Sizing clinical trials when comparing bivariate time‐to‐event outcomes

Clinical trials with multiple primary time‐to‐event outcomes are common. Use of multiple endpoints creates challenges in the evaluation of power and the calculation of sample size during trial design particularly for time‐to‐event outcomes. We present methods for calculating the power and sample size for randomized superiority clinical trials with two correlated time‐to‐event outcomes. We do this for independent and dependent censoring for three censoring scenarios: (i) the two events are non‐fatal; (ii) one event is fatal (semi‐competing risk); and (iii) both are fatal (competing risk). We derive the bivariate log‐rank test in all three censoring scenarios and investigate the behavior of power and the required sample sizes. Separate evaluations are conducted for two inferential goals, evaluation of whether the test intervention is superior to the control on: (1) all of the endpoints (multiple co‐primary) or (2) at least one endpoint (multiple primary). Copyright © 2017 John Wiley & Sons, Ltd.     

Short-term outcomes of patients being treated for chronic intractable pain at a liaison clinic and exacerbating factors of prolonged pain after treatment

Background

Although a multidisciplinary approach is often recommended to treat intractable pain, this approach does not completely prevent uncontrolled pain in some patients. The aim of this retrospective study was to investigate the exacerbating factors of prolonged, intractable pain among patients being treated at a pain liaison clinic.

Denosumab and alendronate treatment in patients with back pain due to fresh osteoporotic vertebral fractures

Introduction

Denosumab specifically inhibits the receptor activator for nuclear factor-kappa B ligand (RANKL), and prevents osteoporotic fractures. Several reports have analyzed the effects of denosumab and alendronate alone on bone mineral density (BMD) or reduction of fracture risk. The objective of this study was to analyze the effects of antiresorptive osteoporosis pharmacotherapy on pain relief in patients with fresh vertebral fracture.

Chemical structures of constituents from the leaves of <Emphasis Type="Italic">Polyscias balfouriana</Emphasis>

A new pyrrolidine derivative, (5S)-hydroxyethyl 2-oxopyrrolidine-5-carboxylate (1), a new flavonol glycoside, tamaraxetin 3,7-di-O-α-l-rhamnopyranoside (2), and a new triterpene saponin, polyscioside A methyl ester (3), along with six known compounds (4–9) were isolated from the leaves of Polyscias balfouriana. Their chemical structures were elucidated on the basis of extensive spectroscopic analysis.     

Influence of nicotine on doxorubicin and cyclophosphamide combination treatment-induced spatial cognitive impairment and anxiety-like behavior in rats

Naunyn-Schmiedeberg's Archives of Pharmacology - In the present study, we examined the effects of nicotine on cognitive impairment, anxiety-like behavior, and hippocampal cell proliferation in...     

Correlation between parametric imaging using contrast ultrasound and the histological differentiation of hepatocellular carcinoma.

Aim: To determine whether parametric imaging correlates with the degree of histological differentiation of hepatocellular carcinoma (HCC). Methods: The samples comprised 49 nodules diagnosed histologically as HCC: 19 well differentiated (w-HCC), 22 moderately differentiated (m-HCC), and eight poorly differentiated (p-HCC). The ultrasound (US) equipment used was SSA-770 A (Toshiba Medical Systems, Otawara, Japan) and the contrast agent was SonoVue (Bracco, Milan, Italy). After 1.5 mL of SonoVue was injected intravenously and staining of the tumors and parenchyma was confirmed, microbubbles in the scanned volume were eliminated using high mechanical index (MI) scanning frames. The "arrival time (T(A)) images," reflecting beta-values, were displayed with color codes at the phase after reperfusion. Images at the phase when the staining reached a plateau (90-180 s) were used as "A images," reflecting A values. These images were compared between each histological grade of differentiation. Results: Analysis of T(A) images indicated that beta-values in m-HCC were higher than those in the adjacent non-tumor parenchyma in all 22 samples and also were significantly higher than in the other HCCs (P < 0.001 for w-HCC; P < 0.05 for p-HCC). Furthermore, beta-values in p-HCC samples had significantly larger variations in terms of time and space than in the other HCCs (P < 0.001 for w-HCC; P < 0.01 for m-HCC). Analysis of A images indicated that the A value for w-HCC was significantly higher than those for either m-HCC or p-HCC (P < 0.001). Conclusion: Both T(A) and A images were useful for diagnosing the histological differentiation of HCC.     

Modified two‐dimensional response as surrogate marker of overall survival in patients with metastatic colorectal cancer

The identification of surrogate markers for long‐term outcomes in patients with metastatic colorectal cancer (mCRC) may help in designing treatment regimens. The aim of this study was to assess whether two‐dimensional response (2‐DR) can serve as a new surrogate marker for overall survival (OS) in patients with mCRC. The study group consisted of 99 patients with mCRC from two independent cohorts who were treated with oxaliplatin‐based chemotherapy plus bevacizumab. Two‐dimensional response was defined as an area enclosed by coordinate points, including early tumor shrinkage at 8 weeks, depth of response at nadir, and 20% increase over nadir at progression. Each variable was weighted by its contribution rate to OS. The model was developed and internally validated in the learning cohort, and the performance of this model was externally verified in the validation cohort. Spearman correlation coefficients for 2‐DR and OS in the learning and validation cohorts were 0.593 and 0.661, respectively. The C‐indexes in predicting OS were 0.724 (95% confidence interval, 0.623–0.815) in the learning cohort and 0.762 (95% confidence interval, 0.651–0.873) in the validation cohort. Overall survival was significantly longer in patients with high 2‐DR values than in patients with low 2‐DR values in both the learning (37.0 vs. 24.1 months, P < 0.001) and validation (41.2 vs. 20.4 months, P < 0.001) cohorts. In contrast, differences in early tumor shrinkage and depth of response were not statistically significant. Multivariate analyses showed that 2‐DR was an independent prognostic factor for OS.