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Biomedical subjects

T G Cooke

Publications and source records attributed to T G Cooke.

At least 19 recordsLinked to original sources
PubMed2006

Bad expression predicts outcome in patients treated with tamoxifen.

AIMS: Activation of the PI3K/Akt signal transduction pathway has been linked to endocrine resistance in tamoxifen treated breast cancer patients. Activation of the PI3K/Akt pathway causes phosphorylation of Bad leading to modulation of cellular apoptosis. The present study was carried out to test the hypothesis that disruption of apoptosis in breast cancer, via Akt activation, is linked with hormone resistance. METHODS: Immunohistochemistry (IHC) was performed on 402 oestrogen receptor (ER) positive breast cancers using antibodies against Bad, pBad (ser 112), Bcl-2, Bcl-xl and Bax. RESULTS: Bad, pBad (ser 112), Bcl-2 and Bax expression was observed in the cellular cytoplasmic compartment only. Patients, whose tumours had high levels of Bad expression, had a significantly improved disease-free survival when compared to patients whose tumours had low levels of Bad expression (P = 0.049). Activation of the PI3K/Akt pathway by either heregulin or oestrogen had no effect on expression of Bad, Bcl-2, Bax or Bcl-xl. However, heregulin increased pBad (ser 112) expression. DISCUSSION: Data presented here shows that Bad expression is associated with relapse in tamoxifen-treated breast cancer patients, supporting our hypothesis that the apoptosis pathway is involved in tamoxifen resistance.

Antineoplastic Agents, Hormonal↗
PubMed2006

Low expression of HER2 protein in breast cancer is biologically significant.

HER2 status is routinely tested using immunohistochemistry or FISH following the licensing of a therapeutic agent targeting HER2. However, neither of these methods provides quantitative information relating to the 70-80% of patients with levels of expression lower than the assay detection thresholds. In this study, radioimmunohistochemistry was used to detect quantitative HER2 protein expression in 178 breast cancers. Survival analysis was performed, as were correlations with known prognostic variables and with overexpression of other HER family members. It is demonstrated that the populations expressing very high and very low levels of HER2 are each associated with increased risk of cancer-specific death on survival analysis (p = 0.0043). The group with low levels of HER2 was more likely to be of higher grade, EGFR-positive and ER/HER3/HER4-negative. HER2-positive cases were frequently ER-negative/HER3-positive, whilst cases with normal HER2 expression were often ER-positive/HER4-positive. The aggressive nature of the tumour group with low HER2 expression may be explained by actions of other HER family members, particularly EGFR, but whether these or other factors have a negative regulatory effect on HER2 expression remains to be determined.

Adult↗
PubMed2005

Does deprivation affect breast cancer management?

We evaluated whether social deprivation affected decision-making for breast cancer surgery. Of 3419 patients, 53.6% had mastectomy and this was predicted by deprivation, age, tumour size and hospital, all of which retained significance on multivariate analysis, except deprivation. Pathological characteristics and surgical decision-making determined choice of operation not deprivation.

Adult↗
PubMed2004

Cyclooxygenase 2 (COX2) expression is associated with poor outcome in ER-negative, but not ER-positive, breast cancer.

AIMS: Inflammation and hormonal signalling induce cyclooxygenase 2 (COX2) expression in solid tumours. COX2 expression is linked to neovascularization and tumour growth. HER2 modulates colorectal cancer COX2 expression. We investigated interactions between COX2 and HER1-4 in breast cancer. METHODS AND RESULTS: COX2 expression was localized to epithelial cells with 21.2% of cases expressing higher levels than normal epithelium. Elevated COX2 expression was not associated with size, grade, high Nottingham prognostic index (NPI) or oestrogen receptor (ER) negativity. No association was observed between COX2 and HER1-4 expression. High COX2 expression was associated with reduced disease-free survival (P = 0.03) and disease-related survival in ER-negative (P = 0.046) but not ER-positive disease (P = 0.835). CONCLUSION: HER1, 2, 3 and 4 are not associated with high breast tumour COX2 expression. COX2 is frequently expressed in breast carcinoma cells and adjacent epithelium. COX2 may be an important factor in promoting tumour progression in ER-negative tumours and a potential drug target in breast tumours.

Adult↗
PubMed2003

A role for BRCA1 in sporadic breast cancer.

