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PURPOSE: Improvement in the control of delayed chemotherapy-induced nausea and vomiting (CINV) is needed. There is limited information on antiemetic prophylaxis for patients undergoing low-emetic-risk chemotherapy (LEC), and the optimal antiemetic treatment is not well understood. Therefore, we analyzed the risk factors for delayed CINV to aid in the development of individualized treatments. PATIENTS AND METHODS: This prospective multicenter study was conducted in 13 hospitals and included patients with solid cancers undergoing LEC. A total of 222 patients were enrolled between September 2013 and November 2014. The participants completed a daily diary for 5 days after the commencement of the first cycle of LEC to describe the daily incidence of CINV (yes/no). Furthermore, the participants described the severity of nausea and the amount of food intake with the help of VAS. RESULTS: Two hundred and ten patients provided their data that were analyzed using multivariate logistic regression to examine the risk factors for delayed CINV. History of CINV, Eastern Cooperative Oncology Group performance status score ≥1, acute CINV, and single-day antiemetic prophylaxis were identified as independent risk factors for delayed CINV. CONCLUSION: The current use of antiemetic prophylaxis according to the recommended guideline appears to effectively control delayed CINV in patients undergoing LEC. Therefore, patients with the abovementioned risk factors should be carefully observed, and their treatment should be adjusted according to their symptoms. The use of multiple-day dexamethasone may be beneficial for those patients who develop acute CINV, especially when it is accompanied by anorexia.
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PURPOSE: The incidence of and the risk factors for nausea and vomiting in patients undergoing low emetic risk chemotherapy (LEC) are unclear. The aim of the study was to provide information on these topics by performing a multicenter, observational, prospective study. METHODS: The study consisted of patients who were administered first-time LEC that was consistent or inconsistent with current guidelines. Using the visual analog scale, patients recorded their daily food intake and the occurrence and severity of nausea over a 5-day treatment period. RESULTS: The overall incidence of chemotherapy-induced nausea and vomiting did not differ significantly between patients undergoing guideline-consistent (n = 89) or guideline-inconsistent (n = 121) prophylaxis (30.3 vs. 22.3%, respectively; P = 0.19). Logistic regression analysis identified a history of nausea and LEC other than taxanes as independent risk factors associated with nausea and vomiting in patients undergoing LEC. The mean daily visual analog scale scores for nausea severity and a decrease in food intake were <25 mm throughout the entire observation period. CONCLUSIONS: Guideline-consistent prophylaxis appeared to control nausea and vomiting effectively in patients undergoing LEC. However, patients with a history of nausea and receiving LEC other than taxanes should be carefully observed and treatment should be adjusted according to their symptoms.
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Antieméticos/uso terapéutico , Antineoplásicos/efectos adversos , Náusea/inducido químicamente , Vómitos/inducido químicamente , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de RiesgoRESUMEN
Background Toll-like receptors (TLRs) may play active roles in both innate and adaptive immune responses in human intrahepatic biliary epithelial cells (HIBECs). The role of TLR3 expressed by HIBECs, however, remains unclear. Methods We determined the in vivo expression of TLRs in biopsy specimens derived from diseased livers immunohistochemically using a panel of monoclonal antibodies against human TLRs. We then examined the response of cultured HIBECs to a TLR3 ligand, polyinosinic-polycytidylic acid (polyI:C). Using siRNAs specific for Toll-IL-1R homology domain-containing adaptor molecule 1 (TICAM-1) and mitochondrial antiviral signaling protein (MAVS), we studied signaling pathways inducing IFN-beta expression. Results The expression of TLR3 was markedly increased in biliary epithelial cells at sites of ductular reaction in diseased livers, including primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and chronic viral hepatitis (CH) as compared to nondiseased livers. Although cultured HIBECs constitutively expressed TLR3 at both the protein and mRNA levels in vitro, the addition of polyI:C to culture media induced only minimal increases in IFN-beta mRNA. In contrast, transfection of HIBECs with polyI:C induced a marked increase in mRNAs encoding a variety of chemokines/cytokines, including IFN-beta, IL-6, and TNF-alpha. The induction of IFN-beta mRNA was efficiently inhibited by an siRNA against MAVS but not against TICAM-1, indicating that the main signaling pathway for IFN-beta induction following polyI:C transfection is via retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5) in HIBECs. Conclusions TLR3 expression by biliary epithelial cells increased at sites of ductular reaction in diseased livers; further study will be necessary to characterize it's in vivo physiological role.
