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Biomedical subjects

M J Kerin

Publications and source records attributed to M J Kerin.

At least 37 records · Page 2Linked to original sources
PubMed1999

Genetic changes associated with telomerase activity in breast cancer.

Telomerase, the enzyme responsible for maintenance of the telomeres, is absent from the vast majority of somatic cells but is present in most tumours. Little is known about how telomerase is activated in cancer, although it is thought vital for immortalisation to occur. The aim of our study was to identify genetic changes associated with telomerase activity. Thirty-three breast carcinomas were assessed for telomerase activity using the PCR based TRAP assay, and genetic changes by comparative genomic hybridisation (CGH). Seventy-five percent of the tumours were telomerase positive, and these were further divided into low or high level telomerase activity groups. A large number of genetic aberrations were identified but 4 chromosomal regions were identified that correlated with the telomerase status of the tumour. Gain of 1q correlated with telomerase negative tumours, gain of 3q correlated with high level telomerase activity. Gain of 8q correlated with telomerase positive tumours and furthermore with high level telomerase activity; deletion of 17p also correlated with high level telomerase activity. CGH analysis of breast tumours in conjunction with telomerase status has supported early results suggesting the involvement of the telomerase hTR, c-myc and p53 genes in the control of telomerase activity. These genes are located on chromosomes 3q, 8q and 17p. Most importantly, our results have identified the involvement of gene(s) located on chromosome 1q in telomerase expression.

Breast Neoplasms↗
PubMed1999

Coexpression of estrogen receptor alpha and beta: poor prognostic factors in human breast cancer?

The cloning of a second estrogen receptor (ER), ER beta, has prompted a reevaluation of the role of ERs in breast cancer. The aim of this study was to determine the expression of both ER isoforms in normal (n = 23) and malignant (n = 60) human breast tissue by reverse transcription-PCR and correlate this information with known prognostic factors including tumor grade and node status. In normal breast tissue, expression of ER beta predominated, with 22% of samples exclusively expressing ER beta; this was not observed in any of the breast tumor samples investigated. Most breast tumors expressed ER alpha, either alone or in combination with ER beta. Interestingly, those tumors that coexpressed ER alpha and ER beta were node positive (P = 0.02; Fisher's exact test) and tended to be of higher grade. Because antiestrogens are agonists when signaling through the AP1 element, overexpression of ER beta in tumors expressing both ER subtypes may explain the failure of antiestrogen therapy in some breast cancer patients. Thus, ER beta may be a useful prognostic factor in patients with breast cancer.

Adult↗
PubMed1999

Dynamic contrast enhanced magnetic resonance imaging of the breast is superior to triple assessment for the pre-operative detection of multifocal breast cancer.

BACKGROUND: Inadequately treated multifocal and multicentric disease results in increased local recurrence following breast-conserving surgery. The accurate preoperative diagnosis of multifocal/ centric breast cancer would facilitate the planning of appropriate surgery and prevent reoperation for residual disease. While triple assessment remains the established diagnostic technique, its sensitivity for the diagnosis of multifocal disease remains poor. Dynamic contrast enhanced Magnetic Resonance Imaging (DCE-MRI) of the breast represents an alternative emerging diagnostic modality that has been shown to be highly sensitive for the delineation of primary breast cancer. The aim of this study was to prospectively compare the diagnostic accuracy of DCE-MRI of the breast with conventional triple assessment for the preoperative diagnosis of multifocal/centric breast cancer. METHODS: Patients were recruited from the symptomatic breast clinics. All patients underwent standard triple assessment and DCE-MRI. The MRI scans were reported by a single radiologist blinded to the results of the triple assessment. Surgery was then planned accordingly to all available scan results and the specimens examined by a single pathologist. All patients who did not undergo surgery have been followed up for a minimum of 18 months. RESULTS: A total of 334 women were recruited. There were 178 (52%) cancers that were histologically confirmed and multifocal/centric breast cancer was diagnosed provisionally by the preoperative investigations in 68 (38%); multifocal n = 33, multicentric n = 35, of these patients. In this group, subsequent histology confirmed multifocal/centric disease in 50 (73.5%): multifocal n = 15, multicentric n = 35. Unifocal cancer was found in 15 (22%) and benign disease in 3 (4.4%). The resultant sensitivity, specificity, positive, and negative predictive values were 18%, 100%, 100%, and 76% for triple assessment and 100%, 86%, 73%, and 100% for DCE-MRI. CONCLUSION: DCE-MRI identified a subgroup of breast cancer patients with multifocal/centric disease not evident on standard triple assessment. MRI of the breast should be considered for the preoperative planning of surgery for primary breast cancer.

