Qualitative and quantitative assessment of taste and smell changes in patients undergoing chemotherapy for breast cancer or gynecologic malignancies.

PURPOSE: Smell and taste changes during chemotherapy are significant complaints of cancer patients. Loss of olfactory/gustatory function can lead to malnutrition, weight loss, and possibly a prolonged morbidity of chemotherapy-induced adverse effects, decreased quality of life, poor compliance, and even decreased therapy response. This prospective study comprehensively investigated, to our knowledge for the first time, smell and taste changes in a cohort of 87 patients undergoing chemotherapy for breast cancer or gynecologic malignancies. PATIENTS AND METHODS: Olfactory function was tested using Sniffin' Sticks (Burghart; Wedel, Germany) and gustatory function was tested using taste strips before, during, and immediately and 3 months after chemotherapy. RESULTS: Olfactory and gustatory function significantly decreased during chemotherapy and recovered almost completely 3 months after chemotherapy. Scores of odor thresholds were affected more than those of discrimination or identification. The olfactory function of older patients was affected more than that of younger patients. There was no difference in the olfactory function during chemotherapy with respect to the chemotherapeutic agent or initial diagnosis (breast or ovarian cancer). Regarding taste, scores of salty taste were affected more than scores of sweet, sour, or bitter taste. The gustatory function did not differ significantly during chemotherapy with respect to age or diagnosis but did differ with respect to the chemotherapeutic agent. Taxane-based chemotherapy caused the most severe disorders. CONCLUSION: 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.

Dislocation of Intravenous Port Systems - Three Case Reports.

BACKGROUND: Many patients with intravenous chemotherapy have an intravenous port system because of high tissue toxicity of most chemotherapeutic agents in the case of paravasation. With more port systems implanted, the rate of complications is increasing. Apart from catheter thrombosis, we primarily know of fracture of the port catheter. CASE REPORT: We describe 3 patients of our chemotherapeutic clinic who experienced complications of the intravenous port system implanted in the vena brachialis. All of them showed fracture and loss of the port catheter, followed in some cases by symptoms such as cardiac problems. CONCLUSION: We have to discuss the use of intravenous port systems. Besides their comfortable use, intravenous port systems have to be handled with care and it has to be considered in every case if there really is the need for an implantation.

HINTERGRUND: Viele Patienten mit intravenöser Chemotherapie besitzen ein intravenös liegendes Portsystem aufgrund der hohen Gewebetoxizität der meisten Chemotherapeutika im Fall eines Paravasates. Je mehr Portsysteme implantiert werden, desto höher ist die Rate der Komplikationen; neben der Portvenenthrombose treten hauptsächlich Katheterkomplikationen auf. FALLBERICHT: Wir berichten von 3 Patientinnen aus unserer Chemoambulanz, die Komplikationen des Portsystems im Bereich der Vena brachialis zeigten, nämlich Katheterdislokationen, was sogar in einem Fall zu kardialen Symptomen geführt hat. ZUSAMMENFASSUNG: Man muss die Verwendung der intravenösen Portsysteme diskutieren. Insbesondere aufgrund des angenehmen Gebrauchs eines Ports muss dieser sorgfältig benutzt werden und in jedem Fall muss die Indikation zur Implantation neu gestellt werden.

Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients.

BACKGROUND: Cancer 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 FINDINGS: We 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. CONCLUSION: Our 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.

Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in a cohort of Caucasian individuals.

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 high-performance 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 to 15 common haplotypes with a frequency of >1%. Rare sequence alterations included a frameshift mutation (295-298delTCAT) and three novel point mutations, 1218G>A (Met406Ile), 1236G>A (Glu412Glu), and 3067C>T (Pro1023Ser). 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 (Ser534Asn) and 2846A>T (Asp949Val). CONCLUSION: This work presents an analysis of DPYD gene variations in a large cohort of Caucasians. The results reflect the genetic and enzymatic variability of DPD in the population and may contribute to further insight into the pharmacogenetic disorder of DPD deficiency.

Detailed analysis of five mutations in dihydropyrimidine dehydrogenase detected in cancer patients with 5-fluorouracil-related side effects.

Complete or partial loss of dihydropyrimidine dehydrogenase (DPD or DYPD) function has been described in cancer patients experiencing severe side effects upon administration of the fluoropyrimidine anticancer drug 5-fluorouracil (5-FU). To investigate a genetic predisposition for 5-FU intolerance due to inherited DPD defects, we established a mutation detection assay based on denaturing HPLC. Analyzing four individuals with symptoms of 5-FU-related toxicity, we detected six distinct sequence variants in the dihydropyrimidine dehydrogenase gene (DPYD): one novel mutation, c.775A>G (K259E); four known missense mutations, c.85T>C (C29R), c.496A>G (M166V), c.1601G>A (S534N), c.1627A>G (I543V); and one silent mutation c.1896T>C affecting the codon for F632. One cancer patient possessing a total of four gene mutations resulting in four amino acid substitutions (C29R, 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.

High-throughput genotyping by DHPLC of the dihydropyrimidine dehydrogenase gene implicated in (fluoro)pyrimidine catabolism.

Dihydropyrimidine dehydrogenase (DPD) is the first and rate-limiting enzyme in the degradation of pyrimidines and pyrimidine base analogs including the anticancer drugs 5-fluorouracil (5-FU) and Xeloda. A decreased DPD enzyme activity has been described in cancer patients experiencing severe and life-threatening toxicity after 5-FU treatment and distinct sequence variants in the DPD gene (DPYD) have been associated with impaired enzyme function. The most prominent mutation in the DPD deficient patient group, a mutation in the splicing donor consensus sequence of intron 14, IVS14+1g>a, resulting in a truncated protein, has been observed in the Caucasian population at frequencies as high as 0.91%-0.94%. This underlines the need for a test system for DPYD mutations in patients undergoing chemotherapy with 5-FU or with Xeloda. To set up a fast and sensitive method to identify variant DPYD alleles, we analyzed 50 healthy individuals by denaturing high performance liquid chromatography (DHPLC). A primer set spanning the whole coding region and the exon-intron boundaries of DPYD was used. In addition, a cDNA-based assay was developed to rapidly identify the 165 base pair deletion in the corresponding RNA of IVS14+1g>a mutation carriers. The optimal mutation detection was elaborated for each of the PCR fragments. DHPLC analysis detected 5 different genetic alterations occurring in the coding region of the gene, as well as 10 intronic sequence variants, respectively. In conclusion, high-throughput screening for DPYD variants by DHPLC may be a reliable tool in the investigation of the molecular basis of DPD deficiency. Furthermore, it will help to identify patients at risk for toxic side effects upon chemotherapy using 5-FU and will facilitate individual treatment of patients.