Multitarget Stool DNA Test Performance in an Average-Risk Colorectal Cancer Screening Population.

INTRODUCTION: We set out to evaluate the performance of a multitarget stool DNA (MT-sDNA) in an average-risk colonoscopy-controlled colorectal cancer (CRC) screening population. MT-sDNA stool test results were evaluated against fecal immunochemical test (FIT) results for the detection of different lesions, including molecularly defined high-risk adenomas and several other tumor characteristics. METHODS: Whole stool samples (n = 1,047) were prospectively collected and subjected to an MT-sDNA test, which tests for KRAS mutations, NDRG4 and BMP3 promoter methylation, and hemoglobin. Results for detecting CRC (n = 7), advanced precancerous lesions (advanced adenoma [AA] and advanced serrated polyps; n = 119), and non-AAs (n = 191) were compared with those of FIT alone (thresholds of 50, 75, and 100 hemoglobin/mL). AAs with high risk of progression were defined by the presence of specific DNA copy number events as measured by low-pass whole genome sequencing. RESULTS: The MT-sDNA test was more sensitive than FIT alone in detecting advanced precancerous lesions (46% (55/119) vs 27% (32/119), respectively, P < 0.001). Specificities among individuals with nonadvanced or negative findings (controls) were 89% (791/888) and 93% (828/888) for MT-sDNA and FIT testing, respectively. A positive MT-sDNA test was associated with multiple lesions (P = 0.005), larger lesions (P = 0.03), and lesions with tubulovillous architecture (P = 0.04). The sensitivity of the MT-sDNA test or FIT in detecting individuals with high-risk AAs (n = 19) from individuals with low-risk AAs (n = 52) was not significantly different. DISCUSSION: In an average-risk screening population, the MT-sDNA test has an increased sensitivity for detecting advanced precancerous lesions compared with FIT alone. AAs with a high risk of progression were not detected with significantly higher sensitivity by MT-sDNA or FIT.

Effect of sequential and daily continuous hormone replacement therapy on indexes of mineral metabolism.

BACKGROUND: Continuous regimens of estrogen-progesterone have recently been favored over sequential regimens because of a lower incidence of withdrawal bleeding. To determine whether the beneficial effects of sequential hormonal therapy on bone metabolism are preserved with the newer continuous regimens, we studied indexes of skeletal metabolism and changes in bone mineral density during a 1-year prospective trial. METHODS: Our subjects were randomized to one of three treatment groups: those in group C-2.5 were treated with 0.625 mg of conjugated estrogen with 2.5 mg of micronized medroxyprogesterone acetate daily continuously; group C-5 received 0.625 mg of conjugated estrogen and 5.0 mg of micronized medroxyprogesterone acetate daily continuously; and group S-5 received 0.625 mg of conjugated estrogen on days 1 through 25 and 5 mg of micronized medroxyprogesterone acetate on days 14 through 25. RESULTS: At 1 year, all groups demonstrated a significant decrease in indexes of bone formation turnover, including decrements in alkaline phosphatase levels of 11% to 30% and in osteocalcin levels of 45% to 60%. Intact parathyroid hormone levels rose 10% to 20%, with a concomitant near-significant decrement in ionized calcium levels at 12 months. In addition, there were significant decrements in the 24-hour urinary calcium-creatinine ratios and hydroxyproline-creatinine ratios of 13% to 28%, measures of bone resorption. Linear regression analyses showed that the subjects with the high bone resorption achieved the greatest increment in bone mineral density in response to hormone therapy. CONCLUSION: The daily continuous estrogen-progesterone regimens are as efficacious as sequential hormonal therapy in decreasing indexes of bone turnover and stabilizing bone mineral density of the spine and proximal femur.

ThinPrep Processor. Clinical trials demonstrate an increased detection rate of abnormal cervical cytologic specimens.

The authors compared the accuracy of conventionally prepared smears and smears prepared by an automated, fluid-based, thin-layer processing device in the detection of cytologic abnormalities. A total of 3218 patients from five centers took part in this study, in which a single cervical sample was split into a matched pair. The conventional smear was made in the routine fashion; the remainder of the cells on the sampling device were rinsed into a transport-fixation fluid. A slide was then prepared from the solution using the thin-layer processor. Diagnostic findings identified on the two preparations were compared in a blinded fashion, and a discrepancy resolution procedure was used to eliminate screening differences. Overall, there was a high correlation in the diagnoses of the two methods. For low-grade or more severe disease, the thin-layer method resulted in a 13% increase in the rate of detection, as compared with the conventional Papanicolaou smear technique.