To test the hypothesis that altered expression of BRCA1 protein may play an important role in sporadic breast cancer development, 50 randomly selected primary breast cancers (frozen sections, 5 years' median follow-up) were immunolabelled with two monoclonal BRCA1 antibodies (MS110 and MS13). MS110 labelling was exclusively nuclear showing no relation to outcome or tumour pathology. Western blotting demonstrated crossreactivity, suggesting antibody nonspecificity. MS13 labelling was predominantly cytoplasmic. Intense labelling predicted decreased overall survival (P=0.012), disease-free survival (P=0.029), oestrogen receptor negativity (P=0.0004) and c-erbB-2 overexpression (P=0.006). Western blotting detected a 110 kDa molecule consistent with BRCA1 delta11b splice variant. BRCA1 protein is postulated to function as a tumour suppressor. We demonstrate cytoplasmic localisation in sporadic breast cancer suggesting excess delta11b splice variant production, reduced production of full-length BRCA1 and thus postulate reduced tumour suppressor activity. BRCA1 protein appears to have a significant role in both sporadic and hereditary breast cancers.

Adult↗
PubMed2003

Chromosome 17 aneusomy is associated with poor prognostic factors in invasive breast carcinoma.

Aberrations of chromosome 17 are common in breast cancer. Fluorescence in situ hybridization (FISH) enables gene or chromosome copy number to be assessed in situ in archival tissues and related to morphology and clinical outcome. In this study direct labeled DNA probes for the chromosome 17 alpha satellite and the HER2/neu gene were applied simultaneously to 5 micron sections of 214 formalin-fixed paraffin-embedded invasive primary breast carcinomas. A high proportion (54%) of invasive breast carcinomas displayed aneusomy of chromosome 17. Polysomy 17 correlated with multiple copies of HER2/neu (p = < 0.001), but not with HER2/neu amplification. Eighty-six patients without HER2/neu amplification had aneusomy 17. Fifty-eight of the 86 patients that had aneusomy 17 had high HER2/neu copy number. Twelve patients with normal copy number for chromosome 17 had amplification of HER2/neu and 30 patients had amplification of HER2/neu with aneusomy 17. Aneusomy 17 was associated with grade 3 carcinoma (p = 0.008), ER negativity (p = 0.0032) and a Nottingham prognostic index of greater than 5.4 (p = 0.039) but was not associated with survival by univariate analysis. In conclusion, the determination of chromosome 17 copy number should be incorporated in assessment of HER2/neu status, as this will give an accurate measure of amplification of HER2/neu and may also be helpful in determining suitability for breast carcinoma trials.

Adult↗
PubMed2002

Mitoxantrone and methotrexate chemotherapy with and without mitomycin C in the regional treatment of locally advanced breast cancer.

Fifty patients with locally advanced breast cancer received regional chemotherapy delivered angiographically via the internal mammary artery and varying vessels supplying the lateral aspect of the breast. Thirty three patients received mitomycin C, methotrexate and mitoxantrone, and 17 patients received methotrexate and mitoxantrone only. There was no significant difference in clinical response between the two groups. However, in patients who received mitomycin C, severe local skin toxicity occurred in nine patients resulting in delay of further therapy and considerable morbidity. Mitomycin C should not be administered regionally in patients with locally advanced breast cancer.

Journal Article↗
PubMed2002

Mucinous breast carcinoma.

A case of mucinous breast carcinoma is discussed in which several unusual features in presentation and difficulties in management are addressed.

Journal Article↗
PubMed2001

Evaluating HER2 amplification and overexpression in breast cancer.

The development of Herceptin (Trazumatab) makes testing for HER2 status important for choosing optimal therapy in breast cancer. This study addresses the precision, accuracy, and reproducibility of HER2 assays. HER2 was assessed retrospectively by immunohistochemistry (IHC) with Dako 'Herceptest', by IHC with the monoclonal antibody CB11, and by fluorescence in situ hybridization (FISH, PathVysion), in a series of 216 formalin-fixed breast carcinomas including 191 for which quantitative HER2 data from radioimmunohistochemistry (Q-IHC) were available. All tests were scored independently by two observers. Positivity rates varied between Herceptest (12.6%), FISH (19.4%), and CB11 IHC (28.5%). Kappa values showed that IHC-based tests were more susceptible to inter-observer variation (kappa=0.67 and 0.74 for Herceptest and CB11, respectively) than FISH (kappa=0.973). Overall test accuracy (see the Materials and methods section) for CB11 IHC (83.8%) was lower than Herceptest (87.4%) or FISH (93.2%). FISH predicted p185 HER2 overexpression (determined by Q-IHC) better (concordance index C.Ind. 0.90) than CB11 IHC (C.Ind.=0.85) or Herceptest (C.Ind.=0.81). Of 42 cases with gene amplification by FISH, 67% were positive in the Herceptest (2+ or 3+) vs. 83% with CB11. Of 174 cases negative by FISH, 96% were negative in the Herceptest and 68% with CB11. In conclusion, FISH is the most accurate, reproducible, and precise predictor of HER2 overexpression in routine diagnostic laboratories.

