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2.
Cancer Immunol Res ; 9(7): 735-747, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33906864

RESUMO

IL11 is a member of the IL6 family of cytokines and signals through its cognate receptor subunits, IL11RA and glycoprotein 130 (GP130), to elicit biological responses via the JAK/STAT signaling pathway. IL11 contributes to cancer progression by promoting the survival and proliferation of cancer cells, but the potential immunomodulatory properties of IL11 signaling during tumor development have thus far remained unexplored. Here, we have characterized a role for IL11 in regulating CD4+ T cell-mediated antitumor responses. Absence of IL11 signaling impaired tumor growth in a sporadic mouse model of colon cancer and syngeneic allograft models of colon cancer. Adoptive bone marrow transfer experiments and in vivo depletion studies demonstrated that the tumor-promoting activity of IL11 was mediated through its suppressive effect on host CD4+ T cells in the tumor microenvironment. Indeed, when compared with Il11ra-proficient CD4+ T cells associated with MC38 tumors, their Il11ra-deficient counterparts displayed elevated expression of mRNA encoding the antitumor mediators IFNγ and TNFα. Likewise, IL11 potently suppressed the production of proinflammatory cytokines (IFNγ, TNFα, IL6, and IL12p70) by CD4+ T cells in vitro, which we corroborated by RNAscope analysis of human colorectal cancers, where IL11RAhigh tumors showed less IFNG and CD4 expression than IL11RAlow tumors. Therefore, our results ascribe a tumor cell-extrinsic immunomodulatory role to IL11 during colon cancer development that could be amenable to an anticytokine-based therapy.See related Spotlight by van der Burg, p. 724.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Neoplasias do Colo/imunologia , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Interleucina-11/metabolismo , Animais , Antígenos CD4/análise , Antígenos CD4/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular Tumoral , Colo/imunologia , Colo/patologia , Neoplasias do Colo/patologia , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Interferon gama/análise , Interferon gama/metabolismo , Subunidade alfa de Receptor de Interleucina-11/análise , Subunidade alfa de Receptor de Interleucina-11/genética , Camundongos , Camundongos Knockout , Neoplasias de Tecido Ósseo , Receptores de Interleucina-11/metabolismo , Microambiente Tumoral/imunologia
3.
Sci Rep ; 10(1): 21319, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33288803

RESUMO

The distal femur is the predominant site for benign bone tumours and a common site for fracture following tumour removal or cementation. However, the lack of conclusive assessment criterion for post-operative fracture risk and appropriate devices for cement augmentation are serious concerns. Hence, a validated biomechanical tool was developed to assess bone strength, depending on the size and location of artificially created tumorous defects in the distal femora. The mechanics of the bone-cement interface was investigated to determine the main causes of reconstruction failure. Based on quantitative-CT images, non-linear and heterogeneous finite element (FE) models of human cadaveric distal femora with simulated tumourous defects were created and validated using in vitro mechanical tests from 14 cadaveric samples. Statistical analyses demonstrated a strong linear relationship (R2 = 0.95, slope = 1.12) with no significant difference between bone strengths predicted by in silico analyses and in vitro tests (P = 0.174). FE analyses showed little reduction in bone strength until the defect was 35% or more of epiphyseal volume, and reduction in bone strength was less pronounced for laterally located defects than medial side defects. Moreover, the proximal end of the cortical window and the most interior wall of the bone-cement interface were the most vulnerable sites for reconstruction failure.


Assuntos
Curetagem , Fêmur/patologia , Fêmur/cirurgia , Neoplasias de Tecido Ósseo/patologia , Neoplasias de Tecido Ósseo/cirurgia , Fenômenos Biomecânicos , Análise de Elementos Finitos , Humanos , Medição de Risco
4.
Clin Orthop Relat Res ; 478(11): 2505-2519, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32510187