Effect of celiprolol, a new beta 1-alpha 2 blocker, on the cardiovascular response to exercise.

The pharmacodynamics of beta blockade with single oral doses of celiprolol 200 and 400 mg, compared with placebo, atenolol 50 and 100 mg, propranolol 80 and 160 mg, metoprolol 100 and 200 mg, and pindolol 5 and 10 mg, were evaluated in an open, incomplete-block study design employing 11 healthy male volunteers. Each subject received five of the 11 possible treatments at weekly intervals. The maximal rate-pressure product (RPP) induced by standardized treadmill exercise was measured 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours after each treatment. During the course of the exercise test, heart rate and systolic blood pressure were recorded at one-minute intervals for five minutes. The maximal RPP, heart rate, and the maximum change from baseline were calculated for each exercise period. The data were analyzed using absolute reduction and percentage reduction of these parameters. All of the beta blockers tested produced significant decreases (P less than .05) in the exercise RPP, ranging from 16% reduction for celiprolol 200 mg to 47% reduction for propranolol 160 mg at peak response. Celiprolol 400 mg reduced the RPP by 31% at peak effect and did not differ significantly from the other treatments. Celiprolol 400 mg and atenolol 100 mg were the only agents that significantly reduced the RPP 24 hours posttreatment (20.7% and 21.7%, respectively) compared with placebo. Celiprolol 400 mg was the only agent to significantly reduce exercise heart rate 24 hours posttreatment (26.6 beats, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption of danazol after administration to different sites of the gastrointestinal tract and the relationship to single- and double-peak phenomena in the plasma profiles.

The absorption of danazol (100 mg) after oral or intraintestinal administration to the proximal jejunum or proximal ileum has been studied in healthy female subjects. The extent of danazol absorption after administration as a solubilized glycerol mono-oleate emulsion formulation was approximately twofold and fourfold greater after oral dosing when compared with jejunal or ileal administration, respectively. Although not statistically significant in this study, the extent of absorption after jejunal administration was generally greater than after ileal administration. After oral dosing, qualitative assessment identified the presence of double peaks or major shouldering characteristics in 14 of the 16 individual danazol plasma concentration-time profiles, whereas only single peaks were present after intraintestinal administration. These data are consistent with the double peaking phenomena after oral administration of the emulsion formulation being stomach-related. The double peaking effect may be explained in terms of a probable combination of gastric emptying regulated absorption (due to the presence of the lipid in the emulsion formulation) and the dependence of danazol solubility on bile salt solubilization within the upper small intestine.

Effect of food and a monoglyceride emulsion formulation on danazol bioavailability.

The bioavailability of a single 100-mg dose of danazol delivered from the commercial formulation (hard gelatin capsule) and from an experimental lipid emulsion formulation of danazol was studied in 11 healthy female volunteers in both fed and fasted states. The emulsion formulation (fasted) increased bioavailability fourfold compared with the capsule (P = .0001); the difference, however, was not significant in the fed state. Food increased the bioavailability of the capsule formulation more than threefold over fasted administration (P = .0001). In a separate study of 12 female volunteers, single doses of the emulsion formulation of danazol administered with food demonstrated essentially dose-proportional pharmacokinetics over the dose range studied (50-200 mg). The authors conclude that factors that increase the extent of solubilization lead to significant enhancement in the bioavailability of danazol.

Cardiac effects of noncardiac neoplasms.

Clinically significant cardiovascular abnormalities may occur as secondary manifestations of noncardiac neoplasms. The principal cardiac effects of noncardiac tumors include the direct results of metastases to the heart or lungs, the indirect effects of circulating tumor products (causing nonbacterial thrombotic endocarditis, myeloma-associated amyloidosis, pheochromocytoma-associated cardiac hypertrophy and myofibrillar degeneration, and carcinoid heart disease), and the undesired cardiotoxicities of chemotherapy and radiotherapy.

Multiresidue determination of sulfonylurea herbicides by capillary electrophoresis for hydrolysis studies in water and sediments.

