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Biomedical subjects

N O'Higgins

Publications and source records attributed to N O'Higgins.

At least 37 records · Page 2Linked to original sources
PubMed2000

Increased gelatinase-A and gelatinase-B activities in malignant vs. benign breast tumors.

Matrix metalloproteinases (MMP) types 2 and 9 (also known as gelatinase A and B) are thought to be causally involved in cancer invasion and metastasis. In normal as well as in malignant tissue, both these MMPs occur in multiple forms such as inactive precursors, active enzymes and enzyme-inhibitor complexes. Using newly developed quantitative activity assays, the levels of active MMP-2, total (active and activatable) MMP-2 and total MMP-9 were found to be significantly higher in breast carcinomas than in fibroadenomas. In addition, active MMP-2 and MMP-9 were detected more frequently in malignant than in benign breast carcinoma. These new quantitative activity assays are likely to be of use in studying the mechanism of action of both MMP-2 and -9, assessing their potential prognostic value in different cancers and in the design of MMP inhibitors for preventing cancer metastasis.

Breast Neoplasms↗
PubMed2000

High levels of TIMP-2 correlate with adverse prognosis in breast cancer.

TIMP-2 is an endogenous inhibitor of MMPs. Most data from model systems suggest that high levels of this inhibitor prevent metastasis. In human breast cancers, however, we show that high levels of TIMP-2 correlate with both shortened disease-free interval and overall survival. In primary breast cancers, TIMP-2 levels showed no significant relationship with either tumor size or axillary node status but correlated inversely with estrogen receptor levels. TIMP-2 levels also correlated significantly with those for TIMP-1. We conclude that high levels of endogenous TIMP-2, like other protease inhibitors such as PAI-1 and TIMP-1, correlate with progression of human breast cancer.

Biomarkers, Tumor↗
PubMed2000

A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer.

BACKGROUND AND PURPOSE: Docetaxel is an active agent in the treatment of metastatic breast cancer. We evaluated the feasibility of docetaxel-based sequential and combination regimens as adjuvant therapies for patients with node-positive breast cancer. PATIENTS AND METHODS: Three consecutive groups of patients with node-positive breast cancer or locally-advanced disease, aged < or = 70 years, received one of the following regimens: a) sequential A-->T-->CMF: doxorubicin 75 mg/m2 q 3 weeks x 3, followed by docetaxel 100 mg/m2 q 3 weeks x 3, followed by i.v. CMF days 1 + 8 q 4 weeks x 3; b) sequential accelerated A-->T-->CMF: A and T were administered at the same doses q 2 weeks; c) combination therapy: doxorubicin 50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks x 4, followed by CMF x 4. When indicated, radiotherapy was administered during or after CMF, and tamoxifen started after the end of CMF. RESULTS: Seventy-nine patients have been treated. Median age was 48 years. A 30% rate of early treatment discontinuation was observed in patients receiving the sequential accelerated therapy (23% during A-->T), due principally to severe skin toxicity. Median relative dose-intensity was 100% in the three treatment arms. The incidence of G3-G4 major toxicities by treated patients, was as follows: skin toxicity a: 5%; b: 27%; c: 0%; stomatitis a: 20%; b: 20%; c: 3%. The incidence of neutropenic fever was a: 30%; b: 13%; c: 48%. After a median follow-up of 18 months, no late toxicity has been reported. CONCLUSIONS: The accelerated sequential A-->T-->CMF treatment is not feasible due to an excess of skin toxicity. The sequential non accelerated and the combination regimens are feasible and under evaluation in a phase III trial of adjuvant therapy.

Adult↗
PubMed1999

High levels of tissue inhibitor of metalloproteinase-1 predict poor outcome in patients with breast cancer.

