Search PubMed⌕ Search

Biomedical subjects

D C Allred

Publications and source records attributed to D C Allred.

At least 73 records · Page 4Linked to original sources
PubMed1993

Expression of estrogen receptor variants.

Recent data suggest that the expression of estrogen receptor (ER) variants may be common in clinical breast cancer. The significance of their expression is complicated by the fact that they are often coexpressed with wild-type ER in the same tumor. We have focused upon one such ER variant which lacks exon 5 within the hormone binding domain of the receptor. This deletion introduces a stop codon, resulting in a truncated ER of 40 kDa which is unable to bind hormone. We have been exploring the hypothesis that this variant may contribute to clinical antiestrogen resistance. Coexpression of the exon 5 variant along with wild-type ER in MCF-7 human breast cancer cells confers resistance to the commonly used antiestrogen, tamoxifen. In addition, we have observed that some metastatic breast lesions overexpress exon 5 ER deletional variant transcripts. We conclude that differences in the relative amounts of several ER variants in the same tumor may interact to determine hormonal responsiveness and metastatic behavior.

Breast Neoplasms↗
PubMed1993

Prognostic significance of p53 gene alterations in node-negative breast cancer.

UNLABELLED: Mutations in the p53 gene can play a role in the transformation of normal to malignant cells. Because these mutations are more frequently reported later in the course of transformation, their presence could reflect a greater malignant potential of the tumor and, thus, an increased probability of metastasis and recurrence after local therapy. In a pilot study using single-stranded conformation polymorphism analysis (SSCP), 200 node-negative breast tumors were examined for mutations in the region encompassing exons 5 through 9 of the p53 gene. Exons 5 through 9 were tested because they contain 80-90% of known p53 gene mutations. The tumors ranged in size from 1 to 3 cm. 28 tumors were found to have an abnormal band pattern on both initial and repeat analysis. 4 of these tumors were sequenced; 3 contained a p53 mutation and the 4th had a rare neutral polymorphism. Disease-free survival (DFS) at 5 years for women with tumors having an abnormal SSCP analysis was 57% (+/- 10%), compared to a 79% (+/- 3%) DFS for the group with a normal pattern. By the log rank test, this difference was highly significant, p < or = 0.01. The relative risk of recurrence for the group with an abnormal SSCP pattern was 2.2. In a multivariate analysis including ER, PgR, ploidy, S-phase, age, and tumor size, an abnormal p53 by SSCP analysis and patient age were the only factors that independently predicted DFS at 5 years. CONCLUSION: Women with node-negative breast cancer who have tumors with alterations in the p53 gene, as indicated by SSCP analysis, have a significantly poorer prognosis and a higher rate of relapse at 5 years. The prognostic significance is maintained in a multivariate analysis including many established prognostic factors.

Base Sequence↗
PubMed1993

William L. McGuire Memorial Symposium. The role and prognostic significance of p53 gene alterations in breast cancer.

Alterations in the p53 tumor suppressor gene are the most frequent genetic changes found in breast cancer, with an incidence reported in a range of 15 to 50%. The incidence of p53 alterations is approximately 15% for in situ carcinoma, while for invasive node-positive disease it is 2 to 3 times higher. This high rate of alteration suggests that the gene plays a central role in the development of breast cancer. The p53 gene functions as a negative regulator of cell growth. Alterations in the gene lead to loss of its usual negative growth regulation and more rapid cell proliferation. Since p53 alteration can reflect a more advanced state of progression and a higher rate of proliferation, breast tumors that have a p53 alteration could have a greater probability of having micrometastasis. p53 alterations could therefore be a prognostic factor for recurrence after primary local therapy. Consistent with this hypothesis, several independent studies using different methodologies have found that breast tumors with altered p53 have a worse prognosis and are also more likely to have other poor prognostic factors.

Amino Acid Sequence↗
PubMed1993

The ER-positive/PgR-negative breast cancer phenotype is not associated with mutations within the DNA binding domain.

