RESUMEN
BACKGROUND: The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. METHODS: We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. RESULTS: Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of -1.4 percentage points (90% confidence interval [CI], -4.9 to 2.2; 95% CI, -5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%). CONCLUSIONS: Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927 .).
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Administración Oral , Antibacterianos/administración & dosificación , Enfermedades Óseas Infecciosas/tratamiento farmacológico , Artropatías/tratamiento farmacológico , Administración Intravenosa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Femenino , Humanos , Análisis de Intención de Tratar , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Radical surgery is the first line treatment for localized prostate cancer (PC), however, several studies have demonstrated that surgical procedures induce tumor cell mobilization from the primary tumor into the bloodstream. METHODS: The number and temporal fluctuations of circulating tumor cells (CTC), cancer associated fibroblasts (CAF) and CTC cluster present in each blood sample was determined. RESULTS: The results show that both CTC and CTC cluster levels significantly increased immediately following primary tumor resection, but returned to baseline within 2 weeks post-surgery. In contrast, the CAF level decreased over time. In patients who experienced PC recurrence within months after resection, CTC, CAF, and cluster levels all increased over time. Based on this observation, we tested the efficacy of an experimental TNF-related apoptosis-inducing ligand (TRAIL)-based liposomal therapy ex-vivo to induce apoptosis in CTC in blood. The TRAIL-based therapy killed approximately 75% of single CTCs and CTC in cluster form. CONCLUSION: Collectively, these data indicate that CTC cluster and CAF levels can be used as a predictive biomarker for cancer recurrence. Moreover, for the first time, we demonstrate the efficacy of our TRAIL-based liposomal therapy to target and kill prostate CTC in primary patient blood samples, suggesting a potential new adjuvant therapy to use in combination with surgery.
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Citotoxicidad Inmunológica/efectos de los fármacos , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Células Neoplásicas Circulantes/inmunología , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Anciano , Biomarcadores de Tumor , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Terapia Combinada , Humanos , Leucocitos/metabolismo , Liposomas , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Células Neoplásicas Circulantes/patología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Recurrencia , Ligando Inductor de Apoptosis Relacionado con TNF/administración & dosificación , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Recent studies have shown that chemotherapy destabilizes the blood vasculature and increases circulating tumor cell (CTC) influx into the circulation of metastatic cancer patients (Met-pa). CTCs are a precursor of cancer metastasis, in which they can migrate as single CTCs or as CTC clusters with stromal cells such as cancer-associated fibroblasts (CAFs) as cell aggregates. METHODS: Blood samples were collected from 52 Met-pa, and the number of CTC and CAF was determined along with the temporal fluctuation of these through the chemotherapy treatment. RESULTS: In this study, CTC level was found to increase two-fold from the initial level after 1 cycle of chemotherapy and returned to baseline after 2 cycles of chemotherapy. Importantly, we determined for the first time that circulating CAF levels correlate with worse prognosis and a lower probability of survival in Met-pa. Based on the CTC release induced by chemotherapy, we evaluated the efficacy of our previously developed cancer immunotherapy to eradicate CTCs from Met-pa blood using an ex vivo approach and demonstrate this could kill over 60% of CTCs. CONCLUSION: Collectively, we found that CAF levels in Met-pa serve as a predictive biomarker for cancer prognosis. Additionally, we demonstrate the efficacy of our therapy to kill primary CTCs for a range of cancer types, supporting its potential use as an anti-metastasis therapy in the clinical setting.
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Movimiento Celular/efectos de los fármacos , Quimioterapia/métodos , Neoplasias/tratamiento farmacológico , Células Neoplásicas Circulantes/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/patología , Femenino , Humanos , Liposomas/química , Liposomas/farmacología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias/sangre , Neoplasias/genética , Neoplasias/patología , Ligando Inductor de Apoptosis Relacionado con TNF/química , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/farmacologíaRESUMEN
Although intratumoral genomic heterogeneity can impede cancer research and treatment, less is known about the effects of phenotypic heterogeneities. To investigate the role of cell migration heterogeneities in metastasis, we phenotypically sorted metastatic breast cancer cells into two subpopulations based on migration ability. Although migration is typically considered to be associated with metastasis, when injected orthotopically in vivo, the weakly migratory subpopulation metastasized significantly more than the highly migratory subpopulation. To investigate the mechanism behind this observation, both subpopulations were assessed at each stage of the metastatic cascade, including dissemination from the primary tumor, survival in the circulation, extravasation, and colonization. Although both subpopulations performed each step successfully, weakly migratory cells presented as circulating tumor cell (CTC) clusters in the circulation, suggesting clustering as one potential mechanism behind the increased metastasis of weakly migratory cells. RNA sequencing revealed weakly migratory subpopulations to be more epithelial and highly migratory subpopulations to be more mesenchymal. Depletion of E-cadherin expression from weakly migratory cells abrogated metastasis. Conversely, induction of E-cadherin expression in highly migratory cells increased metastasis. Clinical patient data and blood samples showed that CTC clustering and E-cadherin expression are both associated with worsened patient outcome. This study demonstrates that deconvolving phenotypic heterogeneities can reveal fundamental insights into metastatic progression. More specifically, these results indicate that migratory ability does not necessarily correlate with metastatic potential and that E-cadherin promotes metastasis in phenotypically sorted breast cancer cell subpopulations by enabling CTC clustering. SIGNIFICANCE: This study employs phenotypic cell sorting for migration to reveal a weakly migratory, highly metastatic breast cancer cell subpopulation regulated by E-cadherin, highlighting the dichotomy between cancer cell migration and metastasis.
