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Purpose: Local recurrence predicts dismal prognosis in eyelid sebaceous carcinoma (SC). Recurrence predictors vary across studies. Accurate recurrence estimation is essential for individualized therapy in eyelid SC. This study aims to identify recurrence predictors and develop a nomogram for personalized prediction in eyelid SC. Methods: We conducted a multicenter retrospective cohort study. Chart reviews were performed in 418 consecutive patients with eyelid SC. All patients were followed up after their initial surgery. Multivariate Cox regression was used to explore the independent predictors of recurrence. A nomogram for recurrence prediction was developed and validated with bootstrap resampling. The predictive accuracy and discriminative ability were compared with the Tumor, Node, Metastasis (TNM) staging system. Results: Over a median of 60-month follow-up, 167 patients (40%) had local recurrence. The median time from diagnosis to recurrence was 14 months. The 1-year cumulative recurrence rate was 18%. Diagnostic delay (hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 1.00-1.01, P = 0.001), orbital involvement (HR = 4.47, 95% CI = 3.04-6.58, P < 0.001), Ki67 (HR = 1.01, 95% CI = 1.00-1.02, P = 0.008) and initial surgery of Mohs micrographic surgery with intraoperative frozen section control (HR = 0.53, 95% CI = 0.35-0.80, P = 0.003) were independent influencing factors of recurrence. A nomogram integrating these four factors combined with pagetoid spread displayed satisfactory discriminative ability (C-index = 0.80-0.83; area under the curve [AUC] = 0.82-0.84), which compared favorably than TNM staging (all P < 0.05). Conclusions: The recurrence rate is high in eyelid SC. Early detection and primary resection with Mohs micrographic surgery are recommended in controlling recurrence. Patients with orbital involvement, high Ki67 expression, and pagetoid spread may require adjuvant measures. This nomogram offers more accurate recurrence estimates, aiding in therapeutic decision making.
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Adenocarcinoma Sebáceo , Neoplasias Palpebrais , Recidiva Local de Neoplasia , Nomogramas , Neoplasias das Glândulas Sebáceas , Humanos , Masculino , Feminino , Estudos Retrospectivos , Neoplasias Palpebrais/patologia , Neoplasias Palpebrais/diagnóstico , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias das Glândulas Sebáceas/diagnóstico , Pessoa de Meia-Idade , Idoso , Adenocarcinoma Sebáceo/patologia , Adenocarcinoma Sebáceo/diagnóstico , Seguimentos , Estadiamento de Neoplasias , Idoso de 80 Anos ou mais , Adulto , PrognósticoRESUMO
BackgroundThis study determined to probe the potential association between somatic copy number alteration (SCNA) in retinoblastoma (RB) aqueous humour (AH) and pathological high-risk factors, clinical features and previous chemotherapy history. METHODS: Single-centre retrospective cohort study from including 58 AH samples collected from 58 patients diagnosed. Among them, 41 samples were collected after enucleation and 17 samples were collected before intravitreal chemotherapy. SCNAs were accessed by conducting shallow whole-genome sequencing in cell-free (cf) DNA of AH. HRs and ORs were applied to measure risk factors. RESULTS: Canonical RB SCNAs including 1q gain (87%), 2p gain (50%), 6p gain (76%), 16q loss (69%) were frequently detected. Non-classical RB SCNAs in AH including 17q gain (53%), 19q loss (43%), 7q gain (35%) were also commonly observed. 19q loss was significantly more common in patients with cT3c or worse stage than others (p=0.034). 2p gain(p=0.001) and 7q gain(p=0.001) were both more common in patients with primary enucleation than those with previous chemotherapy. Interestingly, both 2p gain (HR=1.933, p=0.027) and 7q gain (HR=2.394, p=0.005) might predict enucleation. Correlation analysis with pathological features among enucleated eyes showed that 19q loss can predict a higher risk for both massive choroid invasion (OR=4.909, p=0.038) and postlaminar optic nerve invasion (OR=4.250, p=0.043). DISCUSSION: Sequencing of AH cfDNA in RB can provide sufficient in vivo information. 19q loss was a potential signature of advanced cases clinically and pathologically.Repeated sampling from eyes receiving sequential chemotherapy should be conducted to evaluate fluctuation of SCNA in future study.