RESUMO

BACKGROUND: Reconstruction of defects after resection of malignant bone tumors with liquid nitrogen-sterilized recycled autografts is an alternative to bone allografts and endoprostheses in resource-constrained environments. Most studies reporting favorable outcomes with liquid nitrogen-sterilized autografts for bone reconstruction are geographically restricted to a few countries, and the technical challenges of routinely using liquid nitrogen intraoperatively, especially when using the pedicle freezing technique, has not been documented. QUESTIONS/PURPOSES: (1) What are the technical challenges of liquid nitrogen sterilization of bone tumors for inexperienced surgeons? (2) What are the complications associated with the procedure? METHODS: Between May 2017 and October 2019, 88 patients underwent limb salvage procedures for malignant bone tumors of the extremities at our institution. An endoprosthesis was used for reconstruction of the defect following resection in 45% (40 of 88) of these patients, mostly in adults (median age 21 years; range 9 to 68). In the remaining 55% (48 of 88) of patients undergoing biological reconstruction, liquid nitrogen-sterilized autograft was used in 90% (43 of 48), extracorporeal irradiation-sterilized autograft was used in 4% (2 of 48) and allograft was used in 6% (3 of 48). Of the 43 patients receiving liquid nitrogen-sterilized autograft, 5% (2 of 43) were excluded due to loss to follow-up and the remaining 95% (41 of 43) were included for the analysis. Liquid nitrogen-sterilized autograft was the preferred method of reconstruction at our institution during the study period, unless the patient had an indication for prosthesis reconstruction; extracorporeal irradiation-sterilized autograft was used due to resource constraints with liquid nitrogen and allograft was used when patients insisted.All surgical procedures were performed by the same team of trained orthopaedic oncology surgeons. The medical records of the included 41 patients were retrieved using an institutional database search in this retrospective study, and all were used to ascertain technical challenges associated with the operations as well as early (within 3 weeks of the index procedure) and late complications (those occurring 3 weeks or more after surgery). The technical challenges were defined as follows: the quantity of liquid nitrogen to be used; arranging, storing and handling of liquid nitrogen in the operating room, type and size of the container to be used for sterilization, the positioning of the container during pedicle freezing, level of fibular osteotomy for pedicle freezing of tibia, soft tissue protection, limb rotation during pedicle freezing, managing tourniquet time, and any other intraoperative factors with the use of liquid nitrogen for sterilizing the autograft. As our experience with the technique gradually grew, the answers to the above-mentioned factors were determined. Considering the removal of autograft as the endpoint of interest, survival of the autograft was determined by Kaplan-Meier analysis.The median (range) patient age was 14 years (2 to 49), and 54% (22 of 41) were males. Osteosarcoma was the most common diagnosis (68%, [28 of 41]) followed by Ewing's sarcoma (20%, [8 of 41]). On presentation, 27% of patients (11 of 41) had radiological evidence of pulmonary metastasis. Tumors were seen frequently around the knee (39% [16 of 41] proximal tibia and 22% [9 of 41] distal femur). Before resection 85% (35 of 41) underwent neoadjuvant chemotherapy. Sixty-six percent (27 of 41) underwent pedicle-freezing and the remaining 34% (14 of 41) underwent free-freezing of the tumor segment of the bone. The median (range) duration of surgery was 280 minutes (210 to 510). The patients were followed up for a median (range) duration of 21 months (5 to 30); two patients were lost to follow-up. RESULTS: With gradual experience using liquid nitrogen-sterilization over time at our institution, we determined that the following factors helped us in performing liquid nitrogen-sterilization more efficiently. For every operation 15 L to 20 L of unsterilized liquid nitrogen was arranged, 1 or 2 days before the procedure, and stored in industrial-grade cryocylinders in the operating complex. During the procedure, the operating surgeons wore additional plastic aprons under the surgical gowns, surgical goggles, and rubber boots. The staff managing the liquid nitrogen in the operating room wore thermal protective gloves. For most of the pedicle freezing procedures, we used a cylindrical stainless-steel container that was 30 cm in height and 15 cm in diameter, with a narrow opening. The container was kept on a separate moveable cart that was placed next to the operating table at a slightly lower level, and it was wrapped in multiple cotton rolls, plastic sheets, surgical sheets, and a crepe bandage. For pedicle freezing of the tibia, we performed the fibular osteotomy at least 5 cm away from the planned surgical margin, roughly around the axis of rotation of the limb. The soft tissue at the base of the delivered bone segment was dissected for at least 5 cm beyond the planned surgical margin of bone, and was protected with multiple layers of cotton rolls, plastic drapes, a single roll of Esmarch and crepe bandage. The tumor segment was externally rotated during pedicle freezing for all anatomic sites (proximal tibia, distal tibia, proximal humerus, and proximal femur). The tourniquet was inflated just before pedicle freezing to prevent tumor dissemination and not before the initial incision in all pedicle freezing procedures.Thirty-nine percent of patients (16 of 41) experienced complications associated with the procedures, and 15% (6 of 41) underwent revision surgery. Early complications (occurring within 3 weeks of the index procedure) were skin necrosis in four of 16 patients, intraoperative fracture in one of 16, superficial infection in one of 16, and neurapraxia in one of 16 patients. Late complications (occurring 3 weeks or more after surgery) were resorption of the recycled bone in four of 16 patients, nonunion of the osteotomy site in two of 12, delayed union of the osteotomy site in one of 16, collapse of the recycled bone in one of 16, and local recurrence in 1 of 16 patients. Kaplan-Meier survivorship free from removal of autograft at 2 years after surgery was 92% (95% confidence interval 89 to 96). CONCLUSION: Liquid nitrogen-sterilization is an alternative technique that requires some training and experience for the surgeon to become proficient in treating primary malignant bone tumors. Because it is widely available, it may be an option worth exploring in resource-constrained environments, where allografts and endoprostheses cannot be procured. The methods we developed to address the technical challenges will require more study and experience, but we believe these observations will aid others who may wish to use and evaluate liquid nitrogen sterilization of extremity bone sarcomas. LEVEL OF EVIDENCE: Level IV, therapeutic study.


