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1.
Ann Palliat Med ; 10(8): 8818-8826, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34488370

RESUMO

BACKGROUND: Roughly 30-40% of lung cancer (LC) patients develop bone metastasis during the course of disease. The genetic differences between primary LC and matched bone metastasis are not yet fully understood. METHODS: A total of 40 LC patients with bone metastasis were collected and 450 targeted cancer-related genes were sequenced for genomic-alteration (GA) identification. RESULTS: Among the 40 LC patients, 33 had adenocarcinomas and 7 had squamous cell carcinomas. The metastatic sites of the 33 lung adenocarcinomas (LUADs) were the pelvis (6 patients), spine (16 patients), and limbs (11 patients). A total of 425 and 422 GAs were detected in the primary and metastatic lesions, respectively. The most common GAs were epidermal growth factor receptor (EGFR) mutations, which had mutation rates of 85.0% and 72.5% in the primary and metastatic lesions, respectively, and tumor protein 53 (TP53) mutations, which had mutation rates of 52.5% and 67.5% in the primary and metastatic lesions, respectively. Metastases to the pelvis and spine were most commonly accompanied by factor receptor substrate 2 (FRS2), cyclin-dependent kinase 4 (CDK4), and murine double minute 2 (MDM2) amplification, and cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion. The concordance between primary lung squamous cell carcinoma (LUSC) and corresponding metastasis was significantly higher than that of primary LUAD and corresponding metastasis (P=0.033). Compared to limb and pelvis metastases, the shared mutation in spine metastasis was significantly lower (P=0.016 and P=0.023, respectively). In matched primary LUSCs and bone metastasis lesions, there was no significant difference in the distribution of the tumor mutational burden (TMB) (P=0.9). Conversely, a significant difference of the TMB distribution was detected in pairs of primary LUAD and corresponding bone metastasis lesions (P=0.021). CONCLUSIONS: The consistency of mutation patterns between primary LC lesions and matched bone metastases may vary in terms of metastatic sites, but is very high in general. There was a significant difference in the TMB between primary LUAD and matched bone metastatic lesions. Our findings contribute to molecular understandings of primary LC and matched bone metastatic lesions.


Assuntos
Neoplasias Ósseas , Neoplasias Pulmonares , Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Metástase Neoplásica/genética
2.
Medicine (Baltimore) ; 100(36): e27185, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516519

RESUMO

ABSTRACT: Patients with endometrial cancer (EC) who develop bone metastasis (BM) always imply a poorer prognosis. However, reliable predictive models associated with BM from EC are currently limited.We retrospectively analyzed data on 54,077 patients diagnosed with primary EC in the Surveillance, Epidemiology, and End Results database. Multivariate logistic regression analysis was used to determine independent predictors of BM from EC. Univariate and multivariate Cox regression analyses were used to determine independent prognostic factors for EC with BM. Based on independent predictors and prognostic factors, we constructed a diagnostic nomogram and prognostic nomogram separately. Besides, calibration curves, receiver operating characteristic curves, and decision curve analysis were used to evaluate the models.A total of 54,077 patients with EC from the Surveillance, Epidemiology, and End Results database were included in this study, 364 of whom had BM. Multivariate analysis in the logistic model showed that lung metastasis, liver metastasis, brain metastasis, N stage, T stage, histologic grade, and race were risk factors for BM from EC. Multivariate analysis in the Cox model showed that liver metastasis, brain metastasis, chemotherapy, surgery, and histologic type had a significant effect on overall survival. Moreover, the receiver operating characteristic curve, calibration curve, and decision curve analysis indicated the good performance of both diagnostic and prognostic nomograms.Two clinical prediction model was constructed and validated to predict individual risk and overall survival for EC with BM, respectively. Diagnostic nomogram and prognostic nomogram are complementary, improving the clinician's ability to assess the patient's prognosis and enhancing prognosis-based decision making.


