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BACKGROUND: This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC). METHODS: Patients were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33. RESULTS: Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; Pnoninferiority = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%). CONCLUSIONS: FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC. CLINICAL TRIAL REGISTRATION: JapicCTI-173618, jRCTs031180122.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Demência Frontotemporal , Neoplasias Retais , Humanos , Bevacizumab , Neoplasias Colorretais/patologia , Irinotecano , Trifluridina/efeitos adversos , Demência Frontotemporal/induzido quimicamente , Demência Frontotemporal/tratamento farmacológico , Timina/uso terapêutico , Pirrolidinas , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/induzido quimicamente , Combinação de Medicamentos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: The novel oral nucleoside antineoplastic agent trifluridine/tipiracil was approved for metastatic colorectal cancer in Japan in March 2014. In this post-marketing surveillance study, we investigated the safety and efficacy of trifluridine/tipiracil in a real-world setting, particularly haematological drug reactions classified according to the baseline renal and hepatic functions. METHODS: We investigated patients with metastatic colorectal cancer who received trifluridine/tipiracil during the first four treatment cycles prospectively. The patients typically received 35 mg/m2 trifluridine/tipiracil twice daily on days 1-5 and 8-12 every 28 days. The primary objective was to assess the safety of trifluridine/tipiracil, but its efficacy was also evaluated. RESULTS: Between July 2014 and June 2016, 860 patients were enrolled in the study, and the safety and efficacy of trifluridine/tipiracil were evaluated in 823 patients. Adverse drug reactions occurred in 89.7% of the patients. The most common adverse drug reactions were decreased white blood cell count (67.0%) and neutrophil count (63.9%). Haematological drug reactions of grade ≥3 were observed in 41.7% of the patients with normal renal function; 50.3, 65.6 and 78.9% of the patients had mild, moderate and severe renal impairments, respectively. Hepatic impairment was not associated with a higher incidence of haematological drug reactions. The median overall survival was 8.4 months, with a 1-year survival rate of 33.7%. CONCLUSION: This post-marketing surveillance study further confirmed the safety and tolerability profile of trifluridine/tipiracil observed in a clinical study setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Vigilância de Produtos Comercializados/métodos , Pirrolidinas/uso terapêutico , Timina/uso terapêutico , Trifluridina/uso terapêutico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pirrolidinas/farmacologia , Timina/farmacologia , Trifluridina/farmacologia , Adulto JovemRESUMO
BACKGROUND: The TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC). OBJECTIVE: This exploratory biomarker analysis of TRUSTY investigated the relationship between baseline plasma concentrations of angiogenesis-related factors and cell-free DNA (cfDNA), and the efficacy of FTD/TPI plus bevacizumab in patients with mCRC. PATIENTS AND METHODS: The disease control rate (DCR) and progression-free survival (PFS) were compared between baseline plasma samples of patients with high and low plasma concentrations (based on the median value) of angiogenesis-related factors. Correlations between cfDNA concentrations and PFS were assessed. RESULTS: Baseline characteristics (n = 65) were as follows: male/female, 35/30; median age, 64 (range 25-84) years; and RAS status wild-type/mutant, 29/36. Patients in the hepatocyte growth factor (HGF)-low and interleukin (IL)-8-low groups had a significantly higher DCR (risk ratio [95% confidence intervals {CIs}]) than patients in the HGF-high (1.83 [1.12-2.98]) and IL-8-high (1.70 [1.02-2.82]) groups. PFS (hazard ratio {HR} [95% CI]) was significantly longer in patients in the HGF-low (0.33 [0.14-0.79]), IL-8-low (0.31 [0.14-0.70]), IL-6-low (0.19 [0.07-0.50]), osteopontin-low (0.39 [0.17-0.88]), thrombospondin-2-low (0.42 [0.18-0.98]), and tissue inhibitor of metalloproteinase-1-low (0.26 [0.10-0.67]) groups versus those having corresponding high plasma concentrations of these angiogenesis-related factors. No correlation was observed between cfDNA concentration and PFS. CONCLUSION: Low baseline plasma concentrations of HGF and IL-8 may predict better DCR and PFS in patients with mCRC receiving FTD/TPI plus bevacizumab, however further studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: jRCTs031180122.