We have used in vitro DNA binding assays as a measure of estrogen receptor (ER) function in human breast tumors. We found that the majority of ER+ (25 ER+/progesterone receptor [PgR]+, and 25 ER+/PgR-) tumors we examined were capable of binding consensus estrogen response element (ERE) oligonucleotides in this assay system. We found significant proteolytic activity in many of the tumors such that protease inhibitors were found to be essential during the preparation of tumor extracts. We next applied direct sequence analysis of the ER DNA binding domain of several of these tumors, and determined that the ER+/PgR- breast tumors did not contain mutations within the DNA binding domain which might explain their apparent discordant receptor phenotype. We did identify an alternatively spliced ER variant missing exon 3 of the DNA binding domain. This variant was unable to function as a transcriptional inducer of an estrogen-responsive reporter in a yeast assay system. Furthermore, the exon 3 ER deletion variant was expressed at equivalent levels in all of the ER+ breast tumors, so that it does not appear to be involved in the evolution of the ER+/PgR- breast cancer phenotype.

Base Sequence↗
PubMed1993

Multiple-marker immunohistochemical phenotypes distinguishing malignant pleural mesothelioma from pulmonary adenocarcinoma.

The diagnostic distinction between malignant pleural epithelial mesothelioma and pulmonary adenocarcinoma is often difficult and partially reliant on the use of immunohistochemistry (IHC). While there are several available IHC markers preferentially expressed in adenocarcinomas compared with mesotheliomas, there are no readily available or well-validated markers preferentially expressed in mesotheliomas and no markers are absolutely specific for either tumor. Thus, there always will be an element of doubt regarding the identity of lesions diagnosed by IHC using these markers and an undesirable reliance on negative results if the lesion is truly a mesothelioma. To help optimize the ability of currently available but imperfect markers to resolve adenocarcinoma and mesothelioma and to minimize the impact of false-negative results on their diagnosis, a systematic study was undertaken to identify multiple-marker immunostaining phenotypes that are the most specific and sensitive for each type of tumor. The study involved staining a series of malignant epithelial mesotheliomas (n = 34) and pulmonary adenocarcinomas (n = 103) with eight markers that were selected on the basis of previous reports of their relatively restricted specificities for one or the other of these lesions (and included carcinoembryonic antigen [CEA], tumor-associated glycoprotein 72 [B72.3], Leu-M1, vimentin, thrombomodulin, secretory component, carcinoma antigen-125, and periodic-acid-Schiff with diastase [for mucin]. Considering the markers one, two, and three at a time, all possible combinations of results were analyzed by computer to identify the phenotype most sensitive and specific for adenocarcinoma or mesothelioma. The best single marker was CEA (positive: 97% specific and sensitive for adenocarcinoma; negative: 97% specific and sensitive for mesothelioma). However, because examples of both tumor types expressed CEA, none of the study cases were unequivocally resolved and the risk of false-negative results was relatively high. The best two markers were CEA and B72.3 (both positive: 100% specific and 88% sensitive for adenocarcinoma; both negative: 99% specific and 97% sensitive for mesothelioma). The four possible combinations of results for these two markers resolved 68% of cases (93 of 137 cases), with less risk of false-negative results than a single marker. In general, several three-marker panels resulted in sensitivities and specificities similar to the two-marker panel of CEA and B72.3. In particular, the three-marker panel of CEA, B72.3, and Leu-M1 resulted in eight possible phenotypes that resolved 74% of cases (101 of 137 cases), with even further reduced risk of false-negative results.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1993

Glutathione transferase GST pi in breast tumors evaluated by three techniques.

The glutathione transferases are involved in intracellular detoxification reactions. One of these, GST pi, is elevated in some breast cancer cells, particularly cells selected for resistance to anticancer agents. We evaluated GST pi expression in 60 human breast tumors by three techniques, immunohistochemistry. Northern hybridization, and Western blot analysis. There was a significant positive correlation between the three methods, with complete concordance seen in 64% of the tumors. There was strong, inverse relationship between GST pi expression and steroid receptor status with all of the techniques utilized. In addition, there was a trend toward higher GST pi expression in poorly differentiated tumors, but no correlation was found between tumor GST pi content and DNA ploidy or %S-phase. GST pi expression was also detected in adjacent benign breast tissue as well as infiltrating lymphocytes; this expression may contribute to GST pi measurements using either Northern hybridization or Western blot analysis. These results suggest that immunohistochemistry is the method of choice for measuring GST pi in breast tumors.

