Retinoblastoma Patients Research Articles

A 12-year analysis of presentation, histopathological features, high-risk factors, and survival in retinoblastoma patients undergoing primary enucleation at a tertiary eye care center in Bangladesh

Retinoblastoma is the most common primary intraocular malignancy in children, with approximately 100% survival rates in higher-income countries. The outcomes of retinoblastoma depend on factors such as disease presentation, treatment access, histopathological high-risk factors, and national income level. This retrospective study analyzed 12-year data (2012 – 2023), including presentation, histopathological features, histopathological high-risk factors, and survival outcomes, of 78 retinoblastoma patients who had undergone primary enucleation at a tertiary eye center in Bangladesh. The overall median age was 33 months, with a slightly older median age among females (35 months) and a mild male predominance. The mean symptom duration was 5.68 ± 3.56 months, with earlier presentation in male patients. The most common presenting sign was leukocoria (70.5%), followed by red eye (20.5%). Combined endophytic and exophytic tumor growth (36%) and poor differentiation (44.9%) were prevalent. High-risk factors were present in 84.6% of patients, with massive choroidal invasion (41%) and retrolaminar optic nerve invasion (38.5%) being the most frequent. Approximately 57.7% of patients solely underwent enucleation, and 27% of children died, yielding an overall survival rate of 69.23%. The findings of this study suggest that multiple high-risk factors are often present in advanced tumors, posing challenges in management and increasing the risk for metastasis. Efforts to improve outcomes should focus on raising awareness, promoting early presentation, enhancing histopathological reporting, and developing specialized human resources.

Retinoblastoma programme outcome over a 10-year period in Lebanon: assessment of potential impact of thepandemic and economic crisis.

To evaluate the long-term outcomes of patients enrolled in the retinoblastoma programme at the Children's Cancer Institute of the American University of Beirut Medical Center (AUBMC) and to assess the effects of the Lebanese economic crisis and the COVID-19 pandemic on treatment outcomes. A retrospective review of medical charts was conducted for retinoblastoma patients enrolled in the programme from 2012 to 2022. Parameters included age at diagnosis, gender, nationality, tumour characteristics, treatment modalities, follow-up duration, imaging results, and genetic testing outcomes. Outcomes were reported for the 10-year period and compared before and after 2019(beginning of pandemic). The cohort included 94 patients: 49(52%) with unilateral retinoblastoma(RB) and 45(48%) with bilateral tumours. Mean age at diagnosis was 19.96 ± 16.2 months (14.18 ± 13.33 months for the bilateral group and 25.27 ± 16.94 months for the unilateral group) with no difference between the 2 time periods. Eye preservation over the 10-year period was 58.4% for bilateral disease and 20.8% for unilateral disease. Ocular salvage rate tended to increase from 54.9% to 72.2% after 2019 in the bilateral group and from 14.3% to 38.5% in the unilateral group but without statistical significance. For the whole cohort, positive genetic testing for RB mutation increased from 25% to 46%. In those who underwent testing, detection of RB1 mutation was similar in patients before 2019 (58%) and after 2019 (62.5%). Our retinoblastoma programme demonstrated continued improved outcomes in terms of early detection, treatment, RB mutation detection, and eye preservation, despite the different challenges posed by the economic crisis and pandemic.

EPCO-05. GENOMIC AND CLINICAL INSIGHTS FROM A LARGE-SCALE STUDY OF 172 RETINOBLASTOMAS

Abstract Retinoblastoma, a pediatric ocular cancer, is the only central nervous system tumor visible without specialized tools, readily detectable with the naked eye. This rare childhood cancer is mainly driven by mutations in RB1 or MYCN amplification, posing significant challenges in pediatric oncology. We conducted whole exome sequencing on 172 retinoblastoma tumors along with matched blood DNA from 171 patients, which included 119 unilateral, 49 bilateral, and three trilateral cases. Our analysis identified pathogenic variants in RB1 in 76 patients and MYCN duplication in 79 cases, highlighting their crucial roles in the disease. Additionally, we found mutations in RPTOR and TSC2, components of the mTOR signaling pathway, in two patients. Notably, our copy number alteration analysis revealed recurrent arm-level changes, including gains on 1q (23.3%), 2p (20.9%), and especially 6p (41.3%), along with other changes such as 5p gain (8.1%), 17q gain (8.1%), and 16q loss (5.8%). Our findings link these genetic alterations to specific clinical features; for instance, 6p gains were associated with Rubeosis, subretinal seeds, and tumor LC beyond, while 17q gains were linked to Rubeosis. Furthermore, gene collapsing techniques identified MATR3 and CYP4F2 as additional novel retinoblastoma-related genes, and module identification analysis pinpointed retinoblastoma-associated modules including HLA-DRB1-CBL, LPAR2, RB1, and TRIM28. Our study, the largest cohort of its kind, underscores the importance of next-generation sequencing from understudied populations in uncovering the complex genetic landscape of retinoblastoma, emphasizing the potential of precision medicine to enhance therapeutic strategies and improve outcomes for retinoblastoma patients.