Assuntos
Neoplasias Ósseas/diagnóstico , Carcinoma Endometrioide/diagnóstico , Neoplasias do Endométrio/diagnóstico , Nomogramas , Idoso , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , China , Estudos de Coortes , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Feminino , Humanos , Metástase Neoplásica , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos
3.
Nat Commun ; 12(1): 5196, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465793

RESUMO

Bone metastasis is an incurable complication of breast cancer. In advanced stages, patients with estrogen-positive tumors experience a significantly higher incidence of bone metastasis (>87%) compared to estrogen-negative patients (<56%). To understand the mechanism of this bone-tropism of ER+ tumor, and to identify liquid biopsy biomarkers for patients with high risk of bone metastasis, the secreted extracellular vesicles and cytokines from bone-tropic breast cancer cells are examined in this study. Both exosomal miR-19a and Integrin-Binding Sialoprotein (IBSP) are found to be significantly upregulated and secreted from bone-tropic ER+ breast cancer cells, increasing their levels in the circulation of patients. IBSP is found to attract osteoclast cells and create an osteoclast-enriched environment in the bone, assisting the delivery of exosomal miR-19a to osteoclast to induce osteoclastogenesis. Our findings reveal a mechanism by which ER+ breast cancer cells create a microenvironment favorable for colonization in the bone. These two secreted factors can also serve as effective biomarkers for ER+ breast cancer to predict their risks of bone metastasis. Furthermore, our screening of a natural compound library identifies chlorogenic acid as a potent inhibitor for IBSP-receptor binding to suppress bone metastasis of ER+ tumor, suggesting its preventive use for bone recurrence in ER+ patients.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Exossomos/metabolismo , Sialoproteína de Ligação à Integrina/metabolismo , MicroRNAs/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Exossomos/genética , Feminino , Humanos , Sialoproteína de Ligação à Integrina/genética , Camundongos , Camundongos Knockout , Camundongos Nus , MicroRNAs/genética , Metástase Neoplásica , Osteoclastos/metabolismo , Receptores de Estrogênio/metabolismo
4.
Medicine (Baltimore) ; 100(34): e27070, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449503

RESUMO

ABSTRACT: The objective of the current study is to analyze the clinical and demographic characteristics of patients with bone metastasis of small cell lung cancer (SCLC) and explore their survival predictors.We retrospectively extracted patients with bone metastasis of SCLC from the Surveillance, Epidemiology, and End Results database. We applied Cox regression analyses to identify independent survival predictor of overall survival (OS) and cancer-specific survival (CSS). Only significant predictors from univariable analysis were included for multivariable Cox analysis. Kaplan-Meier method was used to evaluate survival differences between groups by the log-rank test.A total of 5120 patients with bone metastasis of SCLC were identified and included for survival analysis. The 1-year OS and CSS rates of bone metastasis of SCLC were 19.8% and 21.4%, respectively. On multivariable analysis, gender, age, radiotherapy, chemotherapy, liver metastasis, brain metastasis, insurance status, and marital status independently predicted OS and CSS. There was no significant difference of OS and CSS in terms of race and tumor size.Independent predictors of survival were identified among patients with bone metastasis of SCLC, which could be valuable to clinicians in treatment decision. Patients with bone metastasis of SCLC may benefit from radiotherapy and chemotherapy.


Assuntos
Neoplasias Ósseas/secundário , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/secundário , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Programa de SEER , Fatores Sexuais , Carcinoma de Pequenas Células do Pulmão/terapia , Fatores Socioeconômicos , Análise de Sobrevida , Carga Tumoral
5.
Anticancer Res ; 41(8): 4039-4043, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281871

RESUMO

BACKGROUND: Metastases of meningiomas are infrequent and the site of extracranial metastasis such as the bone is extremely rare. CASE REPORT: A 75-year-old male had a history of five sessions of surgery and gamma-knife treatment for brain meningioma over a period of 29 years. He visited our hospital because he noticed a swelling in his anterior chest 2 years and 6 months after the final treatment. After an open biopsy, histopathological analysis revealed the mass to be a metastatic grade II meningioma. We resected the tumor along with the sternum, ribs, pleura, and pericardium. The patient had recurrences in the thoracic cavity and pericardium postoperatively and received radiation therapy. He also had metastasis in the abdominal cavity, which spread rapidly. CONCLUSION: We report on a rare instance of metastasis to the sternum in a case of atypical meningioma, showing rapid growth and invasion after long-term treatment.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias Meníngeas/patologia , Meningioma/patologia , Esterno/patologia , Neoplasias Ósseas/diagnóstico por imagem , Humanos , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Esterno/diagnóstico por imagem , Tomografia Computadorizada por Raios X
6.
Cell Death Dis ; 12(7): 662, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215717