Blotting, Northern↗
PubMed1992

Prognosis and treatment decisions in patients with breast cancer without axillary node involvement.

BACKGROUND: Every month, treatment decisions must be made for more than 6000 patients with breast cancer without axillary node involvement in the United States. Approximately 70% of these patients will survive more than 10 years after surgery and/or radiation treatment without additional systemic adjuvant therapy. If we had good methods to identify patients who are destined to have a recurrence of their disease, only those patients should receive adjuvant therapy. METHODS: The authors reviewed the literature supporting the use of currently available prognostic factors for patients with node-negative breast cancer, and formulated a framework on which prognostic factor information can be based to help make these treatment decisions. RESULTS: The steps involved in making treatment decisions are: use prognostic factors to determine the recurrence probability; calculate the expected treatment benefit; and weigh the expected benefits against the potential risks. CONCLUSIONS: Prognostic factors can be used to help make treatment decisions for patients with breast cancer without axillary node involvement. However, the final treatment decision must take into account all aspects of the patient and her disease, and the physician must help the patient evaluate her prognostic factors, arrive at an understanding of her particular risk of recurrence, and weigh the potential benefits and risks of adjuvant therapy.

Axilla↗
PubMed1992

Inhibition of estrogen receptor action by a naturally occurring variant in human breast tumors.

It is fairly well accepted that the presence of estrogen receptor (ER) and progesterone receptor (PgR) identifies breast cancer patients with a lower risk of relapse and better overall survival. But patients with discordant receptors, the ER+/PgR- phenotype, are often intermediate in clinical response. We focused upon this group of patients and have identified a truncated ER which is abundant in some ER+/PgR- breast tumors and which inhibits the binding of wild-type ER to its cognate response element. This variant interferes in a dominant negative manner with wild-type ER function and may represent a mechanism for modulation of estrogen responsiveness.

Base Sequence↗
PubMed1992

Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer.

Using permanent-section immunohistochemistry, we investigated the role of HER-2/neu in the development and progression of human breast cancer by measuring its overexpression in a series of hyperplastic (n = 30), dysplastic (n = 15), and malignant neoplastic (n = 708) lesions of ductal epithelium and by evaluating the relationships between overexpression and clinicopathologic features known to have prognostic significance in these lesions. The neoplasms included pure ductal carcinoma in situ (DCIS; n = 59) and infiltrating ductal carcinoma (IDC; n = 649). The latter were all node negative and stratified into IDC combined (n = 237) or not combined (n = 412) with a "significant amount" of DCIS (defined as DCIS greater than or equal to 10% of total tumor cellularity). Overexpression of HER-2/neu was not observed in any of the hyperplastic or dysplastic lesions. In contrast, it was present in 56% of pure DCIS and in 77% of the comedo subtype of this group. Only 15% of IDC overexpressed HER-2/neu. However, the rate of overexpression was significantly higher in the subset of IDC combined with DCIS compared with the subset of IDC not combined with DCIS (22% v 11%, respectively; P less than .0001). These results are consistent with the hypothesis that HER-2/neu plays a more important role in initiation than in progression of ductal carcinomas. They also suggest that overexpression decreases within individual tumors as they evolve from in situ to increasingly invasive lesions or, alternatively, that many invasive carcinomas arise de novo (ie, without progressing through a significant in situ stage) by mechanisms not involving HER-2/neu. In addition, overexpression of HER-2/neu was associated with several poor prognostic features (younger patient age, premenopause, negative estrogen receptor status, negative progesterone receptor status, and high nuclear grade) in the subset of IDC combined with DCIS. With one exception (negative estrogen receptor status) these associations were lost in IDC not combined with DCIS, also suggesting that the role of HER-2/neu changes during the progression of human breast cancer.

Biomarkers, Tumor↗
PubMed1992

HER-2/neu in node-negative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma.

