Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas.

BACKGROUND: The polyamine-inhibitory regimen difluoromethylornithine (DFMO)+sulindac has marked efficacy in preventing metachronous colorectal adenomas. Polyamines are synthesised endogenously and obtained from dietary sources. Here we investigate dietary polyamine intake and outcomes in the DFMO+sulindac colorectal adenoma prevention trial. METHODS: Dietary polyamine data were available for 188 of 267 patients completing the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and categorised into two groups: highest (>75-100%) vs the lower three quartiles (0-25, 25-50 and 50-75%). Baseline tissue polyamine concentration and ODC1 genotype were determined. Logistic regression models were used for risk estimation. RESULTS: A significant interaction was detected between dietary polyamine group and treatment with regard to adenoma recurrence (P=0.012). Significant metachronous adenoma risk reduction was observed after DFMO+sulindac treatment in dietary polyamine quartiles 1-3 (risk ratio (RR) 0.19; 95% confidence interval (CI) 0.08-0.42; P<0.0001) but not in quartile 4 (RR 1.51; 95% CI 0.53-4.29; P=0.44). However, a lower number of events in the placebo group within dietary quartile 4 confound the aforementioned risk estimates. CONCLUSION: These preliminary findings reveal complex relationships between diet and therapeutic prevention, and they support further clinical trial-based investigations where the dietary intervention itself is controlled.

Correlation of endogenous hormonal levels, fibroglandular tissue volume and percent density measured using 3D MRI during one menstrual cycle.

BACKGROUND: We measured breast density (BD) on MRI and correlated with endogenous hormonal levels. PATIENTS AND METHODS: Twenty-four premenopausal women received four weekly breast MRI. A blood sample was collected on the same day of MRI. BD was measured using a computer-based algorithm. The generalized estimation equation method was applied to model mean fibroglandular tissue volume (FV) and mean percent density (PD) from predictor variables including estradiol, progesterone, and week during a cycle. RESULTS: In week 3, a borderline significant correlation between estradiol and PD (r = 0.43, P = 0.04), estradiol and FV (r = 0.40, P = 0.05) and between progesterone and FV (r = 0.42, P = 0.04) was noted. The FV and PD measured in weeks 4 and 1 were higher than in weeks 2 and 3, adjusted for variation in endogenous estradiol and progesterone, indicating that the hormone change could not account for the changes in density. No lag effect of endogenous hormone on the change of FV or PD was noted (all P-values > 0.05). CONCLUSIONS: Our results showed that BD is not strongly associated with the endogenous hormone. Their association with breast cancer risk was likely coming from different mechanisms, and they should be considered as independent risk factors.

Independent association of angiogenesis index with outcome in prostate cancer.

New molecular factors have been characterized that are associated with the prognosis of prostate carcinoma patients, including p53 status and angiogenesis. We reported recently that mutant p53 (mp53) was associated with decreased expression of an endogenous inhibitor of angiogenesis, thrombospondin-1 (TSP-1), and increased microvessel density in melanoma and breast cancer. In this study, we performed a similar analysis on primary prostate carcinoma to determine whether these factors were associated with each other or patient outcomes. Paraffin-embedded specimens of 98 cases of primary prostate carcinoma were obtained and examined to confirm tissue diagnosis and Gleason scores. Carcinoma-specific levels of p53, TSP-1, and tumor angiogenesis were determined using semiquantitative immunohistochemistry (IHC) methods. Acquisition of mp53 was significantly associated with decreased TSP-1 (P = 0.002) and increased angiogenesis (P < 0.0001). An angiogenesis index integrating mp53, TSP-1, and angiogenesis (CD31) scores was found to be an independent predictor of survival in univariate and multivariate analyses that included Gleason score, clinical stage, and patient age. Further validation of the angiogenesis index in prostate carcinoma may provide a new tool to stratify patient risk.

The natural history of intravenous catheter-associated phlebitis.