Assuntos
Autoenxertos , Neoplasias de Tecido Ósseo/cirurgia , Nitrogênio , Procedimentos de Cirurgia Plástica , Esterilização/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Extremidades , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Ósseo/patologia , Estudos Retrospectivos , Adulto Jovem
5.
Carcinogenesis ; 41(7): 904-908, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32556091

RESUMO

DNA repair genes are commonly altered in metastatic prostate cancer, but BRCA1 mutations are rare. Preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. We undertook a prospective study among men with prostate cancer in the Health Professionals Follow-up Study and evaluated BRCA1 via immunohistochemical staining on tissue microarrays. BRCA1 was expressed in 60 of 589 tumors. Prevalence of BRCA1 positivity was 43% in the 14 men with metastases at diagnosis compared with 9% in non-metastatic tumors [difference, 33 percentage points; 95% confidence interval (CI), 7-59]. BRCA1-positive tumors had 2.16-fold higher Ki-67 proliferative indices (95% CI, 1.18-3.95), higher tumor aneuploidy as predicted from whole-transcriptome profiling, and higher Gleason scores. Among the 575 patients with non-metastatic disease at diagnosis, we evaluated the association between BRCA1 expression and development of lethal disease (metastasis or cancer-specific death, 69 events) during long-term follow-up (median, 18.3 years). A potential weak association of BRCA1 positivity with lethal disease (hazard ratio, 1.61; 95% CI, 0.82-3.15) was attenuated when adjusting for age, Gleason score and clinical stage (hazard ratio, 1.11; 95% CI, 0.54-2.29). In summary, BRCA1 protein expression is a feature of more proliferative and more aneuploid prostate tumors and is more common in metastatic disease. While not well suited as a prognostic biomarker in primary prostate cancer, BRCA1 protein expression may be most relevant in advanced disease.


Assuntos
Proteína BRCA1/genética , Reparo do DNA/genética , Neoplasias de Tecido Ósseo/genética , Neoplasias da Próstata/genética , Adulto , Idoso , Biomarcadores Tumorais , Progressão da Doença , Seguimentos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Gradação de Tumores , Metástase Neoplásica , Proteínas de Neoplasias/genética , Neoplasias de Tecido Ósseo/patologia , Neoplasias de Tecido Ósseo/secundário , Neoplasias da Próstata/patologia
6.
J Comp Pathol ; 172: 27-30, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31690411

RESUMO

A 7-year-old neutered male domestic shorthair cat was presented with chronic lameness in the right forelimb. A cystic bony lesion was identified in the distal right humerus and amputation was performed. The epiphyseal trabecular bones of the capitulum and trochlea was replaced by a tan to pink, expansile mass that was surrounded by a thin rim of cortical bone. Microscopically, the tumour was composed of a bland, osteoid producing spindle cell population within a well-vascularized fibrous stroma. Radiographical and histological features were consistent with osteoblastoma. Osteoblastoma and the related osteoid osteoma are uncommon, benign osteoblastic tumours that are reported rarely in animals. These tumours should be considered as differential diagnoses for slow growing, cystic bony lesions in cats.


