Biomedical subjects

A D K Hill

Publications and source records attributed to A D K Hill.

At least 19 recordsLinked to original sources

PubMed2006

A positive role for PEA3 in HER2-mediated breast tumour progression.

Overexpression of HER2 is associated with an adverse prognosis in breast cancer. Despite this, the mechanism of its transcriptional regulation remains poorly understood. PEA3, a MAP kinase (MAPK)-activated member of the Ets transcription factor family has been implicated in the transcriptional regulation of HER2. The direction of its modulation remains controversial. We assessed relative levels of PEA3 expression and DNA binding in primary breast cultures derived from patient tumours (n=18) in the presence of an activated MAPK pathway using Western blotting and shift analysis. Expression of PEA3 in breast tumours from patients of known HER2 status (n=107) was examined by immunohistochemistry. In primary breast cancer cell cultures, growth factors induced interaction between PEA3 and its DNA response element. Upregulation of PEA3 expression in the presence of growth factors associated with HER2 positivity and axillary lymph node metastasis (P=0.034 and 0.049, respectively). PEA3 expression in breast cancer tissue associated with reduced disease-free survival (P<0.001), Grade III tumours (P<0.0001) and axillary lymph node metastasis (P=0.026). Co-expression of PEA3 and HER2 significantly associated with rate of recurrence compared to patients who expressed HER2 alone (P=0.0039). These data support a positive role for PEA3 in HER2-mediated oncogenesis in breast cancer.

Axilla↗

PubMed2006

Diagnostic accuracy of core biopsy for ductal carcinoma in situ and its implications for surgical practice.

BACKGROUND: Core biopsy is considered to be a highly accurate method of gaining a preoperative histological diagnosis of breast cancer. Ductal carcinoma in situ (DCIS) is often impalpable and is a more subtle form of breast cancer. AIM: To investigate the accuracy of core biopsy in the diagnosis of cancer in patients with DCIS. METHODS: All patients who had invasive cancer (n = 959) or DCIS (n = 92) that was confirmed by excision between 1999 and 2004 were identified. The diagnostic methods, histology of the core biopsy specimen and excision histology were reviewed in detail. RESULTS: Core biopsy was attempted in 88% (81/92) of patients with DCIS and in 91% (874/959) of those with invasive disease. Of those patients who underwent core biopsy, a diagnosis of carcinoma on the initial core was made in 65% (53/81) of patients with DCIS compared with 92% (800/874) of patients with invasive disease (p<0.0001). Smaller lesion size (p = 0.005) and lower grade (p = 0.03) were associated with increased risk for a negative or non-diagnostic core in patients with DCIS. The nature of the mammographic lesion or the method of biopsy did not affect the probability of an accurate core biopsy. Patients who had a preoperative diagnosis of DCIS by core biopsy had a reoperation rate of 36% compared with 65% of those that did not have a preoperative diagnosis (p = 0.007). CONCLUSION: Although core biopsies are highly accurate forms of obtaining a preoperative diagnosis in patients with invasive breast cancer, this is not the case in DCIS. As the number of surgical procedures can be reduced by core biopsy, it is still of considerable value in the management of DCIS.

Biopsy↗

PubMed2005

Ets2 transcription factor in normal and neoplastic human breast tissue.

The Ets family of transcription factors regulate the expression of multiple genes involved in tumour formation and progression. The aim of this work was to test the hypothesis that the expression of Ets2 in breast cancers was associated with parameters of tumour progression and metastasis. Using reverse-transcriptase polymerase chain reaction (RT-PCR), Ets2 mRNA was detected in 69% of 181 breast carcinomas, 63% of 43 fibroadenomas and 47% of 43 specimens of normal breast tissue. Levels were significantly higher in carcinomas compared with normal breast tissue (P = 0.006). Using Western blotting, Ets2 protein was found to migrate as two bands with molecular masses of 52 kDa (p52) and 54kDa (p54). Levels of both proteins were significantly higher in the carcinomas compared with both fibroadenomas (P = 0.0001) and normal breast tissue (P = 0.0001). In the carcinomas, a significant relationship was found between the p52 and p54 form of Ets2 (r = 0.51, P < 0.0001; Spearman correlation). Also, in the carcinomas, a significant correlation was found between both forms of Ets2 protein and urokinase plasminogen activator (uPA) (for p52, r = 0.43, P = 0.0005, n = 68; for p54, r = 0.50, P = 0.0001, n = 68). As Ets2 binding sites are present on the uPA promoter, Ets2 may be one of the transcription factors regulating uPA expression in human breast cancer.

