RESUMO
Nesta quarta-feira (18), dia em que se lembra a importância do diagnóstico precoce do retinoblastoma, o Ministério da Saúde chama a atenção dos pais e responsáveis a ficarem atentos aos primeiros sinais da doença. O retinoblastoma é um tumor maligno originário das células da retina, que é a parte do olho responsável pela visão, afetando um ou ambos os olhos. É o mais comum tumor maligno intraocular da infância e geralmente ocorre antes dos 5 anos de idade. Pode ocorrer de forma esporádica (70 a 75% dos casos) ou hereditária (25 a 30% dos casos).
Assuntos
Retinoblastoma/diagnóstico , Cegueira , Saúde OcularRESUMO
The patient is a 2-year-old male. The family consulted the Department of Ophthalmology, Shanghai Ninth People's Hospital, after noticing a white reflection in the pupil area of the child's right eye for 6 days. Following a thorough ocular and systemic examination, the patient was diagnosed with retinoblastoma (Group E, cT2bN0M0) of the right eye. The right eye was enucleated and classified as pathological stage pT3cN0M0. Postoperatively, systemic intravenous chemotherapy with the VEC regimen was administered. Genetic testing revealed a germline mutation in the RB1 gene: c.874 (exon9) delT (p.Tyr292fsTer9), necessitating close monitoring of the socket during follow-up visits. Three months after the operation, fundus examination revealed yellow-white lesions in the left eye, and bilateral retinoblastoma was diagnosed (Group E in the right eye, Group C in the left eye). Based on the ICRB and pTNM stages, the patient underwent six rounds of systemic intravenous chemotherapy and three rounds of cryotherapy in the left eye. No recurrence was detected with a 4-year follow-up. The patient was initially diagnosed with unilateral retinoblastoma, but later developed the disease in the contralateral eye during treatment, which was a case of metachronous bilateral retinoblastoma.
Assuntos
Neoplasias da Retina , Retinoblastoma , Humanos , Masculino , Pré-Escolar , Neoplasias da Retina/terapia , Enucleação Ocular , Mutação em Linhagem Germinativa , Proteínas de Ligação a Retinoblastoma/genética , Crioterapia , Ubiquitina-Proteína LigasesRESUMO
PURPOSE: Although Brazil has a high prevalence of retinoblastoma, there is a lack of epidemiological data on the disease. Thus, in this study, we aimed to evaluate the epidemiological profile of patients diagnosed with retinoblastoma in the ophthalmology department of a pediatric tertiary referral hospital in Ceara, Brazil. METHODS: A descriptive and cross-sectional study was conducted by retrospectively analyzing the clinical and socioeconomic data from the medical records of pediatric patients followed-up at the hospital between 2007 and 2021. Retinoblastoma was diagnosed on the basis of a fundoscopic or histopathologic examination. RESULTS: The data of 105 patients were included in the study, and the mean patient age at the time of diagnosis was 1.7 years. Most of the patients were women (50.5%) and hailed from rural areas (57.4%), which was associated with a higher tumor stage. Of the 150 patients, 57.1% initially presented with leukocoria. Ocular hyperemia was associated with more advanced stages of retinoblastoma (p=0.004). Bilateral involvement was observed in 25.7% of the patients and at a significantly younger age (p=0.009). The presence of retinal detachment, vascularized lesions, and vitreous seeds significantly increased the likelihood of requiring enucleation. DISCUSSION: This study presents an epidemiological description of retinoblastoma in Brazil, which highlights the significance of early detection. Delayed diagnosis is associated with a poorer visual prognosis and higher mortality rate, particularly in patients with unilateral disease. Risk factors for a more severe disease were retinal detachment, vascularized lesions, and vitreous seeds. The correlation between histopathological features and clinical outcomes was limited. CONCLUSION: Further studies are required to assess the influence of ocular hyperemia, fundoscopic assessment, and histopathologic findings on the prognosis of retinoblastoma. Moreover, it is critical to devise interventions to reduce the time-to-diagnosis in rural areas.
