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Retinoblastoma stands as a paradigm of success in treating malignancies among pediatric patients. Over recent decades, the approach to managing retinoblastoma has evolved significantly, transitioning from the preservation of patients' lives to the preservation of eyes and vision while minimizing treatment-related complications. Chemotherapy, administered through diverse routes, has solidified its role as the cornerstone of retinoblastoma treatment. In addition to intravenous chemotherapy (IVC), alternative administration routes, including intraarterial (IAC), intravitreal, intracameral, and periocular delivery, have emerged as promising modalities for retinoblastoma management. Numerous studies have demonstrated outstanding outcomes, achieving nearly 100% salvage rates for eyes classified under groups A-C. However, for advanced intraocular retinoblastoma (groups D and E eyes), IAC appears to offer superior local control rates compared to IVC. Intravitreal injection of chemotherapeutic agents, when administered in a controlled and secure manner, holds promise in averting the need for enucleation and radiotherapy in advanced retinoblastoma cases presenting with vitreous seeds. The optimal chemotherapy strategy remains meticulously tailored based on numerous factors. This review provides a comprehensive update on chemotherapy across various routes, encompassing key considerations, dosages, administration methods, treatment outcomes, and potential complications. Furthermore, it explores emerging potential treatments and outlines future directions aimed at enhancing treatment outcomes.
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Antineoplásicos , Neoplasias da Retina , Retinoblastoma , Retinoblastoma/tratamento farmacológico , Humanos , Neoplasias da Retina/tratamento farmacológico , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Injeções IntravítreasRESUMO
MYCN proto-oncogene, bHLH transcription factor (MYCN) amplification is associated with aggressive retinoblastoma (RB) and neuroblastoma (NB) cancer recurrence that is resistant to chemotherapies. Therefore, there is an urgent need to identify new therapeutic tools. This study aimed to evaluate the potential repurposing of ceftriaxone for the treatment of MYCN-amplified RB and NB, based on the clinical observations that the drug was serendipitously found to decrease the volume of the MYCN-driven RB subtype. Using patient-derived tumor organoids and tumor cell lines, we demonstrated that ceftriaxone is a potent and selective growth inhibitor targeting MYCN-driven RB and NB cells. Profiling of drug-induced transcriptomic changes, cell-cycle progression, and apoptotic death indicated cell-cycle arrest and death of drug-treated MYCN-amplified tumor cells. Drug target identification, using an affinity-based proteomic and molecular docking approach, and functional studies of the target proteins revealed that ceftriaxone targeted DEAD-box helicase 3 X-linked (DDX3X), thereby inhibiting translation in MYCN-amplified tumors but not in MYCN-nonamplified cells. The data suggest the feasibility of repurposing ceftriaxone as an anticancer drug and provide insights into the mechanism of drug action, highlighting DDX3X as a potential target for treating MYCN-driven tumors.
