RESUMO
BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.
Assuntos
Neoplasias , Medicina de Precisão , Humanos , Neoplasias/genética , Neoplasias/tratamento farmacológico , Feminino , Medicina de Precisão/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Idoso , Adulto , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão , Adulto Jovem , Doenças Raras/genética , Doenças Raras/tratamento farmacológico , Genômica/métodosAssuntos
Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Sarcoma , Seguimentos , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/epidemiologia , Tumores do Estroma Gastrointestinal/terapia , Humanos , Sarcoma/terapiaAssuntos
Neoplasias Ósseas , Osteossarcoma , Sarcoma , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/epidemiologia , Neoplasias Ósseas/terapia , Seguimentos , Humanos , Osteossarcoma/diagnóstico , Osteossarcoma/epidemiologia , Osteossarcoma/terapia , Sarcoma/diagnóstico , Sarcoma/epidemiologia , Sarcoma/terapiaRESUMO
Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.
Assuntos
Hemangioendotelioma Epitelioide , Sarcoma , Adulto , Criança , Consenso , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/tratamento farmacológico , Humanos , Oncologia , Defesa do Paciente , Sarcoma/diagnóstico , Sarcoma/tratamento farmacológicoRESUMO
Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.
Assuntos
Sarcoma , Tropomiosina , Adulto , Fusão Gênica , Humanos , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases , Receptor trkA/genética , Sarcoma/diagnóstico , Sarcoma/tratamento farmacológico , Sarcoma/genéticaRESUMO
OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.
Assuntos
Cordoma/radioterapia , Cordoma/cirurgia , Margens de Excisão , Sacro/cirurgia , Humanos , Terapia com Prótons/efeitos adversos , Dosagem RadioterapêuticaRESUMO
AIMS: The purpose of this study was to clarify the clinical behaviour, prognosis, and optimum treatment of dedifferentiated low-grade osteosarcoma (DLOS) diagnosed based on molecular pathology. PATIENTS AND METHODS: We retrospectively reviewed 13 DLOS patients (six men, seven women; median age 32 years (interquartile range (IQR) 27 to 38)) diagnosed using the following criteria: the histological coexistence of low-grade and high-grade osteosarcoma components in the lesion, and positive immunohistochemistry of mouse double minute 2 homolog (MDM2) and cyclin-dependent kinase 4 (CDK4) associated with MDM2 amplification. These patients were then compared with 51 age-matched consecutive conventional osteosarcoma (COS) patients (33 men, 18 women; median age 25 years (IQR 20 to 38)) regarding their clinicopathological features. RESULTS: The five-year overall survival (OAS) rates in the DLOS and COS patients were 85.7% and 77.1% (p = 0.728), respectively, and the five-year progression-free survival (PFS) rates were 57.7% and 44.9% (p = 0.368), respectively. A total of 12 DLOS patients received chemotherapy largely according to regimens for COS. Among the nine cases with a histological evaluation after chemotherapy, eight showed a poor response, and seven of these had a necrosis rate of < 50%. One DLOS patient developed local recurrence and five developed distant metastases. CONCLUSION: Based on our study of 13 DLOS cases that were strictly defined by histological and molecular means, DLOS showed a poorer response to a standard chemotherapy regimen than COS, while the clinical outcomes were not markedly different. Cite this article: Bone Joint J 2019;101-B:745-752.
Assuntos
Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Osteossarcoma/patologia , Osteossarcoma/terapia , Adulto , Biomarcadores Tumorais/análise , Estudos de Casos e Controles , Terapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Masculino , Gradação de Tumores , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.