Assuntos
Neoplasias da Retina , Retinoblastoma , Humanos , Retinoblastoma/epidemiologia , Retinoblastoma/patologia , Brasil/epidemiologia , Feminino , Masculino , Estudos Transversais , Lactente , Estudos Retrospectivos , Neoplasias da Retina/epidemiologia , Neoplasias da Retina/patologia , Pré-Escolar , Criança , Fatores Socioeconômicos , Centros de Atenção Terciária/estatística & dados numéricos , Distribuição por Sexo , Fatores de Risco , Distribuição por Idade , Prevalência , Estadiamento de NeoplasiasRESUMO
PURPOSE: With the increased survival of retinoblastoma (RB) patients, it is important to evaluate the quality of life (QoL) of RB survivors as well as caregivers to provide comprehensive care to the children and caregivers. This study aims to assess the QoL of survivors of RB, as perceived by parents and the self-report by patients, through a pediatric QoL (PEDs-QoL) questionnaire. METHODS: The study cohort included 86 RB survivors, 86 age-matched controls, and their primary carers. PedsQL 4.0 generic core scale and structured interview were administered. QoL in physical, social, emotional, and school health was evaluated and correlated with clinical and sociodemographic parameters. RESULTS: The mean age of the RB survivors was 5.7 years with an M:F ratio of 1.1:1. Disease was bilateral in 79% of cases. About 45% (39/86) underwent enucleation, while others received combination therapy (16; 18%), chemotherapy (30; 34%), and radiation (1; 1%). As reported by parents, the QoL of physical health domain of RB survivors was 70.2 SD ± 27.8 and 96.15 ± 13 SD, emotional health was 72.1 ± 27.4 SD and 94.4 ± 12.5 SD, social health was 80.4 ± 24.9 SD and 98.6 ± 6.2 SD; and school health was 71.9 ± 2 6.5 SD and 96.1 ± 12.2 SD. As per the self-report perception, the QoL of physical health was 68.2 ± 27.8 SD and 96.2 ± 13 SD, emotional health was 66.2 ± 28.4 SD and 95.3 ± 12.5 SD, social health was 69.5 ± 24.9 SD and 98.7 ± 6.2 SD, and school health was 63.5 ± 26.5 SD and 95.1 ± 12.2 SD. There was a significant relationship between enucleation and QoL domains, where χ2 = 67.75, degrees of freedom (df) = 36, and P < 0.01. There was a significant association between vision in the better eye (6/18 or better = 8, 6/18-6/60 = 8, 3/60 or worse = 42) and QoL scores (χ2 = 95.36, df = 62, P < 0.01). There was a substantial association between socioeconomic status and QoL domains, where χ2= 88.5, df = 56, P < 0.01. CONCLUSION: The results of the study showed that the QoL of parents of RB survivors and self-proxy reports were negatively affected in many ways, including physical, social, emotional, and school-related dimensions. Despite the small differences, self-proxy reports indicated a lower QoL than the parents' group. The study findings indicate that there are notable correlations between enucleation and visual acuity less than 6/18, as well as socioeconomic status, with various aspects of QoL domains among individuals who have survived RB.
Assuntos
Qualidade de Vida , Neoplasias da Retina , Retinoblastoma , Humanos , Retinoblastoma/psicologia , Retinoblastoma/terapia , Masculino , Feminino , Neoplasias da Retina/psicologia , Neoplasias da Retina/terapia , Índia/epidemiologia , Pré-Escolar , Criança , Inquéritos e Questionários , Centros de Atenção Terciária , Seguimentos , Lactente , Adolescente , Atenção Terciária à Saúde , Estudos Transversais , Sobreviventes/psicologia , Cuidadores/psicologiaRESUMO
BACKGROUND: Some cancer survivors experience difficulties with concentration, attention, and memory; however, there are no studies on neurodevelopment in patients under 5 years of age who are undergoing cancer treatment. Our aim was to evaluate neurodevelopment in cancer patients under 5 years of age using the Early Development Instrument (EDI) test, considering factors such as nutritional status, type of cancer, and treatment effect. METHODS: A cross-sectional study was conducted from February 2018 to March 2019. Patients with cancer diagnoses outside the central nervous system in any phase of cancer treatment were included. RESULTS: A total of 45 patients were included. Regarding fine motor skills, 28% of patients with retinoblastoma and 23% of patients with leukemia or lymphoma had a risk of developmental delay compared to 0% of patients with solid tumors (p = 0.025). The final results showed that 19 (42.2%) patients had normal neurodevelopment (gray), 7 (15.5%) had a delay in neurodevelopment (light gray), and 19 (42.2%) had a risk of developmental delay (black). Regarding developmental delay, 52% of patients in the leukemia and lymphoma group, 71% in the retinoblastoma group, and 23% in the solid tumor group presented developmental delay (p = 0.06). CONCLUSIONS: The risk of delay and lag in neurodevelopment is common in cancer patients under 5 years of age undergoing treatment. However, more studies are required to evaluate the effect of treatment on this group of patients as it may be affected by various factors.
INTRODUCCIÓN: En algunos pacientes supervivientes de cáncer se presentan dificultades de concentración, atención y memoria, sin embargo no hay estudios en relación al neurodesarrollo en pacientes menores de 5 años que se encuentran en tratamiento oncológico. Por lo que el objetivo fue valorar el neurodesarrollo en pacientes con cáncer durante el tratamiento oncológico mediante la prueba EDI tomando en cuenta diversos factores como su estado nutricional, tipo de cancer, y el efecto del tratamiento. MÉTODOS: Se realizó un estudio transversal, de febrero de 2018 a marzo de 2019. Se incluyeron pacientes mayores de 1 año y menores de 5 años con diagnóstico de cáncer fuera del sistema nervioso central, en tratamiento oncológico. RESULTADOS: Se incluyeron 45 pacientes. En el área motor fina el 28% de los pacientes con retinoblastoma y 23% con leucemias y linfomas se encontraron en rojo (retraso) en comparación con 0% de los pacientes con tumores sólidos (p = 0.025). En el resultado global se encontró que 19 (42.2%) pacientes tuvieron neurodesarrollo normal (gris), 7 (15.5%) rezago en el neurodesarrollo (gris claro) y 19 (42.2%) con riesgo de retraso en el desarrollo (negro). De los pacientes que presentaron riesgo de retraso el 52% fueron del grupo de leucemias y linfomas, el 71% en el grupo de retinoblastoma y el 23% del grupo de tumores sólidos (p = 0.06). CONCLUSIONES: La presencia de riesgo de retraso y rezago en el neurodesarrollo es frecuente en menores de 5 años con diagnóstico de cáncer. Se requieren más estudios, para evaluar el efecto del tratamiento en este grupo de pacientes, ya que pueden influir diversos factores.