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UNLABELLED: The predictive role of antinuclear antibodies (ANAs) remains elusive in the long-term outcome of primary biliary cirrhosis (PBC). The progression of PBC was evaluated in association with ANAs using stepwise Cox proportional hazard regression and an unconditional stepwise logistic regression model based on the data of 276 biopsy-proven, definite PBC patients who have been registered to the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). When death of hepatic failure/liver transplantation (LT) was defined as an end-point, positive anti-gp210 antibodies (Hazard ratio (HR) = 6.742, 95% confidence interval (CI): 2.408, 18.877), the late stage (Scheuer's stage 3, 4) (HR = 4.285, 95% CI:1.682,10.913) and male sex (HR = 3.266, 95% CI: 1.321,8.075) were significant risk factors at the time of initial liver biopsy. When clinical progression to death of hepatic failure/LT (i.e., hepatic failure type progression) or to the development of esophageal varices or hepatocellular carcinoma without developing jaundice (Total bilirubin < 1.5 mg/dL) (i.e., portal hypertension type progression) was defined as an end-point in the early stage (Scheuer's stage 1, 2) PBC patients, positive anti-gp210 antibodies was a significant risk factor for hepatic failure type progression [odds ratio (OR) = 33.777, 95% CI: 5.930, 636.745], whereas positive anti-centromere antibodies was a significant risk factor for portal hypertension type progression (OR = 4.202, 95% CI: 1.307, 14.763). Histologically, positive anti-gp210 antibodies was most significantly associated with more severe interface hepatitis and lobular inflammation, whereas positive anticentromere antibodies was most significantly associated with more severe ductular reaction. CONCLUSION: These results indicate 2 different progression types in PBC, hepatic failure type and portal hypertension type progression, which may be represented by positive-anti-gp210 and positive-anticentromere antibodies, respectively.
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Anticuerpos Antinucleares/sangre , Centrómero/inmunología , Cirrosis Hepática Biliar/clasificación , Cirrosis Hepática Biliar/inmunología , Proteínas de Complejo Poro Nuclear/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antinucleares/inmunología , Antígenos Nucleares/inmunología , Autoantígenos/inmunología , Cromatina/inmunología , Progresión de la Enfermedad , Várices Esofágicas y Gástricas/etiología , Femenino , Humanos , Hipertensión Portal/etiología , Cirrosis Hepática Biliar/complicaciones , Fallo Hepático/etiología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Proteínas Nucleares/inmunología , Estudios Prospectivos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Human intrahepatic biliary epithelial cells (HIBECs) may play active roles in both the innate and adaptive immune responses. Little is known, however, about the role of toll-like receptors (TLRs) on HIBECs in inflammatory cholangiopathies. METHODS: The expression of TLR1-9 and the biological responses to their ligands, lipopolysaccharide (LPS) or lipoteichoic acid (LTA), were studied in cultured HIBECs by reverse transcription-polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assay. RESULTS: HIBECs constitutively expressed transcripts encoding TLR1-6 and 9, as well as myeloid differentiation factor 88 (MyD88), MD2, and CD14. Stimulation of HIBECs with LPS resulted in translocation of NF-kappaB subunits from the cytoplasmic to the nuclear fraction, followed by increased secretion of a variety of chemokines/cytokines, including interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and IL-6. Treatment with BAY11-7082 efficiently inhibited the LPS-induced transcription and secretion of these chemokines/cytokines. In HIBECs, the mitogen-activated protein kinases (MAPKs) were also activated by LPS stimulation. These results indicated that LPS activates HIBECs via a TLR4-MyD88-dependent pathway. Stimulation of HIBECs with LTA induced the secretion of a similar profile of cytokines/chemokines via a TLR2-MyD88-dependent pathway. CONCLUSIONS: In HIBECs, at least TLR2 and 4 are capable of mediating innate immune system function in vitro. This result, in conjunction with our recent finding that TLR4 expression is increased in biliary epithelial cells in primary biliary cirrhosis, suggests the involvement of TLRs in the development of chronic inflammatory cholangiopathies.
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Conductos Biliares Intrahepáticos/inmunología , Conductos Biliares Intrahepáticos/metabolismo , Células Epiteliales/inmunología , Inmunidad Innata/fisiología , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , FN-kappa B/fisiología , Receptor Toll-Like 4/fisiología , Enfermedades de los Conductos Biliares/fisiopatología , Conductos Biliares Intrahepáticos/citología , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-6/genética , Interleucina-8/genética , Lipopolisacáridos/farmacología , Nitrilos/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/fisiología , Sulfonas/farmacología , Ácidos Teicoicos/farmacología , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
The sustained antibody response to nuclear envelope gp210 antigen indicates a group of primary biliary cirrhosis (PBC) patients at high risk for the progression to end-stage hepatic failure. To address this issue, we immunohistochemically studied the expression of gp210 antigen in needle liver biopsy specimens from PBC patients using a monoclonal antibody specific for gp210 antigen. The specimens from autoimmune hepatitis (AIH), chronic viral hepatitis B (CHB) and C (CHC) patients served as disease controls. The expression of gp210 antigen was apparently increased on the nuclear envelope of biliary epithelial cells (BECs) of small bile ducts in almost all specimens from PBC. In contrast, the expression of gp210 antigen was negative in BECs of small bile ducts in normal liver, while relatively weak anti-gp210 immunostaining was observed in AIH, CHC and CHB. In addition, the degree of gp210 expression in BECs of small bile ducts was positively correlated to that of portal inflammation, interface hepatitis and lobular inflammation in PBC. These results indicate that the increased expression of gp210 in small bile ducts, which is probably associated with damage to BECs by inflammation, is possibly involved in autoimmune response to gp210 leading to the progression to end-stage hepatic failure in PBC.