Assuntos
Cordoma/terapia , Guias de Prática Clínica como Assunto , Humanos , Recidiva Local de NeoplasiaRESUMO
Diagnosis and treatment of bone metastasis requires various types of measures, specialists and caregivers. To provide better diagnosis and treatment, a multidisciplinary team approach is required. The members of this multidisciplinary team include doctors of primary cancers, radiologists, pathologists, orthopaedists, radiotherapists, clinical oncologists, palliative caregivers, rehabilitation doctors, dentists, nurses, pharmacists, physical therapists, occupational therapists, medical social workers, etc. Medical evidence was extracted from published articles describing meta-analyses or randomised controlled trials concerning patients with bone metastases mainly from 2003 to 2013, and a guideline was developed according to the Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Multidisciplinary team meetings are helpful in diagnosis and treatment. Clinical benefits such as physical or psychological palliation obtained using the multidisciplinary team approaches are apparent. We established a guideline describing each specialty field, to improve understanding of the different fields among the specialists, who can further provide appropriate treatment, and to improve patients' outcomes.
RESUMO
Myxoid/round cell (RC) liposarcomas (MLS) were originally classified into two distinct populations based on histological differences; a myxoid component and a RC component. It is notable that, depending on an increase of the RC component, the prognosis significantly differs. Hence, the RC component is associated with metastasis and poor prognosis. However, the molecular mechanisms that contribute to the malignancy of the RC component still remain largely unknown. Here, we report microRNA-135b (miR-135b), a key regulator of the malignancy, highly expressed in the RC component and promoting MLS cell invasion in vitro and metastasis in vivo through the direct suppression of thrombospondin 2 (THBS2). Decreased THBS2 expression by miR-135b increases the total amount of matrix metalloproteinase 2 (MMP2) and influences cellular density and an extracellular matrix structure, thereby resulting in morphological change in tumor. The expression levels of miR-135b and THBS2 significantly correlated with a poor prognosis in MLS patients. Overall, our study reveals that the miR-135b/THBS2/MMP2 axis is tightly related to MLS pathophysiology and has an important clinical implication. This work provides noteworthy evidence for overcoming metastasis and improving patient outcomes, and sheds light on miR-135b and THBS2 as novel molecular targets for diagnosis and therapy in MLS.
Assuntos
Regulação Neoplásica da Expressão Gênica , Lipossarcoma Mixoide/genética , Lipossarcoma Mixoide/mortalidade , MicroRNAs/genética , Regiões 3' não Traduzidas , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Inativação Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lipossarcoma Mixoide/patologia , Neoplasias Pulmonares/secundário , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Metástase Neoplásica , Prognóstico , Interferência de RNA , Trombospondinas/genética , Carga TumoralRESUMO
Thymic involution is associated with age-related changes of the immune system. Utilizing our innovative technique of transplantation of a thymus as an isolated vascularized graft in MHC-inbred miniature swine, we have previously demonstrated that aged thymi are rejuvenated after transplantation into juvenile swine. Here we have studied the role of insulin-like growth factor (IGF) and forkhead-box protein-N1 (FOXN1) as well as bone marrow (BM) in thymic rejuvenation and involution. We examined thymic rejuvenation and involution by means of histology and flow cytometry. Thymic function was assessed by the ability to induce tolerance of allogeneic kidneys. Aged thymi were rejuvenated in a juvenile environment, and successfully induced organ tolerance, while juvenile thymi in aged recipients involuted and had a limited ability to induce tolerance. However, juvenile BM inhibited the involution process of juvenile thymi in aged recipients. An elevated expression of both FOXN1 and IGF1 receptors (IGF-1R) was observed in juvenile thymi and rejuvenated thymi. Juvenile BM plays a role in promoting the local thymic milieu as indicated by its ability to inhibit thymic involution in aged animals. The expression of FOXN1 and IGF-1R was noted to increase under conditions that stimulated rejuvenation, suggesting that these factors are involved in thymic recovery.
Assuntos
Medula Óssea/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Receptor IGF Tipo 1/metabolismo , Rejuvenescimento/fisiologia , Timo/fisiologia , Envelhecimento/fisiologia , Animais , Diferenciação Celular , Fatores de Transcrição Forkhead/genética , Sobrevivência de Enxerto , Tolerância Imunológica , Receptor IGF Tipo 1/genética , Suínos , Porco Miniatura , Timo/transplanteRESUMO
Resection of malignant bony tumours of the pelvis creates large bone and soft-tissue defects, and is frequently associated with complications such as wound dehiscence and deep infection. We present the results of six patients in whom a rectus abdominis myocutaneous (RAM) flap was used following resection of a malignant tumour of the pelvis. Bony reconstruction was performed using a constrained hip tumour prosthesis in three patients, vascularised fibular graft in two and frozen autograft in one. At a mean follow-up of 63 months (16 to 115), no patients had a problem with the wound. Immediate reconstruction using a RAM flap may be used after resection of a malignant tumour of the pelvis to provide an adequate volume of tissue to eliminate the dead space, cover the exposed bone or implants with well-vascularised soft tissue and to reduce the risk of complications.
