Successful use of uridine triacetate (Vistogard) three weeks after capecitabine in a patient with homozygous dihydropyrimidine dehydrogenase mutation: A case report and review of the literature.

5-fluorouracil and capecitabine are chemotherapeutic agents commonly used to treat solid malignancies. Increased susceptibility to 5-fluorouracil or capecitabine, caused by impaired clearance, dihydropyrimidine dehydrogenase deficiency, or other genetic mutations in the enzymes that metabolize 5-fluorouracil can lead to severe life-threatening toxicities and are typically manifested by an early onset of symptoms. We report and discuss the management and outcome of capecitabine toxicity with the recently FDA approved antidote, uridine triacetate (Vistogard), in a 57-year-old female breast cancer patient with homozygous dihydropyrimidine dehydrogenase deficiency who received treatment beyond the recommended 96 h window from the last dose of capecitabine.

Leveraging Antimicrobial Stewardship in the Emergency Department to Improve the Quality of Urinary Tract Infection Management and Outcomes.

BACKGROUND: The complex and fast-paced emergency department (ED) practice setting presents unique challenges that demand a tailored approach to antimicrobial stewardship. In this article, we describe the strategies applied by 1 institution's antimicrobial stewardship program (ASP) that were successful in improving prescribing practices and outcomes for urinary tract infection (UTI) in the ED. METHODS: Core strategies included pre-implementation research characterizing the patient population, antimicrobial resistance patterns, prescribing behavior, and morbidity related to infection; collaboration across multiple disciplines; development and implementation of a UTI treatment algorithm; education to increase awareness of the algorithm and the background and rationale supporting it; audit and feedback; and early evaluation of post-implementation outcomes. RESULTS: We observed a rapid change in prescribing post-implementation with increased empiric nitrofurantoin use and reduced cephalosporin use (P < .05). Our elevation of nitrofurantoin to firstline status was supported by our post-implementation analysis showing that its use was independently associated with reduced 30-day return visits (adjusted odds ratio, 0.547; 95% confidence interval, 0.312-0.960). Furthermore, despite a shift to a higher risk population and a corresponding decrease in antimicrobial susceptibility rates post-implementation, the preferential use of nitrofurantoin did not result in higher bug-drug mismatches while 30-day return visits to the ED remained stable. CONCLUSIONS: We demonstrate that an outcomes-based ASP can impart meaningful change to knowledge and attitudes affecting prescribing practices in the ED. The success of our program may be used by other institutions as support for ASP expansion to the ED.

Risk factors for early return visits to the emergency department in patients with urinary tract infection.

BACKGROUND: Optimal management of urinary tract infections (UTIs) in the emergency department (ED) is challenging due to high patient turnover, decreased continuity of care, and treatment decisions made in the absence of microbiologic data. We sought to identify risk factors for return visits in ED patients treated for UTI. METHODS: A random sample of 350 adult ED patients with UTI by ICD 9/10 codes was selected for review. Relevant data was extracted from medical charts and compared between patients with and without ED return visits within 30days (ERVs). RESULTS: We identified 51 patients (15%) with 59 ERVs, of whom 6% returned within 72h. Nearly half of ERVs (47%) were UTI-related and 33% of ERV patients required hospitalization. ERVs were significantly more likely (P<0.05) in patients with the following: age≥65years; pregnancy; skilled nursing facility residence; dementia; psychiatric disorder; obstructive uropathy; healthcare exposure; temperature≥38 °C heart rate>100; and bacteremia. Escherichia coli was the most common uropathogen (70%) and susceptibility rates to most oral antibiotics were below 80% in both groups except nitrofurantoin (99% susceptible). Cephalexin was the most frequently prescribed antibiotic (51% vs. 44%; P=0.32). Cephalexin bug-drug mismatches were more common in ERV patients (41% vs. 15%; P=0.02). Culture follow-up occurred less frequently in ERV patients (75% vs. 100%; P<0.05). CONCLUSIONS: ERV in UTI patients may be minimized by using ED-source specific antibiogram data to guide empiric treatment decisions and by targeting at-risk patients for post-discharge follow-up.

Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy.

