ras gene alterations and enhanced levels of ras p21 expression in a spectrum of benign and malignant human mammary tissues.
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Alleles↗
Biomedical subjects
D L Page
Publications and source records attributed to D L Page.
Expression of the 21,000 molecular weight ras protein in a spectrum of benign and malignant human mammary tissues.
Monoclonal antibodies RAP-5 and Y13-259, directed against the ras gene product [a protein with a molecular weight of 21,000 (p21)] have been used to evaluate ras p21 expression in malignant and benign mammary tissues as well as in the lesions of intermediate stature such as atypical hyperplasia using immunohistochemical assays. Invasive carcinoma demonstrated enhanced expression of ras p21, with generally decreasing expression in carcinoma in situ, atypical hyperplasia, and nonatypical hyperplasia, respectively. Heterogeneous expression of ras p21 was observed among primary as well as metastatic mammary carcinomas. Carcinomas from postmenopausal patients generally demonstrated higher levels of ras p21 than those from premenopausal patients, but no significant difference in ras p21 expression in carcinomas between estrogen-receptor rich and estrogen-receptor poor patients was found. Normal mammary epithelium in terminal duct lobular units from patients with hyperplasia generally demonstrated higher levels of ras p21 expression than did epithelium in large ducts. This demonstration of enhanced ras p21 expression by the epithelium of peripheral lobular portion of the breast is consistent with the previous hypothesis that these areas preferentially undergo malignant transformation. Analyses of the limited number of specimens available from patients with 15-yr follow-up revealed a generally higher level of ras p21 in hyperplasia from patients who subsequently developed carcinoma, as compared to those from patients without carcinoma development. However, no conclusions regarding the potential for malignant transformation could be drawn for any individual patient on the basis of ras p21 expression. Concomitant analyses of ras p21 expression in mammary carcinomas and benign lesions using liquid competition radioimmunoassay and immunohistochemical assay demonstrated the complementary nature of these alternative approaches. These results suggest that enhanced ras p21 expression may be involved in the early stages of mammary carcinogenesis but is probably not involved in the maintenance of the transformed phenotype.
Antibodies, Monoclonal↗
Congenital ostial stenosis of the right coronary artery repaired by vein patch angioplasty.
A case of congenital ostial stenosis of the right coronary artery is presented in which revascularization was performed by saphenous vein patch angioplasty.
Angiography↗
Diagnosis and prognosis of adrenocortical neoplasms.
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Adrenal Cortex Neoplasms↗
Breast cancer risk of lobular-based hyperplasia after biopsy: "ductal" pattern lesions.
Three thousand three hundred three women were followed an average of 17 years following benign breast biopsy. These women comprise 84.4% of those originally targeted for follow-up. Risk of invasive breast cancer development was analyzed in relation to the hyperplasia classification scheme of Wellings et al (JNCI 1975; 55:231-73) that is based on terminal ductal-lobular units (ALA). Cancer risk was also assessed with respect to family history of breast cancer in first-degree relatives (FHBC), as well as atypical features of hyperplasia recognized by resemblance to carcinoma in situ of ductal type (ADH). There was a trend of increasing cancer risk with increasing degree of ALA lesion, reaching 1.9 with ALA-IV lesions having both qualitative and quantitative features of advanced atypical hyperplasia. When ADH lesions are removed from the analysis, any predictive power of ALA lesions is lost. ADH recognizes histologic lesions with a four- to fivefold increased risk of breast cancer. FHBC interacts with any hyperplastic lesion so as to approximately double the cancer risk.
Adult↗
Atypical hyperplastic lesions of the female breast. A long-term follow-up study.
