Direct Aryloxylation/Alkyloxylation of Dialkyl Phosphonates for the Synthesis of Mixed Phosphonates.

A strategy for the direct functionalization strategy of inertial dialkyl phosphonates with hydroxy compounds to afford diverse mixed phosphonates with good yields and functional-group tolerance has been developed. Mechanistic investigations involving both NMR studies and DFT studies suggest that an unprecedented highly reactive P species (phosphoryl pyridin-1-ium salt), a key intermediate for this new synthetic transformation, is generated in situ from dialkyl phosphonate in the presence of Tf O/pyridine.

Meta-analysis examining impact of age on overall survival with pemetrexed for the treatment of advanced non-squamous non-small cell lung cancer.

Objective: In clinical practice, elderly patients are often undertreated relative to younger patients. This meta-analysis was designed to determine whether older patients with non-squamous non-small cell lung cancer (NSCLC) could derive an overall survival (OS) benefit from pemetrexed treatment comparable to that experienced by younger patients in the first-line, second-line, or maintenance settings.

Methods: Data from 2671 patients with non-squamous NSCLC participating in four pemetrexed phase III studies were included in a meta-analysis using a random-effects model.

Comparison of KRAS genotype: therascreen assay vs. LNA-mediated qPCR clamping assay.

Background: Kirsten rat sarcoma virus (KRAS) wild-type status determined using a locked nucleic acid (LNA)-mediated quantitative polymerase chain reaction (qPCR) clamping assay (LNA assay) predicted response to therapy in the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) study. A companion KRAS diagnostic tool has been developed for routine clinical use (QIAGEN therascreen kit) (QIAGEN Manchester Ltd, Manchester, UK). We wanted to assess the concordance between the validated US Food and Drug Administration (FDA)-approved therascreen assay and the LNA assay in determining the KRAS status of a subset of patients enrolled in the CRYSTAL study.

Missing data and censoring in the analysis of progression-free survival in oncology clinical trials.

Progression-free survival (PFS) is increasingly used as a primary endpoint in oncology clinical trials. However, trial conduct is often such that PFS data on some patients may be partially missing either due to incomplete follow-up for progression, or due to data that may be collected but confounded by patients stopping randomized therapy or starting alternative therapy prior to progression. Regulatory guidance on how to handle these patients in the analysis and whether to censor these patients differs between agencies.

Attenuation of treatment effect due to measurement variability in assessment of progression-free survival.

For normally distributed data analyzed with linear models, it is well known that measurement error on an independent variable leads to attenuation of the effect of the independent variable on the dependent variable. However, for time-to-event variables such as progression-free survival (PFS), the effect of the measurement variability in the underlying measurements defining the event is less well understood. We conducted a simulation study to evaluate the impact of measurement variability in tumor assessment on the treatment effect hazard ratio for PFS and on the median PFS time, for different tumor assessment frequencies.

Subgroup identification based on differential effect search--a recursive partitioning method for establishing response to treatment in patient subpopulations.

We propose a novel recursive partitioning method for identifying subgroups of subjects with enhanced treatment effects based on a differential effect search algorithm. The idea is to build a collection of subgroups by recursively partitioning a database into two subgroups at each parent group, such that the treatment effect within one of the two subgroups is maximized compared with the other subgroup. The process of data splitting continues until a predefined stopping condition has been satisfied.

Research outcomes and recommendations for the assessment of progression in cancer clinical trials from a PhRMA working group.

Purpose: Progression free survival (PFS) is increasingly used as a primary end-point in oncology clinical trials. This paper provides recommendations for optimal trial design, conduct and analysis in situations where PFS has the potential to be an acceptable end-point for regulatory approval.

Patients And Methods: These recommendations are based on research performed by the Pharmaceutical Research and Manufacturers Association (PhRMA) sponsored PFS Working Group, including the re-analysis of 28 randomised Phase III trials from 12 companies/institutions.

