Sorafenib, an oral multikinase inhibitor, has shown preliminary activity in non-small-cell lung cancer (NSCLC). Patients with advanced NSCLC were treated with erlotinib with or without sorafenib in ...this multicenter phase II trial.
Key eligibility criteria included the following: stage IIIB or IV NSCLC; one to two prior regimens; Eastern Cooperative Oncology Group performance status of 0 to 2; and measurable disease. Patients were randomly assigned 2:1 to sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily) or placebo plus erlotinib and stratified by squamous/nonsquamous histology and prior bevacizumab. Treatment efficacy, measured by progression-free survival (PFS) and overall response rate (ORR), was compared. Treatment of 168 patients allowed detection of 40% improvement in the historical PFS of 2.2 months with single-agent erlotinib.
One hundred sixty-eight patients enrolled from February 2008 to February 2009. Clinical characteristics of the two groups were similar. ORRs for sorafenib/erlotinib and placebo/erlotinib were 8% and 11%, respectively (P = .56); disease control rates were 54% and 38%, respectively (P = .056). Median PFS was 3.38 months for sorafenib/erlotinib versus 1.94 months for placebo/erlotinib (hazard ratio, 0.86; 95% CI, 0.60 to 1.22; P = .196). Seventy-two patients consented to analyses of tumor epidermal growth factor receptor (EGFR). In 67 patients with EGFR wild-type (WT) tumors, median PFS was 3.38 months for sorafenib/erlotinib versus 1.77 months for placebo/erlotinib (P = .018); median overall survival (OS) was 8 months for sorafenib/erlotinib versus 4.5 months for placebo/erlotinib (P = .019). An OS advantage for sorafenib/erlotinib was suggested among 43 patients with fluorescent in situ hybridization (FISH) EGFR-negative tumors (P = .064). Both regimens were tolerable, with modest toxicity increase with sorafenib.
Although there was little difference in ORR or PFS, subset analyses in EGFR WT and EGFR FISH-negative patients suggest a benefit for the combination of erlotinib/sorafenib compared with single-agent erlotinib with respect to PFS and OS.
The goals of this study were to determine whether improvements in metabolic control can ameliorate the cognitive dysfunction associated with type 2 diabetes and evaluate the possibility that such ...improvements are mediated by changes in circulating insulin or insulin resistance.
This randomized double-blind trial enrolled 145 subjects at 18 centers in the U.S. Older adults with type 2 diabetes receiving metformin monotherapy received add-on therapy with either rosiglitazone, a thiazolidinedione insulin sensitizer, or glyburide. Cognitive function was assessed at baseline and week 24 using the Digit Symbol Substitution Test, the Rey Auditory Verbal Learning Test, and the Cambridge Neuropsychological Test Automated Battery.
Pretreatment fasting plasma glucose (FPG) in both groups was similar, and after 24 weeks both treatment groups showed similar significant reductions in FPG (2.1-2.3 mmol/l). Working memory improved with both rosiglitazone (P < 0.001) and glyburide (P = 0.017). Improvement (25-31% reduction in errors) was most evident on the Paired Associates Learning Test and was significantly correlated (r = 0.30) with improved glycemic control as measured by FPG.
Similar and statistically significant cognitive improvement was observed with both rosiglitazone and glyburide therapy, and the magnitude of this effect was correlated with the degree to which FPG improved. These results suggest that a cognitive benefit is achievable with pharmacological interventions targeting glycemic control.
Background
We examined the effect of the oral SIRT1 activator SRT2104 on cardiovascular function in otherwise healthy cigarette smokers.