Assuntos
Úmero/patologia , Neoplasias de Tecido Ósseo/veterinária , Osteoblastoma , Animais , Doenças do Gato/patologia , Doenças do Gato/cirurgia , Gatos , Diagnóstico Diferencial , Úmero/cirurgia , Masculino , Neoplasias de Tecido Ósseo/diagnóstico , Neoplasias de Tecido Ósseo/cirurgia , Osteoblastoma/diagnóstico , Osteoblastoma/patologia , Osteoblastoma/cirurgia
7.
Endokrynol Pol ; 69(2): 205-210, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29442350

RESUMO

BACKGROUND: Tumor induced osteomalacia (TIO) are extremely rare paraneoplastic syndrome with less than 300 reported cases. This report highlights the pitfalls and challenges in diagnosing and localizing TIO in patients with refractory and resistant osteomalacia. PATIENT AND METHODS: 41- year gentleman with 4-year history of musculoskeletal weakness and pathologic fractures presented in wheelchair bound incapacitated state of 1-year duration. Investigations were significant for severe hypophosphatemia, severe phosphaturia, normal serum calcium, reduced 1,25-dihydroxy vitamin-D, elevated ALP, elevated intact parathyroid hormone (iPTH), and pseudo-fractures involving pelvis and bilateral femur. Whole body MRI and 99mTc methylene diphosphonate bone-scan were also normal. Whole body FDG-PET scan involving all 4 limbs revealed a small FDG avid lesion at lateral border of lower end of left femur (SUV max 3.9), which was well characterized on 3-dimensional CT reconstruction. Plasma C-terminal fibroblast growth factor (FGF)-23 was 698 RU/ mL (normal < 150 RU/ml). Wide surgical excision of the tumor was done. Histopathology confirmed mesenchymal tumor of mixed connective tissue variant. Serum phosphorous normalized post-surgery day-1. High dose oral calcium and vitamin-D was continued. FGF-23 normalized post surgery (73RU/ml). Physical strength improved significantly and now he is able to walk independently. CONCLUSION: TIO is frequently confused with normocalcemic hyperparathyroidism and vitamin-D resistant rickets/osteomalacia, which increases patient morbidity. Imaging for tumor localization should involve whole body from head to tip of digits, cause these tumors are notoriously small and frequently involve digits of hands and legs. Complete surgical removal of the localized tumor is key to good clinical outcomes.


Assuntos
Neoplasias de Tecido Ósseo/complicações , Neoplasias de Tecido Conjuntivo/etiologia , Adulto , Cálcio/uso terapêutico , Fêmur/diagnóstico por imagem , Fêmur/cirurgia , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Masculino , Neoplasias de Tecido Ósseo/diagnóstico , Neoplasias de Tecido Ósseo/diagnóstico por imagem , Neoplasias de Tecido Ósseo/cirurgia , Neoplasias de Tecido Conjuntivo/sangue , Neoplasias de Tecido Conjuntivo/diagnóstico , Neoplasias de Tecido Conjuntivo/tratamento farmacológico , Osteomalacia , Síndromes Paraneoplásicas/sangue , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/tratamento farmacológico , Síndromes Paraneoplásicas/etiologia , Vitamina D/uso terapêutico
8.
Mol Cancer Res ; 15(12): 1714-1721, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28860121

