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BACKGROUND: Leiomyosarcomas are among the most common histological types of soft tissue sarcoma (STS), with no effective treatment available for advanced patients. Lung metastasis, the most common site of distant metastasis, is the primary prognostic factor. We analysed the immune environment targeting lung metastasis of STS to explore new targets for immunotherapy. METHODS: We analysed the immune environment of primary and lung metastases in 38 patients with STS using immunohistochemistry. Next, we performed gene expression analyses on primary and lung metastatic tissues from six patients with leiomyosarcoma. Using human leiomyosarcoma cell lines, the effects of the identified genes on immune cells were assessed in vitro. RESULTS: Immunohistochemistry showed a significant decrease in CD8+ cells in the lung metastases of leiomyosarcoma. Among the genes upregulated in lung metastases, epithelial cellular adhesion molecule (EPCAM) showed the strongest negative correlation with the number of CD8+ cells. Transwell assay results showed that the migration of CD8+ T cells was significantly increased in the conditioned media obtained after inhibition or knock down of EPCAM. CONCLUSIONS: EPCAM was upregulated in lung metastases of leiomyosarcoma, suggesting inhibition of CD8+ T cell migration. Our findings suggest that EPCAM could serve as a potential novel therapeutic target for leiomyosarcoma.
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Leiomiossarcoma , Neoplasias Pulmonares , Humanos , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Molécula de Adesão da Célula Epitelial , Linfócitos T CD8-Positivos/patologia , Regulação para Cima , Evasão da Resposta Imune , Neoplasias Pulmonares/genéticaRESUMO
BACKGROUND AND OBJECTIVE: Surgical site infection (SSI) is common in surgery for malignant musculoskeletal tumours, specifically those arising from the trunk. In this study, we investigated the risk factors for SSI after resection of musculoskeletal tumours of the trunk. METHODS: This retrospective observational study included 125 patients (72 males, 53 females) with musculoskeletal tumours of the trunk in our hospital from 1 April 2008 to 31 August 2023. The incidence of SSI and its risk factors were investigated. RESULTS: SSI was observed in 26% (32/125), and the median time to SSI was 22 days. On multivariate analysis, the following were identified as risk factors for SSI: tumours arising caudal to Jacoby's line (hazard ratio [HR] 4.04; P = .0107), soft tissue reconstruction (HR 3.43; P = .0131), and low Geriatric Nutritional Risk Index (GNRI) (HR 0.96; P = .0304). Patients were classified into two risk categories based on GNRI scores: the risk group (GNRI ≤98) and no risk group (>98). The risk group showed a significantly lower overall noninfection survival rate (P = .023). CONCLUSION: Tumours arising caudal to Jacoby line, soft tissue reconstruction, and lower GNRI were risk factors for SSI. Preoperative and postoperative nutritional interventions should be considered to improve GNRI.
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Low-grade central osteosarcoma (LGCOS), which arises from the intramedullary cavity of the metaphysis of long bones, occasionally exhibits extraosseous spread. Approximately 10-30% of patients with LGCOS exhibit dedifferentiation, but it is rare to experience a primary tumor with a dedifferentiated component. A 38-year-old female patient presented with right knee pain for two months. Imaging studies revealed a bone mass with extraosseous involvement. Wide resection was performed, and pathologic examination led to the diagnosis of LGCOS with a dedifferentiated extraosseous lesion. A single defect in the bone cortex constituted the boundary between the low- and high-grade components. The extraosseous high-grade component included more tumor cells with p53 overexpression and more murine double minute 2 (MDM2) copies compared with the low-grade component. These genetic mutations and copy number alterations can be associated with malignant transformation of LGCOS.