During a controlled evaluation of an intravenous therapy (IVT) team, we had the opportunity to follow up 202 episodes of catheter-associated phlebitis. While the IVT team had a considerable effect on the incidence of phlebitis, the clinical course of this complication was not influenced. More than 40% of catheter-associated phlebitis occurred more than 24 hours after withdrawal of the catheter. Premonitory symptoms were not useful in predicting the development of phlebitis. Factors that influenced the duration of phlebitis included the patient's diagnosis and the administration of vancomycin hydrochloride. The duration of phlebitis was prolonged by delayed removal of the catheter after the development of phlebitis.

Intravenous therapy team and peripheral venous catheter-associated complications. A prospective controlled study.

A prospective controlled trial was conducted on four similar inpatient medical wards to test the hypothesis that a trained intravenous therapy (IVT) team would substantially reduce the incidence of peripheral intravenous (IV) catheter-related complications. We followed 863 IV catheters. The overall incidence of phlebitis in the ward staff-maintained IV catheters was 32% as compared with 15% for those maintained by the IVT team. The incidence of two more serious complications (cellulitis and suppurative phlebitis) was reduced tenfold from 2.1% to 0.2%. We conclude that an IVT team can substantially reduce the iatrogenic complications related to IV catheters.

Single-dose administration of Bowman-Birk inhibitor concentrate in patients with oral leukoplakia.

The Bowman-Birk inhibitor (BBI) is a soybean-derived serine protease inhibitor and a potential cancer chemopreventive agent for humans. In this Phase I clinical trial, BBI concentrate was administered as a single oral dose to 24 subjects with oral leukoplakia. Pharmacokinetics of BBI was analyzed, and subjects were monitored clinically for toxic effects. Subjects received between 25 and 800 chymotrypsin inhibitor units (CIU) of the compound in a dose escalation trial. BBI was taken up rapidly, and a metabolic product of BBI was excreted in the urine within 24-48 h. No clinical or laboratory evidence of toxicity was observed in the study. Protease activity was also measured in buccal cells to evaluate usefulness as a biomarker. Single-dose BBI concentrate administered up to 800 CIU was well tolerated and appeared to be nontoxic. Further investigation in Phase II clinical trials is being done.

A method to examine the need for duplicate testing of common coagulation tests.

A statistical protocol for evaluating the need for duplicate coagulation testing was developed. It requires at least 32 sets of duplicate prothrombin times or partial thromboplastin times over the expected range of results. In addition to the statistical procedures, clinical evaluation of the duplicates is required.

Estrogen replacement therapy in endometrial cancer patients: a matched control study.

OBJECTIVE: To determine if estrogen replacement therapy, in women with a history of endometrial cancer, increases the risk of recurrence or death from that disease. METHODS: Two hundred forty-nine women with surgical stage I, II, and III endometrial cancer were treated between 1984 and 1998; 130 received estrogen replacement after their primary cancer treatments and 49% received progesterone in addition to estrogen. Among this cohort, 75 matched treatment-control pairs were identified. The two groups were matched by using decade of age at diagnosis and stage of disease. Both groups were comparable in terms of parity, grade of tumor, depth of invasion, histology, surgical treatment, lymph node status, postoperative radiation, and concurrent diseases. The outcome events included the number of recurrences and deaths from disease. RESULTS: The hormone users were followed for a mean interval of 83 months (95% confidence interval [CI] 71.0, 91.4) and the nonhormone users were followed for a comparable mean interval of 69 months (CI 59.1, 78.7). There were two recurrences (1%) among the 75 estrogen users compared with 11 (14%) recurrences in the 75 nonhormone users. Hormone users had a statistically significant longer disease-free interval than nonestrogen users (P =.006). CONCLUSION: Estrogen replacement therapy with or without progestins does not appear to increase the rate of recurrence and death among endometrial cancer survivors.

Guidelines for organisation and management of external quality assessment using proficiency testing. Expert Panel on Cytometry of the International Council for Standardization in Haematology.

