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Biomedical subjects

M J Duffy

Publications and source records attributed to M J Duffy.

At least 19 recordsLinked to original sources
PubMed1996

High levels of stromelysin-3 correlate with poor prognosis in patients with breast carcinoma.

Stromelysin 3 (ST3) is a matrix metalloprotease (MMP) expressed in fibroblast-like cells of most human invasive carcinomas. In this investigation, ST3 was measured by semiquantitative immunohistochemistry in 111 primary breast cancers. ST3 levels showed no correlation with tumor size, axillary-node status or tumor grade (Scarff-Bloom-Richardson system; SBR) but were significantly associated with higher nuclear grade (modified SBR). In addition, ST3 levels were significantly higher in ductal than in lobular cancers. Patients with high scores of ST3 staining had a shorter disease-free interval and shorter overall survival than patients with low scores. ST3 is thus one of the first MMPs to correlate with patient outcome in breast cancer. These findings are consistent with earlier clinical and experimental observations suggesting that ST3 contributes to breast-cancer progression.

Biomarkers, Tumor↗
PubMed1996

Urokinase plasminogen activator as a predictor of aggressive disease in breast cancer.

Urokinase plasminogen activator (uPA) is a multifunctional protein involved in both extracellular proteolysis and signal transduction. uPA usually mediates its actions while attached to a membrane-bound receptor, termed uPAR. In this study, uPA and its receptor were measured at both protein and mRNA levels in breast cancer. At both levels, concentrations of uPA were significantly correlated with those for uPAR. uPA levels also correlated significantly with cathepsin B and cathepsin D but not with cathepsin L, MMP-8 or MMP-9 levels. Irrespective of the cut-off point used (e.g., median, tertile or quartile values), uPA was a significant prognostic marker for breast cancer.

Blotting, Northern↗
PubMed1995

Urokinase plasminogen activator and urokinase plasminogen activator receptor in breast cancer.

Urokinase plasminogen activator (uPA) is a serine protease involved in cancer invasion and metastasis. uPA mediates its action while attached to a membrane-bound receptor (uPAR). In this investigation we show that uPAR levels correlate with uPA levels in human breast cancers. uPAR levels, however, do not correlate with other components of the plasminogen activator system such as tissue-type plasminogen activator (t-PA), PAI-I or PAI-2. In addition, uPAR levels showed no correlation with tumor size, axillary-node status or estrogen-receptor status. On the basis of an optimum cut-off point, patients with breast cancers containing high levels of uPAR had a worse prognosis than patients with low levels of the receptor. However, as a prognostic marker in breast cancer, uPAR was not as strong as uPA. Our results are consistent with data from model systems suggesting that both uPA and uPAR are necessary for metastasis.

Breast Neoplasms↗
PubMed1995

Assay of matrix metalloproteases types 8 and 9 by ELISA in human breast cancer.

Results from model tumour systems suggest that either increased levels of certain metalloproteases (MMPs) or decreased levels of their inhibitors correlate with metastatic potential. In this study, levels of two MMPs, i.e. MMP-8 and -9, and their inhibitor tissue inhibitor of metalloprotease type 1 (TIMP-1) were measured by enzyme-linked immunosorbent assay in human breast tumours. Levels of MMP-8 and -9 correlated significantly with each other, but neither MMP correlated with urokinase plasminogen activator. Levels of both MMP-8 and -9 were also significantly related to levels of TIMP-1. In contrast, neither MMP correlated with plasminogen activator inhibitor. No relationship was found between MMP-8, MMP-9 or TIMP-1 and either tumour size or metastasis to axillary nodes. MMP-8 and -9 levels were inversely related to levels of oestrogen receptors. MMP-8 but not MMP-9 levels were also inversely correlated with progesterone receptor levels. It is concluded that the assay for MMP-8 and -9 described here will permit the evaluation of these proteases as prognostic markers in cancer.

Biomarkers, Tumor↗
PubMed1995

Can molecular markers now be used for early diagnosis of malignancy?

