Renal function during treatment with adefovir plus peginterferon alfa-2a vs either drug alone in hepatitis B/D co-infection

Long-term safety of treatment with hepatitis B virus (HBV) polymerase inhibitors is a concern. Adefovir dipivoxil (ADV) therapy has previously been associated with impairment of renal function. Limited data are available on the safety of combination therapy with nucleos(t)ide analogues and interferon alfa (IFNα). The aim of this analysis was to assess the renal function during combination therapy with peginterferon alfa-2a (PegIFNα-2a) plus ADV vs either drug alone in patients with hepatitis B/D co-infection. We performed a retrospective analysis of renal function data of patients treated in the Hep-Net/International Delta Hepatitis Intervention Trial 1(HIDIT-1-trial), a European multicenter study to investigate the efficacy of 48 weeks of therapy with PegIFNα-2a+ADV vs either drug alone in 90 patients with chronic hepatitis B/D co-infection. Glomerular filtration rates (GFR) were calculated by Cockcroft-Gault (CG), abbreviated Modification of Diet in Renal Disease (MDRD) study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. After 48 weeks of therapy GFR values were significantly lower in patients receiving adefovir-containing treatment vs PegIFNα-2a alone [mean difference 16.1 mL/min (CG) and 10.2 mL/min (MDRD), respectively, P < 0.05] while no differences were observed between patients receiving adefovir alone vs combination treatment. Twenty-four weeks after treatment GFR values did not differ between treatment arms. A decrease in GFR ≥ 20% was observed more often in patients during adefovir-containing treatment vs PegIFNα-2a alone (P < 0.05) which was confirmed by Kaplan-Meier analysis. Adefovir-containing but not PegIFNα-2a treatment was associated with a decrease in GFR values in about one-fifth of patients. Combination treatment of PegIFNα-2a+ADV in chronic hepatitis B/D co-infection did not lead to any further impairment of kidney function.     

Intratumoral expression of programmed death ligand 1 (PD-L1) in patients with clear cell renal cell carcinoma (ccRCC)

The immunological checkpoints of programmed death 1 and its ligand (PD-L1) are currently in focus as novel therapeutic targets in renal cell carcinoma (RCC). The aim of this study was to evaluate the prognostic association of PD-L1 expression in clear cell (cc) RCC with clinical parameters, tumor aggressiveness and overall survival (OS). Patients who underwent renal surgery due to RCC between 1994 and 2003 were retrospectively evaluated. Tumor specimens were analyzed for PD-L1 expression by immunohistochemistry. One hundred and seventy-seven ccRCC patients were eligible for analysis, in which 140 (79.1 %) were negative and 37 (20.9 %) were positive for PD-L1 expression. PD-L1 positivity was associated with female gender (p = 0.001), lymph node metastasis (p = 0.004), distant metastasis (p = 0.002), higher AJCC stage (p = 0.004), as well as advanced disease (pT3/4 and/or N+ and/or M1) (p < 0.001). Kaplan–Meier analysis revealed a significantly diminished 5- and 10-year overall survival of 46.7 and 28.3 % for PD-L1⁺ compared to PD-L1^? tumors with 66 and 53.4 % (p = 0.005), respectively. Univariate analysis showed a significant negative association of OS with PD-L1 positivity [p = 0.005; HR: 2 (95 % CI 1.2–3.3)], even though PD-L1 positivity only tends to predict independently the OS using multivariate analyses [p = 0.066; HR: 1.6 (95 % CI 0.98–2.7)]. PD-L1 expression in ccRCC is associated with parameters of aggressiveness, as well as with poor OS, even though PD-L1 status was not identified as a significant independent prognostic parameter. However, further studies in larger cohorts are warranted.     

Recent advances in enteric neurobiology: mechanosensitive interneurons

Until recently, it was generally assumed that the only intrinsic sensory neuron, or primary afferent neuron, in the gut was the after-hyperpolarizing AH/Type II neuron. AH neurons excited by local chemical and mechanical stimulation of the mucosa appear to be necessary for activating the peristaltic reflex (oral excitation and anal inhibition of the muscle layers) and anally propagating ring like contractions (peristaltic waves) that depend upon smooth muscle tone. However, our recent findings in the guinea-pig distal colon suggest that different neurochemical classes of interneuron in the colon are also mechanosensitive in that they respond directly to changes in muscle length, rather than muscle tone or tension. These interneurons have electrophysiological properties consistent with myenteric S-neurons. Ascending and descending interneurons respond directly to circumferential stretch by generating an ongoing polarized peristaltic reflex activity (oral excitatory and anal inhibitory junction potentials) in the muscle for as long as the stimulus is maintained. Some descending (nitric oxide synthase +ve) interneurons, on the other hand, appear to respond directly to longitudinal stretch and are involved in accommodation and slow transit of faecal pellets down the colon. This review will present recent evidence that suggests some myenteric S interneurons, in addition to AH neurons, behave as intrinsic sensory neurons.     

