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1.
Commun Biol ; 5(1): 992, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127469

RESUMO

Rhabdomyosarcoma, the most common pediatric sarcoma, has no effective treatment for the pleomorphic subtype. Still, what triggers transformation into this aggressive phenotype remains poorly understood. Here we used Ptch1+/-/ETV7TG/+/- mice with enhanced incidence of rhabdomyosarcoma to generate a model of pleomorphic rhabdomyosarcoma driven by haploinsufficiency of the lysosomal sialidase neuraminidase 1. These tumors share mostly features of embryonal and some of alveolar rhabdomyosarcoma. Mechanistically, we show that the transforming pathway is increased lysosomal exocytosis downstream of reduced neuraminidase 1, exemplified by the redistribution of the lysosomal associated membrane protein 1 at the plasma membrane of tumor and stromal cells. Here we exploit this unique feature for single cell analysis and define heterogeneous populations of exocytic, only partially differentiated cells that force tumors to pleomorphism and promote a fibrotic microenvironment. These data together with the identification of an adipogenic signature shared by human rhabdomyosarcoma, and likely fueling the tumor's metabolism, make this model of pleomorphic rhabdomyosarcoma ideal for diagnostic and therapeutic studies.


Assuntos
Neuraminidase , Rabdomiossarcoma , Animais , Criança , Haploinsuficiência , Humanos , Proteína 1 de Membrana Associada ao Lisossomo , Lisossomos/metabolismo , Camundongos , Neuraminidase/genética , Neuraminidase/metabolismo , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Microambiente Tumoral
2.
Sci Rep ; 12(1): 15631, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115914

RESUMO

Computed tomography (CT) has been widely used for the diagnosis of pelvic rhabdomyosarcoma (RMS) in children. However, it is difficult to differentiate pelvic RMS from other pelvic malignancies. This study aimed to analyze and select CT features by using least absolute shrinkage and selection operator (LASSO) logistic regression and established a Fisher discriminant analysis (FDA) model for the quantitative diagnosis of pediatric pelvic RMS. A total of 121 pediatric patients who were diagnosed with pelvic neoplasms were included in this study. The patients were assigned to an RMS group (n = 36) and a non-RMS group (n = 85) according to the pathological results. LASSO logistic regression was used to select characteristic features, and an FDA model was constructed for quantitative diagnosis. Leave-one-out cross-validation and receiver operating characteristic (ROC) curve analysis were used to evaluate the diagnostic ability of the FDA model. Six characteristic variables were selected by LASSO logistic regression, all of which were CT morphological features. Using these CT features, the following diagnostic models were established: (RMS group)[Formula: see text]; (Non-RMS group)[Formula: see text], where [Formula: see text], [Formula: see text], … and [Formula: see text] are lower than normal muscle density (1 = yes; 0 = no), multinodular fusion (1 = yes; 0 = no), enhancement at surrounding blood vessels (1 = yes; 0 = no), heterogeneous progressive centripetal enhancement (1 = yes; 0 = no), ring enhancement (1 = yes; 0 = no), and hemorrhage (1 = yes; 0 = no), respectively. The calculated area under the ROC curve (AUC) of the model was 0.992 (0.982-1.000), with a sensitivity of 94.4%, a specificity of 96.5%, and an accuracy of 95.9%. The calculated sensitivity, specificity and accuracy values were consistent with those from cross-validation. An FDA model based on the CT morphological features of pelvic RMS was established and could provide an easy and efficient method for the diagnosis and differential diagnosis of pelvic RMS in children.


Assuntos
Neoplasias Pélvicas , Rabdomiossarcoma , Criança , Humanos , Modelos Logísticos , Neoplasias Pélvicas/diagnóstico por imagem , Curva ROC , Rabdomiossarcoma/diagnóstico por imagem , Tomografia Computadorizada por Raios X
3.
Ann Ital Chir ; 92: 331-338, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36052474