The Bloom Syndrome and Retinoblastoma patient exhibits two RB1 gene mutations in the germline.

To report the case of a patient with Bloom Syndrome and retinoblastoma from a genetic perspective. The patient exhibits two RB1 gene mutations in the germline. The patient underwent an ultrasound study, followed by enucleation of the left eye. Peripheral venous blood samples were collected to isolate mononuclear cells for total RNA and DNA extraction. Subsequently, cDNA synthesis and RT-qPCR were performed. The DNA was used for PCR amplification of the 27 exons. The sequence of the exons of RB1 was analysed. The patient with Bloom Syndrome (BS) and retinoblastoma underwent treatment, and blood samples from the patient and a family member were analysed. The results revealed two germline mutations on exons 13 and 17. The levels of RB1 mRNA were found to be low compared to those of a healthy control and a family member. Without a family history of cancer, a patient with retinoblastoma and BS presents two mutations in the germline on the RB1 gene; this results in very low levels of RB1 mRNA systemically, thereby increasing the patient´s risk of developing another type of cancer throughout his life.

IGF2BP3-dependent N6-methyladenosine modification of USP49 promotes carboplatin resistance in retinoblastoma by enhancing autophagy via regulating the stabilization of SIRT1.

Retinoblastoma (RB) poses significant challenges in clinical management due to the emergence of resistance to conventional chemotherapeutic agents, particularly carboplatin (CBP). In this study, we investigated the molecular mechanisms underlying CBP resistance in RB, with a focus on the role of autophagy and the influence of ubiquitin-specific peptidase 49 (USP49). We observed upregulation of USP49 in RB tissues and cell lines, correlating with disease progression. Functional assays revealed that USP49 promoted aggressive proliferation and conferred CBP resistance in RB cells. Furthermore, USP49 accelerated tumor growth and induced CBP resistance in vivo. Mechanistically, we found that USP49 facilitated CBP resistance by promoting autophagy activation. In addition, we identified insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3)-mediated N6-methyladenosine (m6A) modification of USP49 as a regulatory mechanism, wherein IGF2BP3 upregulated USP49 expression in an m6A-dependent manner. Moreover, USP49 stabilized SIRT1, a protein associated with CBP resistance and autophagy, by inhibiting its ubiquitination and degradation. Rescue experiments confirmed the pivotal role of SIRT1 in USP49-mediated CBP resistance. Our findings delineate a novel molecular network involving USP49-mediated autophagy in promoting CBP resistance in RB, offering potential targets for therapeutic intervention to enhance treatment efficacy and improve outcomes for RB patients.

Differentiating MYCN-amplified RB1 wild-type retinoblastoma from biallelic RB1 mutant retinoblastoma using MR-based radiomics: a retrospective multicenter case–control study

MYCN-amplified RB1 wild-type (MYCNampRB1+/+) retinoblastoma is a rare and aggressive subtype, often resistant to standard therapies. Identifying unique MRI features is crucial for diagnosing this subtype, as biopsy is not recommended. This study aimed to differentiate MYCNampRB1+/+ from the most prevalent RB1-/- retinoblastoma using pretreatment MRI and radiomics. Ninety-eight unilateral retinoblastoma patients (19 MYCN cases and 79 matched controls) were included. Tumors on T2-weighted MR images were manually delineated and validated by experienced radiologists. Radiomics analysis extracted 120 features per tumor. Several combinations of feature selection methods, oversampling techniques and machine learning (ML) classifiers were evaluated in a repeated fivefold cross-validation machine learning pipeline to yield the best-performing prediction model for MYCN. The best model used univariate feature selection, data oversampling (duplicating MYCN cases), and logistic regression classifier, achieving a mean AUC of 0.78 (SD 0.12). SHAP analysis highlighted lower sphericity, higher flatness, and greater gray-level heterogeneity as predictive for MYCNampRB1+/+ status, yielding an AUC of 0.81 (SD 0.11). This study shows the potential of MRI-based radiomics to distinguish MYCNampRB1+/+ and RB1-/- retinoblastoma subtypes.

