Dose finding with drug combinations in cancer phase I clinical trials using conditional escalation with overdose control

We present a Bayesian adaptive design for dose finding of a combination of two drugs in cancer phase I clinical trials. The goal is to estimate the maximum tolerated dose (MTD) as a curve in the two‐dimensional Cartesian plane. We use a logistic model to describe the relationship between the doses of the two agents and the probability of dose limiting toxicity. The model is re‐parameterized in terms of parameters clinicians can easily interpret. Trial design proceeds using univariate escalation with overdose control, where at each stage of the trial, we seek a dose of one agent using the current posterior distribution of the MTD of this agent given the current dose of the other agent. At the end of the trial, an estimate of the MTD curve is proposed as a function of Bayes estimates of the model parameters. We evaluate design operating characteristics in terms of safety of the trial design and percent of dose recommendation at dose combination neighborhoods around the true MTD curve. We also examine the performance of the approach under model misspecifications for the true dose–toxicity relationship. Copyright © 2014 John Wiley & Sons, Ltd.     

Thymosin alpha 1: A comprehensive review of the literature

Thymosin alpha 1 is a peptide naturally occurring in the thymus that has long been recognized for modifying, enhancing, and restoring immune function. Thymosin alpha 1 has been utilized in the treatment of immunocompromised states and malignancies, as an enhancer of vaccine response, and as a means of curbing morbidity and mortality in sepsis and numerous infections. Studies have postulated that thymosin alpha 1 could help improve the outcome in severely ill corona virus disease 2019 patients by repairing damage caused by overactivation of lymphocytic immunity and how thymosin alpha 1 could prevent the excessive activation of T cells. In this review, we discuss key literature on the background knowledge and current clinical uses of thymosin alpha 1. Considering the known biochemical properties including antibacterial and antiviral properties, time-honored applications, and the new promising findings regarding the use of thymosin, we believe that thymosin alpha 1 deserves further investigation into its antiviral properties and possible repurposing as a treatment against severe acute respiratory syndrome coronavirus-2.     

Synergistic effect between CD40 and class II signals overcome the requirement for class II dimerization in superantigen-induced cytokine gene expression

Although staphylococcal enterotoxin A (SEA), B (SEB), and toxic shock syndrome toxin 1 (TSST-1) bind to major histocompatibility complex (MHC) class II molecules, they differ in their mode of binding. Signaling induced by these toxins via MHC class II molecules seems to be largely mediated by their mode of interaction. In the present study, we have demonstrated that contrary to SEA, stimulation of the human monocytic cell line THP-1 with SEB or TSST-1 failed to induce interleukin-1β or tumor necrosis factor-α gene expression. Treatment of THP-1 cells with interferon-γ increased the level of MHC class II expression but did not enhance the SEB and TSST-1 response. However, cross-linking of SEB or TSST-1 bound to MHC class II molecules with specific antibodies leads to cytokine gene expression, indicating that dimerization of class II molecules is a requirement for this superantigen-induced response. The presence of anti-CD40 antibodies in the course of SEB or TSST-1 stimulation overcomes this requirement, indicating that certain signal(s) induced via CD40 molecules can replace those induced by dimerization of class II molecules. Pretreatment with anti-lymphocyte functional antigen-1 (LFA-1) antibodies completely inhibited SEA-induced response as well as that induced by SEB or TSST-1 in the presence of CD40 antibodies, supporting the involvement of LFA-1 intercellular adhesion molecule system in these responses. The entirety of these results demonstrate clearly that dimerization of class II molecules is a prerequisite for superantigen-induced T cell-independent cytokine gene expression which can be replaced by signaling via CD40 in an LFA-1-dependent system.     

Diffusion-weighted MR imaging of the liver of hepatitis C patients

Magnetic resonance diffusion-weighted imaging (DWI) of the liver was investigated to determine whether this method could be used to differentiate between the stages of fibrosis and inflammation for hepatitis C viral infection. DWI data were recorded for 18 hepatitis C patients and 10 control subjects using a modified pulse sequence allowing a 52 ms echo time delay. Acquisitions were performed with breath holding using five different b gradient factor values ranging between 50 and 250 s/mm(2) and in the three axes. Apparent diffusion coefficient (ADC) values were measured from a 5.7 cm(2) area in the central region of the liver. The inflammation and fibrosis grades were evaluated histologically on a biopsy sample. The mean ADC values were 2.30 +/- 1.28 x 10(-3) and 1.79 +/- 0.25 x 10(-3) mm(2)/s for hepatitis C patients and control subjects, respectively. Using our technique, no correlation could be found between the ADC values and the inflammation or fibrosis scores, indicating that tissue changes produced by hepatitis C do not appear to be quantifiable by DWI.     

Hepatic and pancreatic involvement in hereditary hemorrhagic telangiectasia: quantitative and qualitative evaluation with 64-section CT in asymptomatic adult patients

Purpose  

To analyse quantitatively and qualitatively asymptomatic hepatic and pancreatic involvement in hereditary haemorrhagic telangiectasia (HHT) using 64-section helical CT.     

Automated segmentation of the aorta from phase contrast MR images: Validation against expert tracing in healthy volunteers and in patients with a dilated aorta

Purpose:

To assess if segmentation of the aorta can be accurately achieved using the modulus image of phase contrast (PC) magnetic resonance (MR) acquisitions.

Materials and Methods:

PC image sequences containing both the ascending and descending aorta of 52 subjects were acquired using three different MR scanners. An automated segmentation technique, based on a 2D+t deformable surface that takes into account the features of PC aortic images, such as flow‐related effects, was developed. The study was designed to: 1) assess the variability of our approach and its robustness to the type of MR scanner, and 2) determine its sensitivity to aortic dilation and its accuracy against an expert manual tracing.

Results:

Interobserver variability in the lumen area was 0.59 ± 0.92% for the automated approach versus 10.09 ± 8.29% for manual segmentation. The mean Dice overlap measure was 0.945 ± 0.014. The method was robust to the aortic size and highly correlated (r = 0.99) with the manual tracing in terms of aortic area and diameter.

Conclusion:

A fast and robust automated segmentation of the aortic lumen was developed and successfully tested on images provided by various MR scanners and acquired on healthy volunteers as well as on patients with a dilated aorta. J. Magn. Reson. Imaging 2010;31:881–888. ©2010 Wiley‐Liss, Inc.     

Supervising the Supervisors—Procedural Training and Supervision in Internal Medicine Residency

BACKGROUND  

At teaching hospitals, bedside procedures (paracentesis, thoracentesis, lumbar puncture, arthrocentesis and central venous catheter insertion) are performed by junior residents and supervised by senior peers. Residents’ perceptions about supervision or how often peer supervision produces unsafe clinical situations are unknown.