Most of the presently available cancer markers are neither specific for malignancy nor allow early diagnosis. However, the recent elucidation of the molecular events occurring during tumorigenesis may provide new markers that are likely to be both specific for cancer and sensitive for early disease. The key molecules undergoing alterations during carcinogenesis are the cellular oncogenes and suppressor genes. Alterations in these genes can be detected in cells shed from malignant and premalignant lesions. Thus, mutant p53 genes have been found in urine from patients with bladder cancer, mutant ras genes in stools from patients with colorectal and pancreatic cancers, and both mutant p53 and ras genes in sputum from patients with lung cancer. These findings show that the genetic alterations in cancer can be detected in fluids or secretions that had contact with the malignant tissue. The preliminary studies, however, had small numbers of both patients and controls and used time-consuming, labor-intensive, and expensive assays. For routine applications, these assays must be simplified, automated, and tested for sensitivity, specificity, and predictive value.

Biomarkers, Tumor↗
PubMed1994

Urokinase plasminogen activator as a prognostic marker in different subgroups of patients with breast cancer.

BACKGROUND: Urokinase plasminogen activator (uPA) is a serine protease involved in cancer invasion and metastasis. Previously, uPA was shown to be an independent prognostic marker in breast cancer. The aim of this study were to evaluate uPA as a prognostic marker in different subgroups of patients with breast cancer. METHODS: Urokinase plasminogen activator was assayed by enzyme-linked immunosorbent assay in detergent extracts of human breast tumors. RESULTS: Using both disease free interval (DFI) and overall survival (OS) as end points, uPA was an indicator of prognosis in the following groups of patients: those with positive axillary nodes, those who were estrogen receptor (ER)-positive, women younger than 50 years of age, and women older than 50 years of age. For patients with negative axillary lymph nodes, uPA was a significant prognostic marker using DFI as an end point and was almost statistically significant (P = 0.055) using OS as end point. In patients who were ER-negative, uPA levels showed no significant relationship with patient outcome. CONCLUSIONS: Urokinase plasminogen activator is a significant prognostic marker in most of the major subgroups of patients with breast cancer and may be a marker for patients with negative axillary lymph nodes.

Animals↗
PubMed1994

Urokinase-type plasminogen activator and outcome in Dukes' B colorectal cancer.

Urokinase-type plasminogen activator (u-PA) is a serine protease involved in cancer metastasis. Using immunohistochemical methods, we examined the relation between u-PA and long-term survival in 70 patients with Dukes' B colorectal cancer. 8-year survival was 81% in patients whose tumours demonstrated low-grade epithelial u-PA staining and 43% in those with high-grade staining (log-rank test, p = 0.01). Survival was unrelated to stromal u-PA staining. These results suggest that u-PA may be useful in the identification of patients with non-metastatic colorectal cancer at risk of tumour recurrence.

Adult↗
PubMed1994

Health risks of failed silicone gel breast implants: a 30-year clinical experience.

The purpose of this paper is an assessment of clinically evident systemic health problems associated with failed silicone gel breast implants. A computer search of the medical records of 2033 patients receiving implants in the years 1962-1992 revealed that between 1970 and 1992, 200 women 14 to 75 years of age underwent secondary silicone gel breast implant procedures by a single surgeon. This allowed determination of the exact integrity status of 681 implants collectively placed in these 200 patients between 1962 and 1992 and followed clinically for a median of 49 months. The common indications for surgical reexploration in these 200 patients were capsulectomy, open capsulotomy, or implant exchange/removal. All patients had a minimum clinical follow-up of 6 months. Surgical findings revealed that 577 (85 percent) implants were intact in 135 (67.5 percent) patients and that in 65 (32.5 percent) patients, 104 (15 percent) implant failures were found. The patients' medical records were reviewed with specific attention to diagnoses suggesting immune-related disorders, siliconoma, acquired non-breast malignancies, metachronous breast cancer, and recurrent breast carcinomas. In this very select subgroup of 65 patients with silicone gel breast implants which had failed or were deteriorating, no excess of expected immune-related disorders or malignancies was identified. Our 30-year clinical experience with silicone gel breast implants for augmentation mammaplasty or breast reconstruction failed to demonstrate that clinically evident adverse health problems are incurred by those women who subsequently experience a silicone gel breast implant failure.

Adolescent↗
PubMed1994

Assay of the c-erbB-2 oncogene encoded protein by ELISA and immunocytochemistry in human breast cancer.

