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Biomedical subjects

A D Thor

Publications and source records attributed to A D Thor.

At least 37 records · Page 2Linked to original sources
PubMed1997

Analysis of Bax and Bcl-2 expression in p53-immunopositive breast cancers.

Bax and Bcl-2 are proteins that regulate programmed cell death and apoptosis. The expression of these proteins can be regulated, at least in part, by the tumor suppressor p53, but the effects of p53 are highly tissue specific. In an effort to better understand the relation between p53 and the in vivo control of the expression of Bax and Bcl-2 in adenocarcinomas of the breast, we evaluated by immunohistochemistry the expression of Bcl-2 and Bax in 149 invasive ductal carcinomas, 135 of which were chosen because of their p53 immunopositivity. The percentages of Bcl-2-immunopositive tumor cells were significantly lower in the p53-positive (median 20%) subsets as compared to the p53-negative (median 85%) subsets (P = 0. 004). Comparisons of the percentages of p53-immunopositive tumor cells with the percentages of Bcl-2- and Bax-positive cells (as continuous variables) revealed a significant inverse correlation between Bcl-2 and p53 (r = -0.41, P < 0.001) but not between Bax and p53. In the p53-positive subset, the percentages of Bax- and Bcl-2-immunopositive tumor cells were correlated positively (r = 0. 27, P = 0.002), suggesting that the expression of these genes may be co-regulated to some extent in these breast cancers. Higher percentages of Bcl-2-positive tumor cells were also associated with estrogen receptor positivity (P = 0.03), low histological tumor grade (P = 0.03), and low T stage (P = 0.02), whereas Bax immunostaining was associated only with c-erbB-2 immunopositivity (P = 0.02). Although the number of cases was small and treatment was non-uniform, preliminary correlations with clinical outcome data suggest that the prognostic significance of Bcl-2 may be enhanced by inclusion of Bax data in patients with p53-immunopositive adenocarcinoma of the breast, at least for patients with node-negative disease. Taken together, these data suggest that, despite the ability of p53 to bind directly to the Bax gene promoter, the regulation of Bax in human breast cancers does not necessarily correlate with p53 status, implying that regulation of this pro-apoptotic gene in these tumors is complex and probably influenced by several factors.

Breast Neoplasms↗
PubMed1996

Loss of heterozygosity in normal tissue adjacent to breast carcinomas.

Loss of heterozygosity (LOH) was detected in morphologically normal lobules adjacent to breast cancers. The most frequent aberration was at chromosome 3p22-25; of ten cases with this LOH in the carcinoma, six displayed the same LOH in adjacent normal lobules. This suggests that in a subset of sporadic breast cancers, a tumor suppresser gene at 3p22-25 may be important in initiation or early progression of tumorigenesis. Among sixteen breast cancers with LOH at 17p13.1 and five breast cancers with LOH at 11p15.5, one case each displayed the same LOH in adjacent normal lobules. Thus the molecular heterogeneity that characterizes invasive breast cancers may occur at the earliest detectable stages of progression.

Alleles↗
PubMed1996

Ovarian, peritoneal, and endometrial serous carcinoma: clonal origin of multifocal disease.

The clonality of disseminated serous carcinoma involving the ovary, peritoneum, and, occasionally, the endometrium is controversial. Histopathologic examination alone cannot unequivocally distinguish between a monoclonal origin and a multicentric origin. Two patients with peritoneal serous carcinoma with minimal ovarian involvement (one with endometrial serous carcinoma), nine patients with stage III bilateral ovarian carcinoma, and one patient with stage III bilateral carcinosarcoma were studied for clonality. One patient with ovarian carcinoma that recurred after chemotherapy was also studied. Previous analyses of single frozen tumor specimens from these patients had identified different p53 gene mutations in each patient. To test the hypothesis that the disseminated cancers had a monoclonal origin, we assayed DNA from numerous foci from each patient to determine whether the known p53 mutation was present in each specimen. Identical mutations were detected in the tumor foci from each patient with peritoneal dissemination and minimal ovarian involvement, including one patient with an endometrial serous carcinoma as well. In all the patients with bilateral ovarian cancer, the genetic change in p53 was identical in both ovarian tumors. Genetic progression was observed in two patients, one of whom showed a loss of heterozygosity involving the p53 gene in a recurrent tumor. In the second patient, a p53 mutation not present in either ovarian tumor was detected in a metastatic tumor from the omentum. These results strongly suggest that disseminated serous carcinomas, whether primary in the ovary, endometrium, or peritoneum, are of monoclonal rather than multicentric origin; that bilateral stage III ovarian cancers are typically of monoclonal origin; and that additional genetic events involving p53 might occur during progression of these tumors.

