Follow-up report of fundus findings of tuberous sclerosis-associated retinal astrocytoma of two siblings.

A late adolescent with tuberous sclerosis (TS) presented with reduced vision in one eye to our tertiary care university hospital 4 years ago. Fundus examination revealed multiple retinal astrocytic hamartomas (RAHs) in both eyes. His younger sibling, who also had TS, was found to have RAH on retinal screening. The swept-source optical coherence tomography (SS-OCT) findings were typical of RAH. We further noted that some of the RAH lesions showed segmental whitening of the outer walls of the arterioles, which traversed through them. The segmental whitening may suggest the enveloping of normal retinal vessels by the tumour. En-face and B-scan SS-OCT angiography of patients with TS showed vascularity within the tumour. The vessels within the tumour appeared to be in continuity with the retinal vasculature. Both siblings were reviewed annually. At the end of 4 years, there was no change in visual acuity, tumour size, number, vascularity and behaviour.

[Isolated primary vitreoretinal lymphoma (case report)]. / Izolirovannaya pervichnaya vitreoretinal'naya limfoma (klinicheskoe nablyudenie).

This case report presents the diagnostic features of isolated primary intraocular lymphoma, which was initially misdiagnosed as neovascular age-related macular degeneration. A comprehensive examination using ultrasound, optical coherence tomography, and fundus autofluorescence revealed changes characteristic of vitreoretinal lymphoma. Molecular genetic analysis of the vitreous body showed the presence of a MYD88 gene mutation and B-cell clonality by immunoglobulin heavy chain (IGH) gene rearrangement tests, which confirmed the diagnosis.

Retinoblastoma - A comprehensive review, update and recent advances.

Retinoblastoma is the most common pediatric ocular malignancy. It is triggered by a biallelic mutation in the RB1 gene or MYCN oncogene amplification. Retinoblastomas can be unilateral (60%-70%) or bilateral (30%-40%); bilateral tumors are always heritable and present at an earlier age as compared to unilateral ones (18-24 months vs. 36 months in India). High prevalence rates, delayed presentation, and inaccessibility to healthcare lead to worse outcomes in developing countries. The past few decades have seen a paradigm change in the treatment of retinoblastomas, shifting from enucleation and external beam radiotherapy to less aggressive modalities for eye salvage. Multimodality treatment is now the standard of care and includes intraarterial or intravenous chemotherapy along with focal consolidation therapies such as transpupillary thermotherapy, cryotherapy, and laser photocoagulation. Intravitreal and intracameral chemotherapy can help in controlling intraocular seeds. Advanced extraocular or metastatic tumors still have a poor prognosis. Genetic testing, counseling, and screening of at-risk family members must be incorporated as essential parts of management. A better understanding of the genetics and molecular basis of retinoblastoma has opened up the path for potential targeted therapy in the future. Novel recent advances such as liquid biopsy, prenatal diagnosis, prognostic biomarkers, tylectomy, and chemoplaque point to promising future directions.

Strategies to improve diagnosis and access to treatment of retinoblastoma in low- and middle-income countries: A systematic review.

Retinoblastoma, the most common intraocular tumor in childhood, still faces challenges in diagnosis and treatment, particularly in low- and middle-income countries. Identifying strategies to improve the time to diagnosis and access to treatment is crucial to enhance survival rates and preserve ocular health. We conducted a systematic review to identify interventions that have demonstrated potential in addressing these challenges. We performed a comprehensive search across databases until March 2023. Out of the studies reviewed, 21 met the inclusion criteria and were categorized into five main areas: surveillance strategies, genetic counseling, education, public assistance, and international partnership. Despite the obstacles faced, the initiatives identified in this review present acts toward improving the time to diagnosis and access to treatment for retinoblastoma. Based on the extracted data, we propose a comprehensive chain of initiatives. We firmly believe that implementing this chain of initiatives can lead to improved clinical outcomes for retinoblastoma patients.

Recent progress in retinoblastoma: Pathogenesis, presentation, diagnosis and management.

