Pretreatment Serum Folate Levels and Toxicity/Efficacy in Colorectal Cancer Patients Treated With 5-Fluorouracil and Folinic Acid.

BACKGROUND: 5-Fluorouracil (5-FU) chemotherapy is associated with severe and unpredictable toxicity in a significant proportion of patients. 5,10-Methylenetetrahydrofolate and 5-fluorodeoxyuridine monophosphate bind to thymidylate synthase and together inhibit its function, resulting in cytotoxicity. We hypothesized that susceptibility to 5-FU toxicity might be related to individual differences in the serum components of folate metabolism affecting intracellular 5,10-methylenetetrahydrofolate levels. PATIENTS AND METHODS: A prospective cohort of chemotherapy-naive colorectal cancer patients scheduled to receive intravenous 5-FU and folinic acid for 5 consecutive days every 4 weeks in both adjuvant and palliative settings was studied. Pretreatment clinical and laboratory data were collected. Biochemical data associated with folate metabolism were also collected. The primary endpoint was the occurrence of grade ≥ 3 toxicity and/or toxicity mandating dose delay or reduction. RESULTS: For the 78 eligible patients studied, multivariable analyses identified only a greater pretreatment serum folate level as an independent predictor of grade ≥ 3 toxicity and/or mandating schedule modification (P = .016). Comparing the patient cohorts among the folate quartile groups revealed increasing toxicity trends in the highest quartile with an odds ratio of 2.58 (P = .19) compared with the combined lower quartiles, and superior relapse-free and overall survival for patients treated in the adjuvant setting. Log-rank analysis showed a significant association between higher folate levels and relapse-free and overall survival. CONCLUSION: The pretreatment serum folate level did not conclusively influence 5-FU toxicity and antitumor efficacy. However, high folate levels showed a trend toward a greater incidence of severe toxicities but also lower rates of disease recurrence and mortality. These results provide promising hypothesis-generating data warranting further investigation. The predictive value of pretreatment folate status should be a priority for study in cancer patients receiving 5-FU-based chemotherapy and should be considered a potentially confounding factor in clinical trials and a modifiable parameter in treatment.

Increase of urinary 5-hydroxyindoleacetic acid excretion but not serum chromogranin A following over-the-counter 5-hydroxytryptophan intake.

BACKGROUND: 5-hydroxyindoleacetic acid (5-HIAA) excretion is commonly measured for biochemical detection of carcinoid tumours. A 77-year-old woman was referred for elevated 24 h urine 5-HIAA excretion (510 micromol/day; normal is less than 45 micromol/day) and serum chromogranin A (CgA) (72.1 U/L; normal is less than 18 U/L), both subsequently normalized after discontinuation of 5-hydroxytryptophan (5-HTP). 5-HTP, a precursor of serotonin, is not commonly listed as a substance that increases 5-HIAA levels in urine. The effect of 5-HTP on CgA has not been previously described. OBJECTIVES: To determine whether, and to what extent, oral 5-HTP increases urine 5-HIAA excretion and serum CgA levels in healthy volunteers. PATIENTS AND METHODS: A randomized, prospective, double-blind, placebo-controlled crossover study, with a four-day washout period, was performed in a general community setting. Eight healthy subjects aged 22 to 58 years were recruited by advertising. Bedtime ingestion of 5-HTP 100 mg/day was compared with placebo ingestion for 10 days. Twenty-four hour urine excretion of 5-HIAA and serum CgA were the main outcome measures. RESULTS: Median (range) urinary 5-HIAA excretion was 204 micromol/day (22 micromol/day to 459 micromol/day) during 5-HTP intake, compared with 18 micromol/day (12 micromol/day to 36 micromol/day) during placebo intake (P=0.017). 5-HTP did not affect clinical symptoms or serum CgA levels. CONCLUSIONS: Oral 5-HTP increases urinary 5-HIAA excretion with considerable interindividual variation. In a small number of subjects, oral 5-HTP did not affect serum CgA levels. Therefore, increased 5-HIAA levels with normal CgA levels may suggest 5-HTP ingestion. The use of over-the-counter 5-HTP should be excluded as the cause of increased urinary 5-HIAA levels before initiating diagnostic tests to search for a carcinoid tumour. 5-HTP should be added to popular references as a substance that may cause increased 5-HIAA excretion.

