Activity and safety of NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma

Background:Hepatocellular carcinoma (HCC) is a highly vascularised and poor-prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels.Methods:Twenty-seven patients with advanced-stage disease resistant to either locoregional (59%; range, 1-3), systemic treatments (52%; range, 1-3) or both (33%) received NGR-hTNF 0.8 gm-2 once every 3 weeks. The primary aim of the study was progression-free survival (PFS).Results:No grade 3-4 treatment-related toxicities were noted. Common toxicity included mild-to-moderate, short-lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7-2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5-10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months.Conclusion:NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest

Prospective assessment of integrating the existing emergency medical system with automated external defibrillators fully operated by volunteers and laypersons for out-of-hospital cardiac arrest: the Brescia Early Defibrillation Study (BEDS)

AIMS: There are few data on the outcomes of cardiac arrest (CA) victims when the defibrillation capability of broad rural and urban territories is fully operated by volunteers and laypersons. METHODS AND RESULTS: In this study, we investigated whether a programme based on diffuse deployment of automated external defibrillators (AEDs) operated by 2186 trained volunteers and laypersons across the County of Brescia, Italy (area: 4826 km(2); population: 1 112 628), would safely and effectively impact the current survival among victims of out-of-hospital CA. Forty-nine AEDs were added to the former emergency medical system that uses manual EDs in the emergency department of 10 county hospitals and in five medically equipped ambulances. The primary endpoint was survival free of neurological impairment at 1-year follow-up. Data were analysed in 692 victims before and in 702 victims after the deployment of the AEDs. Survival increased from 0.9% (95% CI 0.4-1.8%) in the historical cohort to 3.0% (95% CI 1.7-4.3%) (P=0.0015), despite similar intervals from dispatch to arrival at the site of collapse [median (quartile range): 7 (4) min vs. 6 (6) min]. Increase of survival was noted both in the urban [from 1.4% (95% CI 0.4-3.4 %) to 4.0% (95% CI 2.0-6.9 %), P=0.024] and in the rural territory [from 0.5% (95% CI 0.1-1.6%) to 2.5% (95% CI 1.3-4.2%), P=0.013]. The additional costs per quality-adjusted life year saved amounted to euro39 388 (95% CI euro16 731-49 329) during the start-up phase of the study and to euro23 661 (95% CI euro10 327-35 528) at steady state. CONCLUSION: Diffuse implementation of AEDs fully operated by trained volunteers and laypersons within a broad and unselected environment proved safe and was associated with a significantly higher long-term survival of CA victims

Phase Ib study of NGR–hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours

Contains fulltext : 81937timmer-bonte.pdf (publisher's version ) (Closed access)BACKGROUND: Asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF) is a vascular targeting agent exploiting a tumour-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13, overexpressed on tumour blood vessels. Significant preclinical synergy was shown between low doses of NGR-TNF and doxorubicin. METHODS: The primary aim of this phase I trial was to verify the safety of low-dose NGR-hTNF combined with doxorubicin in treating refractory/resistant solid tumours. Secondary objectives included pharmacokinetics (PKs), pharmacodynamics, and clinical activity. In all 15 patients received NGR-hTNF (0.2-0.4-0.8-1.6 microg m(-2)) and doxorubicin (60-75 mg m(-2)), both given intravenously every 3 weeks. RESULTS: No dose-limiting toxicity occurred and the combination was well tolerated. Around two cases of neutropenic fevers, lasting 2 days, and two cases of cardiac ejection-fraction drops, one asymptomatic and the other symptomatic, were registered. Only 11% of the adverse events were related to NGR-hTNF and were short-lasting and mild-to-moderate in severity. There was no apparent PK interaction and the shedding of soluble TNF-receptors did not increase to 0.8 microg m(-2). One partial response (7%), at dose level 0.8 microg m(-2), and 10 stable diseases (66%), lasting for a median duration of 5.6 months, were observed. CONCLUSIONS: NGR-hTNF plus doxorubicin was administered safely and showed promising activity in patients pre-treated with anthracyclines. The dose level of 0.8 microg m(-2) NGR-hTNF plus doxorubicin 75 mg m(-2) was selected for phase II development

Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation

AIMS: To investigate the effects of cardiac resynchronization therapy (CRT) on survival in heart failure (HF) patients with permanent atrial fibrillation (AF) and the role of atrio-ventricular junction (AVJ) ablation in these patients. METHODS AND RESULTS: Data from 1285 consecutive patients implanted with CRT devices are presented: 1042 patients were in sinus rhythm (SR) and 243 (19%) in AF. Rate control in AF was achieved by either ablating the AVJ in 118 patients (AVJ-abl) or prescribing negative chronotropic drugs (AF-Drugs). Compared with SR, patients with AF were significantly older, more likely to be non-ischaemic, with higher ejection fraction, shorter QRS duration, and less often received ICD back-up. During a median follow-up of 34 months, 170/1042 patients in SR and 39/243 in AF died (mortality: 8.4 and 8.9 per 100 person-year, respectively). Adjusted hazard ratios were similar for all-cause and cardiac mortality [0.9 (0.57-1.42), P = 0.64 and 1.00 (0.60-1.66) P = 0.99, respectively]. Among AF patients, only 11/118 AVJ-abl patients died vs. 28/125 AF-Drugs patients (mortality: 4.3 and 15.2 per 100 person-year, respectively, P < 0.001). Adjusted hazard ratios of AVJ-abl vs. AF-Drugs was 0.26 [95% confidence interval (CI) 0.09-0.73, P = 0.010] for all-cause mortality, 0.31 (95% CI 0.10-0.99, P = 0.048) for cardiac mortality, and 0.15 (95% CI 0.03-0.70, P = 0.016) for HF mortality. CONCLUSION: Patients with HF and AF treated with CRT have similar mortality compared with patients in SR. In AF, AVJ ablation in addition to CRT significantly improves overall survival compared with CRT alone, primarily by reducing HF death

Development and characterization of a microfluidic model of the tumour microenvironment

The physical microenvironment of tumours is characterized by heterotypic cell interactions and physiological gradients of nutrients, waste products and oxygen. This tumour microenvironment has a major impact on the biology of cancer cells and their response to chemotherapeutic agents. Despite this, most in vitro cancer research still relies primarily on cells grown in 2D and in isolation in nutrient- and oxygen-rich conditions. Here, a microfluidic device is presented that is easy to use and enables modelling and study of the tumour microenvironment in real-time. The versatility of this microfluidic platform allows for different aspects of the microenvironment to be monitored and dissected. This is exemplified here by real-time profiling of oxygen and glucose concentrations inside the device as well as effects on cell proliferation and growth, ROS generation and apoptosis. Heterotypic cell interactions were also studied. The device provides a live ‘window’ into the microenvironment and could be used to study cancer cells for which it is difficult to generate tumour spheroids. Another major application of the device is the study of effects of the microenvironment on cellular drug responses. Some data is presented for this indicating the device’s potential to enable more physiological in vitro drug screening

the world wide randomized antibiotic envelope infection prevention wrap it trial long term follow up

Abstract Background The WRAP-IT trial reported a 40% reduction in major CIED infection within 12 months of the procedure with the antibacterial-eluting envelope (TYRX). Objective This report describes the longer-term (>12 months) envelope effects on infection reduction and complications. Methods All trial patients that underwent CIED replacement, upgrade, revision, or initial CRT-D implant received standard-of-care infection prophylaxis and were randomized 1:1 to receive the envelope or not. CIED infection incidence, and procedure and system-related complications were characterized through all follow-up (36 months) using Cox proportional hazard regression modeling. Results In total, 6800 patients received their intended randomized treatment (3371 envelope; 3429 control; mean follow-up 21.0±8.3 months). Major CIED-related infection occurred in 32 envelope patients and 51 control patients (KM estimate, 1.3% vs. 1.9%; HR: 0.64, 95% CI: 0.41-0.99; P=0.046). Any CIED-related infection occurred in 57 envelope patients and 84 control patients (KM estimate, 2.1% vs. 2.8%; HR: 0.69, 95% CI: 0.49-0.97; P=0.030). System- or procedure-related complications occurred in 235 envelope patients and 252 control patients (KM estimate, 8.0% vs. 8.2%; HR, 0.95, 95% CI: 0.79-1.13; P Conclusions The effects of the TYRX envelope in reducing the risk of CIED infection are sustained beyond the first year post-procedure, without increased risk of complication

