Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3.

BACKGROUND: GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors. METHODS: The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed. RESULTS: We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated. CONCLUSION: Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.

Conservative treatment using laser diode and systemic chemotherapy for early-stage bilateral retinoblastoma: A 14-year prospective cohort study.

BACKGROUND: Solid evidence of the safety and effectiveness of retinoblastoma (RB) conservative treatment using thermotherapy and systemic chemotherapy with long-term follow-up is scarce, especially in low-resource countries. AIMS: This study examined the outcomes of this treatment and associated predictors in Vietnam to strengthen the current RB treatment protocol focusing on preserving eye and vision in low-resource settings. METHODS AND RESULTS: A prospective cohort study was conducted at Ho Chi Minh City Eye Hospital in Vietnam from 2005 to 2019. All eligible patients with bilateral RB (one eye already removed and another eye classified as group A or B) and without previous treatment were recruited. All patients received thermotherapy and six cycles of systemic three-agent chemotherapy repeated every 4 weeks. A standardized questionnaire was used to collect information on study participants' age, symptoms, tumor characteristics, treatment, and outcomes. Among 50 eyes of all 50 patients with a median age of 9 (4-20) months, 34 eyes were in group B (68%). The median follow-up time was 60 (60-84) months. All 139 preserved tumors regressed mostly to type 4 (70.4%) and type 3 (23.7%) scars. Kaplan-Meier analysis found the overall globe-salvage rate at 5 years of 91.9% (95% CI: 80.1%-97.7%). Most eyes (41/50, 82%, 95% CI: 69.2%-90.2%) had a final visual acuity ≥0.1. The visual acuity is higher when tumors regressed to a type 4 scar (p = .007, AOR = 8.098, 95% CI: 1.79-36.53) which also shows less enucleation than a type 3 scar (p = .002, AOR = 0.06, 95% CI: 0.01-0.37%). Gender effect on visual acuity after treatment was significant and may be due to discrimination. No major complications were recorded. CONCLUSION: Conservative treatment of early-stage RB is safe and effective. Long-term, thorough follow-ups of patients post-treatment are needed. The regression patterns of scars could be a useful indicator of treatment failure.

Scleral ectasia stabilization following intra-arterial chemotherapy in an eye with recurrent retinoblastoma.

Purpose: To report a case of recurrent retinoblastoma following transpupillary thermotherapy (TTT) with development of scleral ectasia, as well as their successful treatment with intra-arterial chemotherapy. Observations: A 15-month-old girl with bilateral retinoblastoma presented with recurrent retinoblastoma and associated scleral ectasia with concern for extraocular extension after receiving multiple round of systemic chemotherapy and TTT. Given her negative systemic evaluation, decision was made to pursue intra-arterial chemotherapy. After completion of six rounds of 3-agent intra-arterial chemotherapy, the recurrent retinoblastoma had completely regressed and the scleral ectasia had improved and fibrosed. Conclusions and importance: The sclera is classically viewed as hyperthermy-resistant to TTT. Here, we describe scleral ectasia due to aggressive TTT with recurrence of the retinoblastoma. Our treatment with intra-arterial chemotherapy not only caused complete regression of the recurrent retinoblastoma, but it also contributed to the stabilization and improvement of the weakened scleral.

Epidemiological and Clinical Presentation of Retinoblastoma among Nepalese Children in 2019.

