PubMed Health⌕ Search

Biomedical subjects

J F Simpson

Publications and source records attributed to J F Simpson.

At least 73 records · Page 4Linked to original sources
PubMed1994

Prognostic relevance of carcinoembryonic antigen and estrogen receptor status in breast cancer patients.

BACKGROUND: Expression of carcinoembryonic antigen (CEA) has been reported in 10-95% of breast cancer. Its value as a predictor of disease progression is controversial. METHODS: The expression of CEA in 202 Stages I and II breast carcinomas was assessed by immunohistochemistry, and the results were correlated with various histologic and clinical parameters to establish CEA's biologic relevance. The mean follow-up of the patients was 6.5 years. The monoclonal antibody used does not cross-react with other molecules in the CEA gene family. RESULTS: One hundred, thirteen (56%) tumors expressed CEA in more than 15% of the cells. Expression of CEA was associated with positive estrogen receptor (ER) status (P = 0.003). Univariate Cox regression analysis showed that, whereas disease free survival (DFS) and overall survival (OS) were not associated significantly with CEA expression, tumor size, nuclear grade, ER status, lymph node metastases, and stage were. When ER status was stratified to CEA expression, patients who were ER negative and had CEA-negative tumors had a 3.9 times higher risk (P = 0.032) of death than did the patients with CEA-positive tumors. Cox regression analysis revealed that ER was the only parameter with significant interacting effect with CEA. Multivariate, stepwise Cox regression analysis showed that CEA expression, tumor size, and nuclear grade were the only significant independent predictors of DFS, and nuclear grade and lymph node metastasis the only significant predictors of OS in the ER-positive group. The only significant independent predictor of DFS and OS in the ER-negative group was CEA. When CEA expression was stratified to ER status, patients whose tumors lacked CEA and ER had threefold higher risk of disease relapse (P = 0.002) and a 5.3-fold higher risk of death (P = 0.0001) than those with ER-positive and CEA-negative tumors. Multivariate analysis showed that the association between CEA and ER was enhanced further after compensating for other parameters with independent predictive value. CONCLUSIONS: The association between CEA and ER was the most important independent predictor of a subgroup of patients (CEA-negative, ER-positive) with the most favorable prognosis. The results imply that the association of several tumor markers may provide tumor profiles with superior predictive value than a single parameter.

Antibodies, Monoclonal↗
PubMed1994

Heterogeneous expression of nm23 gene product in noninvasive breast carcinoma.

BACKGROUND: The two major types of noninvasive breast carcinoma, ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), are quite different in their histopathologic appearance and clinical implications. LCIS is only a marker of an increased risk of later development of invasive carcinoma, whereas most DCIS lesions are at least nonobligate precursors of invasive carcinoma. DCIS is a heterogeneous group of lesions composed of several distinct subtypes, with only the comedo subtype having immediate malignant potential. The authors' purpose was to analyze noninvasive carcinomas for the presence of a gene product (nm23) indicative of a favorable prognosis in invasive carcinomas to determine differences (1) among the different types of CIS and (2) in CIS with and without an accompanying invasive component. METHODS: Immunohistochemical methods were used to detect nm23 gene product in archival material from two groups of patients: Group 1 consisted of 54 cases of purely noninvasive carcinoma, and Group 2 consisted of 55 examples of noninvasive carcinoma associated with an invasive component. RESULTS: Among the cases of CIS with no invasion, LCIS and comedo DCIS expressed more nm23 than noncomedo DCIS (P < or = 0.03). There were no differences among these CIS subtypes in the group with invasion. Comparing subtypes of CIS in the groups with or without invasion, only comedo DCIS was significantly different, with greater expression in the CIS group with no invasion compared with comedo DCIS associated with an invasive component (P = 0.04). CONCLUSIONS: These results support the special nature of LCIS and the heterogeneous nature of DCIS. The in situ component attending an invasive component may be different from anatomically similar lesion without associated invasion. The absence of nm23 in comedo DCIS may be indicative of invasive capacity.

Adult↗
PubMed1994

Non-Hodgkin's lymphoma involving the breast.