Assuntos
Ácidos Nucleicos Livres , Neoplasias do Colo , Neoplasias Colorretais , Demência Frontotemporal , Pirrolidinas , Timina , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Neoplasias Colorretais/patologia , Interleucina-8/uso terapêutico , Uracila/uso terapêutico , Trifluridina/farmacologia , Trifluridina/uso terapêutico , Angiogênese , Demência Frontotemporal/tratamento farmacológico , Inibidor Tecidual de Metaloproteinase-1/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Ácidos Nucleicos Livres/uso terapêutico , Biomarcadores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Amyloid-beta peptide 1-42 (Aß42) plays a key role in the neurotoxicity found in Alzheimer's disease. Mononuclear phagocytes in the brain (microglia), can potentially clear Aß via phagocytosis. Recently, the shuttling-protein nucleolin has been shown to possess scavenger receptor-activity. Here, we investigated whether this receptor interacts specifically with Aß type 1-42 and mediates its phagocytosis by microglia. While monomeric and fibril Aß42 were phagocytosed by mouse microglial EOC2 cells, amyloid ß peptide 1-40 (Aß40) was only weakly phagocytosed. Surface plasmon-resonance analysis revealed that nucleolin strongly associates with Aß42, but only weakly associates with Aß40. Immunofluorescence staining of anti-nucleolin antibody revealed that EOC2 cells and rat primary microglia express nucleolin on their cell surfaces. Further, pretreating EOC2 cells with anti-nucleolin antibody, but not immunoglobulin G (IgG), inhibited phagocytosis of monomeric Aß42 by microglia. Additionally, nucleolin-transfected HEK293 cells phagocytosed monomeric and fibril Aß42 but not monomeric and fibril Aß40. Moreover, AGRO, a nucleolin-specific oligonucleotide aptamer, inhibited phagocytosis of monomeric and fibril Aß42, but not monomeric and fibril Aß40. These results indicate that nucleolin is a receptor that allows microglia to recognize monomeric and fibril Aß42.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Microglia/metabolismo , Sistema Fagocitário Mononuclear , Fagocitose , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Doença de Alzheimer/imunologia , Animais , Linhagem Celular , Células HEK293 , Humanos , Camundongos , Ratos , NucleolinaRESUMO
BACKGROUND: Trifluridine/tipiracil is an oral agent approved for the treatment of patients with metastatic colorectal cancer (mCRC). Trifluridine is an antineoplastic thymidine analogue, and tipiracil improves its bioavailability. A phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with refractory mCRC demonstrated promising efficacy results with mild toxicity profile. It is important that quality of life be preserved in patients with mCRC without compromising their prognosis. Here, we outline the TRiflUridine/tipiracil in Second-line sTudY phase II/III study (JapicCTI-173618), designed to demonstrate non-inferiority in overall survival of trifluridine/tipiracil plus bevacizumab compared with irinotecan, fluoropyrimidine and bevacizumab combination regimens as second-line treatment in patients with mCRC. PATIENTS AND METHODS: Eligible patients have confirmed unresectable advanced or recurrent colorectal adenocarcinoma and have failed to respond to first-line oxaliplatin-based chemotherapy. A total of 524 patients are to be randomly assigned (1:1 ratio) to trifluridine/tipiracil plus bevacizumab or irinotecan, fluoropyrimidine and bevacizumab and stratified according to RAS status (wild type vs mutant). The primary endpoint of the phase II part is disease control rate with trifluridine/tipiracil plus bevacizumab therapy. Secondary endpoints are response rate and safety with trifluridine/tipiracil plus bevacizumab therapy. In the phase III part, the primary endpoint is overall survival, and secondary endpoints include quality of life, progression-free survival, response rate, disease control rate, safety, time to treatment failure, time to post-study treatment failure and the proportion of patients receiving post-study treatment. The first patient was enrolled in October 2017 and the study is anticipated to be completed in 2022. CLINICAL TRIAL REGISTRATION: JapicCTI-173618 (JapicCTI).
RESUMO
PURPOSE: A crown restoration engaged by a clasp as an abutment tooth for a removable partial denture (RPD) occasionally might be removed and eliminated due to secondary caries or apical lesions. However, if the RPD is clinically acceptable without any problems and refabricating the RPD is not recommended, the new crown must be made to retrofit to the existing clasp of the RPD. This in vitro study evaluated the conventional and CAD/CAM procedures for retrofitting crown restorations to the existing clasps by measuring the fitness accuracy and the retentive forces. METHODS: The crown restoration on #44 was fabricated with CP titanium and zirconium on the plaster model with #45 and #46 teeth missing to retrofit to the existing clasp using conventional thin coping and CAD/CAM procedures. The gap distance between the clasp (tip, shoulder, and rest regions) and the fabricated crown was measured using silicone impression material. The retentive force of the clasp was also measured, using an autograph at a crosshead speed of 50mm/min. The obtained data were analyzed by one-way ANOVA/Tukey's multiple comparison test (α=0.05). RESULTS: The CAD/CAM procedure caused significantly smaller gap distances in all of the clasp regions, as compared to the conventional procedure (p<0.05). The retentive force of the CAD/CAM crown was significantly higher than for the conventional one (p<0.05). CONCLUSION: When a crown restoration must be remade to retrofit an existing clasp, CAD/CAM fabrication can be recommended so that both appropriate fitness and retentive force are obtained.