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.
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.
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.
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.
Methods to identify BRCA testing in claims data Lynch, Julie, PhD, RN, MBA; Berse, Brygida, PhD
American journal of obstetrics and gynecology,
07/2016, Volume:
215, Issue:
1
Journal Article
As more veterans seek breast cancer care within the Department of Veterans Affairs, we evaluated whether node-negative, hormone receptor–positive patients received 21-gene Recurrence Score testing to ...predict breast cancer recurrence. Analysis of 2011-2012 Veterans Affairs Central Cancer Registry, chart, and laboratory data revealed that 82 (25%) of 328 eligible veterans underwent the test. Most of the tested patients received guideline-concordant care.
Ensuring guideline-concordant cancer care is a Department of Veterans Affairs (VA) priority, especially as the number of breast cancer patients at VA medical centers (VAMCs) grows. We assessed the utilization and clinical impact of the 21-gene Recurrence Score test, which predicts 10-year risk of breast cancer recurrence and the likelihood of chemotherapy benefit, on veterans newly diagnosed with breast cancer.
We conducted a retrospective cohort study using 2011-2012 VA Central Cancer Registry, chart review, and laboratory test data. Independent variables assessed included patient and site-of-care characteristics. The outcome of interest was whether newly diagnosed, eligible (node negative, hormone-receptor positive, human epidermal growth factor receptor 2 HER2 negative) veterans underwent the 21-gene test. We performed descriptive statistics on all patients and multivariate logistic regression to determine associations. We correlated treatments received with test results.
Among 328 eligible veterans, 82 (25%) had the 21-gene test; 100 eligible veterans (30%) sought care at a VAMC where no tests were ordered. Receiving care at a VAMC that had women's health services (odds ratio OR, 1.84, 95% confidence interval CI, 1.05-3.22) and having tumor characteristics meeting the National Comprehensive Cancer Network 2010 test criteria (OR, 3.06, 95% CI, 1.69-5.57) were positive predictors of testing; increasing age (OR, 0.93, 95% CI, 0.91-0.96 per year) and fee-based care (OR, 0.46, 95% CI, 0.26-0.82) were negative predictors. The majority of tested patients received guideline-concordant care.
Site of care and tumor characteristics were important predictors of test uptake. Facilitating delivery of guideline-concordant cancer care requires improved laboratory informatics and clinical decision support.
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.
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.
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.
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.
Bone morphogenetic proteins (BMPs) have multiple functions in the developing nervous system. A member of this family, BMP-9, was found to be highly expressed in the embryonic mouse septum and spinal ...cord, indicating a possible role in regulating the cholinergic phenotype. In cultured neurons, BMP-9 directly induced the expression of the cholinergic gene locus encoding choline acetyltransferase and the vesicular acetylcholine transporter and up-regulated acetylcholine synthesis. The effect was reversed upon withdrawal of BMP-9. Intracerebroventricular injection of BMP-9 increased acetylcholine levels in vivo. Although certain other BMPs also up-regulated the cholinergic phenotype in vitro, they were less effective than BMP-9. These data indicate that BMP-9 is a differentiating factor for cholinergic central nervous system neurons.
Nerve growth factor (NGF) exerts anti‐apoptotic, trophic and differentiating actions on sympathetic neurons and cholinergic cells of the basal forebrain and activates the expression of genes ...regulating the synthesis and storage of the neurotransmitter acetylcholine (ACh). We have been studying the intracellular signaling pathways involved in this process. Although, in the rat pheochromocytoma cell line PC12, NGF strongly activates the mitogen‐activated protein kinase (MAPK) pathway, prolonged inhibition of MAPK kinase (MEK) activity by PD98059 or U0126 did not affect the ability of NGF to up‐regulate choline acetyltransferase (ChAT) or to increase intracellular ACh levels. In contrast, the treatment with the phosphatidylinositol 3′‐kinase (PI3K) inhibitor LY294002, but not with its inactive analogue LY303511, completely abolished the NGF‐induced production of ACh. Inhibition of PI3K also eliminated the NGF effect on the intracellular ACh level in primary cultures of septal neurons from E18 mouse embryos. Blocking the PI3K pathway prevented the activation of cholinergic gene expression, as demonstrated in RT/PCR assays and in transient transfections of PC12 cells with cholinergic locus promoter‐luciferase reporter constructs. These results indicate that the PI3K pathway, but not the MEK/MAPK pathway, is the mediator of NGF‐induced cholinergic differentiation.
