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1.
BMC Cancer ; 19(1): 55, 2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30634942

RESUMO

BACKGROUND: To date, the cornerstone of treatment in patients with advanced or metastatic cholangiocarcinoma (CCA) is systemic chemotherapy based on a combination of gemcitabine and a platinum derivative. Other therapeutic approaches including targeted agents and tyrosine kinase inhibitors (TKI) have demonstrated disappointing results, highlighting the complexity of CCA. Recently, drugs aiming at the inhibition of HER-receptors have shown first therapeutic benefit in patients with late stage disease. The aim of this phase I study was to test the dose level toxicities (DLTs), safety and efficacy of afatinib, a highly specific panErbB family receptor TKI, in chemotherapy naive patients with advanced CCA in conjunction with an extensive biomarker program. METHODS: Afatinib was administered continuously p. o. as add-on in patients with advanced CCA who received conventional chemotherapy with gemcitabine/cisplatin. A classical 3 + 3 phase I study was employed, while the maximum tolerated dose (MTD) of oral afatinib was determined in a 2 step dose escalation. Safety, overall survival (OS) and progression free survival (PFS) were evaluated for all patients. Finally, a translational biomarker analysis was conducted for the EGFR and VEGF signalling cascades. RESULTS: Overall, 9 patients were enrolled. Further recruitment was discontinued due to lack of efficacy results of the tested drug in other indications. 30 mg afatinib could be safely administered as add-on to 80% of standard dose gemcitabine/cisplatin. The mOS and mPFS were 7.7 and 6.0 months, respectively. Diarrhoea and haematological disorders were the most common observed AEs. Almost all patients overexpressed EGFR on their tumour tissues, whereas none of them expressed mutations in Exons 18, 19 and 21. Non-responders showed a higher variation of VEGF-C, -D, leptin and sEGFR in their sera. CONCLUSIONS: Afatinib failed to show survival benefits in combination with gemcitabine/cisplatin in patients with advanced CCA. Mutational analysis of EGFR and pathways associated with VEGF-C, -D and leptin might show promising results in future studies. CLINICAL TRIALS REGISTRATION: NCT01679405 August, 2012.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Adulto , Afatinib/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/metabolismo , Neoplasias do Sistema Biliar/mortalidade , Biomarcadores , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Transdução de Sinais , Pesquisa Translacional Biomédica , Resultado do Tratamento , Gencitabina
2.
Lancet Diabetes Endocrinol ; 6(2): 114-121, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29199116

RESUMO

BACKGROUND: As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs. METHODS: We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10-15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA1c concentration from baseline after 24 months of treatment. Differences between groups were assessed by linear models. The primary and safety analyses were done in the modified intention-to-treat population (including patients who stopped treatment early because of lack of efficacy). This trial is registered with ClinicalTrials.gov, number NCT00662714. FINDINGS: We enrolled 34 patients in the repaglinide group and 41 in the insulin group, of whom 30 and 37, respectively, were included in the analyses. At 24 months, glycaemic control was similar in the repaglinide and insulin groups (mean change in HbA1c concentration from baseline 0·2% [SD 0·7%], 1·7 mmol/mol [8·1 mmol/mol] with repaglinide vs -0·2% [1·3%], -2·7 mmol/mol, [14·5 mmol/mol] with insulin; mean difference between groups -0·4%, (95% CI -1·1 to 0·2 [-4·4 mmol/mol, -11·5 to 2·7], p=0·15). The most frequent adverse events were pulmonary events (43 [40%] of 107 in the repaglinide group and 60 [45%] of 133 in the insulin group), and the most frequent serious adverse events were pulmonary events leading to hospital admission (five [50%] of ten and seven [54%] of 13, respectively). INTERPRETATION: Repaglinide for glycaemic control in patients with cystic-fibrosis-related diabetes is as efficacious and safe as insulin. FUNDING: Mukoviszidose eV, Vaincre la Mucoviscidose, ABCF Association, and Novo Nordisk.


