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T J O'Leary

Publications and source records attributed to T J O'Leary.

At least 19 recordsLinked to original sources
PubMed2001

Mitotic counting in surgical pathology: sampling bias, heterogeneity and statistical uncertainty.

Mitotic counting in surgical pathology: sampling bias, heterogeneity and statistical uncertainty Although several articles on the methodological aspects of mitotic counting have been published, the effects of macroscopic sampling and tumour heterogeneity have not been discussed in any detail. In this review the essential elements for a standardized mitotic counting protocol are described, including microscopic calibration, specific morphological criteria, macroscopic selection, counting procedure, effect of biological variation, threshold, and the setting of an area of uncertainty ('grey area'). We propose that the use of a standard area for mitotic quantification and of a grey area in mitotic counting protocols will facilitate the application of mitotic counting in diagnostic and prognostic pathology.

Data Interpretation, Statistical↗
PubMed2001

Gastrointestinal stromal tumor workshop.

Gastrointestinal stromal tumor (GIST) has emerged in the past year as a prototypical neoplasm that responds to therapy directed against a single target molecule-the KIT receptor tyrosine kinase protein. Although GIST seldom responds to conventional chemotherapeutic agents, early experience with the tyrosine kinase inhibitor, STI-571 (Gleevec; Novartis, Basel, Switzerland), has been extremely encouraging. Early results have appeared in a recent case report in the New England Journal of Medicine (April 5, 2001),(1) and in early clinical trials from the United States and Europe that were reported at the plenary session of the American Society of Clinical Oncology in San Francisco on May 14, 2001. STI-571 is one of the earliest examples of a nontoxic chemotherapeutic agent (an agent whose anti-cancer activity is not predicated on a cytotoxic mechanism). STI-571 has already shown clinical value in BCR-ABL-positive leukemias. Early clinical results in GIST are so encouraging that oncologists may soon be wrestling with the opportunity of referring every patient with malignant GIST into clinical trials with STI-571. To ensure appropriate treatment, pathologists need to understand the biology and treatment of this tumor and to have standard methods and criteria for providing diagnosis (GIST or not GIST) and consistent prognostic classification (high risk of metastasis or low risk of metastasis).

Benzamides↗
PubMed2001

Pleomorphic (giant and/or spindle cell) carcinoma of lung shows a high percentage of variant CYP1A12.

BACKGROUND: Pleomorphic carcinoma (PC) of the lung is an aggressive epithelial neoplasm composed of giant and/or spindle tumor cells and associated with short survival. Most patients are cigarette smokers. The tumor susceptibility gene P-450 1A1 (CYP1A1) is involved in the activation of polycyclic aromatic hydrocarbons, including benzo[a]pyrene, producing DNA-damaging epoxides that lead to G:C-->T:A point mutations. Isoleucine (Ile)-valine (Val) and Val-Val genotypes of the CYP1A1 exon 7 polymorphism are associated with an increased risk for lung cancer in certain populations. METHODS AND RESULTS: We sought to determine whether 25 archival, formalin-fixed, paraffin-embedded PC samples had a modified CYP1A1 gene profile at exon 7 using allele-specific PCR amplification. KRAS mutation status was available for all samples. Previous investigations have shown 0.88 Ile-Ile, 0.12 Ile-Val, and rarely, Val-Val as normal baseline population frequencies. Conversely, the markedly different PC CYP1A1 population frequencies were more likely to have the heterozygote variant alleles: 0.24 (six cases, Ile-Ile) and 0.76 (19 cases, Ile-Val; P <.001). CYP1A1 genotypes were found to be similar in both tumor and nontumor samples in a given case. All KRAS-mutated cases were Ile-Val heterozygotes. CONCLUSION: The increased propensity for the variant CYP1A1 allele may be the contributing factor to PC pathogenesis and may also result from KRAS mutations in these tumors.

Alleles↗
PubMed2001

Hemochromatosis (HFE) gene sequence analysis of formalin-fixed, paraffin-embedded liver biopsy specimens.

BACKGROUND: Hereditary hemochromatosis (HH) is a common disease predominantly characterized by mutations of the HFE gene. METHODS AND RESULTS: We investigated the utility of HFE gene sequence analysis in the diagnosis of HH in 61 prospectively accrued formalin-fixed, paraffin-embedded liver biopsy specimens with clinical or histologic features suggestive of HH. Mutations in codons 63 or 282 of the HFE gene were identified by direct sequencing; in 21 of these samples, quantitative hepatic iron testing was also performed. Changes characteristic of HH were present in 16 (26%) of the cases, and 54% of the cases showed HFE gene mutations. The most common alteration was homozygous mutation of codon 282 (11 cases, 18%), followed by the combined 63 + 282 heterozygous mutation (3 cases, 5%). Two cases (3%) showed biallelic mutation of codon 63. The other 28 cases (46%) showed no sequence abnormalities. Weak iron staining did not exclude HH; intense staining did not reliably predict HH. CONCLUSION: When HH is clinically and/or histologically suspected, HFE gene sequencing of formalin-fixed, paraffin-embedded liver biopsy specimens is a rapid and cost-effective approach to genotypic diagnosis of HH.