Assuntos
Deficiências do Desenvolvimento , Neoplasias , Humanos , Estudos Transversais , Pré-Escolar , Masculino , Feminino , Lactente , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/etiologia , Retinoblastoma , Estado Nutricional , Desenvolvimento Infantil/fisiologia , Sobreviventes de Câncer/estatística & dados numéricos , Fatores de RiscoRESUMO
We report the successful synthesis of an injectable dendrimer hydrogel (DH) carrying melphalan, a clinical drug for retinoblastoma treatment, in both conjugated and free forms. Polyamidoamine (PAMAM) dendrimer generation 5 (G5) is surface-modified with an acid-sensitive acetal-dibenzocyclooctyne linker and then undergoes azide-alkyne cycloaddition with melphalan-PEG-N3 conjugate to form G5-acetal-melphalan. During the DH gelation between G5-acetal-melphalan and PEG-diacrylate, free melphalan is added, resulting in a hydrogel (G5-acetal-melphalan-DH/melphalan) that carries the drug in both conjugated and free forms. Melphalan is slowly released from G5-acetal-melphalan-DH/melphalan, with the conjugated melphalan released more quickly at pH 5.3 due to acid-triggered acetal bond cleavage. The formulation's in vitro safety and efficacy were established on human corneal epithelia (HCE-2) and retinoblastoma cells (Y79). In an in vivo Y79 tumor xenograft model of retinoblastoma, intratumorally injected G5-melphalan-DH formulation prolonged tumor suppression. This injectable, multimodal, pH-responsive formulation shows promise for intravitreal injection to treat retinoblastoma.
Assuntos
Dendrímeros , Hidrogéis , Melfalan , Retinoblastoma , Dendrímeros/química , Melfalan/administração & dosagem , Melfalan/química , Melfalan/farmacologia , Retinoblastoma/tratamento farmacológico , Retinoblastoma/patologia , Animais , Humanos , Hidrogéis/química , Camundongos , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/patologia , Linhagem Celular Tumoral , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologiaRESUMO
Retinoblastoma (RB) is the most common intraocular malignancy among children and presents a certain mortality risk, especially in low- and middle-income countries. Clarifying the molecular mechanisms underlying the onset and progression of retinoblastoma is vital for devising effective cancer treatment approaches. PRMT1, a major type I PRMT, plays significant roles in cancer development. However, its expression and role in retinoblastoma are still unclear. Our research revealed a marked increase in PRMT1 levels in both retinoblastoma tissues and Y79 cells. The overexpression of PRMT1 in Y79 cells promoted their growth and cell cycle progression. Conversely, the suppression of PRMT1 hindered the growth of Y79 cells and impeded cell cycle progression. Mechanistically, PRMT1 mediated the growth of Y79 retinoblastoma cells by targeting the p53/p21/CDC2/Cyclin B pathway. Additionally, the ability of PRMT1 knockdown to suppress cell proliferation was also observed in vivo. Overall, PRMT1 could function as a potential target for therapeutic treatment in individuals with retinoblastoma.