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Ácidos Nucleicos Livres , Neoplasias da Retina , Retinoblastoma , Humanos , Retinoblastoma/tratamento farmacológico , Retinoblastoma/genética , Retinoblastoma/patologia , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/genética , Neoplasias da Retina/patologia , Variações do Número de Cópias de DNA , Humor Aquoso , Estudos Retrospectivos , Enucleação OcularRESUMO
Purpose: Eyelid sebaceous carcinoma (SeC) is the third most frequent eyelid malignancy worldwide and is relatively prevalent in Asian patients. An eyelid SeC cell line model is necessary for experimental research to explore the etiology and pathogenesis of eyelid SeC. This study established and characterized an eyelid SeC cell line with a TP53 mutation that might be useful for analyzing potential treatment options for eyelid SeC. Methods: The eyelid SeC cell line SHNPH-SeC was obtained from a patient with eyelid SeC at Shanghai Ninth People's Hospital (SHNPH), Shanghai JiaoTong University School of Medicine. Immunofluorescence staining was employed to detect the origination and proliferation activity. Short tandem repeat (STR) profiling was performed for verification. Chromosome analysis was implemented to investigate chromosome aberrations. Whole exome sequencing (WES) was used to discover genomic mutations. Cell proliferation assays were performed to identify sensitivity to mitomycin-C (MMC) and 5-fluorouracil (5-FU). Results: SHNPH-SeC cells were successively subcultured for more than 100 passages and demonstrated rapid proliferation and migration. Karyotype analysis revealed abundant chromosome aberrations, and WES revealed SeC-related mutations in TP53, KMT2C, and ERBB2. An in vivo tumor model was successfully established in NOD/SCID mice. Biomarkers of eyelid SeC, including cytokeratin 5 (CK5), epithelial membrane antigen (EMA), adipophilin, p53, and Ki-67, were detected in SHNPH-SeC cells, original tumors, and xenografts. MMC and 5-FU inhibited the proliferation and migration of SHNPH-SeC cells, and SHNPH-SeC cells presented a greater drug response than non-TP53-mutated SeC cells. Conclusions: The newly established eyelid SeC cell line SHNPH-SeC demonstrates mutation in TP53, the most commonly mutated gene in SeC. It presents SeC properties and malignant characteristics that may facilitate the investigation of cellular behaviors and molecular mechanisms of SeC to explore promising therapeutic strategies.
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Adenocarcinoma Sebáceo , Carcinoma , Neoplasias Palpebrais , Neoplasias das Glândulas Sebáceas , Neoplasias Cutâneas , Animais , Camundongos , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Camundongos SCID , Camundongos Endogâmicos NOD , China , Adenocarcinoma Sebáceo/genética , Adenocarcinoma Sebáceo/diagnóstico , Adenocarcinoma Sebáceo/metabolismo , Aberrações Cromossômicas , Linhagem Celular Tumoral , Pálpebras/patologia , Neoplasias Palpebrais/genética , Neoplasias Palpebrais/diagnóstico , Neoplasias Palpebrais/metabolismo , Neoplasias das Glândulas Sebáceas/genética , Neoplasias das Glândulas Sebáceas/diagnóstico , Neoplasias das Glândulas Sebáceas/metabolismo , Fluoruracila/farmacologiaRESUMO
BACKGROUND: Super-selected intra-arterial chemotherapy has increasingly been used as conservative management for retinoblastoma during the past decade. However, the absence of evidence from randomised controlled trials engendered controversy in the administration route of chemotherapy. We aimed to assess the efficacy and safety of intra-arterial chemotherapy compared with intravenous chemotherapy. METHODS: This open-label, multicentre, randomised trial was done at six hospitals in China. Patients with new-onset unilateral group D or E retinoblastoma (poorly defined, large, or very large tumours, according to the International Intraocular Retinoblastoma Classification) without high-risk clinical factors were included. Patients were randomly assigned (1:1) to receive intra-arterial chemotherapy (injections of 0·5 mg/kg [or depending on age] melphalan with 20 mg carboplatin [first and third cycles] or with 1 mg topotecan [second and fourth