RESUMO

Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT) are rate-limiting enzymes in the NAD+ synthesis pathway. Chondrosarcoma is a malignant cartilage forming bone tumor, in which mutations altering isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) activity have been identified as potential driver mutations. Vulnerability for NAD+ depletion has been reported for IDH1/2-mutant cells. Here, the potency of NAMPT inhibitors as a treatment of chondrosarcoma was explored. Eleven chondrosarcoma cell lines were treated with NAMPT inhibitors, in which the effect on cell viability, colony formation, and 3D collagen invasion was assessed. The expression level of NAMPT and NAPRT transcripts in chondrosarcoma cells was determined by qRT-PCR. Methylation of the NAPRT promoter was evaluated using a previously published dataset of genome-wide methylation. In addition, a methylation dataset was used to determine methylation of the NAPRT promoter in 20 IDH1/2-mutated cartilage tumors. Chondrosarcoma cells showed a dose-dependent decrease in cell viability, 3D collagen invasion, and colony formation upon treatment with NAMPT inhibitors, in which nearly half of the cell lines demonstrated absolute IC50s in the low nanomolar range. Increasing IC50s correlated to increasing NAPRT expression levels and decreasing NAPRT promoter methylation. No correlation between IDH1/2 mutation status and sensitivity for NAMPT inhibitors was observed. Strikingly, higher methylation of the NAPRT promoter was observed in high-grade versus low-grade chondrosarcomas. In conclusion, this study identified NAMPT as a potential target for treatment of chondrosarcoma.Implications: Chondrosarcoma patients, especially those of high histologic grade with lower expression and hypermethylation of NAPRT, may benefit from inhibition of the NAD synthesis pathway. Mol Cancer Res; 15(12); 1714-21. ©2017 AACR.


Assuntos
Condrossarcoma/genética , Citocinas/genética , Isocitrato Desidrogenase/genética , Neoplasias de Tecido Ósseo/genética , Nicotinamida Fosforribosiltransferase/genética , Pentosiltransferases/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Condrossarcoma/tratamento farmacológico , Condrossarcoma/patologia , Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mutação , NAD/antagonistas & inibidores , NAD/biossíntese , NAD/genética , Invasividade Neoplásica/genética , Neoplasias de Tecido Ósseo/tratamento farmacológico , Neoplasias de Tecido Ósseo/patologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Pentosiltransferases/antagonistas & inibidores , Regiões Promotoras Genéticas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
9.
Pathology ; 49(5): 506-513, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28688724

RESUMO

PD-1 and its ligands have been shown to play a significant role in evasion of malignant tumour cells from the immune system. Last year, the Unites States Food and Drug Administration (FDA) approved anti-PD-1 inhibitors for treatment of non-small cell lung carcinoma and recently expanded the use of immunotherapy for metastatic urothelial cell carcinoma and Hodgkin lymphoma. However, studies on expression of PD-1 and its ligand in malignant bone and soft tissue sarcoma are sparse. In this study, we evaluated PD-1 and PD-L1 expression on variants of liposarcomas and rhabdomyosarcomas, osteosarcomas and chondrosarcomas. Tissue microarrays (TMAs) for liposarcomas (well differentiated, myxoid/round cell, and pleomorphic), rhabdomyosarcomas (alveolar, embryonal, pleomorphic, and spindle cell), conventional osteosarcomas and chondrosarcomas were stained for PD-1 and PD-L1 antibodies. Adipose tissue, skeletal muscle, bone, osteochondroma and lipoma were used as control and benign counterparts. Western blot was performed to evaluate expression of PD-1 and PD-L1 in four sarcoma cell lines. Osteosarcomas, chondrosarcomas, and all variants of liposarcomas and rhabdomyosarcomas over-expressed PD-1 relative to normal tissue. Expression of PD-1 in rhabdomyosarcomas was associated with higher tumour stage. Only one case of pleomorphic liposarcoma, one case of pleomorphic rhabdomyosarcoma and two cases of alveolar rhabdomyosarcomas were positive for PD-L1. Normal adipose tissue, skeletal muscle, and bone were negative for both PD-1 and PD-L1 and lipomas and osteochondroma weakly expressed PD-1 but not PD-L1. Western blot confirmed the presence of PD-1 protein in all four sarcoma cell lines. Overall, our results showed cytoplasmic expression of PD-1 in the bone and soft tissue sarcomas, while PD-L1 was negative. Whether these data are an indication for effectiveness of immunotherapy in the management of malignant bone and soft tissue sarcomas remains to be elucidated.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias de Tecido Ósseo/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Sarcoma/metabolismo , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Condrossarcoma/metabolismo , Condrossarcoma/patologia , Feminino , Humanos , Lipossarcoma/metabolismo , Lipossarcoma/patologia , Masculino , Neoplasias de Tecido Ósseo/patologia , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Receptor de Morte Celular Programada 1/genética , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Sarcoma/patologia , Análise Serial de Tecidos
11.
Medicine (Baltimore) ; 96(47): e8650, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29381938

