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Biomedical subjects

I O Ellis

Publications and source records attributed to I O Ellis.

At least 145 records · Page 8Linked to original sources
PubMed1996

Interlaboratory comparison of DNA image analysis.

Interlaboratory quality assurance studies have been conducted for DNA flow cytometry, but not for DNA image analysis systems. The purpose of this study was to investigate if concordance of DNA image analysis systems existed with respect to classification and staining of standardized material. In three separate rounds, human liver cells were measured randomly by means of the image cytometry system present in each participating laboratory. The features integrated optical density (IOD) and AREA were reported. The relationship between the coefficient of variation (CV) of the 2c and 4c peak were compared with three models. In the three rounds the number of participating laboratories was 11, 14 and 11, respectively. Sequential plotting of normalized IOD values yielded useful information about intra-measurement variation. Comparison of measurements in specimens stained in the participating and central laboratory revealed similar CV values. In general, the precision of the instruments, expressed as the 4c/2c and 8c/2c ratios was good. The accuracy of the different laboratories expressed as the CV of IOD for the three rounds varied from 2-17%. The relation of the CVs of the 2c and the 4c peaks was best fit with the model of the addition of two normal distributions. We conclude that interlaboratory comparison of DNA measurements performed on different instruments is certainly feasible and could facilitate improvement in quality standards.

DNA↗
PubMed1995

Immunocytochemical localization of Fos protein in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy.

The nuclear transcription factor Fos is inducible by both steroid hormones and peptide growth factors. It thus forms a potential point of interaction between steroid hormone- and growth factor-directed pathways and may be critical in the subversion of steroid hormone control in breast cancer. In this light, the present study has used immunocytochemistry to demonstrate in clinical primary breast cancer that Fos expression is indeed significantly associated with a failure to respond to endocrine therapy, with preliminary analysis revealing a survival advantage for those patients whose tumours lacked Fos. Sustained elevated levels of Fos expression were significantly associated with further factors, notably peptide growth factors and their receptors (e.g., EGFR, TGF alpha), as well as with the proliferation marker Ki-67, which have been linked previously to endocrine insensitivity in breast cancer. In contrast, there appeared to be a trend for Fos to be absent in those tumours expressing markers of endocrine responsiveness (e.g., oestrogen receptor [ER], and also ER-mediated markers i.e., PR, pS2 or bcl-2). Interestingly, many of these trends were maintained in ER+ patients, suggesting that Fos may be of importance in directing loss of endocrine sensitivity in ER+ disease.

Breast Neoplasms↗
PubMed1995

An evaluation of the cell cycle-associated monoclonal antibody Ki-S1 as a prognostic factor in primary invasive adenocarcinoma of the breast.

Immunohistochemical staining with the novel monoclonal antibody Ki-S1, believed to recognize a cell cycle-associated antigen, was investigated in 110 cases of invasive carcinoma of the breast. Immunoreactivity indices were compared with disease-free interval (DFI), overall survival, and a series of other prognostic indicators. Significant positive correlations were found between the percentage of strongly positive immunoreactive nuclei and tumour size, histological grade and type, vascular invasion, and mitotic count. A significant negative correlation was found with age. No significant correlation was found with either DFI or overall survival. Although a correlation with mitotic count does imply that the Ki-S1 antigen is cell cycle-associated to some extent, Ki-S1 does not appear to be a useful prognostic factor in human breast carcinoma.

Adenocarcinoma↗
PubMed1995

A cautionary note regarding the application of Ki-67 antibodies to paraffin-embedded breast cancers.