cycles]) or intravenous chemotherapy (0·05 mg/kg [or 1·5 mg/m2] vincristine, 5 mg/kg [or 150 mg/m2] etoposide, and 18·6 mg/kg [or 560 mg/m2] carboplatin for six cycles). After intra-arterial chemotherapy, patients received a subcutaneous injection of 0·1 mL nadroparin calcium twice at a 12 h interval. Both intra-arterial and intravenous chemotherapy cycles were completed every 4 weeks. No masking was done, except of independent statisticians, who were masked to the allocation information. The primary outcome was 2-year progression-free globe salvage rate, defined as the time from randomisation to tumour progression or enucleation, whichever occurred first, and was analysed by intention to treat. We also recorded predefined safety outcomes (myelosuppression and ophthalmic arterial stenosis or occlusion) and severe adverse events likely to be related to study treatment. The study is registered with the Chinese Clinical Trial Registry, ChiCTR-IPR-15006469, and is complete. FINDINGS: Between June 1, 2015, and June 1, 2018, 234 patients with newly diagnosed retinoblastoma were screened and 143 eligible patients (median age 23·6 months [IQR 14·0-31·9]) were enrolled and randomly assigned to the intra-arterial chemotherapy group (n=72) or the intravenous chemotherapy group (n=71). At a median follow-up of 35·8 months (IQR 28·4-43·0), the 2-year progression-free globe salvage rate was 53% (38 of 72 patients) in the intra-arterial chemotherapy group and 27% (19 of 71 patients) in the intravenous chemotherapy group (risk ratio 1·97, 95% CI 1·27-3·07, p=0·0020). Myelosuppression was less common in the intra-arterial chemotherapy group than in the intravenous chemotherapy group (37 [51%] of 72 patients vs 50 [70%] of 71 patients; 0·73, 95% CI 0·56-0·96, p=0·021) and less severe (ptrend=0·0070). In the intra-arterial chemotherapy group, two (3%) of 72 patients had ophthalmic artery occlusion and 13 (18%) patients had ophthalmic artery stenosis. INTERPRETATION: Our findings show that intra-arterial chemotherapy could significantly improve the globe salvage rate in children with advanced unilateral retinoblastoma compared with intravenous chemotherapy, with mild systemic complications and no difference in overall survival rate. Intra-arterial chemotherapy could be an acceptable first-line treatment in children with advanced unilateral retinoblastoma. FUNDING: Scientific Research Program of the National Health and Family Planning Commission of China, the Clinical Research Plan of Shanghai Hospital Development Center, the National Natural Science Foundation of China, and the Science and Technology Commission of Shanghai Municipality.
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Neoplasias da Retina , Retinoblastoma , Humanos , Criança , Lactente , Pré-Escolar , Retinoblastoma/tratamento farmacológico , Retinoblastoma/induzido quimicamente , Carboplatina/efeitos adversos , Constrição Patológica/induzido quimicamente , China , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Retinoblastoma, the most prevalent primary intraocular tumor in children, leads to vision impairment, disability and even death. In addition to RB1 inactivation, MYCN activation has been documented as another common oncogenic alteration in retinoblastoma and represents one of the high-risk molecular subtypes of retinoblastoma. However, how MYCN contributes to the progression of retinoblastoma is still incompletely understood. Here, we report that MYCN upregulates YTHDF1, which encodes one of the reader proteins for N6-methyladenosine (m6A) RNA modification, in retinoblastoma. We further found that this MYCN-upregulated m6A reader functions to promote retinoblastoma cell proliferation and tumor growth in an m6A binding-dependent manner. Mechanistically, YTHDF1 promotes the expression of multiple oncogenes by binding to their mRNAs and enhancing mRNA stability and translation in retinoblastoma cells. Taken together, our findings reveal a novel MYCN-YTHDF1 regulatory cascade in controlling retinoblastoma cell proliferation and tumor growth, pinpointing an unprecedented mechanism for MYCN amplification and/or activation to promote retinoblastoma progression.
