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TP53 is the most frequently mutated gene in human cancer. This gene shows not only loss-of-function mutations but also recurrent missense mutations with gain-of-function activity. We have studied the primary bone malignancy osteosarcoma, which harbours one of the most rearranged genomes of all cancers. This is odd since it primarily affects children and adolescents who have not lived the long life thought necessary to accumulate massive numbers of mutations. In osteosarcoma, TP53 is often disrupted by structural variants. Here, we show through combined whole-genome and transcriptome analyses of 148 osteosarcomas that TP53 structural variants commonly result in loss of coding parts of the gene while simultaneously preserving and relocating the promoter region. The transferred TP53 promoter region is fused to genes previously implicated in cancer development. Paradoxically, these erroneously upregulated genes are significantly associated with the TP53 signalling pathway itself. This suggests that while the classical tumour suppressor activities of TP53 are lost, certain parts of the TP53 signalling pathway that are necessary for cancer cell survival and proliferation are retained. In line with this, our data suggest that transposition of the TP53 promoter is an early event that allows for a new normal state of genome-wide rearrangements in osteosarcoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Neoplasias Ósseas , Osteossarcoma , Criança , Adolescente , Humanos , Genes p53 , Osteossarcoma/genética , Osteossarcoma/patologia , Mutação , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Regiões Promotoras Genéticas/genética , Fusão Gênica , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
INTRODUCTION: The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study. MATERIALS AND METHODS: The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models. RESULTS: Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42-65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22-25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles. CONCLUSIONS: Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/terapia , Desdiferenciação Celular , Condrossarcoma/terapia , Terapia Neoadjuvante , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Quimioterapia Adjuvante , Condrossarcoma/mortalidade , Condrossarcoma/secundário , Intervalo Livre de Doença , Europa (Continente) , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/mortalidade , Estudos Prospectivos , Fatores de TempoRESUMO
Osteoblastoma is a locally aggressive tumour of bone. Until recently, its underlying genetic features were largely unknown. During the past two years, reports have demonstrated that acquired structural variations affect the transcription factor FOS in a high proportion of cases. These rearrangements modify the terminal exon of the gene and are believed to stabilise both the FOS transcript and the encoded protein, resulting in high expression levels. Here, we applied in-depth genetic analyses to a series of 29 osteoblastomas, including five classified as epithelioid osteoblastoma. We found recurrent homozygous deletions of the NF2 gene in three of the five epithelioid cases and in one conventional osteoblastoma. These events were mutually exclusive from FOS mutations. Structural variations were determined by deep whole genome sequencing and the number of FOS-rearranged cases was less than previously reported (10/23, 43%). One conventional osteoblastoma displayed a novel mechanism of FOS upregulation; bringing the entire FOS gene under the control of the WNT5A enhancer that is itself activated by FOS. Taken together, we show that NF2 loss characterises a subgroup of osteoblastomas, distinct from FOS-rearranged cases. Both NF2 and FOS are involved in regulating bone homeostasis, thereby providing a mechanistic link to the excessive bone growth of osteoblastoma.
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Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Deleção de Genes , Rearranjo Gênico , Neurofibromina 2/genética , Osteoblastoma/genética , Proteínas Proto-Oncogênicas c-fos/genética , Adolescente , Adulto , Neoplasias Ósseas/patologia , Criança , Pré-Escolar , Elementos Facilitadores Genéticos , Células Epitelioides/patologia , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Osteoblastoma/patologia , Osteogênese , Fenótipo , Proteína Wnt-5a/genética , Adulto JovemRESUMO
A characteristic feature of soft tissue sarcomas is the absence of alarm symptoms such as pain or abnormal laboratory findings. We present two patients where the diagnostic difficulties delayed the definitive diagnosis, in one case with lethal outcome. The two patients highlight the difficulties a clinician may encounter with this particular disease. Even though synovial sarcoma represents around 0,1 % of all cancer forms, we recommend a high degree of awareness and - when in doubt - prompt contact with a Sarcoma center for consultation.
