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2.
Gynecol Oncol ; 156(2): 308-314, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31822399

RESUMO

BACKGROUND: Selinexor is an oral inhibitor of the nuclear export protein Exportin 1 (XPO1) with demonstrated antitumor activity in solid and hematological malignancies. We evaluated the efficacy and safety of selinexor in heavily pretreated, recurrent gynecological malignancies. METHODS: In this phase 2 trial, patients received selinexor (35 or 50 mg/m2 twice-weekly [BIW] or 50 mg/m2 once-weekly [QW]) in 4-week cycles. Primary endpoint was disease control rate (DCR) including complete response (CR), partial response (PR) or stable disease (SD) ≥12 weeks. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. RESULTS: 114 patients with ovarian (N = 66), endometrial (N = 23) or cervical (N = 25) cancer were enrolled. Median number of prior regimens for ovarian, endometrial and cervical cancer was 6 (1-11), 2 (1-5), and 3 (1-6) respectively. DCR was 30% (ovarian 30%; endometrial 35%; cervical 24%), which included confirmed PRs in 8%, 9%, and 4% of patients with ovarian, endometrial, and cervical cancer respectively. Median PFS and OS for patients with ovarian, endometrial and cervical cancer were 2.6, 2.8 and 1.4 months, and 7.3, 7.0, and 5.0 months, respectively. Common Grade 3/4 adverse events (AEs) were thrombocytopenia (17%), fatigue (14%), anemia (10%), nausea (9%) and hyponatremia (9%). Patients with ovarian cancer receiving 50 mg/m2 QW had fewer high-grade AEs with similar efficacy as BIW treatment. CONCLUSIONS: Selinexor demonstrated single-agent activity and disease control in patients with heavily pretreated ovarian and endometrial cancers. Side effects were a function of dose level and treatment frequency, similar to previous reports, reversible and mitigated with supportive care.


Assuntos
Neoplasias dos Genitais Femininos/tratamento farmacológico , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Recidiva Local de Neoplasia/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Neoplasias dos Genitais Femininos/metabolismo , Neoplasias dos Genitais Femininos/patologia , Humanos , Hidrazinas/efeitos adversos , Carioferinas/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Receptores Citoplasmáticos e Nucleares/metabolismo , Triazóis/efeitos adversos , Proteína Exportina 1
3.
Transfus Med ; 28(3): 208-215, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28661062

RESUMO

OBJECTIVES: The primary objective of this feasibility study was to identify quality of life (QoL) scores and symptom scales as tools for measuring patient-reported outcomes (PRO) associated with haemoglobin level in chemotherapy-treated cancer patients. Secondary objectives included comparing QoL and symptoms between randomisation arms. BACKGROUND: Anaemia in cancer patients undergoing chemotherapy is associated with decreased QoL. One treatment option is red blood cell transfusion (RBCT). However, the optimal haemoglobin trigger for transfusion is unknown. METHODS: Patients were randomised to a haemoglobin trigger for RBCT of either < 9·7 g dL-1 (arm A) or < lower normal level, female: 11·5 g dL-1 , male: 13·1 g dL-1 (arm B). Four PROs were used: Functional Assessment of Cancer Therapy-General (FACT-G) and the FACT-Anaemia (FACT-An), a Numeric Rating Scale on symptoms of anaemia and self-reported Performance Status (PS). The association between haemoglobin and PRO variables was assessed using a linear mixed model with random effects. RESULTS: A total of 133 patients were enrolled, of which 86 patients received RBCT (28 in arm A, 58 in arm B). Baseline questionnaires were filled out in 79·7% of cases. Haemoglobin levels were significantly correlated with FACT-An, FACT-An Total Outcome Index (TOI), Functional Well-Being, fatigue and PS. Improvement on several PRO variables was observed in both arms after RBCT, with clinically minimal important differences observed in FACT-G, Physical Well-Being, FACT-An, FACT-An TOI, fatigue and dyspnoea. CONCLUSIONS: QoL scores of physical and functional domains as well as self-reported anaemia-related symptoms correlated well with haemoglobin level in chemotherapy-treated cancer patients.


Assuntos
Anemia , Transfusão de Eritrócitos , Hemoglobinas/metabolismo , Neoplasias , Autorrelato , Inquéritos e Questionários , Idoso , Anemia/sangue , Anemia/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/terapia , Guias de Prática Clínica como Assunto
4.
Vox Sang ; 112(3): 229-239, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28220499

RESUMO

BACKGROUND AND OBJECTIVES: Traditionally, Denmark has had a high rate of allogeneic red blood cell transfusion caused by a liberal transfusion practice despite the existence of restrictive guidelines. We established a Patient Blood Management programme in a tertiary hospital and report the results of the implementation of evidence-based transfusion practice. MATERIALS AND METHODS: Red blood cell transfusion quality indicators were compared with the evidence-based guideline at hospital and department level. Based on this evaluation, wards were selected for interventions targeting doctors and nurses. The implementation process was monitored by transfusion quality and utilization data over a 3-year period with totally 166 341 admissions in 98 960 mixed, adult medical and surgical patients. RESULTS: At the hospital level, transfusion above the upper guideline limit decreased from 23 to 10% (P < 0·001), and transfusion at or below the restrictive haemoglobin trigger of 7·3 g/dl increased from 7 to 19% (P < 0·001). The percentage of single-unit transfusions increased from 72 to 78% (P < 0·001), and the majority of transfusion rates and volumes decreased significantly. Red cell use decreased with 41% in surgical procedures and 28% in admissions (P < 0·001). CONCLUSION: The intervention was associated with a significant and sustained overall increase in compliance with national guidelines for red blood cell transfusion for non-bleeding patients, and led to significantly fewer patients being exposed to transfusion.