Assuntos
Biomarcadores/análise , Carbamatos/uso terapêutico , Fibrose Cística/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Piperidinas/uso terapêutico , Adolescente , Adulto , Glicemia/metabolismo , Criança , Fibrose Cística/fisiopatologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Humanos , Masculino , Prognóstico , Adulto Jovem
3.
Epilepsy Behav ; 27(3): 433-8, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23591262

RESUMO

This study evaluated trends in the resource use of patients with active epilepsy over a 5-year period at an outpatient clinic of a German epilepsy center. Two cross-sectional cohorts of consecutive adults with active epilepsy were evaluated over a 3-month period in 2003 and 2008. Data on socioeconomic status, course of epilepsy, as well as direct and indirect costs were recorded using validated patient questionnaires. We enrolled 101 patients in 2003 and 151 patients in 2008. In both cohorts, 76% of the patients suffered from focal epilepsy, and the majority was on antiepileptic drug (AED) polytherapy (mean AED number: 1.7 (2003), 1.8 (2008)). We calculated epilepsy-specific costs of € 2955 in 2003 and € 3532 in 2008 per 3 months per patient. Direct medical costs were mainly due to anticonvulsants in 2003 (59.4% of total direct costs, 34.0% in 2008) and to hospitalization in 2008 (46.9% of total direct costs, 27.7% in 2003). The proportion of enzyme-inducing anticonvulsants and 'old' AEDs decreased between 2003 and 2008. Indirect costs of € 1689 and € 1847 were mainly due to early retirement (48.4%; 46.0% of total indirect costs in 2003; 2008), unemployment (26.1%; 24.2%), and days off due to seizures (25.5%; 29.8%). This study showed a shift in distribution of direct cost components with increased hospital costs as well as a cost-neutral increase in the prescription of 'newer' AEDs. The amount and distribution of indirect cost components remained unchanged.


Assuntos
Anticonvulsivantes/economia , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Recursos em Saúde/estatística & dados numéricos , Recursos em Saúde/tendências , Medicamentos sob Prescrição , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Custos e Análise de Custo , Estudos Transversais , Epilepsia/economia , Epilepsia/epidemiologia , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Medicamentos sob Prescrição/economia , Medicamentos sob Prescrição/uso terapêutico , Estudos Retrospectivos , Inquéritos e Questionários , Adulto Jovem
4.
Epilepsy Behav ; 23(4): 451-7, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22381385

RESUMO

This study evaluated the resource use of patients with epilepsy in the German district of Marburg-Biedenkopf. A cross-sectional cohort of consecutive adults with epilepsy, irrespective of seizure severity, duration of illness and epilepsy syndrome, was investigated in all health-care sectors. Costs of inpatient and outpatient treatment were derived from billing data of participating hospitals and office-based physicians. Data on socioeconomic status, course of epilepsy and further direct and indirect costs were recorded using patient questionnaires. We enrolled 366 patients from the district of Marburg-Biedenkopf and calculated annual epilepsy-specific costs of €7738 per patient. Direct costs contributed 31.1% (€2406) and indirect costs 68.9% (€5332) of the total costs. Direct medical costs were mainly due to hospitalization (33.2% of total direct costs) and anticonvulsants (26.7%). Costs of admissions were due to status epilepticus (24.4%), video-EEG monitoring (14.8%), newly diagnosed patients (14.4%) and seizure-related injuries (8.8%). Indirect costs were mainly due to early retirement (38.0%), unemployment (35.9%) and days off due to seizures (26.2%). The mean costs of epilepsy found in our study were lower than those found in studies conducted at European epilepsy centers due to the inclusion of patients in all health-care sectors.


Assuntos
Atenção à Saúde/estatística & dados numéricos , Epilepsia , Custos de Cuidados de Saúde/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antieméticos/economia , Antieméticos/uso terapêutico , Estudos de Coortes , Custos e Análise de Custo , Estudos Transversais , Eletroencefalografia , Epilepsia/economia , Epilepsia/epidemiologia , Epilepsia/terapia , Feminino , Alemanha/epidemiologia , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Gravação em Vídeo , Adulto Jovem
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