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Antígenos CD/metabolismo , Neoplasias de la Mama/patología , Cadherinas/metabolismo , Movimiento Celular , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Células Neoplásicas Circulantes/patología , Animales , Antígenos CD/genética , Apoptosis , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Cadherinas/genética , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Metástasis de la Neoplasia , Células Neoplásicas Circulantes/metabolismo , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Several studies have demonstrated the role of platelets in promoting cancer metastasis. Platelets bind to and protect circulating tumor cells (CTCs) from hemodynamic forces and immune cells, and also promote tumor cell arrest in the vasculature and extravasation. Thus, platelets represent a promising vehicle to deliver anticancer therapeutic agents to CTCs. In this study, we developed a novel platelet-mediated TNF-related apoptosis inducing ligand (TRAIL) delivery system to target CTCs and hinder metastasis via "in situ" platelet modification. This platelet-mediated TRAIL delivery significantly reduced the viability of colorectal and breast cancer cells circulating in flowing blood under physiological shear conditions. TRAIL-coated platelets significantly killed over 60% of CTCs in flowing blood from a variety of primary metastatic cancer samples. Platelets have been considered an important player in the regulation of metastasis due to their interaction with cancer cells in the circulation; the current study supports the idea of using platelet-based TRAIL delivery as a promising CTC-targeted cancer therapy.
RESUMEN
TNF-alpha-related-apoptosis-inducing-ligand (TRAIL) has been explored as a therapeutic drug to kill cancer cells. Cancer cells in the circulation are subjected to apoptosis-inducing factors. Despite the presence of these factors, cells are able to extravasate and metastasize. The homotypic and heterotypic cell-cell interactions in a tumor are known to play a crucial role in bestowing important characteristics to cancer cells that leave the primary site. Spheroid cell culture has been extensively used to mimic these physiologically relevant interactions. In this work, we show that the breast cancer cell lines BT20 and MCF7, cultured as 3D tumor spheroids, are more resistant to TRAIL-mediated apoptosis by downregulating the expression of death receptors (DR4 and DR5) that initiate TRAIL-mediated apoptosis. For comparison, we also investigated the effect of TRAIL on cells cultured as a 2D monolayer. Our results indicate that tumor spheroids are enriched for CD44hiCD24loALDH1hi cells, a phenotype that is predominantly known to be a marker for breast cancer stem cells. Furthermore, we attribute the TRAIL-resistance and cancer stem cell phenotype observed in tumor spheroids to the upregulation of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway. We show that inhibition of the COX-2/PGE2 pathway by treating tumor spheroids with NS-398, a selective COX-2 inhibitor, reverses the TRAIL-resistance and decreases the incidence of a CD44hiCD24lo population. Additionally, we show that siRNA mediated knockdown of COX-2 expression in MCF7 cells render them sensitive to TRAIL by increasing the expression of DR4 and DR5. Collectively, our results show the effect of the third-dimension on the response of breast cancer cells to TRAIL and suggest a therapeutic target to overcome TRAIL-resistance.
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Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Esferoides Celulares/patología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Separación Celular , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Dinoprostona/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Células MCF-7 , Modelos Biológicos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fenotipo , ARN Interferente Pequeño/metabolismo , Receptores de Muerte Celular/metabolismo , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Personalized medicine holds great promise for cancer treatment, with the potential to address challenges associated with drug sensitivity and interpatient variability. Circulating tumor cells (CTC) can be useful for screening cancer drugs as they may reflect the severity and heterogeneity of primary tumors. Here we present a platform for rapidly evaluating individualized drug susceptibility. Treatment efficacy is evaluated directly in blood, employing a relevant environment for drug administration, and assessed by comparison of CTC counts in treated and control samples. Multiple drugs at varying concentrations are evaluated simultaneously to predict an appropriate therapy for individual patients.
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Antineoplásicos/farmacología , Estadificación de Neoplasias , Células Neoplásicas Circulantes/efectos de los fármacos , Medicina de Precisión , Recuento de Células Sanguíneas , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
Hydrodynamic shear force plays an important role in the leukocyte adhesion cascade that involves the tethering and rolling of cells along the endothelial layer, their firm adhesion or arrest, and their extravasation or escape from the circulatory system by inducing passive deformation, or cell flattening, and microvilli stretching, as well as regulating the expression, distribution, and conformation of adhesion molecules on leukocytes and the endothelial layer. Similarly, the dissemination of circulating tumor cells (CTCs) from the primary tumor sites is believed to involve tethering, rolling, and firm adhesion steps before their eventual extravasation which leads to secondary tumor sites (metastasis). Of particular importance to both the leukocyte adhesion cascade and the extravasation of CTCs, glycoproteins are involved in all three steps (capture, rolling, and firm adhesion) and consist of a variety of important selectin ligands. This review article provides an overview of glycoprotein glycosylation associated with the abnormal glycan expression on cancer cell surfaces, where well-established and novel selectin ligands that are cancer related are discussed. An overview of computational approaches on the effects of fluid mechanical force on glycoprotein mediated cancer cell rolling and adhesion is presented with a highlight of recent flow-based and selectin-mediated cell capturing/enriching devices. Finally, as an important branch of the glycoprotein family, mucins, specifically MUC1, are discussed in the context of their aberrant expression on cancer cells and their role as cancer cell adhesion molecules. Since metastasis relies heavily on glycoprotein interactions in the bloodstream where the fluid shear stress highly regulates cell adhesion forces, it is important to study and understand the glycomechanics of all relevant glycoproteins (well-established and novel) as they relate to the metastatic cascade.