Sorafenib in Advanced Hepatocellular Carcinoma: A Nationwide Retrospective Study of Efficacy and Tolerability

Background. Advanced HCC is a clinical challenge with limited treatment options. The multikinase inhibitor sorafenib is the first and only agent showing a survival benefit in these patients. In this study we evaluate the efficacy and tolerability of sorafenib in an unselected patient population. Furthermore we explore the role of alpha-fetoprotein (αFP) as a potential biomarker for treatment efficacy and correlation to survival. Methods. Seventy-six patients with advanced HCC, not eligible for locoregional therapy, treated with sorafenib between 2007 and 2009 were included. Followup was until 2011. Results. Patients in PS 0-1 had a median overall survival (mOS) of 6.2 months, compared to 1.8 months in patients with poorer PS (P=0.005). Child-Pugh A patients had a mOS of 6.6 months versus 3.6 months among patients in Child-Pugh B or C (P=0.0001). Serum αFP ≥ 200 at baseline was prognostic for a shorter survival. All patients with radiologically verified tumor response and baseline αFP ≥ 200 experienced a significant decline in αFP within the first four weeks of treatment. Conclusion. The survival of patients with advanced HCC treated with sorafenib is dependent on performance status and liver function. Treatment of patients with compromised liver function and poor performance status cannot be recommended. The correlation between αFP and objective tumor response warrants further investigation

Age and metabolic risk factors associated with oxidatively damaged DNA in human peripheral blood mononuclear cells

Aging is associated with oxidative stress-generated damage to DNA and this could be related to metabolic disturbances. This study investigated the association between levels of oxidatively damaged DNA in peripheral blood mononuclear cells (PBMCs) and metabolic risk factors in 1,019 subjects, aged 18-93 years. DNA damage was analyzed as strand breaks by the comet assay and levels of formamidopyrimidine (FPG-) and human 8-oxoguanine DNA glycosylase 1 (hOGG1)-sensitive sites There was an association between age and levels of FPG-sensitive sites for women, but not for men. The same tendency was observed for the level of hOGG1-sensitive sites, whereas there was no association with the level of strand breaks. The effect of age on oxidatively damaged DNA in women disappeared in multivariate models, which showed robust positive associations between DNA damage and plasma levels of triglycerides, cholesterol and glycosylated hemoglobin (HbA(1c)). In the group of men, there were significant positive associations between alcohol intake, HbA(1c) and FPG-sensitive sites in multivariate analysis. The levels of metabolic risk factors were positively associated with age, yet only few subjects fulfilled all metabolic syndrome criteria. In summary, positive associations between age and levels of oxidatively damaged DNA appeared mediated by age-related increases in metabolic risk factors

Total sitting time and risk of myocardial infarction, coronary heart disease and all-cause mortality in a prospective cohort of Danish adults

BACKGROUND: Evidence suggests that sitting time is adversely associated with health risks. However, previous epidemiological studies have mainly addressed mortality whereas little is known of the risk of coronary heart disease. This study aimed to investigate total sitting time and risk of myocardial infarction, coronary heart disease incidence and all-cause mortality. METHODS: In the Danish Health Examination Survey (DANHES) conducted in 2007-2008 we tested the hypothesis that a higher amount of daily total sitting time is associated with greater risk of myocardial infarction, coronary heart disease and all-cause mortality. The study population consisted of 71,363 men and women aged 18-99 years without coronary heart disease. Participants were followed for myocardial infarction, coronary heart disease and mortality in national registers to August 10, 2012. Cox regression analyses were performed with adjustment for potential confounders and multiple imputation for missing values. RESULTS: During a mean follow-up period of 5.4 years 358 incident cases of myocardial infarction, 1,446 of coronary heart disease, and 1,074 deaths from all causes were registered. The hazard ratios associated with 10 or more hours of daily sitting compared to less than 6 hours were 1.38 (95% CI: 1.01, 1.88) for myocardial infarction, 1.07 (95% CI: 0.91, 1.27) for coronary heart disease and 1.31 (95% CI: 1.09, 1.57). Compared to sitting less than 6 hours per day and being physically active in leisure time, the hazard ratios of sitting more than 10 hours per day and also being physically inactive in leisure time were 1.80 (95% CI: 1.15, 2.82) for myocardial infarction, 1.42 (95% CI: 1.11, 1.81) for coronary heart disease, and 2.29 (95% CI: 1.82, 2.89) for all-cause mortality. CONCLUSIONS: The results suggest that a higher amount of daily total sitting time is associated with all-cause mortality, particularly among inactive adults. In relation to coronary heart, disease results were less clear. This paper adds new evidence to the limited data on the evidence of sitting time and cardiovascular disease and mortality