Immunocytochemical studies examining the Ki-67 proliferation marker in paraffin-embedded material have recently been made possible by the availability of several antibodies, notably MIB-1, which are readily applicable to microwaved sections. Using breast cancer material, the present study examines correlations shown by these new paraffin assays and also by PCNA (proliferating cell nuclear antigen), an existing marker of proliferation, with the established Ki-67 cryosection assay. Paraffin sections were microwaved prior to incubation with Ki-67 or MIB-1 antibodies. Signal detection was carried out with a biotinylated secondary antibody, peroxidase-conjugated streptavidin, and DAB/H2O2 chromogen. The results suggest that caution is required when studying proliferation in paraffin-embedded breast cancers by immunostaining using Ki-67 antibodies. Nuclear staining in wax sections (Ki-Par, MIB-1, PCNA) greatly exceeded that in cryosections (Ki-Froz) and thus correlations were notably absent between Ki-Par or PCNA immunostaining and the routine Ki-Froz assay. Immunostaining with MIB-1 or PCNA may, however, be useful to assess proliferation if cut-offs are applied to eliminate weak immunostaining associated with wax sections. Thus, an approximately linear relationship was seen between MIB-1/Ki-Froz, which was improved if only moderately or moderately/strongly MIB-1-positive cells were scored. Similarly, a significant correlation was also revealed between PCNA/Ki-Froz if such a cut-off was applied.

Antibodies, Monoclonal↗
PubMed1995

Cathepsin D in primary breast carcinoma: adverse prognosis is associated with expression of cathepsin D in stromal cells.

The immunohistochemical expression of the aspartyl protease enzyme cathepsin D was examined in a consecutive series of 103 primary operable breast carcinomas with the polyclonal antibody NCL-CDp. Expression of cathepsin D was identified within the epithelial and stromal components of all tumours examined. No significant associations of increased cathepsin D expression in the epithelial tumour component with conventional prognostic indices such as tumour size, grade, lymph node stage, or patient survival were identified. However, significant associations of increased stromal cathepsin D expression and high tumour grade, chi 2 = 11.40 (df = 2), p = 0.003; increased tendency to local recurrence, chi 2 = 6.87 (df = 1), p = 0.009; regional recurrence, chi 2 = 7.44 (df = 1), p = 0.006; poorer disease free survival, chi 2 = 14.9 (df = 1), p = 0.0001; and poorer overall patient survival, chi 2 = 6.90 (df = 1), p = 0.0086, were identified. Cathepsin D expression is present in all breast tumours. Stromal cathepsin D expression is a neglected immunohistochemical prognostic parameter which could explain some of the previous apparently conflicting reports concerning the effect on patient prognosis of biochemical (i.e. total) and immunohistochemical estimations of cathepsin D in breast cancers.

Breast Neoplasms↗
PubMed1995

Assessment of angiogenesis in breast carcinoma: an important factor in prognosis?

Recent evidence suggests that angiogenesis, as assessed by vascular density, may be an independent prognostic factor in breast carcinoma. The authors chose to examine this hypothesis further using two different methods, both using an immunohistochemical technique to assess vascularity. In the first, tissue sections from 93 patients with human breast carcinoma were immunostained for the endothelial antigen CD 34. Fields were selected at random in sections stained with the monoclonal antibody QBEnd/10, and both the number of blood vessels and percentage of endothelial cells per unit area measured using an interactive image analysis system (SEESCAN). In the second, an additional 72 patients were added and the 165 sections immunostained for CD31 (PECAM 1) using the monoclonal antibody JC 709. The area of highest vascular density was then identified and measured. A statistically significant correlation was found between percentage endothelial area and tumor type (P < .03) using the first method, and, for lymph node-negative patients only, between vascular density and tumor type (P < .02) using the second method. There was no correlation with lymph node status, recurrence, distant metastases, or overall survival using either method (minimum follow-up 12 years). The authors conclude that the evaluation of tumor angiogenesis using these methods does not provide additional prognostic information in this group of patients.

Antibodies, Monoclonal↗
PubMed1995

Safe selection criteria for breast conservation without radical excision in primary operable invasive breast cancer.