Breast involvement by non-Hodgkin's lymphoma is rare. Differences between primary and secondary breast lymphoma have been reported, and a relationship between primary breast lymphoma and lymphomas of mucosa-associated lymphoid tissue has been suggested. We reviewed 61 cases of breast lymphoma (41 primary, 13 secondary, and 7 unclear) that included 28 right-sided masses at presentation, 17 left-sided, 12 bilateral, and 4 in which the side was not known. A subgroup of bilateral breast lymphomas was identified that occurred in young women, four of which were pregnant or postpartum. A high incidence of intermediate- and high-grade lymphomas were present in both cases of primary and secondary lymphomas as was a high frequency of B-cell phenotype. Additional immunohistochemical studies failed to demonstrate evidence of marginal or mantle cell differentiation in seven of eight cases studied. Lymphoepithelial lesions were identified in a majority of cases, including 67% of primary and 64% of secondary lymphomas. This study failed to demonstrate a morphologic difference between primary or secondary lymphomas of the breast and suggests that breast lymphomas differ from other extranodal lymphomas in that the latter are frequently low grade.

Adolescent↗
PubMed1994

Pathology of preinvasive and excellent-prognosis breast cancer.

Concern about the recognition of especially good prognoses continues to be resolute among those who decide, with patients, the course of treatment. Prognostic considerations are paramount in this planning process, and should emphasize precision in case definition and repeated verification in comparable studies. Excellent-prognosis invasive lesions, subtyping of ductal carcinomas in situ, and premalignant indications within otherwise benign breast biopsy specimens are highlighted in this review.

Adult↗
PubMed1994

Cardiac mitochondrial DNA polymerase-gamma is inhibited competitively and noncompetitively by phosphorylated zidovudine.

Zidovudine (azidothymidine [AZT]) inhibits human immunodeficiency virus replication and reduces the severity of acquired immunodeficiency syndrome. A limiting side effect of AZT is a mitochondrial cardiac and skeletal myopathy in which the pharmacologically active derivative of AZT (AZT triphosphate) plays a critical role. The present study determined biochemical mechanisms of AZT-induced mitochondrial toxicity and identified AZT triphosphate as an inhibitor of DNA polymerase-gamma in vitro. Inhibition kinetics were defined using purified bovine cardiac mitochondrial DNA polymerase-gamma and AZT triphosphate in vitro. The Km for deoxythymidine triphosphate was 0.8 +/- 0.3 mumol/L. AZT triphosphate incubation with DNA polymerase-gamma in vitro resulted in mixed kinetics with a competitive Ki of 1.8 +/- 0.2 mumol/L and a noncompetitive Ki' of 6.8 +/- 1.7 mumol/L. These Ki and Ki' values were strikingly higher than values for retroviral reverse transcriptase but lower than values for other cellular DNA polymerases. These data support previous molecular and morphological findings in clinical AZT mitochondrial myopathy and in models of AZT myopathy in vivo. Biochemical findings suggest that inhibition of mitochondrial DNA polymerase-gamma may be integral to the pathogenesis of AZT-induced myopathy.

Animals↗
PubMed1994

Status of breast cancer prognostication based on histopathologic data.

The authors present the current status of histopathologic data for prognostication in breast cancer. Current guidelines for using the combined histologic grade are given, as is a review of clinical settings in which this robust grading system has been proved predictive. Precise guidelines are also presented for recognizing special histologic types of cancer, which are associated with an excellent prognosis. Histopathologic methods for assessing cellular proliferation are also presented. This is a dynamic time in the field of breast histopathology when there is a wider and widening appreciation for the clinical utility of these assessments. Concurrently, these approaches should be used with care and clinical relevance of this information should be presented with clarity.

Breast Neoplasms↗
PubMed1993

Pathology of preinvasive and excellent-prognosis breast cancer.

Recent advances in breast cancer treatment have made recognition of different prognostic groups mandatory. In addition, further experience with screening-detected lesions has resulted in the definition of new associations. Therapeutic approaches to these frequently microscopic lesions continue to be the source of much debate. The subtyping of ductal carcinoma in situ is also an area of continuing controversy. This article reviews recent studies of excellent-prognosis carcinomas as well as premalignant and other histologically defined lesions that indicate an increased risk for the development or recurrence of carcinoma. Advances in fine needle aspiration biopsy and in hormone receptor assays are also reviewed.