RESUMO

RATIONALE: Osteopoikilosis is a rare and asymptomatic disease of the bone, which is often discovered occasionally on radiography for irrelevant complaints. Characterized by multiple, small, circular, or oval-shaped radiodense lesions, it may be confused with bony metastatic tumors. PATIENT CONCERNS: The present study describes a case of a 17-year-old adolescent who suffered from pain and movement limitation of his left thigh following a fall from standing height. DIAGNOSES: Plain radiographs showed spiral fracture in left femoral shaft; besides, multiple scattered sclerotic lesions of variable size were also observed over the bilateral proximal femurs, left distal femur, proximal tibia, and distal tibia and fibula through X-rays, computed tomography, and magnetic resonance imaging. The patient was finally diagnosed with left femoral shaft fracture and osteopoikilosis. INTERVENTIONS: The patient underwent reduction and internal fixation with intramedullary nail a week after injury. OUTCOMES: The patient was discharged without any complications 12 days after the surgery. At the 3-month follow-up, the patient recovered well and remained symptom-free with no changes to his sclerotic lesions. LESSONS: Although this case is not so complicated, we have to be cautious when differentiating osteopoikilosis and bony metastases in clinical practice in future, which should avoid causing undue distress to both the patients and doctors.


Assuntos
Fraturas do Fêmur/diagnóstico , Fêmur , Fíbula/diagnóstico por imagem , Neoplasias de Tecido Ósseo/diagnóstico , Osteopecilose/diagnóstico , Radiografia/métodos , Tíbia/diagnóstico por imagem , Adolescente , Diagnóstico Diferencial , Fraturas do Fêmur/cirurgia , Fêmur/diagnóstico por imagem , Fêmur/lesões , Fixação Intramedular de Fraturas/métodos , Humanos , Achados Incidentais , Imageamento por Ressonância Magnética/métodos , Masculino , Tomografia Computadorizada por Raios X/métodos
12.
Hum Pathol ; 58: 24-34, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27498059

RESUMO

Sclerostin (SOST) is an extracellular Wnt signaling antagonist which negatively regulates bone mass. Despite this, the expression and function of SOST in skeletal tumors remain poorly described. Here, we first describe the immunohistochemical staining pattern of SOST across benign and malignant skeletal tumors with bone or cartilage matrix (n=68 primary tumors). Next, relative SOST expression was compared to markers of Wnt signaling activity and osteogenic differentiation across human osteosarcoma (OS) cell lines (n=7 cell lines examined). Results showed immunohistochemical detection of SOST in most bone-forming tumors (90.2%; 46/51) and all cartilage-forming tumors (100%; 17/17). Among OSs, variable intensity and distribution of SOST expression were observed, which highly correlated with the presence and degree of neoplastic bone. Patchy SOST expression was observed in cartilage-forming tumors, which did not distinguish between benign and malignant tumors or correlate with regional morphologic characteristics. Finally, SOST expression varied widely between OS cell lines, with more than 97-fold variation. Among OS cell lines, SOST expression positively correlated with the marker of osteogenic differentiation alkaline phosphatase and did not correlate well with markers of Wnt/ß-catenin signaling activity. In summary, SOST is frequently expressed in skeletal bone- and cartilage-forming tumors. The strong spatial correlation with bone formation and the in vitro expression patterns are in line with the known functions of SOST in nonneoplastic bone, as a feedback inhibitor on osteogenic differentiation. With anti-SOST as a potential therapy for osteoporosis in the near future, its basic biologic and phenotypic consequences in skeletal tumors should not be overlooked.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Neoplasias Ósseas/metabolismo , Neoplasias de Tecido Ósseo/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Fosfatase Alcalina/metabolismo , Biópsia , Neoplasias Ósseas/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Condroma/metabolismo , Condroma/patologia , Condrossarcoma/metabolismo , Condrossarcoma/patologia , Marcadores Genéticos , Humanos , Imuno-Histoquímica , Neoplasias de Tecido Ósseo/patologia , Osteoblastoma/metabolismo , Osteoblastoma/patologia , Osteogênese , Osteoma Osteoide/metabolismo , Osteoma Osteoide/patologia , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Estudos Retrospectivos , Via de Sinalização Wnt
13.
Skeletal Radiol ; 44(7): 981-93, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25910709

