Improved survival prediction and comparison of prognostic models for patients with hepatocellular carcinoma treated with sorafenib

BACKGROUND: The 'Prediction Of Survival in Advanced Sorafenib-treated HCC' (PROSASH) model addressed the heterogeneous survival of patients with hepatocellular carcinoma (HCC) treated with sorafenib in clinical trials, but requires validation in daily clinical practice. This study aimed to validate, compare and optimize this model for survival prediction. METHODS: Patients treated with sorafenib for HCC at 5 tertiary European centres were retrospectively staged according to the PROSASH model. In addition, the optimized PROSASH-II model was developed using the data of 4 centres (training set) and tested in an independent dataset. These models for overall survival (OS) were then compared with existing prognostic models. RESULTS: The PROSASH model was validated in 445 patients, showing clear differences between the 4 risk groups (OS 16.9-4.6 months). A total of 920 patients (n=615 in training set, n=305 in validation set) were available to develop PROSASH-II. This optimized model incorporated fewer and less subjective parameters: the serum albumin, bilirubin and alpha-fetoprotein, and macrovascular invasion, extrahepatic spread and largest tumour size on imaging. Both PROSASH and PROSASH-II showed improved discrimination (C-index 0.62 and 0.63, respectively) compared with existing prognostic scores (C-index ≤0.59). CONCLUSIONS: In HCC patients treated with sorafenib, individualized prediction of survival and risk group stratification using baseline prognostic and predictive parameters with the PROSASH model was validated. The refined PROSASH-II model performed at least as good with fewer and more objective parameters. PROSASH-II can be used as a tool for tailored treatment of HCC in daily practice and to define pre-planned subgroups for future studies

Total laparoscopic hysterectomy versus total abdominal hysterectomy with bilateral salpingo-oophorectomy for endometrial carcinoma: a randomised controlled trial with 5-year follow-up

This report is on recovery and long-term outcomes in a small-scale randomised controlled trial (RCT) after total laparoscopic hysterectomy versus total abdominal hysterectomy in (potential) endometrial carcinoma patients. An RCT was performed among women with atypical endometrial hyperplasia and endometrial carcinoma scheduled for hysterectomy in a teaching hospital in The Netherlands. Women were randomised to total laparoscopic hysterectomy versus total abdominal hysterectomy both with bilateral salpingo-oophorectomy and were followed until 5 years after the intervention. Patients completed the RAND 36-Item Short Form Health Survey (RAND-36), Quality of Recovery-40 (QoR-40) and Recovery Index-10 (RI-10) until 12 weeks after surgery. Main outcome measure was quality of life and recovery in the first 12 weeks after surgery. A linear mixed model was used for statistical analysis while accounting for baseline values where applicable. Seventeen women were included, of whom 11 allocated to the laparoscopic arm and 6 to the abdominal arm. Laparoscopic hysterectomy performed better on all scales and subscales used in the study. A statistically significant treatment effect, favouring laparoscopic hysterectomy, was found in the total RAND-36 (difference between groups 142 units, 95% confidence interval 46; 236). Clinical follow-up was completed after median 60 months, but this study was too small for conclusions regarding the safety and survival. Laparoscopic hysterectomy results in better postoperative quality of life in the first 12 weeks after surgery when compared with abdominal hysterectomy

Noise Pollution Filters Bird Communities Based on Vocal Frequency

BACKGROUND: Human-generated noise pollution now permeates natural habitats worldwide, presenting evolutionarily novel acoustic conditions unprecedented to most landscapes. These acoustics not only harm humans, but threaten wildlife, and especially birds, via changes to species densities, foraging behavior, reproductive success, and predator-prey interactions. Explanations for negative effects of noise on birds include disruption of acoustic communication through energetic masking, potentially forcing species that rely upon acoustic communication to abandon otherwise suitable areas. However, this hypothesis has not been adequately tested because confounding stimuli often co-vary with noise and are difficult to separate from noise exposure. METHODOLOGY/PRINCIPAL FINDINGS: Using a natural experiment that controls for confounding stimuli, we evaluate whether species vocal features or urban-tolerance classifications explain their responses to noise measured through habitat use. Two data sets representing nesting and abundance responses reveal that noise filters bird communities nonrandomly. Signal duration and urban tolerance failed to explain species-specific responses, but birds with low-frequency signals that are more susceptible to masking from noise avoided noisy areas and birds with higher frequency vocalizations remained. Signal frequency was also negatively correlated with body mass, suggesting that larger birds may be more sensitive to noise due to the link between body size and vocal frequency. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that acoustic masking by noise may be a strong selective force shaping the ecology of birds worldwide. Larger birds with lower frequency signals may be excluded from noisy areas, whereas smaller species persist via transmission of higher frequency signals. We discuss our findings as they relate to interspecific relationships among body size, vocal amplitude and frequency and suggest that they are immediately relevant to the global problem of increases in noise by providing critical insight as to which species traits influence tolerance of these novel acoustics

Lrp4 Modulates Extracellular Integration of Cell Signaling Pathways in Development

The extent to which cell signaling is integrated outside the cell is not currently appreciated. We show that a member of the low-density receptor-related protein family, Lrp4 modulates and integrates Bmp and canonical Wnt signalling during tooth morphogenesis by binding the secreted Bmp antagonist protein Wise. Mouse mutants of Lrp4 and Wise exhibit identical tooth phenotypes that include supernumerary incisors and molars, and fused molars. We propose that the Lrp4/Wise interaction acts as an extracellular integrator of epithelial-mesenchymal cell signaling. Wise, secreted from mesenchyme cells binds to BMP's and also to Lrp4 that is expressed on epithelial cells. This binding then results in the modulation of Wnt activity in the epithelial cells. Thus in this context Wise acts as an extracellular signaling molecule linking two signaling pathways. We further show that a downstream mediator of this integration is the Shh signaling pathway

Chronic ventricular pacing in children: toward prevention of pacing-induced heart disease

In children with congenital or acquired complete atrioventricular (AV) block, ventricular pacing is indicated to increase heart rate. Ventricular pacing is highly beneficial in these patients, but an important side effect is that it induces abnormal electrical activation patterns. Traditionally, ventricular pacemaker leads are positioned at the right ventricle (RV). The dyssynchronous pattern of ventricular activation due to RV pacing is associated with an acute and chronic impairment of left ventricular (LV) function, structural remodeling of the LV, and increased risk of heart failure. Since the degree of pacing-induced dyssynchrony varies between the different pacing sites, ‘optimal-site pacing’ should aim at the prevention of mechanical dyssynchrony. Especially in children, generally paced from a very early age and having a perspective of life-long pacing, the preservation of cardiac function during chronic ventricular pacing should take high priority. In the perspective of the (patho)physiology of ventricular pacing and the importance of the sequence of activation, this paper provides an overview of the current knowledge regarding possible alternative sites for chronic ventricular pacing. Furthermore, clinical implications and practical concerns of the various pacing sites are discussed. The review concludes with recommendations for optimal-site pacing in children