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Sarcoma Sinovial , Neoplasias de Tecidos Moles , Humanos , Encaminhamento e Consulta , Sarcoma Sinovial/diagnóstico , Neoplasias de Tecidos Moles/diagnósticoRESUMO
Conventional osteosarcoma is the most common primary malignancy of bone. This group of neoplasms is subclassified according to specific histological features, but hitherto there has been no correlation between subtype, treatment, and prognosis. By in-depth genetic analyses of a chondroblastoma-like osteosarcoma, we detect a genetic profile that is distinct from those previously reported in benign and malignant bone tumors. The overall genomic copy number profile was less complex than that typically associated with conventional osteosarcoma, and there was no activating point mutation in any of H3F3A, H3F3B, IDH1, IDH2, BRAF, or GNAS. Instead, we found a homozygous CDKN2A deletion, a DMD microdeletion and an FN1-FGFR1 gene fusion. The latter alteration has been described in phosphaturic mesenchymal tumor. This tumor type shares some morphological features with chondroblastoma-like osteosarcoma and we cannot rule out that the present case actually represents an FN1-FGFR1 positive malignant phosphaturic mesenchymal tumor of bone without osteomalacia.
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Neoplasias Ósseas/genética , Condroblastoma/genética , Deleção de Genes , Mesenquimoma/genética , Fusão Oncogênica , Osteossarcoma/genética , Neoplasias Ósseas/patologia , Condroblastoma/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Distrofina/genética , Fibronectinas/genética , Homozigoto , Humanos , Masculino , Mesenquimoma/metabolismo , Pessoa de Meia-Idade , Osteossarcoma/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
BACKGROUND: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. METHODS: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations. RESULTS: Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient. CONCLUSIONS: Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.
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Sarcoma/tratamento farmacológico , Quinases da Família src/antagonistas & inibidores , Adulto , Proteína Tirosina Quinase CSK , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Sarcoma/genética , Sarcoma/patologiaRESUMO
BACKGROUND: Preoperative radiotherapy is often used to facilitate excision of soft-tissue sarcomas. We aimed define factors that affect local tumour control and patient survival. METHODS: A single institution registry study of 89 patients with non-metastatic soft-tissue sarcomas having preoperative radiotherapy between 1994 and 2014. Radiologic (presence of peritumoural oedema and volume change following radiotherapy) and histopathologic (tumour volume, grade and surgical margin) parameters were recorded. Outcomes were the events of local recurrence, amputation, metastasis and death. RESULTS: Local recurrence rate was low (12%) and marginal excision gave equal local control to wide excision. Pelvic localization was associated with a higher risk for amputation. The absence of peritumoural oedema on MRI defined a subgroup of tumours with more favourable oncologic outcome. Reduction of tumour volume following radiotherapy was also associated with better patient survival. Both these radiologic parameters were associated with lower tumour grade. Tumour necrosis was not significant for patient survival. The local complication rate, mainly wound healing problems and infection, was high (40%), but did not lead to any amputation. CONCLUSION: Preoperative radiotherapy of high-risk soft-tissue sarcomas allows for good local control rate at the expense of local wound complications, which are however manageable. Marginal excision is sufficient for local control. Absence of peritumoural oedema on MRI, as well as tumour size reduction following radiotherapy are associated to superior patient survival and can be used ass early prognostic factors.
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To compare clonal evolution in tumors arising through different mechanisms, we selected three types of sarcoma-amplicon-driven well-differentiated liposarcoma (WDLS), gene fusion-driven myxoid liposarcoma (MLS), and sarcomas with complex genomes (CXS)-and assessed the dynamics of chromosome and nucleotide level mutations by cytogenetics, SNP array analysis and whole-exome sequencing. Here we show that the extensive single-cell variation in WDLS has minor impact on clonal key amplicons in chromosome 12. In addition, only a few of the single nucleotide variants in WDLS were present in more than one lesion, suggesting that such mutations are of little significance in tumor development. MLS displays few mutations other than the FUS-DDIT3 fusion, and the primary tumor is genetically sometimes much more complex than its relapses, whereas CXS in general shows a gradual increase of both nucleotide- and chromosome-level mutations, similar to what has been described in carcinomas.