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Neuroblastoma , Neoplasias da Retina , Retinoblastoma , Humanos , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Ceftriaxona , Retinoblastoma/tratamento farmacológico , Retinoblastoma/genética , Simulação de Acoplamento Molecular , Proteômica , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Neuroblastoma/metabolismo , Linhagem Celular Tumoral , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Regulação Neoplásica da Expressão GênicaRESUMO
PURPOSE: To describe the clinical presentation and treatment outcomes of children who received a diagnosis of retinoblastoma in 2017 throughout Asia. DESIGN: Multinational, prospective study including treatment-naïve patients in Asia who received a diagnosis of retinoblastoma in 2017 and were followed up thereafter. PARTICIPANTS: A total of 2112 patients (2797 eyes) from 96 retinoblastoma treatment centers in 33 Asian countries. INTERVENTIONS: Chemotherapy, radiotherapy, enucleation, and orbital exenteration. MAIN OUTCOME MEASURES: Enucleation and death. RESULTS: Within the cohort, 1021 patients (48%) were from South Asia (SA), 503 patients (24%) were from East Asia (EA), 310 patients (15%) were from Southeast Asia (SEA), 218 patients (10%) were from West Asia (WA), and 60 patients (3%) were from Central Asia (CA). Mean age at presentation was 27 months (median, 23 months; range, < 1-261 months). The cohort included 1195 male patients (57%) and 917 female patients (43%). The most common presenting symptoms were leukocoria (72%) and strabismus (13%). Using the American Joint Committee on Cancer Staging Manual, Eighth Edition, classification, tumors were staged as cT1 (n = 441 [16%]), cT2 (n = 951 [34%]), cT3 (n = 1136 [41%]), cT4 (n = 267 [10%]), N1 (n = 48 [2%]), and M1 (n = 129 [6%]) at presentation. Retinoblastoma was treated with intravenous chemotherapy in 1450 eyes (52%) and 857 eyes (31%) underwent primary enucleation. Three-year Kaplan-Meier estimates for enucleation and death were 33% and 13% for CA, 18% and 4% for EA, 27% and 15% for SA, 32% and 22% for SEA, and 20% and 11% for WA (P < 0.0001 and P < 0.0001), respectively. CONCLUSIONS: At the conclusion of this study, significant heterogeneity was found in treatment outcomes of retinoblastoma among the regions of Asia. East Asia displayed better outcomes with higher rates of globe and life salvage, whereas Southeast Asia showed poorer outcomes compared with the rest of Asia. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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Neoplasias da Retina , Retinoblastoma , Criança , Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Retinoblastoma/diagnóstico , Retinoblastoma/epidemiologia , Retinoblastoma/terapia , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/epidemiologia , Neoplasias da Retina/terapia , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do Tratamento , Ásia/epidemiologia , Estudos Retrospectivos , Enucleação OcularRESUMO
BACKGROUND: Recurrence of retinoblastoma (RB) following chemoreduction is common and is often managed with local (intra-arterial/intravitreal) chemotherapy. However, some tumors are resistant to even local administration of maximum feasible drug dosages, or effective tumor control and globe preservation may be achieved at the cost of vision loss due to drug-induced retinal toxicity. The aim of this study was to identify drugs with improved antitumor activity and more favorable retinal toxicity profiles via screening of potentially repurposable FDA-approved drugs in patient-derived tumor organoids. METHODS: Genomic profiling of five RB organoids and the corresponding parental tissues was performed. RB organoids were screened with 133 FDA-approved drugs, and candidate drugs were selected based on cytotoxicity and potency. RNA sequencing was conducted to generate a drug signature from RB organoids, and the effects of drugs on cell cycle progression and proliferative tumor cone restriction were examined. Drug toxicity was assessed with human embryonic stem cell-derived normal retinal organoids. The efficacy/toxicity profiles of candidate drugs were compared with those of drugs in clinical use. RESULTS: RB organoids maintained the genomic features of the parental tumors. Sunitinib was identified as highly cytotoxic against both classical RB1-deficient and novel MYCN-amplified RB organoids and inhibited proliferation while inducing differentiation in RB. Sunitinib was a more effective suppressor of proliferative tumor cones in RB organoids and had lower toxicity in normal retinal organoids than either melphalan or topotecan. CONCLUSION: The efficacy and retinal toxicity profiles of sunitinib suggest that it could potentially be repurposed for local chemotherapy of RB.
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Antineoplásicos , Neoplasias da Retina , Retinoblastoma , Humanos , Retinoblastoma/tratamento farmacológico , Retinoblastoma/genética , Retinoblastoma/patologia , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/genética , Neoplasias da Retina/patologia , Organoides/metabolismoRESUMO
Purpose: To report a case of endogenous panophthalmitis in a patient with COVID-19 during treatment in an Intensive Care Unit. Observation: A 64-year-old woman with COVID-19 and Salmonella septicemia presented with decreased visual acuity, ocular pain, and proptosis in her right eye after treatment with favipiravir, intravenous dexamethasone, and ceftriaxone. An ocular examination of her right eye revealed periorbital tenderness, exophthalmos, and corneal haze. The ultrasonography showed a subretinal abscess. Her right eye lost light perception vision and underwent enucleation. Microbiologic evaluation of the enucleated right eye was negative for organisms. Conclusions and importance: Patents with COVID-19 may develop severe ocular involvement after COVID-19 due to a generalized reduction in immunity. Comorbidities and intensive care unit treatments can predispose COVID-19 patients to endogenous panophthalmitis.