Assuntos
Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21 , Proteína-Arginina N-Metiltransferases , Proteínas Repressoras , Neoplasias da Retina , Retinoblastoma , Proteína Supressora de Tumor p53 , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Retinoblastoma/patologia , Retinoblastoma/metabolismo , Retinoblastoma/genética , Humanos , Proliferação de Células/fisiologia , Neoplasias da Retina/patologia , Neoplasias da Retina/metabolismo , Neoplasias da Retina/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Proteína Quinase CDC2/metabolismo , Proteína Quinase CDC2/genética , Regulação Neoplásica da Expressão Gênica , Animais , Camundongos , Western Blotting , Ciclo Celular/fisiologia , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas , Linhagem Celular Tumoral , Camundongos NusRESUMO
PURPOSE: The impact of heredity and treatment modalities on the development of hematologic second primary malignancies (SPMs) is unclear. This study primarily reviewed the literature on patients with hematologic SPMs after retinoblastoma. METHODS: The PubMed and Web of Science databases were searched to identify all cases of hematologic SPMs after retinoblastoma through December 2023 (International prospective register of systematic reviews CRD42023488273). RESULTS: Sixty-one patients from 35 independent publications and our case were included. Within the cohort, 15 patients (51.7%) were male, and 14 patients (48.3%) were female. Of the 43 cases with known heritability status, 27 (62.8%) were classified as heritable and 16 (37.2%) as nonheritable. The median age at diagnosis was 18 months (IQR: 7.00-36.00). The geographic distribution of patients was diverse, with North America accounting for 35.0% (21/60) of cases. The following treatment strategies were used: 11.9% (5/42) of patients received neither chemotherapy nor radiotherapy, 33.3% (14/42) received chemotherapy alone, 11.9% (5/42) received radiotherapy alone, and 42.9% (18/42) received a combination of chemotherapy and radiotherapy. The median delay between retinoblastoma diagnosis and SPM diagnosis was 40 months (IQR: 22.00-85.00). Among the 61 cases, acute myeloid leukemia accounted for 44.3% (27/61), followed by acute lymphoblastic leukemia in 21.3% (13/61), Hodgkin's lymphoma in 11.5% (7/61), non-Hodgkin's lymphoma in 9.8% (6/61), chronic myeloid leukemia in 3.3% (2/61), and acute natural killer cell leukemia in 1.6% (1/61). CONCLUSIONS: Vigilant systemic surveillance for hematologic SPMs in retinoblastoma survivors, especially those treated with systemic chemotherapy and those with hereditary conditions, is warranted to improve management strategies and patient outcomes.
Assuntos
Segunda Neoplasia Primária , Neoplasias da Retina , Retinoblastoma , Humanos , Retinoblastoma/diagnóstico , Retinoblastoma/terapia , Segunda Neoplasia Primária/diagnóstico , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/terapia , Lactente , Neoplasias Hematológicas/diagnóstico , Pré-Escolar , Feminino , MasculinoRESUMO
OBJECTIVES: To retrospectively investigate clinical characterization and the long-term postoperative outcomes of retinoblastoma (RB) patients receiving enucleation with primary orbital implantation in early infancy (0-6 months old). METHODS: The clinical and follow-up data of 42 RB patients receiving enucleation with primary orbital implantation in early infancy at Beijing Tongren Hospital from December 2009 to January 2020 were analysed. The average follow-up time was 83 months. The patient group included 24 males and 18 females, 30 unilateral and 12 bilateral cases. A total of 44 eyes with 10 in stage D and 34 in stage E underwent 40 unilateral and 2 bilateral surgeries. 17 RB eyes received hydrogel and 27 RB eyes received hydroxyapatite implants. This study was performed by following the guideline of STROBE. RESULTS: Enucleation combined with primary orbital implantation promoted survival and was safe with few and minor complications such as increased secretion, upper eyelid ptosis, and sunken eye sockets which were not affected by stages, lateralities, or implant materials. 55-80% RB patients exhibited satisfactory appearance and obvious or moderate motility of orbital implants according to the evaluation by doctors and family members. Family members were likely more optimistic about the appearance and more pessimistic about motility of the orbital implantation than doctors did.The quality of life was high as indicated by PedsQL3.0 or PedsQL4.0 scores ( ⧠90 for > 75% patients). It was not affected by the stages, laterality, and implant materials, nor affected by the appearance and motility of the implants. CONCLUSIONS: The outcomes of the combination of enucleation and primary orbital implantation for pertinent RB patients in early infancy are generally satisfactory with few and minor complications, high safety, appearance, and overall quality of life. Enucleation combined with primary orbital implantation in early infancy benefits pertinent RB patients in appearance, survival, and quality of life.
Assuntos
Enucleação Ocular , Implantes Orbitários , Qualidade de Vida , Neoplasias da Retina , Retinoblastoma , Humanos , Retinoblastoma/cirurgia , Masculino , Feminino , Lactente , Estudos Retrospectivos , Neoplasias da Retina/cirurgia , Neoplasias da Retina/diagnóstico , Seguimentos , Recém-Nascido , Resultado do Tratamento , Pré-EscolarRESUMO
Background: At present, the few photothermal/chemotherapy studies about retinoblastoma that have been reported are mainly restricted to ectopic models involving subcutaneous implantation. However, eyeball is unique physiological structure, the blood-retina barrier (BRB) hinders the absorption of drug molecules through the systemic route. Moreover, the abundant blood circulation in the fundus accelerates drug metabolism. To uphold the required drug concentration, patients must undergo frequent chemotherapy sessions. Purpose: To address these challenges above, we need to develop a secure and effective drug delivery system (FA-PEG-PDA-DOX) for the fundus. Methods: We offered superior therapeutic efficacy with minimal or no side effects and successfully established orthotopic mouse models. We evaluated cellular uptake performance and targeting efficiency of FA-PEG-PDA-DOX nanosystem and assessed its synergistic antitumor effects in vitro and vivo. Biodistribution assessments were performed to determine the retention time and targeting efficiency of the NPs in vivo. Additionally, safety assessments were conducted. Results: Cell endocytosis rates of the FA-PEG-PDA-DOX+Laser group became 5.23 times that of the DOX group and 2.28 times that of FA-PEG-PDA-DOX group without irradiation. The fluorescence signal of FA-PEG-PDA-DOX persisted for more than 120 hours at the tumor site. The number of tumor cells (17.2%) in the proliferative cycle decreased by 61.6% in the photothermal-chemotherapy group, in contrast to that of the saline control group (78.8%). FA-PEG-PDA-DOX nanoparticles(NPs) exhibited favorable biosafety and high biocompatibility. Conclusion: The dual functional targeted nanosystem, with the effects of DOX and mild-temperature elevation by irradiation, resulted in precise chemo/photothermal therapy in nude mice model.
