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An algebraic model for the kinetics of covalent enzyme inhibition at low substrate concentrations.

This article describes an integrated rate equation for the time course of covalent enzyme inhibition under the conditions where the substrate concentration is significantly lower than the corresponding Michaelis constant, for example, in the Omnia assays of epidermal growth factor receptor (EGFR) kinase. The newly described method is applicable to experimental conditions where the enzyme concentration is significantly lower than the dissociation constant of the initially formed reversible enzyme-inhibitor complex (no &quot;tight binding&quot;). A detailed comparison with the traditionally used rate equation for covalent inhibition is presented. The two methods produce approximately identical values of the first-order inactivation rate constant (kinact). However, the inhibition constant (Ki), and therefore also the second-order inactivation rate constant kinact/Ki, is underestimated by the traditional method by up to an order of magnitude.
Copyright © 2014. Published by Elsevier Inc.

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Comparison of medical costs and healthcare resource utilization of post-menopausal women with HR+/HER2- metastatic breast cancer receiving everolimus-based therapy or chemotherapy: a retrospective claims database analysis.

To analyze medical costs and healthcare resource utilization (HRU) associated with everolimus-based therapy or chemotherapy among post-menopausal women with hormone-receptor-positive, human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC).
Patients with HR+/HER2- mBC who discontinued a non-steroidal aromatase inhibitor and began a new line of treatment with everolimus-based therapy or chemotherapy (index therapy/index date) between July 20, 2012 and April 30, 2014 were identified from two large claims databases. All-cause, BC-related, and adverse event (AE)-related medical costs (in 2014 USD) and all-cause HRU per patient per month (PPPM) were analyzed for both treatment groups across patients’ first four lines of therapies for mBC. Adjusted differences in costs and HRU between the everolimus and chemotherapy treatment group were estimated pooling all lines and using multivariable generalized linear models, accounting for difference in patient characteristics.
A total of 3298 patients were included: 902 everolimus-treated patients and 2636 chemotherapy-treated patients. Compared to chemotherapy, everolimus was associated with significantly lower all-cause (adjusted mean difference = $3455, p &lt; 0.01) and BC-related ($2510, p &lt; 0.01) total medical costs, with inpatient ($1344, p &lt; 0.01) and outpatient costs ($1048, p &lt; 0.01) as the main drivers for cost differences. Everolimus was also associated with significantly lower AE-related medical costs ($1730, p &lt; 0.01), as well as significantly lower HRU (emergency room incidence rate ratio [IRR] = 0.83; inpatient IRR = 0.74; inpatient days IRR = 0.65; outpatient IRR = 0.71; BC-related outpatient IRR = 0.57; all p &lt; 0.01).
This retrospective claims database analysis of commercially-insured patients with HR+/HER2- mBC in the US showed that everolimus was associated with substantial all-cause, BC-related, and AE-related medical cost savings and less utilization of healthcare resources relative to chemotherapy.

Prevalence and predictors of non-evidence based proton pump inhibitor use among elderly nursing home residents in the US.

Proton pump inhibitors (PPIs) can lead to several adverse effects among the elderly, particularly when used inappropriately or in contrast to evidence suggested protocols.
The aim of this study was to examine the prevalence and predictors of non-evidence based PPI use in elderly nursing home residents.
A cross-sectional study was conducted using data from the 2004 National Nursing Home Survey (NNHS). The study sample included nursing home residents 65 years and older. Descriptive statistics were used to examine the prevalence of non-evidence based PPI use. Multivariable logistic regression was used to evaluate the patient and facility-level factors associated with non-evidence based PPI use among the elderly nursing home residents.
A total of 355,600 elderly nursing home residents received at least one PPI for an overall prevalence of 26.99%. Among those elderly receiving PPIs, 48.59% of the use was not evidence based. Multivariable logistic regression revealed that residents with osteoporosis (Odds Ratio (OR): 0.55, 95% CI: 0.45-0.68), SSRI users (OR: 0.81, 95% CI: 0.68-0.97) and those residing in micropolitan area (OR: 0.79, 95% CI: 0.63-0.98) were negatively associated with prescription of PPIs without an indication. Patients with chronic cough (OR: 2.10, 95% CI: 1.12-3.96) and Medicare insurance (OR: 1.23, 95% CI: 1.01-1.50) were positively associated with prescription of PPIs without an indication.
The current study found that almost half of the elderly nursing home residents used PPIs for non-evidence based indications. Given the safety concerns and high non-evidence based use of PPIs in nursing homes, there is an urgent need to optimize PPI use in the elderly.
Copyright © 2016 Elsevier Inc. All rights reserved.