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Purpose: The study aimed to generate a stepwise method to reduce the workload of full-scale RB1 sequencing for germline mutation screening in retinoblastoma (RB) patients. The implication of germline mutation in tumor focality was also determined in this study. Methods: A stepwise method was created on the basis of "hotspot" exons analyzed using data on germline RB1 mutation in the RB1-Leiden Open Variation Database and then tested for mutation screening in the blood DNA of 42 patients with RB. The method was compared with the clinical next-generation sequencing (NGS) panel in terms of sequencing outcomes. The germline RB1 mutation was examined in association with multifocality in RB. Results: Germline RB1 mutation was identified in 61% of all bilateral cases in the first step of the 3 stepwise method and in 78% and 89% for the two and three steps combined, respectively. NGS detected a mosaic variant of RB1 that was not detected by the first two steps and increased the sensitivity from 78% to 83%. Analysis of the relationship between mutation status and tumor focality indicated that multifocality in RB was dependent on germline RB1 mutation, confirming a higher tendency to have a germline RB1 mutation in patients with multifocal RB. Conclusions: A 3 stepwise method reduces the workload needed for sequencing of the RB1 for bilateral cases. NGS outweighs conventional sequencing in terms of the identification of germline mosaic variants. Multifocal tumors in RB may be used to presume germline mutation. Translational Relevance: The presence of "hotspot" exons of germline RB1 mutation in bilateral cases facilitates a mutation screening. However, when genetic testing is not available, multifocality in RB regardless of tumor laterality is predictive of germline RB1 mutation.
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Neoplasias da Retina , Retinoblastoma , DNA , Análise Mutacional de DNA , Mutação em Linhagem Germinativa , Humanos , Mutação/genética , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/genética , Neoplasias da Retina/patologia , Retinoblastoma/diagnóstico , Retinoblastoma/genética , Retinoblastoma/patologia , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
OBJECTIVE: To investigate in a large global sample of patients with retinoblastoma whether sex predilection exists for this childhood eye cancer. METHODS: A cross-sectional analysis including 4351 treatment-naive retinoblastoma patients from 153 countries who presented to 278 treatment centers across the world in 2017. The sex ratio (male/female) in the sample was compared to the sex ratio at birth by means of a two-sided proportions test at global level, country economic grouping, continent, and for selected countries. RESULTS: For the entire sample, the mean retinoblastoma sex ratio, 1.20, was higher than the weighted global sex ratio at birth, 1.07 (p < 0.001). Analysis at economic grouping, continent, and country-level demonstrated differences in the sex ratio in the sample compared to the ratio at birth in lower-middle-income countries (n = 1940), 1.23 vs. 1.07 (p = 0.019); Asia (n = 2276), 1.28 vs. 1.06 (p < 0.001); and India (n = 558), 1.52 vs. 1.11 (p = 0.008). Sensitivity analysis, excluding data from India, showed that differences remained significant for the remaining sample (χ2 = 6.925, corrected p = 0.025) and for Asia (χ2 = 5.084, corrected p = 0.036). Excluding data from Asia, differences for the remaining sample were nonsignificant (χ2 = 2.205, p = 0.14). CONCLUSIONS: No proof of sex predilection in retinoblastoma was found in the present study, which is estimated to include over half of new retinoblastoma patients worldwide in 2017. A high male to female ratio in Asian countries, India in specific, which may have had an impact on global-level analysis, is likely due to gender discrimination in access to care in these countries, rather than a biological difference between sexes.