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Neoplasias da Retina , Retinoblastoma , Criança , Humanos , Retinoblastoma/genética , Retinoblastoma/metabolismo , Retinoblastoma/patologia , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Oncogenes , Neoplasias da Retina/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
BACKGROUND: Metastasis dominates the prognosis of eyelid sebaceous carcinoma (SC). This study aimed to explore risk factors for nodal metastasis and develop a nomogram to predict nodal metastasis in patients with eyelid SC. METHODS: A retrospective case-control study was performed, comprising 320 patients with eyelid SC. Cox analyses were employed to investigate predictors of metastasis-free survival (MFS), and a nomogram was established and validated by the bootstrap method. RESULTS: Forty patients (12.5%) developed nodal metastasis during a median follow-up of 48.0 months, and the median period between the initial treatment and first nodal metastasis was 18.5 months (range 6.0-80.0 months). The 1-year, 3-year and 5-year nodal metastasis rates were 5.5%, 12.5% and 15.4%, respectively. Diffuse pattern (HR: 4.34, 95% CI 1.75 to 10.76, p=0.002), orbital invasion at presentation (HR: 3.22, 95% CI 1.42 to 7.33, p=0.005), perineural invasion (HR: 3.24, 95% CI 1.11 to 9.49, p=0.032) and high Ki-67 percentage (HR: 1.03, 95% CI 1.01 to 1.05, p<0.001) were identified as independent risk factors for nodal metastasis. A nomogram that integrated these four factors had a C-index of 0.785, demonstrating a strong power in predicting nodal metastasis of eyelid SC. CONCLUSIONS: We identified risk factors for nodal metastasis and developed a nomogram to provide individualised estimates of nodal metastasis for eyelid SC patients and guide postoperative management. This nomogram contained clinicopathological factors besides the T category of the TNM staging system and suggesting great clinical value.
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Carcinoma , Neoplasias Palpebrais , Neoplasias Orbitárias , Neoplasias Cutâneas , Humanos , Antígeno Ki-67 , Estudos Retrospectivos , Estudos de Casos e Controles , Neoplasias Orbitárias/patologia , Neoplasias Cutâneas/patologia , Neoplasias Palpebrais/patologia , Prognóstico , Estadiamento de Neoplasias , Pálpebras/patologiaRESUMO
Background: The differential diagnosis of eyelid basal cell carcinoma (BCC) and sebaceous carcinoma (SC) is highly dependent on pathologist's experience. Herein, we proposed a fully automated differential diagnostic method, which used deep learning (DL) to accurately classify eyelid BCC and SC based on whole slide images (WSIs). Methods: We used 116 haematoxylin and eosin (H&E)-stained sections from 116 eyelid BCC patients and 180 H&E-stained sections from 129 eyelid SC patients treated at the Shanghai Ninth People's Hospital from 2017 to 2019. The method comprises two stages: patch prediction by the DenseNet-161 architecture-based DL model and WSI differentiation by an average-probability strategy-based integration module, and its differential performance was assessed by the carcinoma differentiation accuracy and F1 score. We compared the classification performance of the method with that of three pathologists, two junior and one senior. To validate the auxiliary value of the method, we compared the pathologists' BCC and SC classification with and without the assistance of our proposed method. Results: Our proposed method achieved an accuracy of 0.983, significantly higher than that of the three pathologists (0.644 and 0.729 for the two junior pathologists and 0.831 for the senior pathologist). With the method's assistance, the pathologists' accuracy increased significantly (P<0.05), by 28.8% and 15.2%, respectively, for the two junior pathologists and by 11.8% for the senior pathologist. Conclusions: Our proposed method accurately classifies eyelid BCC and SC and effectively improves the diagnostic accuracy of pathologists. It may therefore facilitate the development of appropriate and timely therapeutic plans.
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The most common intraocular pediatric malignancy, retinoblastoma (RB), accounts for ≈10% of cancer in children. Efficient monitoring can enhance living quality of patients and 5-year survival ratio of RB up to 95%. However, RB monitoring is still insufficient in regions with limited resources and the mortality may even reach over 70% in such areas. Here, an RB monitoring platform by machine learning of aqueous humor metabolic fingerprinting (AH-MF) is developed, using nanoparticle enhanced laser desorption/ionization mass spectrometry (LDI MS). The direct AH-MF of RB free of sample pre-treatment is recorded, with both high reproducibility (coefficient of variation < 10%) and sensitivity (low to 0.3 pmol) at sample volume down to 40 nL only. Further, early and advanced RB patients with area-under-the-curve over 0.9 and accuracy over 80% are differentiated, through machine learning of AH-MF. Finally, a metabolic biomarker panel of 7 metabolites through accurate MS and tandem MS (MS/MS) with pathway analysis to monitor RB is identified. This work can contribute to advanced metabolic analysis of eye diseases including but not limited to RB and screening of new potential metabolic targets toward therapeutic intervention.