Blotting, Western↗

PubMed2005

Expression of survivin and its splice variants survivin-2B and survivin-DeltaEx3 in breast cancer.

Alternative splicing of survivin mRNA gives rise to multiple isoforms, that is, survivin and 3 splice variants, survivin-2B, survivin-3B and survivin-DeltaEx3. The aim of this study was to compare the expression of survivin, survivin-2B and survivin-DeltaEx3 in normal breast tissue, fibroadenomas, primary breast cancer and axillary nodal metastases. Survivin, survivin-2B and survivin-DeltaEx3 mRNA were measured using semiquantitative RT-PCR. In the primary carcinomas, we related mRNA for each form of survivin to both survivin protein and apoptosis. For each type of breast tissue, survivin was the predominant form detected, being present in 146 out of 156 (93.6%) primary breast carcinomas, 11 out of 11 (100%) axillary nodal metastases, 21 out of 31 (67.7%) fibroadenomas and five out of 22 (22.7%) specimens of normal breast tissue. Levels of the three forms of survivin were significantly higher in the carcinomas compared to normal breast tissue (P < 0.0001). Levels of both survivin-2B and survivin-DeltaEx3 but not survivin were significantly higher in nodal metastases than primary carcinomas. Survivin mRNA levels correlated significantly with survivin protein. Finally, both survivin and survivin-DeltaEx3 but not survivin-2B correlated positively with apoptosis. Although survivin, survivin-2B and survivin-DeltaEx3 were all detected in both malignant and nonmalignant breast tissue, the predominant form was survivin. Our results suggest that the different forms of survivin may have different roles in apoptosis in breast cancer.

Alternative Splicing↗

PubMed2005

Adjuvant therapies in the treatment of stage II and III malignant melanoma.

BACKGROUND: The incidence of cutaneous melanoma has increased during the past three decades. The development of sentinel lymph node biopsy has facilitated better staging. Despite these improvements, 5-year survival rates for American Joint Committee on Cancer stage II and III disease range from 50%-90%. METHODS: A review of the current literature concerning adjuvant therapies in patients with stage II and III malignant melanomas was undertaken. RESULTS: The focus of adjuvant therapies has shifted from radiotherapy, BCG and levamisole to newer biological agents. Interferon, interleukin and vaccines have been evaluated but none of these agents have demonstrated an increase in overall survival in patients with stage II and III melanoma. Interferon can prolong disease-free interval. CONCLUSION: At present, no adjuvant therapy improves overall survival in patients with stage II and III melanoma. New staging allows more accurate stratification of patients for clinical trials.

Antineoplastic Agents↗

PubMed2005

Meralgia paraesthetica following open appendicectomy.

Meralgia paraesthetica is a painful condition attributed to entrapment or injury to the lateral femoral cutaneous nerve. It has been described following operations which could result in direct injury to the nerve such as iliac crest bone harvesting. It has also been reported following surgery remote from the nerve. Following open appendicectomy injury may occur following direct trauma to an anatomical variant of this nerve, which can occur in up to 25% of the population. We report two cases that became clinically evident immediately following open appendicectomy with subsequent confirmatory electromyography studies. Meralgia paraesthetica following open appendicectomy has not been reported in the medical literature. This is an under-recognised complication of open appendicectomy. Management can be challenging for patient and clinician.

Adult↗

PubMed2004

Inverse relationship between ER-beta and SRC-1 predicts outcome in endocrine-resistant breast cancer.

