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1.
Nat Commun ; 12(1): 5520, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535684

RESUMO

PTEN promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Here we show Pten deletion in a mouse model of FN-RMS results in less differentiated tumors more closely resembling human embryonal RMS. PTEN loss activated the PI3K pathway but did not increase mTOR activity. In wild-type tumors, PTEN was expressed in the nucleus suggesting loss of nuclear PTEN functions could account for these phenotypes. Pten deleted tumors had increased expression of transcription factors important in neural and skeletal muscle development including Dbx1 and Pax7. Pax7 deletion completely rescued the effects of Pten loss. Strikingly, these Pten;Pax7 deleted tumors were no longer FN-RMS but displayed smooth muscle differentiation similar to leiomyosarcoma. These data highlight how Pten loss in FN-RMS is connected to a PAX7 lineage-specific transcriptional output that creates a dependency or synthetic essentiality on the transcription factor PAX7 to maintain tumor identity.


Assuntos
Fator de Transcrição PAX7/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Animais , Cruzamento , Diferenciação Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Integrases/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Knockout , Desenvolvimento Muscular , PTEN Fosfo-Hidrolase/deficiência , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Rabdomiossarcoma/genética
2.
J Clin Oncol ; 39(27): 2979-2990, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34343032

RESUMO

PURPOSE: The VIT-0910 trial was conducted to evaluate efficacy and safety of the vincristine-irinotecan combination with and without temozolomide (VIT and VI, respectively) in relapsed or refractory rhabdomyosarcoma (RMS). METHODS: In this randomized European phase II trial, patients age 0.5-50 years received 21-day cycles combining vincristine (1.5 mg/m2 once a day on day 1 and day 8) and irinotecan (50 mg/m2 once a day from day 1 to day 5) with and without temozolomide (125 mg/m2 once a day from day 1 to day 5 and 150 mg/m2 once a day from cycle 2), until progression or unacceptable toxicity. The primary end point was objective response rate after two cycles. Secondary end points included best response, progression-free survival, overall survival, and adverse events. A Simon 2-stage design was initially planned to separately analyze 40 patients/arm. After amendment, the trial sample size was increased to 120 and a comparison between arms, adjusted for confounding factors, was added to the statistical plan (ClinicalTrials.gov, NCT01355445). RESULTS: Overall, 120 patients (60 per arm) were recruited in 37 European centers. The median age was 11 years (range, 0.75-45); 89% of patients had a relapsed RMS. The objective response rate was 44% (24 of 55 evaluable patients) for VIT versus 31% (18 of 58) for VI (adjusted odds ratio, 0.50; 95% CI, 0.22 to 1.12; P = .09). The VIT arm achieved significantly better overall survival (adjusted hazard ratio, 0.55; 95% CI, 0.35 to 0.84; P = .006) compared with VI, with consistent progression-free survival results (adj-hazard ratio, 0.68; 95% CI, 0.46 to 1.01; P = .059). Overall, patients experienced adverse events ≥ grade 3 more frequently with VIT than VI (98% v 78%, respectively; P = .009), including a significant excess of hematologic toxicity (81% v 61%; P = .025). CONCLUSION: The addition of temozolomide to VI improved chemotherapy efficacy for patients with relapsed RMS, with manageable increase in toxicity. VIT is considered the new standard treatment in these patients in the European paediatric Soft Tissue Sarcoma Group and will be the control arm in the next randomized trial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Irinotecano/uso terapêutico , Rabdomiossarcoma/tratamento farmacológico , Temozolomida/uso terapêutico , Vincristina/uso terapêutico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Lactente , Recém-Nascido , Irinotecano/farmacologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Rabdomiossarcoma/patologia , Temozolomida/farmacologia , Vincristina/farmacologia , Adulto Jovem
3.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360791