Retinoblastoma, the primary ocular malignancy in pediatric patients, poses a substantial threat to mortality without prompt and effective management. The prognosis for survival and preservation of visual acuity hinges upon the disease severity at the time of initial diagnosis. Notably, retinoblastoma has played a crucial role in unraveling the genetic foundations of oncogenesis. The process of tumorigenesis commonly begins with the occurrence of biallelic mutation in the RB1 tumor suppressor gene, which is then followed by a cascade of genetic and epigenetic alterations that correspond to the clinical stage and pathological features of the tumor. The RB1 gene, recognized as a tumor suppressor, encodes the retinoblastoma protein, which plays a vital role in governing cellular replication through interactions with E2F transcription factors and chromatin remodeling proteins. The diagnosis and treatment of retinoblastoma necessitate consideration of numerous factors, including disease staging, germline mutation status, family psychosocial factors, and the resources available within the institution. This review has systematically compiled and categorized the latest developments in the diagnosis and treatment of retinoblastoma which enhanced the quality of care for this pediatric malignancy.

Swept-source optical coherence tomography angiography findings in a case of primary vitreoretinal lymphoma over a three-year follow-up.

BACKGROUND: Vitreoretinal lymphoma (VRL) still represents a diagnostic challenge for retinal specialists. Early diagnosis and treatment are critical for a better prognosis. Several diagnostic tools have proven helpful in the identification of VRL abnormalities. However, swept-source OCT angiography (SS-OCT-A) findings and their long-term follow-up are yet to be explored. CASE PRESENTATION: a 42-year-old man presented with blurred vision in his left eye for 2 weeks. He denied any systemic symptoms. A multimodal imaging examination was performed, raising the clinical suspicion of VRL and guiding the ensuing diagnostic procedures. The patient underwent treatment and at the last FU visit three years later, no disease signs were present on fundus examination, nor on oncologic evaluation. Some novel SS-OCT-A features were identified, and uncommonly reported findings were examined over a long-term follow-up. At baseline multiple hyperreflective alterations were detected on the enface outer retina slabs and choriocapillary analysis revealed low reflectance areas in the foveal and parafoveal areas. One month after the first presentation, multiple hyperreflective retinal lesions in a vertical shape were detected on OCT which appeared on midretinal slabs of enface SS-OCT-A as hyperreflective spots mainly located near second-order retinal vessels. These alterations remarkably reduced after treatment. CONCLUSION: SS-OCT-A may be a useful imaging technique in the detection of VRL, providing ophthalmologists additional findings that assist the diagnosis and follow-up of this disease. This may prove useful for a more timely and precise diagnosis, prompt therapy, and treatment response monitoring. The original aspects found in this case may provide grounds for future studies, ultimately fostering a better understanding of the disease.

Vasoproliferative Tumor Secondary to Sarcoidosis-Associated Intermediate Uveitis.

We report the visual and clinical outcomes of a middle-aged woman who presented with exudative retinal detachment (ERD) secondary to a vasoproliferative tumor (VPT) in an eye with sarcoidosis-associated intermediate uveitis. A 55-year-old woman previously diagnosed with sarcoidosis presented with decreased vision in the left eye (LE). Visual acuity in the LE was counting fingers. She had active vitritis, and a peripheral retinal vascular mass was noted in the superotemporal periphery. The mass was associated with ERD involving the posterior pole. The patient was managed with systemic and intravitreal steroids, and cyclosporine was subsequently added as a steroid-sparing agent. Because of recurrence of ERD, the patient underwent pars plana vitrectomy, and cryotherapy and laser photocoagulation were applied to the VPT. Two months postoperatively, visual acuity in the LE improved to 6/10. There was marked regression of the VPT and total resolution of the ERD. In conclusion, we report a favorable visual and clinical outcome in a patient with VPT-associated ERD who responded to a combination of medical therapy and surgical intervention. VPT may lead to different remote complications, so timely diagnosis of these tumors and proper management of their complications is warranted.