RESUMO

OBJECTIVE: This study aims to investigate the characteristics and related high risk factors of second neoplasms after chemotherapy and radiotherapy in children with solid tumors. METHODS: The detailed clinical data of seven children with malignant solid tumors, who were treated in our department, were retrospectively analyzed, in order to summarize the clinical characteristics of the secondary onset of second neoplasms, and determined the risk factors related to the occurrence of second neoplasms. RESULTS: (1) Clinical characteristics: Among the seven children with malignant solid tumors, three children had rhabdomyosarcoma (3/132, 2.27%), two children had hepatoblastoma (2/313, 0.64%), one child had neuroblastoma (1/305, 0.33%), and one child had inflammatory myofibroblastoma (1/3, 33.33%). Furthermore, among these children, four children were boys and three children were girls, and their onset age ranged within 5-34 months, with a median onset age of 27 months. Moreover, among these children, three children were ≤1 year old. All second neoplasms exhibited symptoms, and the diagnosis was made after the complete remission of the first primary tumor. The time interval between these two tumors was within 17-78 months, and the median time was 38 months. Three of seven children with rhabdomyosarcoma were treated with chemotherapy in combination with radiotherapy, while four children only received the chemotherapy. The chemotherapy cycles were 6-39 times, and the median chemotherapy cycles were 10 times. Among these children, one child with relapsed stage IV rhabdomyosarcoma and one child with stage IV retroperitoneal neuroblastoma had 39 cycles and 33 cycles of chemotherapy respectively. (2) Characteristics of the accumulated doses of high-risk chemotherapy drugs: The accumulated dose of cyclophosphamide in six patients was within 2.47-44.45 g/m2, with a median of 6.14 g/m2. The accumulated dose of ifosfamide in five patients was within 13.63-96.41 mg/m2, with a median of 31.23g/m2. The accumulated dose of etoposide in six patients was within 1,237.35-3,754.95 mg/m2, with a median of 1,548.67 mg/m2. The accumulated dose of anthracyclines in seven patients was within 150.68-843.78 mg/m2, with a median of 329.73 mg/m2. The accumulated dose of vincristine in seven patients was within 3.11-18.89 mg/m2, with a median of 15.92 mg/m2. The accumulated dose of cisplatin in seven patients was within 271.23-1,681.59 mg/m2, with a median of 733.07 mg/m2. Children with abdominal inflammatory myofibroblastic tumors did not apply cyclophosphamide, ifosfamide and etoposide regimens. The main chemotherapy drugs consisted of methotrexate, pirarubicin, cisplatin and vincristine. (3) Radiotherapy doses. (4) Characteristics of second neoplasms: Among the seven children with second neoplasms, five children had leukemia, 3 patients with rhabdomyosarcoma were combined with radiotherapy. The doses of radiation were 40 and 45GY" after "(3) Radiotherapy doses (four children had acute myeloid leukemia and one children had acute B-lymphoblastic leukemia), one child had myelodysplastic syndrome, and one child had myeloid sarcoma. Furthermore, among these seven children, four children (4/7) had abnormal chromosomes, two children were normal, and one child gave up the treatment and underwent the chromosome test after the diagnosis of second neoplasms. CONCLUSION: The incidence of secondary onset of second neoplasms in children with malignant solid tumors is not high, considering that this is correlated to the use of alkylating agents, topoisomerase II inhibitors, platinum-based chemotherapy drugs and radiotherapy, and associated with the chromosomal abnormalities of children. KEY WORDS: Chemotherapy, Children, Radiotherapy, Second malignant neoplasm, Solid tumor.


Assuntos
Antineoplásicos , Segunda Neoplasia Primária , Neuroblastoma , Rabdomiossarcoma , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Cisplatino , Terapia Combinada , Ciclofosfamida , Etoposídeo , Feminino , Humanos , Ifosfamida , Lactente , Masculino , Segunda Neoplasia Primária/etiologia , Neuroblastoma/induzido quimicamente , Neuroblastoma/tratamento farmacológico , Estudos Retrospectivos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/etiologia , Vincristina
4.
Zhongguo Dang Dai Er Ke Za Zhi ; 24(9): 1036-1041, 2022.
Artigo em Chinês | MEDLINE | ID: mdl-36111723