Breast Neoplasms↗
PubMed1993

Medullary carcinoma of the breast. Identification of lymphocyte subpopulations and their significance.

Fifty-two infiltrating breast carcinomas with medullary features (BCMF) were studied immunohistochemically to determine the immunophenotype of the mononuclear tumor inflammatory cells (MTIC) in formalin-fixed, paraffin-embedded material. The neoplasms were also examined for Epstein-Barr virus (EBV) DNA by the polymerase chain reaction (PCR). BCMF were independently classified as medullary carcinoma (MC) or infiltrating ductal carcinoma (IDC) by six observers according to the criteria of Pedersen et al. DNA from 35 BCMF was successfully amplified using PCR, but all were negative for EBV DNA. These included, by 4/6 consensus diagnosis, 16 MC, 18 IDC, and one BCMF which failed to achieve consensus diagnosis. MTIC were present to a mild degree in 19 BCMF (37%) and to moderate to severe degrees in 33 (63%). MTIC were predominantly (> or = 75%) lymphocytic in 31 BCMF (13 MC, 16 IDC, two without consensus diagnostic agreement), and plasmacytic in 10 (six MC, four IDC); equal proportions of lymphocytes and plasma cells occurred in 11 (six MC, five IDC). Lymphocytic MTIC were mostly CD45RO+/CD3+ T-cells in nearly all cases, and showed a predominant CD3+/CD4+ and CD3+/CD4- immunophenotype in 36% and 64% of cases, respectively. Natural killer cells (CD57+) and histiocytes (MAC 387+) were virtually absent. The number, cell type, and T-cell subsets of the MTIC were unrelated to consensus diagnosis, axillary lymph node status, or overall survival. EBV is unassociated with MC, despite the histologic similarities of MC to EBV-associated lymphoepithelial lesions of other organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Loss of expression of fodrin (a structural protein) in cystic changes of human breast.

BACKGROUND: Formation of cysts in the human female breast remains a common clinical problem with few pathogenic theories suggested, and none proven. EXPERIMENTAL DESIGN: We studied the immunohistochemical distribution of a structural protein, fodrin (a nonerythroid spectrin) within benign conditions of the breast. RESULTS: Whereas normal breast epithelium expressed fodrin, all breast cysts were consistently negative for fodrin expression. Both larger, tension cysts as well as the smaller microcysts seen in a special pattern of lobular atrophy were uniformly negative. CONCLUSIONS: Lack of fodrin may be a secondary event in cystic alterations of the breast. However, loss of this structural protein may be responsible for altered structural integrity of breast acini, resulting in or fostering the formation of cysts.

Adult↗
PubMed1992

Expression of mitoses per thousand cells and cell density in breast carcinomas: a proposal.

A method of standardizing mitotic counts is described. This provisional approach, which expresses mitoses as a percentage of breast cancer cells present, holds the promise of facilitating interlaboratory agreement as well as providing a measure of tumor cellularity, probably an independent prognostic indicator in its own right. We suggest that this approach or one similar to it will maximize the evaluation and quantitation of proliferative activity from routinely available histologic material. Furthermore, the method is accomplished with little added effort beyond the customary histologic evaluation.

Breast Neoplasms↗
PubMed1992

Pathology of preinvasive and excellent-prognosis cancers.

Recent advances in breast cancer treatment have made recognition of different prognostic groups mandatory. In addition, further experience with screening-detected lesions has resulted in the definition of new associations. Therapeutic approaches to these frequently microscopic lesions are currently the source of much debate. This article reviews recent studies of excellent-prognosis carcinomas as well as premalignant and other histologically defined lesions that indicate an increased risk for the development or recurrence of carcinoma. Advances in fine-needle aspiration and in hormone receptor assays are also reviewed.

Biopsy, Needle↗
PubMed1992

Intraperitoneal administration of interferon-gamma to carcinoma patients enhances expression of tumor-associated glycoprotein-72 and carcinoembryonic antigen on malignant ascites cells.

