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Biomedical subjects

I O Ellis

Publications and source records attributed to I O Ellis.

At least 19 recordsLinked to original sources
PubMed2005

Sections of the nipple and quadrants in mastectomy specimens for carcinoma are of limited value.

AIM: To assess the value of nipple and quadrant sections in mastectomy specimens for carcinoma in detecting Paget's disease and multifocal carcinoma. METHODS: Two hundred and forty eight consecutive mastectomies performed for carcinoma were reviewed. The presence of Paget's disease of the nipple and mode of identification of any multifocal carcinoma was recorded. RESULTS: Nipple sections showed Paget's disease in eight specimens: in five the diagnosis had been made on previous biopsy and in three (1%) this was a new diagnosis. In the 220 specimens in which all four quadrants were sampled, multifocal disease was identified more often in specimens with invasive carcinoma (39 of 186; 21%) than in those with only ductal carcinoma in situ (0 of 34). In specimens with invasive carcinoma, multifocality was identified macroscopically in 20: on microscopy of tumour sections in four, on microscopic examination of quadrant sections in 11, in the nipple in three, and in both quadrant and nipple sections in one. Overall, multifocality was found on microscopic examination of quadrant or nipple sections in 15 of 220 specimens (7%). CONCLUSIONS: The low frequency of detection of multifocality or Paget's disease in nipple and quadrant sections from mastectomy specimens, combined with the fact that such findings do not affect patient management, suggest that nipple and quadrant sections should only be taken if resources permit.

Breast↗
PubMed2004

Expression of the transcription factor CTCF in invasive breast cancer: a candidate gene located at 16q22.1.

CTCF is a ubiquitous 11-zinc-finger protein that plays a role in gene silencing or activation, chromatin insulation and genomic imprinting. The CTCF gene has been mapped to the chromosome band 16q22.1 that shows frequent loss of heterozygosity in breast cancer. The E-cadherin gene is the known tumour suppressor gene (TSG) at this region in lobular carcinomas; however, the target gene in the more frequent ductal tumours is still unknown. Since CTCF targets include TSGs and oncogenes and it has the ability to inhibit cell growth and proliferation, it has been suggested that it may be the target gene at the 16q22.1 in ductal carcinomas. In the present study, tissue microarray technology was used to study the expression pattern of CTCF immunohistochemically in 344 cases of invasive breast carcinoma and its expression was correlated with clinicopathological variables and patient outcome. Results showed that breast tissues express CTCF in the parenchymal cells of the normal ducts and lobules but with a variable percentage of positive cells. Staining of CTCF was detected in the nuclei and cytoplasm of the malignant cells, but no significant loss or decrease of expression was noticed in association with any specific tumour type. There was a significant correlation between expression of CTCF and histological grades; lower expression was associated with grade 3 tumours. Cytoplasmic expression was associated with increased tumour size and with the presence of vascular invasion. However, no association was found between CTCF expression and tumour type, lymph node stage, oestrogen receptor expression or patient outcome. In conclusion, the current results show that CTCF, although it may play a role in breast carcinogenesis, is unlikely to be the TSG targeted by the 16q22.1 loss in breast cancer and thus another gene or genes at this region remain to be identified.

Adolescent↗
PubMed2004

Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma.

The epidermal growth factor receptor (EGFR) family plays an important role in breast carcinogenesis. Much interest has been focused recently on its members because of their potential role as prognostic indicators in breast cancer and their involvement in cancer therapy. We have evaluated more than 1500 cases of invasive breast carcinoma immunohistochemically using tissue microarray technology to examine the expression of EGFR family receptor proteins. We have found that 20.1 and 31.8% of cases were positive for EGFR and c-erbB-2, respectively, and 45 and 45.1% of tumours overexpressed for c-erbB-3 and c-erbB-4, respectively. The expression of either EGFR or c-erbB-2 was associated with other bad prognostic features and with poor outcome. Neither c-erbB-3 nor c-erbB-4 had any association with survival. c-erbB-2 had an independent prognostic effect on overall and disease-free survival (DFS) in all cases, as well as in the subset of breast carcinoma patients with nodal metastases. Several hetero- and homodimeric combinations have been reported between the EGFR members. Those dimers can evoke diverse signal transduction pathways with variable cellular responses. We stratified cases according to their co-expression of receptors into distinct groups with different receptor-positive combinations. Patients whose tumours co-expressed c-erbB-2 and c-erbB-3, as well as those whose tumours co-expressed EGFR, c-erbB-2 and c-erbB-4 showed an unfavourable outcome compared with other groups, while combined c-erbB-3 and c-erbB-4 expression was associated with a better outcome. In cases showing expression of one family member only (homodimers), we found a significant association between c-erbB-4 homodimer-expressing tumours and better DFS. In contrast, patients with c-erbB-2 homodimer-expressing tumours had a significant poorer DFS compared with other cases. These data imply that the combined profile expression patterns of the four receptor family members together provide more accurate information on the tumour behaviour than studying the expression of each receptor individually.