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Evolução Clonal , Lipossarcoma Mixoide/genética , Lipossarcoma/genética , Recidiva Local de Neoplasia , Sarcoma/genética , Aberrações Cromossômicas , Bandeamento Cromossômico , Cromossomos/ultraestrutura , Seguimentos , Fusão Gênica , Humanos , Mutação , Nucleotídeos/química , Proteínas de Fusão Oncogênica/genética , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Fator de Transcrição CHOP/genéticaRESUMO
INTRODUCTION: The EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.) was the first prospective international study for patients 41-65 years old with high-grade bone sarcoma treated with an intensive chemotherapy regimen derived from protocols for younger patients with high-grade skeletal osteosarcoma. METHODS: Chemotherapy based on doxorubicin, cisplatin, ifosfamide, and methotrexate was suggested, but patients treated with other regimens at the investigators' choice were also eligible for the study. RESULTS: The present report focuses on the subgroup of 218 patients with primary high-grade osteosarcoma. With a median follow-up of 47 months, the 5-year probability of overall survival (OS) was 66% in patients with localized disease and 22% in case of synchronous metastases. The 5-year OS in patients with localized disease was 29% in pelvic tumors, and 70% and 73% for extremity or craniofacial locations, respectively. In primary chemotherapy, tumor necrosis ≥90% was reported in 21% of the patients. There were no toxic deaths; however, hematological toxicity was considerable with 32% of patients experiencing 1 or more episodes of neutropenic fever. The incidence of nephrotoxicity and neurotoxicity (mainly peripheral) was 28% and 24%, respectively. After methotrexate, 23% of patients experienced delayed excretion, in 4 cases with nephrotoxicity. CONCLUSIONS: In patients over 40 years of age with primary high-grade osteosarcoma, an aggressive approach with chemotherapy and surgery can offer the probability of survival similar to that achieved in younger patients. Chemotherapy-related toxicity is significant and generally higher than that reported in younger cohorts of osteosarcoma patients treated with more intensive regimens.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Europa (Continente) , Neutropenia Febril/induzido quimicamente , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Cooperação Internacional , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Osteossarcoma/patologia , Estudos Prospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Myxoid liposarcomas are highly radiosensitive. Consequently radiotherapy is often used pre-operatively to reduce tumor volume and lessen the post-operative deficit. In soft-tissue sarcomas therapy response is mainly evaluated using magnetic resonance imaging (MRI) and the fundamental criterion for a positive response is decreased tumor size. In myxoid liposarcomas an increased fat content is also known to occur as a response to radiotherapy. OBJECTIVE: To highlight the difficulties of MRI for therapy response evaluation in irradiated myxoid liposarcomas, by using MRI Dixon techniques enabling objective quantification of proton density fat fraction (%) and the number of double bonds (ndb; unsaturation degree) of fatty acids. Secondly, to compare quantitative fat fraction measurements versus visual grading of fat content on T1-weighted images. CASE DESCRIPTIONS: Prior to surgery, two patients with myxoid liposarcoma were treated with 50Gy. Following radiotherapy, both tumors on MRI showed reduced size, elevated fat fraction and transformed fat fraction histograms with diverse changes of ndb, while histopathological specimens showed discordant treatment effects; one case having good response and the other having poor response. CONCLUSIONS: A decrease in tumor size and increase in fat content on MRI cannot be interpreted as positive therapy response in radiotherapy of myxoid liposarcomas. Our data also give further supporting evidence that differentiation and maturation of tumor cells is the cause for the lipoma-like areas seen after radiotherapy. Finally, quantitative MRI Dixon techniques are preferable to visual grading for estimating the fat content in lipomatous tumors.
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Ácidos Graxos/química , Lipossarcoma Mixoide/diagnóstico por imagem , Lipossarcoma/diagnóstico por imagem , Imageamento por Ressonância Magnética , Neoplasias de Tecidos Moles/diagnóstico por imagem , Biópsia , Diferenciação Celular , Feminino , Humanos , Lipoma/patologia , Lipossarcoma Mixoide/radioterapia , Masculino , Pessoa de Meia-Idade , Prótons , Estudos Retrospectivos , Neoplasias de Tecidos Moles/radioterapia , Carga TumoralRESUMO
BACKGROUND: Treatment of Ewing sarcoma of the pelvic bones remains one of the most difficult tasks in the treatment of bone sarcomas. Whether surgery or radiation therapy is the best local treatment is still a matter of debate. The aim of the present study was to compare sacral and nonsacral sites with regard to the treatment and outcome of pelvic Ewing sarcomas. METHODS: Patients with Ewing sarcoma of the osseous pelvis diagnosed between 1986 and 2011 were identified through the Scandinavian Sarcoma Group registry. Data regarding tumor size, local treatment (surgery or radiation therapy), metastatic disease, surgical margins, local recurrence, and overall survival were analyzed. RESULTS: Of the 117 patients examined, eighty-eight had tumors in the innominate bones and twenty-nine, in the sacrum. Radiation therapy was the sole local treatment for 40% of the innominate bone tumors in contrast to 79% of the sacral tumors. The five-year disease-free survival rate in the latter group (66%) was greater than that in the group with tumors in the innominate bones (40%) (p = 0.02 adjusted for size). CONCLUSIONS: Disease-free survival among patients with Ewing sarcoma was improved when the tumor was localized in the sacrum compared with the innominate bones, where these tumors are generally larger. Local radiation therapy alone appears to result in good local tumor control and may be the treatment of choice for sacral tumors.
