis can also be used for variant screening, and to help decide variant pathogenicity. DNA was screened by conformation analysis followed by Sanger sequencing. Large deletion/insertions were detected by polymorphism analysis, MLPA and quantitative-PCR. Methylation-specific PCR was used to detect hypermethylation. RNA screening was performed when a DNA pathogenic variant was missing, or to determine effects on splicing.Two hundred and thirteen small coding variants were predicted to affect splicing in 207 patients. Splice donor (sd) variants were nearly twice as frequent as splice acceptor (sa) with the most affected positions being sd + 1 and sa-1. Some missense and nonsense codons altered splicing, while some splice consensus variants did not. Large deletion/insertions can disrupt splicing, but RNA analysis showed that some of these are more complex than indicated by DNA testing. RNA screening found pathogenic variants in 53.8% of samples where DNA analysis did not. RB1 splicing is altered by changes at consensus splice sites, some missense and nonsense codons, deep intronic changes and large deletion/insertions. Common alternatively spliced transcripts may complicate analysis. An effective molecular screening strategy would include RNA analysis to help determine pathogenicity.

Retinoblastoma and vision.

The assessment of vision has a growing importance in the management of retinoblastoma in the era of globe-conserving therapy, both prior to and after treatment. As survival rates approach 98-99% and globe salvage rates reach ever-higher levels, it is important to provide families with information regarding the visual outcomes of different treatments. We present an overview of the role of vision in determining the treatment given and the impact of complications of treatment. We also discuss screening and treatment strategies that can be used to maximise vision.

Changing trends in pseudoretinoblastoma diagnoses: A 10 year review from the United Kingdom.

AIM: To study the different types and frequency of pseudoretinoblastoma (pseudoRB) lesions who present to a retinoblastoma centre due to concern that the condition may be retinoblastoma. METHODS: A retrospective chart review of 341 patients presenting sporadically to the Royal London Hospital from January 2009 to December 2018. RESULTS: 220 patients (65%) were confirmed to have retinoblastoma, while 121 (35%) had pseudoRB. There were 23 differential diagnoses in total. The top 3 differential diagnoses were Coats' disease (34%), Persistent Foetal Vasculature (PFV) (17%) and Combined Hamartoma of Retina and Retinal Pigment Epithelium (CHR-RPE) (13%). PseudoRBs differed with age at presentation. Under the age of 1 (n = 42), the most likely pseudoRB conditions were PFV (36%), Coats' disease (17%) and CHR-RPE (12%). These conditions were also the most common simulating conditions between the ages of 1 and 2 (n = 21), but Coats' disease was the most common in this age group (52%), followed by CHR-RPE (19%) and PFV (14%). Between the ages of 2 and 5 (n = 32), Coats' disease remained the most common (44%) pseudoRB lesion followed by CHR-RPE (13%), or PFV, Retinal Astrocytic Hamartoma (RAH), familial exudative vitreoretinopathy (FEVR) (all 6.3%). Over the age of 5 (n = 26), pseudoRBs were most likely to be Coats' disease (35%), RAH (12%), Uveitis, CHR-RPE, FEVR (all 7.7%). CONCLUSION: 35% of suspected retinoblastoma cases are pseudoRB conditions. Overall, Coats' disease is the most common pseudoRB condition, followed by PFV. Hamartomas (CHR-RPE & RAH) are more prevalent in this cohort, reflecting improvements in diagnostic accuracy from referring ophthalmologists.

Systemic adjuvant chemotherapy for advanced malignant ocular medulloepithelioma.

BACKGROUND: Ocular medulloepithelioma (diktyoma) is a rare and potentially malignant paediatric tumour of the non-pigmented ciliary epithelium. Adjuvant chemotherapy can be given in advanced cases, but the indications and regimens remain to be defined. The aim was to identify whether adjuvant chemotherapy offers treatment benefit in advanced ocular medulloepithelioma. METHODS: This was a retrospective case series of subjects referred to a single specialist ocular oncology centre for advanced ocular medulloepithelioma subsequently treated with enucleation, including those needing adjuvant systemic vincristine, etoposide and carboplatin. A case-note review was performed for included subjects meeting referral criteria. The outcomes were histopathology characteristics, recurrence, metastases and survival. RESULTS: Between March 2010 and June 2017, four male patients (mean age 31 months) underwent enucleation for ocular medulloepithelioma. Adjuvant chemotherapy was commenced in 3 patients (75%) due to malignant histopathological features. With a mean follow-up time of 81.5 months (median 71 months, range 49-135 months) none of the patients have had recurrence, metastases or death from the tumour. CONCLUSIONS: This series is unique in reporting the management of advanced malignant ocular medulloepithelioma with adjuvant systemic vincristine, etoposide and carboplatin for advanced tumours with malignant features. This regimen appears to be safe and may be effective in preventing metastatic spread.

The role of maternal age & birth order on the development of unilateral and bilateral retinoblastoma: a multicentre study.