Aged↗
PubMed1999

Prospective comparison of standard triple assessment and dynamic magnetic resonance imaging of the breast for the evaluation of symptomatic breast lesions.

OBJECTIVE: To compare the sensitivity and specificity of the traditional triple assessment of symptomatic breast lesions with contrast-enhanced dynamic magnetic resonance imaging. BACKGROUND: Although triple assessment is currently the gold standard for the assessment of symptomatic breast disease, its specificity is such that open biopsies are still required in many cases to be confident of the diagnosis. Contrast-enhanced dynamic magnetic resonance imaging of the breast represents an alternative diagnostic modality. METHODS: Patients were recruited from the symptomatic breast clinics. If any of the diagnostic modalities suggested malignancy, the lesion was excised. The remaining patients were followed clinically and radiologically. RESULTS: Two hundred eighty-five patients with a mean age of 43 years (range 21 to 77) were recruited. Malignant lesions were excised in 131 patients and benign lesions in 55 patients. The 99 patients who did not undergo surgery were followed clinically and radiologically for a median of 20 months. The sensitivity of each modality was as follows: clinical examination 84%, mammography 87.6%, fine-needle aspiration cytology 79.1%, triple assessment 99.2%, and magnetic resonance imaging 99.2%. In addition, histologically confirmed multifocal disease was detected in 40 patients on magnetic resonance imaging but in only 9 (22.5%) on mammography. The specificity for the diagnosis of benign disease was as follows: clinical examination 83.1%, ultrasound 88.9%, mammography 86.4%, fine-needle aspiration cytology 97%, triple assessment 59.1%, and magnetic resonance imaging 90.9%. CONCLUSION: Contrast-enhanced dynamic magnetic resonance imaging of the breast is as sensitive and more specific than the combined traditional triple assessment for the diagnosis of malignant breast lesions.

Adult↗
PubMed1999

Expression and secretion of TGF-beta isoforms and expression of TGF-beta-receptors I, II and III in normal and neoplastic human breast.

We investigated gene expression of the TGF-beta signalling system (including peptides and receptors) in normal and malignant breast tissue. Additionally, gene and protein expression was determined in a series of primary epithelial and stromal cultures derived from these tissues. TGF-beta isoforms and their receptors were expressed by both tissue sets, however the percentage of samples expressing each transcript varied. In normal breast, both TGF-beta1 and TGF-beta3 were found in most samples (88 and 89% respectively), with fewer expressing TGF-beta2 (68%). A similar pattern was evident in the tumours. Type I receptor of TGF-beta was constitutively expressed in normal breast and observed in most tumours (90%). Type II and III receptors of TGF-beta were expressed less frequently, although the type II receptor was mainly expressed by tumours (P=0. 0075). All primary cultures produced TGF-beta1 and TGF-beta2. Comparing respective cell populations, tumour stromal cells produced significantly more TGF-beta1 than those derived from normal breast (P<0.0001). Linear regression analysis showed stromal cultures derived from breast tumours exhibited a strong positive correlation (r=0.976) in the production of TGF-beta1 and TGF-beta2. Thus, TGF-beta and TGF-beta-receptors are widely and differentially expressed by normal and malignant breast and secretion of this peptide by epithelial and stromal cultures, in particular those derived from tumours, confirms its potential as an autocrine/paracrine regulator in breast cancer.