RESUMO

OBJECTIVE: To assess the clinical success and costs of computed tomography (CT)-guided radiofrequency ablation (RFA) of osteoblastoma (OB) and spinal osteoid osteoma (OO). MATERIALS AND METHODS: Nineteen patients with OB and eight patients with spinal OO were treated with CT-guided RFA. The OBs were localized in the extremities (n = 10), the vertebral column (n = 2), and (juxta-)articular (n = 7). Dedicated procedural techniques included three-dimensional CT-guided access planning in all cases, overlapping RFA needle positions (median, two positions; range, 1-6 RF-electrode positions) within the OB nidus (multiple ablation technique, n = 15), and thermal protection in case of adjacent neural structure in four spinal OO. The data of eight operated OB and ten operated spinal OO patients were used for comparison. Long-term success was assessed by clinical examination and using a questionnaire sent to all operated and RFA-treated patients including visual analogue scales (VAS) regarding the effect of RFA on severity of pain and limitations of daily activities (0-10, with 0 = no pain/limitation up to 10 = maximum or most imaginable pain/limitation). RESULTS: All patients had a clear and persistent pain reduction until the end of follow-up. The mean VAS score for all spinal OO patients and all OB patients treated either with RFA or with surgical excision significantly decreased for severity of pain at night, severity of pain during the day, and both for limitations of daily and of sports activities. CONCLUSIONS: RFA is an efficient method for treating OB and spinal OO and should be regarded as the first-line therapy after interdisciplinary individual case discussion.


Assuntos
Ablação por Cateter/economia , Neoplasias de Tecido Ósseo/economia , Neoplasias de Tecido Ósseo/cirurgia , Osteotomia/economia , Neoplasias da Coluna Vertebral/economia , Neoplasias da Coluna Vertebral/cirurgia , Adolescente , Adulto , Ablação por Cateter/métodos , Criança , Pré-Escolar , Análise Custo-Benefício/economia , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Ósseo/diagnóstico por imagem , Osteoblastoma/diagnóstico por imagem , Osteoblastoma/economia , Osteoblastoma/cirurgia , Osteoma Osteoide/diagnóstico por imagem , Osteoma Osteoide/economia , Osteoma Osteoide/cirurgia , Osteotomia/métodos , Radiografia , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Resultado do Tratamento , Adulto Jovem
15.
Cancer Treat Res ; 162: 31-63, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25070230

RESUMO

Benign bone lesions are a broad category that demonstrates a spectrum of activities from latent to aggressive. Differentiating the various tumors is important in order to properly determine necessary intervention. This chapter focuses on the presentation, imaging, diagnostic features, and treatment of the most common benign bone tumors in order to help guide diagnosis and management.


Assuntos
Neoplasias Ósseas/diagnóstico , Cistos Ósseos/diagnóstico , Doenças do Desenvolvimento Ósseo/diagnóstico , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Condroblastoma/diagnóstico , Condroma/diagnóstico , Granuloma Eosinófilo/diagnóstico , Displasia Fibrosa Óssea/diagnóstico , Tumores de Células Gigantes/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Neoplasias de Tecido Ósseo/diagnóstico , Osteoblastoma/diagnóstico , Osteocondroma/diagnóstico , Osteoma/diagnóstico , Periósteo/patologia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X
17.
Semin Musculoskelet Radiol ; 18(3): 280-99, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24896744

RESUMO

Spinal tumors consist of a large spectrum of various histologic entities. Multiple spinal lesions frequently represent known metastatic disease or lymphoproliferative disease. In solitary lesions primary neoplasms of the spine should be considered. Primary spinal tumors may arise from the spinal cord, the surrounding leptomeninges, or the extradural soft tissues and bony structures. A wide variety of benign neoplasms can involve the spine including enostosis, osteoid osteoma, osteoblastoma, aneurysmal bone cyst, giant cell tumor, and osteochondroma. Common malignant primary neoplasms are chordoma, chondrosarcoma, Ewing sarcoma or primitive neuroectodermal tumor, and osteosarcoma. Although plain radiographs may be useful to characterize some spinal lesions, magnetic resonance imaging is indispensable to determine the extension and the relationship with the spinal canal and nerve roots, and thus determine the plan of management. In this article we review the characteristic imaging features of extradural spinal lesions.