Age Factors↗
PubMed2001

Apoptosis, bcl-2 expression, and p53 expression in gastrointestinal stromal/smooth muscle tumors.

The authors investigated the relations between outcome and apoptosis, immunohistochemical demonstration of bcl-2 protein, and immunohistochemical staining for p53 protein in patients with gastrointestinal stromal/smooth muscle tumors (GIST). Patients whose tumors demonstrated cellular apoptosis using the terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) assay had an improved survival over those whose tumors did not improve. In contrast, patients whose tumors demonstrated staining for bcl-2 protein had a decreased survival compared with those whose tumors did not demonstrate bcl-2. There was no relation between p53 immunoreactivity and survival. These results suggest that inhibition of apoptosis may be associated with malignant behavior in patients with gastrointestinal stromal/smooth muscle tumors.

Apoptosis↗
PubMed2001

Standardization in immunohistochemistry.

Over the last few years, the role of immunohistochemical analysis has been changing from that of an ancillary diagnostic technique to that of a stand-alone diagnostic method, the results of which determine treatment approach. With this change comes a need for increasing standardization of both preanalytical and analytical methods, so that results emanating from different laboratories are directly comparable. These efforts have been aided to some degree by the development of automated staining systems and by the increased use of test kits, but interlaboratory reproducibility for immunohistochemical methods is still far lower than that of most clinical analytical measurements. In this article, the author presents some approaches to further reduce intra- and interlaboratory variation in the performance of immunohistochemical assays, focusing attention on guidelines recently published by NCCLS.

Animals↗
PubMed2000

A comparison of cervical pathology between United States Air Force women who did and did not serve in the Persian Gulf War.

PURPOSE: The purpose of this study was to look objectively at cervical cytological differences between women Gulf War female veterans (GWFV) and Gulf War-era active duty females not deployed to the Gulf (NDF) during Operation Desert Shield/Desert Storm using Pap smear results. METHODS: A cohort of 6715 active duty Air Force women who also served on active duty between August 7, 1990-March 1, 1991 provided at least one Pap smear as part of routine medical care during 1994. Of these, 1446 were identified as GWFV and 5269 were identified as NDF. Diagnoses were compared using Chi-square tests with Yate's continuity correction. RESULTS: There were no differences between the two groups, overall, in the diagnosis of other than within normal limits (OTWNL), the diagnoses of significant disease or in Bethesda system diagnoses in each of the three years for which comparisons were made. GWFV diagnosed in the 26-30 age group were significantly more likely to have a diagnosis of OTWNL than were NDF in the same age group in 1994. There were no differences between the two groups in any other age category. CONCLUSIONS: The data provide little support for the hypothesis that a difference exists between GWFV and NDF with respect to abnormal cervical cytology.

Adult↗
PubMed2000

Chromosome identification using hidden Markov models: comparison with neural networks, singular value decomposition, principal components analysis, and Fisher discriminant analysis.

The analysis of G-banded chromosomes remains the most important tool available to the clinical cytogeneticist. The analysis is laborious when performed manually, and the utility of automated chromosome identification algorithms has been limited by the fact that classification accuracy of these methods seldom exceeds about 80% in routine practice. In this study, we use four new approaches to automated chromosome identification--singular value decomposition (SVD), principal components analysis (PCA), Fisher discriminant analysis (FDA), and hidden Markov models (HMM)--to classify three well-known chromosome data sets (Philadelphia, Edinburgh, and Copenhagen), comparing these approaches with the use of neural networks (NN). We show that the HMM is a particularly robust approach to identification that attains classification accuracies of up to 97% for normal chromosomes and retains classification accuracies of up to 95% when chromosome telomeres are truncated or small portions of the chromosome are inverted. This represents a substantial improvement of the classification accuracy for normal chromosomes, and a doubling in classification accuracy for truncated chromosomes and those with inversions, as compared with NN-based methods. HMMs thus appear to be a promising approach for the automated identification of both normal and abnormal G-banded chromosomes.

Chromosome Mapping↗
PubMed1999

Advanced laboratory techniques at the Armed Forces Institute of Pathology applicable to diagnosis and research in dermatology.

The Armed Forces Institute of Pathology (AFIP) is well known for providing expert pathology in many specialties and educational courses for civilian and military personnel. Some of the departments at the AFIP have also developed expertise in various advanced laboratory techniques for diagnosis and research that are applicable to dermatology and are not available at most medical centers.