BACKGROUND/OBJECTIVES: Retinoblastoma is a common childhood intraocular malignancy, the bilateral form of which most commonly results from a de novo germline pathogenic variant in the RB1 gene. Both advanced maternal age and decreasing birth order are known to increase the risk of de novo germline pathogenic variants, while the influence of national wealth is understudied. This cohort study aimed to retrospectively observe whether these factors influence the ratio of bilateral retinoblastoma cases compared to unilateral retinoblastoma, thereby inferring an influence on the development of de novo germline pathogenic variants in RB1. SUBJECTS/METHODS: Data from 688 patients from 11 centres in 10 countries were analysed using a series of statistical methods. RESULTS: No associations were found between advanced maternal age, birth order or GDP per capita and the ratio of bilateral to unilateral retinoblastoma cases (p values = 0.534, 0.201, 0.067, respectively), indicating that these factors do not contribute to the development of a de novo pathogenic variant. CONCLUSIONS: Despite a lack of a definitive control group and genetic testing, this study demonstrates that advanced maternal age, birth order or GDP per capita do not influence the risk of developing a bilateral retinoblastoma.

Molecular deregulation induced by silencing of the high mobility group protein A2 gene in retinoblastoma cells.

AIM: To explore the molecular mechanisms deregulated by high mobility group protein A2 (HMGA2) gene silencing in retinoblastoma (RB) cells. METHODS: Synthetic anti-HMGA2 short interfering RNA (siRNA) was used to silence the HMGA2 gene in cultured Y79 RB cells that were subjected to whole genome microarray analysis. The expression of differentially regulated key genes was confirmed with quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) in post-silenced RB cell lines (Y79 and WERI Rb1). These deregulated genes were compared for their constitutive expression in primary RB tumors (n=10). Zymographic determination of matrix metalloproteinase (MMP) activity was performed in RB cells. A cell cycle assay and a proliferation assay were performed in post-transfected RB cells. RESULTS: HMGA2 gene silencing in cultured RB cells results in reduced cell proliferation and transition in the G1/S phase. The whole genome microarray analysis of HMGA2 silenced Y79 cells revealed overall upregulation of 1,132 genes (≥ 1.0 fold) and downregulation of 1,562 genes (≤ -1.0 fold). Specific quantitative pathway analysis of the deregulated genes (using Biointerpreter) revealed 150 upregulated genes and 77 downregulated genes (≥ 1.0 fold) involved in vital pathways, namely, mitogen-activated protein kinase, Janus kinase/signal transducers and activators of transcription, Ras pathway, Ras-induced extracellular signal-regulated protein kinases 1 and 2, and tumor protein p53. The differential expression of genes obtained from microarray analysis (Homo sapiens ELK1, member of ETS oncogene family [ELK1], Homo sapiens cyclin-dependent kinase 6 [CDK6], Homo sapiens E2F transcription factor 4, p107/p130-binding [E2F4], Homo sapiens G-2 and S-phase expressed 1 [GTSE1], Damage-regulated autophagy modulator [DRAM], Homo sapiens cadherin 1, type 1,E-cadherin (epithelial) [CDH1], Homo sapiens snail homolog 1 (Drosophila) [SNAI1], Homo sapiens matrix metallopeptidase 2 [MMP2], and Homo sapiens matrix metallopeptidase 9 [MMP9]) was confirmed with quantitative reverse-transcriptase polymerase chain reaction in post-silenced RB cells. Zymographic analysis revealed that the increase in MMP mRNA expression in the post-silenced RB cells did not correlate with corresponding enzyme activity. CONCLUSIONS: Our study revealed molecular regulatory changes induced by HMGA2 silencing in RB cancer cells, offering mechanistic insights into the anticancer potential. HMGA2 may be considered a promising candidate for gene silencing therapy in RB.

Efficacy and complications of super-selective intra-ophthalmic artery melphalan for the treatment of refractory retinoblastoma.

PURPOSE: To report the efficacy of super-selective intra-ophthalmic artery melphalan (IAM) for the treatment of refractory retinoblastoma and any associated complications of this treatment. DESIGN: A prospective case series. PARTICIPANTS: Eyes with retinoblastoma that had been treated with systemic chemotherapy or local therapy and had a relapse of their condition. METHODS: All patients receiving IAM between May 2009 and September 2010 were included in the study. Intra-ophthalmic artery melphalan was offered to patients who had failed to respond adequately to systemic chemotherapy and local treatment where appropriate or because of a new recurrence of retinoblastoma that could not be treated with local therapies. None of the patients were excluded because of central nervous system abnormalities. Patients received 2 treatments of IAM given 4 weeks apart. All patients received an orthoptic assessment 3 weeks after each treatment and an examination under anesthesia (EUA). A third treatment was given if an unsatisfactory response was observed on EUA after 2 treatments. MAIN OUTCOME MEASURES: The response of the retinoblastoma tumor(s) and any associated local side effects from the treatment. RESULTS: A total of 15 eyes in 14 patients were treated with IAM during the study period. The mean age at the time of IAM was 31.5 months (median 17.3, range 11.2-150.7 months), and the mean follow-up was 8.7 months (3-16.3 months). Tumor control was achieved in 12 eyes (80%), and 12 eyes (80%) had local side effects that included third cranial nerve palsy in 6 (40%), orbital edema in 3 (20%), permanent retinal detachment in 1 (7%), and vitreous hemorrhage in 4 (27%). Seven eyes (47%) developed significant retinal pigment epithelium changes. CONCLUSIONS: Intra-ophthalmic artery melphalan is an effective treatment for retinoblastoma, achieving a high level of remission in refractory tumors. It can be associated with significant local side effects that can result in loss of vision and possible amblyogenesis. Clinicians and parents need to consider the benefits and potential local side effects before embarking on treatment.