Antibodies, Monoclonal↗
PubMed2001

Genetic aberrations of NAT2 and chromosome 8: their association with progression in transitional cell carcinoma of the urinary bladder.

INTRODUCTION/OBJECTIVE: N-acetyltransferase 2 (NAT2), mapped to 8p22, is a polymorphic enzyme which metabolizes aromatic amines. Loss of heterozygosity of 8p22 is associated with an increased risk of bladder cancer. This study evaluated NAT2 and chromosome 8 in sequential tumours from bladder cancer patients to determine if NAT2 alterations increase the risk of progression. MATERIALS AND METHODS: Thirty-seven sequential carcinomas from 19 patients were assessed using fluorescence in situ hybridization. RESULTS: Five carcinomas showed loss of NAT2; 4 of these were from pTa/pT1 tumours. Polysomy 8 was observed in 4 of 14 (29%) primary carcinomas (pTa/pT1), in 4 of 12 (33%) pTa/pT1 recurrences, and in 90% (9/10) of the detrusor muscle invasive tumours (pT2+). 6 of 8 (75%) locally invasive tumours with polysomy 8 were from patients who subsequently developed disease progression (pT2+). In total, 13.5% (5/37) of the carcinomas were abnormal for NAT2, and 46% (17/37) were abnormal for chromosome 8 copy number. Polysomy 8 was associated with high grade (p = 0.01) and stage (p = 0.03) and disease progression (p = 0.03). CONCLUSION: Whilst there does not appear to be an association between loss of NAT2 and risk of progression in transitional cell carcinoma, the high rate of polysomy of chromosome 8 implies that other genes on this chromosome significantly influence disease progression.

Adult↗
PubMed1999

Therapeutic implications of the sentinel lymph node in breast cancer.

Immunohistochemistry of histologically negative axillary lymph nodes in breast-cancer patients resulted in upstaging of the sentinel lymph node in eight (14%) of 52 patients. The resulting information altered clinical management in six of these patients. Thus, this technique may affect clinical decision-making in breast-cancer patients.

Axilla↗
PubMed1998

Is chromosome 9 loss a marker of disease recurrence in transitional cell carcinoma of the urinary bladder?

Investigation of transitional cell carcinoma of the urinary bladder (TCC) patients classified by recurrence and/or progression has demonstrated that loss of chromosome 9, as detected by FISH analysis of the pericentromeric classical satellite marker at 9q12, occurs early. A total of 105 TCCs from 53 patients were analysed in situ by two independent observers for loss of chromosome 9 using quantitative fluorescence in situ hybridization (FISH). All 53 primary tumours were evaluated for chromosomes 9, 7 and 17. Normal ranges for chromosomal copy number were defined for normal skin epidermis and bladder epithelium. Values for chromosome 9 copy number outwith the range 1.51-2.10 (mean +/- 3 x s.d. of normal values) were significantly abnormal. Twenty-five TCCs were detected with consistent monosomic scores. Of 89 TCCs, in which multiple tumour areas were analysed, 85 tumours (96%) demonstrated the same chromosome 9 copy number in all areas (2-6) analysed; only three tumours demonstrated heterogeneity for this locus. A total of 36% (12 out of 33) of patients with subsequent disease recurrence demonstrated loss of chromosome 9 in their primary and all subsequent TCCs analysed. Only a single patient (n = 20) with non-recurrent TCC showed loss of chromosome 9 (P = 0.0085). Of 53 primary tumours, eight showed significant elevation of chromosome 17. Of these patients, six demonstrated elevation in chromosome 7 copy number. No abnormalities were observed in non-recurrent patients. This study describes rapid quantitation of chromosomal copy number by FISH using a pericentromeric probe for chromosome 9 in TCC of the urinary bladder. Routinely fixed and processed material was evaluated without disaggregation. Strict quality control of FISH demonstrated that this technique was reproducible in a clinical environment and could be used to detect genetic changes relevant to patient outcome. It is proposed that loss of chromosome 9 from primary TCC of the urinary bladder identified patients at high risk of recurrence and possible progression.