The oestrogen receptor (ER) interacts with coactivator proteins to modulate genes central to breast tumour progression. Oestrogen receptor is encoded for by two genes, ER-alpha and ER-beta. Although ER-alpha has been well characterized, the role of ER-beta as a prognostic indicator remains unresolved. To determine isoform-specific expression of ER and coexpression with activator proteins, we examined the expression and localisation of ER-alpha, ER-beta and the coactivator protein steroid receptor coactivator 1 (SRC-1) by immunohistochemistry and immunofluorescence in a cohort of human breast cancer patients (n=150). Relative levels of SRC-1 in primary breast cultures derived from patient tumours in the presence of beta-oestradiol and tamoxifen was assessed using Western blotting (n=14). Oestrogen receptor-beta protein expression was associated with disease-free survival (DFS) and inversely associated with the expression of HER2 (P=0.0008 and P<0.0001, respectively), whereas SRC-1 was negatively associated with DFS and positively correlated with HER2 (P<0.0001 and P<0.0001, respectively). Steroid receptor coactivator 1 protein expression was regulated in response to beta-oestradiol or tamoxifen in 57% of the primary tumour cell cultures. Protein expression of ER-beta and SRC-1 was inversely associated (P=0.0001). The association of ER-beta protein expression with increased DFS and its inverse relationship with SRC-1 suggests a role for these proteins in predicting outcome in breast cancer.

Adult↗

PubMed2004

Overexpression of the Ets-1 transcription factor in human breast cancer.

The Ets family of transcription factors regulate expression of multiple genes involved in tumour progression. The aim of this study was to investigate the expression of Ets-1 in a large panel of human breast cancers and relate its levels to the parameters of tumour progression and metastasis. Using RT-PCR, Ets-1 mRNA was detected in 30 out of 42 (71%) fibroadenomas and 131 out of 179 (73%) primary breast carcinomas. Similarly, levels of Ets-1 mRNA were not significantly different in fibroadenomas and primary breast carcinomas. Using Western blotting, four forms of the Ets-1 protein were detected, that is, p33, p42, p51 and p52. Levels of both p51 and p52 but not p33 and p42 were present at significantly higher levels in the carcinomas compared to the fibroadenomas (for p51, P<0.007; for p52, P<0.02; Mann-Whitney U-test). Levels of p52, p51 and p33 correlated significantly with uPA protein levels (P<0.01), while only levels of p52 correlated significantly with HER-2/neu protein levels (P<0.01). Using immunohistochemistry, Ets-1 was found predominantly in tumour cells, but was also detected in some stromal cells surrounding tumour islands. We conclude that, while at the mRNA level, Ets-1 was found at similar levels in fibroadenomas and primary breast carcinomas, higher protein levels were detected in the cancers compared to the benign specimens. Since p52, p51 and p33 correlate with uPA levels, these forms of Ets-1 may play a role in breast cancer metastasis.

Biomarkers, Tumor↗

PubMed2004

Positron emission tomography in the staging and management of breast cancer.

BACKGROUND: Breast cancer is the commonest cause of cancer death in women in the Western world, and imaging is essential in its diagnosis and staging. Metabolic imaging is a novel approach to improving the detection of cancers, as malignant transformation of cells is often associated with increased metabolic activity. This review assesses the possible role of positron emission tomography (PET) as a single non-invasive imaging modality to replace or complement current imaging and surgical practices in the diagnosis and staging of breast cancer. METHODS AND RESULTS: A Medline search was performed and articles were cross-referenced with other relevant material. Evaluation of primary breast cancer with PET has shown a sensitivity of between 64 and 100 per cent and a specificity of 33-100 per cent; diagnostic accuracy appears to be related to tumour size. Difficulties arise in altered fluorodeoxyglucose uptake in lobular carcinoma, carcinoma in situ and benign inflammatory breast disease. In axillary staging, sensitivities of between 25 and 100 per cent have been reported, but with a false-negative of up to 20 per cent. In the assessment of distant metastasis and asymptomatic patients with raised levels of tumour markers, PET was superior to conventional imaging modalities. CONCLUSION: PET is not a single diagnostic and staging tool that can replace current surgical, histological and radiological staging. Its main role in breast cancer lies in the investigation of metastatic disease and the evaluation of pathological response to various chemotherapeutic regimens.