BACKGROUND: The optimal timing to initiate bevacizumab (BV) therapy for recurrent glioblastoma (GBM) is currently unclear. To address this issue, we examined progression-free survival (PFS) and survival time (ST) in a large retrospective cohort of GBM patients treated with BV at different recurrences. METHODS: We identified 468 primary GBM patients who underwent biopsy or surgery followed by radiation therapy and temozolomide (RT/TMZ), and then received BV. PFS and ST were compared between patients stratified by the recurrence that BV was initiated (upfront, first recurrence, second recurrence, or 3+ recurrences). We also examined the effect on PFS and ST of the addition of chemotherapy to BV. In a larger cohort of GBM patients, we determined overall treatment continuation rates at each recurrence and identified variables predictive of inability to continue treatment. RESULTS: BV PFS was similar for all 3 recurrence groups (median, 4.1 months). There were no differences in BV ST (median, 9.8 months). The addition of chemotherapy to BV improved PFS but not ST. Analysis of treatment continuation rates indicated that the number of patients unable to undergo further treatments is modest, and that patients unable to tolerate BV delay can be identified by age ≥60 years and low extent of resection. CONCLUSIONS: Deferred use of bevacizumab is not associated with diminished efficacy. Analysis of treatment continuation rates identified patients who may be unable to delay BV therapy. Our findings suggest that there is a fixed survival after BV initiation and that delayed BV treatment is preferable for most patients.

Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome.

BACKGROUND: Promoter methylation of the DNA repair gene, O-6-methylguanine-DNA methyltransferase (MGMT), is associated with improved treatment outcome for newly diagnosed glioblastoma (GBM) treated with standard chemoradiation. To determine the prognostic significance of MGMT protein expression as assessed by immunohistochemistry (IHC) and its relationship with methylation, we analyzed MGMT expression and promoter methylation with survival in a retrospective patient cohort. METHODS: We identified 418 patients with newly diagnosed GBM at University of California Los Angeles Kaiser Permanente Los Angeles, nearly all of whom received chemoradiation, and determined MGMT expression by IHC, and MGMT promoter methylation by methylation-specific PCR (MSP) and bisulfite sequencing (BiSEQ) of 24 neighboring CpG sites. RESULTS: With use of the median percentage of cells staining by IHC as the threshold, patients with <30% staining had progression-free survival (PFS) of 10.9 months and overall survival (OS) of 20.5 months, compared with PFS of 7.8 months (P < .0001) and OS of 16.7 months (P < .0001) among patients with ≥30% staining. Inter- and intrareader correlation of IHC staining was high. Promoter methylation status by MSP was correlated with IHC staining. However, low IHC staining was frequently observed in the absence of promoter methylation. Increased methylation density determined by BiSEQ correlated with both decreased IHC staining and increased survival, providing a practical semiquantitative alternative to MSP. On the basis of multivariate analysis validated by bootstrap analysis, patients with tandem promoter methylation and low expression demonstrated improved OS and PFS, compared with the other combinations. CONCLUSIONS: Optimal assessment of MGMT status as a prognostic biomarker for patients with newly diagnosed GBM treated with chemoradiation requires determination of both promoter methylation and IHC protein expression.

Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation.

Mutations in isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) are found in a subset of gliomas. Among the many phenotypic differences between mutant and wild-type IDH1/2 gliomas, the most salient is that IDH1/2 mutant glioma patients demonstrate markedly improved survival compared with IDH1/2 wild-type glioma patients. To address the mechanism underlying the superior clinical outcome of IDH1/2 mutant glioma patients, we investigated whether overexpression of the IDH1(R132H) protein could affect response to therapy in the context of an isogenic glioma cell background. Stable clonal U87MG and U373MG cell lines overexpressing IDH1(WT) and IDH1(R132H) were generated, as well as U87MG cell lines overexpressing IDH2(WT) and IDH2(R172K). In vitro experiments were conducted to characterize baseline growth and migration and response to radiation and temozolomide. In addition, reactive oxygen species (ROS) levels were measured under various conditions. U87MG-IDH1(R132H) cells, U373MG-IDH1(R132H) cells, and U87MG-IDH2(R172K) cells demonstrated increased sensitivity to radiation but not to temozolomide. Radiosensitization of U87MG-IDH1(R132H) cells was accompanied by increased apoptosis and accentuated ROS generation, and this effect was abrogated by the presence of the ROS scavenger N-acetyl-cysteine. Interestingly, U87MG-IDH1(R132H) cells also displayed decreased growth at higher cell density and in soft agar, as well as decreased migration. Overexpression of IDH1(R132H) and IDH2(R172K) mutant protein in glioblastoma cells resulted in increased radiation sensitivity and altered ROS metabolism and suppression of growth and migration in vitro. These findings provide insight into possible mechanisms contributing to the improved outcomes observed in patients with IDH1/2 mutant gliomas.