Methods and Results
Twenty‐four otherwise healthy cigarette ...smokers participated in a randomized double‐blind, placebo‐controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Plasma SRT2104 concentrations, serum lipid profile, plasma fibrinolytic factors, and markers of platelet and monocyte activation were measured at baseline and at the end of each treatment period together with an assessment of forearm blood flow during intra‐arterial bradykinin, acetylcholine, and sodium nitroprusside infusions. Three hours postdose, mean plasma SRT2104 concentration was 1328±748 ng/mL after 28 days of active treatment. Compared with placebo, serum lipid profile improved during SRT2104 administration, with reductions in serum total cholesterol (−11.6±20 versus 6±21 mg/dL), low‐density lipoprotein cholesterol (−10±17 versus 3±21 mg/dL), and triglyceride (−39.8±77 versus 13.3±57 mg/dL) concentrations (P<0.05 for all). All vasodilators produced a dose‐dependent increase in blood flow (P<0.0001) that was similar during each treatment period (P>0.05 for all). No significant differences in fibrinolytic or blood flow parameters were observed between placebo and SRT2014.
Conclusions
SRT2104 appears to be safe and well tolerated and associated with an improved lipid profile without demonstrable differences in vascular or platelet function in otherwise healthy cigarette smokers.
Clinical Trial Registration
http://www.clinicaltrials.gov. Unique identifier: NCT01031108.
ObjectiveArterial stiffness increases with age, and is associated with adverse cardiovascular outcome including increased mortality. The effect of the oral small molecule SIRT1 activator, SRT2104, on ...arterial stiffness was examined in otherwise healthy cigarette smokers and participants with type 2 diabetes mellitus.Methods24 otherwise healthy cigarette smokers and 15 people with stable type 2 diabetes were randomised in a double-blind placebo-controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Blood pressure was measured using non-invasive oscillatory sphygmomanometry. Pulse wave analysis and velocity were measured using applanation tonometry at baseline and the end of each treatment period. Owing to the small sample size and similar trends for both groups, data for the two groups were pooled (post hoc analysis).ResultsCompared to placebo, treatment with SRT2104 was associated with a significant reduction in augmentation pressure (p=0.0273) and a trend towards improvement in the augmentation index and corrected augmentation index (p>0.05 for both). However, no changes were observed in pulse wave velocity and time to wave reflection (p>0.05). Systolic and diastolic blood pressures remained unchanged throughout the study. Treatment by cohort interaction was not significant for any of the pulse wave parameters, suggesting that the response to SRT2104 in otherwise healthy smokers and people with diabetes was consistent.ConclusionsSRT2104 may improve measures of arterial stiffness in otherwise healthy cigarette smokers and in participants with type 2 diabetes. Definitive conclusions are not possible given the small sample size and exploratory nature of this analysis.Trial registration numberNCT01031108.
Abstract Background : Type 2 diabetes mellitus is twice as prevalent in African Americans and Hispanic Americans as in non-Hispanic whites. However, the effectiveness and safety profile of ...rosiglitazone maleate used as combination therapy with sulfonylureas in the management of diabetes and its effect on cardiovascular disease (CVD) biomarkers/parameters have not been studied in these populations. Objective : The purpose of this study was to determine the efficacy and tolerability of the addition of rosiglitazone to a regimen of glyburide once daily in African American and Hispanic American patients with type 2 diabetes previously inadequately controlled with sulfonylurea monotherapy. Methods : This randomized, double-blind, placebo-controlled, parallel-group study was conducted at 38 centers in the United States. Eligible patients were aged ≤21 years, had type 2 diabetes, a fasting plasma glucose (FPG) level ≥140 mg/dL, and a glycosylated hemoglobin (HbA1c ) value ≥7.5%, and had been treated with sulfonylurea monotherapy for at least 2 months before screening. Patients were assigned to receive treatment with glyburide 10 or 20 mg/d plus rosiglitazone 8 mg (GLY+RSG) or placebo (GLY+PBO) PO (tablets) QD for 24 weeks. The primary efficacy end point was the change from baseline in HbA1c after 24 weeks of