Axilla↗

PubMed2004

Intraoperative margin assessment and re-excision rate in breast conserving surgery.

AIM: The aim of this study was to assess the efficacy of intraoperative margin assessment in obtaining clear margins in conserving surgery for breast cancer. METHODS: Two hundred and twenty patients undergoing wide local excision (WLE) for core biopsy proven primary invasive breast cancer, during a 30 months period, were included in the study. Following surgical excision the breast specimen was orientated with sutures, inked using India ink and coloured pigments and incised to identify the tumour, maintaining orientation. The distance to the individual radial margins were estimated macroscopically by the pathologist and conveyed intraoperatively to the surgeon. A macroscopic tumour-margin distance of less than 10 mm was considered compromised and the margin(s) in question was then excised if feasible. RESULTS: Eighty-one patients (37%) were judged to have compromised margins following intraoperative macroscopic evaluation and had at least one margin re-excised. Sixteen of the 81 patients (20%) in this subgroup had compromised margins on microscopy and required a second operation. One hundred and thirty-nine patients (63%) were deemed to have clear margins intraoperatively, subsequently confirmed on microscopic examination in 135 patients (97%). Intraoperative macroscopic assessment of margin status was associated with 9.1% of patients requiring a second operation. In the absence of intraoperative assessment of margin status a further 47 patients (21.4%) would have required a second operation. CONCLUSION: Intraoperative macroscopic margin assessment is an effective technique in reducing the number of second operative procedures in patients undergoing conserving surgery for primary invasive breast cancer.

Breast Neoplasms↗

PubMed2004

Needle-localised biopsy of impalpable breast lesions: a novel adjunct to surgical technique and specimen mammography.

Successful screening programmes have resulted in the more frequent detection of early impalpable breast tumours. Effective surgical management of impalpable lesions demands a precise approach to excision which is currently aided by radiologically guided needle-localisation of the lesion prior to operative removal. The surgical specimen procured is most commonly evaluated for tumour presence by specimen mammography intra-operatively or by histological analysis. The latter is more accurate but requires lengthy laboratory processing, which may result in re-operation if the primary excision is inadequate. Although advocated as the standard of care, specimen mammography remains an imperfect technique. In this article we describe a piece of surgical apparatus which attempts to address some of the concerns associated with specimen mammography. It is an inexpensive compression device which reduces operative time, avoids portable fluoroscopy, increased radiation and the necessity for specialised equipment

Biopsy, Needle↗

PubMed2004

Sentinel lymph node biopsy in breast cancer.

The sentinel lymph node (SLN) procedure consists of identifying the first lymph node to receive lymphatic vessels draining a tumour. Sentinel node biopsy is a minimally invasive technique, resulting in lower morbidity than traditional axillary lymph node dissection. Screen detected breast cancers are associated with approximately a 20% incidence of axillary node involvement. Sentinel node biopsy represents a minimally invasive method of accurately staging these patients.

Breast Neoplasms↗

PubMed2004

Expression of SRC-1, AIB1, and PEA3 in HER2 mediated endocrine resistant breast cancer; a predictive role for SRC-1.

