Integrating cytokines and angiogenic factors and tumour bulk with selected clinical criteria improves determination of prognosis in advanced renal cell carcinoma.

BACKGROUND: In two clinical trials of the vascular endothelial growth factor (VEGF) receptor inhibitor pazopanib in advanced renal cell carcinoma (mRCC), we found interleukin-6 as predictive of pazopanib benefit. We evaluated the prognostic significance of candidate cytokines and angiogenic factors (CAFs) identified in that work relative to accepted clinical parameters. METHODS: Seven preselected plasma CAFs (interleukin-6, interleukin-8, osteopontin, VEGF, hepatocyte growth factor, tissue inhibitor of metalloproteinases (TIMP-1), and E-selectin) were measured using multiplex ELISA in plasma collected pretreatment from 343 mRCC patients participating in the phase 3 registration trial of pazopanib vs placebo (NCT00334282). Tumour burden (per sum of longest diameters (SLD)) and 10 other clinical factors were also analysed for association with overall survival (OS; based on initial treatment assignment). RESULTS: Osteopontin, interleukin-6, and TIMP-1 were independently associated with OS in multivariable analysis. A model combining the three CAFs and five clinical variables (including SLD) had higher prognostic accuracy than the International Metastatic Renal Cell Carcinoma Database Consortium criteria (concordance-index 0.75 vs 0.67, respectively), and distinguished two groups of patients within the original intermediate risk category. CONCLUSIONS: A prognostic model incorporating osteopontin, interleukin-6, TIMP-1, tumour burden, and selected clinical criteria increased prognostic accuracy for OS determination in mRCC patients.

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies.

BACKGROUND: HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies. METHODS: In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab. RESULTS: For HER2-positive tumours (n=100), objective response rate was 19.0% (95% confidence interval (CI): 11.8-28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9-34.7). One out of 22 HER2-negative tumour was documented as complete response (n=22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P=0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib. CONCLUSION: Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.

Modification of the Fc region of a primatized IgG antibody to human CD4 retains its ability to modulate CD4 receptors but does not deplete CD4(+) T cells in chimpanzees.

Keliximab, a Primatized IgG1 CD4 mAb, was reconfigured to an IgG4 antibody. The gamma4 constant region was further modified by substituting glutamic acid for serine at position 235 in the CH2 domain (IgG4-E), to remove residual binding to Fcgamma receptors, and substitution of serine with proline at position 228 in the hinge region (IgG4-PE) for greater stability. Pharmacokinetic analysis in rats gave a t(1/2) of approximately 4 days for IgG4-E and 9 days for IgG4-PE, consistent with a greater stability of the IgG4-PE molecule. The effects on T cell subsets were assessed in chimpanzees given escalating doses of IgG4-PE: 0.05 mg/kg on Day 16, 1.5 mg/kg dose on Day 43, and 15 mg/kg on Day 85. Receptor modulation was observed at the two highest doses, but no depletion of T cells at any dose. The in vitro and in vivo results demonstrate the potential of this IgG4-PE mAb for use in human trials.

Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988-1994.

BACKGROUND: Obstructive lung disease (OLD) is an important cause of morbidity and mortality in the US adult population. Potentially treatable mild cases of OLD often go undetected. This analysis determines the national estimates of reported OLD and low lung function in the US adult population. METHODS: We examined data from the Third National Health and Nutrition Examination Survey (NHANES III), a multistage probability representative sample of the US population. A total of 20,050 US adults participated in NHANES III from 1988 to 1994. Our main outcome measures were low lung function (a condition determined to be present if the forced expiratory volume in 1 second-forced vital capacity ratio was less than 0.7 and the forced expiratory volume in 1 second was less than 80% of the predicted value), a physician diagnosis of OLD (chronic bronchitis, asthma, or emphysema), and respiratory symptoms. RESULTS: Overall a mean (SE) of 6.8% (0.3%) of the population had low lung function, and 8.5% (0.3%) of the population reported OLD. Obstructive lung disease (age-adjusted to study population) was currently reported among 12.5% (0.7%) of current smokers, 9.4% (0.6%) of former smokers, 3.1% (1.1%) of pipe or cigar smokers, and 5.8% (0.4%) of never smokers. Surprisingly, 63.3% (0.2%) of the subjects with documented low lung function had no prior or current reported diagnosis of any OLD. CONCLUSIONS: This study demonstrates that OLD is present in a substantive number of US adults. In addition, many US adults have low lung function but no reported OLD diagnosis, which may indicate the presence of undiagnosed lung disease.