Studies from model systems suggest that matrix metalloproteinases (MMPs) are causally involved in tumor progression while tissue inhibitors of MMPs (TIMPs) prevent this progression. Here, we show that concentrations of TIMP-1 are significantly higher in breast carcinomas than in fibroadenomas. In primary breast cancers, TIMP-1 concentrations increased with increasing tumor size but showed an inverse relationship with estrogen receptor concentrations. In primary breast cancers also, TIMP-1 levels were weakly but significantly correlated with those for MMP-1, proMMP-2, active MMP-2, MMP-3 and proMMP-9. Contrary to what might be expected from published data on model systems, high concentrations of TIMP-1 predicted a poor outcome in patients with breast cancer. We conclude that in human breast cancer, endogenous TIMP-1 does not inhibit tumor progression but may enhance the process.

Biomarkers, Tumor↗
PubMed1999

Urokinase plasminogen activator: a prognostic marker in multiple types of cancer.

Urokinase plasminogen activator (uPA) is a serine protease causally involved in cancer invasion and metastasis. Consistent with its role in cancer spread, uPA has been shown to be a prognostic marker in a variety of malignancies, especially breast cancer. Approximately 20 different groups have shown that high levels of uPA in breast tumor tissue predict poor outcome. As a prognostic marker in breast cancer, uPA provides information that is independent of traditionally used factors such as tumor size, tumor grade, axillary node status and estrogen receptor status. Furthermore, uPA is prognostic in node-negative patients, and a clinical trial is currently under way to assess whether uPA and its inhibitor, plasminogen activator inhibitor-1, can differentiate between the majority of node-negative breast cancer patients who are cured by surgery from the minority who might benefit from adjuvant therapy. uPA is also prognostic in other malignancies, such as gastric, colorectal, esophageal, renal, endometrial, and ovarian cancers. uPA may thus be a prognostic indicator for multiple types of adenocarcinoma.

Biomarkers, Tumor↗
PubMed1998

Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3).

BACKGROUND: The study compares letrozole and aminoglutethimide (AG), a standard therapy for postmenopausal women with advanced breast cancer, previously treated with antioestrogens. PATIENTS AND METHODS: 555 women were randomly assigned letrozole 2.5 mg once daily (n = 185), letrozole 0.5 mg once daily (n = 192) or aminoglutethimide 250 mg twice daily with corticosteroid support (n = 178) in an open-label, multicentre trial. The primary endpoint was objective response rate (ORR), with time events as secondary. ORR was analysed nine months after enrollment of the last patient, while survival was analysed 15 months after the last patient was enrolled. We report the results of these analyses plus an extended period of observation (covering a total duration of approximately 45 months) to determine the duration of response and clinical benefit. RESULTS: Overall objective response rates (complete + partial) of 19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg, 0.5 mg and AG respectively. Median duration of response and stable disease was longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg (18 months) and AG (14 months). Letrozole 2.5 mg was superior to AG in time to progression, time to treatment failure and overall survival. Treatment-related adverse events occurred in fewer patients on letrozole (33%) than on AG (46%). Transient nausea was the most frequent event with letrozole (7% on 0.5 mg, 10% on 2.5 mg, 10% on AG), rash with AG (11%, 1% on 0.5 mg, 3% on 2.5 mg letrozole). CONCLUSIONS: Letrozole 2.5 mg offers longer disease control than aminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausal women with advanced breast cancer, previously treated with anti-oestrogens.

Administration, Oral↗
PubMed1998

Assay of matrix metalloproteinases types 1, 2, 3 and 9 in breast cancer.

Matrix metalloproteinases (MMPs) are zinc dependent endopeptidases implicated in cancer invasion and metastasis. Gelatin zymography was performed on 84 human breast carcinomas and seven normal breast tissues. The precursor form of MMP-2 (72 kDa) was found in 11 (12%) samples, while its two activated forms, i.e. 62 kDa and 59 kDa, were found in three (6%) and 34 (40%) samples respectively. In contrast to MMP-2, most of the samples (52%) contained MMP-9 in its precursor form. Using ELISA, MMP-1 levels were found in 12% of the samples while MMP-3 levels were found in only 2% of the samples. Levels of MMP-2, -3 and -9 correlated inversely with numbers of nodal metastases. Neither MMP-2 nor -9 levels were significantly related to patient outcome. However, patients with high levels of a 50-kDa gelatinase band after zymography had a significantly better survival than patients with low levels. This species was never observed in normal breast tissue.