BACKGROUND: In human breast cancer, the growth factor receptor HER2 is associated with disease progression and resistance to endocrine treatment. Growth factor induced mitogen activated protein kinase activity can phosphorylate not only the oestrogen receptor, but also its coactivator proteins AIB1 and SRC-1. AIM: To determine whether insensitivity to endocrine treatment in HER2 positive patients is associated with enhanced expression of coactivator proteins, expression of the HER2 transcriptional regulator, PEA3, and coregulatory proteins, AIB1 and SRC-1, was assessed in a cohort of patients with breast cancer of known HER2 status. METHODS: PEA3, AIB1, and SRC-1 protein expression in 70 primary breast tumours of known HER2 status (HER2 positive, n = 35) and six reduction mammoplasties was assessed using immunohistochemistry. Colocalisation of PEA3 with AIB1 and SRC-1 was determined using immunofluorescence. Expression of PEA3, AIB1, and SRC-1 was correlated with clinicopathological parameters. RESULTS: In primary breast tumours expression of PEA3, AIB1, and SRC-1 was associated with HER2 status (p = 0.0486, p = 0.0444, and p = 0.0012, respectively). In the HER2 positive population, PEA3 expression was associated with SRC-1 (p = 0.0354), and both PEA3 and SRC-1 were significantly associated with recurrence on univariate analysis (p = 0.0345; p<0.0001). On multivariate analysis, SRC-1 was significantly associated with disease recurrence in HER2 positive patients (p = 0.0066). CONCLUSION: Patients with high expression of HER2 in combination with SRC-1 have a greater probability of recurrence on endocrine treatment compared with those who are HER2 positive but SRC-1 negative. SRC-1 may be an important predictive indicator and therapeutic target in breast cancer.

Adult↗

PubMed2004

Factors affecting metastases to non-sentinel lymph nodes in breast cancer.

AIMS: Because sentinel lymph node (SLN) biopsy for breast cancer has become well established, one of the challenges now is to determine which patients require a completion axillary dissection following a positive SLN biopsy. METHODS: A prospective database of patients who underwent SLN biopsy for invasive breast cancer from July 1999 to November 2002 (n = 180) was analysed. Fifty four patients (30%) had one or more positive SLN, and all underwent a completion axillary dissection. This subgroup was further analysed to delineate which factors predicted non-SLN metastasis. RESULTS: Twenty six of the 54 patients with a positive SLN had additional metastases in non-SLNs. Significant variables that predicted non-SLN metastasis included extranodal extension (odds ratio (OR), 17.399; 95% confidence interval (CI), 1.69 to 178.96) and macrometastasis within the SLN (OR, 6.985; 95% CI, 1.291 to 37.785). CONCLUSIONS: In patients with invasive breast cancer and a positive SLN, extranodal extension or macrometastasis within the SLN were both independent predictors of non-SLN involvement.

Adult↗

PubMed2004

Surgical intervention in screen-detected patients versus symptomatic patients with breast cancer.

OBJECTIVES: The impact of population-based screening for breast cancer on the rate of breast-conserving surgery has not been established. We sought to evaluate whether surgical intervention in patients with screen-detected breast cancer differed from those with clinically detected tumours. SETTINGS: St Vincent's University Hospital and the BreastCheck Merrion Unit, part of the Irish National Breast Screening Programme, were the setting for the study. METHODS: A total of 902 patients referred for surgery to St Vincent's University Hospital over a four-year period (2000-2003) were studied. Patients with breast cancers detected during the prevalent round of screening (n=325) were compared with patients presenting with symptomatic disease (n=577). The operative procedure, nature of axillary surgery and histopathological findings were recorded in each case. RESULTS: There was an increase in breast-conserving therapy in the screened population compared with symptomatic cases (68% screened versus 53% symptomatic; p<0.0001), with a corresponding reduction in axillary clearance rates (65% screened versus 81% symptomatic; p<0.0001). Nodal positivity was similar following correction for size in all tumours >1 cm, regardless of method of detection. Sentinel node biopsy was successfully undertaken in 39% of tumours <2 cm (T1 tumours) [corrected] in the screening population. CONCLUSIONS: The screened population was statistically more likely to have breast-conserving therapy than the symptomatic group. Sentinel node biopsy has evolved into an acceptable alternative to axillary clearance in T1 cancers, particularly in screen-detected cases.

Axilla↗

PubMed2003

The prevention of breast cancer.