Quality of life of Retinoblastoma survivors in tertiary care eye hospital in South India.

With the increased survival of retinoblastoma (RB) patients, it is important to evaluate the quality of life (QoL) of RB survivors as well as caregivers to provide comprehensive care to the children and caregivers. This study aims to assess the QoL of survivors of RB, as perceived by parents and the self-report by patients, through a pediatric QoL (PEDs-QoL) questionnaire. The study cohort included 86 RB survivors, 86 age-matched controls, and their primary carers. PedsQL 4.0 generic core scale and structured interview were administered. QoL in physical, social, emotional, and school health was evaluated and correlated with clinical and sociodemographic parameters. The mean age of the RB survivors was 5.7 years with an M:F ratio of 1.1:1. Disease was bilateral in 79% of cases. About 45% (39/86) underwent enucleation, while others received combination therapy (16; 18%), chemotherapy (30; 34%), and radiation (1; 1%). As reported by parents, the QoL of physical health domain of RB survivors was 70.2 SD ± 27.8 and 96.15 ± 13 SD, emotional health was 72.1 ± 27.4 SD and 94.4 ± 12.5 SD, social health was 80.4 ± 24.9 SD and 98.6 ± 6.2 SD; and school health was 71.9 ± 2 6.5 SD and 96.1 ± 12.2 SD. As per the self-report perception, the QoL of physical health was 68.2 ± 27.8 SD and 96.2 ± 13 SD, emotional health was 66.2 ± 28.4 SD and 95.3 ± 12.5 SD, social health was 69.5 ± 24.9 SD and 98.7 ± 6.2 SD, and school health was 63.5 ± 26.5 SD and 95.1 ± 12.2 SD. There was a significant relationship between enucleation and QoL domains, where χ2 = 67.75, degrees of freedom (df) = 36, and P < 0.01. There was a significant association between vision in the better eye (6/18 or better = 8, 6/18-6/60 = 8, 3/60 or worse = 42) and QoL scores (χ2 = 95.36, df = 62, P < 0.01). There was a substantial association between socioeconomic status and QoL domains, where χ2= 88.5, df = 56, P < 0.01. The results of the study showed that the QoL of parents of RB survivors and self-proxy reports were negatively affected in many ways, including physical, social, emotional, and school-related dimensions. Despite the small differences, self-proxy reports indicated a lower QoL than the parents' group. The study findings indicate that there are notable correlations between enucleation and visual acuity less than 6/18, as well as socioeconomic status, with various aspects of QoL domains among individuals who have survived RB.

Retinoblastoma with and without Extraocular Tumor Extension: A Global Comparative Study of 3435 Patients

PurposeTo study the treatment, and outcomes of children with retinoblastoma (RB) with extraocular tumor extension (RB-EOE) and compare them with RB without extraocular tumor extension (RB-w/o-EOE). DesignMulticenter intercontinental collaborative prospective study from 2017 to 2020. RB-EOE cases included those with overt orbital tumor extension in treatment-naïve patients. Cases with microscopic orbital extension detected post-enucleation were excluded from the study. ParticipantsA total of 319 children with RB-EOE and 3116 children with RB-w/o-EOE Intervention(s)Chemotherapy, enucleation, exenteration, radiotherapy. Main outcomes(s)Systemic metastasis and death. ResultsOf the 3435 RB patients included in this study, 309 (9%) were from low-income countries, 1448 (42%) from lower-middle income, 1012 (29%) from upper-middle income, and 666 (19%) patients from high-income countries. There was an inverse relationship between the percentage of RB-EOE and national income level, with 96 (31%) patients from low-income countries, 197 (6%) lower middle-income, 20 (2%) upper-middle income, and 6 (1%) patients from high-income countries (p=0.0001). The outcomes were statistically significant for RB-EOE compared to RB-w/o-EOE: systemic metastasis (32% vs 4% respectively; p=0.0001) and metastasis-related death (63% vs 6% respectively; p=0.0001). Multimodal treatment was the most common form of treatment (n=177; 54%) for RB-EOE, with most cases undergoing a combination of intravenous chemotherapy and enucleation (n=97; 30%). Adjuvant external beam radiotherapy after surgery (enucleation/orbital exenteration) was given in only 68 (21%) cases. Kaplan-Meier analysis for systemic metastasis and metastasis-related death in RB-EOE was 28% and 57% at 1 year, 29% and 60% at 2 years, and 29% and 61% at 3 years, respectively. Cox regression analysis revealed that the risk for death from RB-EOE was greater in patients aged >4 years than <2 years (hazard ratio (HR)=2.912; p<0.001) and for unimodal (surgery or intravenous chemotherapy) and bimodal (surgery and intravenous chemotherapy) treatment than trimodal treatment (surgery, intravenous chemotherapy and external beam radiotherapy) (HR=2.023; p=0.004 and HR 1.819; p=0.027 respectively). ConclusionRetinoblastoma with extraocular tumor extension is associated with a higher risk for metastasis and death. Patients with RB-EOE are likely to benefit from trimodal treatment (intravenous chemotherapy, surgery, and external beam radiotherapy) rather than treatment protocols excluding external beam radiotherapy.