Dermatology↗
PubMed1999

Prognosis of gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site.

Although the significance of various prognostic factors, such as tumor size and mitotic index (MI), has been well established for smooth-muscle tumors of the stomach, the significance of these factors in other sites is less well defined. We studied 1004 patients with gastrointestinal smooth-muscle tumors for whom vital status could be determined. The average MI and tumor size varied significantly among the five major sites examined: esophagus (53 cases), stomach (524 cases), small bowel 252 cases), colon/rectum (108 cases), and omentum/mesentery/peritoneum (67 cases). There was a significant difference in site-specific survival (p = 0.001), with 10-year survival varying between 50% and 70%. Multivariate analysis demonstrated tumor location (p = 0.0320), size (p = 0.0003), MI (p < 0.0001), and patient age (p < 0.0001) to each carry independent prognostic value. The significance of MI was highly site dependent. Separation of survival curves for the stomach, using a threshold for analysis of either 5 or 10 mitotic figures/50 high-power fields, was very good. In contrast, small-bowel tumors showed little separation between survival curves, regardless of whether a threshold of 1, 5, or 10 mitotic figures MF/50 high-power fields was used to distinguish groups. In no site were tumor size and MI alone sufficient to provide an accurate long-term prediction of prognosis. Although tumor location, size, MI, and age have independent value in predicting the prognosis of patients with gastrointestinal smooth-muscle tumors, better methods are still required to accurately predict clinical course.

Adolescent↗
PubMed1999

Cluster of uterine mullerian adenosarcoma in the Washington, DC metropolitan area with high incidence of sarcomatous overgrowth.

Mullerian adenosarcoma is an uncommon variant of uterine sarcoma. Twelve uterine adenosarcomas were diagnosed during a 42-month period at the Washington Hospital Center in Washington, DC. Based on estimated incidence data derived from the US Department of Defense beneficiary population, an estimated relative risk of 15.4 (95% confidence interval, 7.7-31.0) was calculated, indicating a significantly increased incidence of adenosarcoma in the population studied (p<0.0000001). Among 10 patients who underwent hysterectomy, six (60%) of their tumors had sarcomatous overgrowth. In comparison with the previously reported proportion of adenosarcomas with sarcomatous overgrowth, approximately 16%, the proportion with sarcomatous overgrowth was significantly higher than expected (p<0.01). Mullerian adenosarcoma with sarcomatous overgrowth was first described in 1989 and suggests that the cluster of adenosarcomas reported herein may be due in part to the current classification of some uterine tumors as adenosarcoma with sarcomatous overgrowth that previously would have been classified as other types of uterine sarcoma. Nonetheless, even after reviewing and updating the classification of all sarcomas diagnosed at the Washington Hospital Center from 1985 to 1998, the ratio of adenosarcomas to uterine adenocarcinomas during the 1994-1998 period was 4.7 times (p<0.005) that of the 1985-1993 period, suggesting a more modest but real increase in the occurrence of this tumor. Correct classification of mullerian adenosarcomas with sarcomatous overgrowth is important because the limited available data suggest that the prognosis is notably worse than that for adenosarcomas without sarcomatous overgrowth.

Adenosarcoma↗
PubMed1998

PAPNET-assisted rescreening of cervical smears: cost and accuracy compared with a 100% manual rescreening strategy.

CONTEXT: The Food and Drug Administration has recently approved several devices that use computerized image analysis to rescreen Papanicolaou (Pap) smears that have already been examined by cytotechnologists. Physicians and laboratories must decide whether the utility of these devices justifies the cost. OBJECTIVE: To determine the effectiveness and cost of PAPNET-assisted rescreening in identifying cervical abnormalities not identified by manual rescreening. DESIGN: PAPNET-assisted rescreening of 5478 Pap smears obtained in 1994 and 1995 previously identified as "within normal limits" or "benign changes" on both initial and random screening. PATIENTS: Female service members and dependents aged 12 to 88 years. SETTING: Air Force clinics in the United States and Japan. INTERVENTION: Rescreening of Pap smears by PAPNET, followed by reevaluation of abnormal smears by the consensus panel, consisting of 3 cytotechnologists and 3 pathologists. MAIN OUTCOME MEASURES: Proportion of Pap smears initially screened as normal identified as abnormal by both PAPNET and consensus panel; costs of rescreening. RESULTS: PAPNET screening identified 1614 (29%) slides requiring additional microscopic review. On further review, 448 (8% of total) had possibly abnormal cells. Ultimately, 11 of these cases were reviewed by the consensus panel for potentially atypical cells. Of these 11 cases, 5 were reclassified as atypical squamous cells of undetermined significance (ASCUS) and 1 as atypical glandular cells of undetermined significance (AGUS). No additional squamous intraepithelial neoplasia (SIL) was identified in these smears; the patient with a diagnosis of AGUS on rescreening was diagnosed as having a low-grade SIL (LSIL) on follow-up. Costs were $5825 to $33781 for each additional ASCUS or AGUS diagnosis. A cost of $17475 to $101343 is expected for each case of LSIL identified by PAPNET-assisted rescreening and not by traditional manual rescreening. CONCLUSIONS: PAPNET-assisted rescreening identified a few more cases of ASCUS than did manual rescreening, but at a relatively high cost. The costs of rescreening should be carefully compared with the expected efficacy in reducing cervical cancer mortality.