A total of 10,542 breast biopsy specimens obtained between 1950 and 1968 were studied. Examples of atypical "ductal" (ADH) and atypical lobular hyperplasia (ALH), defined as having only some features of carcinoma in situ (CIS), were diagnosed in 3.6% of these specimens. In the same series, CIS was diagnosed in 1.7% of biopsy specimens excluding those with invasive cancer. The subsequent risk of invasive breast carcinoma after ALH or ADH was 4-5 times that of the general population. Follow-up was 90% successful and extended 17 years after biopsy. History of breast cancer in a mother, sister, or daughter doubled the risk of subsequent invasive carcinoma development (to 8 times for ALH and 10 times for ADH). The authors conclude that among the epithelial hyperplastic lesions of the human breast, a minority may be recognized by their resemblance to CIS which have a clinically significant elevation of subsequent breast cancer risk. This risk is one-half that of CIS.
Adult↗
Risk factors for breast cancer in women with proliferative breast disease.
To assess the importance of various risk factors for breast cancer in women with benign proliferative breast lesions, we reevaluated 10,366 consecutive breast biopsies performed in women who had presented at three Nashville hospitals. The median duration of follow-up was 17 years for 3303 women, 1925 of whom had proliferative disease. This sample contained 84.4 per cent of the patients originally selected for follow-up. Women having proliferative disease without atypical hyperplasia had a risk of cancer that was 1.9 times the risk in women with nonproliferative lesions (95 per cent confidence interval, 1.2 to 2.9). The risk in women with atypical hyperplasia (atypia) was 5.3 times that in women with nonproliferative lesions (95 per cent confidence interval, 3.1 to 8.8). A family history of breast cancer had little effect on the risk in women with nonproliferative lesions. However, the risk in women with atypia and a family history of breast cancer was 11 times that in women who had nonproliferative lesions without a family history (95 per cent confidence interval, 5.5 to 24). Calcification elevated the cancer risk in patients with proliferative disease. Although cysts alone did not substantially elevate the risk, women with both cysts and a family history of breast cancer had a risk 2.7 times higher than that for women without either of these risk factors (95 per cent confidence interval, 1.5 to 4.6). This study demonstrates that the majority of women (70 per cent) who undergo breast biopsy for benign disease are not at increased risk of cancer. However, patients with a clinically meaningful elevation in cancer risk can be identified on the basis of atypical hyperplasia and a family history of breast cancer.
Adult↗
Long-term survivors after breast cancer.
A retrospective analysis of two groups of patients, one surviving 16-20 years and the other dying within 10 years after diagnosis and treatment of primary breast cancer has been undertaken to determine whether there were particular clinical or histological features associated with long-term survival. The striking histological difference between the tumours of the two groups of patients was the prevalence of tumours of 'special' invasive types (cribriform, tubular, lobular and medullary) in the long-term survivors. Micro-invasive and non-invasive carcinomas were also more common in the survivors. The tumours of the surviving group which were not of a 'special' type more commonly had a better histological grade than those tumours of patients dying early from breast cancer. In the overall group elastosis was present in significantly more tumours of the survivors whereas tumour necrosis, vascular and lymphatic invasion were all significantly more common in the short-term survival group. Although there was a significantly increased incidence of earlier stage tumours in the long-term survivors, the histological distinctions between the two groups were independent of the differences in clinical features.
Adult↗
Inflammatory carcinoma of the breast. Clinical review and summary of the Vanderbilt experience with multi-modality therapy.
Inflammatory breast cancer is a distinct clinicopathologic entity that accounts for 1 percent of all cases of breast cancer. The diagnosis should be strongly suspected on the basis of the distinctive clinical findings, which include edema of the breast, inflammation, wheals, and a typical reddish-purple color of the overlying skin. Pathologic examination usually shows infiltration of the dermal lymphatics with carcinoma. Evidence of distant metastatic spread is more frequent than with other types of breast cancer and is seen in approximately 30 percent of patients. The five-year disease-free survival rate is less than 5 percent when local therapy alone (mastectomy and/or local radiotherapy) is used. The addition of combination chemotherapy to high-dose local radiotherapy has improved the five-year survival rate to approximately 30 percent. The potential for long-term survival is limited to the subgroup of patients with only local-regional disease at the time of diagnosis. Patients with inflammatory breast cancer should be treated with combined-modality therapy using combination chemotherapy and high-dose radiotherapy to the breast, since this approach is potentially curative. The fatalism formerly associated with this diagnosis is no longer warranted, particularly in patients with local-regional disease. Failure to employ intensive combined-modality treatment will deny some patients a chance for long-term survival.