Suresh B.K. RasailyObjectives Retinoblastoma (RB) is rare but potentially fatal if left untreated. This study aimed to evaluate the epidemiological profile, clinical manifestation, classification, and affordability of RB treatment among Nepalese children in the year 2019. Materials and Method A multicentric, multiethnic hospital-based cross-sectional study after ethical approval from the National Health Research Council was conducted from January 2019 to December 2019 by incorporating ophthalmologists all over the nation. Twenty-seven RB centers were selected. All the RB presented in the RB centers either newly diagnosed or ongoing treatment consented to the study were included and failed to consent for the study, RB survivors were excluded from the study. Data based on demographic profile, clinical manifestation, ethnical and geographical distribution, and treatment received were collected in the customized Google Form. Each case was classified at the time of diagnosis as per the International Classification of Retinoblastoma groups and different treatment modalities offered as per grouping and staging. The affordability of treatment was calculated using a catastrophic approach. Statistical Analysis Data were entered into Microsoft Excel 2010 and analyzed using Statistical Package for Social Sciences version 20. Result A total of 34 RB cases, 21 (61.76%) in ongoing treatment group and 13 (38.2%) in newly diagnosed group presented in the RB centers. Out of total, 32 (64.7%) had unilateral and 12 (35.3%) cases had bilateral involvement. The majority of patients was from Province 1 (35.3%) and belonged to the upper caste (38.2%). Leukocoria was the most common presentation (73.9%) followed by proptosis, red eye, and phthisis bulbi. More than 75% patients presented at advanced group D (54%) and E (21%) and stage 0 (90%). More than 90% of patients received systemic chemotherapy, and 42.6% received transpupillary thermotherapy. The average cost of RB treatment was estimated to be 521% of the nonfood expense of the family which is unaffordable to almost all cases (100%). Conclusion Leukocoria is the most common mode of clinical presentation in both unilateral and bilateral RBs. Early diagnosis and appropriate treatment are key to success for saving life, sight, and eye. However, community awareness programs against RB, active referral networks, and the establishment of chemotherapy centers with trained human resources are needed to reduce loss of life, sight, and eye.

Massive Uveal Relapse of Retinoblastoma Presumed to Be Choroidal Tumorous Involvement: Case Series.

We report the choroidal and ciliary body invasion by retinoblastoma (RB) in a salvaged eye after complete and successful primary treatment. Case 1: A 25-month-old boy was referred due to group B RB lesions based on the International Classification of RB (ICRB; groups A-E) in the right eye (OD). His left eye (OS) was enucleated because of advanced group E RB. After 47 months of uneventful follow-up (F/U), a new lesion recurred and was treated with transpupillary thermotherapy. Four months later, a fast-growing pigmented subretinal mass was detected that was treated by brachytherapy with the apical dose of 80 Gy. Three weeks later, the lesion regressed completely, and no recurrence happened after 6 years of F/U. Case 2: A 4-month-old girl with a deletion in chromosome 13 was referred for bilateral RB. OD was enucleated because of unresponsive RB and anterior segment involvement. In OS, group B lesions had multiple recurrences after systemic chemotherapy. After a while, a single mass appeared in the nasal periphery which was controlled well with brachytherapy. Four months later, AC involvement was controlled with IAC, intravitreal, and intracameral chemotherapy, but posterior synechia and cataract appeared later. One year after the last treatment, UBM showed a ring-shaped ciliary body mass. Her parents refused enucleation again, and she received intravenous chemotherapy. Two years later, magnetic resonance imaging showed orbital and optic canal involvement with a deformed globe. In conclusion, RB recurrence can appear as local choroidal and ciliary body involvement even after a time of complete remission. The role of B-scan and UBM in early diagnosis and successful treatment is valuable.

Retinoblastoma: present scenario and future challenges.

With an average incidence of 1 in every 18,000 live births, retinoblastoma is a rare type of intraocular tumour found to affect patients during their early childhood. It is curable if diagnosed at earlier stages but can become life-threateningly malignant if not treated timely. With no racial or gender predisposition, or even environmental factors known to have been involved in the incidence of the disease, retinoblastoma is often considered a clinical success story in pediatric oncology. The survival rate in highly developed countries is higher than 95% and they have achieved this because of the advancement in the development of diagnostics and treatment techniques. This includes developing the already existing techniques like chemotherapy and embarking on new strategies like enucleation, thermotherapy, cryotherapy, etc. Early diagnosis, studies on the etiopathogenesis and genetics of the disease are the need of the hour for improving the survival rates. According to the Knudson hypothesis, also known as the two hit hypothesis, two hits on the retinoblastoma susceptibility (RB) gene is often considered as the initiating event in the development of the disease. Studies on the molecular basis of the disease have also led to deciphering the downstream events and thus in the discovery of biomarkers and related targeted therapies. Furthermore, improvements in molecular biology techniques enhanced the development of efficient methods for early diagnosis, genetic counseling, and prevention of the disease. In this review, we discuss the genetic and molecular features of retinoblastoma with a special emphasis on the mutation leading to the dysregulation of key signaling pathways involved in cell proliferation, DNA repair, and cellular plasticity. Also, we describe the classification, clinical and epidemiological relevance of the disease, with an emphasis on both the traditional and innovative treatments to tackle retinoblastoma. Video Abstract.

