RESUMEN
BACKGROUND: With the current trend to reduce postoperative opioid use to enhance recovery and address perioperative opioid addiction concerns, the challenge of managing pain after total knee arthroplasty has increased. This study examined the effect of adding a preoperative medication regime to a multimodal postoperative analgesia protocol that included regional anaesthesia. MATERIALS AND METHODS: Sixty patients undergoing elective first-time unilateral knee arthroplasty received celecoxib 100mg, gabapentin 600mg and dexamethasone 10mg po one hour before skin incision. They were compared to a sequential retrospective cohort of 49 patients. All patients routinely received acetaminophen 650mg po q6h, ibuprofen 400mg po q8h, patient-controlled opioid analgesia and continuous adductor canal blocks postoperatively. Pain scores and opioid consumption were recorded at 4, 8, 12, 24 and 48h. RESULTS: Pain scores and cumulative opioid use were statistically and clinically significantly reduced at all time points up to 48h. CONCLUSIONS: Combining preoperative oral celecoxib, gabapentin and dexamethasone had a clinically significantly effect in reducing pain scores and opioid use for at least 48h. Most of this effect is probably due to dexamethasone.
Asunto(s)
Analgésicos Opioides , Artroplastia de Reemplazo de Rodilla , Humanos , Gabapentina/uso terapéutico , Celecoxib/uso terapéutico , Estudios Retrospectivos , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Analgesia Controlada por el Paciente , Dexametasona/uso terapéuticoRESUMEN
Fluctuating oxygen levels characterize the microenvironment of many cancers and tumor hypoxia is associated with increased invasion and metastatic potential concomitant with a poor prognosis. Similarly, the expression of lysyl oxidase (LOX) in breast cancer facilitates tumor cell migration and is associated with estrogen receptor negative status and reduced patient survival. Here we demonstrate that hypoxia/reoxygenation drives poorly invasive breast cancer cells toward a more aggressive phenotype by up-regulating LOX expression and catalytic activity. Specifically, hypoxia markedly increased LOX protein expression; however, catalytic activity (beta-aminopropionitrile inhibitable hydrogen peroxide production) was significantly reduced under hypoxic conditions. Moreover, poorly invasive breast cancer cells displayed a marked increase in LOX-dependent FAK/Src activation and cell migration following hypoxia/reoxygenation, but not in response to hypoxia alone. Furthermore, LOX expression is only partially dependent on hypoxia inducible factor-1 (HIF-1alpha) in poorly invasive breast cancer cells, as hypoxia mimetics and overexpression of HIF-1alpha could not up-regulate LOX expression to the levels observed under hypoxia. Clinically, LOX expression positively correlates with tumor progression and co-localization with hypoxic regions (defined by HIF-1alpha expression) in ductal carcinoma in situ and invasive ductal carcinoma primary tumors. However, positive correlation is lost in metastatic tumors, suggesting that LOX expression is independent of a hypoxic environment at later stages of tumor progression. This work demonstrates that both hypoxia and reoxygenation are necessary for LOX catalytic activity which facilitates breast cancer cell migration through a hydrogen peroxide-mediated mechanism; thereby illuminating a potentially novel mechanism by which poorly invasive cancer cells can obtain metastatic competency.
Asunto(s)
Neoplasias de la Mama/enzimología , Carcinoma Ductal de Mama/enzimología , Movimiento Celular , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteína-Lisina 6-Oxidasa/biosíntesis , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Hipoxia de la Célula , Línea Celular Tumoral , Femenino , Humanos , Peróxido de Hidrógeno/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia , Proteína-Lisina 6-Oxidasa/genéticaRESUMEN
BACKGROUND: Both femoral and obturator nerve blocks have been suggested to be useful in relieving pain after total knee arthroplasty (TKA). We sought to compare their efficacy. METHODS: Sixty patients undergoing elective unilateral TKA under spinal anesthesia received in a randomized, double-blind manner a femoral, obturator, or sham nerve block at the end of surgery. Blocks were performed using nerve stimulation and 20 mL bupivacaine 0.5% containing epinephrine 5 microg/mL. Patient-controlled IV analgesia with fentanyl, celecoxib 100 mg PO bid, and acetaminophen 650 mg PO every 6 h were started on arrival in the recovery room. Pain (0-10 numeric rating scale, NRS) at rest and with movement, analgesic use, and side effects were recorded for 48 h. Maximum knee flexion and total days in hospital were recorded as functional outcomes. RESULTS: There were no significant differences in the obturator block group and the control group in any outcome variable. With baseline pain scores subtracted, femoral block resulted in less pain at rest compared with control (NRS difference from baseline 2.1 +/- 0.4 sem vs 3.4 +/- 0.4, respectively; P = 0.02) and less pain with movement (NRS difference 2.6 +/- 0.6, 4.3 +/- 0.6, P = 0.05) at recovery room discharge. Neither block had a significant effect on opioid use, functional outcome, or side effects. Only one (5%) patient with femoral block developed obturator motor block. CONCLUSION: Femoral nerve blocks rarely block the obturator nerve. Single-injection femoral nerve block improved multimodal analgesia after spinal anesthesia for TKA, but this effect did not persist beyond the day of surgery. Obturator nerve block alone was of no benefit.