Assessing the Metabolic Variations of Invasive and Noninvasive Unilateral Retinoblastoma Patients.

Retinoblastoma (Rb) is a pediatric eye cancer which if diagnosed at later stages can lead to Rb invasion into the choroid, optic nerve, sclera, or beyond, with the potential of undergoing metastasis. Cancer cells, including Rb cells, reprogram their metabolic circuits for their own survival and progression, which provides a great opportunity to monitor the extent of Rb progression based on metabolic differences. Henceforth, the present study aims to map the metabolic variations in patients with invasive (primarily enucleated eyes with high-risk histopathological features) and noninvasive (eyes salvaged with treatment) unilateral retinoblastoma (Rb) using nuclear magnetic resonance (NMR) based serum metabolomics. Quantification of differential metabolites in the serum obtained from 9 patients with invasive and 4 with noninvasive unilateral Rb along with 6 controls (no retinal pathology) was carried out using 1H NMR spectroscopy. A total of 71 metabolites, such as organic acids, amino acids, carbohydrates, and others, were identified in the serum obtained from 9 patients with invasive and 4 with noninvasive unilateral Rb. Partial least-squares discriminant analysis (PLS-DA) models depicted distinct grouping of invasive and noninvasive Rb patients and controls. Differential metabolic fingerprints were observed for invasive and noninvasive Rb patients based on their biostatistical analyses with respect to controls. Remarkable perturbation was observed among various metabolites such as 4-aminobutyrate, 2-phosphoglycerate, O-phosphocholine, proline, Sn-glycero-3-phosphocholine (Sn-GPC), and O-phosphoethanolamine in noninvasive and invasive Rb patients with most of the effects being heightened in the latter group. Metabolic changes unique to invasive and noninvasive Rb patients were also observed. Multivariate receiver operating characteristics (ROC) analysis unveiled the highest accuracy and potency of ROC models 2 and 5 to distinguish the noninvasive and invasive Rb from controls, respectively. Metabolites identified in the serum of patients with invasive and noninvasive Rb may aid in advancing our knowledge about Rb tumor biology. Differential aberrant metabolic variations in patients with invasive Rb compared to those with noninvasive Rb may guide the decision of enucleation versus globe salvage.

Treatment outcomes in retinoblastoma and the effect of tumor topography.

Retinoblastoma, the most common intraocular malignancy in children, has high fatality rates if untreated. It is crucial to monitor treatment effectiveness and explore factors influencing favorable outcomes. Our study aims to examine how tumor location impacts the response to standard treatments and the achievement of favorable outcomes among retinoblastoma patients, while controlling for other tumor-related factors. This retrospective study analyzed medical records of retinoblastoma patients from November 2012 to December 2022 enrolled in the retinoblastoma program at the Children's Cancer Center of Lebanon (established in collaboration with St.yJude Children's Research Hospital, Memphis, TN). Data were extracted from the electronic chart reviews and operative reports of examinations under anesthesia (EUAs), and included patient's demographics, tumor characteristics (size, location), and treatment parameters (treatment type, resolution, recurrence). The study included 42 patients with retinoblastoma, with a total of 57 eyes and 115 tumors/lesions. The median age at diagnosis was 12months (range: 2-36months). Among the patients, 26 (61.9%) were males and 16 (38.1%) were females. A minority of patients (21.4%) presented with unilateral involvement, whereas the majority (78.6%) had bilateral involvement. The locations of retinoblastoma lesions were distributed as follows: optic nerve (4.4%), macula (19.1%), superior (16.5%), inferior (17.4%), nasal (27.8%), and temporal (14.8%). Resolution rate tended to be highest for tumors close to optic nerve and temporal lesions, but no statistical significance was attained (p=.45). Macular lesions tended to have the fastest resolution, but again not significantly (p=.5). Multiple logistic regression revealed that the odds for resolution of tumor was not significantly associated with tumor size (p=.57) or location (p=.52). Location of retinoblastoma lesions was not directly associated with recurrence-free resolution in our cohort. Further research in large retinoblastoma databases is needed to explore the association of tumor characteristics with recurrence and the need for secondary therapeutic interventions.