RESUMO

Rhabdomyosarcoma (RMS) is a malignant soft tissue cancer that develops mostly in children and young adults. With regard to histopathology, four rhabdomyosarcoma types are distinguishable: embryonal, alveolar, pleomorphic and spindle/sclerosing. Currently, increased amounts of evidence indicate that not only gene mutations, but also epigenetic modifications may be involved in the development of RMS. Epigenomic changes regulate the chromatin architecture and affect the interaction between DNA strands, histones and chromatin binding proteins, thus, are able to control gene expression. The main aim of the study was to assess the role of protein arginine methyltransferases (PRMT) in the cellular biology of rhabdomyosarcoma. In the study we used two pan-inhibitors of PRMT, called AMI-1 and SAH, and evaluated their effects on proliferation and apoptosis of RMS cells. We observed that AMI-1 and SAH reduce the invasive phenotype of rhabdomyosarcoma cells by decreasing their proliferation rate, cell viability and ability to form cell colonies. In addition, microarray analysis revealed that these inhibitors attenuate the activity of the PI3K-Akt signaling pathway and affect expression of genes related to it.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Naftalenossulfonatos/farmacologia , Proteína-Arginina N-Metiltransferases , Rabdomiossarcoma , Transdução de Sinais/efeitos dos fármacos , Ureia/análogos & derivados , Linhagem Celular Tumoral , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/enzimologia , Rabdomiossarcoma/patologia , Ureia/farmacologia
4.
Ann R Coll Surg Engl ; 103(10): e327-e329, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34414778

RESUMO

Rhabdomyosarcoma is an infrequent muscular cancer seen in adults. We present a case of ileal intussusception due to pleomorphic rhabdomyosarcoma in a patient diagnosed previously with squamous cell carcinoma of the lung (SCCL). The patient was a 68-year-old man with a history of SCCL. He was admitted to the emergency department for nausea, emesis and obstipation. Surgical investigation of the abdomen revealed an intussusception caused by a tumour located 160cm distal of the ligament of Treitz. Pathological examination showed that tumour was a primary rhabdomyosarcoma of the ileum. This case contributes to the literature by defining an infrequent presentation of rhabdomyosarcoma causing ileal intussusception in an adult patient.


Assuntos
Neoplasias do Íleo/cirurgia , Neoplasias Pulmonares/terapia , Segunda Neoplasia Primária/diagnóstico , Neoplasias de Células Escamosas/terapia , Rabdomiossarcoma/cirurgia , Idoso , Humanos , Doenças do Íleo/etiologia , Doenças do Íleo/cirurgia , Neoplasias do Íleo/complicações , Neoplasias do Íleo/diagnóstico , Neoplasias do Íleo/patologia , Intussuscepção/etiologia , Intussuscepção/cirurgia , Masculino , Segunda Neoplasia Primária/patologia , Rabdomiossarcoma/complicações , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/patologia
5.
Pediatr Radiol ; 51(10): 1940-1951, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34137936

RESUMO

Appropriate imaging is essential in the treatment of children and adolescents with rhabdomyosarcoma. For adequate stratification and optimal individualised local treatment utilising surgery and radiotherapy, high-quality imaging is crucial. The paediatric radiologist, therefore, is an essential member of the multi-disciplinary team providing clinical care and research. This manuscript presents the European rhabdomyosarcoma imaging guideline, based on the recently developed guideline of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) Imaging Committee. This guideline was developed in collaboration between the EpSSG Imaging Committee, the Cooperative Weichteilsarkom Studiengruppe (CWS) Imaging Group, and the Oncology Task Force of the European Society of Paediatric Radiology (ESPR). MRI is recommended, at diagnosis and follow-up, for the evaluation of the primary tumour and its relationship to surrounding tissues, including assessment of neurovascular structures and loco-regional lymphadenopathy. Chest CT along with [F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/CT or PET/MRI are recommended for the detection and evaluation of loco-regional and distant metastatic disease. Guidance on the estimation of treatment response, optimal long-term follow-up, technical imaging settings and standardised reporting are described. This European imaging guideline outlines the recommendations for imaging in children and adolescents with rhabdomyosarcoma, with the aim to harmonise imaging and to advance patient care.


Assuntos
Radiologia , Rabdomiossarcoma , Sarcoma , Adolescente , Criança , Humanos , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Rabdomiossarcoma/diagnóstico por imagem , Rabdomiossarcoma/patologia , Rabdomiossarcoma/terapia , Sarcoma/patologia
6.
Medicine (Baltimore) ; 100(24): e26105, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34128847