Development and evaluation of a baseline‐event‐anticipation score for hepatitis delta

Hepatitis delta is considered the most severe form of viral hepatitis, but variables associated with disease progression are poorly defined. This study aimed to identify risk factors associated with worse clinical outcome in patients with hepatitis delta and to develop a clinical score to determine their risk of experiencing liver‐related morbidity or mortality. We followed 75 HBsAg–anti‐HDV‐positive patients with hepatitis delta for up to 16 years (median 5 years). The baseline‐event‐anticipation score (BEA score) was developed based on variables associated with the development of liver‐related clinical complications. Age, region of origin, presence of cirrhosis, albumin, INR, hyperbilirubinemia and thrombocytopenia were all associated with the development of an event in the training cohort. The BEA score included age, sex, region of origin, bilirubin, platelets and INR. Points were allocated according to hazard ratios, and three risk groups were defined: BEA‐A mild risk, BEA‐B moderate risk and BEA‐C high risk. Hazard ratios of BEA‐B and BEA‐C patients for liver‐related clinical endpoints were 9.01 and 25.27 vs BEA‐A with an area under curve of the receiving operating characteristic curve of 0.88. The accuracy of the BEA score was confirmed in two independent validation cohorts followed in Barcelona (n = 77) and Düsseldorf (n = 62). Delta hepatitis is associated with a very severe long‐term outcome. The BEA score is easy to apply and predicts with a very high accuracy the development of liver‐related complications in patients with hepatitis delta.     

Asthma control and health-related quality of life one year after inpatient pulmonary rehabilitation: the ProKAR Study

Objectives: Although pulmonary rehabilitation (PR) is commonly used for asthmatics in many countries, so far there are no studies addressing the question of whether and for how long an improvement in asthma control (AC) is seen after rehabilitation. The ProKAR study (Prospektive Katamnesestudie Asthma-Rehabilitation) was performed to provide data concerning the short- and long-term impact of PR on AC. Methods: Two-hundred one adult patients with mild to severe persistent asthma were prospectively followed one year after completion of a 3-week PR program. AC, the primary outcome parameter, and health-related quality of life (HRQoL) were monitored using the Asthma Control Test (ACT) and St. George’s Respiratory Questionnaire (SGRQ) at initiation (T0) and end of the PR (T1) and 3, 6 and 12 months thereafter. Pulmonary function, physical fitness (6MWD) and asthmatic inflammation (FENO) were measured at T0 and T1. Results: The proportion of patients with well-controlled asthma (ACT score ≥20) increased from 33.2% to 67.3% after PR and was still at 51% after 12 months. Slight but statistically significant improvements in pulmonary functions and an increase in 6MWD of nearly 60?m were reported at T1. One year after discharge 55.8% of the patients still showed a clinically relevant improvement of at least 4 points in the total SGRQ score. Conclusions: The multidisciplinary inpatient PR program resulted in significant short and long-term improvement in AC and HRQoL in adult asthmatic patients.     

Die Bedeutung von Biomarkern für eine personalisierte Medizin

In this paper the relevance of biomarkers for the benefit/risk assessment of pharmaceuticals and the validation of biomarkers within clinical trials is presented. For this purpose the most important study designs for validation are described and discussed. Using the example of the development of rosuvastatin and the validation of hs-CRP (JUPITER study), aspects that are necessary for the planning of a joint development program for a pharmaceutical drug and a biomarker are discussed. In addition, alternatives considering how the validation of the biomarker could be involved in the entire development program of the pharmaceutical drug are presented.     

Liver Resection of Colorectal Liver Metastases in Elderly Patients

Background  

The percentage of elderly patients with colorectal liver metastases (CLM) has increased. Liver resection remains the only curative therapy; data evaluating the outcome in this age group is limited. Aim of the present study was to determine if postoperative morbidity, mortality, and other independent predictors influence survival in patients ≥70 years undergoing liver resection for CLM.     

Treatment with tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma is associated with drug-induced hyperparathyroidism: a single center experience in 59 patients

Purpose  

Multi-targeted tyrosine kinase inhibitors (MTKIs) are the standard in the treatment of metastatic renal cell carcinoma (mRCC). In spite their clinical activity, interaction with physiological functions has been shown. Here, we report on alterations of the bone mineral metabolism in patients with mRCC treated with MTKIs.