Adenocarcinoma↗
PubMed2004

Consistency of staining and reporting of oestrogen receptor immunocytochemistry within the European Union--an inter-laboratory study.

To assess the variability of oestrogen receptor (ER) testing using immunocytochemistry, centrally stained and unstained slides from breast cancers were circulated to the members of the European Working Group for Breast Screening Pathology, who were asked to report on both slides. The results showed that there was almost complete concordance among readers (kappa=0.95) in ER-negative tumours on the stained slide and excellent concordance among readers (kappa=0.82) on the slides stained in each individual laboratory. Tumours showing strong positivity were reasonably well assessed (kappa=0.57 and 0.4, respectively), but there was less concordance in tumours with moderate and low levels of ER, especially when these were heterogeneous in their staining. Because of the variation, the Working Group recommends that laboratories performing these stains should take part in a external quality assurance scheme for immunocytochemistry, should include a tumour with low ER levels as a weak positive control and should audit the percentage positive tumours in their laboratory against the accepted norms annually. The Quick score method of receptor assessment may also have too many categories for good concordance, and grouping of these into fewer categories may remove some of the variation among laboratories.

Breast Neoplasms↗
PubMed2004

The role of PTEN and its signalling pathways, including AKT, in breast cancer; an assessment of relationships with other prognostic factors and with outcome.

PTEN is a novel tumour suppressor gene located on chromosome 10. PTEN mutations are believed to exert their effects through the putative PI3K-AKT-mTOR signalling pathway. Specifically, loss of PTEN leads to activation of AKT, which in turn promotes anti-apoptotic and pro-cell cycle entry pathways believed to be essential in tumourigenesis. Whilst PTEN mutations are frequent in a variety of sporadic cancers and inherited cancer syndromes, it is not clear how frequently PTEN mutations and immunohistochemical loss of PTEN expression occur in sporadic breast cancer. This study used tissue microarrays (TMAs) to assess wild-type PTEN and pAKT immunohistochemical staining in 670 and 691 cases, respectively, of primary operable breast cancer. Scores of 0, 1, and 2 were given for negative, weakly positive, and strongly positive degrees of immunoreactivity, respectively. In addition, immunohistochemical assessment of epidermal growth factor receptor (EGFR), Her2, and proliferation by MIB1 expression was performed on the same TMAs and the scores were compared with those of PTEN and pAKT. Eight per cent of cases did not express wild-type PTEN. No correlation was observed between patient, tumour and outcome variables and PTEN. pAKT expression correlated inversely with adverse tumour variables such as tumour grade (p< 0.001) and correlated positively with ER status (p< 0.001). No correlation was seen between either PTEN or AKT and EGFR, Her2 or MIB1. No association of PTEN or pAKT was seen in Kaplan-Meier or multivariate analysis for overall survival. The results indicate that loss of PTEN expression is infrequent in breast cancer. PTEN and AKT do not appear to be prognostic markers. The study argues against the current model of a simple linear tumourigenic PTEN-PI3K-AKT-mTOR pathway in breast cancer. It also suggests that, in this group of breast cancers, the most common upstream regulator of AKT may be ER rather than PTEN, EGFR or Her2.

Adult↗
PubMed2004

Woman feels breast lump--surgeon cannot: the role of ultrasound in arbitration.

