Phase I and pharmacokinetic study of DE-310 in patients with advanced solid tumors

PURPOSE: To assess the maximum-tolerated dose, toxicity, and pharmacokinetics of DE-310, a macromolecular prodrug of the topoisomerase I inhibitor exatecan (DX-8951f). in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients received DE-310 as a 3-hour infusion once every 2 weeks (dose, 1.0-2.0 mg/m(2)) or once every 6 weeks (dose, 6.0-9.0 mg/m(2)). Because pharmacokinetics revealed a drug terminal half-life exceeding the 2 weeks administration interval, the protocol was amended to a 6-week interval between administrations also based on available information from a parallel trial using an every 4 weeks schedule. Conjugated DX-8951 (the carrier-linked molecule), and the metabolites DX-8951 and glycyl-DX-8951 were assayed in various matrices up to 35 days post first and second dose. RESULTS: Twenty-seven patients were enrolled into the study and received a total of 86 administrations. Neutropenia and grade 3 thrombocytopenia, and grade 3 hepatotoxicity with veno-occlusive disease, were dose-limiting toxicities. Other hematologic and nonhematologic toxicities were mild to moderate and reversible. The apparent half-life of conjugated DX-8951, glycyl-DX-8951, and DX-8951 was 13 days. The area under the curve ratio for conjugated DX-8951 to DX-8951 was 600. No drug concentration was detectable in erythrocytes, skin, and saliva, although low levels of glycyl-DX-8951 and DX-8951 were detectable in tumor biopsies. One patient with metastatic adenocarcinoma of unknown primary achieved a histologically proven complete remission. One confirmed partial remission was observed in a patient with metastatic pancreatic cancer and disease stabilization was noted in 14 additional patients. CONCLUSIONS: The recommended phase II dose of DE-310 is 7.5 mg/m(2) given once every 6 weeks. The active moiety DX-8951 is released slowly from DE-310 and over an extended period, achieving the desired prolonged exposure to this topoisomerase I inhibitor

R squared effect-size measures and overlap between direct and indirect effect in mediation analysis

In a recent article in this journal (Fairchild, MacKinnon, Taborga & Taylor, 2009), a method was described for computing the variance accounted for by the direct effect and the indirect effect in mediation analysis. However, application of this method leads to counterintuitive results, most notably that in some situations in which the direct effect is much stronger than the indirect effect, the latter appears to explain much more variance than the former. The explanation for this is that the Fairchild et al. method handles the strong interdependence of the direct and indirect effect in a way that assigns all overlap variance to the indirect effect. Two approaches for handling this overlap are discussed, but none of them is without disadvantages

Marine Low Cloud Sensitivity to An Idealized Climate Change: The CGILS LES Intercomparison

Subtropical marine low cloud sensitivity to an idealized climate change is compared in six large-eddy simulation (LES) models as part of CGILS. July cloud cover is simulated at three locations over the subtropical northeast Pacific Ocean, which are typified by cold sea surface temperatures (SSTs) under well-mixed stratocumulus, cool SSTs under decoupled stratocumulus, and shallow cumulus clouds overlying warmer SSTs. The idealized climate change includes a uniform 2 K SST increase with corresponding moist-adiabatic warming aloft and subsidence changes, but no change in free-tropospheric relative humidity, surface wind speed, or CO2. For each case, realistic advective forcings and boundary conditions are generated for the control and perturbed states which each LES runs for 10 days into a quasi-steady state. For the control climate, the LESs correctly produce the expected cloud type at all three locations. With the perturbed forcings, all models simulate boundary-layer deepening due to reduced subsidence in the warmer climate, with less deepening at the warm-SST location due to regulation by precipitation. The models do not show a consistent response of liquid water path and albedo in the perturbed climate, though the majority predict cloud thickening (negative cloud feedback) at the cold-SST location and slight cloud thinning (positive cloud feedback) at the cool-SST and warm-SST locations. In perturbed climate simulations at the cold-SST location without the subsidence decrease, cloud albedo consistently decreases across the models. Thus, boundary-layer cloud feedback on climate change involves compensating thermodynamic and dynamic effects of warming and may interact with patterns of subsidence change

Marine Low Cloud Sensitivity to An Idealized Climate Change: The CGILS LES Intercomparison