PURPOSE: The study was designed to determine whether in vivo interferon gamma (IFN-gamma) administration could enhance tumor antigen expression on the surface of human tumor cells. MATERIALS AND METHODS: Eight patients (six with ovarian and two with gastrointestinal tumors) with a diagnosis of adenocarcinoma with secondary malignant ascites were given weekly escalating doses of IFN-gamma (ie, 0.1 to 100 MU) intraperitoneally (IP) each week for 8 weeks. Tumor cells were isolated from the patients' ascites samples, which were collected three times per week: before and 24 and 48 hours post-IFN-gamma administration. The level of expression of tumor-associated glycoprotein-72 (TAG-72) and carcinoembryonic antigen (CEA) was measured using flow cytometry and immunocytochemistry. RESULTS: IFN-gamma administered IP dramatically increased TAG-72 (as measured by binding of anti-TAG-72 monoclonal antibodies [MoAbs] B72.3 and CC 49) and CEA (measured by MoAb COL-1) expression on the surface of the carcinoma cells. The ascites-derived tumor cells from seven of the eight patients constitutively expressed TAG-72, and the level of TAG-72 expression was increased by IFN-gamma in all seven patients, as evidenced by the enhanced binding of anti-TAG-72 MoAbs to the tumor-cell surface. In some cases, IFN-gamma treatment increased the percentage of MoAb B72.3-reactive tumor cells from 10% to greater than 90%, and those changes were further corroborated by similar increases in the MoAb staining intensity observed with immunoperoxidase analysis. In addition, ascites-derived tumor cells from two patients with gastrointestinal carcinoma also expressed enhanced CEA levels after IFN-gamma. The increased TAG-72 and CEA expression were observed at low IFN-gamma doses (ie, 0.1 to 1.0 MU), which were well tolerated by all patients. CONCLUSIONS: The ability of IFN-gamma given IP to increase TAG-72 and CEA expression on tumor cells in vivo provides additional argument for the use of the cytokine as an adjuvant to enhance MoAb binding to human carcinoma-cell populations.

Antigens, Neoplasm↗
PubMed1992

Altered expression of a structural protein (fodrin) within epithelial proliferative disease of the breast.

Although certain histopathologic patterns of epithelial proliferative breast disease are well established as indicating an increased relative risk for the subsequent development of mammary carcinoma, the biologic characterization of these changes is not known. One evident histologic characteristic of epithelial hyperplasia is the partial or complete loss of normal cellular polarity. Nonerythroid spectrin (fodrin) is a structural protein whose function is related to maintenance of cellular polarity. By immunohistochemical analysis, normal breast luminal epithelia contain fodrin confined to a characteristic basolateral distribution. Proliferative breast disease of the common type partially loses this polarized distribution of fodrin; fodrin immunoreactivity is not limited to a basolateral location but is present around the cell membrane and is inconsistently present at luminal interfaces. Whether this change in distribution of fodrin is a permissive event in the development of proliferative disease or merely an associated finding is not known.

Adult↗
PubMed1992

Invasion in vitro of malignant hamster brain tumor cells is influenced by the number of cells and the mode of malignant progression.

We investigated the capacity of two glial tumor cell lines (CxT24neo3 and CxT3Cl5) to invade through reconstituted basement membrane (Matrigel, MG). The purpose of our experiments was to establish whether the number of cells or the mode of malignant progression would quantitatively modify the invasion of a brain tumor cell population. To accomplish this goal, we used a vital-dye method to assess the fraction of cells that invaded through 30 micrograms MG coated on a polycarbonate filter (8 microns pore size). Our experiments demonstrated that the fraction of invasive CxT24neo3 and CxT3Cl5 cells in vitro reproducibly differed as a function of the number of initially seeded cells. This showed that invasion through MG was subject to quantitative changes caused by the number of cells present. Since CxT24neo3 and CxT3Cl5 became malignant by transfection with different oncogenes, the results also indicated that the type of quantitative change was influenced by the mode of malignant progression.

Animals↗
PubMed1991

Characterization of the colorectal carcinoma-associated antigen defined by monoclonal antibody D612.