The role of ultrasound scanning (USS) in patients complaining of a breast lump where the clinical examination (CE) is normal is not clearly defined. To determine this in greater detail, all patients complaining of a breast lump underwent CE. Where no lump could be found, but was still reported by the patient, an USS was performed. All lesions underwent biopsy and/or aspiration, as well as mammography in suspicious cases or those over 40 years of age. This cohort represented 5% of all referrals in the study period. Four hundred and twenty women were prospectively studied in this way. Median follow up is 3.4 years (range 2.5-4.2 years). Twenty two had solid lumps (of which 3 were cancers) and 48 had cysts. Nineteen patients re-presented with symptoms in the same breast (median time = 12 months (range 4.5-20 months), all of which were imaged on USS: 15 cysts and 4 further cancers (3 in the same quadrant as the original lump, one contralateral) were identified. Women with symptomatic breast lumps and a normal CE can be considered a reliable indication that cancer is very unlikely to be present (negative predictive value = 0.98). Ultrasound may be a suitable complimentary investigation, which will relieve symptoms in those with cysts and can detect small clinically--and sometimes mammographically--occult breast cancers.

Adolescent↗
PubMed2004

Identification of carcinoma cells in peripheral blood samples of patients with advanced breast carcinoma using RT-PCR amplification of CK7 and MUC1.

We have undertaken a pilot study to attempt to identify circulating carcinoma cells in a series of patients with advanced breast carcinoma, using reverse transcription-polymerase chain reaction (RT-PCR) to amplify mRNA of epithelial specific antigens. Using this method to amplify mRNA of MUC1 and cytokeratin 7 (CK7) the sensitivity of the technique was demonstrated by means of diluted concentrations of "spiked MCF7" cells in whole blood, showing a detection limit of 1 in 10(6) (CK7) and 1 in 10(5) (MUC1). Positive results were obtained from the peripheral blood of all nine female patients with advanced breast cancer for CK7 and eight of the nine patients for MUC1. CK7 was however detected in five of 11 healthy controls (eight females, three males) and MUC1 in one of the 11 controls. None of the control group were positive for both CK7 and MUC1, in contrast to eight of the nine patients with advanced breast carcinoma who were positive for both markers. The RT-PCR method thus appears sufficiently sensitive to identify circulating tumour cells in peripheral blood samples from patients with advanced breast carcinoma. However a high proportion of false-positive results was seen in the control population. More extensive investigation is required before the technique is likely to be of benefit clinically.

Adult↗
PubMed2004

Are medullary breast cancers an indication for BRCA1 mutation screening? A mutation analysis of 42 cases of medullary breast cancer.

Recommended guidelines have limited breast cancer gene ( BRCA1 ) mutation testing to individuals with a personal or family history of early onset breast and/or ovarian cancer, and those with multiple affected close relatives. Such large breast cancer families are rare in the general population, limiting the clinical application of the BRCA1 discovery. Previous reports have suggested an association between medullary breast cancer and BRCA1 mutation carriers. To test the feasibility of using these rare histological subtypes as an alternative to epidemiological factors, 42 cases of medullary cancer unselected for family history were screened for BRCA1 point mutations and large exon rearrangements. The large majority (83%) of these patients did not have significant family of breast or ovarian cancer. Two deleterious mutations resulting in a premature stop codon, and one exon 13 duplication were found. All mutations were detected in patients with typical medullary cancer, who had family history of multiple breast and ovarian cancers. Our findings suggest that medullary breast cancers are not an indication for BRCA1 mutation screening in the absence of significant family risk factors.

Breast Neoplasms↗
PubMed2004

Phenotypic similarities in bilateral breast cancer.

Bilateral breast cancers that develop at similar times in an individual are likely to have been subjected to similar hormonal, environmental and genetic influences during tumourogenesis compared with metachronous tumours. As such, it is possible that tumour phenotype in synchronous bilateral breast cancer may display similar biological characteristics. The aim of this study was to identify phenotypic similarities between synchronous and metachronous bilateral breast cancers which may suggest a common origin. Thirty-three cases of synchronous and 46 cases of metachronous bilateral breast cancer that displayed similar tumour type were analysed for concordance in relation to various histological and immunohistochemical parameters. A higher level of concordance was demonstrated for synchronous cases with the highest level seen for oestrogen receptor. It is likely that this is related to similar tumourogenic pathways occurring at equivalent exposure times to various environmental and hormonal influences, although, in a proportion of cases, inherited genetic factors may play a role.