Low fitness is associated with abdominal adiposity and low-grade inflammation independent of BMI

Up to 30% of obese individuals are metabolically healthy. Metabolically healthy obese (MHO) individuals are characterized by having low abdominal adiposity, low inflammation level and low risk of developing metabolic comorbidity. In this study, we hypothesize that cardiorespiratory fitness (fitness) is a determinant factor for the MHO individuals and aim to investigate the associations between fitness, abdominal adiposity and low-grade inflammation within different BMI categories.Data from 10,976 individuals from the general population, DANHES 2007-2008, on waist circumference, fitness and C-reactive protein (hsCRP) were analysed using multiple linear and median quantile regressions.In men, an inverse association between fitness (+5 mL min-1 kg-1) and waist circumference (-1.45 cm; 95% CI: -1.55 to -1.35 cm; p<0.001), and an inverse association between fitness (+5 mL min-1 kg-1) and hsCRP (-0.22 mg/L; 95% CI: -0.255 to -0.185 mg/L; p<0.001) was found, all independent of BMI. Similarly in women, an inverse association between fitness (+5 mL min-1 kg-1) and waist circumference (-1.15 cm; 95% CI: -1.25 to -1.0 cm; p<0.001), and an inverse association between fitness (+5 mL min-1 kg-1) and hsCRP (-0.26 mg/L; 95% CI: -0.3 to -0.22 mg/L; p<0.001) was found, all independent of BMI. Additionally, significant positive associations between waist circumference and hsCRP were found for both men and women, independently of BMI.Fitness was found to be inversely associated with both abdominal adiposity and low-grade inflammation independent of BMI. These data suggest that, in spite of BMI, high fitness levels lead to a reduction in abdominal fat mass and low-grade inflammation

A predictive model for bone marrow disease in cytopenia based on noninvasive procedures

Bone marrow specimens are the core of the diagnostic workup of patients with cytopenia. To explore whether next-generation sequencing (NGS) could be used to rule out malignancy without bone marrow specimens, we incorporated NGS in a model to predict presence of disease in the bone marrow of patients with unexplained cytopenia. We analyzed the occurrence of mutations in 508 patients with cytopenia, referred for primary workup of a suspected hematologic malignancy from 2015 to 2020. We divided patients into a discovery (n = 340) and validation (n = 168) cohort. Targeted sequencing, bone marrow biopsy, and complete blood count were performed in all patients. Mutations were identified in 267 (53%) and abnormal bone marrow morphology in 188 (37%) patients. Patients with isolated neutropenia had the lowest frequency of both mutations (21%) and abnormal bone marrow morphology (5%). The median number of mutations per patient was 2 in patients with abnormal bone marrow morphology compared with 0 in patients with a nondiagnostic bone marrow morphology (P < .001). In a multivariable logistic regression, mutations in TET2, SF3B1, U2AF1, TP53, and RUNX1 were significantly associated with abnormal bone marrow morphology. In the validation cohort, a model combining mutational status and clinical data identified 34 patients (20%) without abnormal bone marrow morphology with a sensitivity of 100% (95% confidence interval: 93%-100%). Overall, we show that NGS combined with clinical data can predict the presence of abnormal bone marrow morphology in patients with unexplained cytopenia and thus can be used to assess the need of a bone marrow biopsy