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Doxorrubicina , Indóis , Terapia Fototérmica , Polímeros , Retinoblastoma , Animais , Retinoblastoma/terapia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Doxorrubicina/administração & dosagem , Camundongos , Terapia Fototérmica/métodos , Humanos , Indóis/química , Indóis/farmacocinética , Indóis/farmacologia , Linhagem Celular Tumoral , Polímeros/química , Distribuição Tecidual , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Camundongos Nus , Nanopartículas/química , Sistemas de Liberação de Medicamentos/métodos , Neoplasias da Retina/terapia , Neoplasias da Retina/tratamento farmacológico , Camundongos Endogâmicos BALB C , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/administração & dosagem , Modelos Animais de Doenças , Ensaios Antitumorais Modelo de Xenoenxerto , Sistemas de Liberação de Fármacos por Nanopartículas/química , Sistemas de Liberação de Fármacos por Nanopartículas/farmacocinéticaRESUMO
PURPOSE: To describe the epidemiological and clinical profile of hospitalized patients with retinoblastoma in Brazil. METHODS: Using data from the Hospital Cancer Registry of the Instituto Nacional de Câncer, patients with the morphological codes of retinoblastoma who were diagnosed between 2000 to 2018, aged 0-19 years, and followed up in registered hospitals (analytical cases) were selected. The relative and absolute frequencies of demographic, clinical, diagnostic, therapeutic, and outcome variables were described. Hospital performance indicators were calculated and compared between hospitals qualified and not qualified to treat pediatric oncology cases and between hospitals with different case volumes (<20, 20-75, >75 cases). RESULTS: Of the 2,269 identified analytical cases from 86 institutions, 48% were from the Southeast, 54% were male, and 66% were aged <4 years. The proportion of missing data (NA) was too high for several variables. Approximately 84% of the patients were from the public health system, 40% had a positive family history, and 88% had unilateral involvement. The first treatment included surgery in 58.3% of the patients (NA=2), Approximately 36.6% of these patients achieved complete remission, 10.8% achieved partial remission, and 12.7% died (NA=59%). Hospital performance indicators were within the target in >90% of the patients. The median time between the first appointment and diagnosis (6 days, interquartile range [IQR] 1-14) was significantly lower and the median time to death was longer (343 days, IQR, 212-539) in high-volume hospitals (>75 cases) than in medium- and low-volume hospitals. CONCLUSIONS: Despite the high proportion of missing data, we found that the delay in diagnosis is due to prehospital factors. Additionally, there is a need for educational programs for healthcare professionals and families that emphasize early identification and referral to specialized centers. Future studies should focus on the impact of Hospital Cancer Registry data completeness on outcomes, causes of delay in diagnosis, regional inequalities, and barriers to accessing specialized services.
Assuntos
Hospitalização , Neoplasias da Retina , Retinoblastoma , Humanos , Retinoblastoma/terapia , Retinoblastoma/epidemiologia , Retinoblastoma/diagnóstico , Brasil/epidemiologia , Masculino , Lactente , Pré-Escolar , Feminino , Criança , Adolescente , Hospitalização/estatística & dados numéricos , Adulto Jovem , Neoplasias da Retina/terapia , Neoplasias da Retina/epidemiologia , Neoplasias da Retina/diagnóstico , Recém-Nascido , Sistema de RegistrosRESUMO
PURPOSE: Retinoblastoma (RB) is one of the most common intraocular cancers, with the highest prevalence among infants and young children under the age five. Numerous findings across the literature illustrate the involvement and significance of circular RNAs (circRNAs) in human malignancies, including RB. The current investigation attempted to decipher the exact roles and underlying mechanisms of a novel circRNA, hsa_circ_0078136, in RB progression. METHODS: The hsa_circ_0078136 expression was evaluated in RB tumors and cell lines via qRT-PCR. The significance of hsa_circ_0078136 in RB was examined by performing CCK8 assay, transwell assays, western blotting of apoptotic and IL-17 signaling ligand molecules, and a subcutaneous xenograft tumor model. In addition, the interaction of circRNA and eukaryotic translation initiation factor 4A3 (EIF4A3) was determined with bioinformatics, western blot, and RIP assay. RESULTS: The hsa_circ_0078136 expression was reduced in RB tumor samples and cells. Additionally, its overexpression restricted the oncogenic properties of RB cells in vitro. Moreover, hsa_circ_0078136 overexpression lowered the protein levels of cytokine ligand molecules of IL-17 signaling pathway in RB cell lines. In vivo, hsa_circ_0078136 overexpression in subcutaneous tumor xenografts reduced tumor growth. We also observed that EIF4A3 binds to the downstream flanking sequence of hsa_circ_0078136 in the SHRPH pre-mRNA transcript, and EIF4A3 overexpression reduced hsa_circ_0078136 expression, suggesting that EIF4A3 inhibited hsa_circ_0078136 formation. CONCLUSIONS: Our results demonstrate that hsa_circ_0078136 is regulated by EIF4A3 and functions as a tumor suppressor via the IL-17 signaling pathway in RB.