Ruthenium plaque radiotherapy in the current era of retinoblastoma treatment.

BACKGROUND: Two major treatment modalities for retinoblastoma, intraarterial chemotherapy (IAC) and intravitreal chemotherapy (IVitC), have superseded external beam radiotherapy for eye salvage. In this new setting our objectives were to evaluate the indications for plaque radiotherapy, complications, and recurrence rates. METHODS: Retrospective detailed review of patient's charts was performed for all subjects treated with plaque radiotherapy for retinoblastoma between January 2015 and December 2020. RESULTS: A total of 12 eyes of 12 patients were included. Mean age at plaque insertion was 45 months (median 29, range 17-150). The treatment dose was 40 Gy to the tumor apex. The indication for plaque radiotherapy was salvage therapy in 11 eyes (92%) and primary treatment in one eye (8%). At last follow-up from plaque insertion (mean 36 months, range 3-67), four (33%) patients had visual acuity better than 0.5 LogMAR and four (33%) had visual acuity worse than 1.0 LogMAR. Radiation-related complications were: one (8%) vitreous haemorrhage, two (16%) non-proliferative radiation retinopathy and one (8%) cataract. Recurrence was detected in four (33%) patients at a mean of 7.8 months (median 5, range 1-20) post-plaque. Globe salvage rate was 75%, as three eyes required enucleation, one to treat recurrence of the tumor treated with plaque and two to treat recurrence of other tumors. CONCLUSIONS: In the current era of retinoblastoma management, a role for plaque radiotherapy remains for salvage or primary treatment in eyes with localised active tumor, providing tumor control in 66%. Close observation is recommended to both detect recurrence and radiation-related complications.

PRELP Regulates Cell-Cell Adhesion and EMT and Inhibits Retinoblastoma Progression.

Retinoblastoma (RB) is the most common intraocular pediatric cancer. Nearly all cases of RB are associated with mutations compromising the function of the RB1 tumor suppressor gene. We previously demonstrated that PRELP is widely downregulated in various cancers and our in vivo and in vitro analysis revealed PRELP as a novel tumor suppressor and regulator of EMT. In addition, PRELP is located at chromosome 1q31.1, around a region hypothesized to be associated with the initiation of malignancy in RB. Therefore, in this study, we investigated the role of PRELP in RB through in vitro analysis and next-generation sequencing. Immunostaining revealed that PRELP is expressed in Müller glial cells in the retina. mRNA expression profiling of PRELP-/- mouse retina and PRELP-treated RB cells found that PRELP contributes to RB progression via regulation of the cancer microenvironment, in which loss of PRELP reduces cell-cell adhesion and facilitates EMT. Our observations suggest that PRELP may have potential as a new strategy for RB treatment.

Sex, gender, and retinoblastoma: analysis of 4351 patients from 153 countries.

OBJECTIVE: To investigate in a large global sample of patients with retinoblastoma whether sex predilection exists for this childhood eye cancer. METHODS: A cross-sectional analysis including 4351 treatment-naive retinoblastoma patients from 153 countries who presented to 278 treatment centers across the world in 2017. The sex ratio (male/female) in the sample was compared to the sex ratio at birth by means of a two-sided proportions test at global level, country economic grouping, continent, and for selected countries. RESULTS: For the entire sample, the mean retinoblastoma sex ratio, 1.20, was higher than the weighted global sex ratio at birth, 1.07 (p < 0.001). Analysis at economic grouping, continent, and country-level demonstrated differences in the sex ratio in the sample compared to the ratio at birth in lower-middle-income countries (n = 1940), 1.23 vs. 1.07 (p = 0.019); Asia (n = 2276), 1.28 vs. 1.06 (p < 0.001); and India (n = 558), 1.52 vs. 1.11 (p = 0.008). Sensitivity analysis, excluding data from India, showed that differences remained significant for the remaining sample (χ2 = 6.925, corrected p = 0.025) and for Asia (χ2 = 5.084, corrected p = 0.036). Excluding data from Asia, differences for the remaining sample were nonsignificant (χ2 = 2.205, p = 0.14). CONCLUSIONS: No proof of sex predilection in retinoblastoma was found in the present study, which is estimated to include over half of new retinoblastoma patients worldwide in 2017. A high male to female ratio in Asian countries, India in specific, which may have had an impact on global-level analysis, is likely due to gender discrimination in access to care in these countries, rather than a biological difference between sexes.