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Neoplasias da Retina , Retinoblastoma , Criança , Estudos Transversais , Países em Desenvolvimento , Feminino , Humanos , Índia/epidemiologia , Recém-Nascido , Masculino , Neoplasias da Retina/epidemiologia , Retinoblastoma/epidemiologiaRESUMO
BACKGROUND: The aim of this study was to report 2 cases of pulmonary air embolism developing several hours after choroidal melanoma endoresection without the use of air infusion during the surgery, with fatality in 1 patient. METHODS: The method of this study was case report. PARTICIPANTS: Two patients with large choroidal melanomas who collapsed several hours after endoresection without air infusion as a result of pulmonary air embolism. RESULTS: A 72-year-old man collapsed 4 h and 30 min after endoresection without air infusion. Computerized tomography angiography confirmed air embolism. The patient died after 86 min of cardiopulmonary resuscitation. A 41-year-old woman collapsed 5 h and 30 min after endoresection, performed without air infusion and with close monitoring, which included right internal jugular vein catheterization intraoperatively. Transthoracic and transesophageal echography, performed preoperatively, intraoperatively, and postoperatively, revealed air embolism only after collapse occurred. Imaging showed the embolism to be biventricular because of patent foramen ovale. The patient was treated promptly with extracorporeal membrane oxygenation and mechanical ventilation, which resulted in a full recovery. CONCLUSIONS: Air embolism can develop after endoresection for choroidal melanoma, despite avoiding air infusion. Further studies are needed to understand how this occurs. Special measures are indicated to detect this complication and to treat it promptly and effectively.
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Purpose: MYCNOS (MYCN opposite strand) is co-amplified with MYCN in pediatric cancers, including retinoblastoma. MYCNOS encodes several RNA variants whose functions have not been elucidated in retinoblastoma. Thus, we attempted to identify MYCNOS variants in retinoblastoma and aimed to decipher the role of MYCNOS variant 1 (MYCNOS1) on the activity of MYCN-amplified retinoblastoma. Methods: The profiles of MYCNOS variants and MYCN status were determined in 17 retinoblastoma tissues, cell lines, retinas, and retinal organoids. A functional study of MYCNOS1 expression was conducted in patient-derived tumor cells and in retinoblastoma cell lines via short hairpin RNA-mediated gene silencing. We carried out MYCN expression, cell viability, cell cycle, apoptosis, soft agar colony formation, and transwell assays to examine the role of MYCNOS1 in MYCN and cell behaviors. We analyzed a transcriptome of MYCN-amplified retinoblastoma cells deficient for MYCNOS1 and, finally, tested the responses of these cells to chemotherapeutic agents. Results: Expression of MYCNOS1 was associated with the expression and copy number of MYCN. Knockdown of MYCNOS1 caused instability of the MYCN protein, leading to cell cycle arrest and impaired proliferation and chemotaxis-directed migration in MYCN-amplified retinoblastoma cells in which RB1 was intact. MYCNOS1 expression was associated with gene signatures of photoreceptor cells and epithelial-mesenchymal transition. MYCNOS1 silencing enhanced the response of retinoblastoma cells to topotecan but not carboplatin. Conclusions: MYCNOS1 supports progression of retinoblastoma. Inhibition of MYCNOS1 expression may be necessary to suppress MYCN activity when treating MYCN-amplified cancers without RB1 mutation.