RESUMO

RATIONALE: Skeletal muscle tumors are traditionally classified as rhabdomyomas or rhabdomyosarcomas. However, some soft tissue tumors cannot easily be identified as benign or malignant. We report a case of a histiocyte-rich rhabdomyoblastic tumor, with pathologic characteristics distinct from either rhabdomyoma or rhabdomyosarcoma. In contrast to rhabdomyosarcomas, the tumor cells exhibited low mitotic activity, lacking obvious morphologic atypia. Clinically, the tumor followed a very indolent course. Overall, the tumor did not fit classification criteria for either benign or malignant. PATIENT CONCERNS: A 58-year-old Chinese man was admitted to Qilu Hospital on September 8, 2018, with a >20 year history of a mass in the middle of the left thigh. A few months prior to admission, he had experienced the pain from the mass extending to the distal left lower extremity. He had no prior history of significant disease or relevant family history. DIAGNOSES: Microscopically, numerous histiocytes and foamy cells covered the actual tumor cells that were positive for desmin, MyoD1, and myogenin, suggesting striated skeletal muscle cell differentiation. However, cross-striations were not detected in the tumor cells. The tumor was characterized by a non-infiltrative growth pattern and a low level of Ki67. A diagnosis of histiocyte-rich rhabdomyoblastic tumor was suggested. INTERVENTIONS: The thigh mass was surgically resected September 12, 2018. OUTCOMES: The patient recovered well postoperatively, and was free of tumor recurrence or metastasis, followed to September 12, 2020 (23 months). LESSONS: Histiocyte-rich rhabdomyoblastic tumor cells have minor atypia, indicating possible malignant potential. However, the tumor behavior was quit indolent. Due to the conflicting clinical and pathologic aspects of the tumor, to label it as rhabdomyosarcoma seemed inaccurate, potentially prompting over treatment. Interestingly, mutations were detected in NF1, AXIN2, CHEK2, DNMT3A, KMT2D, and RB1 through next-generation sequencing. These mutations suggest disruptions in Ras signaling, the Wnt pathway, methyltransferases, and the cell cyclepotentially influencing the development of this histiocyte-rich rhabdomyoblastic tumor. This unusual tumor should be incorporated into the WHO Classification of Soft Tissue Tumors owing to its unique characteristics.


Assuntos
Histiócitos/patologia , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Biomarcadores Tumorais/genética , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Coxa da Perna/patologia
7.
Int J Radiat Biol ; 97(7): 943-957, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33979259

RESUMO

PURPOSE: Herein we describe the in vitro and in vivo activity of FK228 (Romidepsin), an inhibitor of class I HDACs, in counteracting and radiosensitizing embryonal (ERMS, fusion-negative) and alveolar (ARMS, fusion-positive) rhabdomyosarcoma (RMS). METHODS: RH30 (ARMS, fusion-positive) and RD (ERMS, fusion-negative) cell lines and human multipotent mesenchymal stromal cells (HMSC) were used. Flow cytometry analysis, RT-qPCR, western blotting and enzymatic assays were performed. Irradiation was delivered by using an x-6 MV photon linear accelerator. FK228 (1.2 mg/kg) in vivo activity, combined or not with radiation therapy (2 Gy), was assessed in murine xenografts. RESULTS: Compared to HMSC, RMS expressed low levels of class I HDACs. In vitro, FK228, as single agents, reversibly downregulated class I HDACs expression and activity and induced oxidative stress, DNA damage and a concomitant growth arrest associated with PARP-1-mediated transient non-apoptotic cell death. Surviving cells upregulated the expression of cyclin A, B, D1, p27, Myc and activated PI3K/Akt/mTOR and MAPK signaling, known to be differently involved in cancer chemoresistance. Interestingly, while no radiosensitizing effects were detected, in vitro or in vivo, on RD cells, FK228 markedly radiosensitized RH30 cells by impairing antioxidant and DSBs repair pathways in vitro. Further, FK228 when combined with RT in vivo significantly reduced tumor mass in mouse RH30 xenografts. CONCLUSION: FK228 did not show antitumor activity as a single agent whilst its combination with RT resulted in radiosensitization of fusion-positive RMS cells, thus representing a possible strategy for the treatment of the most aggressive RMS subtype.


Assuntos
Transformação Celular Neoplásica , Depsipeptídeos/farmacologia , Fenótipo , Radiossensibilizantes/farmacologia , Rabdomiossarcoma/patologia , Animais , Apoptose/efeitos da radiação , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos da radiação , Linhagem Celular Tumoral , Humanos , Camundongos
8.
Ann Surg Oncol ; 28(13): 9048-9059, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34057567