Breast↗
PubMed1998

Principles and guidelines for surgeons--management of symptomatic breast cancer. On behalf of the European Society of Surgical Oncology.

The European Society of Surgical Oncology is actively involved in the promotion of a high standard of surgical oncology throughout Europe. Such an ambition involves recognition of Centres of Excellence in the management of cancer patients throughout Europe. These centres have a multi-disciplinary system involved in the total care of patients with cancer and are concerned with the delivery of care to the highest available standards. It is accepted that not all patients with cancer can, nor should, necessarily be treated in such highly specialized centres. Yet all cancer patients should be guaranteed a high standard of care. High surgical standards can be ensured if surgeons treating cancer are trained in specialist centres and, when in independent practice, follow established guidelines or protocols of treatment. In common with many national surgical oncology societies, the European Society of Surgical Oncology is in the process of establishing good practice guidelines in the treatment of solid tumours. This document on the management of symptomatic breast cancer is the first of a series of guidelines to be proposed by ESSO. It draws heavily on excellent documents already in existence from the British Association of Surgical Oncology and from the Danish Breast Cancer Co-Operative Group. It is hoped that this document will be sufficiently clear and purposeful to be of help to the individual surgeon and yet sufficiently flexible to allow it to be adopted in the different medical systems throughout Europe.

Breast Neoplasms↗
PubMed1998

European guidelines for quality assurance in the surgical management of mammographically detected lesions. European Breast Cancer Working Group.

The European Guidelines developed for mammography screening have contributed to the general discussion on quality assurance and the important tasks of the health professionals dealing with breast cancer screening. The cooperation of each medical discipline is of utmost importance in order to achieve optimal results and eventually a mortality reduction. The following guidelines are based on the British NHS quality assurance guidelines for surgeons in breast cancer screening and modified to meet the different needs in the European Countries. The term "surgeon" denotes a medical doctor trained and involved in the surgical treatment of breast diseases. The members of the working group who participated in order to adapt these guidelines are listed above. We hope that this document will contribute towards a more comprehensive approach of breast cancer screening-detected lesions throughout Europe.

Breast Neoplasms↗
PubMed1997

Principles and guidelines for surgeons--management of symptomatic breast cancer. European Society of Surgical Oncology.

The European Society of Surgical Oncology is actively involved in the promotion of a high standard of surgical oncology throughout Europe. Such an ambition involves recognition of Centres of Excellence in the management of cancer patients throughout Europe. These centres have a multi-disciplinary system involved in the total care of patients with cancer and are concerned with the delivery of care to the highest available standards. It is accepted that not all patients with cancer can, nor should, necessarily be treated in such highly specialized centres. Yet all cancer patients should be guaranteed a high standard of care. High surgical standards can be ensured if surgeons treating cancer are trained in specialist centres and, when in independent practice, follow established guidelines or protocols of treatment. In common with many national surgical oncology societies, the European Society of Surgical Oncology is in the process of establishing good practice guidelines in the treatment of solid tumours. This document on the management of symptomatic breast cancer is the first of a series of guidelines to be proposed by ESSO. It draws heavily on excellent documents already in existence from the British Association of Surgical Oncology and from the Danish Breast Cancer Co-Operative Group. It is hoped that this document will be sufficiently clear and purposeful to be of help to the individual surgeon and yet sufficiently flexible to allow it to be adopted in the different medical systems throughout Europe.

Adult↗
PubMed1997

Assay of E-cadherin by ELISA in human breast cancers.