RESUMO

Bone is a frequent metastatic site of non-small cell lung cancer (NSCLC), and bone metastasis (BoM) presents significant challenges for patient survival and quality of life. Osteolytic BoM is characterised by aberrant differentiation and malfunction of osteoclasts through modulation of the TGF-ß/pTHrP/RANKL signalling pathway, but its upstream regulatory mechanism is unclear. In this study, we found that lncRNA-SOX2OT was highly accumulated in exosomes derived from the peripheral blood of NSCLC patients with BoM and that patients with higher expression of exosomal lncRNA-SOX2OT had significantly shorter overall survival. Additionally, exosomal lncRNA-SOX2OT derived from NSCLC cells promoted cell invasion and migration in vitro, as well as BoM in vivo. Mechanistically, we discovered that NSCLC cell-derived exosomal lncRNA-SOX2OT modulated osteoclast differentiation and stimulated BoM by targeting the miRNA-194-5p/RAC1 signalling axis and TGF-ß/pTHrP/RANKL signalling pathway in osteoclasts. In conclusion, exosomal lncRNA-SOX2OT plays a crucial role in promoting BoM and may serve as a promising prognostic biomarker and treatment target in metastatic NSCLC.


Assuntos
Neoplasias Ósseas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Movimento Celular , Exossomos/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Osteoclastos/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Células A549 , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Exossomos/genética , Exossomos/transplante , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Neuropeptídeos , Osteoclastos/patologia , Células RAW 264.7 , RNA Longo não Codificante/genética , Transdução de Sinais , Proteínas rac1 de Ligação ao GTP/genética
7.
Anticancer Res ; 41(8): 3917-3923, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34281854

RESUMO

BACKGROUND/AIM: Side effects of zolendronic acid (ZA) and RANKL inhibitors (RANKL-I) include impaired wound healing and osteonecrosis of the jaw. Platelet rich fibrin (PRF) enhances wound healing and bone remodelling in vivo and in vitro. However, the topical use PRF in the surgical treatment of patients with medicament-related osteonecrosis of the jaw is relatively new and not thoroughly investigated. Furthermore, the potential attenuation of the PRF effect following antiresorptive treatment remains unclear. Therefore, we investigated the concentration of growth factors within the PRF in healthy volunteers and in patients with antiresorptive treatment. PATIENTS AND METHODS: Blood samples from healthy volunteers and patients were used to produce PRF. The levels of EGF, VEGF, PDGF-BB, TGF-ß1, BMP-2, and CD31 in the PRF was investigated by ELISA. RESULTS: ZA treatment induced a significant decrease in EGF and TGF-ß1 levels, whereas RANKL-I caused lower TGF-ß1 levels. CONCLUSION: Reduced EGF levels in PRF after ZA treatment may explain the delayed wound healing and question the positive effect of PRF in these patients. PRF use in patients undergoing RANKL-I treatment seems to be more justified.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Denosumab/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Fibrina Rica em Plaquetas/efeitos dos fármacos , Ácido Zoledrônico/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/sangue , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Denosumab/uso terapêutico , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Osteólise/sangue , Osteólise/tratamento farmacológico , Contagem de Plaquetas , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Adulto Jovem , Ácido Zoledrônico/uso terapêutico
8.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206757

RESUMO

Metastatic bone cancer occurs in every type of cancer but is prevalent in lung, breast, and prostate cancers. These metastases can cause extensive morbidity, including a range of skeletal-related events, often painful and linked with substantial hospital resource usage. The treatment used is a combination of chemotherapy and surgery. However, anticancer drugs are still limited due to severe side effects, drug resistance, poor blood supply, and non-specific drug uptake, necessitating high toxic doses. Bisphosphonates are the main class of drugs utilized to inhibit metastatic bone cancer. It is also used for the treatment of osteoporosis and other bone diseases. However, bisphosphonate also suffers from serious side effects. Thus, there is a serious need to develop bisphosphonate conjugates with promising therapeutic outcomes for treating metastatic bone cancer and osteoporosis. This review article focuses on the biological outcomes of designed bisphosphonate-based conjugates for the treatment of metastatic bone cancer and osteoporosis.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Difosfonatos/uso terapêutico , Osteoporose/tratamento farmacológico , Animais , Conservadores da Densidade Óssea/química , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Difosfonatos/química , Humanos
9.
J Comput Assist Tomogr ; 45(3): 431-441, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34297512