RESUMO

OBJECTIVES: To study the clinical features of children with rhabdomyosarcoma (RMS) and the influencing factors for prognosis. METHODS: A retrospective analysis was performed on the clinical and follow-up data of 20 children with RMS who were admitted to the Department of Pediatric Hematology, Xiangya Hospital of Central South University, from June 2014 to September 2020. RESULTS: The most common clinical symptoms of the 20 children with RMS at the first visit were painless mass (13/20, 65%), exophthalmos (4/20, 20%), and abdominal pain (3/20, 15%). According to the staging criteria of Intergroup Rhabdomyosarcoma Study Group (IRSG), there was 1 child (5%) with stage I RMS, 4 (20%) with stage II RMS, 9 (45%) with stage III RMS, and 6 (30%) with stage IV RMS. The median follow-up time was 19 months for the 20 children (range: 3-93 months), with a 2-year overall survival (OS) rate of 79.5% (95%CI: 20.1-24.3) and a 2-year event-free survival (EFS) rate of 72.0% (95%CI: 19.5-23.9). Pleomorphic RMS was associated with the reduced 2-year OS rate (P<0.05), and distant metastasis, IRSG stage IV RMS, and high-risk RMS were associated with the reduced 2-year EFS rate (P<0.05). CONCLUSIONS: RMS has no specific clinical symptoms at the first visit, with painless mass as the most common symptom. Distant metastasis, IRSG stage, and risk degree may be associated with the prognosis of children with RMS.


Assuntos
Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Criança , Humanos , Prognóstico , Estudos Retrospectivos , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/terapia , Taxa de Sobrevida
5.
Afr J Paediatr Surg ; 19(4): 251-253, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36018208

RESUMO

Rhabdomyosarcoma (RMS) is one of the common malignant soft-tissue sarcomas affecting children. It originates from the embryonic mesenchyme precursor of striated muscle and is frequently seen in the head-and-neck region, genitourinary system and extremities. Occasionally, it arises from the retroperitoneum, biliary tract and abdomen and is rarely seen in the sacrococcygeal area. A 4-month-male child presented with a nodule over the sacrum. Based on histopathology and immunohistochemical marker studies, a final diagnosis of RMS was rendered. There was no evidence of any teratomatous elements.


Assuntos
Rabdomiossarcoma , Neoplasias de Tecidos Moles , Teratoma , Criança , Humanos , Masculino , Região Sacrococcígea
6.
Cell Rep ; 40(9): 111267, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36044855

RESUMO

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood characterized by the inability to exit the proliferative myoblast-like stage. The alveolar fusion positive subtype (FP-RMS) is the most aggressive and is mainly caused by the expression of PAX3/7-FOXO1 oncoproteins, which are challenging pharmacological targets. Here, we show that the DEAD box RNA helicase 5 (DDX5) is overexpressed in alveolar RMS cells and that its depletion and pharmacological inhibition decrease FP-RMS viability and slow tumor growth in xenograft models. Mechanistically, we provide evidence that DDX5 functions upstream of the EHMT2/AKT survival signaling pathway, by directly interacting with EHMT2 mRNA, modulating its stability and consequent protein expression. We show that EHMT2 in turns regulates PAX3-FOXO1 activity in a methylation-dependent manner, thus sustaining FP-RMS myoblastic state. Together, our findings identify another survival-promoting loop in FP-RMS and highlight DDX5 as a potential therapeutic target to arrest RMS growth.


Assuntos
RNA Helicases DEAD-box , Rabdomiossarcoma Alveolar , Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Linhagem Celular Tumoral , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Proteínas de Fusão Oncogênica/metabolismo , Fatores de Transcrição Box Pareados/genética , RNA Helicases/metabolismo , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Alveolar/patologia
7.
Asian Pac J Cancer Prev ; 23(8): 2805-2811, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-36037137

RESUMO

INTRODUCTION: There is limited data available on the treatment outcomes of pediatric rhabdomyosarcoma (RMS) in Asian populations. Therefore, we aimed to review the baseline characteristics, clinical outcomes, and prognostic factors in children with RMS from Thailand. METHODS: The data of children under 15 years of age diagnosed with RMS between 2003 and 2019 from a large tertiary hospital in Southern Thailand were retrospectively reviewed. Descriptive statistics were utilized to describe the clinical characteristics. The Kaplan-Meier method was utilized to estimate survival. Cox proportional hazards regression analysis was utilized to determine prognostic factors that affect survival. RESULTS: A total of 42 children RMS were included in this study. The median age at diagnosis was 6.4 years (IQR, 2.4-10.2). Among these patients, 11 (26%) were older than 10 years, and 13 (31%) presented with metastatic disease at diagnosis. The 5-year overall survival (OS) rate was 39% for all children. Age greater than 10 years (hazard ratio (HR): 3.3, 95% CI: 1.2-9.2) and metastatic disease at diagnosis (hazard ratio (HR): 2.8, 95% CI: 1.1-7.5) were independently associated with poorer survival. The 3-year OS for children with metastatic disease (stage IV) was 15% (95% CI: 4.3-55). CONCLUSION: The percentage of metastatic disease in our cohort was higher than that in previous reports and may have contributed to a poorer outcome. Age greater than 10 years and metastatic disease at diagnosis were noted as adverse prognostic factors.