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Neoplasias da Retina , Retinoblastoma , Humor Aquoso/metabolismo , Criança , Humanos , Aprendizado de Máquina , Reprodutibilidade dos Testes , Neoplasias da Retina/diagnóstico , Retinoblastoma/diagnóstico , Espectrometria de Massas em TandemRESUMO
BACKGROUND: The clinical and pathological risk factors for worse T stage and prognosis in eyelid and periocular squamous cell carcinomas (SCCs) remain unclear. P63 was reported to predict a worse prognosis in other SCCs; however, this correlation was not validated in eyelid and periocular SCCs. METHODS: We reported on a retrospective case series of 85 consecutive patients with eyelid and periocular SCCs from 1995 to 2019. Cox proportional hazards regression models and logistic regression models were applied for risk factor analysis. RESULTS: Thirty-nine (45.8%) patients were diagnosed with T4 SCCs. Four (5.1%) patients developed nodal metastasis, and five (6.4%) patients developed distant metastasis during the follow-up. 2-year and 5-year disease-specific survival rates were 95.3% and 86.4%, respectively. Poorly or moderately differentiated eyelid and periocular SCCs were associated with worse T stage (p=0.001; p=0.008). Poor differentiation was associated with a higher risk of recurrence (p=0.024). Disease-specific death was more common in patients with T4 stage SCCs (p=0.038, HR=9.05). P63 expression was more common in patients with T3c or worse stage (p=0.008, OR=3.77). P63 expression alone was associated with worse differentiation (p=0.029), higher risk of perineural invasion (p=0.042, OR=4.61) and metastasis (p=0.009, HR=3.99). P63 expression (p=0.012, HR=7.80), coexpression of P63 and Ki67 (p=0.007, HR=9.21) and distant metastasis (p=0.001, HR=11.23) were associated with disease-specific death. CONCLUSION: Patients presented with more aggressive orbital invasion features and a higher rate of distant metastasis in this cohort. P63 and coexpression of Ki67 predicted a worse stage, differentiation and prognosis, including metastasis and death due to disease.
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Carcinoma de Células Escamosas , Neoplasias Palpebrais , Carcinoma de Células Escamosas/patologia , Neoplasias Palpebrais/diagnóstico , Pálpebras/patologia , Seguimentos , Humanos , Antígeno Ki-67 , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de RiscoRESUMO
PURPOSE: This study aims to evaluate the efficacy and safety of intralesional diode laser pretreatment for facilitating surgery for orbital venous malformations (OVMs). METHODS: This is a retrospective, non-comparative, interventional cohort involving 23 consecutive OVM patients undergoing intralesional laser pretreatment followed by surgical excision. The main outcome measures included volumetric changes, exophthalmometry, cosmesis, and symptom scores as well as treatment-related adverse events. RESULTS: Following intralesional diode laser, the mean volume dropped significantly from 2366 ± 1887 to 129 ± 119 mm3 (t = 5.716; p < 0.001). After a single treatment session, a mean 90 ± 13% volume shrinkage was achieved in all 23 OVM. The mean Hertel exophthalmometry decreased significantly from 14 ± 3 to 13 ± 1 mm (t = 2.515; P < 0.02). The resolution of periocular dyschromasia and swelling were evident in 20 patients (87%). Symptom scores improved significantly from 6.5 ± 1.4 (very intense discomfort or effect on daily living) to 1.2 ± 1.0 (very mild discomfort or effect on daily living; p < 0.001). Short-term bruises and swelling were reported in 20 patients (87%). CONCLUSION: Intralesional laser pretreatment is effective to facilitate surgery especially for the deep involving orbital venous malformations.