Differences between the activity of penicillin, amoxycillin, and co-amoxyclav against 5,252 Streptococcus pneumoniae isolates tested in the Alexander Project 1992-1996.

A number of published studies have shown that the MICs of amoxycillin and/or co-amoxyclav are lower than those of ampicillin and/or penicillin for Streptococcus pneumoniae. Other published studies have concluded that the activities of amoxycillin and co-amoxyclav are comparable with that of penicillin for S. pneumoniae. A collection of 5252 S. pneumoniae isolates obtained during a 5 year period (1992-1996) was analysed to determine differences between the MICs of penicillin, amoxycillin and co-amoxyclav. Among the isolates analysed, 3788 (72%) were penicillin-susceptible, 615 (12%) were penicillin-intermediate and 849 (16%) were penicillin-resistant. Differences between the agents were assessed by examination of MIC distribution functions and simultaneous 95% CIs. In addition, penicillin-intermediate and -resistant isolates were analysed to determine the number and percentage of isolates which had an amoxycillin and co-amoxyclav MIC less than, equal to, or greater than the penicillin MIC. Results showed that the amoxycillin and co-amoxyclav MIC90s were one two-fold dilution lower than those of penicillin for all isolates collected between 1992-1993 and 1994-1996. Simultaneous 95% CIs showed that the mean differences between MICs of amoxycillin and penicillin, and between MICs of co-amoxyclav and penicillin, were less than zero. The majority of the penicillin-intermediate and penicillin-resistant isolates had an amoxycillin and co-amoxyclav MIC less than the penicillin MIC. In conclusion, amoxycillin and co-amoxyclav MICs were shown to be lower than the penicillin MICs for the S. pneumoniae isolates analysed in this study.

Estimation of confidence intervals for area under the curve from destructively obtained pharmacokinetic data.

The area under the curve (AUC) of the concentration-time curve for a drug or metabolite, and the variation associated with the AUC, are primary results of most pharmacokinetic (PK) studies. In nonclinical PK studies, it is often the case that experimental units contribute data for only a single time point. In such cases, it is straightforward to apply noncompartmental methods to determine an estimate of the AUC. In this report, we investigate noncompartmental estimation of the AUC using the long-trapezoidal rule during the elimination phase of the concentration-time profile, and we account for the underlying distribution of data at each sampling time. For data that follow a normal distribution, the log-trapezoidal rule is applied to arithmetic means at each time point of the elimination phase of the concentration-time profile. For data that follow a lognormal distribution, as is common with PK data, the log-trapezoidal rule is applied to geometric means at each time point during elimination. Since the log-trapezoidal rule incorporates nonlinear combinations of mean concentrations at each sampling time, obtaining an estimate of the corresponding variation about the AUC is not straightforward. Estimation of this variance is further complicated by the occurrence of lognormal data. First-order approximations to the variance of AUC estimates are derived under the assumptions of normality, and lognormality, of concentrations at each sampling time. AUC estimates and variance approximations are utilized to form confidence intervals. Accuracies of confidence intervals are tested using simulation studies.

Concomitant cortical expression of TNF-alpha and IL-1 beta mRNAs follows early response gene expression in transient focal ischemia.

The expression of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) mRNAs was significantly increased in the rat ischemic cortex following temporary occlusion of the middle cerebral artery (TMCAO) with reperfusion. Northern blot analysis demonstrated that the induction of TNF-alpha and IL-1 beta mRNAs occurred as early as 1 h after reperfusion, exhibiting a 4.6-fold increase (p < 0.05, n = 4) and 6.8-fold increase (p < 0.05, n = 4) in the ischemic cortex over control, respectively. TNF-alpha mRNA reached its peak at 3 h (8.0-fold, p < 0.05), whereas IL-1 beta mRNA reached its peak at 6 h (29.5-fold, p < 0.05). Both cytokine mRNA levels remained elevated for up to 2 d after reperfusion. In contrast to the time course of these cytokine mRNAs, c-fos and zif268 mRNAs, two early response genes, displayed a greater and earlier time-response profile. The early induction of c-fos and zif268 mRNAs in temporary brain ischemia with reperfusion suggests their roles in transcriptional regulation. The later concomitant expression of TNF-alpha and IL-1 beta suggests that these cytokines play an important role in the inflammatory response associated with focal ischemia.