Ocular Survival Following Intravitreal Melphalan as Adjuvant Treatment for Vitreous Retinoblastoma Seeding.

Purpose: To evaluate the efficacy of intravitreal chemotherapy for vitreous seeding in patients with retinoblastoma (Rb). Design: Retrospective, single-arm cohort study. Methods: This study was conducted at a tertiary eye center. Between 2013 and 2021, 27 patients (27 eyes) with vitreous Rb receiving adjuvant intravitreal melphalan (IVM) as secondary/salvage treatment in one eye were included. Patients who were unable to follow-up or treated elsewhere were excluded. Survival analysis was performed to assess the incidence of enucleation in the melphalan-treated group, as well as in bilateral cases with eyes receiving melphalan and those receiving standard treatment, consisting of chemotherapy, thermotherapy, and enucleation according to the disease stage. Results: The median (interquartile range) follow-up time was 65 months (range, 34-83 months). Seventeen patients (63%) had bilateral disease. Sixteen eyes (59%) were saved. The Kaplan-Meier survival estimates for eyes receiving melphalan were 100% at 1 year (95% confidence interval [CI]:11.2-14.3), 75% (95% CI:14.2-48.9) at 3 years, and 50% at 5 years. Melphalan-treated patients with bilateral disease showed a significantly higher number of saved eyes than the standard treatment group (P=0.002). Tumor recurrence was the primary cause of enucleation, accounting for 36% of the cases. In the vitreous hemorrhage group, the odds of enucleation were 13 times higher (95% CI:1.04-165.28) than in the group without this condition. Conclusion: IVM is an effective treatment option for vitreous seeds. After 3 years of follow-up, the estimated survival rate for saved eyes decreased, and vitreous hemorrhage significantly increased the likelihood of enucleation. Further studies are required to determine the precise effects of IVM.

Translational screening platform to evaluate chemotherapy in combination with focal therapy for retinoblastoma.

Retinoblastoma is the most common pediatric eye cancer. It is currently treated with a limited number of drugs, adapted from other pediatric cancer treatments. Drug toxicity and relapse of the disease warrant new therapeutic strategies for these young patients. In this study, we developed a robust tumoroid-based platform to test chemotherapeutic agents in combination with focal therapy (thermotherapy) - a treatment option widely used in clinical practice - in accordance with clinically relevant trial protocols. The model consists of matrix-embedded tumoroids that retain retinoblastoma features and respond to repeated chemotherapeutic drug exposure similarly to advanced clinical cases. Moreover, the screening platform includes a diode laser (810 nm, 0.3 W) to selectively heat the tumoroids, combined with an on-line system to monitor the intratumoral and surrounding temperatures. This allows the reproduction of the clinical settings of thermotherapy and combined chemothermotherapy treatments. When testing the two main drugs currently used in clinics to treat retinoblastoma in our model, we observed results similar to those clinically obtained, validating the utility of the model. This screening platform is the first system to accurately reproduce clinically relevant treatment methods and should lead to the identification of more efficient drugs to treat retinoblastoma.

The association between maternal nutrient intake during pregnancy and the risk of sporadic unilateral retinoblastoma among offspring.