Twelve sulfonylurea herbicides (bensulfuron-methyl, sulfometuron-methyl, ethametsulfuron-methyl, triasulfuron, tribenuron-methyl, nicosulfuron, chlorimuron-ethyl, thifensulfuron-methyl, primisulfuron-methyl, metsulfuron-methyl, chlorsulfuron, and amidosulfuron) were separated by free zone capillary electrophoresis with migration times less than 20 min. The additional simultaneous determination of the 2,3-dihydro-3-oxobenzisosulfonazole (saccharin) degradation product was possible after application of a temperature and voltage gradient. Detector responses (absorbances) at 239 and 220 nm were linear between 0.1 and 10.0 microg/ml. After extraction with acetonitrile, recoveries for the same concentration range from two different sediments were higher than 90% with variation coefficients lower than 16%. Dissociation constants of the sulfonylurea herbicides were determined.

Clinical and cost implications of new technologies for cervical cancer screening: the impact of test sensitivity.

OBJECTIVE: To compare the available techniques for cervical cancer screening, including several new technologies, using actual program utilization patterns. STUDY DESIGN: Longitudinal cohort model. PATIENTS AND METHODS: The model followed a cohort of 100,000 women who underwent screening from age 20 through 65 years. The model was run with a weighted average of screening intervals to model the actual utilization of the cervical cancer screening program in the United States. RESULTS: The model demonstrated that new technologies with significantly increased test sensitivity have the potential to reduce the number of cancers by 45% to 60% depending on the screening frequency in fully compliant populations. At screening intervals of 2 years or more, these new technologies had cost-effectiveness ratios below $50,000 per life-year saved. Assuming existing utilization patterns, the model predicted there would be 13.2 cancers per year in the 100,000 women screened with the conventional Pap smear, and new technologies with increased test sensitivity could reduce the annual incidence to 9.5 cancers per 100,000 women screened. CONCLUSIONS: The model suggests that to achieve further dramatic reduction in cervical cancer mortality, significant improvements in test sensitivity, as reflected in the new screening technologies, may be the most realistic and cost-effective approach.

Factors influencing transformation rates and formation of products of phenylurea herbicides in soil.

Transformation rates of phenylurea herbicides and their products were measured in native soil, sterile soil, soil suspensions, and soil inoculated with pure cultures of microorganisms. In native soil, transformation rates generally increased with decreasing adsorption of the herbicides, but correlations with adsorption coefficients were poor. In sterile soil, substitution patterns of the compounds influenced transformation rates. In soil suspensions, transformation rates increased with lipophilicity of the herbicides. In sterilized soil inoculated with specific microorganisms, transformation was mainly influenced by substrate specificities of the microorganisms to reactive sites of the phenylureas. In all cases, N-demethylation was an important, but not the only, transformation pathway. The data indicate that transformation rates of phenylureas in soils are affected by several parameters, related to the soil, the compounds, and the type of transformation. Although the results were gained in the laboratory under artificial conditions, they form a basis to establish quantitative structure-reactivity relationships and provide explanations for quality and quantity of the formed products.

Detecting semen antisperm antibodies in the clinical laboratory.

Although antisperm antibodies are associated with infertility, many hospital laboratories do not test for these antibodies. This study included 520 males who were referred for infertility evaluation. Semen samples from all patients were tested for antisperm antibodies by using the mixed antiglobulin reaction and immunobead binding tests. These results were correlated with the findings of semen analyses, postcoital tests, and sperm penetration assays. Eighty-eight men (16.9%) tested positive for IgG, IgA, or IgM antisperm antibodies. More samples tested positive for IgG antibodies by the mixed antiglobulin reaction than by the immunobead test (n = 71 vs n = 42); 57 samples tested IgA positive. Both methods showed good reproducibility (97.6%). Antibody-positive males had a higher incidence of abnormal semen analyses (92% vs 74%) and other immune-related fertility test results (94.2% vs 38.4%). The presence of antisperm antibodies correlates with other abnormal semen parameters. Testing for these antibodies should be included in an infertility evaluation and could be readily implemented in a clinical laboratory.

Parallel pathologies? Vulvar vestibulitis and interstitial cystitis.