Assuntos
Rabdomiossarcoma , Criança , Humanos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Tailândia/epidemiologia , Resultado do Tratamento
8.
Nat Cancer ; 3(8): 961-975, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35982179

RESUMO

Rhabdomyosarcoma (RMS) is a common childhood cancer that shares features with developing skeletal muscle. Yet, the conservation of cellular hierarchy with human muscle development and the identification of molecularly defined tumor-propagating cells has not been reported. Using single-cell RNA-sequencing, DNA-barcode cell fate mapping and functional stem cell assays, we uncovered shared tumor cell hierarchies in RMS and human muscle development. We also identified common developmental stages at which tumor cells become arrested. Fusion-negative RMS cells resemble early myogenic cells found in embryonic and fetal development, while fusion-positive RMS cells express a highly specific gene program found in muscle cells transiting from embryonic to fetal development at 7-7.75 weeks of age. Fusion-positive RMS cells also have neural pathway-enriched states, suggesting less-rigid adherence to muscle-lineage hierarchies. Finally, we identified a molecularly defined tumor-propagating subpopulation in fusion-negative RMS that shares remarkable similarity to bi-potent, muscle mesenchyme progenitors that can make both muscle and osteogenic cells.


Assuntos
Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Criança , Humanos , Músculo Esquelético/patologia , Rabdomiossarcoma/genética , Análise de Célula Única , Células-Tronco/patologia
9.
BMJ Case Rep ; 15(8)2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-35999020

RESUMO

In developing tropical countries, rhino-orbital-cerebral mucormycosis has been a cause of severe morbidity and mortality during the COVID-19 pandemic. Classically, it develops as an aggressive angioinvasive destruction of nasal, orbital and cerebral involvement. Blindness is a major disabling complication. The association of mucor in cancer is linked with immunosuppression caused by radiation and/or chemotherapy. In this case report, we tried to explore the diverse possibilities of neck swelling, nasal discharge, ocular swelling and dimness of vision in a teenage boy. Rhabdomyosarcoma is a rare tumour of the soft tissue, connective tissue or bone. This type of unusual association or coexistence of rhabdomyosarcoma with mucormycetes is rarely seen in literature.


Assuntos
COVID-19 , Oftalmopatias , Mucormicose , Doenças Orbitárias , Neoplasias Orbitárias , Rabdomiossarcoma , Adolescente , Oftalmopatias/complicações , Humanos , Masculino , Mucormicose/complicações , Mucormicose/diagnóstico , Doenças Orbitárias/complicações , Neoplasias Orbitárias/complicações , Pandemias , Rabdomiossarcoma/complicações , Rabdomiossarcoma/terapia
10.
Artigo em Chinês | MEDLINE | ID: mdl-35959585

RESUMO

In this article we reported 13 cases of the substantial nasal mass in children. Among 13 these patients, 3 cases were septal hemangioma, 2 cases were maxillary hemangioma, 1 case was nasal infantile fibromatosis, 1 case was osteoblastoma of the nasal cavity and sinuses, 2 cases were lymphoma of nasopharynx, 1 case was maxillary lymphoma, 1 case was rhabdomyosarcoma of nasopharynx, 1 case was maxillary squamous-cell carcinoma, 1 case was squamous-cell carcinoma of nasopharynx.All 13 cases were treated with surgery, 1 case with nasal infantile fibromatosis, 2 cases with lymphoma of nasopharynx, 1 case with rhabdomyosarcoma of nasopharynx, 1 case with nasopharyngeal carcinoma and 1 case with maxillary carcinoma were taken postoperative radiotherapy and chemotherapy. The most common substantial nasal mass in children was hemangioma. This study included 2 cases with nasal invasive benign tumors, 1 case with nasal infantile fibromatosis and 1 case with osteoblastoma of the nasal cavity and sinuses. The functional nasal endoscopic surgery of mass resection was the main method for the treatment of mass in this area and had achieved satisfied effect. Lymphoma and rhabdomyosarcoma were the most common nasal malignant tumor in children. Nasopharyngeal carcinoma and maxillary carcinoma were not uncommon.