Aged↗
PubMed1995

Tumor angiogenesis as a prognostic assay for invasive ductal breast carcinoma.

BACKGROUND: Tumor angiogenesis, as assayed by microvessel density, has been proposed as an independent prognostic marker for clinical outcome in breast cancer patients. PURPOSE: The present study evaluated the microvessel density assay and assessed its utility, alone and together with the evaluation of other tumor characteristics, in predicting outcome in patients with invasive ductal carcinomas. METHODS: In a blinded design, cases of invasive ductal carcinoma were selected from a registry containing the records of and tumor specimens from 386 breast cancer patients treated at the Massachusetts General Hospital from 1977 through 1982. After the exclusion of ineligible patients and inadequate specimens, 220 patients were included in the study; their median time of follow-up was 11.5 years. Half of these patients (n = 110) were positive for axillary lymph node metastases. Histologic sections of the tumors were stained immunocytochemically for factor VIII, a coagulation protein expressed by blood vessel endothelium, and for p53 protein. Independently, two analysts counted microvessels in three microscope fields selected from separate vascular regions of the tumor. Variability in microvessel scores between analysts and among different fields of the same tumor was summarized by the coefficient of variation. The kappa statistic tested for agreement between the analysts while correcting for chance agreement. The effects of tumor characteristics on metastasis-free survival and overall survival were tested univariately by the Harrington-Fleming rank test procedure. The effect of multiple factors on survival was tested under a Cox multivariate proportional hazards model. RESULTS: Microvessel count showed considerable variability between the two analysts and among regions within each tumor, with an overall concordance for tumor classification of 73%. Univariate analysis revealed no association between microvessel count and any other tumor or patient characteristic. Multivariate analysis indicated, for these patients, that nodal status and p53 staining predicted metastasis-free survival and that nodal status, estrogen receptor (ER) status and tumor grade predicted overall survival. CONCLUSIONS: Microvessel count showed much variation among different regions of each tumor. It did not predict metastasis-free survival or overall survival. Nodal status was the most powerful criterion to stratify these patients with invasive ductal carcinoma of the breast into different survival groups. Only ER status, tumor grade, and p53 staining had additional prognostic utility for these patients after they had been stratified by nodal status.

Analysis of Variance↗
PubMed1995

p53 gene analysis of ovarian borderline tumors and stage I carcinomas.

Mutations of the p53 gene are common in human ovarian carcinomas; however, their role in the early development of ovarian cancer is unclear. Twelve ovarian borderline tumors (BTs; eight of them p53 immunopositive) and 10 stage I carcinomas (four of them p53 immunopositive) were studied for genetic alterations in the p53 gene. The study was based on single-strand conformation polymorphism (SSCP) analysis and DNA sequencing of exons 2 through 11 of the p53 gene using DNA preparations from microdissected tumors. Mutations were found in 40% of the carcinomas (including a borderline component adjacent to carcinoma in one lesion) but in none of the pure BTs. These findings suggest that p53 mutations may not be commonly associated with the borderline phenotype of ovarian epithelial tumors but may occur during malignant transformation.

Adult↗
PubMed1995

Cyclin D1 (PRAD1) protein expression in breast cancer: approximately one-third of infiltrating mammary carcinomas show overexpression of the cyclin D1 oncogene.