Assuntos
Neoplasias da Coluna Vertebral/patologia , Doenças Ósseas/patologia , Condrossarcoma/patologia , Cordoma/patologia , Diagnóstico por Imagem , Hemangioma/patologia , Histiocitose de Células de Langerhans/patologia , Humanos , Neoplasias de Tecido Ósseo/patologia , Tumores Neuroectodérmicos Primitivos/patologia
18.
J Cell Physiol ; 229(12): 2049-56, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24812032

RESUMO

Ewing sarcoma is an aggressive pediatric small round cell tumor that predominantly occurs in bone. Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS/FLI interacts with numerous lineage-essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS/FLI binds the osteogenic transcription factor RUNX2 and prevents osteoblast differentiation. In this study, we investigated the role of another Runt-domain protein, RUNX3, in Ewing sarcoma. RUNX3 participates in mesenchymal-derived bone formation and is a context dependent tumor suppressor and oncogene. RUNX3 was detected in all Ewing sarcoma cells examined, whereas RUNX2 was detected in only 73% of specimens. Like RUNX2, RUNX3 binds to EWS/FLI via its Runt domain. EWS/FLI prevented RUNX3 from activating the transcription of a RUNX-responsive reporter, p6OSE2. Stable suppression of RUNX3 expression in the Ewing sarcoma cell line A673 delayed colony growth in anchorage independent soft agar assays and reversed expression of EWS/FLI-responsive genes. These results demonstrate an important role for RUNX3 in Ewing sarcoma.


Assuntos
Subunidade alfa 3 de Fator de Ligação ao Core/biossíntese , Neoplasias de Tecido Ósseo/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Ewing/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias de Tecido Ósseo/patologia , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/patologia
19.
Transfusion ; 54(6): 1469-77, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24411009

RESUMO

BACKGROUND: Few studies have systematically identified factors associated with blood loss in musculoskeletal tumor surgery. We aimed to identify risk factors for requiring large-volume transfusion in musculoskeletal tumor surgery and created an interactive model to predict red blood cell transfusion requirements based on patient characteristics. These data will facilitate planning in hospital blood banks and aid identification of specific groups for future interventions targeted at reducing blood utilization. Only one similar study has been published and there are minimal data surrounding interventions designed to minimize blood loss in musculoskeletal tumor surgery. STUDY DESIGN AND METHODS: We retrospectively analyzed a database containing 1322 consecutive surgeries, performed at a quaternary referral center in Melbourne, Australia. Using logistic regression analysis and a negative truncated binomial logistic regression model, we developed prediction models for transfusion requirement. RESULTS: The following factors were associated with large-volume transfusion: malignant tumors, bone tumors, sacral and pelvic tumors, high American Society of Anesthesiologists (ASA) score, and tumor size of more than 5 cm. High ASA score was also strongly associated with 30-day mortality. CONCLUSIONS: Preoperative planning in high-risk patients is critical to ensure adequate blood product supply, minimize wastage, and optimize the patient's general health before surgery. These patients would be ideal targets for future randomized studies aimed at reducing blood utilization.


Assuntos
Perda Sanguínea Cirúrgica , Transfusão de Sangue/métodos , Sistema Musculoesquelético/patologia , Sistema Musculoesquelético/cirurgia , Neoplasias de Tecido Ósseo/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
20.
Semin Musculoskelet Radiol ; 17(2): 203-20, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23673551

RESUMO

Primary osseous spinal tumors are relatively rare in comparison with metastatic disease, myeloma, and lymphoma. Despite their rarity, the interpreting radiologist must be aware of the typical imaging features to provide appropriate diagnosis for guidance of clinical management. The age of occurrence, distribution longitudinally in the spine, and distribution axially within the vertebra combined with typical imaging appearances can help indicate the correct diagnosis. This article reviews the diagnostic features of benign and malignant primary bone spinal tumors.


Assuntos
Cordoma/diagnóstico , Diagnóstico por Imagem/métodos , Neoplasias de Tecido Ósseo/diagnóstico , Sarcoma/diagnóstico , Neoplasias da Coluna Vertebral/diagnóstico , Doenças Ósseas/diagnóstico , Diagnóstico Diferencial , Hemangioma/diagnóstico , Humanos
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