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Ossos Pélvicos , Sacro , Sarcoma de Ewing/mortalidade , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia , Prognóstico , Estudos Prospectivos , Sarcoma de Ewing/patologia , Sarcoma de Ewing/radioterapia , Adulto JovemRESUMO
Purpose. Penile cancer rarely gives symptomatic skeletal metastases. Methods. We present 2 patients with squamous carcinoma of the penis who were surgically treated for metastases in the femur. Results. Both patients had pathological fractures and were operated on. In one case, the skeletal metastasis preceded any lymphatic spread of the disease, suggesting early haematogenous dissemination. Conclusions. Endoprosthetic reconstruction resulted in pain relief and restored the ambulatory capacity. Clinicians should be aware of the possibility for symptomatic bone metastases with a risk for pathological fracture in patients with penile cancer.
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BACKGROUND AND PURPOSE: Metastases engaging the acetabulum result in significant disability. We investigated the outcome after curettage and reconstruction of the defect with a protrusio cage, retrograde screws, and a cemented total hip arthroplasty. PATIENTS AND METHODS: We retrospectively identified 70 consecutive patients who were surgically treated for metastatic disease of the acetabulum between 1995 and 2012 using the above technique. The type of primary tumor, extent of the disease, degree of acetabular erosion, and type of implant used were identified. Patient and implant survival, complications, and functional outcome were recorded. RESULTS: There were no mortalities in the perioperative period (30 days after surgery). Median overall patient survival was 12 months. Prosthesis survival was 92% at 1 year and 89% at 5 years. One third of the patients suffered a complication, the most frequent one being dislocation. The functional outcome was good. Multiple skeletal or visceral metastases and specific types of cancer were associated with poor patient survival. INTERPRETATION: Reconstruction of metastatic acetabular defects using a protrusio cage stabilized with retrograde screws and a cemented total hip arthroplasty is a safe procedure that provides efficient relief of symptoms. Patients with extensive disease, especially when diagnosed with specific types of cancer, have a very poor prognosis. The complication rate is substantial, the most frequent being dislocation. However, revision surgery is seldom required and prosthesis survival is high.
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Acetábulo/cirurgia , Neoplasias Ósseas/cirurgia , Acetabuloplastia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril/métodos , Parafusos Ósseos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos de Cirurgia Plástica/métodos , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: Our study aimed to describe the clinical outcome of patients with superficial soft-tissue sarcomas (SSTS), define prognostic factors and provide evidence for a rational surveillance scheme. METHODS: Data for 622 consecutive, surgically treated SSTS patients were retrieved from the Scandinavian Sarcoma Group Register. We assessed the rates of local recurrence (LR) and metastasis (M), as well as overall survival (OS), local recurrence free-survival (LRFS) and metastasis-free survival (MFS) of the cohort. RESULTS: The incidence of LR and M was 9% and 12%, respectively. OS at 5 years was 79%, LRFS was 74% and MFS 76%. Factors that affected OS, LRFS, and MFS were tumor size and patient age. Additionally, tumor grade was an independent prognostic factor for LRFS. The majority of LR and M events were observed the first 2 years of follow-up. Clear surgical margins were correlated to lower risk for LR. Selected patients benefited from adjuvant radiotherapy. CONCLUSIONS: SSTS have a favourable prognosis, which is mainly determined by tumour-associated factors. Adequate surgical margins are important for local control, whereas radiotherapy has a secondary role. The data support current surveillance schemes, with a closer follow-up the first 2 years after surgery.