Subtropical marine low cloud sensitivity to an idealized climate change is compared in six large-eddy simulation (LES) models as part of CGILS. July cloud cover is simulated at three locations over the subtropical northeast Pacific Ocean, which are typified by cold sea surface temperatures (SSTs) under well-mixed stratocumulus, cool SSTs under decoupled stratocumulus, and shallow cumulus clouds overlying warmer SSTs. The idealized climate change includes a uniform 2 K SST increase with corresponding moist-adiabatic warming aloft and subsidence changes, but no change in free-tropospheric relative humidity, surface wind speed, or CO2. For each case, realistic advective forcings and boundary conditions are generated for the control and perturbed states which each LES runs for 10 days into a quasi-steady state. For the control climate, the LESs correctly produce the expected cloud type at all three locations. With the perturbed forcings, all models simulate boundary-layer deepening due to reduced subsidence in the warmer climate, with less deepening at the warm-SST location due to regulation by precipitation. The models do not show a consistent response of liquid water path and albedo in the perturbed climate, though the majority predict cloud thickening (negative cloud feedback) at the cold-SST location and slight cloud thinning (positive cloud feedback) at the cool-SST and warm-SST locations. In perturbed climate simulations at the cold-SST location without the subsidence decrease, cloud albedo consistently decreases across the models. Thus, boundary-layer cloud feedback on climate change involves compensating thermodynamic and dynamic effects of warming and may interact with patterns of subsidence change

CGILS: Results From The First Phase of An International Project to Understand The Physical Mechanisms of Low Cloud Feedbacks in Single Column Models

CGILS—the CFMIP-GASS Intercomparison of Large Eddy Models (LESs) and single column models (SCMs)—investigates the mechanisms of cloud feedback in SCMs and LESs under idealized climate change perturbation. This paper describes the CGILS results from 15 SCMs and 8 LES models. Three cloud regimes over the subtropical oceans are studied: shallow cumulus, cumulus under stratocumulus, and well-mixed coastal stratus/stratocumulus. In the stratocumulus and coastal stratus regimes, SCMs without activated shallow convection generally simulated negative cloud feedbacks, while models with active shallow convection generally simulated positive cloud feedbacks. In the shallow cumulus alone regime, this relationship is less clear, likely due to the changes in cloud depth, lateral mixing, and precipitation or a combination of them. The majority of LES models simulated negative cloud feedback in the well-mixed coastal stratus/stratocumulus regime, and positive feedback in the shallow cumulus and stratocumulus regime. A general framework is provided to interpret SCM results: in a warmer climate, the moistening rate of the cloudy layer associated with the surface-based turbulence parameterization is enhanced; together with weaker large-scale subsidence, it causes negative cloud feedback. In contrast, in the warmer climate, the drying rate associated with the shallow convection scheme is enhanced. This causes positive cloud feedback. These mechanisms are summarized as the “NESTS” negative cloud feedback and the “SCOPE” positive cloud feedback (Negative feedback from Surface Turbulence under weaker Subsidence—Shallow Convection PositivE feedback) with the net cloud feedback depending on how the two opposing effects counteract each other. The LES results are consistent with these interpretations

Measuring the depth of invasion in vulvar squamous cell carcinoma: interobserver agreement and pitfalls

Aims: The depth of invasion is an important prognostic factor for patients with vulvar squamous cell carcinoma (SCC). The threshold of 1 mm distinguishes between FIGO stages IA and ≥IB disease and guides the need for groin surgery. Therefore, high interobserver agreement is crucial. The conventional and the alternative method are described to measure the depth of invasion. The aims of this study were to assess interobserver agreement for classifying the depth of invasion using both methods and to identify pitfalls. Methods and results: Fifty slides of vulvar SCC with a depth of invasion approximately 1 mm were selected, digitally scanned and independently assessed by 10 pathologists working in a referral or oncology centre and four pathologists in training. The depth of invasion was measured using both the conventional and alternative method in each slide and categorised into ≤1 and >1 mm. The percentage of agreement and Light’s kappa for multi-rater agreement were calculated, and 95% confidence intervals were calculated by bootstrapping (1000 runs). The agreement using the conventional method was moderate (κ = 0.57, 95% confidence interval = 0.45–0.68). The percentage of agreement among the participating pathologists using the conventional method was 85.0% versus 89.4% using the alternative method. Six pitfalls were identified: disagreement concerning which invasive nest is deepest, recognition of invasive growth and where it starts, curved surface, carcinoma situated on the edge of the tis

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]