This document is intended to assist towards the WHO objective that external quality assessment (EQA) schemes be established at national and/or regional levels world-wide. Quality assurance is defined as all steps taken by the director of a laboratory to ensure reliability of laboratory results and to increase accuracy, reproducibility and between-laboratory comparability. This includes the use of internal quality control procedures and participation in external quality assessment. Internal quality control provides the means for evaluation of analytic test results at the time of testing in order to decide whether they are reliable enough to be released to the requesting clinicians. EQA, on the other hand, refers to a system of retrospective and objective comparison of results from different laboratories by means of proficiency testing (PT) organised by an external agency. The main purpose is to establish between-laboratory and between-method (including between-instrument) comparability, and agreement with a reference standard where one exists. Internal quality control and EQA complement each other and must never be considered as alternatives.

Loading dose of quinine in African children with cerebral malaria.

The majority of deaths from cerebral malaria occur within 48 h after admission to hospital. Because of the possibility of inadequate treatment within this period, the use of a loading dose of quinine has been proposed. We reviewed clinical and laboratory data for 113 children with cerebral malaria, who were treated with intravenous quinine, 10 mg/kg every 8 h, at Macha Mission Hospital in rural Zambia. In 1990-1991, 39 children were not given a loading dose of quinine while, in 1992-1993, 74 children received a loading dose of 20 mg/kg. Elevated serum iron levels, as reflected in transferrin saturation, were strongly associated with higher mortality. A loading dose of quinine was associated with faster recovery from coma and enhanced clearance of parasitaemia and fever. The loading dose was also associated with trends to lower mortality and higher haemoglobin levels, but these differences were not statistically significant.

Effect of iron chelation therapy on mortality in Zambian children with cerebral malaria.

To examine the effect of iron chelation on mortality in cerebral malaria, we enrolled 352 children in a trial of deferoxamine in addition to standard quinine therapy at 2 centres in Zambia, one rural and one urban. Entrance criteria included age < 6 years, Plasmodium falciparum parasitaemia, normal cerebral spinal fluid, and unrousable coma. Deferoxamine (100 mg/kg/d infused for a total of 72 h) or placebo was added to a 7 d regimen of quinine that included a loading dose. Mortality overall was 18.3% (32/175) in the deferoxamine group and 10.7% (19/177) in the placebo group (adjusted odds ratio 1.8; 95% confidence interval 0.9-3.6; P = 0.074). At the rural study site, mortality was 15.4% (18/117) with deferoxamine compared to 12.7% (15/118) with placebo (P = 0.78, adjusted for covariates). At the urban site, mortality was 24.1% (14/58) with deferoxamine and 6.8% (4/59) with placebo (P = 0.061, adjusted for covariates). Among survivors, there was a non-significant trend to faster recovery from coma in the deferoxamine group (adjusted odds ratio 1.2; 95% confidence interval 0.97-1.6; P = 0.089). Hepatomegaly was significantly associated with higher mortality, while splenomegaly was associated with lower mortality. This study did not provide evidence for a beneficial effect on mortality in children with cerebral malaria when deferoxamine was added to quinine, given in a regimen that included a loading dose.

Mixture models in haematology: a series of case studies.

Two specific applications of finite mixture distributions in haematology include (1) the analysis of the distribution of red blood cell volumes to characterize and quantify alterations in erythrocyte subpopulations in anaemia and (2) the analysis of the distribution of transferrin saturation to estimate subpopulation parameters based on individual genotype for haemochromatosis. For these applications, we describe the comprehensive approach that was taken to distribution modeling. The choice of distributions and the number of mixture components to be fit were based upon theoretical and physiological considerations and a variety of additional statistical problems were considered. These included fitting mixtures of doubly-truncated data and evaluating model fit in the presence of extremely large sample sizes. As a result of the comprehensive approach taken to statistical problem solving in haematology, methods developed for analysis of red blood cell volume distributions have now been adopted by the International Council for Standardization in Haematology. Additionally, analysis of population transferrin saturation distributions from the white population of the USA has led to an independent estimate of the prevalence of homozygotes for haemochromatosis, confirming that the gene for haemochromatosis is common.