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BACKGROUND: The management of pain in patients with rotator cuff tears can be challenging. Neuropathic pain is reportedly associated with pain occurrence in musculoskeletal diseases. However, to date, few studies have reported on the prevalence of neuropathic pain in patients with rotator cuff tears or identified the factors associated with neuropathic pain in a multicenter study. METHODS: A total of 391 patients (205 males and 186 females; median age, 67.7 years; range, 27-92 years) with rotator cuff tears were included in this study. The prevalence of neuropathic pain in rotator cuff tears was investigated using the Japanese version of the painDETECT questionnaire for all patients. In addition, factors significantly associated with the occurrence of neuropathic pain were examined using multivariate logistic regression analysis. RESULTS: Twenty-eight patients (7.2%) were classified into the neuropathic pain group (score ≥19), 97 (24.8%) into the uncertainty regarding neuropathy group (score 13-18), and 266 (68.0%) into the nociceptive pain group (score ≤12). According to the multivariate logistic regression analysis, the independent predictors of neuropathic pain were the VAS score (most severe pain during the past 4 weeks; odds ratio, 1.55; 95% confidence interval [CI], 1.23-2.09) and UCLA shoulder score (odds ratio, 0.81; 95% CI, 0.65-0.97). CONCLUSIONS: Based on the study findings, the prevalence of neuropathic pain in patients with rotator cuff tear was 7.2%. It is important to investigate the presence or absence of neuropathic pain when treating patients with painful rotator cuff tears, because neuropathy associated with rotator cuff tears may adversely affect patient outcomes.
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Neuralgia , Lesões do Manguito Rotador , Masculino , Feminino , Humanos , Idoso , Lesões do Manguito Rotador/complicações , Lesões do Manguito Rotador/epidemiologia , Prevalência , Dor de Ombro/diagnóstico , Dor de Ombro/epidemiologia , Dor de Ombro/etiologia , Neuralgia/diagnóstico , Neuralgia/epidemiologia , Neuralgia/etiologia , CausalidadeRESUMO
BACKGROUND: Dedifferentiated chondrosarcoma (DDCS) is an aggressive bone tumour with a poor prognosis and no effective treatment. Because changes in DNA methylation play critical roles in DDCS, we explored the roles that DNA methylation plays in oncogenesis to potentially identify an effective epigenetic treatment. METHODS: We identified genes downregulated in DDCS vs. conventional chondrosarcoma (CCS) due to DNA methylation using in silico analysis. The results were validated in DDCS clinical samples, and the molecular functions of the genes of interest were investigated in multiple chondrosarcoma cell lines (NDCS-1, SW1353, and OUMS-27). The therapeutic effect of decitabine, a DNA methyltransferase inhibitor, was evaluated in vitro and in vivo. RESULTS: PRKCZ was specifically downregulated by DNA methylation in DDCS. Overexpression of PRKCZ decreased the proliferation of NDCS-1 and SW1353 cells. PRKCZ directly bound to and activated ATM, which was followed by phosphorylation of CHK2 and subsequent apoptosis. Decitabine increased PRKCZ expression through de-methylating the promoter region of PRKCZ, which activated the ATM/CHK2 pathway and inhibited cell proliferation by inducing apoptosis. CONCLUSIONS: Increased DNA methylation and reduced expression of PRKCZ prevents apoptosis via inactivation of the ATM/CHK2 pathway in DDCS. Decitabine-induced expression of PRKCZ represents a promising therapy for DDCS.
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Apoptose , Condrossarcoma , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Quinase do Ponto de Checagem 2/genética , Quinase do Ponto de Checagem 2/metabolismo , Condrossarcoma/tratamento farmacológico , Condrossarcoma/genética , Condrossarcoma/metabolismo , Metilação de DNA , Decitabina/metabolismo , Decitabina/farmacologia , Humanos , Proteína Quinase CRESUMO
OBJECTIVE: The aim of this study was to investigate the efficacy and safety of tranexamic acid in patients undergoing surgery for bone and soft tissue tumors. METHODS: Data were retrospectively collected from 454 consecutive patients with bone and soft tissue tumors who underwent open biopsy, marginal resection, curettage or wide resection between January 2017 and December 2018. We performed propensity score matching of patients who received tranexamic acid with those who did not. The primary outcome variables were intra-operative, peri-operative and estimated blood loss (IBL, PBL and EBL, respectively). RESULTS: Tranexamic acid (+) and tranexamic acid (-) groups were defined according to whether patients received tranexamic acid or not. Among the 454 patients, open biopsy was performed in 102, marginal resection in 175, curettage in 54 and wide resection in 123. Intra-operative blood loss was significantly lower in the tranexamic acid (+) group than in the tranexamic acid (-) group for both marginal and wide resection (marginal resection: 17.3 vs. 70.3 g, respectively, P = 0.045; wide resection: 128.8 vs. 273.1 g, respectively, P = 0.023). Peri-operative blood loss and estimated blood loss were also significantly lower in the tranexamic acid (+) group for wide resection (peri-operative blood loss: 341.5 vs. 686.5 g, respectively, P = 0.0039; estimated blood loss: 320.7 vs. 550.6 ml, respectively, P = 0.030). No venous thromboembolism occurred in either group. CONCLUSION: This study suggests that TXA administration safely and effectively reduces blood loss, in particular for wide resection, with no increase in the rate of adverse events.
