RESUMO
The tyrosine kinase inhibitor sorafenib improves hepatopulmonary syndrome (HPS) in an experimental model. However, the efficacy and adverse effect profile in patients with HPS are unknown. We aimed to determine the effect of sorafenib on the alveolar-arterial oxygen gradient (AaPO2 ) at 3 months in patients with HPS. We performed a randomized, double-blind, placebo-controlled parallel trial of sorafenib in patients with HPS at 7 centers. A total of 28 patients with HPS were randomized to sorafenib 400 mg by mouth daily or a matching placebo in a 1:1 ratio. We found no statistically significant difference in the median change in AaPO2 from baseline to 12 weeks between the patients allocated to sorafenib (4.5 mm Hg; IQR, -3.8 to 7.0 mm Hg) and those allocated to placebo (-2.4 mm Hg; IQR, -4.8 to 8.2 mm Hg; P = 0.70). There was also no difference between the groups in terms of degree of intrapulmonary shunting by contrast echocardiography. Sorafenib significantly reduced circulating levels of angiogenic markers, including vascular endothelial growth factor receptors (P < 0.01) and TIE2-expressing M2 monocytes (P = 0.03), but it reduced the mental component scores of the Short Form 36 (P = 0.04), indicating a worse quality of life. In conclusion, sorafenib did not change the AaPO2 or other disease markers at 3 months in patients with HPS. Alternative antiangiogenic therapies or treatments targeting other pathways should be investigated.
Assuntos
Síndrome Hepatopulmonar/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Qualidade de Vida , Sorafenibe/administração & dosagem , Biomarcadores/sangue , Método Duplo-Cego , Ecocardiografia , Feminino , Síndrome Hepatopulmonar/sangue , Síndrome Hepatopulmonar/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/sangue , Neovascularização Patológica/diagnóstico , Placebos/administração & dosagem , Placebos/efeitos adversos , Estudo de Prova de Conceito , Inibidores de Proteínas Quinases/efeitos adversos , Sorafenibe/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Prospective and longitudinal studies have examined liver donors' medical outcomes beyond the first 1 to 2 years postdonation. There is no analogous longitudinal evidence on long-term psychosocial outcomes, including patient-reported clinically significant mental health problems and perceptions of physical well-being. We examined prevalence, descriptive characteristics, and predictors of diagnosable mental health conditions and self-reported physical health problems, including fatigue and pain, in the long-term years after liver donation. METHODS: Donors from 9 centers who initially completed telephone interviews at 3 to 10 years postdonation (mean, 5.8 years; SD, 1.9) were reinterviewed annually for 2 years using validated measures. Outcomes were examined descriptively. Repeated-measures regression analyses evaluated potential predictors and correlates of outcomes. RESULTS: Of 517 donors initially interviewed (66% of those eligible), 424 (82%) were reassessed at least once. Prevalence rates of major depression and clinically significant pain were similar to general population norms; average fatigue levels were better than norms. All prevalence rates showed little temporal change. Anxiety and alcohol use disorder rates exceeded normative rates at 1 or more assessments. Longer postdonation hospitalization, female sex, higher body mass index, concerns about donation-related health effects, and burdensome donation-related financial costs were associated with increased risk for most outcomes (P's < 0.05). Men were at higher risk for alcohol use disorder (P < 0.001). CONCLUSIONS: Anxiety and alcohol use disorders were more common than would be expected; they may warrant increased research attention and clinical surveillance. Surveillance for long-term problems in the areas assessed may be optimized by targeting donors at higher risk based on identified predictors and correlates.