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Genes do Retinoblastoma/genética , Proteína Proto-Oncogênica N-Myc/genética , Proteínas de Neoplasias/genética , RNA Longo não Codificante/genética , Neoplasias da Retina/genética , Retinoblastoma/genética , Linhagem Celular , Criança , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Masculino , Mutação/genética , RNA Interferente Pequeno/genéticaRESUMO
PURPOSE: To investigate the clinical presentations and outcomes of retinoblastoma in relation to the advent of new multimodal treatments in Thailand. Patients and Methods. Retrospective case series. We evaluated the clinical presentation, staging, details of treatment, and treatment outcomes of retinoblastoma patients who were treated at Ramathibodi Hospital, Bangkok, Thailand, between January 1, 2007, and December 31, 2018. The log-rank test was used to explore clinical characteristics and treatment modalities that affected globe salvage and survival curves. RESULTS: This study included 124 eyes of 81 patients with retinoblastoma. Forty-three patients (53.1%) had bilateral retinoblastoma. The median age at diagnosis was 8 months (range, 1-48 months). Of 124 eyes, 9 eyes (7.3%) had extraocular retinoblastoma and 115 eyes (92.7%) had intraocular retinoblastoma, which were classified by the International Classification of Retinoblastoma (ICRB) as group A, 4 eyes (3.5%); group B, 19 eyes (16.5%); group C, 6 eyes (5.2%); group D, 31 eyes (27%); and group E, 56 eyes (47.8%). Treatment included systemic chemotherapy, intra-arterial chemotherapy, ruthenium-106 plaque brachytherapy, external beam radiation therapy, cryotherapy, transpupillary thermotherapy, subtenon chemotherapy, and intravitreal chemotherapy. At the median follow-up period of 38.4 months (range, 0.2-148.2 months), the overall globe salvage rate of intraocular retinoblastoma was 51.7%. For unilateral retinoblastoma, globe salvage rate was 37.5% (group B, 100%; group C, 100%; group D, 50%; and group E, 18.8%). For bilateral intraocular retinoblastoma, the globe salvage rate was 57.8% (group A, 100 %; group B, 94.4%; group C, 100%; group D, 64.7%; and group E, 28.2%). The overall survival rate was 93.8%. CONCLUSIONS: Recent advanced treatment modalities have improved the probability of globe salvage. However, enucleation remains an important life-saving intervention in many advanced cases.
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Retinoblastoma is a retinal cancer that is initiated in response to biallelic loss of RB1 in almost all cases, together with other genetic/epigenetic changes culminating in the development of cancer. RB1 deficiency makes the retinoblastoma cell-of-origin extremely susceptible to cancerous transformation, and the tumor cell-of-origin appears to depend on the developmental stage and species. These are important to establish reliable preclinical models to study the disease and develop therapies. Although retinoblastoma is the most curable pediatric cancer with a high survival rate, advanced tumors limit globe salvage and are often associated with high-risk histopathological features predictive of dissemination. The advent of chemotherapy has improved treatment outcomes, which is effective for globe preservation with new routes of targeted drug delivery. However, molecularly targeted therapeutics with more effectiveness and less toxicity are needed. Here, we review the current knowledge concerning retinoblastoma genesis with particular attention to the genomic and transcriptomic landscapes with correlations to clinicopathological characteristics, as well as the retinoblastoma cell-of-origin and current disease models. We further discuss current treatments, clinicopathological correlations, which assist in guiding treatment and may facilitate globe preservation, and finally we discuss targeted therapeutics for future treatments.
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PURPOSE: To study the safety and efficacy of intra-arterial chemotherapy (IAC) as a treatment for intraocular retinoblastoma in Thailand. DESIGN: Retrospective, interventional case series. METHODS: In this study, IAC was performed as primary or secondary treatment for patients with intraocular retinoblastoma using melphalan with or without additional topotecan or carboplatin. Survival rate, globe salvage rate, and treatment complications were recorded and analyzed. RESULTS: Of 27 eyes of 26 patients with retinoblastoma, 7 (26%) had IAC as primary treatment and 20 (74%) had IAC as secondary treatment. The eyes were classified by International Classification of Retinoblastoma (ICRB) as group B (n = 3, 11%), group C (n = 1, 4%), group D (n = 12, 44%), and group E (n = 11, 41%). Catheterization was successful in 75 (94%) of 80 sessions. The median number of IAC sessions was 3 (range, 1-7). At a mean follow-up of 32 months (range, 3-95 months), the overall globe salvage rate was 52%, with 100% in groups B and C, 75% in group D, and 9% in group E. Complications of IAC included occlusive vasculopathy (n = 4, 15%), vitreous hemorrhage (n = 3, 11%), retinal artery precipitation (n = 2, 7%), strabismus (n = 2, 7%), and transient ischemic attack (n = 1, 4%). The overall survival rate was 96% (n = 25). CONCLUSIONS: Our experience suggests that IAC is a safe and effective treatment for patients with ICRB group B, C, D, and some group E retinoblastoma. Careful patient selection and experienced surgeons are critical for achieving the best treatment outcome.