BACKGROUND: Despite advances in the early detection and treatment of breast carcinoma, the mortality and morbidity rates associated with this disease remain high. Primary prevention, therefore, offers the best chance of making a major impact on outcome. METHODS: The aim was to review the rationale, current stage of development and adverse effects of the strategies involved in the primary prevention of breast carcinoma. A review of the literature was undertaken by searching the MEDLINE database for the period 1966-2002 without language restrictions. RESULTS AND CONCLUSION: Currently, the only agent to have general approval for chemoprevention of breast carcinoma is tamoxifen. Women who derive the greatest benefit in terms of risk reduction from tamoxifen are premenopausal with a 5-year Gail risk factor of more than 1.66 per cent, postmenopausal with a 5-year Gail risk factor of more than 3 per cent, and postmenopausal without a uterus. In these specific subgroups, tamoxifen should be considered for the chemoprevention of breast carcinoma. Raloxifene, retinoids, aromatase inhibitors and cyclo-oxygenase 2 inhibitors require further clinical investigation before adoption in this context. Surgical intervention should largely be limited to those women who have a BRCA1 or BRCA2 mutation.

Antineoplastic Agents, Hormonal↗

PubMed2003

Lack of prognostic effect of Cox-2 expression in primary breast cancer on short-term follow-up.

AIMS: Cyclo-oxygenase (Cox) catalyses the conversion of arachidonic acid into prostaglandins (PG) and other eciosanoids. The prostaglandins, especially PGE(2) are implicated in tumorigenesis via angiogenesis and suppression of immune reactivity. There are two known isoforms of the enzyme, Cox-1, which is constitutively expressed and the inducible isoform, Cox-2. Cox-2 is induced in response to inflammatory mediators, growth factors, oncogenes and mitogens. Non-selective Cox inhibitors may reduce the relative risk of colonic and breast carcinoma. METHODS: We studied the expression of Cox-2 by immunohistochemistry in 106 primary breast carcinoma specimens collected over a three-year period, using a commercially available polyclonal antibody on formalin-fixed, paraffin-embedded tissue. The slides were examined independently by two pathologists. Tumours were classified according to accepted criteria and an immunohistochemical score (IHS) was calculated for each specimen. The IHS combines the percentage of immunoreactive cells (quantity score) and an estimate of staining intensity (staining intensity score). RESULTS: All patients were female. The mean age was 53 years, range 28-86 years. Forty percent (n=42) of tumours were node negative and 60% (n=64) node positive. Forty-nine percent (n=52) of tumours were grade 3, a further 49% (n=52) grade 2 and 2% (n=2) grade 1. There was no statistically significant correlation between IHS and tumour size, grade, histology, nodal status, estrogen receptor or progesterone receptor positivity. A trend was observed showing an IHS of zero is associated with prolonged survival compared with an IHS of 9-12. CONCLUSION: Cox-2 expression in primary breast cancer does not correlate with accepted pathological or biochemical prognostic indicators.

Adult↗

PubMed2003

Intradermal radioisotope injection optimises sentinel lymph node identification in breast cancer.

AIM: Currently there is no consensus on the optimal technique for sentinel lymph node (SLN) identification in patients with breast cancer. The aim was to compare the efficacy of intraparenchymal and intradermal isotope injection in sentinel lymph node mapping for breast cancer. METHODS: One hundred and twenty-five patients with histologically confirmed invasive breast cancer underwent SLN mapping using radioisotope and isosulphan blue dye followed by a back-up axillary dissection. The first 80 patients had intraparenchymal (IP) injection of radioisotope given in four portions around the tumor. The remaining 45 patients had an intradermal (ID) injection given at a single site over the tumour. Both groups had isosulphan blue dye injected around the tumour. Sentinel node(s) were identified using a combination of lymphoscintigraphy, blue dye and an intra-operative hand held gamma probe. RESULTS: The preoperative lymphoscintigram (LSG) demonstrated a SLN significantly more often in the ID isotope group compared to the IP isotope group (P=0.002). A combination of blue dye and isotope successfully located the SLN in 96% of the intraparenchymal group and 100% of the intradermal group. CONCLUSION: Our results suggest that intradermal isotope injection in combination with intraparenchymal blue dye optimises the localization of the sentinel lymph node in breast cancer.

Axilla↗