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Lasers Semicondutores , Malformações Vasculares , Humanos , Injeções Intralesionais , Lasers Semicondutores/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Malformações Vasculares/diagnóstico , Malformações Vasculares/tratamento farmacológico , Malformações Vasculares/cirurgia , Veias/cirurgiaRESUMO
PURPOSE: To report three-decade changes of clinical characteristics, progress of treatments, and risk factors associated with mortality and enucleation in patients with retinoblastoma in China. DESIGN: Retrospective cohort study. METHODS: This multicenter study included 2552 patients diagnosed with retinoblastoma in 38 medical centers in 31 provinces in China from 1989 to 2017, with follow-up data. Kendall's tau-b value was used to describe correlation coefficients between the three eras (between 1989 and 2008, between 2009 and 2013, and between 2014 and 2017) and clinical or demographic features. Hazard ratios and odds ratios were applied to measure risk factors. RESULTS: A total of 324 (13%) patients died and 1414 (42%) eyes were removed. The 1-year, 3-year, and 5-year overall survival rates were 95%, 86%, and 83%, respectively. Patients were diagnosed at a better stage by International Classification for Retinoblastoma over time (Kendall's tau-b value = -0.084, P < .001). Pathological risk factors were also observed less in recent eras. New conservative therapies were adopted and used in more patients. The eye removal rate gradually decreased (Kendall's tau-b value = -0.167, P < .001). The overall survival rates were 81%, 83%, and 91% in the three eras. By multivariate Cox regression, bilateral tumors and extraocular extension were identified as risk factors for death. Among intraocular disease, Group E indicated higher risk of mortality. By multivariate logistics regression, unilateral tumors, earlier era of diagnosis, and extraocular extension were risk factors for eye salvage failure. Among intraocular retinoblastoma, Groups D and E had higher risk of eye salvage failure. CONCLUSIONS: Patients were diagnosed at an earlier stage in recent eras. Conservative therapies, including intra-arterial chemotherapy, were increasingly being used. The above changes may contribute to the decreasing enucleation rate. Although no significant impact was identified on the mortality by the three eras, a decreasing trend was shown.
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Neoplasias da Retina , Retinoblastoma , Enucleação Ocular , Humanos , Lactente , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/epidemiologia , Neoplasias da Retina/terapia , Retinoblastoma/diagnóstico , Retinoblastoma/epidemiologia , Retinoblastoma/terapia , Estudos Retrospectivos , Terapia de SalvaçãoRESUMO
PURPOSE: This study attempted to estimate the impact of eye-preserving therapies for the long-term prognosis of patients with advanced retinoblastoma with regard to overall survival and ocular salvage. DESIGN: Retrospective cohort study covering all 31 provinces (38 retinoblastoma treating centers) of mainland China. PARTICIPANTS: One thousand six hundred seventy-eight patients diagnosed with group D or E retinoblastoma from January 2006 through May 2016. METHODS: Chart review was performed. The patients were divided into primary enucleation and eye-preserving groups, and they were followed up for survival status. The impact of initial treatment on survival was evaluated by Cox analyses. MAIN OUTCOME MEASURES: Overall survival and final eye preservation. RESULTS: After a median follow-up of 43.9 months, 196 patients (12%) died, and the 5-year overall survival was 86%. In total, the eyeball preservation rate was 48%. In this cohort, 1172 patients (70%) had unilateral retinoblastoma, whereas 506 patients (30%) had bilateral disease. For patients with unilateral disease, 570 eyes (49%) underwent primary enucleation, and 602 patients (51%) received eye-preserving therapies initially. During the follow-up (median, 45.6 months), 59 patients (10%) from the primary enucleation group and 56 patients (9.3%) from the eye-preserving group died. Multivariate Cox analyses indicated no significant difference in overall survival between the 2 groups (hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.85-1.84; P = 0.250). For patients with bilateral disease, 95 eyes (19%) underwent primary enucleation, and 411 patients (81%) received eye-preserving therapies initially. During the follow-up (median, 40.1 months), 12 patients (13%) from the primary enucleation group and 69 patients (17%) from the eye-preserving group died. For bilateral retinoblastoma with the worse eye classified as group E, patients undergoing primary enucleation exhibited better overall survival (HR, 2.35; 95% CI, 1.10-5.01; P = 0.027); however, this survival advantage was not evident until passing 22.6 months after initial diagnosis. CONCLUSIONS: Eye-preserving therapies have been used widely for advanced retinoblastoma in China. Patients with bilateral disease whose worse eye was classified as group E and who initially underwent eye-preserving therapies exhibited a worse overall survival. The choice of primary treatment for advanced retinoblastoma should be weighed carefully.