Previous studies have associated maternal diet during pregnancy with the development of sporadic unilateral retinoblastoma (RB), but few studies have focused on the role of individual nutrients. The aim of this study is to investigate the association between maternal nutrient intake during pregnancy and the development of sporadic unilateral RB in the offspring. A modified food frequency questionnaire, with additional questions on supplement use, was completed via a phone interview. Cases were recruited from hospitals and controls were comprised of friends and relatives of the patient without a history of cancer. Overall, 168 sporadic unilateral RB cases and 145 controls were included in case-control study. We performed logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CI), adjusting for child's age, child's sex, parental race/ethnicity, maternal education, total calorie intake during pregnancy, maternal age at birth, maternal smoking during pregnancy, pre-pregnancy body mass index, maternal weight gain during pregnancy, paternal age at birth, and maternal multivitamin use in the year before pregnancy. In the adjusted model, the interquartile (IQR) increase in vitamin A intake, which was measured in retinol activity equivalent (RAE; OR: 0.64, 95 % CI: 0.46-0.90), and vitamin D intake (OR: 0.62, 95 % CI: 0.42-0.91) significantly reduced the risk of sporadic unilateral RB. These findings suggest that a higher intake of vitamins A and D can be a protective factor for sporadic unilateral RB. Further analyses in consideration of multi-exposures such as parental occupational exposures are warranted to discover the complex etiology of sporadic unilateral RB. In addition, the role of nutritional epigenetics for how maternal nutrient intake influences the risk of sporadic unilateral RB in the offspring still needs to be explored.

The predictive capacity of in vitro preclinical models to evaluate drugs for the treatment of retinoblastoma.

Retinoblastoma is a rare childhood cancer of the eye. Of the small number of drugs are used to treat retinoblastoma, all have been repurposed from drugs developed for other conditions. In order to find drugs or drug combinations better suited to the improved treatment of retinoblastoma, reliable predictive models are required, which facilitate the challenging transition from in vitro studies to clinical trials. In this review, the research performed to date on the development of 2D and 3D in vitro models for retinoblastoma is presented. Most of this research was undertaken with a view to better biological understanding of retinoblastoma, and we discuss the potential for these models to be applied to drug screening. Future research directions for streamlined drug discovery are considered and evaluated, and many promising avenues identified.

Follow-up of retinoblastoma using RetCam fluorescein angiography and correlation with clinical findings.

PURPOSE: To report RetCam fluorescein angiographic (FA) changes and correlation with clinical findings in the follow-up of retinoblastoma (RB) after frontline intravenous chemotherapy and other treatments. METHODS: Patients having RB who underwent post-treatment RetCam fundus photography and FA under general anesthesia between February 2020 and February 2022 were retrospectively analyzed. RESULTS: 78 eyes of 70 patients with RB were included. In 55 (70.5%) eyes with type 1, 2 or 3 regression patterns, the main tumor started to show hyperfluorescence in arterial phase in 24 eyes (43.6%), in early venous phase in 24 (43.6%) eyes, and in late venous phase in 7 (12.7%) eyes. Of thirty-six (46.2%) eyes with chorioretinal scars developing after focal treatments (cryotherapy and transpupillary thermotherapy), window defects and visible choroidal vessels were found in all eyes, scleral staining in 10 (27.8%), and gliosis on scar tissue in 8 (22.2%). Vitreous seeds showed hyperfluorescence if they were calcified (6 eyes, 7.7%) and hypofluorescence if non-calcified (11 eyes, 14.1%). Retrohyaloid seeds (11 eyes, 14.1%) were hypo/isofluorescent while subretinal seeds (6 eyes, 7.7%) were hyperfluorescent. Leakage from peripheral retinal vessels was detected in 14 (17.9%) eyes and non-perfusion in 6 (7.7%) eyes. CONCLUSION: RetCam wide-angle FA is useful to evaluate the tumor and associated vascular and retinal changes after treatment in RB. Regressed tumors demonstrate later fluorescein uptake in venous phases. Fluorescein angiographic changes in chorioretinal scars include window defects, visibility of choroidal vessels, scleral staining, and leakage from vessels. Retinal vascular leakage and peripheral non-perfusion can be seen in eyes with regressed stable tumors.

Intravitreal Carboplatin as Salvage Treatment for Progressive Vitreous Disease in Retinoblastoma: A Phase I Clinical Trial.