Low expression of NR1D1 and NR2E3 is associated with advanced features of retinoblastoma.

PURPOSE: To investigate the expression of nuclear receptor subfamily 1 group D member 1 (NR1D1) and nuclear receptor subfamily 2 group E Member 3 (NR2E3) in retinoblastoma (RB) and their correlation with the clinical and pathological features of RB. METHODS: Immunohistochemical (IHC) assays were performed to detect and evaluate the expression levels of NR1D1 and NR2E3 in paraffin-embedded tissue samples. The relationship between the expression levels and clinicopathological characteristics of RB patients was analyzed using the χ2 test or Fisher exact test. RESULTS: A total of 51 RB patients were involved in this research. The expression levels of NR1D1 (P = 0.004) and NR2E3 (P = 0.024) were significantly lower in RB tumor tissues than in normal retina. The expression levels of NR1D1 and NR2E3 were less positive in RB patients with advanced stages (P = 0.007, P = 0.015), choroidal infiltration (P = 0.003, P = 0.029), and optic nerve infiltration (P = 0.036, P = 0.003). In addition, a low expression level of NR2E3 was associated with high-risk pathology (P = 0.025) and necrosis (P = 0.035) of RB tissues. CONCLUSION: The expression levels of NR1D1 and NR2E3 were decreased in RB and closely associated with the clinical stage and high invasion of the disease. These findings provide new insights into the mechanism of RB progression and suggest that NR1D1 and NR2E3 could be potential targets for treatment strategies.

Multifocal Unilateral Orange Fundus Tumors in a Young Man.

A 38-year-old man had an asymptomatic, orange, macular choroidal mass with macular choroidal folds and a retinal pigment epithelial detachment in the right eye and a second orange mass nasal to the optic disc also in the right eye. What would you do next?

Circulating Tumor DNA Posttreatment Measurements and Clinical Correlates in Retinoblastoma.

Importance: Plasma measurements of RB1 circulating tumor DNA (ctDNA) after completion of treatment may be associated with the development of metastases in patients with retinoblastoma. Objective: To determine if the absence of previously detectable plasma ctDNA is associated with metastasis-free survival in patients with a minimum of 1 year follow-up after treatment of retinoblastoma. Design, Setting, and Participants: This cohort study was conducted from June 2019 to September 2023. Patients with retinoblastoma who had measurable ctDNA levels at diagnosis and had repeated ctDNA measurements after ocular treatment (enucleation or intra-arterial chemotherapy) with a minimum of 1 year of follow-up (mean [SD], 28.2 [10.3] months) were included in the study. Patients were recruited from a single-center, tertiary cancer hospital. Exposure: Memorial Sloan Kettering's New York State-approved gene test, which interrogates 129 known cancer genes (called ACCESS), was performed on plasma samples before and after ocular treatments. All exons of the RB1 gene are included in the test and listed as ctDNA in this article. Main Outcomes and Measures: Plasma ctDNA level before treatment, after completion of ocular treatment, and development or absence of metastases. Results: A total of 24 patients (mean [SD] age, 20.7 [17.1] months; 15 female [62.5%]) were included in the study. None of the 23 patients who had a measurable ctDNA level and then no detectable ctDNA level after completion of ocular treatment developed metastases with a minimum of 1 year of follow-up. One patient had persistent measurable ctDNA after initial treatment and developed metastases. Conclusion and Relevance: Patients with retinoblastoma who had a measurable ctDNA level at diagnosis did not develop metastases if the plasma ctDNA level became unrecordable after ocular treatment; 1 patient who had persistent measurable ctDNA after treatment did develop metastasis.

Captains on call: A qualitative investigation of an intervention to support children with retinoblastoma undergoing regular eye examinations.