Effects of difluoromethylornithine chemoprevention on audiometry thresholds and otoacoustic emissions.

OBJECTIVES: To determine the effects of long-term, low-dose difluoromethylornithine (DFMO) on audiometric thresholds and distortion product otoacoustic emission (DPOAE) levels in humans. DESIGN: A prospective, randomized, placebo-controlled phase 2 clinical trial of DFMO in participants with a prior adenomatous colonic polyp. SETTING: Academic tertiary care referral center. PARTICIPANTS: One hundred twenty-three volunteer subjects with colorectal polyps and normal hearing for the frequencies 250 through 2000 Hz. INTERVENTIONS: Subjects were randomized to receive placebo or oral DFMO at daily dosages between 0.075 and 0.4 g/m(2) of body surface area for 12 months. OUTCOME MEASURES: Pure-tone audiometric thresholds for the frequencies 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz and DPOAE levels were measured at baseline and 1, 3, 6, 9, and 12 months after starting treatment with DFMO or placebo and 3 months after cessation of treatment if there was a suggestion of possible changes at the 12-month measurement. RESULTS: At these low dosages, there was little evidence for shifts in auditory pure-tone thresholds, and there were no statistically significant shifts in DPOAE levels. For auditory pure-tone thresholds, there was a subtle, approximately 2- to 3-dB hearing level decrease in hearing sensitivity for the 2 higher DFMO dosages, but only at the 2 lowest frequencies, 250 and 500 Hz. CONCLUSIONS: Administration of low-dose DFMO for 12 months did not produce hearing loss, in contrast to prior studies that used higher dosages.

Resident knowledge of charges: are we asking the right questions?

Physician knowledge of costs and charges for medical services is thought to have substantial relevance for cost containment. Unfortunately, numerous studies have demonstrated the difficulties in using educational techniques to improve knowledge and reduce charges. Furthermore, reductions in charges, when achieved, have not correlated with improved physician knowledge. The authors examined several methods of ascertaining physician knowledge of charges and they suggest that previous methods may have been too insensitive. Previous reports may have underestimated physician knowledge of costs and charges.

Uniformity of liver density and nonheme (storage) iron distribution.

The extent of variation in tissue density and hepatic nonheme iron concentration has been examined at autopsy in 21 adult livers. Samples were taken from each liver at inferior and superior sites in the midaxillary, anterior axillary, and midclavicular lines. Histologic examination showed diffuse metastatic carcinoma, cirrhosis, fibrosis, necrosis, steatosis, or congestion in 19 livers; two livers were normal. Density was determined by saline displacement of 0.5- to 1.0-g specimens. Nonheme iron concentration was measured at each site in samples of the size obtained by wedge (0.5 to 1.0 g) and percutaneous needle (0.005 to 0.010 g) biopsy using specially developed chemical assays. Density was uniform within each liver. Despite the inclusion of diseased tissues, the variation in density among the 21 livers was small (coefficient of variation, 1.25%). The mean (+/- 1 SD) hepatic density was 1.051 +/- 0.013 g/mL (range, 1.017 to 1.077 g/mL). Within each liver, the nonheme iron also was uniformly distributed among the six sites. Chemical measurements of nonheme iron concentration were not significantly different in samples of the size obtained by wedge or percutaneous liver biopsy. All the hepatic nonheme iron determinations were below the upper 95% confidence limit of concentrations in adult males (480 micrograms/g). In the absence of focal lesions, the uniformity in hepatic density and nonheme iron distribution supports the assumption of several clinical methods for measuring liver storage iron (wedge and needle biopsy, determination of hepatic magnetic susceptibility, computed tomography, and magnetic resonance imaging) that one sample of liver tissue is representative of the whole organ.