Asunto(s)
Analgesia/métodos , Anestésicos Locales , Artroplastia de Reemplazo de Rodilla , Bupivacaína , Nervio Femoral , Bloqueo Nervioso , Nervio Obturador , Dolor Postoperatorio/prevención & control , Acetaminofén/uso terapéutico , Anciano , Analgesia Controlada por el Paciente , Analgésicos no Narcóticos/uso terapéutico , Analgésicos Opioides/uso terapéutico , Celecoxib , Inhibidores de la Ciclooxigenasa/uso terapéutico , Método Doble Ciego , Femenino , Fentanilo/uso terapéutico , Humanos , Rodilla/fisiopatología , Rodilla/cirugía , Tiempo de Internación , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Dolor Postoperatorio/fisiopatología , Pirazoles/uso terapéutico , Recuperación de la Función , Sulfonamidas/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
Lysyl oxidase (LOX) is an extracellular matrix (ECM) enzyme that catalyzes the cross-linking of collagens or elastin in the extracellular compartment, thereby regulating the tensile strength of tissues. However, recent reports have demonstrated novel roles for LOX, including the ability to regulate gene transcription, motility/migration, and cell adhesion. These diverse functions have led researchers to hypothesize that LOX may have multiple roles affecting both extra- and intracellular cell function(s). Particularly noteworthy is aberrant LOX expression and activity that have been observed in various cancerous tissues and neoplastic cell lines. Both down and upregulation of LOX in tumor tissues and cancer cell lines have been described, suggesting a dual role for LOX as a tumor suppressor, as well as a metastasis promoter gene--creating a conundrum within the LOX research field. Here, we review the body of evidence on LOX gene expression, regulation, and function(s) in various cancer cell types and tissues, as well as stromal-tumor cell interactions. Lastly, we will examine putative mechanisms in which LOX facilitates breast cancer invasion and metastasis. Taken together, the literature demonstrates the increasingly important role(s) that LOX may play in regulating tumor progression and the necessity to elucidate its myriad mechanisms of action in order to identify potentially novel therapeutics.
Asunto(s)
Neoplasias/enzimología , Proteína-Lisina 6-Oxidasa/metabolismo , Cobre/metabolismo , Células Epiteliales/citología , Células Epiteliales/fisiología , Epitelio/fisiología , Matriz Extracelular/enzimología , Regulación Enzimológica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias/patología , Proteína-Lisina 6-Oxidasa/genética , Células del Estroma/citología , Células del Estroma/fisiología , Especificidad por SustratoRESUMEN
We have previously demonstrated that lysyl oxidase (LOX) is expressed in invasive breast cancer cells compared to poorly invasive cells. Additionally, we have recently shown that LOX regulates cell migration, a key step in the invasion process, through a hydrogen peroxide-dependent mechanism involving the focal adhesion kinase (FAK)/Src signaling complex. Here we further elucidate the role of LOX in cell motility/migration by examining the role of LOX in actin filament polymerization. We demonstrate that inhibition of LOX leads to an increase in phalloidin staining, directly associated with an increase in actin stress fiber formation. This increase in staining was confirmed by activity assays showing an increase in Rho activity with decreased LOX activity. Additionally, Rac and Cdc42 activity decreased with the reduction in LOX activity. Taken together, these data demonstrate a loss of a motogenic phenotype with decreased LOX activity. Finally, in order to elucidate the mechanism by which LOX regulates actin polymerization, we have demonstrated that LOX facilitates p130(Cas) phosphorylation, which allows for the binding to CAS related kinase (Crk) and formation of the p130(Cas)/Crk/DOCK180 signaling complex. Formation of this complex leads to an increase in Rac-GTP, which decreases actin stress fiber formation and increases formation of lamellipodium. These data demonstrate that LOX regulates cell motility/migration through changes in actin filament polymerization, which involve the regulation of the p130(Cas)/Crk/DOCK180 signaling pathway. Elucidating the role of LOX in the regulation of cell motility will allow the development of more effective therapeutic strategies to treat invasive/metastatic breast cancer.
Asunto(s)
Citoesqueleto de Actina/metabolismo , Neoplasias de la Mama/metabolismo , Proteína Sustrato Asociada a CrK/metabolismo , Complejos Multiproteicos/metabolismo , Proteína-Lisina 6-Oxidasa/metabolismo , Proteínas Proto-Oncogénicas c-crk/metabolismo , Transducción de Señal , Proteínas de Unión al GTP rac/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular , Femenino , Humanos , Invasividad NeoplásicaRESUMEN
We have previously shown that lysyl oxidase (LOX) mRNA is up-regulated in invasive breast cancer cells and that catalytically active LOX facilitates in vitro cell invasion. Here we validate our in vitro studies by showing that LOX expression is up-regulated in distant metastatic breast cancer tissues compared with primary cancer tissues. To elucidate the mechanism by which LOX facilitates cell invasion, we show that catalytically active LOX regulates in vitro motility/migration and cell-matrix adhesion formation. Treatment of the invasive breast cancer cell lines, Hs578T and MDA-MB-231, with beta-aminopropionitrile (betaAPN), an irreversible inhibitor of LOX catalytic activity, leads to a significant decrease in cell motility/migration and adhesion formation. Conversely, poorly invasive MCF-7 cells expressing LOX (MCF-7/LOX32-His) showed an increase in migration and adhesion that was reversible with the addition of betaAPN. Moreover, a decrease in activated focal adhesion kinase (FAK) and Src kinase, key proteins involved in adhesion complex turnover, was observed when invasive breast cancer cells were treated with betaAPN. Additionally, FAK and Src activation was increased in MCF-7/LOX32-His cells, which was reversible on betaAPN treatment. Hydrogen peroxide was produced as a by-product of LOX activity and the removal of hydrogen peroxide by catalase treatment in invasive breast cancer cells led to a dose-dependent loss in Src activation. These results suggest that LOX facilitates migration and cell-matrix adhesion formation in invasive breast cancer cells through a hydrogen peroxide-mediated mechanism involving the FAK/Src signaling pathway. These data show the need to target LOX for treatment of aggressive breast cancer.