BACKGROUND: Retinoblastoma is a rare childhood ophthalmic cancer that requires frequent eye examinations under anaesthesia and painful or distressing procedures. This can cause significant anxiety for children and their families. OBJECTIVE: We evaluated a Starlight Children's Foundation programme, 'Captains on Call', at the Queensland Children's Hospital, which aims to provide positive distraction and reduce stress, anxiety and pain during the perioperative journey for children in the retinoblastoma treatment pathway. This study examined the impact of the programme on the perioperative experience of the children and their families, using a qualitative design. METHODS: This study was conducted in a paediatric operating suite at a tertiary-level children's hospital in Australia. We interviewed a parent from 20 families (from a cohort of 40 families, including 44 children), whose children received treatment or screening for retinoblastoma, focusing on the programme's impact on the child and family at various stages during the perioperative journey. We undertook a thematic analysis of transcribed interviews. RESULTS: We identified two themes, each with two sub-themes: (1) the programme positively contributed to the overall treatment journey, by addressing different needs at different times, and helping to reframe a traumatic medical experience, and (2), the programme supported the whole family unit by empowering children through play, and adopting a family systems approach which recognised the impact of cancer treatment on the whole family. CONCLUSION: This study highlights the value of the Captains on Call programme in supporting children with retinoblastoma and their families during perioperative visits. The Captains, particularly as non-medicalised professionals in a healthcare setting, built trust and rapport with the children through play over repeated episodes of care. The interprofessional collaborative approach with a reflective cycle of practice extended it beyond a programme providing simple distraction. Other retinoblastoma services may benefit from implementing a similar approach.

Impact of RB1 gene screening from blood collected on a single day from 411 family members of 113 Retinoblastoma survivors in India.

OBJECTIVES: To analyse the profile and implication of genetic testing in a cohort of retinoblastoma (RB) patients and their families conducted on a single day during World Retinoblastoma Awareness Week 2017. METHODS: Retrospective analysis of blood samples were collected from 411 subjects, including 113 probands at a camp organised for RB awareness and were analysed for RB1 mutations by Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). If germline mutations were detected, the parents and siblings of the proband were tested for the same mutation. RESULTS: Germline RB1 mutations were identified in 61/113(54%) probands with a mutation detection rate of 96% (47/49) and 22% (14/64) for bilateral and unilateral RB, respectively. Ten novel pathogenic mutations were identified. Splice mutation was most common (31%) followed by nonsense mutation (26%). The mean age at RB diagnosis was significantly lower in patients having germline RB1 mutation (mean 10.7 months ±2.5) compared to those without (mean 27.2 months ±6.5) (p = <0.0001). Parental transmission of the mutant allele was detected in 15/61(25%) cases of which 11(18%) parents were unaffected indicating incomplete penetrance. The origin of the variant allele was both paternal (n = 7) and maternal (n = 4) wherein 5 were bilateral and 6 unilateral. CONCLUSIONS: The detection of a germline mutation impacts the proband and family members due to its implications on change in prognosis, frequency of subsequent evaluations, screening for ocular and non-ocular cancers, and surveillance of family and future progeny.

The Potential of Aqueous Humor Sampling in Diagnosis, Prognosis, and Treatment of Retinoblastoma.

Retinoblastoma (RB) is a rare malignant tumor that arises in the developing retina in one or both eyes of children. Pathogenic variants of the RB1 tumor suppressor gene drive the majority of germline and sporadic RB tumors. Considering the risk of tumor spread, the biopsy of RB tumor tissue is contraindicated. Advancement of chemotherapy has led to preservation of more eye globes. However, this has reduced access to tumor material from enucleation specimens. Recently, liquid biopsy of aqueous humor (AH) has advanced the RB tumor- or eye-specific genetic analysis. In particular, nucleic acid analysis of AH demonstrates the genomic copy number profiles and RB1 pathogenic variants akin to that of enucleated RB eye tissue. This advance reduces the previous limitation that genetic assessment of the primary tumor could be done only after enucleation of the eye. Additionally, nucleic acid evaluation of AH allows the exploration of the genomic landscape of RB tumors at diagnosis and during and after treatment. This review explores how AH sampling and AH nucleic acid analysis in RB patients assist in diagnosis, prognosis, and comprehending the pathophysiology of RB, which will ultimately benefit individualized treatment decisions to carefully manage this ocular cancer in children.