Assuntos
Neoplasias Ósseas , Carcinoma de Células Escamosas , Fibroma , Hemangioma , Linfoma , Neoplasias Nasofaríngeas , Neoplasias Nasais , Osteoblastoma , Rabdomiossarcoma , Carcinoma de Células Escamosas/patologia , Criança , Fibroma/patologia , Humanos , Cavidade Nasal/patologia , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasais/patologia , Neoplasias Nasais/terapia , Osteoblastoma/patologia
11.
Pediatr Blood Cancer ; 69(11): e29924, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35969120

RESUMO

In this article, we will discuss the genesis, evolution, and progress of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT), which aims to foster international research and collaboration focused on pediatric soft tissue sarcoma. We will begin by highlighting the current state of clinical research for pediatric soft tissue sarcomas, including rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma. We will then explore challenges and research priorities, describe the development of INSTRuCT, and discuss how the consortium aims to address key research priorities.


Assuntos
Rabdomiossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Criança , Humanos , Sarcoma/terapia , Neoplasias de Tecidos Moles/terapia
12.
BMJ Case Rep ; 15(8)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36038153

RESUMO

In this report, we describe the case of an adolescent male with an unusual case of fusion-negative, paratesticular alveolar rhabdomyosarcoma who presented with spontaneous tumour lysis syndrome and diffuse bony metastases throughout the axial and appendicular skeleton with additional significant bone marrow involvement. Both spontaneous tumour lysis syndrome and diffuse bony metastases are extremely unusual for rhabdomyosarcoma. On the backbone of standard vincristine, dactinomycin and cyclophosphamide (VAC) chemotherapy, the only local control was orchiectomy at 15 weeks, with no radiation administered due to the initially diffuse nature of the disease and rapid response to chemotherapy. Following 43 weeks of VAC, a year-long maintenance phase with pazopanib was given which was well tolerated. The patient remains in remission now 4 years after completion of therapy.


Assuntos
Doenças da Medula Óssea , Neoplasias Ósseas , Neoplasias dos Genitais Masculinos , Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Síndrome de Lise Tumoral , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica , Doenças da Medula Óssea/induzido quimicamente , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Ciclofosfamida , Dactinomicina/uso terapêutico , Neoplasias dos Genitais Masculinos/tratamento farmacológico , Humanos , Masculino , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/patologia , Rabdomiossarcoma Embrionário/tratamento farmacológico , Síndrome de Lise Tumoral/etiologia , Vincristina
13.
Biomolecules ; 12(8)2022 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-36009022

RESUMO

Metastatic alveolar rhabdomyosarcoma (aRMS) is an aggressive paediatric cancer with a poor prognosis. Downregulation of critical tumour genes using targeted siRNA remains an obstacle, but association with nanoparticles could help to deliver, protect, target, and enhance penetration. siRNA towards two genes was investigated: (i) Human αB-crystallin (CRYAB) and Heat Shock Protein Family B (Small) Member 2 (HSPB2), and (ii) Keratin 17 (KRT17). A mesoporous silica based nanosystem was linked to siRNA via disulfide bonds and loaded with IR820 dye. Transfection efficiency and signalling was evaluated, and the metabolic effects and cell proliferation were monitored in 2D culture and 3D spheroid models. The bound siRNA was protected from degradation with RNase I for at least 24 h. The delivered siRNA showed significant suppression of viability; 53.21 ± 23.40% for CRYAB and HSPB2 siRNA, and 88.06 ± 17.28% for KRT17 siRNA. After 72 h this increased to >50% cell apoptosis and necrosis. Intracellular total glutathione (GSH) levels were also compared with fibroblasts, and the RMS cell lines showed a several-fold increase. IR820 cellular uptake rate and penetration depth was significantly improved by nanoparticle delivery. Targetted siRNA delivery may pave the way for less invasive and more effective treatments of aRMS.


Assuntos
Nanopartículas , Rabdomiossarcoma , Linhagem Celular Tumoral , Criança , Glutationa/genética , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , RNA Interferente Pequeno/genética , Rabdomiossarcoma/genética , Transfecção , Cadeia B de alfa-Cristalina/metabolismo
15.
Turk J Pediatr ; 64(3): 519-530, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35899565