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Antifibrinolíticos , Neoplasias de Tecidos Moles , Ácido Tranexâmico , Antifibrinolíticos/efeitos adversos , Perda Sanguínea Cirúrgica/prevenção & controle , Transfusão de Sangue , Humanos , Pontuação de Propensão , Estudos Retrospectivos , Ácido Tranexâmico/efeitos adversosRESUMO
PURPOSE: Baseplate positioning may affect clinical outcome after reverse total shoulder arthroplasty (RTSA). The aim of this study was to evaluate the risk of penetration of the baseplate peg in RTSA. METHODS: Forty-four patients with rotator cuff arthropathy or massive rotator cuff tears were included. Using their computed tomography data, ten insertion patterns of the baseplate pegs were simulated. First, in the axial plane, the baseplate was placed perpendicular to the Friedman axis (Friedman placement) and parallel to the glenoid surface (glenoid placement). Second, each of these placements were classified into the following groups: The baseplate peg was placed 2 mm anterior to the long axis of the glenoid (group A2), 1 mm anterior (group A1), on the long axis (group C0), 1 mm posterior (group P1), and 2 mm posterior (group P2). Cases in which the baseplate peg was within the scapular neck were defined as non-penetration, and the non-penetration rates among each group were evaluated and compared between sexes, and their relationship with patient height was evaluated. RESULTS: In both the Friedman and glenoid placements, the non-penetration rate was significantly higher in groups A2 (68.2% and 70.5%) and A1 (65.9% and 65.9%) compared with groups P1 (18.2% and 29.5%) and P2 (9.1% and 13.6%; p < 0.001) and in males than in females (p < 0.05). Furthermore, the non-penetration rate tended to be higher as the patient's height increased. CONCLUSIONS: It is recommended that the baseplate peg be placed anterior to the long axis of the glenoid.
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Artroplastia do Ombro , Artropatias , Articulação do Ombro , Artroplastia do Ombro/efeitos adversos , Artroplastia do Ombro/métodos , Feminino , Humanos , Artropatias/cirurgia , Masculino , Manguito Rotador/cirurgia , Escápula/cirurgia , Articulação do Ombro/diagnóstico por imagem , Articulação do Ombro/cirurgia , Tomografia Computadorizada por Raios XRESUMO
Chronic inflammation is associated with up-regulation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and excessive inflammatory cytokine secretion by M1 macrophages. The anti-inflammatory cytokine interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory and tissue-regenerative M2 phenotype, thus reducing inflammation and enhancing tissue regeneration. We have generated NF-κB responsive, or constitutively active IL-4 expression lentiviral vectors transduced into murine bone marrow-derived mesenchymal stromal cells (MSCs). MSCs with a constitutively active IL-4 expression vector produced large quantities of IL-4 continuously, whereas IL-4 secretion was significantly induced by lipopolysaccharide (LPS) in the NF-κB sensing MSCs. In contrast, LPS had no effect on MSCs with IL-4 secretion driven by a constitutively active promoter. We also found that intermittent and continuous LPS treatment displayed distinct NF-κB activation profiles, and this regulation was independent of IL-4 signaling. The supernatant containing IL-4 from the LPS-treated MSCs suppressed M1 marker (inducible nitric oxide synthase [iNOS] and tumor necrosis factor alpha [TNFα]) expression and enhanced M2 marker (Arginase 1, CD206 and IL1 receptor antagonist [IL1Ra]) expression in primary murine macrophages. The IL-4 secretion at the basal, non-LPS induced level was sufficient to suppress TNFα and enhance Arginase 1 at a lower level, but had no significant effects on iNOS, CD206 and IL1Ra expression. Finally, IL-4 secretion at basal or LPS-induced levels significantly suppressed osteogenic differentiation of MSCs. Our findings suggest that the IL-4 secreting MSCs driven by NF-κB sensing or constitutive active promoter have great potential for mitigating the effects of chronic inflammation and promoting earlier tissue regeneration.