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Carboplatina/administração & dosagem , Melfalan/administração & dosagem , Retina/diagnóstico por imagem , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Centros de Atenção Terciária , Topotecan/administração & dosagem , Adolescente , Adulto , Cateterismo Periférico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Humanos , Incidência , Infusões Intra-Arteriais , Masculino , Pessoa de Meia-Idade , Oftalmoscopia , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/epidemiologia , Retinoblastoma/diagnóstico , Retinoblastoma/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Tailândia/epidemiologia , Fatores de Tempo , Ultrassonografia , Adulto JovemRESUMO
PURPOSE: There is no established therapy for exudative-hemorrhagic complications in primary retinal arteriolar macroaneurysm (RAM). METHODS: Retrospective multicenter interventional study of anti-vascular endothelial growth factor in symptomatic RAMs. Central macular thickness in µm and best-corrected visual acuity in logMar were correlated with the RAM size and distance to the macula. Statistical analyses were performed using paired comparisons and Pearson correlation. RESULTS: Thirty-two eyes (32 patients) were treated with a mean of 2.7 injections over a mean follow-up of 16.6 months. Initial best-corrected visual acuity correlated with the RAM size and distance to the macula (P = 0.02). Central macular thickness decreased by 131,180, and 211 µm at 1, 2, and 3 months after the first injection (P < 0.001). Best-corrected visual acuity improved by 0.47 and 0.38 Early Treatment Diabetic Retinopathy Study lines at 2 and 3 months (P = 0.005). Anti-vascular endothelial growth factor response correlated with the RAM size (P = 0.04) and the distance to the macula (P = 0.009). CONCLUSION: Symptomatic RAMs can be treated successfully with anti-vascular endothelial growth factor injections, leading to a decrease in macular edema.
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Bevacizumab/administração & dosagem , Macula Lutea/patologia , Ranibizumab/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Macroaneurisma Arterial Retiniano/tratamento farmacológico , Acuidade Visual , Inibidores da Angiogênese/administração & dosagem , Quimioterapia Combinada , Exsudatos e Transudatos , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Humanos , Injeções Intravítreas , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Macroaneurisma Arterial Retiniano/diagnóstico , Estudos Retrospectivos , Tomografia de Coerência Óptica , Resultado do TratamentoRESUMO
Asia-Pacific region bears a significant global burden of retinoblastoma (RB), therefore understanding RB in Asia-Pacific region is important. Based on the year 2013 population estimates, 43% (3452 of 8099 children) of the global burden of RB lives in 6 countries of Asia-Pacific region: 1486 children in India, 1103 children in China, 277 children in Indonesia, 260 children in Pakistan, 184 children in Bangladesh, 142 children in Philippines. There exists a wide disparity, technological and socio-economical, within countries in this region resulting in a varied pattern of clinical presentation and survival varies. Challenges in developing nations are not just technological, but also social. Opportunities emerge for research to study and understand the socio-economical aspects of the disease to develop interventions that are relevant culturally and feasible economically. Possible steps include disease education and counselling, universal screening, highly subsidized/free of cost treatment for low socioeconomic strata, raising funds through the government and non-governmental organizations, sensitization and training of man-power in screening, diagnosis and treatment, and developing new specialized centers with tele-ophthalmology services.
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Neoplasias da Retina/epidemiologia , Retinoblastoma/epidemiologia , Ásia/epidemiologia , Humanos , Morbidade/tendênciasRESUMO
Persistent or recurrent retinoblastoma (RB) is associated with the presence of vitreous or/and subretinal seeds in advanced RB and represents a major cause of therapeutic failure. This necessitates the development of novel therapies and thus requires a model of advanced RB for testing candidate therapeutics. To this aim, we established and characterized a three-dimensional, self-organizing organoid model derived from chemotherapy-naïve tumors. The responses of organoids to drugs were determined and compared to relate organoid model to advanced RB, in terms of drug sensitivities. We found that organoids had histological features resembling retinal tumors and seeds and retained DNA copy-number alterations as well as gene and protein expression of the parental tissue. Cone signal circuitry (M/L+ cells) and glial tumor microenvironment (GFAP+ cells) were primarily present in organoids. Topotecan alone or the combined drug regimen of topotecan and melphalan effectively targeted proliferative tumor cones (RXRγ+ Ki67+) in organoids after 24-h drug exposure, blocking mitotic entry. In contrast, methotrexate showed the least efficacy against tumor cells. The drug responses of organoids were consistent with those of tumor cells in advanced disease. Patient-derived organoids enable the creation of a faithful model to use in examining novel therapeutics for RB.