Amplification of chromosome 11q13 has been observed in 10-20% of breast carcinomas and numerous other tumors, including squamous cell carcinomas of the head, neck, and esophagus; transitional cell carcinomas of the urinary bladder; and epithelial ovarian tumors. Cyclin D1/PRAD1 is a likely "driver" gene for this amplicon because of its role in cell cycle control and because it has been specifically implicated as an oncogene in parathyroid adenomas and B-cell lymphomas with 11q13 translocation breakpoints. We examined cyclin D1 protein expression in 48 consecutive cases of infiltrating mammary carcinoma using an affinity-purified polyclonal antisera to cyclin D1 and a microwave/citrate buffer antigen retrieval system. Staining data were correlated with clinicopathological features, protein detection by immunoblots, and 11q13 DNA amplification. Definite nuclear staining was seen in 17/48 (35%) tumors (16 infiltrating ductal carcinomas, predominantly grade 2/3, and one infiltrating lobular carcinoma). There was no nuclear staining of normal breast epithelium, fat cells, or admixed lymphocytes. Tumors with overexpression of cyclin D1 were estrogen receptor-positive (P < .005) and usually progesterone receptor-positive (P < .005) but otherwise were similar to other negative cases in the study group. Correlation between Western blot and immunostaining data was excellent (P < .01). Five of the 22 cases studied showed 11q13 DNA amplification as well as increased levels of cyclin D1 protein by Western blot and immunostaining. Four cases with increased cyclin D1 protein by both western blots and immunohistochemistry did not have detectable 11q13 amplification. Nuclear cyclin D1 protein can be detected in approximately one-third of infiltrating breast carcinomas using an immunohistochemical technique on formalin-fixed, paraffin-embedded tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer.

BACKGROUND: The role of molecular markers in predicting the response to treatment of breast cancer is poorly defined. The Cancer and Leukemia Group B (CALGB) conducted a randomized adjuvant-chemotherapy trial (CALGB 8541) comparing three doses (high, moderate, and low) of cyclophosphamide, doxorubicin, and fluorouracil in 1572 women with node-positive breast cancer. This study (CALGB 8869) was designed to determine whether the DNA index, the S-phase fraction, c-erbB-2 expression, or p53 accumulation could be used as a marker to identify a subgroup of patients more likely than others to benefit from high doses of chemotherapy. METHODS: Tissue blocks were obtained from 442 patients randomly selected from the larger CALGB trial. Paraffin sections from the primary lesions were analyzed for DNA content, S-phase fraction, c-erbB-2 expression, and p53 accumulation. RESULTS: Patients randomly assigned to the high-dose regimen of adjuvant chemotherapy had significantly longer disease-free and overall survival if their tumors had c-erbB-2 overexpression. No further information was gained by adding the data on S-phase fraction or p53 accumulation to the analysis. There was no clear evidence of a dose-response effect in patients with minimal or no c-erbB-2 expression. CONCLUSIONS: There is a significant dose-response effect of adjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil in patients with overexpression of c-erbB-2 but not in patients with no c-erbB-2 expression or minimal c-erbB-2 expression. Overexpression of c-erbB-2 may be a useful marker to identify the patients who are most likely to benefit from high doses of adjuvant chemotherapy.

Adult↗
PubMed1994

p53 expression in ovarian borderline tumors and stage I carcinomas.

Seventy-nine ovarian serous and mucinous borderline tumors, 36 stage I carcinomas and 39 stage II-IV carcinomas were studied for p53 protein accumulation with monoclonal antibody PAb1801.p53 protein was expressed in 14% of borderline tumors, 36% of stage I carcinomas, and 64% of higher stage carcinomas. All immunopositive carcinomas accumulated p53 protein in the primary tumor, and 95% of them showed concordance in staining among different tissue blocks. A difference in frequency of p53 protein accumulation between stage I and higher stage serous carcinomas was not statistically significant. p53 positivity was associated with microinvasion, microcarcinoma and coexistent carcinoma in mucinous borderline tumors (P = .025). An association between p53 protein expression and poor tumor differentiation in Stage I carcinomas as statistically significant (P = .03). p53 positivity was observed in a poorly differentiated endometrioid carcinoma as well as in adjacent benign endometriotic tissue. These results suggest that p53 abnormalities may be early events in ovarian cancer, possibly contributing to malignant transformation of some borderline tumors, endometriosis and other carcinoma precursors.

Adenocarcinoma, Mucinous↗
PubMed1994

Prognostic value of Cathepsin D expression in breast cancer: immunohistochemical assessment and correlation with radiometric assay.