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Sistemas de Liberação de Medicamentos/métodos , Interleucina-4/metabolismo , Células-Tronco Mesenquimais/fisiologia , NF-kappa B/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Osteogênese , Regiões Promotoras Genéticas , Transdução de Sinais , Transgenes , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Impingement is a common complication of reverse shoulder arthroplasty. Placement of the baseplate with a wide impingement-free angle is ideal; however, there are few studies on Asian populations, which have smaller height and physique, and there is a lack of guidance on achieving optimal outcomes. The purpose of the present study was to explore the impingement-free range of motion reverse shoulder arthroplasty and analyze the suitable baseplate position or tilt for the Asian population using simulation software. METHODS: We uploaded computed tomography scan data from 20 Asian patients to three-dimensional (3D) simulation software. The implantation of the reverse shoulder arthroplasty component was performed on the 3D humerus and scapula using software, and range of motion was assessed until impingement occurred. RESULTS: The range of motion in flexion significantly improved when the baseplate was lowered up to 3 mm inferiorly. Range of motion in abduction and internal and external rotation significantly improved as the baseplate was lowered up to 4 mm. There was no significant difference in range of motion in any motion after changing the inferior tilt, except in internal and external rotation. CONCLUSIONS: The range of motion in abduction, flexion, and internal and external rotations significantly improved with increased inferior offset. These results may prove valuable in determining the optimal baseplate position for RSA, particularly in Asian populations.
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Artroplastia do Ombro , Articulação do Ombro , Humanos , Ombro/cirurgia , Artroplastia do Ombro/métodos , Articulação do Ombro/diagnóstico por imagem , Articulação do Ombro/cirurgia , Artroplastia , Escápula/cirurgia , Amplitude de Movimento ArticularRESUMO
Prognosis after neoadjuvant chemotherapy (NAC) for osteosarcoma is generally predicted using manual necrosis-rate assessments; however, necrosis rates obtained in these assessments are not reproducible and do not adequately reflect individual cell responses. We aimed to investigate whether viable tumor cell density assessed using a deep-learning model (DLM) reflects the prognosis of osteosarcoma. Seventy-one patients were included in this study. Initially, the DLM was trained to detect viable tumor cells, following which it calculated their density. Patients were stratified into high and low-viable tumor cell density groups based on DLM measurements, and survival analysis was performed to evaluate disease-specific survival and metastasis-free survival (DSS and MFS). The high viable tumor cell density group exhibited worse DSS (p = 0.023) and MFS (p = 0.033). DLM-evaluated viable density showed correct stratification of prognosis groups. Therefore, this evaluation method may enable precise stratification of the prognosis in osteosarcoma patients treated with NAC.
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BACKGROUND: Small-sized tumors tend to be resected without thorough assessment and are often managed in a sarcoma center after a malignancy is diagnosed. The lack of knowledge about the features of smallsized sarcomas may lead to unplanned resection. The features of small-sized soft tissue sarcomas were investigated by comparing them with those of small benign soft tissue tumors. METHODS: We included 17 soft tissue sarcoma cases (7 on the hands and feet and 10 on the limbs and trunk) with a diameter of under 2 cm. The features of small-sized sarcomas were compared to those of 39 benign soft tissue tumors with a diameter of under 2 cm and non-specific imaging findings (30 on the hands and feet and 9 on the limbs and trunk). The investigated features were age, sex, presence of pain, subjective increasing tumor size, and duration of observation. RESULTS: When we compared the tumors in the hands and feet, those <40 years of age (5/7 [71%] vs. 8/30 [27%], p=0.03) experiencing pain (7/7 [100%] vs. 13/30 [43%], p=0.007) were more common in patients with sarcomas than in patients with benign tumors. When we compared the tumors in the limbs and trunk, there was no significant difference in all investigated features. CONCLUSION: Although clinical features were ineffective in distinguishing malignancy in most small-sized soft tissue tumors, we should pay attention to painful tumors of the hands and feet in younger patients.