RESUMO

BACKGROUND: The tumor localization/extent and imaging characteristics of rhabdomyosarcomas (RMSs) especially parameningeal type, could overlap with the common tumors of the head and neck (H&N) such as lymphoma and nasopharyngeal carcinoma (NPC). Our goal was to investigate magnetic resonance imaging (MRI) features that could favor the diagnosis of RMS over lymphoma and NPC in H&N region. METHODS: Pretreatment MRI of 42 pediatric patients (mean: 9.7±5.1 years, min-max: 2-18 years) with a recent diagnosis of RMS (n=12), lymphoma (n=14) and NPC (n=16) were retrospectively studied. Tumor localization, extension and spread were evaluated. Signal and enhancement characteristics of the tumors and the presence of necrosis were noted. ADC values were measured by using both the small sample and single slice methods. For comparison of three groups, the Kruskal Wallis test and Pairwise comparisons were used. The intra-class correlation coefficient (ICC) was calculated for the assessment of inter-observer agreement. RESULTS: Nasopharynx ±parapharyngeal space involvement was detected in 58.3% of RMSs. Rhabdomyosarcoma was more heterogeneous in T2 images compared to lymphoma (p=0.014). Rhabdomyosarcoma showed significantly higher frequency of heterogeneous enhancement (p < 0.001) and necrosis (p < 0.001) among these tumors. The mean ADC values of lymphoma were significantly lower than the values of RMS (p < 0.001) and NPC (p < 0.01) for both observers. The mean ADC values were higher in RMSs than NPCs (p > 0.05). Intra-class correlation in ADC measurements was higher for the single slice method (ICC=0.997) than the small sample method (ICC=0.989). CONCLUSIONS: Rhabdomyosarcoma tends to have higher ADC values than lymphoma and has a higher frequency of heterogeneous enhancement and necrotic parts than both lymphoma and nasopharyngeal carcinoma. These features could help radiologists to differentiate RMS from the above-mentioned mimickers.


Assuntos
Neoplasias de Cabeça e Pescoço , Linfoma , Neoplasias Nasofaríngeas , Rabdomiossarcoma , Criança , Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Humanos , Linfoma/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnóstico por imagem , Neoplasias Nasofaríngeas/patologia , Necrose , Estudos Retrospectivos , Rabdomiossarcoma/diagnóstico por imagem
16.
Nat Commun ; 13(1): 4297, 2022 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-35879366

RESUMO

Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression of PAX3-FOXO1 in muscle progenitor cells is not only sufficient to increase sensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibit increased sensitivity to structurally diverse inhibitors of ATR. Mechanistically, ATR inhibition leads to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increases sensitivity of ARMS cells to PARP1 inhibition in vitro, and combined treatment with ATR and PARP1 inhibitors induces complete regression of primary patient-derived ARMS xenografts in vivo. Lastly, a genome-wide CRISPR activation screen (CRISPRa) in combination with transcriptional analyses of ATR inhibitor resistant ARMS cells identifies the RAS-MAPK pathway and its targets, the FOS gene family, as inducers of resistance to ATR inhibition. Our findings provide a rationale for upcoming biomarker-driven clinical trials of ATR inhibitors in patients suffering from ARMS.


Assuntos
Rabdomiossarcoma Alveolar , Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição PAX3/genética , Fatores de Transcrição Box Pareados/genética , Rabdomiossarcoma/genética , Rabdomiossarcoma Alveolar/tratamento farmacológico , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Embrionário/genética
17.
Sci Transl Med ; 14(653): eabq2096, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35857643

RESUMO

Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1-governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1+ RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1-related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.


Assuntos
Rabdomiossarcoma Alveolar , Rabdomiossarcoma , Carcinogênese/genética , Linhagem Celular Tumoral , Criança , Proteína Forkhead Box O1/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fator de Transcrição PAX3/genética , Fator de Transcrição PAX3/metabolismo , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Fatores de Transcrição Box Pareados/uso terapêutico , Rabdomiossarcoma/genética , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Alveolar/patologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-35840496