Clinical characteristics, management, and survival of retinoblastoma patients: a five-year study at an Indonesian tertiary eye hospital

Background Studies on the clinical characteristics of retinoblastoma in Indonesia have been limited, even though retinoblastoma is the most common pediatric ocular malignancy worldwide and the second-most common pediatric malignancy in Indonesia. The estimated patient survival rate in lower-middle-income countries is 77%, and survival is highly dependent on early diagnosis and therapy. Objective To identify the clinical characteristics of retinoblastoma in patients at the Cicendo National Eye Hospital, as an Indonesian tertiary eye hospital. Methods This retrospective, observational study included pediatric patients &lt;18 years of age diagnosed with retinoblastoma at the Cicendo National Eye Hospital, Bandung, West Java, between January 2018 and December 2022. We collected patients’ medical record data on age, gender, laterality, chief complaints, stage of disease, grouping, histopathologic features, therapy, and survival. Results Of 247 retinoblastoma patients (328 eyes) enrolled, 53.85% presented at 1-2 years of age and 50.61% were males. Patients mostly presented with unilateral (67.21%) retinoblastoma, leukocoria (51.82%) as the chief complaint, and classified as International Retinoblastoma Staging System (IRSS) stage III (33.20%). Tumors were mostly intraocular (58.84%), particularly group E (39.02%). Most tumors showed undifferentiated (45.43%) and high-risk features (54.27%). Most eyes were treated with combination therapy (74.09%), particularly local and systemic therapy (59.45%). Survival was noted at 18.62% of patients, but 62.75% of patients were lost to follow-up. Conclusion Most patients present with advanced retinoblastoma. Most histopathological results shows undifferentiated and high-risk features of the tumor. Delays in diagnosis and therapy may occur due to a lack of awareness and knowledge regarding clinical manifestations of retinoblastoma, which leads to worse prognosis.

Clinical characterization and long-term postoperative outcomes of retinoblastoma patients receiving enucleation and primary orbital implantation in early infancy: an observational study

ObjectivesTo retrospectively investigate clinical characterization and the long-term postoperative outcomes of retinoblastoma (RB) patients receiving enucleation with primary orbital implantation in early infancy (0–6 months old).MethodsThe clinical and follow-up data of 42 RB patients receiving enucleation with primary orbital implantation in early infancy at Beijing Tongren Hospital from December 2009 to January 2020 were analysed. The average follow-up time was 83 months. The patient group included 24 males and 18 females, 30 unilateral and 12 bilateral cases. A total of 44 eyes with 10 in stage D and 34 in stage E underwent 40 unilateral and 2 bilateral surgeries. 17 RB eyes received hydrogel and 27 RB eyes received hydroxyapatite implants. This study was performed by following the guideline of STROBE.ResultsEnucleation combined with primary orbital implantation promoted survival and was safe with few and minor complications such as increased secretion, upper eyelid ptosis, and sunken eye sockets which were not affected by stages, lateralities, or implant materials. 55-80% RB patients exhibited satisfactory appearance and obvious or moderate motility of orbital implants according to the evaluation by doctors and family members. Family members were likely more optimistic about the appearance and more pessimistic about motility of the orbital implantation than doctors did.The quality of life was high as indicated by PedsQL3.0 or PedsQL4.0 scores ( ≧ 90 for > 75% patients). It was not affected by the stages, laterality, and implant materials, nor affected by the appearance and motility of the implants.ConclusionsThe outcomes of the combination of enucleation and primary orbital implantation for pertinent RB patients in early infancy are generally satisfactory with few and minor complications, high safety, appearance, and overall quality of life. Enucleation combined with primary orbital implantation in early infancy benefits pertinent RB patients in appearance, survival, and quality of life.

Overall survival and cause-specific mortality in a hospital-based cohort of retinoblastoma patients in São Paulo, Brazil.