Adult↗
Adenomas of the breast and ectopic breast under lactational influences.
The tubular adenomas, lactating adenomas, and ectopic lactation- or gestation-associated benign lesions of the breast diagnosed during a 22-year period are reported. Forty-two breast adenomas (in 28 patients) that demonstrated lactational changes are reviewed, with special attention to classification and clinical presentation. Five ectopic lactating adenomas--three axillary or in the chest wall and two vulvar, the latter occurring in the same patient--were identified in three patients. The lesions in the remaining cases were fibroadenomas with lactational changes (16 patients) and lactating or tubular adenomas (nine patients). Striking histologic and clinical similarities between the tubular and lactating adenomas and the lesions identified as lactational changes within a fibroadenoma were observed, with foci of tubular adenomatous change present within otherwise typical fibroadenomas. The overlapping morphologic spectrum and the strong association with pregnancy or lactational influences blur the distinction between these entities and suggest a common pathogenesis. The cytologic features of lactational lesions of the breast and ectopic breast pose special problems in diagnosis by fine needle aspiration.
Adenofibroma↗
Cell specificity of rat cytokeratin p39 during azo dye-induced hepatocarcinogenesis.
Monoclonal or affinity-purified antibodies specific to Novikoff hepatoma cytokeratin p39 were employed to study the origin and fate of p39-containing cell types during hepatocarcinogenesis induced with N,N-dimethyl-p(m-tolylazo)aniline. Frozen sections were obtained from the livers of animals autopsied temporally during carcinogen feeding and were assayed immunohistochemically. In normal, untreated liver or in liver from animals fed the hepatotoxin alpha-naphthyl-isothiocyanate, the localization of p39 was restricted to bile duct epithelial cells while hepatocytes were non-reactive. However, during carcinogen treatment we observed a sequential appearance of immunoreactive cells which were similar morphologically to the classical 'oval' cells of hepatocarcinogenesis; eventually these cell types were enriched around the preneoplastic hepatocyte nodules. Occasional transformed hepatocytes within the nodules exhibited strong immunoreactivity. In the later stages of hepatocarcinogenesis, these antibodies stained the epithelial cells in areas of severe adenosis as well as the neoplastic epithelial cells of cholangiomas and some, but not all, hepatocellular carcinomas. Our results document the presence of p39 in the 'oval' cells of hepatocarcinogenesis and indicate that some populations of transformed hepatocytes exhibit this cytokeratin after transformation.
Animals↗
Aortic intimal sarcoma with embolic metastases.
A 46-year-old woman died from massive bowel infarction. At autopsy, a primary sarcoma was found growing along the intimal surface of the aorta at the level of the celiac axis. Tumor emboli were found in distal aortic branches and most abdominal organs. Immunoperoxidase for Factor VIII and electron microscopy (EM) did not support an endothelial origin. EM showed myofibroblastic differentiation. Review of the literature yields an array of diagnostic histologic terms for these tumors, hampering case comparison. The literature does suggest, however, that the clinical presentation of these rare neoplasms correlates nicely with the location and gross morphology of the lesion. We therefore propose a clinicopathologic classification, categorizing the lesions as intimal (obstructive and nonobstructive) and mural. The former are typically pleomorphic sarcomas and are probably of myofibroblastic origin, whereas the latter are usually leiomyosarcomas or fibrosarcomas that probably originate in the media or adventitia.
