The annual Papanicolaou test. Women's safety and public policy.
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Adenocarcinoma↗
Biomedical subjects
D D Davey
Publications and source records attributed to D D Davey.
Reparative changes and the false-positive/false-negative Papanicolaou test: a study from the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology .
CONTEXT: Reparative changes can be a diagnostic challenge on Papanicolaou tests and must be distinguished from epithelial cell abnormalities. Both squamous intraepithelial lesions (SIL) and carcinoma may be underdiagnosed as repair. This study examines laboratory and cytologist performance in the diagnosis of repair. OBJECTIVES: To determine if laboratories and cytologists can consistently distinguish reparative changes from SIL and carcinoma and to document how often SIL and carcinoma are mistaken for repair in a standardized educational slide program. DESIGN: Results for reparative changes, SIL, and carcinoma slides from the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology for 1998 were analyzed. Only results from validated referenced slide responses were used. RESULTS: The concordancy rate for reparative-change slides, that is, any response of within normal limits or benign cellular changes, ranged from 91% to 94% for cytotechnologist, pathologist, and laboratory responses. False-negative rates for squamous carcinoma and adenocarcinoma, high-grade SIL, and low-grade SIL ranged from 0.47% to 5.41%; the proportion of false-negative diagnoses of reparative changes ranged from 24% to 62% of all discordant responses. CONCLUSIONS: Of all benign cellular changes and within normal limits categories in the Interlaboratory Comparison Program in Cervicovaginal Cytology, repair most often elicits a false-positive laboratory response. Underdiagnosing epithelial abnormalities as repair is also a source of false-negative Papanicolaou test results.
Cervix Uteri↗
Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa.
Factor Xa plays a critical role in the formation of blood clots. This serine protease catalyzes the conversion of prothrombin to thrombin, the first joint step that links the intrinsic and extrinsic coagulation pathways. There is considerable interest in the development of factor Xa inhibitors for the intervention in thrombic diseases. This paper presents the structure of the inhibitor ZK-807834, also known as CI-1031, bound to factor Xa and provides the details of the protein purification and crystallization. Results from mass spectrometry indicate that the factor Xa underwent autolysis during crystallization and the first EGF-like domain was cleaved from the protein. The crystal structure of the complex shows that the amidine of ZK-807834 forms a salt bridge with Asp189 in the S1 pocket and the basic imidazoline fits snugly into the S4 site. The central pyridine ring provides a fairly rigid linker between these groups. This rigidity helps minimize entropic losses during binding. In addition, the structure reveals new interactions that were not found in the previous factor Xa/inhibitor complexes. ZK-807834 forms a strong hydrogen bond between an ionized 2-hydroxy group and Ser195 of factor Xa. There is also an aromatic ring-stacking interaction between the inhibitor and Trp215 in the S4 pocket. These interactions contribute to both the potency of this compound (K(I) = 0.11 nM) and the >2500-fold selectivity against homologous serine proteases such as trypsin.
1-Carboxyglutamic Acid↗
Incredibly low false-negative proportion: watch out!
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Benchmarking↗
HPV primary screening for cervical cancer: more pain than protection.
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Adult↗
Diagnostic and clinical implications of lineage fidelity in acute leukemia patients undergoing allogeneic stem cell transplantation.
We report on a series of five acute leukemia patients who have undergone allogeneic bone marrow transplantation. Initially, these patients were classified as having biphenotypic leukemia; however, subsequent developments in the perception of what constitutes lineage fidelity has resulted in controversy regarding the diagnosis. Flow cytometry and non-random cytogenetic results have had a major impact on redefining the concept of biphenotypic disease. In this report we review the diagnostic dilemma associated with defining acute leukemia lineage fidelity as diagnostic techniques evolve. While our unique focus on the treatment of biphenotypic leukemia patients represents a small population, we verify the single most promising therapy where otherwise the diagnosis is dismal.
Acute Disease↗
Atypical epithelial cells and specimen adequacy: current laboratory practices of participants in the college of American pathologists interlaboratory comparison program in cervicovaginal cytology.