RESUMO

INTRODUCTION: Nuclear protein of the testis (NUT) carcinoma (formerly NUT midline carcinoma) is an aggressive tumor with characteristic BRD4-NUTM1 translocation and a poor prognosis. The primary objective of this study was to describe the clinical and radiologic features, treatment response, and survival of NUT carcinoma (NC). MATERIALS AND METHODS: This retrospective single-center study was based on the review of medical records of NC patients with a specific genetic rearrangement or positive anti-NUT nuclear staining. Overall survival (OS) was analyzed according to primary tumor location. RESULTS: This series of 22 patients had a mean age of 36.27 ± 2.68 years with 68% women and 32% men. The median age at diagnosis was 34 years (range, 17-55 years). The primary tumor was located in the chest (n = 12/22; 55%), head and neck (n = 9/22; 40%), and 1 patient had a renal tumor. About 68% (n = 15/22) patients presented with regional lymph nodal involvement and 77% (n = 17/22) had distant metastases. All the bone metastases were lytic (100%) with mixed lytic and sclerotic metastases in 5 patients. Only 18% (n = 4/22) of the patients showed response to treatment, with progression in the remaining 18 patients. The median OS was 7 months. The OS was significantly (P = 0.024) more in patients with primary head and neck NC (n = 9; OS, 16 months) versus those with pulmonary and other locations (n = 13; OS, 6 months). CONCLUSIONS: Nuclear protein of the testis carcinoma is an aggressive disease refractory to conventional therapy. Imaging with the complementary use of computed tomography, magnetic resonance imaging, and positron emission tomography/computed tomography is important for staging, guiding management, assessing the treatment response, and surveillance.


Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Carcinoma/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias Renais/diagnóstico por imagem , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Adolescente , Adulto , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Carcinoma/metabolismo , Carcinoma/mortalidade , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Adulto Jovem
10.
Aging (Albany NY) ; 13(13): 17302-17315, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226298

RESUMO

The molecular mechanism of bone metastasis in breast cancer is largely unknown. Herein, we aimed to identify the key genes and long non-coding RNAs (lncRNAs) related to the bone metastasis of breast cancer using a bioinformatics approach. We screened differentially expressed genes and lncRNAs between normal breast and breast cancer bone metastasis samples using the GSE66206 dataset from the Gene Expression Omnibus. We also constructed a differentially expressed lncRNA-mRNA interaction network and analyzed the node degrees to identify the driving genes. After finding potential pathogenic modules of breast cancer bone metastasis, we identified breast cancer bone metastasis-related modules and functional enrichment analysis of the genes and lncRNAs in the modules. Based on the above analysis, we constructed a differentially expressed lncRNA-mRNA network related to bone metastasis in breast cancer and identified core driver genes, including BNIP3 and the lncRNA RP11-317-J19.1. The role of core driver genes and lncRNAs in the network implies their biological functions in regulating bone development and remodeling. Thus, targeting the core driver genes and lncRNAs in the network may be a promising therapeutic strategy to manage bone metastasis.


Assuntos
Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Biologia Computacional , Regulação Neoplásica da Expressão Gênica/genética , Genes Neoplásicos/genética , RNA Longo não Codificante/genética , Desenvolvimento Ósseo/genética , Remodelação Óssea/genética , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Humanos , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas/genética
11.
Aging (Albany NY) ; 13(13): 17442-17461, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34229299