BACKGROUND: The prognostic significance of Cathepsin D and optimal methodologies to measure Cathepsin D in breast cancers are controversial. PATIENTS AND METHODS: Quantitative (immunoradiometric) and semiquantitative (immunohistochemical) assays for Cathepsin D expression were compared using 25 breast carcinomas. Immunohistochemical Cathepsin D results were derived using 3 different anti-Cathepsin D antibodies and significant associations between immunohistochemical and radiometric Cathepsin D data were observed for each reagent. Immunohistochemical analysis of Cathepsin D expression was performed on nearly 500 fixed-embedded archival breast cancers with long-term patient follow-up using 2 anti-Cathepsin D antibodies (CDR2-11/23, IC11). RESULTS: The immunohistochemical reagents recognized generally overlapping subsets of Cathepsin D positive tumors (correlation co-efficient 0.54; p = 0.00016). Correlations between Cathepsin D data and clinical, histologic or biologic features differed for each antibody. For the node-negative patient subset, Cathepsin D immunopositivity correlated with erbB-2 and stress-response protein 27 overexpression but not survival. Cathepsin D positivity was associated with subsequent distant metastasis and estrogen receptor positivity in node positive patients. Univariate analysis of all patients suggested that Cathepsin D immunopositivity may be predictive of a reduced metastasis-free but not overall survival. Multivariate analysis, however, failed to confirm an independent prognostic value for Cathepsin D in breast cancer patients. CONCLUSIONS: These data do not confirm an independent prognostic significance for Cathepsin D using immunohistochemical methods on breast cancers.

Breast Neoplasms↗
PubMed1994

p53 abnormalities in human parathyroid carcinoma.

Two cell cycle regulators have been implicated in the pathogenesis of parathyroid neoplasms: rearrangement/overexpression of the PRAD1/cyclin D1 gene in parathyroid adenomas and inactivation of the retinoblastoma tumor suppressor gene in parathyroid carcinomas. We examined parathyroid tumors for evidence of molecular genetic abnormalities in another cell cycle regulator, the p53 tumor suppressor gene. Allelic loss of the p53 gene was observed in parathyroid carcinomas from 2 of 6 genetically informative patients. Moreover, 2 of 9 patients' parathyroid carcinomas had nuclear p53 protein detectable by immunohistochemical analysis, a finding that often reflects mutational stabilization of the p53 protein. Of these two p53-immunopositive carcinomas, 1 had p53 allelic loss and 1 was genetically uninformative. In contrast, none of 20 informative parathyroid adenomas exhibited p53 allelic loss; 1 of 19 adenomas had a focal region of nuclear p53 protein staining. Single strand conformation polymorphism analysis of exons 5-9 of the p53 gene did not reveal mutations in any parathyroid neoplasm, suggesting that such mutations in parathyroid tumors may lie outside of these conserved regions. The finding of both p53 allelic loss and abnormal p53 protein expression in parathyroid carcinomas implicates p53 in the pathogenesis of a subset of these tumors.

Adenoma↗
PubMed1994

p53 expression in cutaneous malignant melanoma: an immunohistochemical study of 87 cases of primary, recurrent, and metastatic melanoma.

Recent studies on the role of the p53 gene in human melanoma have largely been contradictory. To further assess p53 expression in melanoma, we have studied p53 immunoreactivity in 87 cases of primary, recurrent, and metastatic melanoma. Routine immunostaining was performed on paraffin sections with the monoclonal antibody PAb1801 and a streptavidin-biotin method. All specimens were blindly and independently assessed by two observers for number of melanoma cells with granular nuclear staining. Seven melanomas (8%) exhibited from 1 to 50% positive cells and another eight cases (9%) showed p53 immunoreactivity in < 1% of cells. All of the melanomas found to be positive for p53 with one exception (< 1.50 mm) were either thicker than 1.50 mm, recurrent, or metastatic. We conclude that these findings provide little evidence for significant p53 alteration in the initiation and development of melanoma.

Humans↗
PubMed1993

p53 gene mutations and protein accumulation in human ovarian cancer.

Mutations of the p53 gene on chromosome 17p are a common genetic change in the malignant progression of many cancers. We have analyzed 38 malignant tumors of ovarian or peritoneal müllerian type for evidence of p53 variations at either the DNA or protein levels. Genetic studies were based on single-strand conformation polymorphism analysis and DNA sequencing of exons 2 through 11 of the p53 gene; mutations were detected in 79% of the tumors. These data show a statistically significant association between mutations at C.G pairs and a history of estrogen therapy. Two of 20 patients whose normal tissue could be studied carried germ-line mutations of p53. Immunohistochemical analysis of the p53 protein was carried out using monoclonal antibody PAb1801. Ninety-six percent of the missense mutations were associated with abnormal accumulation of p53 protein, but nonsense mutations, a splicing mutation, and most deletions did not result in p53 protein accumulation. A statistically significant association between p53 protein accumulation in poorly differentiated stage III serous carcinomas and small primary tumor size at diagnosis was found, perhaps suggesting that p53 protein accumulation accelerates the metastatic spread from a primary tumor. Overall, our findings indicate that alterations of p53 play a major role in ovarian cancer, including predisposition to the disease in some patients, and suggest a possible mechanism for somatic mutations leading to this cancer.

