5FU continuous infusion in heavily pretreated advanced breast cancer patients.

BACKGROUND: Despite advances in the first- and secondline treatment of advanced breast cancer, optimal therapy thereafter remains controversial. Treatment of heavily pretreated patients is not standardized, often of low efficacy, and limited by comorbidity. In these patients, an effective treatment with low toxicity is needed. PATIENTS AND METHODS: We retrospectively analyzed all metastatic breast cancer patients treated with 5-fluorouracil as continuous infusion (CI-5FU) with daily doses of 150-300 mg/m(2). RESULTS: 43 patients were treated with CI-5FU until disease progression. The median number of metastatic sites was 3. Most patients were heavily pretreated with a median of 3 palliative chemotherapies (range 1-11). 42 patients were evaluable for objective response; among them 5 (12%) showed a partial response (PR) and 6 (15%) showed stable disease (SD) lasting at least 6 months, leading to a clinical benefit (CB) rate (complete response + PR + SD ≥ 6 months) of 27%. The median time to progression of patients with CB was 10 months (range 3-22). Overall survival of all patients from the start of CI-5FU was 8 months (range 1-75) and from the time of first metastases 42 months (range 9-281). Toxicity was low even in patients with hepatic insufficiency. CONCLUSION: CI-5FU showed a positive efficacy/toxicity ratio. Taking into account the high number of previous treatments, it results in a remarkable CB rate of 27%.

Extraction of diethylhexylphthalate by home total parenteral nutrition from polyvinyl chloride infusion lines commonly used in the home.

OBJECTIVES: Recently, our group detected that polyvinyl chloride (PVC) perfusion lines leach large amounts of the toxic plasticizer diethylhexylphthalate (DEHP) under conditions typical of intensive care units. In the present study, we investigated the extraction of DEHP from PVC connecting tubes that are commonly used for total parenteral nutrition (TPN) solutions. The aim of the study was to estimate the amount of DEHP to which children receiving home TPN are exposed for months and years. MATERIALS AND METHODS: 1000 mL of TPN, identical in constitution and amount to the home TPN of 1 of our patients, were perfused through 5 different connecting tube systems and collected in hexane-rinsed glass bottles. The concentration of DEHP in the TPN was analyzed before and after perfusion. RESULTS: Before perfusion of the lines, the solution had a DEHP concentration of 0.05 to 0.69 microg/mL (baseline value). After perfusion of the lines, the load of DEHP in the solution varied between 1.41 and 2.07 microg/mL. This TPN was established for children weighing 20 kg. The daily dosage is between 71 and 104 microg x kg(-1) x day(-1). TPN is administered at home for many months and years. The monthly charge of DEHP is between 42.3 and 62.1 mg. Children weighing 20 kg therefore receive a dosage between 2.1 and 3.1 mg x kg(-1) x month(-1). CONCLUSIONS: Diethylhexylphthalate and its metabolite monoethylhexylphthalate have been demonstrated to be carcinogenic, embryotoxic, hepatotoxic, pneumotoxic, and cardiotoxic and are known to disrupt endocrine pathways and liver detoxifying capacity in animals. They are suspected of having multiple effects in humans as well. The doses presented above should therefore be avoided in children receiving home TPN by the use of tubing systems that are completely free of DEHP. Such systems are available.

Kinetics of diethylhexyl-phthalate extraction From polyvinylchloride-infusion lines.

BACKGROUND: For infusion therapy, polyvinylchloride (PVC)-infusion lines are commonly used. In this study, we examined the temperature dependency and the dynamics of extraction in the time course of infusion. METHODS: PVC-infusion lines used on the newborn ICU were perfused with a typical 24-hour fat infusion. We collected the perfused solution and measured the concentration of DEHP. This procedure was carried out at 27 degrees C and 33 degrees C. In another experiment, we examined the extraction rate in the time course of a 24-hour infusion. The infusion was collected every 4 hours. RESULTS: We discovered that extraction of DEHP depends highly on the surrounding temperature. Whereas at 27 degrees C, the extraction of DEHP was 422.78 microg/mL, the leaching reached 540.78 microg/mL at 33 degrees C under otherwise identical conditions. This is important because the temperature on a newborn ICU is between 31 and 37 degrees C in an incubator. In the other experiment, we found out that the extraction rate rose from 25.44 microg/mL in the first 4 hours to 478.1 microg/mL after 24 hours. CONCLUSIONS: The result of this study is that the actual daily load of DEHP for a 2-kg newborn is 30% higher than measured before. The rate of extraction is dependent on the time of contact between solution and tubing. If PVC-infusion systems are used, solutions should be as cold as possible, and infusion time should be as short as possible.

Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21.

OBJECTIVE: Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator-activator receptor (PPAR) alpha-dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARalpha, might modify FGF-21 levels. RESEARCH DESIGN AND METHODS: The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARgamma activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks. RESULTS: Oleate and linoleate increased FGF-21 expression and secretion in a PPARalpha-dependent fashion, as demonstrated by small-interfering RNA-induced PPARalpha knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect. CONCLUSIONS: The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity.

Methylene blue in the evaluation of gastrointestinal tract integrity: potential limitations.

INTRODUCTION: The integrity of the gastrointestinal tract can be evaluated by oral or rectal application of methylene blue. In the presence of anastomotic leaks or fistulas, methylene blue can be recovered in adjacent drains. However, parts of the dye can biochemically be reduced by intestinal bacteria to its colorless form leucomethylene blue, limiting the prediction of the test. MATERIALS AND METHODS: Diluted methylene blue was added to different concentrations of bacterial suspensions of Escherichia coli and Enterococcus faecalis. The time for discoloration of the suspension was measured. RESULTS: Reduction of methylene blue to leucomethylene blue was observed in both types of bacterial suspension. A 10(8) bacterial concentration discolorated the dye within 1 h in the E. faecalis suspension, respectively 2.5 h in the E. coli suspension. Longer bacterial interaction with methylene blue reduced the bacterial concentration required to achieve complete discoloration. DISCUSSION: Methylene blue can reliably be used as routine diagnostic test for the assessment of upper gastrointestinal integrity, where bacterial load is low. In the lower gastrointestinal tract, where bacterial load is generally higher, the dye can indicate leaks, only if extended intestinal passage after oral ingestion is avoided. In all other cases, the examiner has to be aware of false-negative results by bacterial discoloration of methylene blue.