Aorta, Abdominal↗
Hypertension in a patient with multiple renal and adrenal masses.
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Adrenal Gland Neoplasms↗
Characterization of monoclonal antibodies to novikoff hepatoma cytokeratin antigen p39.
Three stable monoclonal antibody-producing mouse hybridoma lines have been developed which produce high-titer, immunoglobulin M antibodies specific for the Novikoff ascites hepatoma (NAH) Mr 39,000 cytokeratin antigen (p39). Immunotransfer assays of cytoskeletal protein-enriched fractions indicated p39 to be present in a range of rat tissues, including colon, breast, lung, and uterus. Two-dimensional gel immunoblots confirmed that immunoreactivity in the latter tissues was for polypeptides with similar isoelectric points to those of NAH p39; however, reactivity in the colon contained a wide range of additional isomeric forms. Immunohistochemical localization studies with these antibodies revealed enrichment of p39 in the simple epithelia or ductular structures of organs containing this antigen. In all sections examined, glandular epithelia were observed to be only weakly immunoreactive. Additional immunoblot and immunocytochemical analyses with the monoclonal antibodies and polyspecific antisera to NAH cytokeratin suggest the human Mr 40,000 cytokeratin to be similar to but not identical to NAH p39.
Animals↗
Infiltrating lobular carcinoma of the breast: an evaluation of the incidence and consequence of bilateral disease.
A histological review of 1003 invasive breast carcinomas identified 103 patients with infiltrating lobular carcinoma, for whom clinical and survival data were collected in each case. Six patients had bilateral carcinoma at diagnosis and 14 developed a contralateral carcinoma during the period of follow-up. The major factor predicting patients at risk of developing a contralateral carcinoma was histological type. Analysis of survival data on the patients with bilateral disease showed poor survival in the group with synchronous bilateral disease, but no difference in survival between patients with metachronous bilateral and unilateral disease. This suggests that the development of a metachronous contralateral carcinoma does not necessarily reduce the probability of survival of patients with infiltrating lobular carcinoma.
Breast Neoplasms↗
Chromosomal protein antigens formed in experimental hepatocarcinogenesis by azo dyes.
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Adenocarcinoma↗
Cytokeratin and nonhistone protein antigenic changes in rat liver during azo dye but not hepatotoxin feeding.
Chromosomal proteins from rat liver have been assessed immunologically for changes in specific cytokeratins or primary tumor nonhistone proteins during treatment with an azo dye hepatocarcinogen (3'-methyl-4-dimethylaminoazobenzene), (3'-Me-DAB) or the hepatotoxin alpha-naphthyl-iso-thiocyanate (alpha-NIT). Fisher rats were fed laboratory diets supplemented with either agent and sacrificed sequentially at various intervals. Chromosomal proteins from these livers were electrophoresed in the presence of sodium dodecyl sulfate, transferred to nitrocellulose sheets and reacted with rabbit antisera to Novikoff hepatoma cytokeratin or 3'-Me-DAB induced primary hepatoma dehistonized chromatin. Livers from carcinogen-fed animals exhibited distinct, sequential changes in antigenic nonhistone proteins until the immunological specificity characteristic of the hepatoma was achieved concomitant with the induction of neoplasia. No antigenic changes were observed to occur in hepatotoxin-fed animals. The rat carcinoma-specific cytokeratin antigens p39 and p49 in Novikoff hepatoma were observed to appear as early as three weeks after the start of carcinogen feeding and were present maximally in 23 week livers with in situ carcinoma. These cytokeratins were not detected in alpha-NIT-fed animals. Our results support the concept that the carcinogenic process can be related to temporal changes in the expression of cell-specific cytokeratins in addition to nonhistone chromosomal proteins. Furthermore, these data suggest the expression of these antigenic species to not be the direct result of changes in liver structure and cellular composition associated with carcinogen toxicity; rather, neoplastic transformation is apparently required.
1-Naphthylisothiocyanate↗