RESUMO

BACKGROUND: Our aim is to show whether the sentinel node procedure (SNP) is recommendable for pediatric patients with extremity rhabdomyosarcoma (RMS). Lymph node metastases are an important prognostic factor in pediatric patients with extremity RMS. Accurate nodal staging is necessary to treat the patient accordingly. An alternative to the current recommended lymph node sampling is the sentinel node procedure (SNP). METHODS: A systematic review was performed summarizing all published cases of SNP in addition to 13 cases from our hospital and 8 cases from two other hospitals that have not been published before. RESULTS: For all patients (n = 55), at least one SLN was identified, but the SNP technique used was not uniform. The SNP changed the nodal classification of eight patients (17.0%) and had a false-negative rate of 10.5%. CONCLUSIONS: The SNP is recommendable for pediatric patients with extremity RMS. It can change lymph node status and can be used to sample patients in a more targeted way than nodal sampling alone. Therefore, we recommend use of the SNP in addition to clinical and radiological nodal assessment for pediatric patients with extremity RMS.


Assuntos
Rabdomiossarcoma , Linfonodo Sentinela , Criança , Extremidades/patologia , Extremidades/cirurgia , Humanos , Excisão de Linfonodo , Linfonodos/patologia , Linfonodos/cirurgia , Estadiamento de Neoplasias , Estudos Retrospectivos , Rabdomiossarcoma/patologia , Rabdomiossarcoma/cirurgia , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia , Biópsia de Linfonodo Sentinela
9.
Pediatr Blood Cancer ; 68 Suppl 2: e28254, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33818882

RESUMO

Rhabdomyosarcoma is a heterogeneous disease both in presentation and histology. Improvements in a multimodality therapy resulted in the improved overall survival for patients with a low-risk and intermediate-risk disease but not for patients with a metastatic disease. We reviewed and contrasted the North American and European practice patterns, though ultimately the principles of staging, surgery, radiation therapy, and chemotherapy are similar in both Children's Oncology Group and International Society of Paediatric Oncology treatment approaches. Efforts are underway to investigate improved local control rates in higher risk patients using radiation dose escalation strategies, and delayed primary excision in select cases. The prognostic significance of imaging-based chemotherapy response, proton therapy, novel biomarkers, and targeted drugs will be determined in upcoming clinical trials.


Assuntos
Rabdomiossarcoma/terapia , Criança , Terapia Combinada , Humanos , Prognóstico , Rabdomiossarcoma/patologia , Taxa de Sobrevida
10.
Strahlenther Onkol ; 197(8): 690-699, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33914102

RESUMO

BACKGROUND: Treatment of extremity rhabdomyosarcomas (RMS) includes chemotherapy, surgery, and radiotherapy. Lymph node irradiation is recommended in the presence of regional node involvement at diagnosis. The aim of this study was to analyze the correlation between the pattern of relapse of non-metastatic extremity RMS and the initial therapies delivered. METHODS: All patients with localized extremity RMS prospectively treated in France in the MMT-95 and RMS-05 protocols were selected. Extent of disease and pattern of relapse were evaluated by clinical examination and imaging. RESULTS: We identified 59 patients with clinical characteristics corresponding to unfavorable prognostic factors. Twenty patients (34%) were considered to have lymph node involvement at diagnosis. Regional node biopsy was performed in 32 patients (54%) and modified the lymph node stage in 8 of the 59 patients (14%). Seventy-three percent of patients received radiotherapy. Fifty-two patients achieved first remission. Overall, 26 patients underwent complete tumor resection, 17 had R1 margins, and 5 were not operated due to early tumor progression. With a median follow-up of 82 months (range: 5-287), 18 relapses had occurred, at least locoregional in 12 cases. The 5­year local and nodal control rates were 73% (63-86%) and 86% (77-95%), respectively. Five-year progression-free and overall survival were 57% (95%CI [45-72%]) and 70% (95%CI [58-84%]), respectively. CONCLUSION: The main sites of extremity RMS relapse are locoregional. Nodal failures in non-irradiated fields are not uncommon. We recommend systematic biopsy of in-transit nodes, especially in alveolar RMS and/or RMS with regional positive nodes at diagnosis to ensure their negativity.


Assuntos
Extremidades/patologia , Recidiva Local de Neoplasia/patologia , Rabdomiossarcoma/patologia , Rabdomiossarcoma/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Linfonodos/patologia , Masculino , Estadiamento de Neoplasias , Estudos Retrospectivos , Rabdomiossarcoma/radioterapia , Rabdomiossarcoma/cirurgia
11.
Cell ; 184(8): 2033-2052.e21, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33765443

RESUMO

Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment. Our data demonstrate that IL12-GEMy treatment reverses immune suppression in the pre-metastatic niche by activating antigen presentation and T cell activation, resulting in reduced metastatic and primary tumor burden and improved survival of tumor-bearing mice. We demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer.