RESUMO

Metastatic cancer especially bone metastasis (BM) is the lethal end-stage of castration-resistant prostate cancer (CRPC). To understand the possible molecular mechanisms underlying the development of the distant metastasis is of potential clinical value. We sought to identify differentially expressed genes between patient-matched primary and bone metastatic CRPC tumors. Functional enrichment, protein-protein interaction networks, and survival analysis of DEGs were performed. DEGs with a prognostic value considered as candidate genes were evaluated, followed by genetic analysis of tumor infiltrating immune cells based on Wilcoxon test and immunofluorescence identification. Expression profiles analysis showed that 381 overlapping genes were screened as differentially expressed genes (DEGs), of which 16 DEGs were randomly selected to be validated and revealed that most of these genes showed a transcriptional profile similar to that seen in the datasets (Pearson's r = 0.76). Six core genes were found to be involved in regulation of extracellular matrix receptor interaction and chemotactic activity, and four of them were significantly correlated with the survival of PCa patients with bone metastases. Immune infiltration analysis showed that the expressions levels of COL3A1, RAC1, FN1, and SDC2 in CD4+T cells were significantly higher than those in tumor cells, especially regulatory T cell infiltration was significantly increased in BM tumors. We analyzed gene expression signatures specifically associated with the development of bone metastases of CRPC patients. Characterization of genes associated with BM of mCRPC is critical for identification of predictive biomarkers and potential therapeutic targets.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Neoplasias da Próstata/patologia , Linfócitos T Reguladores/patologia , Idoso , Neoplasias Ósseas/genética , Linfócitos T CD4-Positivos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/genética , Mapas de Interação de Proteínas , Transdução de Sinais/genética , Análise de Sobrevida
12.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199096

RESUMO

Integrins participate in the pathogenesis and progression of tumors at many stages during the metastatic cascade. However, current evidence for the role of integrins in breast cancer progression is contradictory and seems to be dependent on tumor stage, differentiation status, and microenvironmental influences. While some studies suggest that loss of α2ß1 enhances cancer metastasis, other studies suggest that this integrin is pro-tumorigenic. However, few studies have looked at α2ß1 in the context of bone metastasis. In this study, we aimed to understand the role of α2ß1 integrin in breast cancer metastasis to bone. To address this, we utilized in vivo models of breast cancer metastasis to bone using MDA-MB-231 cells transfected with an α2 expression plasmid (MDA-OEα2). MDA cells overexpressing the α2 integrin subunit had increased primary tumor growth and dissemination to bone but had no change in tumor establishment and bone destruction. Further in vitro analysis revealed that tumors in the bone have decreased α2ß1 expression and increased osteolytic signaling compared to primary tumors. Taken together, these data suggest an inverse correlation between α2ß1 expression and bone-metastatic potential. Inhibiting α2ß1 expression may be beneficial to limit the expansion of primary tumors but could be harmful once tumors have established in bone.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Expressão Gênica , Integrina alfa2beta1/genética , Animais , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Invasividade Neoplásica , Osteólise/genética , Osteólise/metabolismo , Fenótipo
13.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202300

RESUMO

Cancer-induced bone degradation is part of the pathological process associated with both primary bone cancers, such as osteosarcoma, and bone metastases originating from, e.g., breast, prostate, and colon carcinomas. Typically, this includes a cancer-dependent hijacking of processes also occurring during physiological bone remodeling, including osteoclast-mediated disruption of the inorganic bone component and collagenolysis. Extensive research has revealed the significance of osteoclast-mediated bone resorption throughout the course of disease for both primary and secondary bone cancer. Nevertheless, cancer cells representing both primary bone cancer and bone metastasis have also been implicated directly in bone degradation. We will present and discuss observations on the contribution of osteoclasts and cancer cells in cancer-associated bone degradation and reciprocal modulatory actions between these cells. The focus of this review is osteosarcoma, but we will also include relevant observations from studies of bone metastasis. Additionally, we propose a model for cancer-associated bone degradation that involves a collaboration between osteoclasts and cancer cells and in which both cell types may directly participate in the degradation process.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Comunicação Celular , Osteoclastos/metabolismo , Osteossarcoma/complicações , Osteossarcoma/patologia , Animais , Neoplasias Ósseas/diagnóstico por imagem , Remodelação Óssea , Reabsorção Óssea/diagnóstico , Progressão da Doença , Suscetibilidade a Doenças , Humanos , Osteogênese
14.
Nat Commun ; 12(1): 4310, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262026