Adult↗
PubMed2004

Best Practice No 176: Updated recommendations for HER2 testing in the UK.

This paper serves to update previously published guidance on rationale and methodology for HER2 laboratory testing following the recommendation for the use of HER2 targeted treatment in the management of advanced breast cancer in the UK. Emphasis is placed on the standardisation of methodology and assessment and strategies to achieve high quality performance. A two phase testing algorithm based on first line immunocytochemistry evaluation and second line fluorescence in situ hybridisation assessment of borderline cases is recommended. To ensure maintenance of expertise, an annual caseload volume of at least 250 cases is recommended for laboratories providing a testing service.

Algorithms↗
PubMed2004

Best Practice No 179. Guidelines for breast needle core biopsy handling and reporting in breast screening assessment.

Non-operative diagnosis has become the norm in breast disease assessment and, until relatively recently, fine needle aspiration cytology has been the sampling method of choice. The introduction of automated core biopsy guns in the mid 1990s led to the additional introduction of core biopsy in assessment units. This paper presents a summary of the guidance on handling and routine reporting of breast needle core biopsy specimens in the context of breast disease multidisciplinary assessment. This guidance has been produced by the UK National Coordinating Committee for Breast Screening Pathology and is endorsed by the European Commission working group on breast screening pathology.

Biopsy, Needle↗
PubMed2004

Discrepancies in current practice of pathological evaluation of sentinel lymph nodes in breast cancer. Results of a questionnaire based survey by the European Working Group for Breast Screening Pathology.

AIMS: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision. METHODS: A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further. RESULTS: Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines. CONCLUSIONS: Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.

Biomarkers, Tumor↗
PubMed2003

Diagnosis of axillary nodal metastases by ultrasound-guided core biopsy in primary operable breast cancer.

The purpose of this study was to examine the use of ultrasound (US)-guided core biopsy of axillary nodes in patients with operable breast cancer. The ipsilateral axillae of 187 patients with suspected primary operable breast cancer were scanned. Nodes were classified based on their shape and cortical morphology. Abnormal nodes underwent US-guided core biopsy/fine needle aspiration (FNA), and the results correlated with subsequent axillary surgery. The nodes were identified on US in 103 of 166 axillae of patients with confirmed invasive carcinoma. In total, 54 (52%) met the criteria for biopsy: 48 core biopsies (26 malignant, 20 benign node, two normal) and six FNA were performed. On subsequent definitive histological examination, 64 of 166 (39%) had axillary metastases. Of the 64 patients with involved nodes at surgery, preoperative US identified nodes in 46 patients (72%), of which 35 (55%) met the criteria for biopsy and 27 (42%) of these were diagnosed preoperatively by US-guided biopsy. In conclusion, US can identify abnormal nodes in patients presenting with primary operable breast cancer. In all, 65% of these nodes are malignant and this can often be confirmed with US-guided core biopsy.

Adult↗
PubMed2003

Correlation between immunohistochemistry (HercepTest) and fluorescence in situ hybridization (FISH) for HER-2 in 426 breast carcinomas from 37 centres.

Accurate diagnostic assessment of HER-2 is essential for the appropriate application of the humanized anti-HER-2 monoclonal antibody trastuzumab (Herceptin) to the treatment of patients with metastatic breast cancer. The diagnostic test needs to be applicable to archival, fixed tissue removed at excision, in many cases several years earlier. We compared the assessment of HER-2 by immunohistochemistry (IHC; HercepTest) and fluorescence in situ hybridization (FISH) in 426 breast carcinomas from patients being considered for trastuzumab therapy. The tumours were tested in three reference centres having been sent in from 37 hospitals. Only 2/270 (0.7%) IHC 0/1+ tumours were FISH positive. Six of 102 (5.9%) IHC 3+ tumours were FISH negative. Five of the six had between 1.75 and 2.0 HER-2 gene copies per chromosome 17 and the sixth had multiple copies of chromosome 17. Thirteen per cent of tumours were IHC 2+ and overall 48% of these were FISH positive but this proportion varied markedly between the centres. Sixty IHC-stained slides selected to be enriched with 2+ cases were circulated between the three laboratories and scored. There were 20 cases in which there was some discordance in scoring. Consideration of the FISH score in these cases led to concordance in the designation of positivity/negativity in 19 of these 20 cases. These data support an algorithm in which FISH testing is restricted to IHC 2+ tumours in reference centres. The results may not extrapolate to laboratories with less experience or using different methodologies.