CONTEXT: The Bethesda System for reporting cervical/vaginal cytologic diagnoses introduced terminology for atypical squamous and glandular cells and categories for specimen adequacy. OBJECTIVES: To analyze current laboratory reporting practices and compare trends to previous surveys. DESIGN: Questionnaire surveys were mailed to 2000 laboratories in 1996 and 1997. PARTICIPANTS: Laboratories enrolled in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology. MAIN OUTCOME MEASURES: Laboratory policies, criteria, and reporting rates for Bethesda System categories. RESULTS: The 1996 specimen adequacy survey had 1166 respondents, and 768 laboratories returned the 1997 questionnaire focusing on atypical squamous cells of undetermined significance (ASCUS) and glandular cells of undetermined significance (AGUS). Nearly all laboratories (92%) routinely reported specimen adequacy, an increase from the 66% rate in 1991. The median rate for unsatisfactory specimens was 0.5% (mean 0.95%), and the median rate for the satisfactory but limited category was 5.8% (mean 9.3%). The Bethesda criteria for designating a specimen unsatisfactory were used by more than 90% of laboratories. Nearly all laboratories (97%) used the term ASCUS in 1997, and more than 80% of laboratories used the Bethesda criteria for this category. Median reporting rates for epithelial abnormalities were as follows: ASCUS, 4.5%; AGUS, 0.3%; low-grade squamous intraepithelial lesion (SIL), 1.6%; and high-grade SIL, 0.5%. The median ASCUS/SIL ratio was 2.0, with 80% of laboratories reporting ratios between 0.64 and 4.23. The median ASCUS rate and ASCUS/SIL ratio were higher than 1993 survey results. Nearly all laboratories attempted follow-up studies on patients with abnormal cytology results, and midsized laboratories achieved the highest rates of follow-up. Median rates of abnormalities following an ASCUS or AGUS diagnosis were 20% and 15%, respectively. Laboratory respondents commonly used written recommendations in ASCUS/AGUS reports. CONCLUSIONS: Most laboratories that responded to the surveys had adopted Bethesda terminology and criteria for specimen adequacy and ASCUS/AGUS. Reporting rates for SIL and adequacy categories have remained stable, but median ASCUS rates and ASCUS/SIL ratios are higher than in 1993. The AGUS category is reported infrequently, but can be associated with significant pathology.
Clinical Laboratory Techniques↗
Quality management in gynecologic cytology using interlaboratory comparison.
OBJECTIVE: To describe a comprehensive integrated laboratory quality management plan for gynecologic cytology. DESIGN AND SETTING: Cytopathology laboratory performance monitors with interlaboratory comparison. RESULTS: Utilizing College of American Pathologists Q-Probes studies, the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology, and other published data, a quality management program for gynecologic cytology involving diagnostic statistics, screening limits and competency assessment, retrospective rescreening, real-time rescreening, cytology-biopsy correlation, follow-up of patients with abnormal cytology results, turnaround time, examination of unknown slides (survey programs), and new technology is described. CONCLUSION: Regular coordinated monitoring of performance, with longitudinal and interlaboratory comparison utilizing the methods described, provides an opportunity to optimize gynecologic cytology service.
Clinical Competence↗
ThinPrep Pap Test: performance and biopsy follow-up in a university hospital.
BACKGROUND: The ThinPrep Pap Test (TP), a liquid-based cervical cytology preparation, was approved for use in the U.S. in 1996. The purpose of this study was to compare TP performance and biopsy follow-up studies with a similar population of high risk patients sampled by conventional Papanicolaou (Pap) smear (CS). METHODS: Diagnostic and specimen adequacy interpretations for 2727 TP direct-to-vial Pap tests from a high risk university hospital practice were compared with 5000 CS preparations from the same physicians taken 1 year previously. Biopsy follow-up studies for the categories of squamous intraepithelial lesion (SIL), carcinoma, and atypical squamous cells of undetermined significance (ASCUS) for each time period and technique were contrasted. RESULTS: The SIL/carcinoma detection rate increased from 7.7% to 10.5% (P < 0.01) and the ASCUS rate decreased from 12.5% to 6.9% (P < 0.01); the percentage of satisfactory but limited specimens decreased from 19.4% to 10.5% (P < 0.01). Low grade SIL cases increased by 57% (P < 0.01) whereas the 26% increase in high grade SIL cases was not statistically significant. Greater than 90% of ungraded SIL, high grade SIL, and carcinoma cases had abnormal biopsies by both the TP and CS methods. The number of biopsy-confirmed high grade dysplasias and carcinomas was similar in the two groups. A low grade SIL detected by TP was less likely to have an abnormal biopsy (70% vs. 85% for CS). Nevertheless, the 57% increase in low grade SIL diagnoses by TP resulted in more TP patients with dysplastic biopsy diagnoses. Follow-up studies for ASCUS cases diagnosed by either TP or CS were similar, and 21-24% of patients eventually were found to have dysplasia. CONCLUSIONS: The TP technique appears to lead to the increased detection of low grade SIL lesions, decreased satisfactory but limited samples, and fewer equivocal specimens. No increase in biopsy-confirmed high grade dysplasias and carcinomas was found. Follow-up studies for the ASCUS category were nearly identical to those for CS.
Adult↗
Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors.
A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. The evolution from the photochemically unstable bisamidine (Z,Z)-BABCH to potent bisamidine compounds with a pyridine heterocycle as the core scaffold has been achieved. The most potent compound in the series, 6h, has a Ki for human factor Xa of 12 nM. The selectivity of 6h against bovine trypsin and human thrombin was greater than 90- and 1000-fold, respectively. Two proposed modes of binding of 6h to factor Xa are made based on the crystal structures of 6h by itself and of 6h bound to bovine trypsin.