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Carcinogênese/patologia , Modelos Biológicos , Organoides/patologia , Retinoblastoma/tratamento farmacológico , Retinoblastoma/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lactente , Melfalan/farmacologia , Melfalan/uso terapêutico , Estadiamento de Neoplasias , Organoides/efeitos dos fármacos , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/patologia , Retinoblastoma/genética , Topotecan/farmacologia , Topotecan/uso terapêuticoRESUMO
Purpose: Retinoblastoma (RB) is a retinal tumor that most commonly occurs in children. Approximately 40% of RB patients carry germline mutations in the RB1 gene. RB survivors with germline mutations are at increased risk of passing on the disease to future offspring and of secondary cancer in adulthood. This highlights the importance of genetic testing in disease management and counseling. This study aimed to identify germline RB1 mutations and to correlate the mutations with clinical phenotypes of RB patients. Methods: Genomic DNA was extracted from peripheral blood mononuclear cells isolated from 52 RB patients (27 unilaterally and 25 bilaterally affected probands). Mutations in the RB1 gene, including the promoter and exons 1-27 with flanking intronic sequences, were identified by direct sequencing. The samples with negative test results were subjected to multiplex ligation-dependent probe amplification (MLPA) to detect any gross mutations. A correlation of germline RB1 mutations with tumor laterality or age at diagnosis was determined for RB patients. Age at diagnosis was examined in regard to genetic test results and the presence of extraocular tumor extension. Results: Germline RB1 mutations were detected in 60% (31/52) of patients. RB1 mutations were identified in 92% (22/25) of bilateral RB patients, and a high rate of germline RB1 mutations was found in unilateral RB cases (33% or 9/27). Whole gene and exon deletions were reported in five patients. Twenty-three distinct mutations as a result of base substitutions and small deletions were identified in 26 patients; seven mutations were novel. Nonsense and splicing mutations were commonly identified in RB patients. Furthermore, a synonymous mutation was detected in a patient with familial RB; affected mutation carriers in this family exhibited differences in disease severity. The types of germline RB1 mutations were not associated with age at diagnosis or laterality. In addition, patients with positive and negative test results for germline RB1 mutations were similar in age at diagnosis. The incidence of extraocular tumors was high in patients with heritable RB (83% or 5/6), particularly in unilateral cases (33% or 3/9); the mean age at diagnosis of these patients was not different from that of patients with intraocular tumors. Conclusions: This study provides a data set of an RB1 genotypic spectrum of germline mutations and clinical phenotypes and reports the distribution of disease-associated germline mutations in Thai RB patients who attended our center. Our data and the detection methods could assist in identifying a patient with heritable RB, establishing management plans, and informing proper counseling for patients and their families.