OBJECTIVE: To determine if epithelial defects found only with periodic acid-Schiff/colloidal iron staining and Van Gieson counterstaining of the bladder in interstitial cystitis (IC) exist in the vulva in vulvar vestibulitis syndrome (VVS) and to determine if immunofluorescence seen in IC exists in VVS. STUDY DESIGN: Vulvar biopsies from 16 prospective and 16 retrospective cases of VVS were stained with Van Gieson stain, as were 30 controls of normal vulvar vestibule from biopsies obtained for benign lesions. Sixteen prospective vulvar biopsies from patients with VVS were evaluated for immunofluorescence. RESULTS: No obvious epithelial defects were found with Van Gieson staining in VVS. Three cases were eliminated for diagnoses other than VVS. Nine of 13 cases showed + to +3 complement (P = .0000005). Seven of 13 showed +IgM (P = .0000005). CONCLUSION: Vulvar epithelium stained with Van Gieson stain did not show defects in VVS but did show complement deposition along the dermoepithelial junction and perivascular IgM. Vascular injury associated with altered central neuronal processing could mediate the positive immunofluorescence findings in both VVS and IC.

Using the Pathfinder system to reduce missed abnormal cervical cytologic smear cases in a rescreening program.

OBJECTIVE: To evaluate the effect of Pathfinder (CompuCyte Corp., Cambridge, Massachusetts, U.S.A.), a process control instrument for microscopes used by cytotechnologists to monitor the mechanical aspects of their screening process, on the false negative cervical cytologic smear rate as detected in daily quality assurance rescreening. STUDY DESIGN: Pathfinder was put into routine use in a large cytology laboratory. After cytotechnologists were trained in its use, they monitored their time spent screening each slide, the area (percent) of the slide screened and the average percentage of overlap of fields of view. The number of abnormal cases missed in screening before and after the introduction of Pathfinder was determined by rescreening a random 10% of the "negative" cases. The evaluation took place over a nine-month period. RESULTS: A decrease in the number of missed abnormal cases was identified. The false negative rate for atypical cells of undetermined significance (ASCUS) fell from 37/2,336 (1.6%) to 12/1,772 (0.7%), for a 56% decrease. The change in the number of squamous intraepithelial lesion cases, even over a nine-month period, was too small for comment. CONCLUSION: The effect of the continuous feedback and process standardization provided by the Pathfinder system was a decrease in the number of abnormal cases missed. This was due primarily to a marked decrease in the number of ASCUS cases missed. The Pathfinder provides a number of innovative management tools to ensure consistent high quality screening.

Statistical quality assurance in cytology. Use of the Pathfinder to continuously assess screener process control in real time.

OBJECTIVE: To evaluate the suitability of the Pathfinder (CompuCyte Corp., Cambridge, Massachusetts, U.S.A.), an innovative instrument for monitoring the mechanical aspects of cytology screening, as a training aid and workstation component for cytotechnologists for daily work flow in a large cytology laboratory. STUDY DESIGN: The impact of the implementation of the Pathfinder was assessed by comparing the performance of a group of senior cytotechnologists with the Pathfinder features enabled (displayed) and disabled (not displayed). When enabled, statistical parameters, including the percentage of screenable slide surface viewed, the amount of time spent viewing the slide and the percentage of overlap of the fields of view, were continuously displayed to the cytotechnologist on a small, dedicated video display terminal. Areas of the slide requiring additional review by the pathologist were indicated by a series of electronic icons placed by the cytotechnologists. RESULTS: The Pathfinder was found to provide critical insight into the variability that exists among cytotechnologists in their approach to screening. By establishing laboratory performance criteria for the aforementioned parameters, variability in performance could be reduced immediately. CONCLUSION: The continuous feedback provided by the Pathfinder to the cytotechnologist during the actual screening process could help to diminish false negative cervical cytologic smear evaluations due to correctable unsuspected errors in the practice of screening.

Quantitative structure-transformation relationships of phenylurea herbicides.

Quantitative relationships between the structure of phenylurea herbicides and their transformation in different matrices have been developed. Experimental data on microbial transformation by pure and mixed cultures of soil micro-organisms in inoculated and native soil, as well as on chemical transformation by hydrolysis in sterile soil and water, were available from previous studies. Around 60 experimental or calculated descriptors were used. Quantum chemical calculations were performed with three different semi-empirical methods. Models developed with multiple linear regression were generally easier to interpret than those derived with partial least-squares projection to latent structures. Quite simple and interpretable models could be found to predict transformation rates by pure cultures from lipophilicity, by mixed cultures from adsorption distribution coefficients, and by chemical or enzymatic hydrolysis from electronic properties. Transformation in inoculated soil could not be predicted, but for native soil the use of a quantum chemical descriptor for reactivity (energy of LUMO) together with molar refraction resulted in a general model.