PURPOSE: To determine the safety and toxicity profile of intravitreal carboplatin as salvage treatment for retinoblastoma with vitreous disease. DESIGN: Single-institution, interventional prospective clinical trial. PARTICIPANTS: Patients with progressive or recurrent vitreous seeds after completion of primary treatment for intraocular retinoblastoma. METHODS: Eligible eyes received an intravitreal injection of carboplatin every 14 to 21 days with simultaneous focal therapy (laser, thermotherapy, and brachytherapy) provided at the discretion of the ocular oncologist. The evaluation with examination under anesthesia, ultrasound biomicroscopy, and electroretinography (ERG) were performed before each injection to assess for tumor response and drug-related toxicity. A serious adverse event resulted in dose recalculation and ultimately early closure of the study. MAIN OUTCOME MEASURES: Regression pattern of vitreous disease and incidence of dose-limiting toxicities. RESULTS: Four patients were enrolled at an initial dose of 0.3 mg. Complete regression of vitreous seeds was noted in all patients after 5, 2, 2, and 1 injections (respectively). Two patients developed recurrent vitreous disease at 3 and 25 months after complete regression and ultimately required enucleation. A serious adverse event occurred in 1 patient who developed acute vision loss with extinguished ERG response 72 hours after the second injection; ultimately, this eye developed a cataract and required enucleation. After temporary suspension and dose modification, 3 patients were enrolled at an injection dose of 3 µg and treated with a total of 5, 2, and 1 injections, respectively. Complete regression of vitreous disease was not achieved in any patient though ERG amplitudes remained stable. After removal from protocol, all 3 patients had a complete response to intravitreal melphalan. Concern for dose escalation and further toxicity in the setting of an effective and safe alternative (melphalan) led to the termination of the study. CONCLUSIONS: Intravitreal carboplatin may be effective in treating progressive vitreous seeding at higher doses, but permanent retinal toxicity was observed. Other alternative agents should be considered. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Caring for a child with retinoblastoma: Experience of Ethiopian parents.

OBJECTIVE: This study explored the lived experience of parents of children with retinoblastoma. DESIGN AND METHOD: A phenomenological qualitative study design was used, and a purposive sampling technique to recruit parents of children with retinoblastoma. Semi-structured interviews were conducted to document the lived experience of participants, who were asked to narrate their experiences caring for a child with retinoblastoma, thinking back to the day they learned about their child's condition, as well as their thoughts about the future. The interviews were conducted in Amharic and Oromo language, and audio recordings were transcribed and translated to English. Data were analyzed using thematic analysis. RESULTS: Thirteen parents (seven mothers, six fathers) participated in the study. Collectively, the children of the participants represented all the stages of the retinoblastoma journey (i.e., diagnosis, treatment, remission, and recurrence). Five major themes emerged from the thematic data analysis: (a) reactions when learning the child's condition; (b) receiving health care; (c) costs of caregiving; (d) support; and (e) uncertainties. CONCLUSION: The lived experiences of parents of children with retinoblastoma revealed a significant mental health and psychosocial burden. The sources of mental distress were found to be complex and varied. Holistic care for retinoblastoma should include programs that address the biopsychosocial needs of caregivers.

Primary Subretinal Seeding in Retinoblastoma: Clinical Presentation and Treatment Outcomes.