RESUMO

Patients with primary and bone metastatic breast cancer have significantly reduced survival and life quality. Due to the poor drug delivery efficiency of anti-metastasis therapy and the limited response rate of immunotherapy for breast cancer, effective treatment remains a formidable challenge. In this work, engineered macrophages (Oxa(IV)@ZnPc@M) carrying nanomedicine containing oxaliplatin prodrug and photosensitizer are designed as near-infrared (NIR) light-activated drug vectors, aiming to achieve enhanced chemo/photo/immunotherapy of primary and bone metastatic tumors. Oxa(IV)@ZnPc@M exhibits an anti-tumor M1 phenotype polarization and can efficiently home to primary and bone metastatic tumors. Additionally, therapeutics inside Oxa(IV)@ZnPc@M undergo NIR triggered release, which can kill primary tumors via combined chemo-photodynamic therapy and induce immunogenic cell death simultaneously. Oxa(IV)@ZnPc@M combined with anti-PD-L1 can eliminate primary and bone metastatic tumors, activate tumor-specific antitumor immune response, and improve overall survival with limited systemic toxicity. Therefore, this all-in-one macrophage provides a treatment platform for effective therapy of primary and bone metastatic tumors.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Macrófagos/transplante , Fotoquimioterapia/métodos , Animais , Apoptose/efeitos dos fármacos , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Portadores de Fármacos/química , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Morte Celular Imunogênica/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Indóis/administração & dosagem , Indóis/química , Indóis/farmacologia , Raios Infravermelhos , Macrófagos/química , Nanomedicina , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Oxaliplatina/administração & dosagem , Oxaliplatina/química , Oxaliplatina/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/farmacologia
15.
Medicine (Baltimore) ; 100(25): e26384, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160415

RESUMO

RATIONALE: A hormone-active metastatic Hürthle cell thyroid carcinoma (HCTC) and Graves disease (GD) present a therapeutic challenge and is rarely reported. PATIENT CONCERNS: We present a 64-year-old male patient, who had dyspnea and left hip pain lasting 4 months. He had clinical signs of hyperthyroidism and a tumor measuring 9 cm in diameter of the left thyroid lobe, metastatic neck lymph node and metastases in the lungs, mediastinum, and bones. DIAGNOSIS: Laboratory findings confirmed hyperthyroidism and GD. Fine-needle aspiration biopsy and cytological investigation revealed metastases of HCTC in the skull and in the 8th right rib. A CT examination showed a thyroid tumor, metastatic neck lymph node, metastases in the lungs, mediastinum and in the 8th right rib measuring 20 × 5.6 × 4.5 cm, in the left acetabulum measuring 9 × 9 × 3 cm and parietooccipitally in the skull measuring 5 × 4 × 2 cm. Histology after total thyroidectomy and resection of the 8th right rib confirmed metastatic HCTC. INTERVENTIONS: The region of the left hip had been irradiated with concomitant doxorubicin 20 mg once weekly. When hyperthyroidism was controlled with thiamazole, a total thyroidectomy was performed. Persistent T3 hyperthyroidism, most likely caused by TSH-R-stimulated T3 production in large metastasis in the 8th right rib, was eliminated by rib resection. Thereafter, the patient was treated with 3 radioactive iodine-131 (RAI) therapies (cumulative dose of 515 mCi). Unfortunately, the tumor rapidly progressed after treatment with RAI and progressed 10 months after therapy with sorafenib. OUTCOMES: Despite treatment, the disease rapidly progressed and patient died due to distant metastases. He survived for 28 months from diagnosis. LESSONS: Simultaneous hormone-active HCTC and GD is extremely rare and prognosis is dismal. Concomitant external beam radiotherapy and doxorubicin chemotherapy, followed by RAI therapy, prevented the growth of a large metastasis in the left hip in our patient. However, a large metastasis in the 8th right rib presented an unresolved problem. Treatment with rib resection and RAI did not prevent tumor recurrence. External beam radiotherapy and sorafenib treatment failed to prevent tumor growth.


Assuntos
Adenoma Oxífilo/diagnóstico , Doença de Graves/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Adenoma Oxífilo/complicações , Adenoma Oxífilo/secundário , Adenoma Oxífilo/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia por Agulha Fina , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Quimiorradioterapia Adjuvante/métodos , Evolução Fatal , Doença de Graves/complicações , Doença de Graves/terapia , Humanos , Radioisótopos do Iodo/uso terapêutico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Metástase Linfática/diagnóstico , Metástase Linfática/terapia , Masculino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/secundário , Neoplasias do Mediastino/terapia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/patologia , Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/secundário , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia
16.
Medicine (Baltimore) ; 100(25): e26496, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160464

