RESUMO
CONTEXT: Atypical femoral fractures (AFFs) are very rare atraumatic or mild trauma fractures in the subtrochanteric region or femoral shaft. Some unique genetic variants in Asian populations might confer susceptibility to AFF, since the incidence of AFFs is higher in Asian populations. OBJECTIVE: Because rare variants have been found to be causative in some diseases and the roles of osteomalacia causative genes have not been reported, we investigated rare variants in genes causing abnormal mineralization. METHODS: Exome sequencing was performed to detect variants in gene coding and boundary regions, and the frequencies of deleterious rare alleles were compared between Japanese patients with AFF (nâ =â 42) and controls of the 4.7KJPN panel of Tohoku Medical Megabank by whole genome sequencing (nâ =â 4773). RESULTS: The frequency of the deleterious rare allele of ENPP1 was significantly increased in AFF (Pâ =â .0012, corrected P [Pc]â =â .0155, OR 4.73, 95% CI 2.15-10.40). In multigene panel analysis, the frequencies of deleterious rare alleles of candidate genes were increased in AFF (Pâ =â .0025, OR 2.72, 95% CI 1.49-4.93). Principal component analysis of bone metabolism markers identified a subgroup of patients with AFF with higher frequencies of deleterious rare alleles in ENPP1 (Pâ =â 4.69 × 10-5, Pcâ =â .0006, OR 8.47, 95% CI 3.76-19.09) and the candidate genes (Pâ =â 1.08 × 10-5, OR 5.21, 95% CI 2.76-9.86). CONCLUSION: AFF is associated with genes including ENPP1 that cause abnormal mineralization, suggesting that osteomalacia is an underlying condition predisposing to AFF and that higher incident rates of AFFs in Asian populations might be explained by the genetic risk factors including ENPP1.
Assuntos
Conservadores da Densidade Óssea , Doenças Ósseas , Raquitismo Hipofosfatêmico Familiar , Fraturas do Fêmur , Osteomalacia , Alelos , Conservadores da Densidade Óssea/efeitos adversos , Doenças Ósseas/genética , Difosfonatos/efeitos adversos , Raquitismo Hipofosfatêmico Familiar/complicações , Feminino , Fraturas do Fêmur/epidemiologia , Fraturas do Fêmur/genética , Humanos , Masculino , Osteomalacia/genéticaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ósseas , Linfonodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Sarcoma de Ewing , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biópsia/métodos , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Deterioração Clínica , Diagnóstico Diferencial , Fluordesoxiglucose F18/farmacologia , Humanos , Imuno-Histoquímica , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Masculino , Mediastino , Cuidados Paliativos , Compostos Radiofarmacêuticos/farmacologia , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/patologia , Parede Torácica/diagnóstico por imagem , Parede Torácica/patologiaRESUMO
Platelet-activating antibodies, which recognize platelet factor 4 (PF4)/heparin complexes, induce spontaneous heparin-induced thrombocytopenia (HIT) syndrome or fondaparinux-associated HIT without exposure to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). This condition mostly occurs after major orthopedic surgery, implying that surgery itself could trigger this immune response, although the mechanism is unclear. To investigate how surgery may do so, we performed a multicenter, prospective study of 2069 patients who underwent total knee arthroplasty (TKA) or hip arthroplasty. Approximately half of the patients received postoperative thromboprophylaxis with UFH, LMWH, or fondaparinux. The other half received only mechanical thromboprophylaxis, including dynamic (intermittent plantar or pneumatic compression device), static (graduated compression stockings [GCSs]), or both. We measured anti-PF4/heparin immunoglobulins G, A, and M before and 10 days after surgery using an immunoassay. Multivariate analysis revealed that dynamic mechanical thromboprophylaxis (DMT) was an independent risk factor for seroconversion (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.34-3.02; P = .001), which was confirmed with propensity-score matching (OR, 1.99; 95% CI, 1.17-3.37; P = .018). For TKA, the seroconversion rates in patients treated with DMT but no anticoagulation and in patients treated with UFH or LMWH without DMT were similar, but significantly higher than in patients treated with only GCSs. The proportion of patients with ≥1.4 optical density units appeared to be higher among those treated with any anticoagulant plus DMT than among those not treated with DMT. Our study suggests that DMT increases risk of an anti-PF4/heparin immune response, even without heparin exposure. This trial was registered to www.umin.ac.jp/ctr as #UMIN000001366.
