Modulation of cholinergic locus expression by glucocorticoids and retinoic acid is cell-type specific

AbstractModulation of mRNA expression of choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT) by the glucocorticoid dexamethasone and by retinoic acid was examined in two neuronal cell lines: basal forebrain-derived SN56 and pheochromocytoma PC12. Dexamethasone up-regulated ChAT and VAChT in SN56 cells, while it had inhibitory effects on these genes in PC12 cells. Retinoic acid stimulated the cholinergic markers in both cell types, but in SN56 cells its effect was partially additive with that of dexamethasone, whereas it was much smaller and abrogated by dexamethasone in PC12 cells. Acetylcholine content correlated with these mRNA changes. The presence of a glucocorticoid response element consensus sequence in the VAChT/ChAT gene locus suggests direct transcriptional regulation by glucocorticoids

Underutilization and disparities in access to EGFR testing among Medicare patients with lung cancer from 2010 – 2013

Abstract Background Tumor testing for mutations in the epidermal growth factor receptor (EGFR) gene is indicated for all newly diagnosed, metastatic lung cancer patients, who may be candidates for first-line treatment with an EGFR tyrosine kinase inhibitor. Few studies have analyzed population-level testing. Methods We identified clinical, demographic, and regional predictors of EGFR & KRAS testing among Medicare beneficiaries with a new diagnosis of lung cancer in 2011–2013 claims. The outcome variable was whether the patient underwent molecular, EGFR and KRAS testing. Independent variables included: patient demographics, Medicaid status, clinical characteristics, and region where the patient lived. We performed multivariate logistic regression to identify factors that predicted testing. Results From 2011 to 2013, there was a 19.7% increase in the rate of EGFR testing. Patient zip code had the greatest impact on odds to undergo testing; for example, patients who lived in the Boston, Massachusetts hospital referral region were the most likely to be tested (odds ratio (OR) of 4.94, with a 95% confidence interval (CI) of 1.67–14.62). Patient demographics also impacted odds to be tested. Asian/Pacific Islanders were most likely to be tested (OR 1.63, CI 1.53–1.79). Minorities and Medicaid patients were less likely to be tested. Medicaid recipients had an OR of 0.74 (CI 0.72–0.77). Hispanics and Blacks were also less likely to be tested (OR 0.97, CI 0.78–0.99 and 0.95, CI 0.92–0.99), respectively. Clinical procedures were also correlated with testing. Patients who underwent transcatheter biopsies were 2.54 times more likely to be tested (CI 2.49–2.60) than those who did not undergo this type of biopsy. Conclusions Despite an overall increase in EGFR testing, there is widespread underutilization of guideline-recommended testing. We observed racial, income, and regional disparities in testing. Precision medicine has increased the complexity of cancer diagnosis and treatment. Targeted interventions and clinical decision support tools are needed to ensure that all patients are benefitting from advances in precision medicine. Without such interventions, precision medicine may exacerbate racial disparities in cancer care and health outcomes

Clinical decisions surrounding genomic and proteomic testing among United States veterans treated for lung cancer within the Veterans Health Administration

Abstract Background Current clinical guidelines recommend epidermal growth factor receptor (EGFR) mutational testing in patients with metastatic non-small cell lung cancer (NSCLC) to predict the benefit of the tyrosine kinase inhibitor erlotinib as first-line treatment. Proteomic (VeriStrat) testing is recommended for patients with EGFR negative or unknown status when erlotinib is being considered. Departure from this clinical algorithm can increase costs and may result in worse outcomes. We examined EGFR and proteomic testing among patients with NSCLC within the Department of Veterans Affairs (VA). We explored adherence to guidelines and the impact of test results on treatment decisions and cost of care. Methods Proteomic and EGFR test results from 2013 to 2015 were merged with VA electronic health records and pharmacy data. Chart reviews were conducted. Cases were categorized based on the appropriateness of testing and treatment. Results Of the 69 patients with NSCLC who underwent proteomic testing, 33 (48%) were EGFR-negative and 36 (52%) did not have documented EGFR status. We analyzed 138 clinical decisions surrounding EGFR/proteomic testing and erlotinib treatment. Most decisions (105, or 76%) were concordant with clinical practice guidelines. However, for 24 (17%) decisions documentation of testing or justification of treatment was inadequate, and 9 (7%) decisions represented clear departures from guidelines. Conclusion EGFR testing, the least expensive clinical intervention analyzed in this study, was significantly underutilized or undocumented. The records of more than half of the patients lacked information on EGFR status. Our analysis illustrated several clinical scenarios where the timing of proteomic testing and erlotinib diverged from the recommended algorithm, resulting in excessive costs of care with no documented improvements in health outcomes