RESUMO

ABSTRACT: Esophageal cancer (EC) is relatively common; at the time of diagnosis, 50% of cases present with distant metastases, and most patients are men. This study aimed to examine and compare the clinicopathological characteristics and metastatic patterns of male EC (MEC) and female EC (FEC). In addition, risk factors associated with MEC prognosis were evaluated.The present study population was extracted from the Surveillance Epidemiology and End Results database. MEC characteristics and factors associated with prognosis were evaluated using descriptive analysis, the Kaplan-Meier method, and the Cox regression model.A total of 12,558 MEC cases were included; among them, 3454 cases had distant organ metastases. Overall, 27.5% of the entire cohort were patients with distant organ metastases. Compared with patients with non-metastatic MEC, patients with metastatic MEC were more likely to be aged ≤60 years, of Black and White race, have a primary lesion in the overlapping esophagus segments, and have a diagnosis of adenocarcinoma of poorly differentiated and undifferentiated grade that was treated with radiotherapy and chemotherapy rather than surgery; moreover, they were also more likely to be married and insured. In addition, patients with MEC were more likely to be aged ≤60 years, White race, and diagnosed with a primary lesion in the lower third of the esophagus and overlapping esophagus segments, and treated without chemotherapy, compared with those with FEC. Patients in the former group were also more likely than those in the latter group to be unmarried and have bone metastasis only and lung metastasis only. Liver, lung, and bone metastases separately, and simultaneous liver and lung metastases were associated with poor survival in MEC patients.Metastatic MEC is associated with clinicopathological characteristics and metastatic patterns different from those associated with non-metastatic MEC and metastatic FEC. Metastatic MEC and FEC patients may have similar prognoses. Distant organ metastasis may be associated with poor prognosis in patients with MEC and FEC.


Assuntos
Neoplasias Ósseas/epidemiologia , Neoplasias Encefálicas/epidemiologia , Neoplasias Esofágicas/patologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Pulmonares/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Quimiorradioterapia/estatística & dados numéricos , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/secundário , Neoplasias Esofágicas/terapia , Esofagectomia/estatística & dados numéricos , Esôfago , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Estado Civil/estatística & dados numéricos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Programa de SEER/estatística & dados numéricos , Fatores Sexuais , Adulto Jovem
17.
Theranostics ; 11(14): 6873-6890, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093859

RESUMO

Rationale: Chemoresistance is a major obstacle in prostate cancer (PCa) treatment. We sought to understand the underlying mechanism of PCa chemoresistance and discover new treatments to overcome docetaxel resistance. Methods: We developed a novel phenotypic screening platform for the discovery of specific inhibitors of chemoresistant PCa cells. The mechanism of action of the lead compound was investigated using computational, molecular and cellular approaches. The in vivo toxicity and efficacy of the lead compound were evaluated in clinically-relevant animal models. Results: We identified LG1980 as a lead compound that demonstrates high selectivity and potency against chemoresistant PCa cells. Mechanistically, LG1980 binds embryonic ectoderm development (EED), disrupts the interaction between EED and enhancer of zeste homolog 2 (EZH2), thereby inducing the protein degradation of EZH2 and inhibiting the phosphorylation and activity of EZH2. Consequently, LG1980 targets a survival signaling cascade consisting of signal transducer and activator of transcription 3 (Stat3), S-phase kinase-associated protein 2 (SKP2), ATP binding cassette B 1 (ABCB1) and survivin. As a lead compound, LG1980 is well tolerated in mice and effectively suppresses the in vivo growth of chemoresistant PCa and synergistically enhances the efficacy of docetaxel in xenograft models. Conclusions: These results indicate that pharmacological inhibition of EED-EZH2 interaction is a novel strategy for the treatment of chemoresistant PCa. LG1980 and its analogues have the potential to be integrated into standard of care to improve clinical outcomes in PCa patients.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Descoberta de Drogas/métodos , Resistencia a Medicamentos Antineoplásicos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Complexo Repressor Polycomb 2/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Sinergismo Farmacológico , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Complexo Repressor Polycomb 2/química , Complexo Repressor Polycomb 2/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Quinases Associadas a Fase S/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Survivina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Medicine (Baltimore) ; 100(23): e26206, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115004