Amidines↗
Crystallographic analysis of potent and selective factor Xa inhibitors complexed to bovine trypsin.
Factor Xa is a serine protease which activates thrombin (factor IIa) and plays a key regulatory role in the blood-coagulation cascade. Factor Xa is, therefore, an important target for the design of anti-thrombotics. Both factor Xa and thrombin share sequence and structural homology with trypsin. As part of a factor Xa inhibitor-design program, a number of factor Xa inhibitors were crystallographically studied complexed to bovine trypsin. The structures of one diaryl benzimidazole, one diaryl carbazole and three diaryloxypyridines are described. All five compounds bind to trypsin in an extended conformation, with an amidinoaryl group in the S1 pocket and a second basic/hydrophobic moiety bound in the S4 pocket. These binding modes all bear a resemblance to the reported binding mode of DX-9065a in bovine trypsin and human factor Xa.
Animals↗
Granulocyte-colony stimulating factor (G-CSF)-primed, delayed marrow harvests as a source of hematopoietic stem and progenitor cells for allogeneic transplantation.
We evaluated the ability of G-CSF to increase the number of hematopoietic stem cells obtained by "delayed" BM harvest for allogeneic transplantation. Five normal donors received G-CSF @ 10 mcg/kg/day x 5 followed by repeat PB and BM assays at day 6 and 16, and BM harvest at day 16. Stem cells were not increased in the BM at day 16. Five patients underwent BMT and engrafted at +10 to +19 days. While the tested strategy offers no intrinsic advantages, its potential cannot be evaluated fully without alternative timing and/or additional, "early acting" growth factors.
Blood Donors↗
Interobserver variability in subclassification of squamous intraepithelial lesions: Results of the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology.
OBJECTIVE: To determine whether, on a national cytology proficiency test, a competent cytologist can consistently distinguish grades of squamous intraepithelial lesions. DESIGN: Results for low- and high-grade squamous intraepithelial lesion referenced slides from the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology for 1996 and 1997 were analyzed including educational, nongraded vs graded validated slides. RESULTS: The discrepant rate between low- and high- grade lesions ranged from 9.8% to 15% for cytotechnologist, pathologist, laboratory, and all responses. There was a statistically significant difference in performance on graded, validated slides vs educational slides with better performance on validated slides. CONCLUSION: This significant interobserver variability in subclassification of squamous lesions should be considered in management guidelines for abnormal Papanicolaou test results and implementation of national cytology proficiency testing.
Carcinoma, Squamous Cell↗
Issues in cytologic screening and evaluation.
A variety of cytologic specimens may be useful in the screening and evaluation of patients for neoplastic processes. Fine needle aspiration cytology is an example of a cost-effective procedure for mass lesions and may provide a definitive diagnosis for treatment purposes. The sensitivity of a single cytologic procedure varies from 70% to more than 90% depending on specimen type and procurement methods. Communication with the laboratory, including provision of clinical information, is important to ensure proper specimen submission and handling and will also clarify cytologic terminology and appropriate follow-up measures.
Biopsy, Needle↗
Discovery of N-[2-[5-[Amino(imino)methyl]-2-hydroxyphenoxy]-3, 5-difluoro-6-[3-(4, 5-dihydro-1-methyl-1H-imidazol-2-yl)phenoxy]pyridin-4-yl]-N-methylgl y cine (ZK-807834): a potent, selective, and orally active inhibitor of the blood coagulation enzyme factor Xa.
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Administration, Oral↗
Prognostic significance of DNA cytometry of postirradiation cervicovaginal smears.
BACKGROUND: Cytologic sampling is performed routinely after radiotherapy for cervical carcinoma. The prognostic significance of postirradiation dysplastic and atypical cells is uncertain because of difficulties in distinguishing preneoplastic and cancerous changes from benign radiation changes. DNA cytometry studies may provide a more objective method of identifying significant lesions. METHODS: Postirradiation cervical carcinoma patients with cervical/vaginal smears containing atypical or dysplastic cells were identified prospectively. Papanicolaou smears were destained, restained with a Feulgen stain, and evaluated for DNA content using image cytometry. Pathologic and clinical records were monitored on each patient for evidence of recurrence or biopsy-proven dysplasia. RESULTS: Of 46 patients, 14 had been diagnosed on cytology as having atypical squamous cells, 4 as having atypical/suspicious cells, 12 with low grade squamous intraepithelial lesions (SIL), 3 with high grade SIL, and 13 with ungraded SIL. DNA histograms were classified as follows: 14 diploid, 19 polyploid, and 13 aneuploid. Cytologic diagnosis and histogram type were correlated significantly and both correlated with clinical outcome. The probability of either postirradiation dysplasia or recurrence was as follows: SIL, 82%; suspicious, 100%; polyploid, 79%; and aneuploid, 92%. Patients with atypical squamous cells of undetermined significance or diploidy most frequently had negative follow-up (57% each). All patients with both SIL and aneuploidy developed either dysplasia or recurrence. The stage of disease did not correlate with outcome or histogram pattern. CONCLUSIONS: DNA analysis of postirradiation cytologic smears demonstrating atypia or dysplasia may provide useful ancillary information. The presence of aneuploidy usually signifies either recurrence or dysplasia. Polyploidy most frequently occurs in dysplastic processes, whereas diploid histograms usually denote a benign disease course.