Monoclonal antibody (MAb) D612 recognizes an antigen expressed on the cell surface of normal and malignant gastrointestinal epithelium. It is a murine IgG2a/kappa which has been previously shown to mediate killing of human colon carcinoma cells using human effector cells (which could be enhanced in the presence of interleukin-2). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analyses of MAb D612 immunoprecipitates of extracts of L-[35S]methionine-, L-[3H]leucine-, and D-[3H]glucosamine-labeled human colon carcinoma cells showed that the D612 antigen is a Mr 48,000 glycoprotein. Similar estimates of molecular mass were obtained from SDS-PAGE analyses of MAb D612 immuno-precipitates of radioiodinated extracts of surgically resected colon carcinoma and adjacent normal colonic mucosa. D612 antigen was not detectable in immunoprecipitates of supernatant media from radiolabeled cell cultures, suggesting that the antigen is not readily shed from the surface of cultured cells. The D612 antigen was shown to be clearly distinct from previously described gastrointestinal carcinoma-associated glycoproteins: the D612 antigen shows a migration pattern of SDS-PAGE distinct from those of the antigens recognized by MAbs KS1/4 and GA733, and reciprocal immunodepletion analyses of D-[3H]glucosamine-labeled colon carcinoma cells utilizing MAbs D612 and GA733 revealed no cross-reactivity between these antibodies. Similarly, competitive binding studies between MAbs 17-1A and KS1/4 and MAb D612 revealed no similarity between the epitopes recognized by MAb D612 and MAbs 17-1A and KS1/4. MAbs D612 and 17-1A were also titered in immunoperoxidase staining assays on serial frozen sections of normal and malignant colon. MAb D612 showed a higher titer of immunostaining reactivity with both normal and malignant colon than did MAb 17-1A. MAb D612 showed roughly equivalent immunostaining titers against normal and malignant colon; whereas MAb 17-1A showed higher titer of immunostaining reactivity against the normal colon tissue than against the malignant colon. Flow cytometric analysis of phosphatidylinositol-specific phospholipase C-treated colon carcinoma cells revealed no loss of D612 antigen from the cell surface, suggesting that the mechanisms of attachment of the D612 antigen to the cell surface does not involve linkage to a phosphatidylinositol glycan.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1991

Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease.

We have stratified the cancer risk implications of lobular pattern in situ neoplasias of the breast by separating marked examples of this histologic spectrum (lobular carcinoma in situ [LCIS]) from lesser examples (atypical lobular hyperplasia). The lesser-developed examples have been shown previously to have a lower relative risk (RR) of later invasive carcinoma of the breast (IBC). Forty-eight examples of LCIS were found in 10,542 otherwise benign breast biopsies, representing an incidence of 0.5%. Nine patients were excluded from follow-up because of bilateral mastectomy within 6 months of entry biopsy, IBC within 6 months of entry biopsy, or prior IBC. Follow-up of the remaining 39 patients was complete, averaged 18 years, and revealed an RR of subsequent IBC of 6.9 (P less than .00001). Average overall follow-up for LCIS patients was 19 years; it was 25 years for those alive and free of IBC at the time of their follow-up interview. Neither family history of IBC nor postmenopausal estrogen therapy further affected risk. The absolute risk of IBC after LCIS was 17% at 15 years (adjusted for withdrawals), and the RR was 8.0 in the first 15 years of follow-up compared with the general population. An analysis based on a time-dependent hazards model found that during the first 15 years following biopsy women with LCIS had 10.8 times the risk of breast cancer compared with biopsied women of comparable age who lacked proliferative disease. Some previously published articles reporting lobular neoplasia (LN) suggest that those series with the greatest incidences of LN (whether termed LN or LCIS) have the lowest RR of subsequent breast cancer. Those series with higher incidences of LN include less well-developed histologic patterns of LN (atypical lobular hyperplasia). We conclude that our study of LN and studies performed by others support the higher risk of IBC after histologically flagrant examples (LCIS, about nine times higher) and a relatively lower but definable risk after more histologically subtle examples (atypical lobular hyperplasia, four to five times lower). This relative cancer risk is probably not constant over more than 15 years; thus, cancer risk 15 to 25 years after initial diagnosis of LCIS is uncertain.

Adult↗