Algorithms↗
PubMed2003

Prognostic significance of BRCA1 expression in sporadic breast carcinomas.

BRCA1 is a tumour suppresser gene frequently mutated in familial breast cancer and thought to influence the progression of sporadic breast cancer. Decreased BRCA1 mRNA and protein expression has been identified in breast cancer cell lines and sporadic breast tumours. Here the prognostic significance of reduced BRCA1 protein expression is investigated in primary operable breast cancer. Immunohistochemical analysis was used to determine the level of BRCA1 protein expression in 100 breast cancers. BRCA1 expression was compared with known prognostic factors and survival to investigate its prognostic significance. BRCA1 nuclear expression was reduced by varying amounts in breast carcinomas. A progressive loss of BRCA1 expression correlated well with higher histological grade (p = 0.002) and an excess of medullary/atypical medullary/grade 3 ductal carcinomas (p = 0.0001). When adjusted for grade, patients with loss of BRCA1 expression had a significantly longer disease-free survival time. Loss of BRCA1 expression associated with high-grade breast tumours suggests that BRCA1 may play an important role in the pathogenesis of sporadic breast cancer.

Adult↗
PubMed2003

Loss of CD59 expression in breast tumours correlates with poor survival.

CD59 (protectin), a phosphatidylinositol-anchored glycoprotein, is a member of the cell membrane-bound complement regulatory proteins that inhibits the formation of the terminal membrane attack complex (MAC) of complement. In this study, the expression of CD59 was evaluated in 520 breast carcinomas from patients with a mean follow-up of 87 months. This expression was correlated with clinicopathological features and patient survival. Marked variation in the intensity of CD59 expression, which correlated with histological grade and Nottingham prognostic index (NPI), was found, with higher expression of CD59 found more often in well and moderately differentiated tumours and those of good prognosis (NPI < or = 3.4). In contrast, high grade and poor prognosis (NPI > 5.4) carcinomas significantly demonstrated lack of CD59 expression (p < 0.001). Moreover, it was found that the percentage of CD59-positive cells correlated significantly with patient survival, ie patients with a high percentage of positive cells (>50%) had a better overall survival (p = 0.006). A correlation was also found between the percentage of CD59-positive cells and tumour type and also the development of distant metastases. No association was found between either the intensity or the percentage of cells expressing CD59 and vascular invasion, lymph node stage, tumour size, patient age or menopausal status. In multivariate analysis, CD59 percentage positivity was of independent prognostic significance with grade and lymph node stage. These findings indicate that loss of CD59 may offer a selective advantage for breast cancers, resulting in more aggressive tumours and conferring a poor prognosis for patients.

Adult↗
PubMed2003

Expression of p27kip1 in breast cancer and its prognostic significance.

p27kip1 is a member of the KIP/CIP family of cyclin-dependent kinase inhibitors and is a negative cell-cycle regulator that is thought to play a role in tumour suppression. Reduced levels of this protein have been observed in a number of human cancers. However, evidence is conflicting as to whether p27kip1 has a role to play in breast cancer, including predicting behaviour and prognosis. The present investigation aimed to provide a definitive study of 830 breast cancer cases with median patient follow-up of 104 months to determine the true prognostic significance, if any. Immunohistochemical analysis of tissue microarrays and three scoring methods were used to assess p27kip1 expression. Univariate analysis showed a significant relationship between reduced p27kip1 expression and increasing tumour grade, nuclear pleomorphism, mitosis, and decreasing tubule formation (all p<0.001). Significant associations between reduced p27, negative oestrogen receptor status, and ductal/no special type tumours were also observed. Survival analysis demonstrated that patients with tumours with high p27kip1 levels had an improved survival compared with those with cancers with low expression. On multivariate analysis, when compared with existing factors, p27kip1 was not, however, an independent prognostic factor. It is concluded that the inverse relationship between p27kip1 levels and histological grade and individual grade components suggests a role for p27kip1 in both cell proliferation and differentiation, but is not clinically useful.

Adult↗