In a previous series from this unit of 263 women with primary operable breast cancer treated by macroscopic lumpectomy and breast irradiation, local recurrence was high. An audit at a median follow up of 36 months showed 56 (21%) ipsilateral breast recurrences. Eighteen of these recurrences were aggressive and uncontrolled. Multivariate analysis shows patient age, lymphovascular invasion, tumour size and nodal status to be predictive of local recurrence (Locker AP, et al., Br J Surgery 1989, 76, 890-894). New selection criteria for breast conservation were defined based on these data and also on securing an adequate clear margin of excision. In a subsequent prospective series of 275 women fulfilling these criteria, 6 women (2.2%) developed ipsilateral breast recurrence at the same median follow up of 36 months. In none was this uncontrolled and aggressive. Breast conservation, without radical excision, is safe as long as the selection criteria described are followed.

Adult↗
PubMed1995

Assessment of the new proliferation marker MIB1 in breast carcinoma using image analysis: associations with other prognostic factors and survival.

The 'growth fraction' of tumours can now be assessed on paraffin sections of tissues using the monoclonal antibody MIB1 by a microwave antigen retrieval technique. The MIB1 labelling index was studied using a CAS 200 image analyser in 177 tumours from women with primary operable breast carcinoma in whom long-term follow-up data were known. Statistical analysis showed a strong association between the MIB1 labelling index and histological grade (P < 0.001), tumour size (P = 0.002), tumour type (P < 0.001) and also patient survival (P < 0.001). No association with lymph node stage (P = 0.974) or regional recurrence (P = 0.185), the presence or absence of distant metastases (P = 0.418), patient age (P = 0.309), menopausal status (P = 0.181) or oestrogen receptor status (P = 0.401) was found in this group of patients. In multivariate analysis for survival, when histological grade, lymph node stage and tumour size were included as well as the MIB1 labelling index, each was found to be of independent significance. If histological grade was not included, MIB1 replaced it as the most important variable predicting for survival in this group of patients. The results suggest that the tumour growth fraction, as assessed by the MIB1 labelling index, is an important predictor of survival.

Antibodies, Monoclonal↗
PubMed1995

Expression of ras p21, p53 and c-erbB-2 in advanced breast cancer and response to first line hormonal therapy.

Several oncogenes and tumour-suppressor genes have been identified that may have an important role in the development of human breast carcinoma. Furthermore, some of these gene alterations may be linked to the development of invasion and subsequent metastasis. Alterations in the expression of ras p21, p53 and c-erbB-2 have all been linked to tumours with rapid cellular proliferation, but the evidence that they are of prognostic importance in patients with breast cancer is conflicting. This study explores the relationship between expression of these oncoproteins and clinical outcome in 92 patients with either locally advanced or metastatic breast cancer treated with primary endocrine therapy. Specimens of the primary carcinoma were available for analysis of hormone receptor, Ki67 labelling index, epidermal growth factor receptor (EGFR), c-erbB-2, p53 and ras p21. Clinical response was measured according to UICC criteria after 6 months of treatment and all patients were followed for time to progression and overall survival. As shown previously, oestrogen receptor (ER) negativity, high Ki67 labelling index and EGFR overexpression were associated with a shorter time to progression and overall survival. However, no statistically significant relationship existed between expression of ras p21, p53 or c-erbB-2 and response to treatment, time to progression or overall survival. We conclude that staining for these three oncoproteins has no role in therapeutic decision-making in patients with advanced breast cancer. The negative finding implies that while abnormal expression of these genes may have an important role in the development of breast cancer, the variations in growth characteristics of advanced breast cancer may be influenced by other factors.

Adult↗
PubMed1995

The assessment of multiple variables on breast carcinoma fine needle aspiration (FNA) cytology specimens: method, preliminary results and prognostic associations.