RESUMO

ABSTRACT: This study aimed to evaluate the clinical use of choline-PET/CT for discriminating viable progressive osteoblastic bone metastasis from benign osteoblastic change induced by the treatment effect and evaluating the response of bone metastasis to treatment in metastatic castration-resistant prostate cancer (mCRPC) patients. Thirty patients with mCRPC underwent a total of 56 11C-choline-PET/CT scans for restaging, because 4 patients received 1 scan and 26 had 2 scans. Using 2 (pre- and post-treatment) 11C-choline-PET/CT examinations per patient, treatment response was assessed according to European Organization for Research and Treatment of Cancer (EORTC) criteria in 20 situations, in which only bony metastases were observed on 11C-choline-PET/CT scans. Viable bone metastases and osteoblastic change induced by the treatment effect were identified in 53 (94.6%) and 29 (51.8%) of 56 11C-choline-PET/CT scans, respectively. In 27 cases (48.2%), 11C-choline-PET/CT scans could discriminate the 2 entities. The mean SUVmax of the metastatic bony lesions was 5.82 ±â€Š3.21, 5.95 ±â€Š3.96, 6.73 ±â€Š5.04, and 7.91 ±â€Š3.25 for the osteoblastic, osteolytic, mixed, and invisible types, respectively. Of the 20 situations analyzed, CMR, PMR, SMD, and PMD, as determined by the EORTC, were seen in 1, 2, 3, and 14 cases, respectively. Of the 13 patients with increasing PSA trend, all 13 showed PMD. Of the 2 patients with PSA response of <50%, both 2 showed SMD. Of the 5 patients with PSA response of ≥50%, 1 showed CMR, 2 showed PMR, 1 showed SMD, and 1 showed PMD. Choline-PET/CT is very useful to discriminate viable progressive osteoblastic bone metastasis from osteoblastic change, and assess treatment response of bone metastases in mCRPC.


Assuntos
Neoplasias Ósseas/secundário , Colina/farmacologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/normas , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/etiologia , Colina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico por imagem , Metástase Neoplásica/fisiopatologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/instrumentação , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos/farmacologia , Compostos Radiofarmacêuticos/uso terapêutico
20.
Medicine (Baltimore) ; 100(23): e26322, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115046

RESUMO

RATIONALE: Severe tension pneumocephalus can lead to drowsiness, coma, and even brain hernia and death. The occurrence of delayed pneumocephalus after spinal surgery is rarely reported and often ignored. Herein, we report a case of delayed pneumocephalus after repeated percutaneous aspiration following spinal surgery. PATIENT CONCERNS: A 55-year-old man was admitted in October 2020 because of aggravation in bilateral lower limb weakness and dysuria for seven days. He was diagnosed with liver cancer a year ago, and he underwent several operations because of tumor recurrence. The patient underwent thoracic vertebrae tumor excision on this admission, and no cerebrospinal fluid leakage was discovered during surgery. After the third drainage by percutaneous aspiration, the patient complained of severe headache and vomiting on postoperative day 16. DIAGNOSIS: Emergency brain computed tomography revealed massive pneumocephalus. INTERVENTIONS: Thereafter, suction drainage was discontinued, and he was placed on bed rest and administered intravenous mannitol. OUTCOMES: Repeated computed tomography showed complete resolution of the pneumocephalus after five days. LESSONS: Wound exudates and cystic fluid after spinal surgery should be differentiated from cerebrospinal fluid leakage. Reckless percutaneous aspirations can form pneumocephalus in patients with an occult dural injury, and pneumocephalus can occur up to 16 days after surgery. Early diagnosis of pneumocephalus is crucial to avoid severe consequences.


Assuntos
Neoplasias Ósseas , Descompressão Cirúrgica/efeitos adversos , Drenagem/efeitos adversos , Procedimentos Ortopédicos , Complicações Pós-Operatórias , Vértebras Torácicas , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Neoplasias Ósseas/cirurgia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Descompressão Cirúrgica/métodos , Diuréticos Osmóticos/administração & dosagem , Drenagem/métodos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Manitol/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neuroimagem/métodos , Procedimentos Ortopédicos/efeitos adversos , Procedimentos Ortopédicos/métodos , Pneumocefalia/diagnóstico , Pneumocefalia/etiologia , Pneumocefalia/fisiopatologia , Pneumocefalia/terapia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/fisiopatologia , Complicações Pós-Operatórias/terapia , Reoperação/efeitos adversos , Reoperação/métodos , Vértebras Torácicas/patologia , Vértebras Torácicas/cirurgia , Resultado do Tratamento
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