Assuntos
Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Autoanticorpos/sangue , Tromboembolia/prevenção & controle , Idoso , Anticoagulantes/uso terapêutico , Autoanticorpos/imunologia , Autoantígenos/imunologia , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Fondaparinux , Heparina/imunologia , Heparina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Dispositivos de Compressão Pneumática Intermitente , Masculino , Pessoa de Meia-Idade , Fator Plaquetário 4/imunologia , Polissacarídeos/uso terapêutico , Meias de CompressãoAssuntos
Artralgia/etiologia , Neoplasias Ósseas/complicações , Neoplasias Ósseas/diagnóstico , Doenças da Unha/etiologia , Osteoma Osteoide/complicações , Osteoma Osteoide/diagnóstico , Adolescente , Artralgia/diagnóstico , Diagnóstico Diferencial , Edema/diagnóstico , Edema/etiologia , Humanos , Masculino , Doenças da Unha/diagnóstico , Radiografia , Articulação do Dedo do Pé/diagnóstico por imagem , Articulação do Dedo do Pé/patologiaRESUMO
BACKGROUND: Maspin is a 42 kDa protein known to act as a tumor suppressor. Although its function has not been fully elucidated, numerous reports have investigated the prognostic impact of maspin in patients with several types of cancer. However, there have been no reports on the association between maspin expression and the prognosis of patients with soft tissue sarcomas (STS). The aim of this study was thus to explore the association of maspin expression with the prognosis of patients with STS. METHODS: One-hundred and eight paraffin-embedded STS tissue samples were immunohistochemically analyzed using antibodies for maspin and Ki-67 antigen. The patients were followed up for 1 to 300 months (median: 33 months) and the prognostic value was evaluated by log-rank test and Cox's regression hazard model. RESULTS: Cytoplasmic maspin expression was observed in 48.1% of specimens, and was significantly correlated with a higher FNCLCC grade (P = 0.002) and the presence of distant metastases (P = 0.001), and those with cytoplasmic maspin expression had both shorter disease-free survival (DFS) and overall survival (OS) by log-rank test (P <0.001, P = 0.001, respectively). By Cox's multivariate analysis, the presence of distant metastases was the only prognostic factor for DFS and OS. CONCLUSIONS: This is the first report to reveal an association between maspin expression and the prognosis of patients with STS. Although further studies with a larger series of patients and a longer follow-up period will be needed, cytoplasmic maspin expression could be an indicator of unfavorable prognosis in patients with STS. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_205.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Sarcoma/metabolismo , Serpinas/metabolismo , Adenocarcinoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Citoplasma/metabolismo , Progressão da Doença , Intervalo Livre de Doença , Feminino , Genes Supressores de Tumor , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Sarcoma/patologia , Adulto JovemRESUMO
Proliferative fasciitis (PF) is a benign, discrete proliferation of fibroblasts or myofibroblasts in soft tissue. Proliferative fasciitis mostly occurs in adults and is often confused with a sarcoma because of its rapid growth and peculiar histological features. We report a case of PF mimicking a sarcoma which developed in a 13-year-old boy, who noticed a painful tumor, with gradual enlargement, in his right lower leg. Magnetic resonance imaging revealed that the tumor measured 34 mm × 20 mm × 41 mm and was located in the subcutaneous tissue. The tumor was surgically resected. Pathologically, the tumor was composed of a proliferation of atypical spindle cells, admixed with larger ganglion-like cells. Immunohistochemically, the tumor cells were positive for vimentin, cytokeratin, smooth muscle actin, HHF-35 and Fli-1. The tumor was subsequently diagnosed as a PF, although it was difficult to differentiate from a sarcoma. Five years after surgery, the postoperative course has been uneventful with no recurrence or metastasis.