Reduction of myocardial reperfusion injury with human soluble complement receptor type 1 (BRL 55730).

This study was designed to evaluate the cardioprotective effects of a solubilized human complement receptor, sCR1, in the rat subjected to myocardial infarction. Following coronary artery occlusion for 0.5 h and reperfusion for 24 h (MI/R group), myocardial infarct size (determined by planimetric analysis) was 18.3 +/- 2.1% of the left ventricle (n = 16), while myeloperoxidase activity (a biochemical marker of neutrophil activation) was increased from 0.94 +/- 0.09 U/g tissue in the sham occluded + vehicle group to 2.96 +/- 0.17 U/g tissue in the MI/R + vehicle treated group (P < 0.01). Injection of sCR1 (5 mg/kg i.v., 5 min prior to coronary artery occlusion) produced plasma concentrations of 154 +/- 4 microgram/ml 1 min prior to coronary artery occlusion, and concentrations of 86 +/- 2 and 58 +/- 3 micrograms/ml at 40 min and 125 min after dosing (n = 6). sCR1 reduced myocardial infarct size to 11.3 +/- 2.2% of the left ventricle, and attenuated the increase in myeloperoxidase activity to 2.11 +/- 0.20 U/g tissue (n = 18; P < 0.01, compared to the MI/R + vehicle group). Administration of sCR1 5 min prior to reperfusion afforded a 25.3% non-significant reduction in myocardial injury. These results suggest a beneficial effect of sCR1 in myocardial ischemia/reperfusion injury by reducing the infiltration of neutrophils and attenuating the extent of myocardial injury.

Effects of coronary angioplasty on plasma platelet-activating factor in man.

Platelet activating factor (PAF) is a mediator of ischemia and reperfusion-induced tissue damage which was found to be synthesized in culture by endothelial cells. We hypothesized that PAF levels may be increased in the coronary system following coronary angioplasty. PAF levels were measured in the great cardiac vein of 16 patients before, during and following angioplasty of the left anterior coronary artery. PAF concentration was significantly higher in the cardiac vein than in the peripheral circulation at all time points. Interestingly, while PAF levels tended to decrease in the periphery they tended to increase in the coronary system over time. We conclude that PAF levels are higher in the coronary system than in the peripheral circulation in patients undergoing coronary angioplasty and that PAF may be released into the coronary artery following the procedure.

Neuroprotective effects of SKF 10,047 in cultured rat cerebellar neurons and in gerbil global brain ischemia.

BACKGROUND AND PURPOSE: Excitatory amino acids and their receptors are involved in mediating ischemic neuronal damage. The sigma-agonists are believed to interact with the N-methyl-D-aspartate receptor. Therefore, we studied the neuroprotective, hypothermic, and motor deficit effects of the sigma-agonist SKF 10,047 and the N-methyl-D-aspartate antagonist MK-801. METHODS: Neuroprotective effects were compared using an in vitro ischemia model of cultured rat cerebellar granule cells and the gerbil model of global brain ischemia induced by 5 minutes of bilateral carotid artery occlusion followed by 7 days of reperfusion. RESULTS: In vitro, (+)MK-801 protected against 100 microM glutamate with a 50% protective concentration of 30 nM, followed by (-)MK-801 (150 nM), cyclazocine (0.5 microM), (+)SKF 10,047 (3.3 microM), pentazocine (5 microM), and (-)SKF 10,047 (10 microM). In vivo, (+)SKF 10,047 pretreatment (60 mg/kg) or multiple postischemic treatments provided neuroprotection comparable with MK-801 pretreatment (10 mg/kg). When ischemic animals were administered the multiple dosing regimen of (+)SKF 10,047, no hypothermic effect was noted in the temporalis muscle over 4 hours' postischemia. Motor deficits monitored by a swing grid test showed that 50% recovery from (+)SKF 10,047 was 5.5 times faster than recovery from MK-801. CONCLUSIONS: These results are the first to report a hypothermia-free, in vivo neuroprotective effect of (+)SKF 10,047, a prototypical drug of the sigma-agonist class.