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Sarcoma , Neoplasias de Tecidos Moles , Humanos , Sarcoma/diagnóstico , Sarcoma/patologia , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia , Pé , Recidiva Local de Neoplasia/patologia , Dor , Estudos RetrospectivosRESUMO
Aims: To evaluate mid-to long-term patient-reported outcome measures (PROMs) of endoprosthetic reconstruction after resection of malignant tumours arising around the knee, and to investigate the risk factors for unfavourable PROMs. Methods: The medical records of 75 patients who underwent surgery between 2000 and 2020 were retrospectively reviewed, and 44 patients who were alive and available for follow-up (at a mean of 9.7 years postoperatively) were included in the study. Leg length discrepancy was measured on whole-leg radiographs, and functional assessment was performed with PROMs (Toronto Extremity Salvage Score (TESS) and Comprehensive Outcome Measure for Musculoskeletal Oncology Lower Extremity (COMMON-LE)) with two different aspects. The thresholds for unfavourable PROMs were determined using anchor questions regarding satisfaction, and the risk factors for unfavourable PROMs were investigated. Results: The thresholds for favourable TESS and COMMON were 64.8 and 70.4 points, respectively. Multivariate analysis showed that age at surgery (p = 0.004) and postoperative leg length discrepancy (p = 0.043) were significant risk factors for unfavourable TESS results, while age at surgery (p < 0.001) was a significant risk factor for unfavourable COMMON-LE results. Following receiver operating characteristic analysis, the threshold for both TESS and COMMON-LE was 29 years of age at surgery. Additionally, a leg length discrepancy of 8.2 mm was the threshold for unfavourable TESS. Conclusion: Patients aged > 29 years at the time of surgery require appropriate preoperative counselling and adequate postoperative physical and socioemotional support. Reconstruction equivalent to the length of the resected bone can reduce the risk of functional disabilities in daily living.
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To our knowledge, only one previous report described the treatment of osteochondral autograft for steroid-induced osteonecrosis of the humeral head (ONHH) in a middle-aged patient. The present report describes a 20-year-old man who was found to have avascular osteonecrosis of the right humeral head after corticosteroid pulse treatment, followed by oral corticosteroid therapy. The patient complained of serious right shoulder pain and limited range of motion (ROM). Anteroposterior (AP) radiographs of the right shoulder revealed a crescent sign at the humeral head, indicating subchondral bone collapse with a linear sclerotic change and normal articular surface of the glenoid. The case was categorized as Stage 3 according to the Cruess classification. In general, Cruess classification Stage 3 is treated with humeral head replacement and shoulder arthroplasty. The patient underwent surgical treatment involving osteochondral autograft transplantation. Autografts were harvested from the right knee. At the 1.5-year follow-up, the patient was pain-free and showed an improved active ROM. Furthermore, AP radiographs demonstrated that the glenohumeral joint space was maintained, and no progression of humeral head collapse was observed. This case may be helpful in decision-making if young patients with ONHH require surgical treatment. Furthermore, osteochondral autograft transplantation may be an effective treatment for ONHH.
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Cabeça do Úmero , Osteonecrose , Masculino , Pessoa de Meia-Idade , Humanos , Adulto Jovem , Adulto , Cabeça do Úmero/transplante , Autoenxertos , Osteonecrose/induzido quimicamente , Osteonecrose/diagnóstico , Corticosteroides , EsteroidesRESUMO
Periosteal chondrosarcoma is an extremely rare malignant cartilage-forming tumour that originates from the periosteum and occurs on the surface of bone. Often, it is difficult to distinguish periosteal chondrosarcoma from other tumours, and reports in the literature are scarce. This study aims to investigate the characteristics of periosteal chondrosarcoma, focusing particularly on medullary invasion. Among 33 periosteal cartilaginous tumours, seven patients with pathologically proven periosteal chondrosarcoma were identified retrospectively. The average tumour size was 5.4 cm in the long axis; two tumours were smaller than 3.0 cm. Six tumours were resected with a wide margin, and the remaining tumour had a marginal margin. Histology revealed that six tumours (85.7%) had invaded the medullary cavity; three of these did not show invasion into the medullary cavity on MRI evaluation. Neither local recurrence nor metastasis was observed among these patients. The frequency of invasion of the medullary cavity was higher than that reported previously. The recommended treatment for periosteal chondrosarcoma is resection with an adequate margin. Therefore, surgeons should consider the possibility of medullary invasion when attempting to achieve a histologically negative margin, even if the tumour does not show invasion into the medullary cavity on MRI.