Assuntos
Neoplasias Ósseas/cirurgia , Procedimentos Ortopédicos/métodos , Ossos Pélvicos , Procedimentos de Cirurgia Plástica/métodos , Reto do Abdome/transplante , Transplante de Pele/métodos , Retalhos Cirúrgicos , Adulto , Neoplasias Ósseas/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Synovial sarcoma is a high-grade soft tissue malignancy characterized by a specific reciprocal translocation t(X;18), which leads to the fusion of the SS18 (SYT) gene to one of three SSX genes (SSX1, SSX2 or SSX4). The resulting chimeric SS18-SSX protein is suggested to act as an oncogenic transcriptional regulator. Despite multimodal therapeutic approaches, metastatic disease is often lethal and the development of novel targeted therapeutic strategies is required. Several expression-profiling studies identified distinct gene expression signatures, implying a consistent role of Wnt/ß-catenin signaling in synovial sarcoma tumorigenesis. Here we investigate the functional and therapeutic relevance of Wnt/ß-catenin pathway activation in vitro and in vivo. Immunohistochemical analyses of nuclear ß-catenin and Wnt downstream targets revealed activation of canonical Wnt signaling in a significant subset of 30 primary synovial sarcoma specimens. Functional aspects of Wnt signaling including dependence of Tcf/ß-catenin complex activity on the SS18-SSX fusion proteins were analyzed. Efficient SS18-SSX-dependent activation of the Tcf/ß-catenin transcriptional complex was confirmed by TOPflash reporter luciferase assays and immunoblotting. In five human synovial sarcoma cell lines, inhibition of the Tcf/ß-catenin protein-protein interaction significantly blocked the canonical Wnt/ß-catenin signaling cascade, accompanied by the effective downregulation of Wnt targets (AXIN2, CDC25A, c-MYC, DKK1, CyclinD1 and Survivin) and the specific suppression of cell viability associated with the induction of apoptosis. In SYO-1 synovial sarcoma xenografts, administration of small molecule Tcf/ß-catenin complex inhibitors significantly reduced tumor growth, associated with diminished AXIN2 protein levels. In summary, SS18-SSX-induced Wnt/ß-catenin signaling appears to be of crucial biological importance in synovial sarcoma tumorigenesis and progression, representing a potential molecular target for the development of novel therapeutic strategies.
Assuntos
Proteínas de Fusão Oncogênica/fisiologia , Sarcoma Sinovial/metabolismo , Via de Sinalização Wnt , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Perileno/análogos & derivados , Perileno/farmacologia , Pirimidinonas/farmacologia , Sarcoma Sinovial/tratamento farmacológico , Triazinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética , beta Catenina/metabolismoRESUMO
BACKGROUND: The surgical management of soft tissue sarcoma (STS) in elderly patients has only been addressed in a few studies. The objective of the current study was to assess surgical outcomes in patients with STS aged 70 years and older and the association of older age with the survival after complete resection. METHODS: A retrospective analysis was conducted in 158 elderly patients with localized STS who visited 11 institutions participating in Japanese Musculoskeletal Oncology Group between 1995 and 2006 and were treated by surgical resection. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Median follow-up period was 38 months. Histologically high-grade tumors were detected in 71% of the patients. Wide resection with adequate margins was performed in 66% of the cases. Systemic chemotherapy was performed in only 5 patients. Univariate analysis identified histological grade and gender as statistically significant prognostic factors for sarcoma-specific survival. Multivariate analysis did not identify significant prognostic factors for sarcoma-specific survival, although high grade sarcoma emerged as a potentially significant prognostic factor (P = 0.050). Local recurrence was detected in 19% of the patients. Multivariate analysis of local recurrence-free survival showed that tumor site and surgical margins were statistically significant prognostic factors. CONCLUSIONS: Older age was not identified as a prognostic factor for sarcoma-specific survival, which is not consistent with the findings of previous studies showing that older age was associated with decreased sarcoma-specific survival. Complete resection should be indicated and can lead to optimal treatment outcome for properly selected elderly patients.