Assuntos
Carcinogênese , Fator de Iniciação 4A em Eucariotos , Interleucina-17 , RNA Circular , Neoplasias da Retina , Retinoblastoma , Transdução de Sinais , Retinoblastoma/genética , Retinoblastoma/metabolismo , Retinoblastoma/patologia , Humanos , Neoplasias da Retina/genética , Neoplasias da Retina/metabolismo , Neoplasias da Retina/patologia , RNA Circular/genética , Interleucina-17/metabolismo , Interleucina-17/genética , Camundongos , Fator de Iniciação 4A em Eucariotos/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Animais , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Proliferação de Células , Camundongos Nus , Apoptose , Masculino , Células Tumorais Cultivadas , Linhagem Celular Tumoral , Feminino , RNA Helicases DEAD-boxRESUMO
PURPOSE: Retinoblastoma, a curable childhood cancer, has been identified as a tracer cancer in the WHO Global Initiative for Childhood Cancer. To document the outcomes of children with retinoblastoma in South Africa, treated as per the first prospective standard national treatment guidelines for childhood cancer in South Africa. PATIENTS AND METHODS: All children diagnosed with retinoblastoma between 2012 and 2016 in five South African pediatric oncology units were treated with a standard treatment on the basis of the International Society of Pediatric Oncology-Pediatric Oncology in Developing Countries guidelines for high-income settings. Treatment included focal therapy with/without chemotherapy, or enucleation with/without chemotherapy, and orbital radiotherapy, depending on enucleated eye histology. The end point was survival at 24 months, using Kaplan-Meier curves with log-rank (Mantel-Cox) and chi-square (χ2) tests with respective P values reported. RESULTS: A total of 178 children were included in the study; 68% presented with unilateral disease. The median age was 27 months (range 0-118 months) with a male:female ratio of 1:0.75. The overall survival was 79% at 24 months with significant association with stage at diagnosis (P < .001) and older age over 2 years as opposed to younger than 2 years (P < .001). Causes of death were disease progression/relapses in 90% (34 of 38) and unknown in 2% (1 of 38), whereas treatment abandonment was 1.7% (3 of 178). CONCLUSION: Efficacy with national treatment guidelines was confirmed, and feasibility of implementing standard national childhood cancer treatment guidelines was documented, involving multidisciplinary teams in South Africa. Outcome was significantly associated with stage at diagnosis and age.
Assuntos
Guias de Prática Clínica como Assunto , Neoplasias da Retina , Retinoblastoma , Humanos , Retinoblastoma/terapia , Retinoblastoma/mortalidade , Retinoblastoma/diagnóstico , Retinoblastoma/patologia , África do Sul/epidemiologia , Masculino , Feminino , Pré-Escolar , Lactente , Criança , Recém-Nascido , Neoplasias da Retina/terapia , Neoplasias da Retina/mortalidade , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/patologia , Resultado do Tratamento , Enucleação OcularRESUMO
Retinoblastoma are childhood eye tumors arising from retinal precursor cells. Two distinct retinoblastoma subtypes with different clinical behavior have been described based on gene expression and methylation profiling. Using consensus clustering of DNA methylation analysis from 61 retinoblastomas, we identify a MYCN-driven cluster of subtype 2 retinoblastomas characterized by DNA hypomethylation and high expression of genes involved in protein synthesis. Subtype 2 retinoblastomas outside the MYCN-driven cluster are characterized by high expression of genes from mesodermal development, including NKX2-5. Knockdown of MYCN expression in retinoblastoma cell models causes growth arrest and reactivates a subtype 1-specific photoreceptor signature. These molecular changes suggest that removing the driving force of MYCN oncogenic activity rescues molecular circuitry driving subtype 1 biology. The MYCN-RB gene signature generated from the cell models better identifies MYCN-driven retinoblastoma than MYCN amplification and can identify cases that may benefit from MYCN-targeted therapy. MYCN drives tumor progression in a molecularly defined retinoblastoma subgroup, and inhibiting MYCN activity could restore a more differentiated and less aggressive tumor biology.