Blinded independent central review of progression in cancer clinical trials: results from a meta-analysis.

Purpose: Progression free survival (PFS) is increasingly used as a primary end-point in oncology clinical trials. This paper provides observations and recommendations on the use of a blinded independent central review (BICR) for progression.

Patients And Methods: The findings and recommendations are based on extensive simulations and a meta-analysis based on 27 previously conducted randomised phase III trials with BICR performed by the Pharmaceutical Research and Manufacturers Association (PhRMA) sponsored PFS Independent Review Working Group.

A two-stage sample size recalculation procedure for placebo- and active-controlled non-inferiority trials.

Many non-inferiority trials of a test treatment versus an active control may also, if ethical, incorporate a placebo arm. Inclusion of a placebo arm enables a direct assessment of assay sensitivity. It also allows construction of a non-inferiority test that avoids the problematic specification of an absolute non-inferiority margin, and instead evaluates whether the test treatment preserves a pre-specified proportion of the effect of the active control over placebo.

Semen and sperm reference ranges for men 45 years of age and older.

The most widely used reference values for human semen and sperm variables were developed by the World Health Organization (WHO) to help assess the fertility status of men interested in reproduction (typically a younger population). In this retrospective analysis, data from a large population of men aged 45 years or older were analyzed to derive semen and sperm reference ranges for an older population. Baseline semen samples were obtained from 1174 men with no or mild erectile dysfunction (ED) during the screening phase of two clinical trials evaluating the effects of a drug on human spermatogenesis.

Portal vein thrombosis after laparoscopic gastric bypass.

Splanchnic vessel thrombosis has been described after several laparoscopic operations. However, this complication to date has not been reported after laparoscopic gastric bypass. We present and discuss a case of a patient who developed vague abdominal complaints 3 weeks after laparoscopic gastric bypass, and was diagnosed with portal venous thrombosis by computed tomography.

Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: analysis of data from tadalafil clinical trials.

Aims/hypothesis: A retrospective analysis of pooled data from twelve placebo-controlled trials was conducted to characterise the efficacy and safety of tadalafil for the treatment of erectile dysfunction in men with diabetes compared with that in men without diabetes.

Methods: Patients were randomly allocated to tadalafil 10 mg, 20 mg, or placebo, taken as needed for 12 weeks. The study population comprised 637 men with diabetes (mean age 57 years) and 1681 men without diabetes (mean age 56 years).

The efficacy and safety of tadalafil: an update.

Objective: To provide an update on the efficacy and safety of tadalafil, a phosphodiesterase-5 inhibitor, in the treatment of erectile dysfunction (ED).

Patients And Methods: In all, 2102 men (mean age 56 years) with mild-to-severe ED of various causes were randomized to placebo or tadalafil, taken as needed with no food restrictions, at fixed 'on-demand' doses of 10 or 20 mg in 11 randomized, double-blind, placebo-controlled trials lasting 12 weeks. The three co-primary outcomes were changes from baseline in the erectile function domain of the International Index of Erectile Function (IIEF) and the proportion of 'yes' responses to questions 2 and 3 of the Sexual Encounter Profile (SEP).

A multicenter, randomized, double-blind, crossover study to evaluate patient preference between tadalafil and sildenafil.

Purpose: To assess patient preference for erectile dysfunction treatment between either sildenafil or tadalafil, each administered with their respective dosing instructions, and to evaluate preference for either sildenafil or tadalafil dosing instructions during tadalafil therapy.

Methods: We conducted a randomized, double-blind, crossover study consisting of four treatment arms. Because the dosing instructions for sildenafil and tadalafil are different, a unique methodology using sham placebo arms was employed to maintain the blind.

Long-term safety and tolerability of tadalafil in the treatment of erectile dysfunction.

Objective: To assess the long-term safety and tolerability of tadalafil for patients with erectile dysfunction (ED).

Patients And Methods: This was a multicentre, open-label, 24-month extension trial involving 1173 men with ED. The mean age was 57 (range 23-83) years and 74.