PURPOSE: Amplification and/or overexpression of the HER-2/neu oncogene have been shown to correlate with poor clinical outcome in patients with axillary node-positive breast cancer. In contrast, the prognostic significance of HER-2/neu in node-negative disease is controversial. This study was undertaken to evaluate further the relationship between HER-2/neu and clinical outcome in node-negative disease. PATIENTS AND METHODS: Overexpression of HER-2/neu was evaluated by permanent-section immunohistochemistry in tumors from 613 patients with long-term clinical follow-up enrolled in the Intergroup Study 0011. Patients were stratified into low-risk (n = 307) and high-risk (n = 306) groups on the basis of tumor size and estrogen-receptor (ER) status. Low-risk patients were defined as having small (less than 3 cm), ER-positive tumors and were observed without additional treatment after initial surgery. High-risk patients had either ER-negative or large (greater than or equal to 3 cm), ER-positive tumors and were randomized to be observed (n = 146) or to receive adjuvant chemotherapy (n = 160) after surgery. RESULTS: The rate of HER-2/neu overexpression was 14.3% in all tumors combined and was higher in invasive carcinomas with (21.5%) than without (11.2%) a significant noninvasive or in situ histologic component (P less than .0001). There was no relationship between overexpression and clinical outcome in the natural history setting of combined low-risk and high-risk patients not receiving adjuvant therapy (n = 453). Based on the reasoning that the influence of HER-2/neu may have been obscured by high-risk features and/or the presence of noninvasive carcinoma, we also analyzed the subset of patients with low-risk lesions not containing a significant in situ component (n = 179). Patients of this group with HER-2/neu-positive tumors showed only 40% disease-free survival (DFS) at 5 years, compared with over 80% in patients with HER-2/neu-negative tumors (P less than .0001). A similar inverse correlation was observed between overexpression and overall survival in the same group of patients (P = .0001). In a separate analysis involving patients receiving adjuvant chemotherapy, those with HER-2/neu-negative tumors showed significantly improved DFS in response to therapy compared with patients with HER-2/neu-positive tumors. CONCLUSION: Overexpression of HER-2/neu is associated with poor clinical outcome in a subset of node-negative patients with small, ER-positive, predominantly invasive tumors and may play a role in resistance to adjuvant chemotherapy.

Breast Neoplasms↗
PubMed1992

Treatment decisions in axillary node-negative breast cancer patients.

Treatment decisions must be made on 9000 axillary node-negative breast cancer patients each month in the United States. Which of these patients will benefit from adjuvant therapy is a major question. Valid methods are needed to distinguish those patients who are "cured" from those who will suffer a cancer recurrence. A complex network of prognostic variables enters into the treatment decision, together with a risk-versus-benefit assessment. We are using a neural-network-based form of artificial intelligence that, once "trained" with data representing an event and its outcome, can identify subsets of patients with low recurrence risks. Larger data sets are being evaluated with the hope of introducing the neural-network technique to routine clinical practice.

Breast Neoplasms↗
PubMed1991

Acquired tamoxifen resistance: correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen.

Acquired tamoxifen resistance represents a major cause of treatment failure in breast cancer. We implanted estrogen receptor-positive MCF-7 human breast cancer cells in athymic nude BALB/c mice as a model to study in vivo acquired tamoxifen resistance. After 4-6 months of tumor growth suppression by trans-tamoxifen, tumor progression was observed despite continued tamoxifen administration. Acquired resistance was not due to loss of estrogen receptors, to alterations in serum or tumor estrogen levels, or to changes in tamoxifen or its major metabolites in serum. Tamoxifen-resistant tumors remained estrogen dependent in vivo. However, resistance was also associated with the ability of tamoxifen to stimulate tumor growth. Resistant tumors were characterized by markedly lower intracellular tamoxifen levels and by isomerization of the potent antiestrogenic metabolite trans-4-hydroxy-tamoxifen to the less potent cis isomer. Metabolic tolerance, as manifested by alterations in cellular concentrations of tamoxifen and its metabolites, may thus be one mechanism for acquired tamoxifen resistance in breast cancer.