Cell-Free DNA Extraction of Vitreous and Aqueous Humor Specimens for Diagnosis and Monitoring of Vitreoretinal Lymphoma.

Vitreoretinal lymphoma (VRL) represents an aggressive lymphoma, often categorized as primary central nervous system diffuse large B-cell lymphoma. To diagnose VRL, specimens such as vitreous humor and, more recently, aqueous humor are collected. Diagnostic testing for VRL on these specimens includes cytology, flow cytometry, and molecular testing. However, both cytopathology and flow cytometry, along with molecular testing using cellular DNA, necessitate intact whole cells. The challenge lies in the fact that vitreous and aqueous humor typically have low cellularity, and many cells get destroyed during collection, storage, and processing. Moreover, these specimens pose additional difficulties for molecular testing due to the high viscosity of vitreous humor and the low volume of both vitreous and aqueous humor. This study proposes a method for extracting cell-free DNA from vitreous and aqueous specimens. This approach complements the extraction of cellular DNA or allows the cellular component of these specimens to be utilized for other diagnostic methods, including cytology and flow cytometry.

Three-Dimensional Ultrasound Imaging of Retinoblastoma and Its Correlation With Pathology.

BACKGROUND AND OBJECTIVE: Monitoring the response of retinoblastoma to globe-salvaging therapies is based on subjective assessments of changes determined by fundoscopy, ultrasound, and optical coherence tomography. Advances in organ-preserving therapies have increased the need for objective, quantitative estimates of tumor response to treatment. Primary tumor volume is a metric that can be objectively determined as a surrogate measure of treatment response. PATIENTS AND METHODS: We evaluated the correlation of objective, quantitative estimates of tumor volume made with two-dimensional (2D) and three-dimensional (3D) ultrasound with gold standard pathological tumor volumes derived by analysis of enucleation specimens. RESULTS: Twelve eyes in 12 patients undergoing primary enucleation were evaluated by 2D and 3D ultrasound during ophthalmic examination under anesthesia prior to enucleation. 2D- and 3D-ultra-sound measurements of tumor volume were both strongly correlated with pathological estimates of tumor volume (r = 0.69, P = 0.018; and r = 0.66, P = 0.027, respectively). CONCLUSIONS: 2D- and 3D-ultrasound measurements of retinoblastoma primary tumor volume are highly correlated with pathological estimates. 3D measurements are easy to perform with volumetric probes and consider the irregular morphology of the tumor. Further study should be undertaken to evaluate the performance of these metrics as surrogate markers of tumor response to treatment. [Ophthalmic Surg Lasers Imaging Retina 2024;55:136-140.].

Retinoblastoma treatment in a Brazilian population. Presentation and long-term results.

INTRODUCTION: Retinoblastoma is a malignant tumor with a high cure potential when proper therapy is used. The purpose of this paper is to report the clinical features and outcomes of patients with retinoblastoma who were treated with a combination of local and systemic chemotherapy-based protocols. METHOD: We retrospectively studied patients treated with systemic chemotherapy plus local treatment between 2003 and 2015 with a follow-up ≥2 years. We correlated clinical and pathological characteristics with decimal visual acuity (VA) and death. RESULTS: Among 119 patients, 60% had unilateral disease (UNI), and 52% were male. The median presentation age was 19.5 months, 10% had a positive family history, and the most frequent sign was leukocoria (68.8%). Advanced disease was more frequent in eyes with UNI (98.4%) than in eyes with bilateral retinoblastoma (BIL: 55.3%). Enucleation was performed in 97% of UNI eyes and in 55.8% of BIL eyes. The overall globe salvage was 26.6%, 44.25% of BIL eyes. Bilateral enucleation was required in 5%. High-risk pathologic features occurred in 50% and 37% of eyes enucleated without and with neoadjuvant chemotherapy, respectively. High-risk features were related to the presence of goniosynechiae in the pathologic specimen and were more frequent in children younger than 10 months or older than 40 months. Extraocular disease was present in 5% of patients, and the death rate related to metastasis of the tumor was 8%. The final VA was ≥ 0.7 in 72.8% and ≥0.1 in 91% of BIL patients. CONCLUSIONS: Treatment of retinoblastoma with conservative systemic-based chemotherapy was associated with an excellent survival rate (92%). Albeit the low overall globe salvage rate, in BIL patients, approximately half the eyes were conserved, and a satisfactory functional visual result was achieved The evaluated protocol is an important treatment option, especially in developing countries.