Activin Receptors, Type I↗
PubMed1999

Evidence for transcriptional activation of ERalpha by IL-1beta in breast cancer cells.

Estrogen is mitogenic in breast cancer where IL-1beta also fulfils a role. The aim of this study was to determine any relationship between IL-1beta and ERalpha in breast cancer. By RT-PCR, 26/77 tumours expressed IL-1beta, and 57/77 expressed ERalpha. Samples which were IL-1beta positive were categorised against those which expressed ERalpha. Of the 26 tumours which expressed IL-1beta, all were ERalpha positive. We next examined whether IL-1beta could directly activate ERalpha. MCF-7 cells stably transfected with a plasmid reporter (ERE-TK-LUC) were incubated with either 17beta-estradiol (E2, 10-9-10-13 M), IL-1beta (10 ng/ml), the pure antiestrogen ZM 182780 (10 nM) or combinations of these substances. Transcriptional activity was measured in cell lysates 48 h later. E2 caused a dose-dependent increase in luciferase activity. With IL-1beta, transcriptional activity was typically half of the E2 response. To determine the role of the IL-1 receptor, parallel cultures were incubated with IL-1 receptor antagonist. This reduced, but did not completely block the effect of IL-1beta, suggesting that IL-1beta was affecting transcriptional activity via another pathway. Confirmation that the effect was via ERalpha was verified using the pure antiestrogen, ZM 182370, which completely abrogated the effects of E2, when added alone or in combination with IL-1beta. These results provide compelling evidence for direct transcriptional activation of ERalpha by IL-1beta. Interactions of these factors may thus modulate hormonal activity in human breast tumours.

Breast Neoplasms↗
PubMed1999

Optimal education techniques for basic surgical trainees: lessons from education theory.

"Calmanisation" of surgical training and the introduction of the "New Deal" on doctor's hours has led to a reduction in "in service" training and a proliferation of training courses. Little research has been done into the optimum design of these courses. Education theory has shown that individuals have optimal learning styles and that these styles tend to be generalised across professional groups. It was decided, therefore, to investigate the optimal learning styles of basic surgical trainees. A learning style inventory was used to assess the preferred learning style of 52 basic surgical trainees. The predominant learning styles (86.5%) were convergent (n = 31) or accommodative (n = 14) whilst only 5 (9.6%) assimilative and 2 (3.9%) divergent styles were detected. Convergent and accommodative learners rely principally on hands on experience and problem solving as their optimal learning technique. Given the shorter hours and duration of Basic Surgical Training, in service practical training and surgical courses should be structured accordingly.

Adult↗
PubMed1998

Interactive multimedia information program for use by breast-care nurses--a patient acceptability study.

AIMS: To design an interactive multimedia program for use by breast-care nurses and evaluate the acceptability of this technology to patients in the clinical setting. METHODS: In order to ensure that the clarity of the information was maintained the multimedia program was developed by a multidisciplinary team, including non-medical personnel and patients. A prospective analysis of the subjective impressions of patients with symptomatic breast disorders and breast-care nurses to a multimedia patient information system was then performed using a standard questionnaire and semi-structured interviews. RESULTS: Fifty women were recruited for the study. Thirty-six (72%) considered the multimedia counselling to be superior to the traditional modalities. Forty-nine (98%) graded the system as good or better. No patient regarded the technology as anxiety-provoking or inferior to the traditional leaflet-based approach. Women over 55 years old found the system as acceptable and easy to use as the younger women. CONCLUSIONS: The multimedia breast counselling programme was acceptable to patients and was considered superior to the traditional leaflet-based approach by the majority. The inherent advantages of this technology will lead to its increasing utilization in the clinical setting.

Adult↗
PubMed1998

Vascular endothelial growth factor in premenopausal women--indicator of the best time for breast cancer surgery?