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BACKGROUND Giant cell tumor of bone (GCTB) is a locally aggressive, intermediate tumor that rarely metastasizes. GCTB typically affects the ends of long bones and rarely involves the ribs. Curettage is typically the treatment of choice for GCTB in long bones. However, the optimal treatment of GCTB in ribs remains unclear. We report the case of a patient with asymptomatic GCTB of the first rib that was successfully treated with combined preoperative denosumab therapy and surgery via a transmanubrial approach without resection of the clavicle. CASE REPORT A healthy 27-year-old woman presented with a bone tumor involving the left first rib that was incidentally discovered on routine chest X-ray. Histological examination of core-needle biopsy specimens of the lesion led to a pathological diagnosis of GCTB. After preoperative denosumab treatment for 6 months, en bloc resection via a transmanubrial approach was performed. There were no serious postoperative complications. The patient remained free of symptoms and had no recurrence 4.5 years after surgery. CONCLUSIONS Compared with other ribs, masses located in the first rib can be challenging to treat surgically because of the clavicle and neighboring neurovascular structures. This report is the first to describe GCTB located on the anterior aspect of the first rib that was successfully treated with combined preoperative denosumab therapy and surgery via a transmanubrial approach, with no recurrence or functional impairment of the shoulder girdle.
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Conservadores da Densidade Óssea , Tumor de Células Gigantes do Osso , Adulto , Denosumab/uso terapêutico , Feminino , Tumor de Células Gigantes do Osso/diagnóstico por imagem , Tumor de Células Gigantes do Osso/tratamento farmacológico , Tumor de Células Gigantes do Osso/cirurgia , Humanos , Recidiva Local de Neoplasia , Costelas/cirurgiaRESUMO
BACKGROUND CIC-rearranged sarcoma (CRS) is a recently described subset of undifferentiated small-round-cell sarcomas of bone and soft tissue. DUX4 is the most common gene involved in CRS. CRS usually presents in the soft tissue of the trunk and extremities, and is recognized as being clinically aggressive, with poor prognosis. Our case highlights an unusual presentation of CRS with cardiac tamponade. CASE REPORT A 48-year-old man presented with hypotension caused by hemorrhagic cardiac tamponade. ¹8F-fluorodeoxyglucose-positron emission tomography showed increased uptake in multiple lesions, including lesions in the left proximal humerus and several lymph nodes. Biopsy specimens of the humerus revealed proliferation of round-shaped cells. In addition, CIC-DUX4 gene rearrangement was detected by polymerase chain reaction and direct sequencing, leading to a diagnosis of cardiac tamponade caused by CRS. Although the patient received systemic chemotherapy as well as radiotherapy to the mediastinal lesion and left humerus, he died of progressive disease 12 months after diagnosis. CONCLUSIONS Because CRS is a recently proposed entity that is distinct from Ewing sarcoma, the clinical presentation and outcome of CRS has not been well documented in the literature. This is the first case report of CRS presenting as cardiac tamponade. Although cardiac tamponade due to metastatic sarcoma is extremely rare, CRS can be included in the differential diagnosis.