treatment. Secondary end points included change in FPG; proportion of patients achieving HbA1c targets (<7.0% and <6.5%); and changes in biomarkers for CVD risk, including C-reactive protein (CRP), plasminogen activator inhibitor (PAI)-I activity, fibrinogen, tissue plasminogen activator (tPA) antigen, von Willebrand factor (vWF), soluble vascular cell adhesion molecule (sVCAM), lipoprotein-associated phospholipase A 2 activity, and urinary albumin/creatinine ratio (UACR). Tolerability was assessed using physical examination, including vital-sign measurement, clinical laboratory tests, and adverse event (AE) reports collected at each study visit. Results : A total of 245 patients (101 African American and 144 Hispanic American) were enrolled. Demographic characteristics were comparable between the GLY+RSG and GLY+PBO groups: mean (SD) age (52 11.9 vs 53 10.4 years), HbA1c (9.2% 1.3% vs 9.4% 1.4%), sex (men/women, 45.3%/54.7% vs 48.3%/51.7%), race (African American/Hispanic American, 43.6%/56.4% vs 37.9%/62.1%), and mean (SD) weight (86.3 18.8 vs 88.3 19.4 kg). In the overall study population, treatment with GLY+RSG was associated with a significantly greater mean (95% CI) reduction from baseline in HbA1c compared with GLY+PBO (between-group Δ, −1.4% −1.7% to −1.1%; P < 0.001). When assessed by ethnicity, HbA1c values were significantly reduced with GLY+RSG compared with GLY+PBO in African American patients (between-group Δ, -1.4%) and in Hispanic American patients (between-group Δ, −1.5%) (both, P < 0.001), as were FPG levels (between-group Δs, −3.1 mmol/L 57 mg/dL and −3.8 mmol/L −69 mg/dL, respectively; both, P < 0.001). With GLY+RSG, 9151 (17.6%) African American patients and 17/66 (25.8%) Hispanic American patients achieved HbA1c <7%, compared with 2/44 (4.5%) and 1/72 (1.4%) patients, respectively, who achieved this goal with GLY+PBO. Homeostasis model assessment estimates of insulin sensitivity and β-cell function were significantly improved with GLY+RSG compared with GIX+PBO (between-group Δs, 29.3% and 78.4%, respectively; both, P < 0.001). With regard to CVD biomarkers, there were potentially deleterious changes compared with baseline in the GLY+PBO group for CRP (+29.4%; P = 0.042), PAI-1 activity (+27.0%; P = 0.006), fibrinogen (+15.7%; P = 0.007), and sVCAM (+7.0%; P = 0.035), whereas there were no significant increases in these factors in the GLY+RSG group. In the GLY+RSG group, there were significant improvements in tPA (−17.8%; P < 0.001 ), vWF (−11.3%; P = 0.019), and UACR (−17.2%; P = 0.028) over 24 weeks' treatment, whereas there were no significant changes in any of these factors in the GLY+PBO group. As a result, significant treatment effects were observed for CRP (−29.2%; P = 0.019), tPA (−18.4%; P < 0.001), vWF (−12.9%; P < 0.015), and UACR (−26.7%; P = 0.006) with GLY+RSG compared with GLY+PBO. The most frequently reported AEs with GLY+RSG were edema and weight increase (both 121121 9.9% patients) and with GLY+PBO were upper respiratory tract infection (18/124 14.5% patients). AEs were reported in 83/121 (68.6%) patients in the GLY+RSG group, of which 6/121 (5.0%) were assessed as severe, compared with 70/124 ( 56.5 % ) patients who received GLY+PBO, of which 31124 (2.4%) were assessed as severe. Conclusion : Add-on rosiglitazone administered for 24 weeks was effective and well tolerated in these African American and Hispanic American patients with type 2 diabetes previously inadequately controlled on sulfonylurea monotherapy.
ABSTRACT
Objective: To compare the effects of rosiglitazone added to metformin with dose escalation of metformin on cardiovascular risk biomarkers in type 2 diabetes mellitus.
Research design and ...methods: Cardiovascular biomarkers were assessed in a sub-population of 122 subjects with type 2 diabetes mellitus (mean age 54.6 and 56.0 years, BMI 34.7 and 32.1 kg/m² for the rosiglitazone plus metformin and metformin groups, respectively) from the multicenter (63 centers in the USA), double-blind, randomized parallel-group Escalation of Metformin theraPy vs. Initiation of Rosiglitazone Early (EMPIRE) study. Treatment group sizes were slightly imbalanced owing to central, rather than local, randomization. Subjects receiving metformin 1000 mg/day at baseline were randomized to rosiglitazone 4 mg/day plus metformin 1000 mg/day (RSG + MET) or metformin 1500 mg/day (up-titrated MET) for 24 weeks. At 8‐weeks, rosiglitazone was increased to 8 mg/day in RSG + MET recipients and metformin to 2000 mg/day in up-titrated MET recipients.