Adult↗
Assessment of fine-needle aspiration sampling technique in thyroid nodules.
BACKGROUND: A prospective two-yr study was undertaken to assess the heterogeneity of thyroid nodules using the fine-needle aspiration (FNA) technique of systematic regional sampling. In addition, we determined the number of regions to be sampled to minimize non-diagnostic results, and to optimally characterize thyroid nodules. DESIGN: FNA was performed on 74 nodules > or = 1.5 cm. in diameter in five distinct regions in sequence (center, then four quadrants starting at 12:00, clockwise). Slides from each region were coded, randomized, subjected to blind review, and categorized as non-diagnostic (ND), benign (B), indeterminate (ID), suspicious/neoplastic (S/N), or malignant (M). Final cytologic diagnosis (CD) was made from all slides of each nodule. RESULTS: The ND rate for center FNAs alone was 16%, but addition of the 12:00 region decreased it to 5.3%. With 3, 4, or 5 sequential sites the nondiagnostic rates were 4, 2.6, and 2.6%. The center region diagnosis was identical to the final CD in 71% of the cases. Addition of the 12:00 region increased the concordance to 88%. Three sequential regions equaled the CD in 93% of cases, and 4 regions equaled the CD in 99% of cases. All nodules characterized as M or S/N were resected as were 76% of the ID nodules. Of the 43 nodules characterized as B, 3 were resected, 24 involuted, 6 were unchanged, and 10 were lost to follow-up. All 3 M nodules proved malignant by histology, as did 7/10 S/N, 0/17 ID, and 0/43 B nodules; 3/10 S/N, 1/17 ID and 1/43 B were adenomas. Likelihood ratios for diagnosing neoplasia were ND:0, B:0.10, ID:0.21, S/N:infinity, M:infinity. CONCLUSIONS: Sampling of at least four distinct regions accurately assesses thyroid nodules while minimizing ND results. Regional sampling also addresses intranodular heterogeneity.
Biopsy, Needle↗
Clinicopathologic correlation of the unsatisfactory Papanicolaou smear.
BACKGROUND: The 1991 Bethesda System for cervical/vaginal cytology reporting defined adequacy criteria for the unsatisfactory designation. Most laboratories have implemented these criteria, but clinical implications have not been established. METHODS: Researchers at two university hospitals retrieved by computer search all unsatisfactory Papanicolaou (Pap) smears taken between January 1994 and July 1995. Of 71,872 total Pap smears, 208 (0.3%) were unsatisfactory (corresponding atypical rate of 9% and a dysplasia/carcinoma rate of 6.5%). Time interval to follow-up and clinicopathologic outcome were determined. RESULTS: Approximately 26% of unsatisfactory Pap smears were from patients with a history of epithelial abnormalities. The majority (129 of 208 specimens; 62%) of follow-up Pap smears or biopsies occurred within 6 months, 5.7% within 6-12 months, and 1.4% in 12-18 months. Approximately 31% had no follow-up. The first repeat Pap smear or histologic specimen in 144 patients with follow-up was negative in 107 (74%), unsatisfactory in 6 (4%), atypical squamous cells of undetermined significance in 15 (10%), squamous intraepithelial lesion (SIL) in 13 (9%), and malignant in 3 (2%). Nonmalignant conditions contributing to the unsatisfactory smears on histologic specimens (12%) included cervicitis, endometritis, endometrial hyperplasia, and polyps. Progressive abnormalities after the first repeat specimen were noted in 7 patients (5%). A total of 23 of 144 initial unsatisfactory specimens (16% )were found to be from patients diagnosed with SIL or malignancy when all follow-up specimens were analyzed. CONCLUSIONS: The majority of patients with unsatisfactory Pap smears had follow-up studies within 6 months. A significant number (16%) of those with follow-up had eventual diagnoses of SIL or neoplasia. Benign pathologic conditions also contributed to unsatisfactory smears. This patient subset was more likely to have a history of abnormalities, confirming the importance of peer/hierarchical review of unsatisfactory smears.
Diagnosis, Differential↗