Assuntos
Fasciite/patologia , Perna (Membro)/patologia , Sarcoma/patologia , Adolescente , Diagnóstico Diferencial , Humanos , MasculinoRESUMO
BACKGROUND: Osteosarcoma is the most frequent primary malignant bone tumor. In Europe and the United States, its prognosis has been greatly improved by the use of multimodal treatment, including preoperative and postoperative chemotherapy as well as surgery. In Japan, however, only a few clinical studies on osteosarcoma have been carried out. METHODS: To evaluate the efficacy of neoadjuvant chemotherapy on nonmetastatic, operable osteosarcoma arising in the extremities, a prospective multi-institutional phase II trial, the Neoadjuvant Chemotherapy for Osteosarcoma (NECO) study, was conducted. Preoperative chemotherapy included high-dose methotrexate (HD-MTX), cisplatin (CDDP), and adriamycin (ADR). If the induction therapy was assessed as not effective, high-dose ifosfamide (IFO) was added to the chemotherapy regimen. A total of 124 patients were enrolled in this trial, and ultimately 113 patients were eligible. RESULTS: The 5-year overall survival (OAS) and event-free survival (EFS) rates in the NECO study were 77.9% and 65.5%, respectively. A good histological response to the induction chemotherapy resulted in favorable OAS (78.7%). The patients assessed as poor histological responders with progressive disease after the induction chemotherapy exhibited comparable outcomes (OAS 89.5%, EFS 68.2%). There were no significant differences between the OAS and EFS rates of the patients in terms of response to preoperative chemotherapy. CONCLUSIONS: We analyzed the results of the intensive neoadjuvant chemotherapy and the effects of adding IFO on patients with osteosarcoma in Japan. The results suggest efficacy of the high-dose IFO addition to the standard three-drug chemotherapy regimen. However, a randomized clinical study is needed to establish the true impact of IFO on patients with osteosarcoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Terapia Neoadjuvante/métodos , Invasividade Neoplásica/patologia , Osteossarcoma/tratamento farmacológico , Adolescente , Adulto , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Neoplasias Ósseas/cirurgia , Criança , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Japão , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Estadiamento de Neoplasias , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Osteossarcoma/cirurgia , Cuidados Pré-Operatórios/métodos , Estudos Prospectivos , Medição de Risco , Estatísticas não Paramétricas , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Skeletally immature children with a primary malignant tumor in the distal end of the femur are candidates for limb-salvage surgery; however, functional impairment due to subsequent limb-length discrepancy must be considered. Our aim was to evaluate the long-term clinical outcome of limb salvage in patients with a sarcoma of the distal end of the femur who were eleven years old or less, focusing on limb-length discrepancy and complications. METHODS: The cases of forty children were retrospectively reviewed in a multicenter study based on the responses to a questionnaire. Twenty-eight patients had had endoprosthetic reconstruction, and twelve had had biological reconstruction. Functional evaluation was based on the Musculoskeletal Tumor Society scoring system, with numerical values from 0 to 5 points assigned for each of the following six categories: pain, function, emotional acceptance, use of supports, walking ability, and gait. These values were added, and the functional score was presented as a percentage of the maximum possible score. Limb-length discrepancy was measured with orthoroentgenograms. Complications and their treatment were analyzed. Patient survival and the survival of the reconstructions were analyzed with use of the Kaplan-Meier method. RESULTS: Seven patients died and thirty-three remained alive, for a survival rate of 82% at ten years postoperatively. For the surviving patients, the mean follow-up periods (and standard deviations) were similar for the twenty-two who had endoprosthetic reconstruction (13.2 +/- 3.9 years) and the eleven who had biological reconstruction (10.4 +/- 4.4 years). All patients had reached skeletal maturity. The mean final functional score was 74% +/- 18% in the endoprosthetic reconstruction group and 68% +/- 17% in the biological reconstruction group (p = 0.37). For the nineteen patients who underwent limb-lengthening, the mean functional score increased significantly from 65% +/- 21% before the procedure to 81% +/- 11% after the lengthening (p = 0.0016). There were five early and twenty-eight late complications. In the endoprosthetic reconstruction group, the most frequent complications were deep infection and aseptic loosening. In the biological reconstruction group, the most frequent complications were implant breakage and nonunion. Revision surgeries were required in seventeen patients, including five who had an amputation. The rate of survival of the endoprosthetic reconstructions was 77% at five years and 51% at ten years postoperatively, whereas the rate of survival of the biological reconstructions was 46% at both five and ten years postoperatively. CONCLUSIONS: Endoprosthetic or biological reconstructions as limb salvage provided good functional outcome in skeletally immature children with a malignant bone tumor of the distal aspect of the femur despite a high rate of revisions and limb-lengthening procedures.