The c-erbB-2 gene is amplified in a wide variety of different adenocarcinomas. Generally, gene amplification correlates with increased expression of the c-erbB-2 oncoprotein. Previous assays for the c-erbB-2 oncoprotein have been qualitative or semi-quantitative. In this investigation using human breast cancers, c-erbB-2 oncoprotein levels as measured by enzyme-linked immunosorbent assay (ELISA) correlated significantly with semi-quantitation by immunocytochemistry (r = 0.843, P < 0.0001, n = 97). The cut-off point for the ELISA which gave the strongest agreement with immunocytochemistry was 15 units/micrograms protein. It is concluded that detection of c-erbB-2 oncoprotein by ELISA is quantitative and objective.

Biomarkers, Tumor↗
PubMed1994

The superficial-plane rhytidectomy revisited.

Complex procedures for aesthetic facial rejuvenation, such as the deep-plane, extended SMAS, subperiosteal, and composite rhytidectomies, have received significant attention in the literature and at recent symposia. Young plastic surgeons striving to achieve excellent results may be intimidated by these procedures and find them difficult to perform. We suggest a renewed interest in the superficial plane approach for facial rejuvenation. On the basis of our experience with a synthesis of result-oriented technical modifications in 750 patients, we present a procedure to offer not only the beginning but also the more experienced surgeon a safe and satisfactory surgical alternative that will provide both predictable and lasting results while limiting risks and avoiding complications.

Adult↗
PubMed1993

Anticonvulsant activities of some arylsemicarbazones displaying potent oral activity in the maximal electroshock screen in rats accompanied by high protection indices.

Various semicarbazones derived from aryl aldehydes, phenylalkyl aldehydes, and phenylalkyl ketones as well as some related compounds were evaluated for anticonvulsant activity. Most of the compounds displayed anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens accompanied by neurotoxicity when given to mice by the intraperitoneal route. However quantitative data revealed protection indices (TD50/ED50) of less than 4 in general. Oral administration of the compounds to rats led to excellent potency in the MES screen accompanied by high protection indices while virtually no activity in the scPTZ test was displayed. These observations support the theory that one large hydrophobic group (in this case the aryl ring) and two electron donor atoms (present in the semicarbazono group) are requirements for protection in the MES screen. In general, the semicarbazones had rapid onsets of action, and one of the ways in which these compounds displayed their anticonvulsant activity is likely to be interaction with chloride channels. Empirical and semiempirical conformational calculations indicated that certain molecular fragments and hydrophobicity of these molecules affect bioactivity.

Administration, Oral↗
PubMed1993

Management of ductal carcinoma in situ of the breast.

Ductal carcinoma in situ (DCIS) of the breast is thought to represent a number of biologically different processes, ranging in clinical presentation from a palpable mass to a mammographically-detected abnormality. The optimal management of DCIS is controversial. We reviewed our experience in 40 patients with DCIS, 26 with gross disease and 14 with microscopic disease. Treatment was by total mastectomy (n = 21), complete local excision (n = 16), and local excision followed by radiotherapy (n = 3). At a mean follow-up of 34 months (range 3-120), 35 patients (88%) are disease-free. All patients treated by mastectomy remained disease-free, but 3 patients (16%) treated by breast conservation surgery have had local recurrences. All local recurrences were in the same area as the original lesion, two manifesting the same subtype of DCIS and one an invasive carcinoma. The margins of excision were close to the resection margin in all cases that recurred. All four recurrences were successfully managed by mastectomy. Mastectomy is still the most secure and reliable management for DCIS, but pathologically verified wide local excision may be appropriate.

Breast Neoplasms↗
PubMed1993

Cellular oncogenes and suppressor genes as prognostic markers in cancer.

Activation of cellular or c-oncogenes and loss of function of suppressor genes appears to be the key event in the formation of most human cancers. Altered forms of these genes or their protein products have the potential to provide a new generation of cancer markers. As cancer markers, the most useful application of c-oncogenes and suppressor genes so far, has been in providing prognostic information. The correlation of N-myc gene amplification with poor prognosis in neuroblastoma was one of the first examples of prognostic data supplied by a c-oncogene. Most, but not all investigators, find that either amplification or increased expression of c-erbB-2 gene correlates with poor prognosis in breast cancer. Other potential prognostic markers in breast cancer include amplification of the c-myc gene, and increased expression of both EGFR and p53 protein. Although c-oncogenes and suppressor genes have the potential to supply prognostic information in a broad range of cancers, many of the results are still preliminary with conflicting conclusions.