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Sarcoma/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/epidemiologia , Vigilância da População , Prognóstico , Sistema de Registros , Sarcoma/patologia , Sarcoma/cirurgia , Países Escandinavos e Nórdicos/epidemiologia , Análise de Sobrevida , Adulto JovemRESUMO
Hydatid disease of the bone is a very rare manifestation of the disease, and is often associated with debilitating symptoms. We present a rare case of skeletal hydatidosis in a 56-year-old man who had been misdiagnosed for many years. Massive involvement of the pelvic bones and soft tissues was evident. An extended hemipelvectomy was performed in order to achieve resection of the affected segments with a clear surgical margin. The patient recovered uneventfully and there are no signs of recurrence of the disease.
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Equinococose/diagnóstico , Equinococose/cirurgia , Echinococcus/patogenicidade , Hemipelvectomia/métodos , Pelve/cirurgia , Animais , Equinococose/patologia , Fêmur/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Pelve/patologia , Espaço Retroperitoneal/patologia , Resultado do TratamentoRESUMO
Limb-preserving surgery using modular megaprostheses for the reconstruction of large skeletal defects is currently the preferred treatment for sarcomas. The authors report the postoperative outcomes after skeletal resection for lower extremity sarcomas and the use of the METS cemented modular implant system (Stanmore Implants, Hertfordshire, United Kingdom) for reconstruction. They retrospectively studied 52 consecutive patients operated on from 2003 to 2012. There were 27 distal femur prostheses, 13 proximal femur, 11 proximal tibia, and 1 total femur implants. Patients were followed for a mean of 4.3 years. Overall patient survival, prosthesis survival, limb salvage rate, and secondary complications were documented. Five years postoperatively, prosthesis survival was 79%. Complications warranting implant revision surgery were documented in 15% of patients, whereas complications warranting surgery of any kind were observed in 27% of the patients. Nonmechanical complications, namely local relapse of the tumor and prosthetic infection, were the most common cause of prosthetic failure, accounting for 88% of major revision surgeries and 100% of amputations. Mechanical complications were rare, observed in only 6% of patients. No patients required secondary revision surgery. The limb salvage rate was 89%. Overall patient survival was 79% at 5 years and 71% at 10 years. The low risk for mechanical complications and the high limb salvage rate support the use of the METS modular megaprostheses for the reconstruction of skeletal defects following lower limb sarcoma surgery.
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Membros Artificiais/classificação , Neoplasias Ósseas/cirurgia , Salvamento de Membro/métodos , Extremidade Inferior/cirurgia , Procedimentos Ortopédicos/métodos , Procedimentos de Cirurgia Plástica/métodos , Sarcoma/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Amputação Cirúrgica , Neoplasias Ósseas/mortalidade , Criança , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Desenho de Prótese , Falha de Prótese , Estudos Retrospectivos , Sarcoma/mortalidade , Taxa de Sobrevida , Resultado do Tratamento , Reino Unido , Adulto JovemRESUMO
Gene fusions are neoplasia-associated mutations arising from structural chromosomal rearrangements. They have a strong impact on tumor development and constitute important diagnostic markers. Malignant soft tissue tumors (sarcomas) constitute a heterogeneous group of neoplasms with >50 distinct subtypes, each of which is rare. In addition, there is considerable morphologic overlap between sarcomas and benign lesions. Several subtypes display distinct gene fusions, serving as excellent biomarkers. The development of methods for deep sequencing of the complete transcriptome (RNA-Seq) has substantially improved the possibilities for detecting gene fusions. With the aim of identifying new gene fusions of biological and clinical relevance, eight sarcomas with simple karyotypes, ie, only one or a few structural rearrangements, were subjected to massively parallel paired-end sequencing of mRNA. Three different algorithms were used to identify fusion transcripts from RNA-Seq data. Three novel (KIAA2026-NUDT11, CCBL1-ARL1, and AFF3-PHF1) and two previously known fusions (FUS-CREB3L2 and HAS2-PLAG1) were found and could be verified by other methods. These findings show that RNA-Seq is a powerful tool for detecting gene fusions in sarcomas but also suggest that it is advisable to use more than one algorithm to analyze the output data as only two of the confirmed fusions were reported by more than one of the gene fusion detection software programs. For all of the confirmed gene fusions, at least one of the genes mapped to a chromosome band implicated by the karyotype, suggesting that sarcomas with simple karyotypes constitute an excellent resource for identifying novel gene fusions.