Results: Reductions from baseline in HbA1c at week 24 (mean ± SD) occurred in both groups (RSG + MET: –0.61% ± 1.16%; up-titrated MET: –0.65% ± 1.18%). Post-prandial glucose levels (AUC0–3h) decreased with RSG + MET (–3.5 mmol/L.h; 95% confidence interval CI: –5.2 to –1.8) and up-titrated MET (–1.3 mmol/L.h; 95% CI: –3.8 to 1.1). Homeostasis Model Assessment (HOMA)-estimated insulin sensitivity increased by 37.7% (95% CI: 22.8 to 54.5) in RSG + MET and 6.9% (95% CI: –6.2 to 21.9) in up-titrated MET recipients. RSG + MET reduced C‐reactive protein (CRP; –23.9%; 95% CI: –40.4 to –2.8), plasminogen activator inhibitor‐1 (PAI‐1) activity (–30.1%; 95% CI: –44.5 to –11.9), PAI‐1 antigen (–15.5%; 95% CI: –28.3 to –0.3) and matrix metalloproteinase‐9 (MMP‐9; –13.8%; 95% CI: –25.1 to –0.9), but increased tumor necrosis factor‐α (TNF‐α; 27.0%; 95% CI: 6.8 to 50.9). Corresponding values for up-titrated MET were CRP –9.3% (95% CI: –36.9 to 30.2), PAI‐1 activity –7.2% (95% CI: –28.2 to 20.0), PAI‐1 antigen –1.5% (95% CI: –17.4 to 17.5), MMP‐9 29.0% (95% CI: –1.3 to 68.6) and TNF‐α –6.0% (95% CI: –22.0 to 13.2).
Conclusions: These results suggest that rosiglitazone plus metformin has positive cardiovascular effects against a background of similar glycemic improvements.
Optical imaging techniques such as spectral imaging show promise for the assessment of tissue health during surgery; however, the validation and translation of such techniques into clinical practise ...is limited by the lack of representative tissue models. In this paper, we demonstrate the application of an organ perfusion machine as an ex vivo tissue model for optical imaging. Three porcine livers are perfused at stepped blood oxygen saturations. Over the duration of each perfusion, spectral data of the tissue are captured via diffuse optical spectroscopy and multispectral imaging. These data are synchronised with blood oxygen saturation measurements recorded by the perfusion machine. Shifts in the optical properties of the tissue are demonstrated over the duration of the each perfusion, as the tissue becomes reperfused and as the oxygen saturation is varied.
Diapycnal mixing plays a primary role in the thermodynamic balance of the ocean and, consequently, in oceanic heat and carbon uptake and storage. Though observed mixing rates are on average ...consistent with values required by inverse models, recent attention has focused on the dramatic spatial variability, spanning several orders of magnitude, of mixing rates in both the upper and deep ocean. Away from ocean boundaries, the spatio-temporal patterns of mixing are largely driven by the geography of generation, propagation and dissipation of internal waves, which supply much of the power for turbulent mixing. Over the last five years and under the auspices of US CLIVAR, a NSF- and NOAA-supported Climate Process Team has been engaged in developing, implementing and testing dynamics-based parameterizations for internal-wave driven turbulent mixing in global ocean models. The work has primarily focused on turbulence 1) near sites of internal tide generation, 2) in the upper ocean related to wind-generated near inertial motions, 3) due to internal lee waves generated by low-frequency mesoscale flows over topography, and 4) at ocean margins. Here we review recent progress, describe the tools developed, and discuss future directions.
Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, ...open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population.
We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival.
The median overall survival was 9.2 months (95% confidence interval CI, 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P=0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group.
Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.).
PDF