Nerve growth factor (NGF) is a trophic and survival factor for cholinergic neurons, and it induces the expression of several genes that are essential for synthesis and storage of acetylcholine (ACh), ...specifically choline acetyltransferase, vesicular ACh transporter (VAChT), and choline transporter. We have found previously that the phosphatidylinositol 3'-kinase pathway, but not the MEK/MAPK pathway, is the mediator of NGF-induced cholinergic differentiation. Here we demonstrate, in the rat pheochromocytoma cell line PC12 and in primary mouse neuronal cultures, that NGF-evoked up-regulation of these three cholinergic-specific genes is mediated by the anti-apoptotic signaling molecule Akt/protein kinase B. Inhibition of Akt activation by the pharmacological inhibitor 1L-6-hydroxymethyl-chiro-inositol 2(R)-2-O-methyl-3-O-octadecylcarbonate (HIMO), or by a peptide fragment derived from the proto-oncogene TLC1, eliminated NGF-stimulated increases in cholinergic gene expression, as demonstrated by RT-PCR and reporter gene assays. Moreover, treatment with HIMO reversed NGF-evoked increases in choline acetyltransferase activity and ACh production. In co-transfection assays with the reporter construct, a dominant-negative Akt plasmid and Akt1-specific small interfering RNA also attenuated NGF-induced cholinergic promoter activity. Our data indicate that, in addition to its well-described role in promoting neuronal survival, Akt can also mediate signals necessary for neurochemical differentiation.
Choline acetyltransferase (ChAT), the enzyme that synthesizes the neurotransmitter acetylcholine (ACh), is thought to be present in kinetic excess in cholinergic neurons. The rate-limiting factor in ...ACh production is the provision of choline to ChAT. Cholinergic neurons are relatively unique in their expression of the choline transporter 1 (CHT1), which exhibits high-affinity for choline and catalyzes its uptake from the extracellular space to the neuron. Multiple lines of evidence indicate that the activity of CHT1 is a key determinant of choline supply for ACh synthesis. We examined the interaction of ChAT and ChT activity using mice heterozygous for a null mutation in the Chat gene (Chat+/-). In these mice, brain ChAT activity was reduced by 40-50% relative to the wild type, but brain ACh levels as well as ACh content and depolarization-evoked ACh release in hippocampal slices were normal. However, the amount of choline taken up by CHT1 and ACh synthesized de novo from choline transported by CHT1 in hippocampal slices, as well as levels of CHT1 mRNA in the septum and CHT1 protein in several regions of the CNS, were 50-100% higher in Chat+/- than in Chat+/+ mice. Thus, haploinsufficiency of ChAT leads to an increased expression of CHT1. Increased ChT activity may compensate for the reduced ChAT activity in Chat+/- mice, contributing to the maintenance of apparently normal cholinergic function as reflected by normal performance of these mice in several behavioral assays.
Abstract Synthesis, storage and release of acetylcholine (ACh) require the expression of several specialized enzymes, including choline acetyltransferase (ChAT), vesicular acetylcholine transporter ...(VAChT) and the high-affinity choline transporter (CHT). Extracellular factors that regulate CHT expression and their signaling pathways remain poorly characterized. Using the NSC-19 cholinergic cell line, derived from embryonic spinal cord, we compared the effects of the second messenger cAMP on the expression of CHT and the cholinergic locus containing the ChAT and VAChT genes. Treatment of NSC-19 cells with dbcAMP and forskolin, thus increasing intracellular cAMP levels, significantly reduced CHT mRNA expression, while it upregulated ChAT/VAChT mRNA levels and ChAT activity. The cAMP-induced CHT downregulation was independent of PKA activity, as shown in treatments with the PKA inhibitor H-89. The alternative Epac-Rap pathway, when stimulated by a specific Epac activator, led to significant downregulation of CHT and ChAT, and, to a lesser extent, VAChT. In contrast, the PKA activator 6-BNZ-cAMP stimulated the expression of all three genes, but with varying concentration-dependence profiles. Our results indicate that elevations of intraneuronal cAMP concentration have differential effects on the cholinergic phenotype, depending on the involvement of different downstream effectors. Interestingly, although CHT is expressed predominantly in cholinergic cells, its regulation appears to be distinct from that of the cholinergic locus.
Basal forebrain cholinergic neurons (BFCN) participate in processes of learning, memory, and attention. Little is known about the genes expressed by BFCN and the extracellular signals that control ...their expression. Previous studies showed that bone morphogenetic protein (BMP) 9 induces and maintains the cholinergic phenotype of embryonic BFCN. We measured gene expression patterns in septal cultures of embryonic day 14 mice and rats grown in the presence or absence of BMP9 by using species-specific microarrays and validated the RNA expression data of selected genes by immunoblot and immunocytochemistry analysis of their protein products. BMP9 enhanced the expression of multiple genes in a time-dependent and, in most cases, reversible manner. The set of BMP9-responsive genes was concordant between mouse and rat and included genes encoding cell-cycle/growth control proteins, transcription factors, signal transduction molecules, extracellular matrix, and adhesion molecules, enzymes, transporters, and chaperonins. BMP9 induced the p75 neurotrophin receptor (NGFR), a marker of BFCN, and Cntf and Serpinf1, two trophic factors for cholinergic neurons, suggesting that BMP9 creates a trophic environment for BFCN. To determine whether the genes induced by BMP9 in culture were constituents of the BFCN transcriptome, we purified BFCN from embryonic day 18 mouse septum by using fluorescence-activated cell sorting of NGFR+cells and profiled mRNA expression of these and NGFR-cells. Approximately 30% of genes induced by BMP9 in vitro were overexpressed in purified BFCN, indicating that they belong to the BFCN transcriptome in situ and suggesting that BMP signaling contributes to maturation of BFCN in vivo.
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