Studies are lacking on long-term effects among retinoblastoma patients in low- and middle-income countries. Therefore, we examined cause-specific mortality in a retrospective cohort of retinoblastoma patients treated at Antonio Candido de Camargo Cancer Center (ACCCC), São Paulo, Brazil from 1986 to 2003 and followed up through December 31, 2018. Vital status and cause of death were ascertained from medical records and multiple national databases. We estimated overall and cause-specific survival using the Kaplan-Meier survival method, and estimated standardized mortality ratios (SMRs) and absolute excess risk (AER) of death. This cohort study included 465 retinoblastoma patients (42% hereditary, 58% nonhereditary), with most (77%) patients diagnosed at advanced stages (IV or V). Over an 11-year average follow-up, 80 deaths occurred: 70% due to retinoblastoma, 22% due to subsequent malignant neoplasms (SMNs) and 5% to non-cancer causes. The overall 5-year survival rate was 88% consistent across hereditary and nonhereditary patients (p = .67). Hereditary retinoblastoma patients faced an 86-fold higher risk of SMN-related death compared to the general population (N = 16, SMR = 86.1, 95% CI 52.7-140.5), corresponding to 42.4 excess deaths per 10,000 person-years. This risk remained consistent for those treated with radiotherapy and chemotherapy (N = 10, SMR = 90.3, 95% CI 48.6-167.8) and chemotherapy alone (N = 6, SMR = 80.0, 95% CI 35.9-177.9). Nonhereditary patients had only two SMN-related deaths (SMR = 7.2, 95% CI 1.8-28.7). There was no excess risk of non-cancer-related deaths in either retinoblastoma form. Findings from this cohort with a high proportion of advanced-stage patients and extensive chemotherapy use may help guide policy and healthcare planning, emphasizing the need to enhance early diagnosis and treatment access in less developed countries.

RB1 circulating-tumor DNA in the blood of Retinoblastoma patients increases in untreated patients.

Circulating tumor DNA (ctDNA) in plasma has been identified in many cancers, including retinoblastoma at diagnosis. We have previously shown that with treatment (enucleation or ophthalmic artery chemosurgery (OAC)) all ctDNA disappears; and if there is persistent plasma ctDNA after treatment metastases develop. The purpose of this study was to determine how the ctDNA RB1 variant allele frequency (VAF) changes in patients with retinoblastoma who have delayed treatment. Circulating tumor DNA RB1 was detected and VAF was measured at diagnosis and again prior to any intervention at some time later ranging from 2 to 28 days. Four patients with five ctDNA RB1 mutations were detected at diagnosis and VAF was increased on re-evaluation of the same RB1 mutations in ctDNA. In this small cohort, every patient (4) and every RB1 mutation (5) plasma level VAF% increased when measured at two time periods before treatment was instituted suggesting that growing tumors demonstrate increasing plasma ctDNA.

Targeting GPC2 on Intraocular and CNS Metastatic Retinoblastomas with Local and Systemic Delivery of CAR T Cells.

Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory intraocular and metastatic disease. Chimeric antigen receptor (CAR) T cells targeting glypican-2 (GPC2) are a potential new therapeutic strategy. GPC2 expression and its regulation by the E2F1 transcription factor were studied in retinoblastoma patient samples and cellular models. In vitro, we performed functional studies comparing GPC2 CAR T cells with different costimulatory domains (4-1BB and CD28). In vivo, the efficacy of local and systemic administration of GPC2 CAR T cells was evaluated in intraocular and leptomeningeal human retinoblastoma xenograft models. Retinoblastoma tumors, but not healthy retinal tissues, expressed cell surface GPC2, and this tumor-specific expression was driven by E2F1. GPC2-directed CARs with 4-1BB costimulation (GPC2.BBz) were superior to CARs with CD28 stimulatory domains (GPC2.28z), efficiently inducing retinoblastoma cell cytotoxicity and enhancing T-cell proliferation and polyfunctionality. In vivo, GPC2.BBz CARs had enhanced persistence, which led to significant tumor regression compared with either control CD19 or GPC2.28z CARs. In intraocular models, GPC2.BBz CAR T cells efficiently trafficked to tumor-bearing eyes after intravitreal or systemic infusions, significantly prolonging ocular survival. In central nervous system (CNS) retinoblastoma models, intraventricular or systemically administered GPC2.BBz CAR T cells were activated in retinoblastoma-involved CNS tissues, resulting in robust tumor regression with substantially extended overall mouse survival. GPC2-directed CAR T cells are effective against intraocular and CNS metastatic retinoblastomas.