Amino Acid Sequence↗
PubMed1993

Primary leiomyosarcoma of the fallopian tube.

Primary leiomyosarcoma of the fallopian tube is an extremely uncommon neoplasm. We report a 39-year-old premenopausal woman with leiomyosarcoma confined to the right fallopian tube, who is alive without evidence of disease 2 years after surgical resection followed by adjuvant doxorubicin and cisplatin chemotherapy. An accompanying literature review indicates that the clinical signs and symptoms of fallopian tube sarcomas are usually nonspecific and include lower abdominal pain and pelvic pressure. The age at diagnosis varies from 21 to 70 years, with a median of 47 years. Prognosis is poor, however, several longterm survivors have been reported. The primary treatment remains surgical excision, although adjunctive chemotherapy or radiation may be of some benefit.

Adult↗
PubMed1993

Comparative study of p53 gene and protein alterations in human astrocytic tumors.

The p53 gene is a tumor suppressor gene involved in many common malignancies, including astrocytomas. Genetic analysis of the p53 gene and immunohistochemistry of the p53 protein have each been used to screen astrocytomas. To compare these methods, we performed immunohistochemistry with the monoclonal antibody PAb 1801 and single-strand conformational polymorphism (SSCP) with sequence analysis on 34 astrocytic tumors (WHO grades II, III and IV). Seven cases had detectable p53 protein and gene mutations, while twelve cases had neither detectable protein nor gene mutations. Four tumors had frameshift mutations in the p53 gene that were not revealed by immunohistochemistry. One tumor had a genetic polymorphism and no detectable p53 protein. Ten tumors had p53 protein accumulation but no mutations by SSCP; these cases may represent p53 mutations outside of the conserved exons or elevated levels of wild-type p53 protein. Thus, some p53 mutations are missed with PAb 1801 immunohistochemistry alone. p53 immunohistochemistry, however, may reveal p53 accumulation independent of mutations in the conserved portions of the gene. Finally, we suggest that glioblastomas with p53 mutations in the conserved region of the gene may be a subset that are more common in women and in younger patients.

Adolescent↗
PubMed1992

Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers.

BACKGROUND: Mutations of the tumor suppressor gene p53 have been identified in breast cancer cell lines, and some breast carcinomas are detectable by immunohistochemical assay because of p53 protein accumulation. PURPOSE: This study was designed to determine whether p53 protein accumulation in breast cancers correlates with p53 gene mutation, with survival, and with five pathobiologic factors associated with prognosis. METHODS: IgG1 monoclonal antibody to human p53 protein (PAb 1801) and immunohistochemical methods were used to detect p53 protein accumulation in archival formalin-fixed, paraffin-embedded, randomly selected carcinomas. We studied 295 invasive ductal carcinomas from the Massachusetts General Hospital; 151 were determined to be sporadic (not hereditary). We also studied 97 invasive ductal carcinomas--21 sporadic and 76 familial (hereditary)--from Creighton University. In addition, we examined 31 archival in situ carcinomas, 15 snap-frozen invasive ductal carcinomas, primary cell cultures from three benign breast tissue samples, and breast carcinoma cell lines MDA-MB-231 and MDA-MB-468. RESULTS: Nuclear p53 protein was observed in 16% of the 31 in situ carcinomas, 22% of the 172 sporadic carcinomas, 34% of the 50 tumors from patients with familial breast cancer, 52% of the 23 tumors from patients with the familial breast and ovarian cancer syndrome, and all three tumors from two patients with the Li-Fraumeni syndrome. There was complete concordance between p53 gene mutation and p53 protein accumulation in the 15 snap-frozen carcinomas and in both breast carcinoma cell lines. Statistically significant associations of p53 protein accumulation with estrogen receptor negativity and with high nuclear grade were found. There were statistically significant associations, independent of other prognostic factors, between p53 protein accumulation and metastasis-free and overall survival, for randomly accrued and for both sporadic and familial tumors. CONCLUSIONS: Immunohistochemically detected p53 protein accumulation was an independent marker of shortened survival and was seen more often in familial than in sporadic carcinomas. Our findings also suggest a correlation between p53 protein accumulation and p53 gene mutation.

Age Factors↗