Adolescent↗
PubMed1998

Flow cytometry in diagnostic cytology.

Flow cytometry (FCM) is a useful adjunct to cytologic examination, because the quantitative biochemical information it provides complements the morphologic information gained during visual examination. It aids in the interpretation of bladder washings, and is particularly useful for the assessment of lymphoid lesions, whether they originate from fine-needle aspiration, cerebrospinal fluid, or effusions. Optimal use of FCM frequently requires assessment of more than one parameter; simultaneous use of cell differentiation markers and nuclear DNA quantitation is often significantly more useful than either alone. Despite the utility of FCM, however, the potential for future development appears to be limited. Improvements in image cytometry allow reasonable assessment of ploidy and S-fraction to be made from specimens prepared on glass slides. Multiparameter measurements may also be accomplished with imaging techniques, which allow the further advantage of visual identification of cells with equivocal morphologic changes. The development of artificial intelligence methods for use with imaging technology has also significantly exceeded that of FCM. Finally, image cytometry is often more useful for samples with few cells. Other challenges are posed by immunocytochemical methods which compete with flow cytometry as tools for assessment of proliferation. Given the relatively high cost of FCM instrumentation, survival of FCM as an ancillary technique in cytopathology will require further technical refinements to offset the advantages currently associated with image cytometry and immunocytochemistry.

Biopsy, Needle↗
PubMed1998

Loss of heterozygosity on chromosome 11p15 during histological progression in microdissected ductal carcinoma of the breast.

Microdissection of histologically identifiable components from formalin-fixed, paraffin-embedded tissue sections allows molecular genetic analyses to be correlated directly with pathological findings. In this study, we have characterized loss of heterozygosity (LOH) at chromosome 11p15 at different stages of progression in microdissected tumor components from 115 ductal carcinomas of the breast. Microdissected foci of intraductal, infiltrating, and metastatic tumors were analyzed to determine the stage of progression at which LOH at 11p15 occurs. LOH was detected in 43 (37%) of 115 cases. Foci of intraductal carcinoma could be microdissected from 85 cases, of which 30 (35%) showed LOH at some stage of progression. LOH was detected in the intraductal component in 26 of these 30 cases. Interstitial deletions were characterized by using a panel of 10 highly polymorphic markers. The smallest region of overlap (SRO) for LOH at 11p15 was bounded by the markers D11S4046 and D11S1758. LOH at 11p15.5 showed no correlation with estrogen receptor status, the presence of positive lymph nodes, tumor size, histological grade, or long-term survival. We conclude that 11p15 LOH usually occurs early in breast cancer development but less frequently does not develop until the infiltrating or metastatic stages of tumor progression.

Breast Neoplasms↗
PubMed1998

KIT mutation portends poor prognosis in gastrointestinal stromal/smooth muscle tumors.

Gastrointestinal stromal/smooth muscle tumors (GISTs) are uncommon neoplasms for which current criteria for the diagnosis of malignancy (location, size, and mitotic index) do not always reliably predict patient outcome. Recently, mutation of KIT oncogene exon 11 has been observed in some of these tumors, but the relationship between mutation and clinical outcome has not yet been determined. DNA was obtained from the formalin-fixed, paraffin-embedded tissue of 35 gastric GISTs. A segment of exon 11 was amplified by PCR and sequenced on an ABI 377 sequencer. The relationship between the presence or absence of mutation, tumor size, and mitotic index was investigated using correlation analysis, and the relationship between mutation and outcome was investigated using Kaplan-Meier plots, the Cox-Mantel statistic, and the Cox regression model. Exon 11 deletion mutations were identified in 10 cases, and point mutations were identified in an additional 3 cases; 22 cases demonstrated no KIT mutations. KIT mutation was associated with decreased survival (p = 0.001), with fewer than 30% of patients surviving more than 3 years, compared with over 65% survival for patients whose tumors did not bear the mutation. KIT mutation did not correlate with either the mitotic index or the tumor size. In conclusion, KIT mutation is associated with poor prognosis in patients with gastrointestinal stromal tumors. Whether the KIT mutation will prove to be an independent prognostic factor awaits the completion of larger studies.

Amino Acid Sequence↗