Assuntos
Proteína Proto-Oncogênica N-Myc , Retinoblastoma , Humanos , Retinoblastoma/genética , Retinoblastoma/patologia , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Metilação de DNA , Neoplasias da Retina/genética , Neoplasias da Retina/patologia , Neoplasias da Retina/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Desdiferenciação Celular/genética , Feminino , Masculino , Pré-EscolarRESUMO
Retinoblastoma is the most common pediatric intraocular malignant tumor affecting 1:15 000-1:20 000 live births. Even though the survival rate in developed countries is over 90â¯%, more efficient treatment options are needed for better vision salvage and reduction of the adverse effects. Therefore, we investigated fluorescein-labeled PL3 peptide targeting properties towards the Y79 retinoblastoma cell line in vitro. Through the application of cellular imaging and flow cytometry techniques, the PL3 peptide exhibited a rapid and specific internalization within Y79 cells, with subsequent translocation to the cell nuclei, showcasing notable accumulation in the nucleoli. This phenomenon was not present in other investigated cell lines and was not observable with similarly charged and length control peptide. However, the exact mechanism behind this Y79 cell line-specific nuclear and nucleolar targeting pattern remains elusive. In the future, this targeting process could facilitate specific treatment modalities of retinoblastoma with PL3 peptide-coupled drug delivery technologies.
Assuntos
Nucléolo Celular , Retinoblastoma , Retinoblastoma/metabolismo , Retinoblastoma/tratamento farmacológico , Humanos , Linhagem Celular Tumoral , Nucléolo Celular/metabolismo , Nucléolo Celular/efeitos dos fármacos , Peptídeos/farmacologia , Neoplasias da Retina/metabolismo , Neoplasias da Retina/tratamento farmacológico , Peptídeos Penetradores de Células/farmacologiaRESUMO
Retinoblastoma (RB) is the most common intraocular malignancy in childhood. The causal variants in RB are mostly characterized by previously used short-read sequencing (SRS) analysis, which has technical limitations in identifying structural variants (SVs) and phasing information. Long-read sequencing (LRS) technology has advantages over SRS in detecting SVs, phased genetic variants, and methylation. In this study, we comprehensively characterized the genetic landscape of RB using combinatorial LRS and SRS of 16 RB tumors and 16 matched blood samples. We detected a total of 232 somatic SVs, with an average of 14.5 SVs per sample across the whole genome in our cohort. We identified 20 distinct pathogenic variants disrupting RB1 gene, including three novel small variants and five somatic SVs. We found more somatic SVs were detected from LRS than SRS (140 vs. 122) in RB samples with WGS data, particularly the insertions (18 vs. 1). Furthermore, our analysis shows that, with the exception of one sample who lacked the methylation data, all samples presented biallelic inactivation of RB1 in various forms, including two cases with the biallelic hypermethylated promoter and four cases with compound heterozygous mutations which were missing in SRS analysis. By inferring relative timing of somatic events, we reveal the genetic progression that RB1 disruption early and followed by copy number changes, including amplifications of Chr2p and deletions of Chr16q, during RB tumorigenesis. Altogether, we characterize the comprehensive genetic landscape of RB, providing novel insights into the genetic alterations and mechanisms contributing to RB initiation and development. Our work also establishes a framework to analyze genomic landscape of cancers based on LRS data.
Assuntos
Metilação de DNA , Neoplasias da Retina , Proteínas de Ligação a Retinoblastoma , Retinoblastoma , Humanos , Retinoblastoma/genética , Retinoblastoma/patologia , Proteínas de Ligação a Retinoblastoma/genética , Neoplasias da Retina/genética , Neoplasias da Retina/patologia , Masculino , Feminino , Mutação , Ubiquitina-Proteína Ligases/genética , Pré-Escolar , Criança , Lactente , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento Completo do Genoma/métodosRESUMO
Retinoblastoma (RB) is a pediatric malignancy, typically diagnosed at birth or during early childhood. The pathogenesis of RB is marked by the amplification of the Basic Helix-Loop-Helix (BHLH) Transcription Factor MYCN, which serves as a transcriptional regulator capable of binding to Dickkopf 3 (DKK3). However, the precise role of DKK3 in the malignant progression of RB cells caused by MYCN remains elusive. In the present study, the expression of MYCN was either overexpressed or interfered in RB cells. Subsequently, the expression level of DKK3 was assessed through quantitative real-time polymerase chain reaction and western blot analysis. Cell proliferation was evaluated using the Cell Counting Kit-8 assay and 5-ethynyl-2'-deoxyuridine staining, while cell cycle progression and apoptosis were analyzed by flow cytometry and western blot analysis, respectively. Additionally, the expression of proteins involved in the Wnt/ß-catenin/Fra-1/p53 signaling pathway was evaluated via western blot analysis. To gain further insights, Wnt agonists and the P53 inhibitor PFT-α were introduced into exploration. The current investigation revealed a negative correlation between the expression levels of MYCN and DKK3 in RB cells. Additionally, DKK3 overexpression inhibited cell proliferation, promoted cell apoptosis, and arrested cell cycle in RB cells with high expression of MYCN. Moreover, enhanced DKK3 expression inhibited proliferation, promoted cell cycle arrest and apoptosis of RB cells by modulating the wnt/ßcatenin/Fra-1/p53 signaling pathway. Furthermore, in vivo experiments revealed that overexpression of DKK3 inhibits the growth of RB tumors. Collectively, our findings elucidate that MYCN stimulates the Wnt/ß-catenin/Fra-1 pathway by suppressing DKK3 expression, ultimately suppressing p53 activity and contributing to malignant progression of RB.