Biomarkers, Tumor↗
PubMed1992

CA 15-3 in patients with locoregional and metastatic breast carcinoma.

BACKGROUND: The value of circulating CA 15-3 levels was assessed in 129 patients with recurrent breast carcinoma. METHODS: Patients were divided into four subgroups, according to the following: Group A, locoregional recurrence alone; Group B, locoregional and subsequent systemic recurrence; Group C, combined locoregional and systemic recurrence; and Group D, differing sites of systemic disease. RESULTS: One of 14 patients with locoregional disease alone had increased levels of CA 15-3 (> 25 U/ml). However, 96% of patients (22 of 23 patients) with combined local and systemic disease had increased tumor marker levels. The difference in CA 15-3 levels in patients with combined disease compared with patients with local disease alone was statistically significant (117.0 versus 17.5 U/ml, respectively; P < 0.02). Twenty-four patients with locoregional recurrence later had distant metastasis develop. In this group, patients with an increased CA 15-3 value had a significantly shorter lead time to the development of distant metastases compared with patients with normal tumor marker levels (20.8 +/- 3.3 versus 10.3 +/- 2.7 months, respectively; P < 0.03). CA 15-3 values at diagnosis were increased in 88% of 115 patients with metastatic disease. There was no significant difference in CA 15-3 levels among metastases to lung, liver, and bone nor was there any difference between single and multiple sites of distant metastasis. CA 15-3 is an excellent marker for systemic recurrence of breast carcinoma. CONCLUSIONS: Increased levels and no clinical evidence of recurrence strongly indicate the presence of occult metastatic disease.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1992

Type-1 plasminogen activator inhibitor in human breast carcinomas.

We have investigated the occurrence of type-1 inhibitor of plasminogen activators (PAI-1) in human breast tumors. PAI-1 levels, measured by enzyme-linked immunosorbent assay, were significantly higher in malignant breast carcinomas (n = 178) than in benign breast tumors (n = 25). The levels of PAI-1 were found to be correlated with those of urokinase-type plasminogen activator (u-PA). The presence of PAI-1 in tumor extracts was also demonstrated by immunoblotting analysis. Immunohistochemical investigations by the use of monoclonal and polyclonal antibodies showed that PAI-1 was mostly localized in the tumor islands, associated with the tumor cells; in addition, it was present in vessel walls and in normal duct epithelia, but absent from the stroma. Analysis of RNA extracted from tumors by polymerase chain reaction revealed the presence of PAI-1 mRNA. We conclude that PAI-1 is present in human breast carcinoma cells, and that it is--at least partially-- produced locally, either by the cancer cells or by other cells in the tumors. We have previously demonstrated that a high level of u-PA in human breast carcinomas is associated with poor prognosis. These results, combined with our present findings, present 2 possibilities: either the cancer cells need PAI-1 in order to utilize the u-PA-mediated pathway of plasminogen activation for invasion and metastasis; or PAI-1 represents a defense mechanism against tumor invasion.

Animals↗
PubMed1992

Synthesis and cytotoxic evaluation of some 6-arylidene-2-(alpha-hydroxyamino-alpha-arylmethyl)cyclohexanone oximes and related compounds.

Reaction of 2,6-bis-(phenylmethylene)cyclohexanone (1) with a 4-molar excess of hydroxylamine hydrochloride and sodium acetate to produce the corresponding oxime 2 gave rise to 2-(alpha-hydroxyamino-alpha-phenylmethyl)-6-phenylmethylenecyclohexan one oxime (5a), whose structure was deduced from high-resolution proton nuclear magnetic resonance spectroscopy and confirmed by X-ray analysis. Compound 2 was eventually prepared from 1 with hydroxylamine per se and not with a mixture of hydroxylamine hydrochloride and sodium acetate. Ten analogues of 5a, namely 5b-5k, were prepared and evaluated for cytotoxicity. Six of the 11 compounds in series 5, as well as 1, showed activity in the 240-950 microM range against murine mammary EMT6 cells. Series 5 was also examined for cytotoxicity in an in vitro screen conducted by the National Cancer Institute with approximately 54 cell lines, and four compounds demonstrated selective toxicity toward various groups of tumors.

Animals↗