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Fusão Gênica/genética , Proteínas de Fusão Oncogênica/genética , RNA Mensageiro/análise , Sarcoma/genética , Análise de Sequência de RNA/métodos , Adulto , Feminino , Humanos , RNA Mensageiro/genéticaRESUMO
Aneurysmal bone cysts are benign bone tumors that usually present in childhood and early adulthood. They usually manifest as expansile osteolytic lesions with a varying potential to be locally aggressive. Since their first description in 1942, a variety of treatment methods has been proposed. Traditionally, these tumors were treated with open surgery. Either intralesional surgical procedures or en bloc excisions have been described. Furthermore, a variety of chemical or physical adjuvants has been utilized in order to reduce the risk for local recurrence after excision. Currently, there is a shift to more minimally invasive procedures in order to avoid the complications of open surgical excision. Good results have been reported during percutaneous surgery, or the use of embolization. Recently, sclerotherapy has emerged as a promising treatment, showing effective consolidation of the lesions and functional results that appear to be superior to the ones of open surgery. Lastly, non-invasive treatment, such as pharmaceutical intervention with denosumab or bisphosphonates has been reported to be effective in the management of the disease. Radiotherapy has also been shown to confer good local control, either alone or in conjunction to other treatment modalities, but is associated with serious adverse effects. Here, we review the current literature on the methods of treatment of aneurysmal bone cysts. The indication for each type of treatment along reported outcome of the intervention, as well as potential complications are systematically presented. Our review aims to increase awareness of the different treatment modalities and facilitate decision-making regarding each individual patient.
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PURPOSE: Undifferentiated pleomorphic sarcoma (UPS) is defined as a sarcoma with cellular pleomorphism and no identifiable line of differentiation. It is typically a high-grade lesion with a metastatic rate of about one third. No tumor-specific rearrangement has been identified, and genetic markers that could be used for treatment stratification are lacking. We performed transcriptome sequencing (RNA-Seq) to search for novel gene fusions. EXPERIMENTAL DESIGN: RNA-Seq, FISH, and/or various PCR methodologies were used to search for gene fusions and rearrangements of the PRDM10 gene in 84 soft tissue sarcomas. RESULTS: Using RNA-Seq, two cases of UPS were found to display novel gene fusions, both involving the transcription factor PRDM10 as the 3' partner and either MED12 or CITED2 as the 5' partner gene. Further screening of 82 soft tissue sarcomas for rearrangements of the PRDM10 locus revealed one more UPS with a MED12/PRDM10 fusion. None of these genes has been implicated in neoplasia-associated gene fusions before. CONCLUSIONS: Our results suggest that PRDM10 fusions are present in around 5% of UPS. Although the fusion-positive cases in our series showed the same nuclear pleomorphism and lack of differentiation as other UPS, it is noteworthy that all three were morphologically low grade and that none of the patients developed metastases. Thus, PRDM10 fusion-positive sarcomas may constitute a clinically important subset of UPS.
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Proteínas de Ligação a DNA/genética , Fusão Gênica/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Fatores de Transcrição/genética , Cariótipo Anormal , Humanos , Hibridização in Situ Fluorescente , Complexo Mediador/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/genéticaRESUMO
INTRODUCTION: Aneurysmal bone cysts are benign tumours that usually present in childhood. Aggressive forms have been described, which are often treated with surgery that entails major resection and reconstruction. Polidocanol sclerotherapy has recently been reported to have excellent results and promises to replace operative treatments, but its efficacy in the case of aggressive aneurysmal bone cysts has not been documented. CASE PRESENTATION: An 18-year-old woman from Sweden presented with pain in her shoulder and a rapidly progressing cystic bone lesion. The differential diagnosis was a rare, aggressive form of aneurysmal bone cyst or a sarcoma of the proximal humerus. She was successfully treated using sequential percutaneous injections of polidocanol after exclusion of malignancy. CONCLUSIONS: Management of aggressive aneurysmal bone cysts has thus far relied on open surgery. We propose that non-operative treatment with polidocanol is efficient even in the aggressive form of the aneurysmal bone cyst.