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proliferação de Células , Proteína Proto-Oncogênica N-Myc , Retinoblastoma , Proteína Supressora de Tumor p53 , Via de Sinalização Wnt , Humanos , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Retinoblastoma/metabolismo , Retinoblastoma/genética , Retinoblastoma/patologia , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Animais , Camundongos , Apoptose , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos Nus , beta Catenina/metabolismoRESUMO
Retinoblastoma, a pediatric ocular malignancy, presents significant challenges in comprehending its molecular underpinnings and targeted therapeutic approaches. The dysregulated activity of histone deacetylases (HDACs) has been associated with retinoblastoma pathogenesis, influencing critical cellular processes like cell cycle regulation or retinal ganglion cell apoptosis. Through their deacetylase activity, HDACs exert control over key tumor suppressors and oncogenes, influencing the delicate equilibrium between proliferation and cell death. Furthermore, the interplay between HDACs and the retinoblastoma protein pathway, a pivotal aspect of retinoblastoma etiology, reveals a complex network of interactions influencing the tumor microenvironment. The examination of HDAC inhibitors, encompassing both established and novel compounds, offers insights into potential approaches to restore acetylation balance and impede retinoblastoma progression. Moreover, the identification of specific HDAC isoforms exhibiting varying expression in retinoblastoma provides avenues for personalized therapeutic strategies, allowing for interventions tailored to individual patient profiles. This review focuses on the intricate interrelationship between HDACs and retinoblastoma, shedding light on epigenetic mechanisms that control tumor development and progression. The exploration of HDAC-targeted therapies underscores the potential for innovative treatment modalities in the pursuit of more efficacious and personalized management strategies for this disease.
Assuntos
Inibidores de Histona Desacetilases , Histona Desacetilases , Retinoblastoma , Retinoblastoma/genética , Retinoblastoma/metabolismo , Retinoblastoma/patologia , Humanos , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Animais , Neoplasias da Retina/genética , Neoplasias da Retina/metabolismo , Neoplasias da Retina/patologia , Epigênese Genética , Acetilação , Microambiente Tumoral , Regulação Neoplásica da Expressão Gênica , Proteína do Retinoblastoma/metabolismo , Proteína do Retinoblastoma/genéticaRESUMO
BACKGROUND: Retinoblastoma (RB) is an intraocular malignant tumor detected in early childhood with variable global impact. Histopathological classification of the tumor in enucleated globes with RB is the key for the decision of adjuvant chemotherapy use. We aim to validate the use of adjuvant chemotherapy in cases with combined pre-laminar/intralaminar optic nerve (ON) invasion and focal choroidal invasion according to the American Joint Committee on Cancer (AJCC) 8th classification. METHODS: This is a retrospective study conducted at King Abdulaziz University Hospital (KAUH) and King Khalid Eye Specialist Hospital (KKESH) in Riyadh, Saudi Arabia of all RB cases who underwent enucleation over 22 years (2000 to 2021). The histopathological findings were reviewed to identify the enucleated globes classified as pT2a tumors, as an inclusion criterion. Basic demographic and clinical data were collected via chart review Simple descriptive and basic statistical analysis of the data was used where applicable. RESULTS: Thirty-one patients who had an enucleated globe with RB that fit into the above classification were included. Sixteen were males and 15 were females. The median age was 14 months (IQR = 14 months). Most of the patients (93.5%) had no family history of RB. The commonest presentation was leukocoria in 87.1% followed by squint in 32.3%. Fourteen patients (45.2%) were treated by enucleation alone while 17 patients (54.8%) received adjuvant chemotherapy. Out of these, 7 patients had unilateral RB and the remaining 10 patients had bilateral RB. None of our patients developed recurrence or metastatic disease irrespective of the indication for adjuvant chemotherapy use after a maximum period of follow up reaching 17.84 years and a median of 10.6 years (IQR = 5.92). CONCLUSIONS: In patients with 8th AJCC histopathological classification of pT2a, chemotherapy following enucleation might not be justified. The outcome in our untreated group of patients did not differ from the treated group with the absence of metastasis after a relatively long period of follow up with a median exceeding 10 years in both groups. Therefore, the risk and benefit of post enucleation adjuvant chemotherapy in the treatment of unilateral RB should be carefully decided and discussed with the primary caregivers taking into consideration the most recent evidence and recommendations in the literature.