Introduction: The aim of this study was to describe the clinical features and treatment outcomes of primary subretinal seeding (SRS) in patients with intraocular retinoblastoma (RB). Methods: Descriptive analysis of primary SRS in 47 patients (50 eyes) with RB was performed. Results: Mean age was 19 months (range, 2-72 months), and 55% (n = 26) of the subjects were male. At presentation, the SRS involved two or more quadrants in 88% of eyes. Most seeds appeared yellowish gray (66%) and round to oval in shape (48%). Two-thirds of SRS were seen posterior to the equator and within 5 mm from the main tumor. Associated features included subretinal fluid in 50 eyes (100%), total retinal detachment in 28 eyes (56%), and vitreous seeds in 20 eyes (40%). Treatment included intravenous chemotherapy (IVC) (n = 47; 94%), enucleation (n = 2; 4%), and intra-arterial chemotherapy (n = 1; 2%). SRS treatment included adjunct use of focal transpupillary thermotherapy and/or cryotherapy (n = 20; 40%). Retinal tumor control was achieved in 36 eyes (76%) with 32 eyes (78%) showing a type 3 regression pattern, while SRS completely regressed in 24 (48%) eyes, partially in 15 (30%) and worsened in 2 (4%) eyes. Over a mean follow-up of 30 months (range, 3-68 months), SRS recurrence was noted in 12 eyes (29%), globe salvage was achieved in 39 eyes (78%), and 1 (4%) patient died of presumed metastasis. Conclusion: Primary SRS pose a therapeutic challenge during RB treatment. The SRS responds moderately to systemic IVC, with one-third cases showing SRS recurrence and one-fifth ultimately requiring enucleation.

Retinal and optic nerve relapse in retinoblastoma secondary to epiretinal and epipapillary vitreous seeds implantation documented by optical coherence tomography.

BACKGROUND: Retinal retinoblastoma growth phenotypes can be endophytic, exophytic, diffuse infiltrating or anterior diffuse. Herein, we describe a novel tumor growth pattern in two patients. MATERIAL AND METHODS: Imaging with spectral-domain optical coherence tomography (SD-OCT). RESULTS: Both cases were diagnosed with unilateral group D retinoblastoma treated with first-line or bridge intra-arterial chemotherapy (IAC). Case 1 had a new intravitreal/epiretinal relapse 3 months after brachytherapy and intravitreal chemotherapy. SD-OCT showed a disruption of the inner limiting membrane (INL) underneath a parapapillary epiretinal seed. The intravitreal/epiretinal disease completely regressed with intravitreal melphalan. Three months later, an isolated intraretinal growth was documented on SD-OCT at the site of previously INL disruption, which was treated by thermotherapy. He remained disease-free at 1-year follow-up with 0.6 visual acuity. Case 2 was seen 2 months after treatment interruption due to the COVID-19 pandemic. Fundus examination showed a massive intravitreal/epipapillary invasion completely obscuring the papilla. Salvage treatment of this seeing eye consisted of combined intra-arterial and intravitreal melphalan and topotecan injections. An infraclinical papillary regrowth 4 months later was treated with additional IAC. Six months later, enucleation was performed due to an infraclinical papillary relapse with suspicion of intralaminar invasion. Histopathology showed retrolaminar optic nerve invasion with tumor-free surgical section. The child received four cycles of adjuvant chemotherapy and remained disease-free at 1-year follow-up. CONCLUSION: Epiretinal/epipapillary vitreous seeding can be the source of a secondary intraretinal/optic nerve head relapse. SD-OCT is instrumental to follow such cases. Enucleation remains the safest option if secondary optic nerve invasion is suspected.

The clinical diagnostic value of plasma miR-592 and miR-217-3p levels in retinoblastoma.

Background: This study was designed to investigate the abnormal expression of plasma miR-592 and miR-217-3p in retinoblastoma (Rb) and explore the clinical diagnostic value of their expression levels for Rb. Methods: The 100 Rb patients who came to Nanchang Hongdu Hospital of Traditional Chinese Medicine from January 2018 to January 2019 were selected as the Rb group, and 100 healthy patients who came to the physical examination centre during the same period were selected as the control group. Real-time fluorescence quantitative PCR (qRT-PCR) was used to detect the expression levels of plasma miR-592 and miR-217-3p in all subjects; analyse the relationship between plasma miR-592 and miR-217-3p levels and the clinicopathological characteristics of Rb. Pearson correlation analysis evaluated the relationship between plasma miR-592 and miR-217-3p levels and overall survival. Results: Plasma levels of miR-592 and miR-217-3p in the Rb group were significantly higher than those in the control group (p<0.0001), and the expression of miR-592 was significantly correlated with family genetic history (p 0.0001), tumour bias (p=0.0081), lymph node metastasis (p=0.0048) and pathological grade (p=0.0025), and the expression of miR-217-3p was significantly related to family genetic history (p 0.0001), optic nerve infiltration (p 0.0001), lymph node metastasis (p=0.0090), and pathological grade (p 0.0001). The high expression of miR-592 and miR-217-3p presents a more serious pathological manifestation of Rb, and the overall survival of patients is significantly shortened with the increase of miR-592 (r=-0.2276, p=0.0052) and miR-217-3p levels (r=-0.6461, p 0.0001). Conclusions: and miR-217-3p are highly expressed in the plasma of Rb patients, and their elevated levels present severe pathological manifestations of Rb and shortened overall survival, which is expected to become biomarkers for clinical diagnosis of Rb.