Inhibition of APN/CD13 leads to suppressed progressive potential in ovarian carcinoma cells

<p>Abstract</p> <p>Background</p> <p>Aminopeptidase N (APN/CD13), a 150-kDa metalloprotease, is a multifunctional cell surface aminopeptidase with ubiquitous expression. Recent studies have suggested that APN/CD13 plays an important role in tumor progression of several human malignancies. In the current study, we investigated the role of APN/CD13 in ovarian carcinoma (OVCA) progression.</p> <p>Methods</p> <p>We first examined the expression of APN/CD13 at the protein level in a variety of OVCA cell lines and tissues. We subsequently investigated whether there was a correlation between APN/CD13 expression and invasive potential of various OVCA cell lines. Moreover, we investigated the function of APN/CD13 in OVCA cells using bestatin, an APN/CD13 inhibitor, or transfection of siRNA for APN/CD13.</p> <p>Results</p> <p>We confirmed that APN/CD13 was expressed in OVCA tissues and cell lines to various extents. There was a positive correlation between APN/CD13 expression and migratory potential in various OVCA cell lines with accordingly enhanced secretion of endogenous MMP-2. Subsequently, we found a significant decrease in the proliferative and migratory abilities of OVCA cells after the addition of bestatin or the inhibition of APN/CD13 expression by siRNA. Furthermore, in an animal model, daily intraperitoneal administration of bestatin after inoculation of OVCA cells resulted in a decrease of peritoneal dissemination and in prolonged survival of nude mice.</p> <p>Conclusion</p> <p>The current data indicate the possible involvement of APN/CD13 in the development of OVCA, and suggest that clinical use of bestatin may contribute to better prognosis for ovarian carcinoma patients.</p

IGD Motifs, Which Are Required for Migration Stimulatory Activity of Fibronectin Type I Modules, Do Not Mediate Binding in Matrix Assembly

Picomolar concentrations of proteins comprising only the N-terminal 70-kDa region (70K) of fibronectin (FN) stimulate cell migration into collagen gels. The Ile-Gly-Asp (IGD) motifs in four of the nine FN type 1 (FNI) modules in 70K are important for such migratory stimulating activity. The 70K region mediates binding of nanomolar concentrations of intact FN to cell-surface sites where FN is assembled. Using baculovirus, we expressed wildtype 70K and 70K with Ile-to-Ala mutations in 3FNI and 5FNI; 7FNI and 9FNI; or 3FNI, 5FNI, 7FNI, and 9FNI. Wildtype 70K and 70K with Ile-to-Ala mutations were equally active in binding to assembly sites of FN-null fibroblasts. This finding indicates that IGD motifs do not mediate the interaction between 70K and the cell-surface that is important for FN assembly. Further, FN fragment N-3FNIII, which does not stimulate migration, binds to assembly sites on FN-null fibroblast. The Ile-to-Ala mutations had effects on the structure of FNI modules as evidenced by decreases in abilities of 70K with Ile-to-Ala mutations to bind to monoclonal antibody 5C3, which recognizes an epitope in 9FNI, or to bind to FUD, a polypeptide based on the F1 adhesin of Streptococcus pyogenes that interacts with 70K by the β-zipper mechanism. These results suggest that the picomolar interactions of 70K with cells that stimulate cell migration require different conformations of FNI modules than the nanomolar interactions required for assembly