DPYD genotyping and dihydropyrimidine dehydrogenase (DPD) phenotyping in clinical oncology. A clinically focused minireview.

BACKGROUND: In clinical oncology, systemic 5-fluorouracil (5-FU) and its oral pro-drugs are used to treat a broad group of solid tumours. Patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency are at elevated risk of toxicity if treated with standard doses of 5-FU. DPYD genotyping and measurements of plasma uracil concentration (DPD phenotyping) can be applied as tests for DPD deficiency. In April 2020, the European Medicines Agency recommended pre-treatment DPD testing to reduce the risk of 5-FU-related toxicity. OBJECTIVES: The objective of this study is to present the current evidence for DPD testing in routine oncological practice. METHODS: Two systematic literature searches were performed following the PRISMA guidelines. We identified studies examining the possible benefit of DPYD genotyping or DPD phenotyping on the toxicity risk. FINDINGS: Nine and 12 studies met the criteria for using DPYD genotyping and DPD phenotyping, respectively. CONCLUSIONS: The evidence supporting either DPYD genotyping or DPD phenotyping as pre-treatment tests to reduce 5-FU toxicity is poor. Further evidence is still needed to fully understand and guide clinicians to dose by DPD activity.

[Phenotype- or genotype test for dihydropyrimidin dehydrogenase deficiency before treatment with a fluoropyrimidine].

Some patients may have partial or complete deficiency of dihydropyrimidin dehydrogenase (DPD) and be more likely to experience severe toxicity with 5-fluorouracil. Since the spring of 2020, the Danish Medicines Agency has recommended genotype or phenotype testing before treatment with a fluoropyrimidine, but the most appropriate test strategy is debated. In this review, we present polymorphisms in the genes coding for DPD and summarise the evidence for DPD-enzyme deficiency testing and pharmacokinetic guided dosing.

Postponement of Death by Pharmacological Heart Failure Treatment: A Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Outcome postponement has been proposed as an effect measure for preventive drug treatment. It describes the average delay of the investigated unwanted clinical event, achieved by taking medication. The objective was to estimate postponement of death for the following heart failure medications compared to placebo: beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), ARB added to ACE inhibitors, aldosterone antagonists, ivabradine, and renin antagonists. METHODS: We searched Medline and Embase from inception of databases until October 2017. Eligibility criteria were randomized placebo-controlled heart failure trials, including at least 1000 participants, with survival as a prespecified outcome and a minimum trial duration of 1 year. We calculated the outcome postponement by modeling the area between survival curves. This area was modeled on the basis of the hazard ratio or relative risk, the rate of mortality in the placebo group, and the trial duration. All results were standardized to a 3-year trial duration to ensure comparability between treatments. RESULTS: We identified 14 eligible trials, with a total of 52,014 patients. The results in terms of postponement of all-cause mortality was: beta-blockers 43.7 days (95% confidence interval [95% CI], 20.8-66.5), ACE inhibitors 41.0 days (95% CI, 18.8-63.3), and aldosterone-antagonists 41.3 days (95% CI, 14.3,68.4). CONCLUSION: The modeled outcome postponement estimates reiterate beta-blockers, ACE inhibitors, and aldosterone antagonists as the mainstay of heart failure treatment. Furthermore, ivabradine or ARBs added to ACE inhibitors results in no statistically significant gain in survival.

Association between aortic valve calcification measured on non-contrast computed tomography and aortic valve stenosis in the general population.

BACKGROUND: Aortic valve calcification (AVC) measured on non-contrast computed tomography (CT) has shown correlation to severity of aortic valve stenosis (AS) and mortality in patients with known AS. The aim of this study was to determine the association of CT verified AVC and subclinical AS in a general population undergoing CT. METHODS: CT scans from 566 randomly selected male participants (age 65-74) in the Danish cardiovascular screening study (DANCAVAS) were analyzed for AVC. All participants with a moderately or severely increased AVC score (≥300 arbitrary units (AU)) and a matched control group were invited for a supplementary echocardiography. AS was graded by indexed aortic valve area (AVAi) on echocardiography as moderate 0.6-0.85 cm(2)/m(2) and severe < 0.6 cm(2)/m(2), respectively. ROC- and regression analyses were performed. RESULTS: Due to prior valve surgery, and artifacts from ICD leads 16 individuals were excluded from the AVC scoring. Moderate or severe increased AVC was observed in 10.7% (95% CI: 8.4-13.7). Echocardiography was performed in 101 individuals; 32.7% (95% CI: 21.8 to 46.0) with moderate or high AVC score had moderate or severe AS, while none with no or low AVC. A ROC analysis defined an AVC score ≥588 AU to be suggestive of moderate or severe AS (AUC 0.89 ± 0.04, sensitivity 83% and specificity 87%). In the univariate analyses, AVC was the only variable significantly associated with AS. CONCLUSIONS: This study indicates an association between CT verified AVC and subclinical AS.