We have assessed the multiple biological variables on breast carcinoma FNA specimens using a Cytoblock technique. The growth fraction (MIB1), oestrogen receptor (ER), progesterone receptor (PR), p53 mutant protein, c-erbB-2, epidermal growth factor receptor (EGFR), NCRC11/epithelial membrane antigen (EMA) and DNA plopidy were examined. Objective quantification using image analysis (CAS 200) was applied as appropriate. Fifty cases were examined in this preliminary study. Excellent correlation between the Cytoblock preparations and parallel tissue sections was seen. Of the cancers, 81% were aneuploid with only 19% diploid in character, but 67% of the carcinomas were of histological grade 3. The mean nuclear area staining with MIB1 was 31.3% and with ER was 26.7%. Twenty-four percent (24.1%) of the nuclear area showed immunoreactivity with PR. Significant EGFR and EMA, respectively. A significant association between histological grade of the resected tumours and both MIB1 (P = 0.04) and EGFR (P = 0.02) expression in the Cytoblock samples was seen. p53 (P = 0.03) and EGFR (P = 0.01) immunoreactivity showed an association with tumour size. EGFR (P = 0.04) immunostaining also showed a relationship with the lymph node status of the patient. The technique is, we believe, a useful one for the assessment of multiple variables on breast cytology specimens; these preliminary data suggest that some of these may be useful in predicting prognosis in breast cancer patients.

Analysis of Variance↗
PubMed1995

Phyllodes tumours of the breast: a clinicopathological review of thirty-two cases.

We have reviewed the histological features and clinical outcome in 32 women with phyllodes tumours of the breast diagnosed in Nottingham between 1975 and 1990. We assessed 23 tumours as histologically benign, four as borderline and five as malignant. After clinical follow up for periods ranging from 36 months to 221 months (median 135 months), six of 23 benign tumours have recurred locally; in all these cases the original tumours had been incompletely excised. There were no recurrences amongst 10 benign tumours in which excision had been complete. Benign tumours which recurred showed a tendency to greater stromal cellularity and more pronounced stromal overgrowth than incompletely excised lesions which did not recur, but these differences were not statistically significant. The recurrent tumours resembled the respective original lesions histologically, except in one case in which two local recurrences were histologically malignant. The recurrent tumours were controlled by further excision or mastectomy in all cases and none have metastasized. All four borderline tumours were completely excised at initial surgery and none have recurred or metastasized. One of the five malignant tumours recurred within two months of incomplete excision, with widespread infiltration of the chest wall, although the patient died of unrelated causes. The other four malignant tumours have not recurred. We conclude that presence of tumour at the margins of the excised specimen is the major determinant of local recurrence in phyllodes tumours and that the histological features are of secondary importance. These findings are discussed in relation to other published series in the literature.

Adult↗
PubMed1995

Pathological prognostic factors in breast cancer. IV: Should you be a typer or a grader? A comparative study of two histological prognostic features in operable breast carcinoma.

In a study of 1529 patients with primary operable breast carcinoma we have assessed the effect of applying both histological grade and tumour type to determine their comparative value as prognostic factors in human breast cancer. The prognostic group the patient was placed in, based on histological type alone, was less accurate than using grade and type together for many tumours. The importance of performing histological grading of ductal/no special type carcinoma (50% of the women in this series) is confirmed in this series. The 10-year-survival varied from 76% for women with grade 1 carcinoma to 39% for those with grade 3 tumours. Some of the 'special types' of breast carcinoma including tubular, tubulo-lobular, invasive cribriform and grade 1 mucinous carcinomas behaved as would be predicted, with a greater than 80% 10-year-survival in this series. Others, including grade 2 mucinous carcinomas, however, behaved less well with a 60% to 80% 10-year-survival. Indeed, many of the histological tumour types including tubular mixed, ductal/no special type, mixed ductal with special type and lobular carcinomas of classical, solid or mixed types showed a variation in behaviour that could not be predicted by typing alone. Histological grade and tumour type, when used together, more accurately predicted prognosis. In multivariate analysis of a larger group of 2658 cases of primary breast carcinomas (including the 1529 study cases) when histological grade, lymph node status and tumour size were entered, grade was the most important factor in predicting for survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Mammographic features of invasive lobular and invasive ductal carcinoma of the breast: a comparative analysis.