Assuntos
Transfusão de Eritrócitos , Adulto , Bases de Dados Factuais , Dinamarca , Prática Clínica Baseada em Evidências , Feminino , Seguimentos , Hemoglobinas/análise , Humanos , Unidades de Terapia Intensiva , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Centros de Atenção Terciária
5.
Clin Pharmacol Ther ; 102(3): 547-553, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28224612

RESUMO

Paclitaxel is mainly eliminated by CYP2C8 in the liver. CYP2C8 is strongly inhibited by the clopidogrel metabolite acyl-ß-D-glucuronide. To determine if this interaction has clinical relevance, we identified 48 patients treated with clopidogrel and paclitaxel using databases and a prescription register. Peripheral sensory neuropathy was retrospectively evaluated from medical charts and compared to that of 88 age- and sex-matched controls treated with paclitaxel and low-dose aspirin. By a cumulative dose of 1,500 mg paclitaxel, 35% of the patients had developed severe neuropathy. The overall hazard ratio between clopidogrel use and severe paclitaxel neuropathy was 1.7 (95% confidence interval, 0.9-3.0). Among those receiving a high-dose paclitaxel regimen, the hazard ratio was 2.3 (95% confidence interval, 1.1-4.5). Our study indicates that clopidogrel is associated with a clinically relevant increased risk of neuropathy in patients treated with high-dose paclitaxel.


Assuntos
Citocromo P-450 CYP2C8/metabolismo , Paclitaxel/administração & dosagem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Inibidores da Agregação Plaquetária/administração & dosagem , Ticlopidina/análogos & derivados , Idoso , Aspirina/administração & dosagem , Clopidogrel , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Doenças do Sistema Nervoso Periférico/epidemiologia , Farmacoepidemiologia , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Estudos Retrospectivos , Índice de Gravidade de Doença , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Ticlopidina/farmacocinética
6.
Biomarkers ; 19(6): 437-43, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24857368

RESUMO

CONTEXT: Bile duct cancer (BDC) is a disease with a very grave prognosis, often diagnosed too late. OBJECTIVE: The aim of this review is to evaluate available literature on tumor markers in serum from patients with BDC. METHODS: Using the search words "serum markers", "bile duct cancer", "cholangiocarcinoma", "biomarker" and "tumor marker", a search was carried out. RESULTS: Seventy-five studies were included in the review. CONCLUSION: CA19-9 is by far the most studied and most promising diagnostic and/or prognostic marker in BDC. But also the different mucins are interesting as new markers of BDC in serum.


Assuntos
Neoplasias dos Ductos Biliares/sangue , Antígeno CA-19-9/sangue , Antígeno Carcinoembrionário/sangue , Neoplasias dos Ductos Biliares/diagnóstico , Humanos , Mucinas/sangue
7.
Clin Biochem ; 47(7-8): 599-604, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24530340

RESUMO

BACKGROUND: High levels of intact and cleaved forms of the urokinase-type plasminogen activator receptor (uPAR) in both tissue and blood are associated with poor survival in several cancer diseases. The prognostic significance of uPAR in cholangiocarcinoma is unknown. The aims of this study were to determine if pre-treatment serum levels of uPAR forms and a decrease in levels during chemotherapy are predictive of survival in patients with inoperable cholangiocarcinoma. DESIGN AND METHODS: Patients with inoperable cholangiocarcinoma were consecutively included in the training set (n=108). A test set included patients from a different hospital using similar treatment guidelines (n=60). Serum levels of the different uPAR forms were determined using time-resolved fluorescence immunoassays (TR-FIA). The Cox proportional hazards model was used for the uni- and multivariate survival analyses. RESULTS: Baseline level of uPAR(I-III)+uPAR(II-III) was an independent predictor of survival (HR=2.08, 95% CI:1.46-2.97, p<0.0001). Applying the linear predictor from the training set to the test set, it was validated that uPAR(I-III)+uPAR(II-III) predicted overall survival (p=0.049). A high level of uPAR(I-III)+uPAR(II-III) after 2cycles of chemotherapy was associated with poor survival (HR=1.79, 95% CI:1.08-2.97, p=0.023, n=57). This predictor, however, was not significant in the test set (p=0.21, 26 events in 27 patients). CONCLUSION: The baseline level of uPAR(I-III)+uPAR(II-III) is a predictor of survival in inoperable cholangiocarcinoma patients.


Assuntos
Colangiocarcinoma/sangue , Colangiocarcinoma/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto Jovem
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