Timing of surgery in premenopausal patients with breast cancer remains controversial. Angiogenesis is essential for tumour growth and vascular endothelial growth factor (VEGF) is one of the most potent angiogenic cytokines. We aimed to determine whether the study of VEGF in relation to the menstrual cycle could help further the understanding of this issue of surgical intervention. Fourteen premenopausal women were recruited, along with three post-menopausal women, a woman on an oral contraceptive pill and a single male subject. Between eight and 11 samples were taken per person, over one menstrual cycle (over 1 month in the five controls) and analysed for sex hormones and VEGF165. Serum VEGF was significantly lower in the luteal phase and showed a significant negative correlation with progesterone in all 14 premenopausal women. No inter-sample variations of VEGF were noted in the controls. Serum from both phases of the cycle from one subject was added to MCF-7 breast cancer cells; VEGF expression in the supernatant was lower in the cells to which the luteal phase serum was added. The lowering of a potent angiogenic cytokine in the luteal phase suggests a possible decreased potential for micrometastasis establishment in that phase. This fall in VEGF may be an effect of progesterone and should be the focus of future studies.

Analysis of Variance↗
PubMed1998

Short-term primary culture of epithelial cells derived from human breast tumours.

As experimental models for breast cancer, most studies rely on established human breast cancer cell lines. However, many of these lines were established over 20 years ago, many from pleural effusions rather than the primary tumour, so the validity of using them as representative models is questionable. This paper describes our experiences, over a 3-year period, in establishing short-term epithelial-cell-enriched preparations from primary breast tumours based on differential centrifugation followed by culture in selective media. Epithelial cells were successfully cultured from 55% of samples, but culture success did not appear to be correlated with tumour histology, stage, grade or node status. Epithelial cell-enriched cultures were immunopositive for broad-spectrum cytokeratin and epithelial membrane antigen (EMA). Positivity for keratin 19 confirmed that the cultures contained tumour-derived cells, which additionally showed significantly higher activity of the reductive pathway of the steroid-converting enzyme 17beta-hydroxysteroid dehydrogenase type I. That the cultures contained tumour and not normal epithelial cells was further substantiated by the complete absence of the calmodulin-like gene NB-1 in tumour-derived cultures; this is only associated with normal breast epithelia. Eighty-five per cent of cultures established from oestrogen receptor (ER)-positive tumours expressed ER in vitro; this was functional in 66% of cultures, although ER-positive phenotype was gradually lost over time. In conclusion, epithelial cells can be isolated and maintained as short-term cultures from primary breast tumours irrespective of histopathological or clinical details, providing a model system with a greater biological and clinical relevance than breast cancer cell lines.

17-Hydroxysteroid Dehydrogenases↗
PubMed1998

Multiple cell populations in colorectal carcinomas: analysis by 3-colour fluorescence in situ hybridization.

A three-colour FISH approach using centromere-specific DNA probes was used to analyse the number of chromosomes 7, 17 and 18 found within individual tumour cells and the results were correlated with total DNA ploidy determined by image analysis. FISH analysis showed a high level of heterogeneity in the majority of tumour samples with only 7 out of 44 samples having a single chromosome profile occurring in greater than 40% of the cells. Analysis of the modal chromosome number showed that a diploid 2/2/2 profile for chromosome 7, 17 and 18 respectively occurred most commonly. The DNA ploidy index for biopsies with a 2/2/2 profile varied between 0.93-2.06. No gain of chromosome was observed in the adenoma samples or Dukes A tumours but a loss of chromosome 18 was seen in 50% of these early carcinomas. A modal chromosome profile of 4/2/2 was commonly found in Dukes B and C tumours suggesting that endoreduplication with the relative loss of chromosome 17 and 18 is common in advanced cancers. The DNA ploidy index for the more advanced tumours was also variable but significantly higher than that found in the early tumours and non-tumour controls. In conclusion, this work shows that tumours are highly heterogeneous and that the majority of tumours consist of a large number of cell sub-populations with respect to the expression of chromosomes 7, 17 and 18.

