Chemotherapy has a significant but transient effect on olfactory and gustatory function, possibly causing reduced appetite, a low energy intake, and weight loss. Additional spices and flavoring may compensate for this diminished chemosensory function, enhancing patient compliance and quality of life.

BackgroundCancer patients carrying mutations in the dihydropyrimidine dehydrogenase gene (DPYD) have a high risk to experience severe drug-adverse effects following chemotherapy with fluoropyrimidine drugs such as 5-fluorouracil (5-FU) or capecitabine. The pretreatment detection of this impairment of pyrimidine catabolism could prevent serious, potentially lethal side effects. As known deleterious mutations explain only a limited proportion of the drug-adverse events, we systematically searched for additional DPYD variations associated with enhanced drug toxicity.Methodology/Principal FindingsWe performed a whole gene approach covering the entire coding region and compared DPYD genotype frequencies between cancer patients with good (n = 89) and with poor (n = 39) tolerance of a fluoropyrimidine-based chemotherapy regimen. Applying logistic regression analysis and sliding window approaches we identified the strongest association with fluoropyrimidine-related grade III and IV toxicity for the non-synonymous polymorphism c.496A>G (p.Met166Val). We then confirmed our initial results using an independent sample of 53 individuals suffering from drug-adverse-effects. The combined odds ratio calculated for 92 toxicity cases was 4.42 [95% CI 2.12–9.23]; p (trend)<0.001; p (corrected) = 0.001; the attributable risk was 56.9%. Comparing tumor-type matched sets of samples, correlation of c.496A>G with toxicity was particularly present in patients with gastroesophageal and breast cancer, but did not reach significance in patients with colorectal malignancies.ConclusionOur results show compelling evidence that, at least in distinct tumor types, a common DPYD polymorphism strongly contributes to the occurrence of fluoropyrimidine-related drug adverse effects. Carriers of this variant could benefit from individual dose adjustment of the fluoropyrimidine drug or alternate therapies.

Purpose: Complete or partial loss of dihydropyrimidine dehydrogenase (DPD) function has been described in cancer patients with intolerance to fluoropyrimidine drugs like 5-fluorouracil (5-FU) or Xeloda. The intention of this population study is to assess and to evaluate gene variations in the entire coding region of the dihydropyrimidine dehydrogenase gene (DPYD), which could be implicated in DPD malfunction. Experimental Design: A cohort of 157 individuals was genotyped by denaturing highperformance liquid chromatography; 100 of these genotypes were compared with functional studies on DPD activity and mRNA expression. Results: Twenty-three variants in coding and noncoding regions of the DPYD gene were detected, giving rise to15 common haplotypes with a frequency of >1%. Rare sequence alterations included a frameshift mutation (295-298delTCAT) and three novel point mutations, 1218G>A (Met Ser). DPD enzyme activity showed high variation in the analyzed population and correlated with DPD mRNA expression. In particular, the novel variants were not accompanied with decreased enzyme activity. However, a statistically significant deviation from the median DPD activity of the population was associated with the mutations 1601G>A (Ser Dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2) is the initial and rate-limiting enzyme in the catabolism of pyrimidines. The homodimeric protein catalyzes the reduction of uracil and thymine in an NADPH-dependent manner and, furthermore, plays a critical role in the pharmacokinetics of fluoropyrimidine-based anticancer drugs. Eighty percent to 85% of administered standard doses of the common chemotherapeutic agent 5-fluorouracil (5-FU) are rapidly degraded by DPD to inactive compounds followed by excretion of a-fluoroh-alanine within 24 hours (1 -3). The rationally designed orally administered fluoropyrimidine drug Xeloda (capecitabine) is converted in situ into 5-FU due to intracellular thymidine phosphorylase activity. Capecitabine has been shown to be safer and more effective than 5-FU and has greater patient convenience (4, 5).

M166V, S534N, I543V) displayed significantly reduced DPD activity. The rare combination of the highly conserved mutation sites M166V and S534N was additionally found in one of the other patients. DPD enzyme activity was low, but yet within normal range. The K259E mutation did not provoke a decrease in DPD function in a heterozygous individual. Based on the protein structure of crystalline pig DPD and the deduced homology models, we have additionally investigated the amino acid positions in their three-dimensional network which correspond to the five missense mutations discovered in the patients.

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The new german guidelines for the treatment of hypertensive disorders in pregnancy have some important differentiations. The aim of the new guidelines is to avoid the early premature birth and to reduce the fetal and maternal morbidity and mortality. For the first time there ist the possibility and the recommendation for the prolongation of pregnancy. This means that the treatment of hypertensive disorders should start not before a blood pressure of >or=170/110 mmHg; thus the nutrition of the fetus will not be worsened and the worse perfusion of the placenta will be avoided. Further more the selection of antihypertensive treatment has changed: the first choice is not longer Dihydralazin (Nepresol) but Nifedipin (Adalat). In the treatment of HELLP-Syndrom there ist only one difference to the treatment of preeclampsia: the use of glucocorticosteroids. In the treatment of both hypertensive disorders in pregnancy there is the aim to finish the fetal lung mature induction before the delivery is planned or necessary. A new point of view in the german guidelines is the possibility of prediction and prevention of hypertensive disorders in pregnancy: patients who had already a hypertensive disorder in the pregnancy before or patients who have a pathologic flow in the Art. uterinae have a significant higher risk for a preeclampsia in this pregnancy. They should receive a preventive therapy with ASS. Because of these changes in the german guidelines the prolongation of pregnancy and the reduced rate of premature birth becomes more importance and helps to avoid a high rate of neonatal mortality and morbidity.

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