Uncategorized – Page 15973 – 1stOncology™: Cancer Intelligence Service

Construction of a Sequencing Library from Circulating Cell-Free DNA.

Circulating DNA is cell-free DNA (cfDNA) in serum or plasma that can be used for non-invasive prenatal testing, as well as cancer diagnosis, prognosis, and stratification. High-throughput sequence analysis of the cfDNA with next-generation sequencing technologies has proven to be a highly sensitive and specific method in detecting and characterizing mutations in cancer and other diseases, as well as aneuploidy during pregnancy. This unit describes detailed procedures to extract circulating cfDNA from human serum and plasma and generate sequencing libraries from a wide concentration range of circulating DNA. © 2016 by John Wiley &amp; Sons, Inc.
Copyright © 2016 John Wiley &amp; Sons, Inc.

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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.

[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity.

Deoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds-[(18)F]Clofarabine; 2-chloro-2′-deoxy-2′-[(18)F]fluoro-9-β-d-arabinofuranosyl-adenine ([(18)F]CFA) and 2′-deoxy-2′-[(18)F]fluoro-9-β-d-arabinofuranosyl-guanine ([(18)F]F-AraG)-for dCK and deoxyguanosine kinase (dGK), a dCK-related mitochondrial enzyme. We demonstrate that, in the tracer concentration range used for PET imaging, [(18)F]CFA is primarily a substrate for dCK, with minimal cross-reactivity. In contrast, [(18)F]F-AraG is a better substrate for dGK than for dCK. [(18)F]CFA accumulation in leukemia cells correlated with dCK expression and was abrogated by treatment with a dCK inhibitor. Although [(18)F]CFA uptake was reduced by deoxycytidine (dC) competition, this inhibition required high dC concentrations present in murine, but not human, plasma. Expression of cytidine deaminase, a dC-catabolizing enzyme, in leukemia cells both in cell culture and in mice reduced the competition between dC and [(18)F]CFA, leading to increased dCK-dependent probe accumulation. First-in-human, to our knowledge, [(18)F]CFA PET/CT studies showed probe accumulation in tissues with high dCK expression: e.g., hematopoietic bone marrow and secondary lymphoid organs. The selectivity of [(18)F]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [(18)F]CFA PET as a new cancer biomarker for treatment stratification and monitoring.

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.

A high-content EMT screen identifies multiple receptor tyrosine kinase inhibitors with activity on TGFβ receptor.

An epithelial to mesenchymal transition (EMT) enables epithelial tumor cells to break out of the primary tumor mass and to metastasize. Understanding the molecular mechanisms driving EMT in more detail will provide important tools to interfere with the metastatic process. To identify pharmacological modulators and druggable targets of EMT, we have established a novel multi-parameter, high-content, microscopy-based assay and screened chemical compounds with activities against known targets. Out of 3423 compounds, we have identified 19 drugs that block transforming growth factor beta (TGFβ)-induced EMT in normal murine mammary gland epithelial cells (NMuMG). The active compounds include inhibitors against TGFβ receptors (TGFBR), Rho-associated protein kinases (ROCK), myosin II, SRC kinase and uridine analogues. Among the EMT-repressing compounds, we identified a group of inhibitors targeting multiple receptor tyrosine kinases, and biochemical profiling of these multi-kinase inhibitors reveals TGFBR as a thus far unknown target of their inhibitory spectrum. These findings demonstrate the feasibility of a multi-parameter, high-content microscopy screen to identify modulators and druggable targets of EMT. Moreover, the newly discovered &quot;off-target&quot; effects of several receptor tyrosine kinase inhibitors have important consequences for in vitro and in vivo studies and might beneficially contribute to the therapeutic effects observed in vivo.

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Category: Uncategorized

Construction of a Sequencing Library from Circulating Cell-Free DNA.

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

[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity.

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.

A high-content EMT screen identifies multiple receptor tyrosine kinase inhibitors with activity on TGFβ receptor.