Familial retinoblastoma: variations in clinical presentation and management based on paternal versus maternal inheritance.

BACKGROUND: Several studies have demonstrated the effect of parent-of-origin on retinoblastoma penetrance. The purpose of the current study was to assess differences in clinical presentation of paternally versus maternally inherited retinoblastoma. METHODS: The clinical records of all children with familial retinoblastoma treated on a tertiary Ocular Oncology Service between December 1975 and May 2020 were reviewed retrospectively. RESULTS: A total of 179 patients with familial retinoblastoma were included. Paternal inheritance (PI) was identified in 109 (61%) patients and maternal inheritance (MI) in 70 patients (39%). A comparison (PI vs MI) revealed PI patients were older at presentation (57.2 vs 24.4 months [P = 0.002]) with no difference in patient sex (53% females vs 57% males [P = 0.606]) or number of family members affected (3.2 vs 3.0 family members [P = 0.255]). PI patients had more advanced classification according to the International Classification of Retinoblastoma (ICRB) (group E: 31% vs 8% [P = 0.012)] and greater largest tumor in basal diameter (9.0 vs 6.2 mm [P = 0.040]) and thickness (5.6 vs 4.0 mm [P = 0.038]); they were also less likely to be located in the macula (40% vs 60% [P = 0.004]). There was no difference in tumor laterality (69% vs 64% bilaterality [P = 0.530]). PI patients required enucleation more frequently (34% vs 14% [P = 0.007]). There was no difference in need for plaque radiotherapy (P = 0.86) or chemotherapy (P = 0.85). One PI patient developed metastatic retinoblastoma, and there were no retinoblastoma-related deaths. CONCLUSIONS: Patients with paternally inherited retinoblastoma presented at an older age, with larger, more peripheral tumors and more advanced ICRB group, and were more likely to require enucleation compared to those with maternally inherited retinoblastoma.

The association between race and age of diagnosis of retinoblastoma in United States children.

PURPOSE: To explore the associations between race and retinoblastoma diagnosis in United States children. METHODS: In this analytical nonconcurrent cohort study, we used 1988-2018 data from the Surveillance, Epidemiology, and End-Results (SEER) database. Children ages 0-17 with retinoblastoma were included (n = 758); those with missing data were excluded (n = 11; final cohort: n = 747). The exposure variable was race (White, Black, Asian/Pacific Islanders, American Indian/Alaska Native), and the outcome variable was diagnosis of retinoblastoma before versus after 2 years of age. Covariates included sex, rural-urban continuum, ethnicity, decade of diagnosis, and laterality of disease. Unadjusted and adjusted logistic regression analyses were performed to calculate odds ratios and 95% confidence intervals. RESULTS: No statistically significant association was found between racial/ethnic groups (OR = 0.61-0.99; P = 0.92) and age at diagnosis (OR = 0.86; P = 0.66). Females were more likely to be diagnosed earlier than males (OR = 0.62; 95% CI, 0.44-0.88; P = 0.042). No association was found between urban versus rural subjects (OR = 1.02; 95% CI, 0.60-1.75) or between decades (OR = 0.81; 95% CI, 0.54-1.22 and OR 0.96; 95% CI, 0.62-1.47). CONCLUSIONS: We found no statistically significant difference between racial/ethnic groups for diagnosis of children with retinoblastoma after 2 years of age. Future studies could explore why females are more likely than males to be diagnosed before 2 years of age.