Retinoblastoma patients treated in Sri Lanka from 2014 to 2020: epidemiology, clinical status and correlates of lag time in seeking tertiary care services

BackgroundRetinoblastoma (RB) is a tumour of children < 5 years with a incidence of 1 in 20,000. Around 20 RB cases are diagnosed yearly in Sri Lanka, a lower middle-income country with high literacy levels and healthcare free at point of delivery. Incidence, local and systemic severity and mortality related to RB are reportedly high in low- and middle- income countries in comparison to higher income countries. Aims of this study were to describe demographic, socioeconomic, and clinical characteristics of Sri Lankan RB patients attending the designated RB unit at the Lady Ridgeway Hospital (LRH), Colombo between January 2014 to December 2020, and determine correlates of lag time (LT) for first tertiary care visit after detecting the first symptom/sign.MethodsTwo descriptive cross-sectional studies (DCSS) were conducted, one on 171 RB patients with demographic and clinical data collected between 2017 and 2020. In 2021, the second DCSS took place where socioeconomic and further demographic data were collected using telephone interviews, recruiting a subgroup of 90 (53%), consenting and contactable RB patient/ parent pairs. Bivariate and multivariable analyses were applied to determine correlates of LT of > 4 weeks for first tertiary care visit. Results were expressed as odds ratios and 95% confidence intervals.ResultsLRH survey (N = 171): Median age at diagnosis was 15 months (range 1–94 months; IQR: 8–27); 89 (52%) were females. Groups D and E tumours were 25.7% (n = 44) and 62.6% (n = 107) respectively with 121 (71%) enucleations. The number of deaths were 2 (1.2%). Telephone survey (N = 90): Proportion with LT of > 4 weeks for first tertiary care visit was 58% (n = 52). None of the putative risk factors (ethnicity, parental educational level, socioeconomic status, distance from residence to tertiary care unit and receiving financial assistance) were associated with LT in both analyses.ConclusionDespite a high proportion with groups D and E tumours and enucleations, mortality rate was low, most likely due to availability of designated tertiary care. No correlates for LT of > 4 weeks for tertiary care presentation were identified. Early RB detection needs rigorous implementation of screening strategies and increased awareness among primary care health workers and parents.

Development of a Patient-Centered Pathway of Care for Retinoblastoma Patients: A Mixed-Methods Pilot Study.

Introduction Retinoblastoma treatment and follow-up is complex and varies between patients. Pathways of care can enhance quality of care, patient outcomes, safety, satisfaction, and resource optimization. Developing a pathway of care for retinoblastoma was identified as a top research priority by the retinoblastoma community. This study aimed to co-design and pilot a pathway of care called the "Retinoblastoma Journey Map" tailored for caregivers of newly diagnosed children with retinoblastoma. Methods A working group of patients, health professionals and researchers used human-centred design to ideate, prototype and refine the Retinoblastoma Journey Map. Caregivers of affected children were recruited to use and evaluate the Map. Mixed-methods data was collected on feasibility, acceptability, usability and perceived impact on communication, self-efficacy, anxiety, depression, and the quality of physician-patient interaction. Results The Retinoblastoma Journey Map consisted of an illustrated roadmap with 25 child-friendly stickers covering clinical treatment, medical education and milestones. Quantitative analysis revealed that the Map was feasible, acceptable, and usable; however, no significant effect on communication, self-efficacy, anxiety, depression or quality of physician-patient interaction was observed. Qualitative analysis identified 6 themes: Primary Use, Challenges, Impact, Limitations, Feasibility, Acceptability and Usability, and Unmet Needs. Conclusion A pathway of care for retinoblastoma, co-designed by researchers, health professionals and patients, was usable, acceptable, and feasible by caregivers of children with retinoblastoma. While significant effects on communication and physician-patient interaction were not observed, 'legacy building' - documentation of the pathway of care by families for later education of their child - emerged as an unanticipated yet important use of the Retinoblastoma Journey Map.

Follow-up of Cystic Pineal Glands in Retinoblastoma Patients Does Not Increase Detection of Pineal Trilateral Retinoblastoma

PurposeTo evaluate the effectiveness of baseline screening and follow-up with MRI to detecting trilateral retinoblastoma (TRb) and assessing the risk of TRb development. DesignProspective multicenter cohort study MethodsA total of 607 retinoblastoma patients from 2012 through 2022 were included and followed up until 1-9-2023. At each center a neuroradiologist categorized pineal glands on baseline and follow-up scans into four groups: (A) normal, (B) cystic gland, (C) suspicious gland, or (D) TRb. Different follow-up schedules were assigned to each category. Categories (B) and (C) were followed-up with MRI after approximately 3-months and after another 3 months if suspicion remained. On each MRI, they measured the height and width, evaluated the aspect (solid, partly cystic and completely cystic) of the pineal gland and evaluated radiological features suspicious of pineal TRb. The effectiveness of the current TRb screening method was assessed by evaluating its sensitivity and specificity to detect TRb. Determining the TRb incidence was a secondary outcome measure. ResultsHeritable retinoblastoma patients had a risk of 3.78% to develop TRb. One out of four pineal TRbs was detected during a follow-up scan and four out of five non-pineal TRbs were detected on the baseline MRI. Screening for pineal TRb had a sensitivity of 25% and specificity of 100%, for non-pineal TRb the sensitivity was 80%. It required 494 follow-up scans to detect one pineal TRb. However, when restricting the follow-up to solely suspicious glands, only 22 scans were required to detect one pineal TRb. ConclusionDuring extended follow-up after baseline MRI, only one pineal trilateral retinoblastoma was detected in our study. Follow-up after three months should be restricted to patients with a suspicious pineal gland defined as irregularly thickening of the cyst wall (>2mm), fine nodular aspect of the cyst wall or when a solid or cystic gland exceeds the upper 99% prediction interval for size; patients with an unsuspicious cystic gland should not be followed up. Baseline MRI screening was able to detect most non-pineal trilateral retinoblastomas.