Assuntos
Imunossupressão , Células Mieloides/metabolismo , Imunidade Adaptativa , Animais , Linhagem Celular Tumoral , Engenharia Genética , Humanos , Interleucina-12/genética , Interleucina-12/metabolismo , Pulmão/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/citologia , Células Mieloides/imunologia , Metástase Neoplásica , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Taxa de Sobrevida , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral
12.
Ann Diagn Pathol ; 52: 151735, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33770660

RESUMO

Loss of histone 3 lysine 27 trimethylation (H3K27me3) has been described as a diagnostic marker for malignant peripheral nerve sheath tumor (MPNST), also discriminating MPNST with rhabdomyoblastic differentiation (malignant Triton tumor) from rhabdomyosarcoma (RMS). We studied the immunohistochemical expression of H3K27me3 in embryonal RMSs (ERMSs), performed methylation profiling in order to support the diagnosis and RNA-sequencing for comparison of the transcriptome of H3K27me3-positive and -negative cases. Of the 25 ERMS patients, 17 were males and 8 were females with an age range from 1 to 67 years (median, 6 years). None were known with neurofibromatosis type 1. One patient had Li-Fraumeni syndrome. Tumor localization included paratesticular (n = 9), genitourinary (n = 6), head/neck (n = 5), retroperitoneal (n = 4) and lower arm (n = 1). Five MPNSTs served as reference group. All ERMS had classical features including a variable spindle cell component. Immunohistochemical loss (partial or complete) of H3K27me3 was detected in 18/25 cases (72%). Based on methylation profiling, 22/22 cases were classified as ERMS. Using RNA sequencing, the ERMS group (n = 14) had a distinct gene expression profile in contrast to MPNSTs, confirming that the H3K27me3 negative ERMS cases do not represent malignant Triton tumors. When comparing H3K27me3-negative and -positive ERMSs, gene set enrichment analysis revealed differential expression of genes related to histone acetylation and normal muscle function with H3K27me3 negative ERMSs being associated with acetylation. Conclusion: Loss of H3K27me3 frequently occurs in ERMSs and correlates with H3K27 acetylation. H3K27me3 is not a suitable marker to differentiate ERMS (with spindle cell features) from malignant Triton tumor.


Assuntos
Histonas/genética , Neurofibrossarcoma/patologia , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/patologia , Rabdomiossarcoma/patologia , Acetilação , Adolescente , Adulto , Idoso , Diferenciação Celular , Criança , Pré-Escolar , Metilação de DNA , Diagnóstico Diferencial , Feminino , Histonas/metabolismo , Humanos , Imuno-Histoquímica/métodos , Lactente , Masculino , Pessoa de Meia-Idade , Neurofibrossarcoma/diagnóstico , Neurofibrossarcoma/genética , RNA-Seq/métodos , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/genética , Rabdomiossarcoma Embrionário/diagnóstico , Transcriptoma , Adulto Jovem
13.
J Pediatr Hematol Oncol ; 43(5): e625-e629, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33625089

RESUMO

The objectives of this study were to describe the clinicopathologic features and treatment outcomes of childhood rhabdomyosarcoma in a resource-constrained setting. All cases of childhood rhabdomyosarcoma seen over a 10-year period (July 2006 to June 2016) at the University College Hospital, Ibadan, Nigeria were reviewed. Data were extracted from the database of the pediatric Hematology/Oncology Unit of the hospital and analyzed. Ethical approval was obtained from the Institutional Ethics Committee. Fifty children were seen comprising 30 men and 20 women with bimodal ages of 4 and 5 years. Median duration of illness was 16 weeks and the most common primary tumor site was the head-and-neck region in 27 (54%) of cases. The histologic subtypes were embryonal in 30 (60%), alveolar in 9 (18%), and not specified in 11 (22%). The Intergroup Rhabdomyosarcoma Study group TNM Pretreatment stages were stage I in 15 (30%), stage III in 17 (34%), and stage IV in 18 (36%). Treatment included chemotherapy, surgery, and radiotherapy and abandoned in 20 (40%) cases. Median survival was 45 weeks (95% confidence interval: 16.4-73.6) and 5 (10%) patients were alive and disease free, 4 years or more after diagnosis. Outcome of childhood rhabdomyosarcoma is poor and early diagnosis and improved access to treatment are recommended.