Animals↗
PubMed1991

Differential antigen preservation during tissue autolysis.

Immediate fixation or snap freezing of tissue is ordinarily done to maximize antigen preservation for immunocytochemistry; however, delay in tissue allocation or spontaneous lymph node infarction can render tissue suboptimal for immunostaining. To test the effects of tissue autolysis/necrosis on the preservation of various lymphoid, epithelial, and mesenchymal markers, two lymph nodes (one with reactive lymphoid hyperplasia and one with metastatic ductal breast carcinoma) were evaluated for immunocytochemically demonstrated antigen preservation at 0-, 4-, 8-, 12-, 24-, 48-, and 72-hour intervals of autolysis at 37 degrees C. All specimens were stained by frozen section and formalin-fixed paraffin section immunocytochemical reactions with antibodies against CLA (CD45), UCHL-1 (CD45RO), L-26, kappa, lambda, anti-epithelial keratins (AE-1 and AE-3), epithelial membrane antigen, and vimentin. Frozen sections were additionally stained for Leu-1 (CD5), Leu-2a (CD8), Leu-3a+b (CD4), Leu-4 (CD3), and Leu-14 (CD22). The most resilient lymphoid antigen preservation was observed with CLA and UCHL-1, both exhibiting immunoreactivity at 72 hours in both frozen and fixed preparations. L-26 showed similar reactivity in frozen sections, but detectable antigen was observed only up to 24 hours in formalin-fixed tissue. Leu-2a proved to be the most labile antigen, persisting for only 12 hours in frozen sections. The epithelial markers epithelial membrane antigen and AE-1 exhibited excellent antigenic preservation in both frozen and fixed preparations; AE-3 persisted well in frozen section but was not demonstrated in fixed tissue. Vimentin immunoreactivity was vastly superior in frozen, as compared with fixed, tissue sections. Most antigens showed remarkable preservation despite morphologic degradation; however, differential antigenic resilience was demonstrated. Knowledge of this variation in antigen decay is critical for evaluation of immunoperoxidase phenotypic studies of autolyzed or necrotic tissue.

Antigens↗
PubMed1991

A comparison of foreign body and hypersensitivity granuloma formation in the mouse: kinetic development, anergy, angiotensin converting enzyme levels, and response to captopril therapy.

Pulmonary granuloma size, anergy, serum and lung angiotensin converting enzyme (ACE) levels, and responsiveness to captopril therapy were measured in both pulmonary hypersensitivity granuloma (HSG) and foreign body granuloma (FBG) murine models. The kinetic development of the granuloma was similar in both models, peaking at 3 days and resolving by 14 days. The granuloma size of the FBG model was significantly larger than the HSG model at 1 and 3 days. The FBG model further differed from the HSG model in that anergy was observed at 3 days and lung ACE levels were increased at 1, 7, and 14 days. In the HSG model anergy was not observed and lung ACE levels were significantly elevated only at 1 and 7 days. Furthermore, the HSG model was shown to be responsive to captopril therapy whereas the FBG model was not. This study shows that two murine pulmonary granuloma models, although displaying similar growth and resolution kinetics, differ in terms of granuloma size, anergy, lung ACE activity, and responsiveness to captopril therapy, suggesting that the mechanism(s) involved in the inflammatory response of the two models may be different.

Animals↗
PubMed1991

Enhancement of immunoreactivity among lymphoid malignant neoplasms in paraffin-embedded tissues by refixation in zinc sulfate-formalin.

It has been previously demonstrated that improved cytomorphologic detail can be obtained from tissue blocks initially fixed in 4% formaldehyde solution by means of a "run-back" procedure to an aqueous phase of solution, allowing refixation with a protein-precipitating agent, such as zinc sulfate-4% formaldehyde solution. Because anecdotal experience with immunostaining such reprocessed tissues had suggested improved results, we performed a prospective trial involving 13 cases to compare the intensity of immunoreactivity before and after such reprocessing. In 10 of 13 cases studied with a variety of antibody reagents, we noted a definite improvement of staining, preferentially among those with the weakest original immunoreactivity.

Antibodies, Neoplasm↗