A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction.

Background: Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor approved in >30 countries for the treatment of erectile dysfunction (ED). It has been shown to improve erectile function compared with placebo in Phase III studies, but clinical experience comparing tadalafil with the PDE5 inhibitor sildenafil citrate is lacking.

Objective: This study compared patient preference for tadalafil 20 mg or sildenafil 50 mg during initial treatment for ED.

Time course of the interaction between tadalafil and nitrates.

Objectives: This study was designed to determine the time course of nitrate interaction with tadalafil, a phosphodiesterase 5 (PDE5) inhibitor with a half-life (t(1/2)) of 17.5 h.

Background: The PDE5 inhibitors augment the blood pressure (BP)-lowering effects of nitrates, yet the time course of this interaction is unclear.

Sample-size redetermination for repeated measures studies.

Clinical trialists recently have shown interest in two-stage procedures for updating the sample-size calculation at an interim point in a trial. Because many clinical trials involve repeated measures designs, it is desirable to have available practical two-stage procedures for such designs. Shih and Gould (1995, Statistics in Medicine 14, 2239-2248) discuss sample-size redetermination for repeated measures studies but under a highly simplified setup.

Overview of EPA Superfund human health research program.

This paper presents major research needs for the Superfund program, and provides an overview of the EPA Office of Research and Development's (ORDs) current human health research program designed to fill some of those data gaps. Research is presented in terms of the risk paradigm and covers exposure, effects, and assessment activities directly funded by Superfund, as well as research not funded by Superfund but directly applicable to Superfund research needs. Research on risk management is not covered.

Monitoring a clinical trial with multiple hypotheses concerning the treatment effect on a single primary endpoint.

In a number of clinical trials there is interest in testing more than one hypothesis concerning the treatment effect on a single primary endpoint. For instance, a sponsor of a trial to demonstrate that a test treatment (T) is non-inferior to an active control (R) may also be interested in showing that T is superior to R, if this is the case. Using the closed testing method for constructing tests of multiple hypotheses which control the multiple level of significance, we provide a framework for testing these hypotheses sequentially during a trial at pre-planned interim analyses.

Sample size recalculation using conditional power.

The sample size required to achieve a given power at a prespecified absolute difference in mean response may depend on one or more nuisance parameters, which are usually unknown. Proposed methods for using an internal pilot to recalculate the sample size using estimates of these parameters have been well studied. Most of these methods ignore the fact that data on the parameter of interest from within this internal pilot will contribute towards the value of the final test statistic.

Estimation following extension of a study on the basis of conditional power.

Proschan and Hunsberger (1) propose a method based on conditional power for designed extension of a study beyond its originally intended sample size. Their data-dependent sampling method can be viewed as a two-stage procedure in which the target total sample size is dependent upon the data observed at the first stage. We demonstrate that the maximum likelihood estimate of the parameter of interest upon completion may be biased, and that this bias is similar in direction and magnitude to that commonly associated with estimation following a group sequential test with predetermined target total sample size.

Estimating the sample size for a t-test using an internal pilot.

If the sample size for a t-test is calculated on the basis of a prior estimate of the variance then the power of the test at the treatment difference of interest is not robust to misspecification of the variance. We propose a t-test for a two-treatment comparison based on Stein's two-stage test which involves the use of an internal pilot to estimate variance and thus the final sample size required. We evaluate our procedure's performance and show that it controls the type I and II error rates more closely than existing methods for the same problem.

The determinants of iron status in early pregnancy.

In pregnancy, the additional demands for Fe are thought to be met principally through increased maternal dietary Fe absorption and by mobilization of maternal Fe stores. In a general population sample of 576 women we examined the maternal and dietary characteristics which influenced Fe stores (assessed by serum ferritin concentration) in early pregnancy. The effects of these characteristics on two measures of functional Fe status (mean cell volume and haemoglobin concentration) were also considered.