Adenocarcinoma↗
PubMed1998

Preoperative serum vascular endothelial growth factor can predict stage in colorectal cancer.

Neovascularization has been shown to be essential for the growth of solid tumors. Vascular endothelial growth factor (VEGF) is one of the most important mediators of angiogenesis. This study was conducted to determine the significance of this cytokine as a tumor marker for staging colorectal cancer. Preoperative serum VEGF was measured in 108 colorectal cancer patients and in 136 normal healthy controls. The results of this study showed a significant difference between the four T classes, Union International Contre Cancer (UICC) stages, and Dukes' stages. In comparison to serum levels in controls (median, 173.8 pg/ml), VEGF levels were significantly elevated in T2 (P = 0.003), T3, and T4 (P < 0.0005); UICC I (P = 0.001), UICC II, UICC III, and UICC IV (P < 0.0005); and Dukes' A (P = 0.001), Dukes' B, and Dukes' C (P < 0.0005). Serum VEGF showed a significant elevation over control in node-negative (P < 0.0005) and in node-positive colorectal cancer (P < 0.0005) patients. Node-positive cancer had a significant elevation of serum VEGF compared to node-negative cancer (P = 0.008). This study reveals that preoperative serum VEGF can detect all but very early colorectal cancer i.e., T1 (P = 0.06).

Adult↗
PubMed1998

Advanced colorectal cancer is associated with impaired interleukin 12 and enhanced interleukin 10 production.

Interleukin 12 (IL-12) is a heterodimeric cytokine that has been demonstrated to have a major role in stimulating a cell-mediated antitumor response. IL-10, a product of T helper 2 lymphocytes, is its most potent inhibitor. The aim of this study was to investigate whether patients with colorectal cancer had an imbalance in production of IL-12 and IL-10 preoperatively, and whether this was associated with advanced disease at surgery. Blood was obtained before surgery from 60 patients with colorectal cancer and from 30 controls. Peripheral blood mononuclear cells were incubated with Staphylococcus aureus Cowan's strain 1 in vitro for 24 h to assess IL-12 expression after stimulation, and serum was used for IL-10 measurement. IL-12 and IL-10 levels were assessed by ELISA. A single pathologist staged the tumors according to the tumor-node-metastasis (TNM) and Dukes' classifications. Patients with colorectal cancer had significantly lower levels of IL-12 (P <0.001) and higher levels of IL-10(P = 0.004) compared to controls. In addition, lower levels of IL-12 were detected in those patients who were node positive (P<0.05), had Dukes' C lesions (P < or = 0.001), and T3 or T4 lesions (P<0.033) when compared to controls. Patients with Dukes' B and C lesions (P<0.01) and T3 and T4 lesions (P<0.05) also had higher levels of IL-10 compared to controls. This study is the first to demonstrate that patients with colorectal cancer have decreased IL-12 production and increased serum IL-10. This suggests an impaired T helper 1 cell-mediated antitumor response and provides some justification for exogenous IL-12 therapy or anti-IL-10 therapy in these patients.

Adult↗
PubMed1998

Primary small intestinal tumours: increased incidence of lymphoma and improved survival.

Small intestinal malignancies are rare and may have a delayed presentation owing to insidious growth. We have reviewed the case notes of 25 patients presenting with primary small bowel tumours over a 10-year period. Abdominal pain, weight loss and vomiting were the most common symptoms. The median duration of symptoms was 6 months. Physical examination was normal in 24% of patients. An abdominal mass was present in 46% of cases. Emergency laparotomy was undertaken in 28% of patients. Lymphomas were identified in 72% and adenocarcinomas were present in 16%. The predominance of small bowel lymphoma is an unusual finding and may be related to the high incidence of coeliac disease in the region. The median survival in the lymphoma group was 36 months, which compares favourably with reported series.

Adenocarcinoma↗