Cyst-like recurrence of retinoblastoma diagnosed by multimodal imaging.

Purpose: To illustrate the diagnosis and management of an atypical, cyst-like recurrence of retinoblastoma. Observations: A 4-month-old boy was diagnosed with Group B retinoblastoma in the right eye, consisting of a 10 x 9 × 3.6 mm retinal tumor temporal to the macula. He was treated with one session of intra-arterial ophthalmic artery chemotherapy using melphalan, followed by three sessions of diode laser transpupillary thermotherapy (TTT), after which complete tumor regression was achieved. 45 weeks after initial treatment, a cystic lesion was detected adjacent to superior margin of the regressed tumor scar. The differential diagnosis included pigment epithelial detachment, retinal gliosis, secondary retinoschisis, and local tumor recurrence. Multimodal imaging including OCT angiography confirmed the diagnosis of local recurrence manifesting as a vascularized cyst-like lesion. Two additional sessions of TTT achieved sustained tumor regression through 16 months of additional follow-up. Conclusions and Importance: Recurrence of retinoblastoma following chemotherapy typically manifests as enlargement of a previously regressed tumor, or seeding into the vitreous or subretinal space. An unusual cyst-like recurrence of retinoblastoma at the margin of a previously regressed tumor was diagnosed by multimodal imaging. Focal diode laser transpupillary thermotherapy was curative.

Legumain affects the PI3K/AKT tumor progression pathway in retinoblastoma.

Known as a common malignant tumor among children, retinoblastoma (RB) is highly malignant and has poor prognosis, damages children's vision and degrades quality of life. To identify a potential molecular mechanism of RB, we conducted this study on legumain (LGMN), which is highly expressed in multiple tumors. In this study, we found that LGMN was significantly upregulated in RB cells and was positively expressed in RB tissues. We confirmed that LGMN overexpression (LGMN-OE) can promote RB cell proliferation and inhibit cell apoptosis through CCK8 experiments and flow cytometry. In addition, real-time quantitative polymerase chain reaction (RT‒qPCR) and Western blot results showed that LGMN-OE could regulate the expression of epithelial-mesenchymal transformation-related genes and proteins, related to tumor invasion and metastasis. Moreover, after LGMN knock down, the result was the opposite., RNA sequence analysis revealed 1159 differentially expressed genes between LGMN-OE and the negative control (NCOE), of which 564 were upregulated and 595 were downregulated. The first 10 genes were verified by RT‒qPCR based on P value and fold change. Interestingly, we found that LGMN could regulate the expression of recoverin (RCVRN)through a gene responsible for cancer-related retinopathy. We also screened and verified that LGMN partially activated the PI3K/AKT pathway in RB. Furthermore, we evaluated the effect of legumain inhibitors (e.g., esomeprazole) on RB, and the results suggest that esomeprazole may provide a reference for the clinical adjuvant treatment of RB. In conclusion, legumain can serve as an attractive target for RB therapy and hopefully provide new insights and ideas for the development of targeted drugs and precise personalized clinical therapy.

Retinoblastoma in Adults: Clinical Features, Gene Mutations and Treatment Outcomes: A Study of Six Cases.