Visual prognosis in retinoblastoma patients with multimodality treatments: Visual Prognosis in Retinoblastoma Patients

PurposeThis study evaluates factors associated with globe preservation and long-term visual outcomes according to clinical characteristics and treatment modalities in intraocular retinoblastoma patients. DesignA retrospective review of medical records enrolled intraocular retinoblastoma patients between January 1, 2007, and June 30, 2020. Methods•Setting: Single-centered.•Patient or study population: Intraocular retinoblastoma patients treated at Ramathibodi Hospital, Bangkok, Thailand.•Main outcome measure: A statistically significant factor associated with visual prognosis corresponds to baseline characteristics, staging, anatomical involvement, and multimodal treatments. Results86 patients (124 eyes) were included. Median age of disease bilaterality onset was significantly younger than unilaterality. Three-quarters of patients were in advanced stages (groups D or E in either ICRB or IIRC and up to cT2a from AJCC). Globe salvage rate was 54.0 % (67 eyes). ICRB Groups D-E, IIRC Groups D-E, and AJCC cT2a and more advanced stages are the globe removal-associated independent risk factors (adjusted odds ratio [AOR] [95 % CI] = 7.40 [1.36, 40.09], 8.33 [1.55, 44.73], 14.73 [1.55, 139.79], respectively). Compared to other classification, IIRC provided the highest statistical correlation from univariate analysis. IIRC Groups A-C is a good visual acuity-associated independent risk factor (AOR [95 % CI] = 4.64 [1.05, 20.43] and P = 0.042). Macular involvement is a worse visual acuity-associated independent risk factor (AOR [95 % CI] = 0.14 [0.02, 0.82] and P = 0.03). Systemic chemotherapy (86.29 %) is the mainstay treatment in our study and is the only good visual outcome-associated treatment. Subgroup analysis of all eyes receiving systemic chemotherapy reveals statistically significant preventive factors for globe removal for tumor staging with ICRB and IIRC groups A-C and AJCC stages cT1a–cT1b (odds ratio [95 % CI] = 15.75 [4.38, 56.65], 15.67 [4.34, 56.53], 9.97 [2.75, 36.18], respectively; P=<0.001) and prevents the worse visual outcome in these stages, (odds ratios [95 % CI] = 4.57 [1.28, 16.27], 6.61 [1.74, 25.11], and 7.50 [1.86, 30.16], respectively; P =< 0.05). ConclusionsAll recent advanced clinical stagings are globe removal outcome-associated independent risk factors. IIRC staging is the best visual results predictor. IIRC Groups A-C were associated with a good visual outcome. Macular involvement tumors are strongly associated with poor visual outcome, despite successful globe preservation from multimodality treatment. Systemic chemotherapy remains a crucial globe-saving treatment and prevents worse vision–especially in ICRB and IIRC Groups A-C and AJCC stage cT1a-cT1b.

Systemic Metastase in Late Management of Group D Retinoblastoma: A Case Report

Background: Retinoblastoma (RB) is a common malignancy that affects children and is fatal if left untreated. This case report aims to raise awareness the importance of starting therapy immediately in RB patients. Case presentation: A girl aged 1 year 9 months, came with complaints that her left eye (LE) appeared white for 2 weeks. Anterior segment examination was normal. On funduscopic examination, optic nerve was difficult to evaluate, covered by a mass, multiple mass scars on the retina, a size of &gt; 6 mm at the posterior pole, and vitreous seeding. Ultrasound examination and CT scan showed an intraocular mass with calcification. The patient was diagnosed with group D intraocular LE RB and was planned for enucleation but was postponed due to cost constraints. The patient came back after 1 year and was diagnosed with extraocular LE RB stage IVB. Conclusion: Early diagnosis without adequate therapy leads to tumor spread and reduces patient survival.