Assuntos
Neoplasias de Cabeça e Pescoço/terapia , Rabdomiossarcoma/terapia , Pré-Escolar , Gerenciamento Clínico , Feminino , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Nigéria/epidemiologia , Estudos Retrospectivos , Rabdomiossarcoma/epidemiologia , Rabdomiossarcoma/patologia , Resultado do Tratamento
14.
Cancer Lett ; 505: 1-12, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33610729

RESUMO

The aim of this work was to investigate whether Caveolin-1 (Cav-1), a membrane scaffolding protein widely implicated in cancer, may play a role in radiation response in rhabdomyosarcoma (RMS), a pediatric soft tissue tumor. For this purpose, we employed human RD cells in which Cav-1 expression was stably increased via gene transfection. After radiation treatment, we observed that Cav-1 limited cell cycle arrest in the G2/M phase and enhanced resistance to cell senescence and apoptosis via reduction of p21Cip1/Waf1, p16INK4a and Caspase-3 cleavage. After radiotherapy, Cav-1-mediated cell radioresistance was characterized by low accumulation of H2AX foci, as confirmed by Comet assay, marked neutralization of reactive oxygen species (ROS) and enhanced DNA repair via activation of ATM, Ku70/80 complex and DNA-PK. We found that Cav-1-overexpressing RD cells, already under basal conditions, had higher glutathione (GSH) content and greater catalase expression, which conferred protection against acute treatment with hydrogen peroxide. Furthermore, pre-treatment of Cav-1-overexpressing cells with PP2 or LY294002 compounds restored the sensitivity to radiation treatment, indicating a role for Src-kinases and Akt pathways in Cav-1-mediated radioresistance. These findings were confirmed using radioresistant RD and RH30 lines generated by hypofractionated radiotherapy protocol, which showed marked increase of Cav-1, catalase and Akt, and sensitivity to PP2 and LY294002 treatment. In conclusion, these data suggest that concerted activity of Cav-1 and catalase, in cooperation with activation of Src-kinase and Akt pathways, may represent a network of vital mechanisms that allow irradiated RMS cells to evade cell death induced by oxidative stress and DNA damage.


Assuntos
Caveolina 1/fisiologia , Reparo do DNA , Estresse Oxidativo , Tolerância a Radiação , Rabdomiossarcoma/radioterapia , Apoptose , Linhagem Celular Tumoral , Humanos , Proteínas Proto-Oncogênicas c-akt/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Quinases da Família src/fisiologia
15.
Oncogene ; 40(10): 1868-1883, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33564071

RESUMO

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, is an aggressive cancer with a poor prognosis. Despite current management, the 5-year survival rate for patients with metastatic RMS is ∼30%; underscoring the need to develop better treatment strategies. We have recently reported that pannexin 1 (PANX1) levels are downregulated in RMS and that restoring its expression inhibits RMS progression. Here, we have surveyed and characterized the molecular changes induced by PANX1 re-expression in RMS. We cataloged transcriptomic changes in this context by RNA sequencing. At the protein level, we unveiled PANX1 interactors using BioID, complemented by co-immunoprecipitation coupled to high-performance liquid chromatography/electrospray ionization tandem mass spectrometry performed in PANX1-enriched fractions. Using these data, we generated searchable public databases for the PANX1 interactome and changes to the RMS transcriptome occurring when PANX1 expression is restored. STRING network analyses revealed a PANX1 interactome involving plasma membrane and cytoskeleton-associated proteins including the previously undescribed interactor AHNAK. Indeed, AHNAK knockdown abrogated the PANX1-mediated reduction in RMS cell viability and migration. Using these unbiased approaches, we bring insight to the mechanisms by which PANX1 inhibits RMS progression, identifying the cell migration protein AHNAK as a key modifier of PANX1-mediated changes in RMS malignant properties.


