Major reductions in unnecessary aspartate aminotransferase and blood urea nitrogen tests with a quality improvement initiative.

BACKGROUND/CONTEXT: Unnecessary laboratory testing leads to considerable healthcare costs. Aspartate aminotransferase (AST), commonly ordered with alanine aminotransferase (ALT) and blood urea nitrogen (BUN), commonly ordered with creatinine (Cr), often add little value to patient management at significant cost. We undertook a choosing wisely based quality improvement initiative to reduce the frequency of testing. OBJECTIVES: To reduce the ratio of AST/ALT and BUN/Cr to less than 5% for all inpatient and outpatient test orders. MEASURES: Absolute number and ratio of AST/ALT and BUN/Cr; AST, ALT, BUN and Cr tests per 100 hospital days; projected annualised cost savings and monthly acute inpatient bed days. IMPROVEMENTS: We created guidelines for appropriate indications of AST and BUN testing, provided education with audit and feedback and removed AST and BUN from institutional order sets. IMPACT/RESULTS: The ratios of AST/ALT and BUN/Cr decreased significantly over the study period (0.37 to 0.14, 0.57 to 0.14, respectively), although the goal of 0.05 was not achieved due to a delay in adopting the choosing wisely strategies during the study time period by some inpatient units. The number of tests per 100 hospital days decreased from 20 to 7 AST (95% CI 19 to 20.5, 5.6 to 8.7, p<0.001) and from 72 to 17 BUN (95% CI 70 to 73.4, 16.6 to 22.9, p<0.001). The initiative resulted in a projected annualised cost savings of C$221 749. DISCUSSION: A significant decrease in the AST/ALT and BUN/Cr ratios can be achieved with a multimodal approach and will result in substantial healthcare savings.

Severe Erosive Pill Esophagitis Induced by Crizotinib Therapy: A Case Report and Literature Review.

Previous case reports have described esophagitis thought to be secondary to crizotinib, an oral tyrosine-kinase inhibitor used in the treatment of anaplastic lymphoma kinase- (ALK-) positive non-small cell lung cancer (NSCLC). In those reports, the interval development of esophagitis was between two days and three months after initiating or reinitiating crizotinib therapy. We present a woman who developed ulcerative esophagitis ten months after beginning crizotinib therapy, which is highly unusual. We believe the provoking factor was a change in her medication administration routine, done to accommodate religious practices during the period of Ramadan. This case illustrates the mechanism of pill esophagitis and reinforces the importance of patient education when it comes to medication administration. Clinicians may consider early imaging or investigations in patients with concerning symptomatology in the context of crizotinib therapy or other offending medications. Future research may help to uncover additional risk factors for this exceedingly rare diagnosis in this patient population. Most importantly, this case highlights nonpharmacologic ways to improve tolerability and decrease adverse effects of a highly effective chemotherapeutic agent.

TEL-JAK2 constitutively activates the extracellular signal-regulated kinase (ERK), stress-activated protein/Jun kinase (SAPK/JNK), and p38 signaling pathways.

The ets transcription factor, TEL, undergoes chromosomal rearrangements with the tyrosine kinase JAK2. TEL-JAK2 is constitutively active, confers cell line factor independence, and activates signal transducer and activator of transcription-1 (STAT1), STAT3, and STAT5. Data from bone marrow transplantation models suggest that STAT5 activation does not account for the entire disease phenotype induced by TEL-JAK2. This study examined additional signaling pathways that are activated by TEL-JAK2. TEL-JAK2 expression in Ba/F3 cells results in constitutive association and tyrosine phosphorylation of Shc and Ship-1 and, consequently, recruitment of Grb2 to TEL-JAK2. Direct Grb2 recruitment is also possible because a putative Grb2 binding site, Tyr314, is present on TEL-JAK2(5-19) and TEL-JAK2(5-12). Studies with a TEL-JAK2(5-19)Tyr314Phe mutant support a role for Tyr314 in Grb2 recruitment, because Grb2 association with TEL-JAK2(5-19)Tyr314Phe is significantly reduced. Interestingly, TEL-JAK2(5-19)Tyr314Phe shows reduced Ras activation when compared with TEL-JAK2(4-17), TEL-JAK2(5-12), and TEL-JAK2(5-19). Analysis of extracellular signal-regulated kinase-1/2 (ERK1/2), stress-activated protein/Jun kinase (SAPK/JNK), and p38 demonstrates the activation of SAPK/JNK and phosphorylation of p38 by all TEL-JAK2 isoforms. TEL-JAK2(5-12) and TEL-JAK2(5-19) preferentially phosphorylate ERK2, whereas TEL-JAK2(4-17) phosphorylated ERK2 at lower levels. Inhibition studies demonstrated that ERK1/2 activation was necessary for Ba/F3 factor independence mediated by TEL-JAK2(5-19), while inhibition of SAPK/JNK or p38 activity had no effect. Our data reveal the requirement of ERK activation by TEL-JAK2(5-19) in Ba/F3 cells and suggest that TEL-JAK2 leukemogenic potential may be mediated in part through ERK1/2.