The mammographic appearances of 86 invasive lobular carcinomas were compared with those of 86 invasive ductal carcinomas of no special type matched for age, size and stage. There was no significant difference in the frequency of a mammographic abnormality consistent with malignancy between the lobular carcinoma (90%) and ductal carcinoma (96%) groups. A spiculate mass was the commonest feature in both groups (69% and 63%, respectively). There were no differences in the imaging features of masses in the two groups. In the lobular carcinoma group any mammographic abnormality was more likely to be seen on only one view and calcifications were less frequently observed. Multiple lesions were more frequent in the ductal carcinoma group. However, although these differences appeared to reach statistical significance, as they were only apparent in a study with a large number of comparisons, it is unlikely that these differences are practically significant. Analysis of the lobular invasive group failed to demonstrate any significant differences in the imaging features of the classical and mixed sub-types, a spiculate mass being the most common single abnormality in both. No mammographic differences of practical use to distinguish invasive lobular from invasive ductal carcinoma of no special type were demonstrated.

Adult↗
PubMed1994

Immunocytochemical localization of BCL-2 protein in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy.

The protein product of the bcl-2 gene is though to be involved in inhibition of apoptosis; it may therefore be important in the modulation of hormonal/anti-hormonal responsiveness exhibited by tumours. This study immunocytochemically investigates (i) relationships between bcl-2 protein expression in primary breast cancers and other markers of prognostic and therapeutic value and (ii) associations of the bcl-2 protein with breast cancer responsiveness to endocrine therapy. The bcl-2 protein was found within the tumour epithelial cell cytoplasm of 32/46 breast cancer specimens; inter-patient staining was heterogeneous. Immunostaining for steroid hormone receptors was strongly associated with that for the bcl-2 protein, and it is thus possible that this protein, like progesterone receptor, is under oestrogen regulation via oestrogen receptor. The protein was inversely related to 2 markers of endocrine insensitivity, epidermal growth factor receptor (EGFR) and c-erbB-2 oncoprotein, while no associations were observed with either transforming growth factor (TGF)-alpha or Ki-67 proliferative status. A highly significant relationship was observed between response to endocrine therapy and the presence of bcl-2 protein. Indeed, bcl-2 immunostaining proved to be a more accurate predictor of response than oestrogen receptor status. Patients with elevated bcl-2 immunostaining (particularly those who coexpressed high oestrogen receptor levels) appeared to derive the greatest benefit from endocrine therapy. Our results are paradoxical since it was expected that the bcl-2 protein would counteract the tumour inhibitory effects of endocrine therapies as it is thought to prevent programmed cell death.

Apoptosis↗
PubMed1994

Transforming growth factor-alpha and endocrine sensitivity in breast cancer.

The expression of transforming growth factor-alpha (TGF-alpha) has been evaluated in 51 breast cancers of known responsiveness to endocrine therapy using immunohistochemistry. High levels of TGF-alpha were observed in 65% of tumors and showed no relationship with tumor estrogen receptor or epidermal growth factor receptor status or Ki67 immunostaining. TGF-alpha levels did, however, relate to the endocrine sensitivity of the disease, with unresponsive tumors frequently showing high levels of TGF-alpha immunoreactivity. This relationship was observed in estrogen receptor-positive disease and was independent of the epidermal growth factor receptor status of the tumor. No quantitative association between TGF-alpha and Ki67 immunostaining was observed in any of the subcategories of tumors. These data infer a role for TGF-alpha in the development of endocrine insensitivity in estrogen receptor-positive breast cancer by mechanisms which appear independent of tumor growth fraction, as determined by Ki67 immunostaining.

Biomarkers, Tumor↗