RESUMO

OBJECTIVE: This systematic review aimed to identify the molecular alterations of head and neck rhabdomyosarcomas (HNRMS) and their prognostic values. STUDY DESIGN: An electronic search was performed using PubMed, Embase, Scopus, and Web of Science with a designed search strategy. Inclusion criteria comprised cases of primary HNRMS with an established histopathological diagnosis and molecular analysis. Forty-nine studies were included and were appraised for methodological quality using the Joanna Briggs Institute Critical Appraisal tools. Five studies were selected for meta-analysis. RESULTS: HNRMS predominantly affects pediatric patients (44.4%), and the parameningeal region (57.7%) is the most common location. The alveolar variant (43.2%) predominates over the embryonal and spindle cell/sclerosing types, followed by the epithelioid and pleomorphic variants. PAX-FOXO1 fusion was observed in 103 cases of alveolar RMS (79.8%). MYOD1 mutation was found in 39 cases of sclerosing/spindle cell RMS (53.4%). FUS/EWSR1-TFCP2 gene fusions were identified in 21 cases of RMS with epithelioid and spindle cell morphologies (95.5%). The 5-year overall survival rate of patients was 61.3%, and MYOD1 mutation correlated with significantly higher mortality. CONCLUSION: The genotypic profile of histologic variants of HNRMS is widely variable, and MYOD1 mutation could be a potential prognostic factor, but more studies are required to establish this.


Assuntos
Rabdomiossarcoma , Criança , Proteínas de Ligação a DNA/genética , Humanos , Mutação , Rabdomiossarcoma/genética , Fatores de Transcrição/genética
19.
J Colloid Interface Sci ; 626: 916-929, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-35835042

RESUMO

Sialic acid is a fundamental component of the tumor microenvironment, modulates cell-cell and cell-extracellular matrix interactions and is associated with bad prognosis and clinical outcomes in different cancers. Capitalizing on the ability of boric acid to form cyclic esters with diols, in this work, we design self-assembled multi-micellar colloidal systems of an amphiphilic poly(vinyl alcohol)-g-poly(methyl methacrylate) copolymer surface-modified with boric acid for the active targeting of solid tumors that overexpress sialic acid. Nanoparticles display sizes in the 100-200 nm range and a spherical morphology, as determined by dynamic light scattering and high resolution-scanning electron microscopy, respectively. The uptake and anti-proliferative activity are assessed in 2D and 3D models of rhabdomyosarcoma in vitro. Surface boration increases the nanoparticle permeability and uptake, especially in rhabdomyosarcoma spheroids that overexpress sialic acid to a greater extent than 2D cultures. The biodistribution of non-borated and borated nanoparticles upon intravenous injection to a subcutaneous rhabdomyosarcoma murine xenograft model confirm a statistically significant increase in the intertumoral accumulation of the modified nanocarriers with respect to the unmodified counterparts and a sharp decrease in major clearance organs such as the liver. Overall, our results highlight the promise of these borated nanomaterials to actively target hypersialylated solid tumors.


Assuntos
Nanopartículas , Rabdomiossarcoma , Animais , Ácidos Bóricos , Humanos , Camundongos , Ácido N-Acetilneuramínico , Polímeros , Polimetil Metacrilato , Distribuição Tecidual , Microambiente Tumoral
20.
Eur J Cancer ; 172: 367-386, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35839732

RESUMO

Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence of 1-2/million. Inter/intra-tumour heterogeneity raise challenges in clinical, pathological and biological research studies. Risk stratification in European and North American clinical trials previously relied on clinico-pathological features, but now, incorporates PAX3/7-FOXO1-fusion gene status in the place of alveolar histology. International working groups propose a coordinated approach through the INternational Soft Tissue SaRcoma ConsorTium to evaluate the specific genetic abnormalities and generate and integrate molecular and clinical data related to patients with RMS across different trial settings. We review relevant data and present a consensus view on what molecular features should be assessed. In particular, we recommend the assessment of the MYOD1-LR122R mutation for risk escalation, as it has been associated with poor outcomes in spindle/sclerosing RMS and rare RMS with classic embryonal histopathology. The prospective analyses of rare fusion genes beyond PAX3/7-FOXO1 will generate new data linked to outcomes and assessment of TP53 mutations and CDK4 amplification may confirm their prognostic value. Pathogenic/likely pathogenic germline variants in TP53 and other cancer predisposition genes should also be assessed. DNA/RNA profiling of tumours at diagnosis/relapse and serial analyses of plasma samples is recommended where possible to validate potential molecular biomarkers, identify new biomarkers and assess how liquid biopsy analyses can have the greatest benefit. Together with the development of new molecularly-derived therapeutic strategies that we review, a synchronised international approach is expected to enhance progress towards improved treatment assignment, management and outcomes for patients with RMS.


Assuntos
Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Neoplasias de Tecidos Moles , Adolescente , Criança , Consenso , Humanos , Técnicas de Diagnóstico Molecular , Recidiva Local de Neoplasia , Estudos Prospectivos , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Rabdomiossarcoma/terapia , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/terapia , Medição de Risco , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia
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