E-cadherin is a membrane-bound adhesion glycoprotein. Loss of E-cadherin has been correlated with invasion and metastasis in model systems. Using a new ELISA, we found higher levels of E-cadherin in fibroadenomas than in primary breast cancers. Levels in primary cancers showed no significant relationship with either tumour size, nodal status or oestrogen receptor levels. Patients with breast cancers containing low levels of the adhesion protein had a significantly shorter disease-free interval than patients with high levels (P = 0.041). The prognostic value of E-cadherin, for disease-free interval, was also found in node-negative patients as well as in patients presenting with small tumors (< or = 2 cm). In conclusion, loss of E-cadherin expression in human breast cancers is associated with increased metastatic potential as has previously been found in model systems. Loss of E-cadherin is thus likely to contribute to breast cancer progression.

Biomarkers, Tumor↗
PubMed1997

Plasminogen activator inhibitor type 2 in breast cancer.

The serine protease urokinase plasminogen activator (uPA) is causally involved in cancer invasion and metastasis. Activity of this protease in vivo is controlled principally by two inhibitors, one of which is plasminogen activator inhibitor type 2 (PAI-2). In this study, we show that PAI-2 levels were significantly higher in primary breast carcinomas (n = 152) than benign breast tumours (n = 18). In the primary cancers, PAI-2 levels correlated weakly but significantly with those of uPA and PAI-1, but not with tissue type plasminogen activator (tPA) or uPA receptor (uPAR) levels. Using Northern blotting, mRNA for PAI-2 was found in 28.6% of 49 primary breast cancers. In contrast to findings at the protein level, PAI-2 mRNA levels failed to correlate with those for uPA or PAI-1. After immunocytochemistry with primary cancers, PAI-2 was detected predominantly in the malignant cells of primary carcinomas but was also present in stromal cells. Using the median value as a cut-off point, PAI-2 showed no significant relationship with either disease-free interval or overall survival. However, using an optimum cut-off value, patients with low levels of PAI-2 had a worse outcome than those with a high level. We conclude that, unlike PAI-1, high levels of PAI-2 may be a favourable prognostic marker in breast cancer.

Age Factors↗
PubMed1996

Continuing medical education in oncology in Europe.

A European Conference on Continuing Medical Education (CME) in Oncology was designed and organised in Dublin (Ireland), on 12th and 13th October 1995 by the European School of Oncology in collaboration with University College Dublin and with the financial support of the European Commission (Europe Against Cancer Programme). Two experts were invited from each Member State and all attended the Conference with the sole exception of the representatives of Luxembourg, who did not attend due to unexpected important commitments. Observers were invited to contribute to the discussion as representatives of organisations that were involved either directly or indirectly in CME. The Conference took the format of a plenary session coupled with the identification of five discussion groups formed to debate key areas in CME at a European level in oncology (Table 1). As a result of these discussions and subsequent consultations, an agreement was reached on the following statements: (a) Continuing Medical Education (CME) is an ethical duty and an individual responsibility for each doctor. Although CME should remain voluntary at the present time, it is nevertheless a professional obligation since almost 50% of medical knowledge becomes obsolete after ten years. It should be organised with clear guidelines for medical personnel working in hospitals, in primary health care and in private practice. (b) The CME system within the European Union (EU) should remain self-directed without the necessity for interval examinations: it should be interdisciplinary and must be driven and controlled by the profession itself. (c) A common concept and system within a CME framework may have a considerable impact on EU integration. It should certainly be developed, maintained and monitored at national level but on the basis of a common European model to ensure scientific and cultural interchange among Member States. (d) It was agree that a credit system is needed to help doctors keep track of their CME activities: the system should be based on the accumulation of credit points (one credit equalling one hour of continuing medical education) and monitored at a national level. Credit transfer among Member States is vital to facilitate exchange between Member States. (e) Oncology provides a very useful model of CME within which guidelines can be proposed and tested. Harmonisation of CME systems among the different European cancer organisations and scientific societies within this model system may represent a useful basis that other specialities can follow.

Education, Medical, Continuing↗
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↗