Assuntos
Sarcoma/mortalidade , Sarcoma/cirurgia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Quimioterapia Adjuvante , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Imageamento por Ressonância Magnética , Masculino , Gradação de Tumores , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Fatores de Risco , Sarcoma/diagnóstico , Sarcoma/epidemiologia , Sarcoma/patologia , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
SUMMARY: Postmenopausal hemodialysis patients are at risk of complications related to renal mineral and bone disorder, and postmenopausal osteoporosis. In 112 postmenopausal hemodialysis patients, free estrogen index was positively correlated with bone mineral density (BMD) Z-score and the annual percent change of BMD in multiple regression analysis. Endogenous estrogen may prevent bone loss in postmenopausal hemodialysis patients throughout life. INTRODUCTION: Women on dialysis are not only at risk of developing mineral and bone disorder, but also suffer from postmenopausal osteoporosis. We assessed the effect of sex hormones on bone metabolism in postmenopausal hemodialysis patients. METHODS: We enrolled 112 postmenopausal hemodialysis patients with a mean age of 68.4 ± 10.4 years. We measured the serum levels of estradiol, testosterone, sex hormone-binding globulin (SHBG), and intact parathyroid hormone (intact-PTH), as well as bone metabolism parameters and radial bone mineral density (BMD). The free estrogen index (FEI) was calculated from the estradiol and SHBG values. After conventional dialysis was performed for 12 months, BMD was measured again and the annual percent change was calculated. Estradiol and SHBG were also measured in 25 postmenopausal women without chronic kidney disease. RESULTS: Estradiol levels were higher in the hemodialysis patients than in the postmenopausal women without chronic kidney disease. In patients with relatively normal bone turnover (intact-PTH: from 150 to 300 pg/ml), the FEI showed a positive correlation with the BMD Z-score. The annual percent change of BMD showed a positive correlation with the FEI according to multiple regression analysis. CONCLUSIONS: Endogenous estrogen may prevent bone loss in postmenopausal hemodialysis patients throughout life.
Assuntos
Estradiol/fisiologia , Osteoporose Pós-Menopausa/etiologia , Diálise Renal/efeitos adversos , Idoso , Densidade Óssea/fisiologia , Osso e Ossos/metabolismo , Estradiol/sangue , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/fisiopatologia , Rádio (Anatomia)/fisiopatologia , Globulina de Ligação a Hormônio Sexual/metabolismoRESUMO
The development of cancer is due to the growth and proliferation of transformed normal cells. Recent evidence suggests that the nature of oncogenic stress and the state of the cell of origin critically affect both tumorigenic activity and tumor histological type. However, this mechanistic relationship in mesenchymal tumors is currently largely unexplored. To clarify these issues, we established a mouse osteosarcoma (OS) model through overexpression of c-MYC in bone marrow stromal cells (BMSCs) derived from Ink4a/Arf (-/-) mice. Single-cell cloning revealed that c-MYC-expressing BMSCs are composed of two distinctly different clones: highly tumorigenic cells, similar to bipotent-committed osteochondral progenitor cells, and low-tumorigenic tripotent cells, similar to mesenchymal stem cells (MSCs). It is noteworthy that both bipotent and tripotent cells were capable of generating histologically similar, lethal OS, suggesting that both committed progenitor cells and MSCs can become OS cells of origin. Shifting mesenchymal differentiation by depleting PPARγ in tripotent MSC-like cells and overexpressing PPARγ in bipotent cells affected cell proliferation and tumorigenic activity. Our findings indicate that differentiation potential has a key role in OS tumorigenic activity, and that the suppression of adipogenic ability is a critical factor for the development of OS.