Assuntos
Conexinas/genética , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Rabdomiossarcoma/genética , Transcriptoma/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Mapas de Interação de Proteínas/genética , RNA-Seq , Rabdomiossarcoma/patologia , Sequenciamento Completo do Exoma
16.
Oncogene ; 40(12): 2182-2199, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33627785

RESUMO

The PAX3-FOXO1 fusion protein is the key oncogenic driver in fusion positive rhabdomyosarcoma (FP-RMS), an aggressive soft tissue malignancy with a particularly poor prognosis. Identifying key downstream targets of PAX3-FOXO1 will provide new therapeutic opportunities for treatment of FP-RMS. Herein, we demonstrate that Forkhead Box F1 (FOXF1) transcription factor is uniquely expressed in FP-RMS and is required for FP-RMS tumorigenesis. The PAX3-FOXO1 directly binds to FOXF1 enhancers and induces FOXF1 gene expression. CRISPR/Cas9 mediated inactivation of either FOXF1 coding sequence or FOXF1 enhancers suppresses FP-RMS tumorigenesis even in the presence of PAX3-FOXO1 oncogene. Knockdown or genetic knockout of FOXF1 induces myogenic differentiation in PAX3-FOXO1-positive FP-RMS. Over-expression of FOXF1 decreases myogenic differentiation in primary human myoblasts. In FP-RMS tumor cells, FOXF1 protein binds chromatin near enhancers associated with FP-RMS gene signature. FOXF1 cooperates with PAX3-FOXO1 and E-box transcription factors MYOD1 and MYOG to regulate FP-RMS-specific gene expression. Altogether, FOXF1 functions downstream of PAX3-FOXO1 to promote FP-RMS tumorigenesis.


Assuntos
Carcinogênese/genética , Proteína Forkhead Box O1/genética , Fatores de Transcrição Forkhead/genética , Fator de Transcrição PAX3/genética , Rabdomiossarcoma/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Desenvolvimento Muscular/genética , Proteína MyoD/genética , Miogenina/genética , Rabdomiossarcoma/patologia
17.
Virchows Arch ; 479(2): 419-424, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33595736

RESUMO

Ectomesenchymoma is an exceedingly rare biphasic malignant tumor characterized by the presence of mesenchymal and neuroectodermal elements. The majority of patients are infants or children. We describe the first case of this entity diagnosed as a primary uterine tumor. A 72-year-old female presented with post-menopausal bleeding. Dilatation and curettage showed irregular mesenchymal proliferation of uncertain nature. In the hysterectomy specimen, a myxoid spindle cell tumor with areas of skeletal muscle and neural differentiation was found in the uterus, with direct invasion of the small intestine, and biphasic differentiation into rhabdomyosarcoma and ganglioneuroblastoma was unequivocally seen in a lymph node metastasis. The morphological findings were validated by immunohistochemistry. Massive parallel sequencing identified TP53, PTEN, and DICER1 mutations in the tumor. This report describes the presence of ectomesenchymoma in an unusual primary organ and in an uncharacteristic age and presents novel data regarding the genetic characteristics of this tumor.


Assuntos
Biomarcadores Tumorais/genética , RNA Helicases DEAD-box/genética , Ganglioneuroblastoma/genética , Mesenquimoma/genética , Mutação , Rabdomiossarcoma/genética , Ribonuclease III/genética , Neoplasias Uterinas/genética , Idoso , Análise Mutacional de DNA , Feminino , Ganglioneuroblastoma/patologia , Ganglioneuroblastoma/cirurgia , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Histerectomia , Mesenquimoma/patologia , Mesenquimoma/cirurgia , PTEN Fosfo-Hidrolase/genética , Fenótipo , Rabdomiossarcoma/patologia , Rabdomiossarcoma/cirurgia , Proteína Supressora de Tumor p53/genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia
18.
Cancer Res ; 81(11): 2930-2942, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33589519

RESUMO

Targeted monotherapies usually fail due to development of resistance by a subgroup of cells that evolve into recurrent tumors. Alveolar rhabdomyosarcoma is an aggressive myogenic soft-tissue cancer that is associated with a characteristic PAX3-FOXO1 gene fusion encoding a novel fusion transcription factor. In our myoblast model of PAX3-FOXO1-induced rhabdomyosarcoma, deinduction of PAX3-FOXO1 simulates a targeted therapy that antagonizes the fusion oncoprotein. This simulated therapy results initially in regression of the primary tumors, but PAX3-FOXO1-independent recurrent tumors eventually form after a delay. We report here that upregulation of FGF8, a direct transcriptional target of PAX3-FOXO1, is a mechanism responsible for PAX3-FOXO1-independent tumor recurrence. As a transcriptional target of PAX3-FOXO1, FGF8 promoted oncogenic activity in PAX3-FOXO1-expressing primary tumors that developed in the myoblast system. In the recurrent tumors forming after PAX3-FOXO1 deinduction, FGF8 expression was necessary and sufficient to induce PAX3-FOXO1-independent tumor growth through an autocrine mechanism. FGF8 was also expressed in human PAX3-FOXO1-expressing rhabdomyosarcoma cell lines and contributed to proliferation and transformation. In a human rhabdomyosarcoma cell line with reduced PAX3-FOXO1 expression, FGF8 upregulation rescued oncogenicity and simulated recurrence after PAX3-FOXO1-targeted therapy. We propose that deregulated expression of a PAX3-FOXO1 transcriptional target can generate resistance to therapy directed against this oncogenic transcription factor and postulate that this resistance mechanism may ultimately be countered by therapeutic approaches that antagonize the corresponding downstream pathways. SIGNIFICANCE: In a model of cancer initiated by a fusion transcription factor, constitutive activation of a downstream transcriptional target leads to fusion oncoprotein-independent recurrences, thereby highlighting a novel progression mechanism and therapeutic target.