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Neoplasias da Retina/terapia , Retinoblastoma/terapia , Terapia de Salvação , Antineoplásicos/uso terapêutico , Braquiterapia , Pré-Escolar , China , Terapia Combinada , Crioterapia , Enucleação Ocular , Feminino , Seguimentos , Humanos , Lactente , Fotocoagulação a Laser , Masculino , Neoplasias da Retina/mortalidade , Neoplasias da Retina/patologia , Retinoblastoma/mortalidade , Retinoblastoma/patologia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Retinoblastoma (Rb) is the most common primary intraocular childhood malignancy and one of the main causes of blindness in children. In China, most tumors are diagnosed at an advanced stage and have relatively poor outcomes compared to developed countries. Here, we aimed to update the clinical manifestations and RB transcriptional corepressor 1 (RB1) mutation spectrum in Chinese Rb patients. Medical charts of 184 eyes in 145 Chinese Rb patients belonging to unrelated families were reviewed. Genomic DNA was isolated from peripheral blood of the patients and their parents. Mutation analysis of whole coding regions, promoter regions and flanking splice sites in the RB1 gene was performed. In addition, multiplex ligation-dependent probe amplification (MLPA) was done to detect gross aberrations. Germline RB1 mutations were observed in 37.2% (54/145) of Rb patients. RB1-mutated patients presented with earlier age of diagnosis (p = 0.019), with a significantly larger proportion of bilateral cases (p = <0.001) and secondary malignancies (p = 0.027) relative to those without RB1 mutations. For ocular clinical presentations, RB1-mutated retinoblastomas presented with a larger proportion of ectropion uveae (p = 0.017) and iris neovascularization (p = 0.001). These RB1 mutations comprised of 13 (24.1%) nonsense mutation, 13 (24.1%) splicing mutations, 11 (20.4%) frameshift deletions, 11 (20.4%) gross mutations, 3 (5.6%) missense mutations, 2 (3.7%) promoter mutations and 1 (1.9%) non-frameshift deletion. In addition, 8 novel RB1 mutations were identified. These germline RB1 mutations were not related to age at diagnosis or laterality. Here, we provide a comprehensive spectrum of RB1 germline mutations in Chinese Rb patients and describe correlations between RB1 mutations and clinical presentations. Our study also provides new evidence that will inform management and genetic counselling of Rb patients and families.
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Povo Asiático/genética , Mutação em Linhagem Germinativa/genética , Mutação , Neoplasias da Retina/genética , Proteínas de Ligação a Retinoblastoma/genética , Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Criança , Pré-Escolar , China/epidemiologia , Análise Mutacional de DNA , Feminino , Genes do Retinoblastoma , Humanos , Lactente , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase Multiplex , Neoplasias da Retina/diagnóstico , Retinoblastoma/diagnóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Long non-coding RNAs (lncRNAs) have been identified as important epigenetic regulators that play critical roles in human cancers. However, the regulatory functions of lncRNAs in tumorigenesis remains to be elucidated. Here, we aimed to investigate the molecular mechanisms and potential clinical application of a novel lncRNA, retinoblastoma associated transcript-1 (RBAT1), in tumorigenesis. METHODS: RBAT1 expression was determined by real-time PCR in both retinoblastoma (Rb) and bladder cancer (BCa) cell lines and clinical tissues. Chromatin isolation using RNA purification (ChIRP) assays were performed to identify RBAT1-interacting proteins. Patient-derived xenograft (PDX) retinoblastoma models were established to test the therapeutic potential of RBAT1-targeting GapmeRs. RESULTS: Here, we found that RBAT1 expression was significantly higher in Rb and BCa tissues than that in adjacent tissues. Functional assays revealed that RBAT1 accelerated tumorigenesis both in vitro and in vivo. Mechanistically, RBAT1 recruited HNRNPL protein to E2F3 promoter, thereby activating E2F3 transcription. Therapeutically, GapmeR-mediated RBAT1 silencing significantly inhibited tumorigenesis in orthotopic xenograft retinoblastoma models derived from Rb cell lines and Rb primary cells. CONCLUSIONS: RBAT1 overexpression upregulates a known oncogene, E2F3, via directly recruiting HNPNPL to its promoter and cis-activating its expression. Our finding provides a novel mechanism of lncRNA biology and provides potential targets for diagnosis and treatment of Rb and BCa.
