Impact of a multifaceted prevention program on ventilator-associated pneumonia including selective oropharyngeal decontamination.

PURPOSE: We describe the impact of a multifaceted program for decreasing ventilator-associated pneumonia (VAP) after implementing nine preventive measures, including selective oropharyngeal decontamination (SOD). METHODS: We compared VAP rates during an 8-month pre-intervention period, a 12-month intervention period, and an 11-month post-intervention period in a cohort of patients who received mechanical ventilation (MV) for > 48 h. The primary objective was to assess the effect on first VAP occurrence, using a Cox cause-specific proportional hazards model. Secondary objectives included the impact on emergence of antimicrobial resistance, antibiotic consumption, duration of MV, and ICU mortality. RESULTS: Pre-intervention, intervention and post-intervention VAP rates were 24.0, 11.0 and 3.9 VAP episodes per 1000 ventilation-days, respectively. VAP rates decreased by 56% [hazard ratio (HR) 0.44, 95% CI 0.29-0.65; P < 0.001] in the intervention and by 85% (HR 0.15, 95% CI 0.08-0.27; P < 0.001) in the post-intervention periods. During the intervention period, VAP rates decreased by 42% (HR 0.58, 95% CI 0.38-0.87; P < 0.001) after implementation of eight preventive measures without SOD, and by 70% after adding SOD (HR 0.30, 95% CI 0.13-0.72; P < 0.001) compared to the pre-intervention period. The incidence density of intrinsically resistant bacteria (to colistin or tobramycin) did not increase. We documented a significant reduction of days of therapy per 1000 patient-days of broad-spectrum antibiotic used to treat lower respiratory tract infection (P < 0.028), median duration of MV (from 7.1 to 6.4 days; P < 0.003) and ICU mortality (from 16.2 to 13.5%; P < 0.049) for patients ventilated > 48 h between the pre- and post-intervention periods. CONCLUSIONS: Our preventive program produced a sustained decrease in VAP incidence. SOD provides an additive value.

Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis.

BACKGROUND: Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. PATIENTS AND METHODS: A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19-21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] RESULTS: Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. CONCLUSION: Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.

Phase I and pharmacodynamic study of high-dose NGR-hTNF in patients with refractory solid tumours.

BACKGROUND: NGR-hTNF exploits the peptide asparagine-glycine-arginine (NGR) for selectively targeting tumour necrosis factor (TNF) to CD13-overexpressing tumour vessels. Maximum-tolerated dose (MTD) of NGR-hTNF was previously established at 45 µg m(-2) as 1-h infusion, with dose-limiting toxicity being grade 3 infusion-related reactions. We explored further dose escalation by slowing infusion rate (2-h) and using premedication (paracetamol). METHODS: Four patients entered each of 12 dose levels (n=48; 60-325 µg m(-2)). Pharmacokinetics, soluble TNF receptors (sTNF-R1/sTNF-R2), and volume transfer constant (K(trans)) by dynamic imaging (dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)) were assessed pre- and post-treatment. RESULTS: Common related toxicity included grade 1/2 chills (58%). Maximum-tolerated dose was not reached. Both C(max) (P<0.0001) and area under the plasma concentration-time curve (P=0.0001) increased proportionally with dose. Post-treatment levels of sTNF-R2 peaked significantly higher than sTNF-R1 (P<0.0001). Changes in sTNF-Rs, however, did not differ across dose levels, suggesting a plateau effect in shedding kinetics. As best response, 12/41 evaluable patients (29%) had stable disease. By DCE-MRI, 28/37 assessed patients (76%) had reduced post-treatment K(trans) values (P<0.0001), which inversely correlated with NGR-hTNF C(max) (P=0.03) and baseline K(trans) values (P<0.0001). Lower sTNF-R2 levels and greater K(trans) decreases after first cycle were associated with improved survival. CONCLUSION: asparagine-glycine-arginine-hTNF can be safely escalated at doses higher than MTD and induces low receptors shedding and early antivascular effects.