Assuntos
Biomarcadores Tumorais/metabolismo , Fator 8 de Crescimento de Fibroblasto/metabolismo , Regulação Neoplásica da Expressão Gênica , Recidiva Local de Neoplasia/patologia , Proteínas de Fusão Oncogênica/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Rabdomiossarcoma/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Feminino , Fator 8 de Crescimento de Fibroblasto/genética , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , Rabdomiossarcoma/genética , Rabdomiossarcoma/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Int J Oncol ; 58(2): 266-274, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33491749

RESUMO

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, has an unfavorable outcome in advanced tumor stages with less than 30% failure­free survival. Curcumin (CUR) is a promising drug in complementary oncology with few side effects but proven efficacy in various adult oncological entities. The present study analyzed the effects of CUR on pediatric (RMS) cell lines in vitro. RMS cell lines (RD and RH30), and skeletal muscle cells (SKMC) were treated with different doses of CUR (1.5­30 µM) alone, with phototherapy (PDT, 488 nm) or in combination with vincristine (VCR) or dactinomycin (DAC). MTT assays were used for analysis of RMS tumor cell viability. Clonal cell growth was assessed via colony forming assays and migration of the cells was analyzed with scratch tests. Annexin V staining was used to determine apoptosis in flow cytometry. Possible RMS resistance towards CUR after long­term treatment was analyzed with MTT assays. CUR decreased cell viability in all assessed RMS cell lines in a concentration­dependent manner with IC50=14­20 µM. CUR enhanced the effects of the cytotoxic drugs VCR or DAC, and led to reduced migration and increased cell apoptosis. In combination with PDT, CUR decreased the cell viability in minute quantities with up to a 10­fold lower IC50 than without PDT. CUR effectively inhibited the malignant properties of pediatric RMS cells and should be focused on as a useful additional agent in standard chemotherapy of RMS in children.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Curcumina/farmacologia , Fototerapia/métodos , Rabdomiossarcoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Criança , Terapia Combinada/métodos , Curcumina/uso terapêutico , Dactinomicina/farmacologia , Dactinomicina/uso terapêutico , Sinergismo Farmacológico , Humanos , Concentração Inibidora 50 , Rabdomiossarcoma/patologia , Transdução de Sinais/efeitos dos fármacos , Vincristina/farmacologia , Vincristina/uso terapêutico
20.
Pediatr Dev Pathol ; 24(2): 87-95, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33439112

RESUMO

Rhabdomyosarcoma, the most common soft tissue sarcoma in childhood, has challenged and intrigued soft tissue pathologists ever since the original descriptions. Once based on the identification of rhabdomyoblastic cells with elongate eosinophilic cytoplasm, the diagnosis has evolved to include tumors composed only of primitive mesenchymal cells but now relies heavily on immunohistochemical stains for desmin, myogenin, and MyoD. Rhabdomyosarcomas show a variety of histological patterns, giving rise to classifications that have included embryonal, alveolar, botryoid, pleomorphic, spindle cell, and sclerosing subtypes. These have been linked to prognosis and treatment assignment in the past, but that concept has been superseded by the identification of PAX3-FOXO1 or PAX7-FOXO1 fusions. Fusion testing results are more predictive of outcome and have become standard practice in clinical management. However, high risk tumors with alveolar histology or metastatic disease continue to resist oncologic treatment.


Assuntos
Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/terapia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/terapia , Biomarcadores Tumorais/genética , Criança , Diagnóstico Diferencial , Fusão Gênica , Humanos , Prognóstico , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
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