Assuntos
Adipogenia/fisiologia , Neoplasias Ósseas/metabolismo , Transformação Celular Neoplásica/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Osteossarcoma/metabolismo , Proteínas Proto-Oncogênicas c-myc/biossíntese , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Diferenciação Celular/fisiologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Condrócitos/metabolismo , Condrócitos/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Immunoblotting , Imuno-Histoquímica , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteossarcoma/genética , PPAR gama/biossíntese , PPAR gama/genética , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/metabolismo , Células-Tronco/patologia , Células Estromais/metabolismo , Células Estromais/patologiaRESUMO
Synovial sarcomas account for 5-10% of all soft tissue sarcomas and the majority of synovial sarcomas display characteristic t(X;18) translocations that result in enhanced transcription of the insulin-like growth factor-2 (IGF-2) gene. IGF-2 is an essential fetal mitogen involved in the pathogenesis of different tumours, leading to cellular proliferation and inhibition of apoptosis. Here we asked whether activation of IGF signalling is of functional importance in synovial sarcomas. We screened human synovial sarcomas for expression of IGF-2 and the phosphorylated IGF-1 receptor (IGF-1R), which mainly mediates the proliferative and anti-apoptotic effects of IGF-2. Since both the phosphatidylinositol 3'-kinase (PI3K)-AKT pathway and the MAPK signalling cascade are known to be involved in the transmission of IGF-1R signals, expression of phosphorylated (p)-AKT and p-p44/42 MAPK was additionally assessed. All tumours expressed IGF-2 and 78% showed an activated IGF-1R. All tumours were found to express p-AKT and 92% showed expression of activated p44/42 MAPK. To analyse the functional and potential therapeutic relevance of IGF-1R signalling, synovial sarcoma cell lines were treated with the IGF-1R inhibitor NVP-AEW541. Growth was impaired by the IGF-1R antagonist, which was consistently accompanied by a dose-dependent reduction of phosphorylation of AKT and p44/42 MAPK. Functionally, inhibition of the receptor led to increased apoptosis and diminished mitotic activity. Concurrent exposure of selected cells to NVP-AEW541 and conventional chemotherapeutic agents resulted in positive interactions. Finally, synovial sarcoma cell migration was found to be dependent on signals transmitted by the IGF-1R. In summary, our data show that the IGF-1R might represent a promising therapeutic target in synovial sarcomas.
Assuntos
Receptor IGF Tipo 1/fisiologia , Sarcoma Sinovial/metabolismo , Transdução de Sinais/fisiologia , Adulto , Antineoplásicos/farmacologia , Apoptose , Western Blotting/métodos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Imunofluorescência , Humanos , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Pirróis/farmacologia , RNA Mensageiro/análise , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Sarcoma Sinovial/patologia , Transdução de Sinais/efeitos dos fármacosAssuntos
Neoplasias do Sistema Nervoso Central/secundário , Efeito Enxerto vs Tumor , Transplante de Células-Tronco Hematopoéticas/métodos , Recidiva Local de Neoplasia/terapia , Sarcoma de Ewing/terapia , Adulto , Neoplasias do Sistema Nervoso Central/terapia , Feminino , Humanos , Sarcoma de Ewing/patologia , Irmãos , Transplante HomólogoRESUMO
We evaluated the construct validity of the Musculoskeletal Tumour Society rating scale (Enneking score) as a functional measure for patients with sarcoma involving the upper limb. We compared the Enneking score by examining the correlation between two patient-derived outcome measures, the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire and the Medical Outcomes Study Short Form-36 (SF-36) as indicators of functional status in 40 patients with malignant or aggressive benign bone and soft-tissue tumours of the upper limb who had undergone surgical treatment. The frequency distributions were similar among the three scoring systems. As for the validity, Spearman's rank correlation coefficient of the Enneking score to the DASH questionnaire was -0.79 and that of the Enneking to the SF-36 subscales ranged from 0.38 to 0.60. Despite being a measure from the surgeon's perspective, the Enneking score was shown to be a valid indicator of physical disability in patients with malignant or aggressive benign tumours of the upper limb and reflected their opinion.