Prostate needle biopsy infection after four or six dose ciprofloxacin.

OBJECTIVE: This retrospective analysis is to determine rates of clinical infection after prostate needle biopsy with four versus six doses of ciprofloxacin to previous literature. MATERIALS AND METHODS: Two groups were treated with pre and post biopsy 500 mg of ciprofloxacin twice daily by either six doses (n=337) or four doses (n=288) with the first dose given 24 or 12 hours prior to the procedure respectively. RESULTS: Six (0.96%) of the 625 patients had symptomatic urinary tract infections with a positive urinalysis and/or culture. One (0.3%) infection occurred among patients receiving six doses of ciprofloxacin, and five infections (1.7%), were identified among four dose patients. Two febrile episodes occurred in the four dose group, one requiring hospitalization. CONCLUSION: A low infection rate associated with prophylactic regimens. Six doses of ciprofloxacin appears more effective than four doses in reducing the clinical and febrile infection rate following ultrasound guided biopsy of the prostate. No obvious financial benefit was observed.

Serial serum ferritin measurements in untreated HFE C282Y homozygotes in the Hemochromatosis and Iron Overload Screening Study.

Hemochromatosis has often been associated with progressive iron overload, but the natural history of iron accumulation in untreated C282Y homozygotes has been reported infrequently. The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101 168 primary care participants for iron overload using transferrin saturation, unbound iron-binding capacity, Serum ferritin (SF), and HFE C282Y and H63D genotyping. SF was measured at initial screening (IS) and again when selected participants returned for a clinical examination (CE). The change in SF over the observation period (defined as ferritin rate of change) was analyzed according to age, gender, initial SF, initial SF/age, transferrin saturation, and iron removed by phlebotomy in C282Y homozygotes. Seventy-four male and 133 female untreated C282Y homozygotes were observed over a median of 112 days (34-924 days) between IS and CE. In men, SF increased in 54% and decreased in 46%. In women, SF increased in 50% and decreased in 50%. The significant variables affecting the SF rate were initial log SF (P = 0.0027) and transferrin saturation (P < 0.0001). Male C282Y homozygotes with higher SF rates (n = 27, upper 50th percentile) had significantly greater iron removed by phlebotomy (mean 4.93 g, range 1.0-17 g) than those with lower SF rates (n = 26, lower 50th percentile) (mean 2.6 g, 0.42-7.1, P < 0.05). SF was as likely to decrease as increase in untreated C282Y homozygotes over this relatively brief observation period. Incremental increases in SF are not inevitable in untreated C282Y homozygotes.

A genome-wide linkage scan for iron phenotype quantitative trait loci: the HEIRS Family Study.

Iron overload phenotypes in persons with and without hemochromatosis are variable. To investigate this further, probands with hemochromatosis or evidence of elevated iron stores and their family members were recruited for a genome-wide linkage scan to identify potential quantitative trait loci (QTL) that contribute to variation in transferrin saturation (TS), unsaturated iron-binding capacity (UIBC), and serum ferritin (SF). Genotyping utilized 402 microsatellite markers with average spacing of 9 cM. A total of 943 individuals, 64% Caucasian, were evaluated from 174 families. After adjusting for age, gender, and race/ethnicity, there was evidence for linkage of UIBC to chromosome 4q logarithm of the odds (LOD) = 2.08, p = 0.001) and of UIBC (LOD = 9.52), TS (LOD = 4.78), and SF (LOD = 2.75) to the chromosome 6p region containing HFE (each p < 0.0001). After adjustments for HFE genotype and other covariates, there was evidence of linkage of SF to chromosome 16p (LOD = 2.63, p = 0.0007) and of UIBC to chromosome 5q (LOD = 2.12, p = 0.002) and to chromosome 17q (LOD = 2.19, p = 0.002). We conclude that these regions should be considered for fine mapping studies to identify QTL that contribute to variation in SF and UIBC.