Measurement of cortisol in human hair as a biomarker of systemic exposure.

PURPOSE: Current methods for measuring long-term endogenous production of cortisol can be challenging due to the need to take multiple urine, saliva or serum samples. Hair grows approximately 1 centimeter per month, and hair analysis accurately reflects exposure to drug abuse and environmental toxins. Here we describe a new assay for measurement of cortisol in hair, and determined a reference range for non-obese subjects. METHODS: For measurement of cortisol in hair we modified an immunoassay originally developed for measuring cortisol in saliva. We compared hair samples obtained from various parts of the head, and assessed the effect of hair dying. We analyzed hair samples from non-obese subjects, in whom we also obtained urine, saliva and blood samples for cortisol measurements. RESULTS: The mean extraction recovery for hair cortisol standards of 100 ng/ml, 50 ng/ml and 2 ng/ml (n=6) was 87.9%, 88.9% and 87.4%, respectively. Hair cortisol levels were not affected by hair color or by dying hair samples after they were obtained. Cortisol levels were decreased in hair that was artificially colored before taking the sample. The coefficient of variation was high for cortisol levels in hair from different sections of the head (30.5 %), but was smaller when comparing between hair samples obtained from the vertex posterior (15.6%). The reference range for cortisol in hair was 17.7-153.2 pg/mg of hair (median 46.1 pg/mg). Hair cortisol levels correlated significantly with cortisol in 24-hour urine (r=0.33; P=0.041). CONCLUSION: The correlation of hair cortisol with 24-hour urine cortisol supports its relevance as biomarker for long-term exposure.

Outcome validation of the Beckman Coulter access analyzer in a second-trimester Down syndrome serum screening application.

BACKGROUND: Mid-trimester maternal serum alpha-fetoprotein (AFP) and unconjugated estriol (uE3) are 30% lower and human chorionic gonadotropin (hCG) is twofold higher in Down syndrome pregnancies compared with unaffected pregnancies. In maternal serum screening, patient-specific risks are calculated using published gaussian frequency distribution parameters for these three markers obtained with previously available immunoassays. New immunoassays must generate similar distribution parameters if the accuracy of assigned risks and overall performance of prenatal screening are to be maintained. METHODS: Agreement between the Beckman Coulter Access and the Bayer Immuno 1 assays for AFP and hCG and the Amersham Amerlex-M RIA for uE3 was assessed in 558 fresh sera. Precision was measured over 6 weeks. Median concentrations were calculated by regression of 568 Caucasian singleton pregnancy samples against gestational age in days. Frozen mid-trimester sera from 44 confirmed Down syndrome singleton pregnancies (cases) were selected without conscious bias for reanalysis, and each case was matched with five control specimens from unaffected pregnancies. Serum markers were expressed as the multiple of the median (MoM) concentration derived from the control samples, corrected for maternal weight and converted to their log-equivalent values. Normality was assessed using probability plots and the Shapiro-Wilk W-test. Gaussian distribution parameters were compared with established values, and Down syndrome risk calculations were assessed with a commonly used risk algorithm. RESULTS: The Access AFP and hCG assays had consistent proportional agreement with the established assays, whereas agreement between the uE3 methods was less consistent. Analytical imprecision was 3-6% at mid-trimester concentrations. Normal distributions were obtained for the log MoM values of all three markers in both the Down syndrome and unaffected populations, and their gaussian distribution parameters compared well with established values. The performance of the Access assays in an established trivariate risk algorithm for Down syndrome was equal to the performance exhibited by traditional methods. CONCLUSION: The Beckman Coulter Access analyzer provides valid mid-trimester serum AFP, uE3, and hCG results and risk assessments when applied in a prenatal Down syndrome screening service.