Purpose: To report six Asian adult patients with retinoblastoma (RB). Design: Retrospective and observational small case series. Participants: Six patients with a white dome-shaped tumor of the retina were evaluated from May 10, 1995, to September 10, 2021. Main Outcome Measures: Initial tumor and associated fundus features, pathology, gene mutation, treatment, tumor course on follow-up, and salvage globe outcome. Results: The six affected Asian patients consisted of three men and three women. The mean age at the time of diagnosis was 36.5 years (median: 31 years, range: 20-55 years). All patients were unilateral. In all cases, the tumors were white, dome-shaped, with full-thickness retinal involvement, and mushroom-like protrusions into the vitreous cavity. The mean tumor thickness measured by ultrasonography was 4.5 mm (median: 3.2 mm, range: 3.2-6.8 mm). Associated characteristic symptoms included dilated retinal feeding artery and draining vein (100%), surrounding subretinal infiltration (83%), exudative retinal detachment (83%), and vitreous seeds (67%). Local tumor resection was performed in three patients, I-125 plaque brachytherapy combined with transpupillary thermotherapy (TTT) and intravitreous injection of melphalan (combination treatment) in one patient, I-125 plaque brachytherapy in two patients, and enucleation in one (20%) patient. RB1 gene testing was carried out on four patients and pathological diagnosis on five patients. Genetic analysis revealed that the RB1 mutation was a mosaic c.709dupG (p.Glu237GlyfsTer4) duplication in one patient, a mosaic c.763C>T(p.Arg255Ter) mutation in another patient, while the remaining two patients were RB1 negative. At the end of the follow-up, none of the patients had developed tumor-related metastasis or died. The findings were consistent in all patients who had an adequate follow-up. This study focused on this rare lesion to distinguish it from other intraocular white lesions in adults, including choroidal osteoma, vitreoretinal lymphoma, and retinal capillary hemangioma, all of which are different clinical entities. Conclusion: In adults, RB is typically a white, full-thickness retinal mass that is unilateral, often combining with retinal feeding vessels, subretinal infiltration, and vitreous seeds. Genetic studies on adult-onset RB are essential and still require elucidation. Despite RB being a malignant tumor, patient survival was minimally affected.

Dual-Target Multifunctional Superparamagnetic Cationic Nanoliposomes for Multimodal Imaging-Guided Synergistic Photothermal/Photodynamic Therapy of Retinoblastoma.

Background: With high malignancy, retinoblastoma (RB) commonly occurs in infants and has incredible difficulty with the early diagnosis. In recent years, the integrated theranostics of multimodal imaging-guided therapy has shown promising potential for oncotherapy. Purpose: To prepare folate/magnetic dual-target theranostic nanoparticles integrating with US/PA/MR imaging and the synergistic photothermal treatment (PTT)/photodynamic treatment (PDT) for the early diagnosis and timely intervention of RB cancer. Methods: Folate/magnetic dual-target cationic nanoliposomes (CN) encapsulating indocyanine green (ICG) and perfluorohexane(PFH)(FA-CN-PFH-ICG-Fe3O4, FCNPIFE) were synthesized and characterized. Then we evaluated their targeting ability, US/PA/MR imaging effects, and the efficacy of synergistic PTT/PDT in vitro and in vivo. Finally, we explored the mechanism of synergistic PTT/PDT in Y79 tumor-bearing mice. Results: FCNPIFEs were stable and uniform in 7 days. They showed excellent in vitro targeting ability with a 95.29% cell uptake rate. The in vitro US/PA/MRI imaging results of FCNPIFEs showed a concentration-dependent manner, and in vitro therapy FCNPIFEs exhibited an enhanced anticancer efficacy against Y79 cells. In vivo analysis confirmed that FCNPIFEs enabled a targeted synergistic PTT/PDT under US/PA/MR imaging guidance in Y79 tumor-bearing mice, achieving almost complete tumor regression. Immunofluorescence results displayed weaker fluorescence intensity compared with other single treatment groups, confirming that PTT/PDT synergistic therapy effect was achieved by down-regulating the expression of HIF-1α and HSP70. Conclusion: FCNPIFEs were verified as promising theranostic nanoliposomes for RB oncotherapy and showed great potential in clinical application.