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Transformação Celular Neoplásica/genética , Fator de Transcrição E2F3/genética , Regulação da Expressão Gênica , RNA Longo não Codificante/genética , Ribonucleoproteínas/genética , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Fator de Transcrição E2F3/metabolismo , Inativação Gênica , Humanos , Imuno-Histoquímica , Camundongos , Modelos Biológicos , Regiões Promotoras Genéticas , Ligação Proteica , Interferência de RNA , Retinoblastoma/genética , Retinoblastoma/metabolismo , Ribonucleoproteínas/metabolismo , Transdução de Sinais , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Orbital/periorbital plexiform neurofibroma (OPPN) can compromise physical appearance and visual function. However, the clinical characteristics and NF1 mutation landscape in patients with heritable OPPN have not been reported. METHODS: The medical charts of 26 Chinese patients with OPPN from 12 families were reviewed. Mutation analysis of the entire coding region and flanking splice sites of the NF1 gene was performed using next-generation sequencing (NGS). Novel NF1 mutations were confirmed by Sanger sequencing. RESULTS: Compared to the parental generation, a significantly larger proportion of OPPN patients in the successive generation presented with earlier onset (p = 0.001), amblyopia (p = 0.034), motility disorders (p = 0.009) and bony orbital expansion (p = 0.019). Six novel NF1 mutations were identified in 11 (91.67%) families, including 6 (42.9%) single-base substitutions, 4 (28.5%) splicing mutations, 3 (21.4%) frameshift deletions, and 1 (7.14%) intron mutation. CONCLUSIONS: The successive generation of OPPN patients presented with earlier onset and exhibited more severe ocular signs than did their parents or grandparents. Special attention should be paid to successive generations of OPPN patients. Considering that 6 mutations were novel, comprehensive NF1 mutation analysis is required or necessary or proposed for genetic counselling.
Assuntos
Genes da Neurofibromatose 1 , Mutação , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Órbita/patologia , Adolescente , Adulto , Criança , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: The decision to perform Mohs micrographic surgery (MMS) or wide local excision (WLE) for eyelid sebaceous carcinoma (SC) is controversial. OBJECTIVE: To compare local recurrence, metastasis, and tumor-related mortality of patients with eyelid SC who were initially treated with MMS versus with WLE. METHODS: A multicenter cohort study. Medical records were reviewed for factors associated with recurrence, metastasis, and tumor-related mortality. All eligible patients were followed up. The impact of initial surgical modality on the prognoses were determined by Cox analyses after control for all confounders. RESULTS: Of the 360 patients included in this cohort, 115 (31.9%) underwent MMS as primary resection, whereas 245 (68.1%) underwent WLE. After a median follow-up period of 60.0 months, local recurrence was observed in 18 patients (15.7%) in the MMS group and 97 patients (39.6%) in the WLE group. Metastasis occurred in 9 patients (7.8%) who underwent MMS and 38 (15.5%) who underwent WLE. In all, 6 patients in the MMS group (5.2%) and 21 in the WLE group (8.6%) died of metastatic SC. Multivariable Cox regression indicated that compared with the WLE group, the MMS group exhibited more favorable local recurrence control (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.24-0.73; P = .002) but a comparable metastasis rate (HR, 1.38; 95% CI, 0.60-3.18; P = .453) and comparable tumor-related mortality (HR, 1.70; 95% CI, 0.59-4.93; P = .329). However, this beneficial effect became nonremarkable for patients with pagetoid intraepithelial neoplasia (HR, 1.73; 95% CI, 0.37-8.21; P = .488). LIMITATIONS: Retrospective nature of the study. CONCLUSION: MMS should be proposed for eyelid SC without orbital involvement to achieve recurrence control; however, this surgical procedure did not change the long-term outcomes in terms of metastasis or tumor-related mortality. Patients with pagetoid intraepithelial neoplasia may require adjuvant measures.