Improved inter-observer agreement of an expert review panel in an oncology treatment trial–Insights from a structured interventional process.

Oncologic imaging is a key for successful cancer treatment. While the quality assurance (QA) of image acquisition protocols has already been focussed, QA of reading and reporting offers still room for improvement. The latter was addressed in the context of a prospective multicentre trial on fluoro-deoxyglucose (FDG)-positron-emission tomography (PET)/CT-based chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC).
An expert panel was prospectively installed performing blinded reviews of mediastinal NSCLC involvement in FDG-PET/CT. Due to a high initial reporting inter-observer disagreement, the independent data monitoring committee (IDMC) triggered an interventional harmonisation process, which overall involved 11 experts uttering 6855 blinded diagnostic statements. After assessing the baseline inter-observer agreement (IOA) of a blinded re-review (phase 1), a discussion process led to improved reading criteria (phase 2). Those underwent a validation study (phase 3) and were then implemented into the study routine. After 2 months (phase 4) and 1 year (phase 5), the IOA was reassessed.
The initial overall IOA was moderate (kappa 0.52 CT; 0.53 PET). After improvement of reading criteria, the kappa values improved substantially (kappa 0.61 CT; 0.66 PET), which was retained until the late reassessment (kappa 0.71 CT; 0.67 PET). Subjective uncertainty was highly predictive for low IOA.
The IOA of an expert panel was significantly improved by a structured interventional harmonisation process which could be a model for future clinical trials. Furthermore, the low IOA in reporting nodal involvement in NSCLC may bear consequences for individual patient care.
Copyright © 2015 Elsevier Ltd. All rights reserved.

T Cells as Antigen Carriers for Anti-tumor Vaccination.

The exploitation of the physiologic processing and presenting machinery of dendritic cells (DCs) by in vivo loading of tumor-associated antigens may improve the immunogenic potential and clinical efficacy of DC-based cancer vaccines. The approach developed by our group was based on the clinical observation that some patients treated with the infusion of donor lymphocytes transduced to express the HSV-TK suicide gene for relapse of hematologic malignancies, after allogeneic hematopoietic stem cell transplantation, developed a T cell-mediated immune response specifically directed against the HSV-TK gene product.We demonstrated that lymphocytes genetically modified to express HSV-TK as well as self/tumor antigens, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice. The infusion of TRP-2-transduced lymphocytes induced the establishment of protective immunity and long-term memory in tumor-bearing mice by cross-presentation of the antigen mediated by the CD11c(+)CD8a(+) DCs subset. A similar approach was applied in a clinical setting. Ten patients affected by MAGE-3(+) metastatic melanoma were treated with autologous lymphocytes retrovirally transduced to express the MAGE-3 tumor antigen. In three patients, the treatment led to the increase of MAGE-3 specific CD8+ and CD4+ effectors and the development of long-term memory, which ultimately correlated with a favorable clinical outcome. Transduced lymphocytes represent an efficient way for in vivo loading of tumor-associated antigens of DCs.

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An algebraic model for the kinetics of covalent enzyme inhibition at low substrate concentrations.

Comparison of medical costs and healthcare resource utilization of post-menopausal women with HR+/HER2- metastatic breast cancer receiving everolimus-based therapy or chemotherapy: a retrospective claims database analysis.

Prevalence and predictors of non-evidence based proton pump inhibitor use among elderly nursing home residents in the US.

Improved inter-observer agreement of an expert review panel in an oncology treatment trial–Insights from a structured interventional process.

T Cells as Antigen Carriers for Anti-tumor Vaccination.