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Tamponamento Cardíaco , Sarcoma de Ewing , Sarcoma de Células Pequenas , Sarcoma , Neoplasias de Tecidos Moles , Biomarcadores Tumorais , Tamponamento Cardíaco/diagnóstico , Tamponamento Cardíaco/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão OncogênicaRESUMO
Periprosthetic osteolysis remains as a major complication of total joint replacement surgery. Modulation of macrophage polarization with interleukin-4 (IL-4) has emerged as an effective means to limit wear particle-induced osteolysis. The aim of this study was to evaluate the efficacy of local IL-4 delivery in treating preexisting particle-induced osteolysis. To this end, recently established 8 week modification of murine continuous femoral intramedullary particle infusion model was utilized. Subcutaneous infusion pumps were used to deliver polyethylene (PE) particles into mouse distal femur for 4 weeks to induce osteolysis. IL-4 was then added to the particle infusion for another 4 weeks. This delayed IL-4 treatment (IL-4 Del) was compared to IL-4 delivered continuously (IL-4 Cont) with PE particles from the beginning and to the infusion of particles alone for 8 weeks. Both IL-4 treatments were highly effective in preventing and repairing preexisting particle-induced bone loss as assessed by µCT. Immunofluorescence indicated a significant reduction in the number of F4/80 + iNOS + M1 macrophages and increase in the number of F4/80 + CD206 + M2 macrophages with both IL-4 treatments. Reduction in the number of tartrate resistant acid phosphatase + osteoclasts and increase in the amount of alkaline phosphatase (ALP) + osteoblasts was also observed with both IL-4 treatments likely explaining the regeneration of bone in these samples. Interesting, slightly more bone formation and ALP + osteoblasts were seen in the IL-4 Del group than in the IL-4 Cont group although these differences were not statistically significant. The study is a proof of principle that osteolytic lesions can be repaired via modulation of macrophage polarization.
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Remodelação Óssea/efeitos dos fármacos , Interleucina-4/uso terapêutico , Prótese Articular/efeitos adversos , Osteólise/tratamento farmacológico , Osteólise/etiologia , Animais , Artroplastia de Substituição/efeitos adversos , Interleucina-4/administração & dosagem , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB CRESUMO
Pazopanib, trabectedin, and eribulin are administered for the treatment of soft tissue sarcomas (STSs); however, there is little consensus on which agent should be preferentially used in a clinical setting. This study assessed whether peripheral immune-related markers served as a useful reference when selecting pazopanib, trabectedin, or eribulin. This study included 63 patients who were administered pazopanib, trabectedin, or eribulin for advanced STSs between March 2015 and December 2020. Patients were divided into three groups based on the first drug administered among these three drugs. Differences in overall survival (OS) or progression-free survival (PFS) among the three groups were analyzed. OS showed no significant differences among the drugs administered first. For patients with low neutrophil-to-lymphocyte ratio (NLR), the OS of patients administered pazopanib as the first choice was shorter than the others (hazard ratio [HR] = 9.53, 95% confidence interval [CI] = 1.94-18.13, p = 0.0018). In the low platelet-to-lymphocyte ratio (PLR) subgroup, the OS of the patients administered eribulin for the first choice was longer than that of the others (HR = 0.32, 95%CI = 0.10-0.98, p = 0.046). Therefore, NLR and PLR might be used as prognostic indicators to dictate whether STS patients receive pazopanib, trabectedin, or eribulin.
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"Senile osteoporosis" is defined as significant aging-associated bone loss, and is accompanied by increased fat in the bone marrow. The proportion of adipocytes in bone marrow is inversely correlated with bone formation, and is associated with increased risk of fracture. NF-κB is a transcription factor that functions as a master regulator of inflammation and bone remodeling. NF-κB activity increases during aging; furthermore, constitutive activation of NF-κB significantly impairs skeletal development in neonatal mice. However, the effects of NF-κB activation using a skeletally mature animal model have not been examined. In the current study, an osteoprogenitor (OP)-specific, doxycycline-regulated NF-κB activated transgenic mouse model (iNF-κB/OP) was generated to investigate the role of NF-κB in bone remodeling in skeletally mature mice. Reduced osteogenesis in the OP-lineage cells isolated from iNF-κB/OP mice was only observed in the absence of doxycycline in vitro. Bone mineral density in the metaphyseal regions of femurs and tibias was reduced in iNF-κB/OP mice. No significant differences in bone volume fraction and cortical bone thickness were observed. Osmium-stained bone marrow fat was increased in epiphyseal and metaphyseal areas in the tibias of iNF-κB/OP mice. These findings suggest that targeting NF-κB activity as a therapeutic strategy may improve bone healing and prevent aging-associated bone loss in aged patients.