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Mutação em Linhagem Germinativa , Fenótipo , Neoplasias da Retina/genética , Proteínas de Ligação a Retinoblastoma/genética , Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Sequência de Bases , Criança , Pré-Escolar , Éxons , Feminino , Expressão Gênica , Genótipo , Humanos , Lactente , Padrões de Herança , Masculino , Reação em Cadeia da Polimerase Multiplex , Linhagem , Regiões Promotoras Genéticas , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/patologia , Retinoblastoma/diagnóstico , Retinoblastoma/patologia , Índice de Gravidade de Doença , TailândiaRESUMO
OBJECTIVE: This study aimed to study the prevalence and characteristics of idiopathic polypoidal choroidal vasculopathy (IPCV) in Thai patients with clinical and angiographic choroidal neovascularization (CNV). PATIENTS AND METHODS: A consecutive case study of 140 patients presenting with CNV was conducted in nine large referral eye centers throughout Thailand. The demographic data, fundus photographs, fundus fluorescein angiography and indocyanine green angiography of the patients were analyzed. RESULTS: Of 129 patients with clinical and angiographic CNV, IPCV was diagnosed in 100 patients (77.52%), idiopathic CNVs in 16 patients (12.40%) and age-related macular degeneration (AMD) in 12 patients (9.30%). Of the 107 eyes with IPCV, 90 eyes (84.11%) had both branching venous networks (BVNs) and polypoidal lesions. Most IPCV patients (93%) had unilateral involvement and were at a younger age than AMD patients. In all, 79 eyes (73.83%) had lesions found in the macular area, 14 eyes (13.08%) in the temporal to vascular arcades, ten eyes (9.35%) in the peripapillary area and four eyes (3.74%) in both macular and peripapillary areas. The clinical manifestations of IPCV at presentation were categorized into two patterns. There were 95 eyes (88.79%) of a hemorrhagic pattern and 12 eyes (11.21%) of an exudative pattern. CONCLUSION: IPCV is the most common macular disease in Thai patients with CNV. Most IPCVs have both BVNs and polypoidal lesions located in the macular area and present with a hemorrhagic pattern.
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IMPORTANCE: Report of an acquired immunodeficiency syndrome (AIDS) patient with Epstein-Barr virus (EBV)-associated iris smooth muscle tumor. OBSERVATIONS: A 14-year-old African American female diagnosed with AIDS developed a painless iris mass in the right eye for 10 months. Iridocyclectomy was performed, and the pathology indicated EBV-associated iris smooth muscle tumor with epithelioid morphology. Immunohistochemical stains and in situ hybridization for EBV-encoded ribonucleic acid are very useful diagnostic tools for definite diagnosis. At 14-month follow-up, the patient did not have any tumor recurrence. CONCLUSION: This is the case report of EBV-associated iris smooth muscle tumor in a person diagnosed with AIDS with a unique epithelioid morphologic feature.
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PURPOSE: The purpose was to evaluate the features of circumscribed choroidal hemangioma using spectral-domain enhanced depth imaging optical coherence tomography (EDI-OCT). DESIGN: Retrospective observational case series. PARTICIPANTS: Ten patients with newly diagnosed circumscribed choroidal hemangioma. METHODS: Spectral-domain EDI-OCT was performed with a Heidelberg Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany). MAIN OUTCOME MEASURES: Tumor thickness and EDI-OCT features. RESULTS: The mean tumor diameter for all eyes was 5.4 mm and mean tumor thickness was 1187 µm by EDI-OCT compared to 2400 µm by ultrasonography. EDI-OCT imaged all tumors as smooth with a gently sloping anterior contour, gradual choroidal expansion, expansion of medium and large size choroidal vessels without compression of choriocapillaris, and intact Bruch's membrane (n = 10, 100%). The height of the medium and large choroidal vessels within the tumor compared to normal medium and large vessels was comparatively increased by a mean of 265% (medium vessels) and 576% (large vessels). Outer retinal abnormalities included subretinal fluid (n = 7, 70%), lipofuscin deposition (n = 1, 10%), irregularity and thinning of retinal pigment epithelium and absence or irregularity of the ellipsoid layer (n = 4, 40%), absent external limiting membrane (n = 2, 20%), and disruption of the outer nuclear layer and outer plexiform layer (n = 3, 30%). The inner retinal abnormalities included irregularity of inner nuclear layer and structural loss or edema of inner plexiform layer (n = 3, 30%). The ganglion cell layer and nerve fiber layer were intact (n = 10, 100%). CONCLUSION: EDI-OCT of circumscribed choroidal hemangiomas depicts a smooth, gently sloping choroidal mass with expansion of medium and large size choroidal vessels without compression of the choriocapillaris. Structural abnormalities of outer and inner retinal layers were noted.