Assuntos
Neoplasias Femorais/cirurgia , Desigualdade de Membros Inferiores/etiologia , Salvamento de Membro/efeitos adversos , Sarcoma/cirurgia , Adolescente , Adulto , Fatores Etários , Criança , Feminino , Neoplasias Femorais/mortalidade , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Sarcoma/mortalidade , Inquéritos e Questionários , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
Arpp, a protein including an ankyrin-repeat, P EST motif, and p roline-rich region, is a recently identified protein that is exclusively expressed in striated muscles. This study comprehensively analyzed its expression among soft tissue sarcomas of various histological types and evaluated its potential use for the differential diagnosis of rhabdomyosarcoma (RMS). Formalin-fixed, paraffin-embedded tissues, including 37 RMS cases, 88 non-RMS sarcomas, and 38 carcinomas, were analyzed for Arpp expression. Arpp was detected in 33 (89.2%) of 37 RMS cases by immunohistochemistry. Western blot analysis revealed expression of Arpp in all RMS cases tested. High expression of Arpp was generally associated with morphological evidence of skeletal muscle differentiation of tumor cells. In contrast, Arpp displayed 6.3% (8/126) positivity among the non-RMS tumors. Focal or weak expression was seen in malignant fibrous histiocytoma (2/27), synovial sarcoma (1/11), Ewing sarcoma (1/5), and epithelioid sarcoma (3/5), whereas one epithelioid sarcoma displayed strong expression for Arpp. A comparative analysis of the Arpp profile with that of myogenic markers in RMS revealed that the sensitivity of Arpp (89.2%) was higher than that of myoglobin (59.6%) and comparable with that of myogenin (88.2%), MyoD (80.6%), muscle-specific actin (83.8%), and desmin (89.2%). These results suggested that Arpp is sensitive to and specific for RMS. Thus, we proposed that Arpp is a novel skeletal muscle-specific marker, which is useful for differential diagnosis of RMS.
Assuntos
Biomarcadores Tumorais/análise , Proteínas Nucleares/biossíntese , Proteínas Repressoras/biossíntese , Rabdomiossarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Western Blotting , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Proteínas Musculares , Músculo Esquelético/metabolismo , Inclusão em Parafina , Rabdomiossarcoma/metabolismo , Neoplasias de Tecidos Moles/metabolismoRESUMO
The development of the attachment zones of the anterior cruciate ligament (ACL) is an important consideration when examining the structural properties. The aim of this study was to elucidate the morphological changes and the distribution of proliferating cells and collagen types I, II and III at the attachment zones of the rat ACL during postnatal growth. The majority of proliferating cell nuclear antigen (PCNA) immunostained cells were noted near the ligament insertion, especially at the tibial site, and these cells gradually changed to fibrochondrocyte-like cells but still produced collagen types I and III at birth until one month old when rapid longitudinal growth of the ACL took place. After one month when the rate of the ligament growth decreased to one thirtieth of that during the first month and the epiphyseal cartilage at the attachment zone had been replaced by bone, these fibrochondrocyte-like cells began to produce collagen type II and reveal safranin O staining. The immunolabelling pattern to collagen type III was similar to that of PCNA immunostaining during the growth phase. Our findings show that the fibrochondrocytes at the attachment zone may develop from the ligament cells and act as a growth zone for the ligament during the period of ligament growth, and that subsequently, these cells begin to synthesis collagen type II and proteoglycans after epiphyseal ossification. These observations mainly occurred at the tibial attachment zone.