Aged↗
PubMed1998

Sentinel node localization in patients with breast cancer.

BACKGROUND: Intraoperative lymphatic mapping and identification of the first draining lymph node (the sentinel node) may allow some patients with breast cancer to avoid the morbidity of formal axillary clearance. The aim of this pilot study was to establish the reliability of the technique in predicting axillary node status. METHODS: Sixty-eight consecutive patients with breast cancer, 38 undergoing mastectomy and 30 wide local excision, were included. Some 2-4 ml of 2.5 per cent Patent Blue dye was injected into adjacent breast tissue on the axillary side of the primary tumour. After 5-10 min, the axilla was explored. Blue-stained lymphatics were dissected to the sentinel node, which was removed for frozen-section examination, followed by routine histology. Formal axillary dissection was then completed. RESULTS: A sentinel lymph node was identified successfully in 56 (82 per cent) of 68 patients. Histology of the sentinel node accurately predicted axillary node status in 53 (95 per cent). There were three false negatives (5 per cent). In each case, only a single non-sentinel node was tumour positive. Sensitivity and specificity were 83 and 100 per cent respectively. CONCLUSION: This technique would allow a selective policy of formal axillary dissection in only node-positive patients; however, further experience and refinement are needed.

Adult↗
PubMed1998

Prospective assessment of the hepatic perfusion index in patients with colorectal cancer.

BACKGROUND: This prospective study was designed to test the hypothesis that abnormal liver blood flow is related to poor prognosis in patients with colorectal cancer. METHODS: The hepatic perfusion index (HPI), measured by dynamic hepatic scintigraphy, was assessed in 202 patients with colorectal cancer. Assessment for overt hepatic metastasis included liver palpation at laparotomy and perioperative computed tomography (CT). Follow-up at a dedicated clinic included regular abdominal ultrasonography and CT. RESULTS: The HPI was abnormal (greater than 0.37) in 92 (88 per cent) of 105 patients with overt liver metastases. Of 89 patients with no evidence of overt metastases or residual tumour after primary resection, 52 had an abnormal and 37 a normal HPI. At a median follow-up of 39 (range 13-76) months, 25 of 38 patients with recurrence had an abnormal HPI. Some 31 of 45 patients who died had an abnormal HPI. The HPI predicted overall recurrence (P=0.04, log rank test). Multivariate analysis showed the HPI was independent of Dukes stage for predicting disease-free survival (P=0.04, relative risk 1.94 (95 per cent confidence interval (c.i.) 1.03-3.67)) but this just failed to attain significance for overall survival (P=0.055, relative hazard 1.88 (95 per cent c.i. 1.00-3.58)). CONCLUSION: The HPI predicts a poor outcome in patients with colorectal cancer and may be useful in patient selection for adjuvant chemotherapy.

Adult↗
PubMed1998

BRCA1 and BRCA2 proteins: roles in health and disease.

Between 5% and 10% of all breast cancer is hereditary, with patients having a strong family history of the disease. The remaining 90-95% of cases are classed as sporadic. Within the inherited group, 80-90% of cases are the result of germline mutations affecting two recently identified genes: BRCA1 and BRCA2. Since the sequencing of these genes, considerable research on the genetics of the mutation carriers has been performed, with less attention having been focused on the BRCA1 and BRCA2 proteins themselves. The structure and function of the protein products thus continues to hold mystery and might be the key to the full understanding of this complex disease.

Animals↗
PubMed1998

Doppler perfusion index: an interobserver and intraobserver reproducibility study.

PURPOSE: To assess the potential of Doppler perfusion index (DPI) measurement as a routine diagnostic tool in the detection of occult colorectal liver metastases. MATERIALS AND METHODS: By using color doppler ultrasound, two independent sonologists performed DPI measurements blindly in 20 patients aged 30-82 years; interobserver reproducibility was assessed. A second group of 20 patients aged 37-88 years were examined to assess the level of intraobserver reproducibility of DPI measurements attained by one sonologist. For each patient in this group, the DPI was measured three times in succession, and the variability between measurements was analyzed. Calculations of the intraclass correlation coefficient and the coefficient of variation (CV) were used to determine the levels of reproducibility. The data were also analyzed by using the Student paired t test, with significance established at P less than .05. RESULTS: The interobserver CV and intraobserver CV were 20% and 16%, respectively. The two sonologists who examined the first group of patients agreed independently on the DPI status in 18 of 20 (90%) patients. CONCLUSION: In this study, both the intraobserver reproducibility and the interobserver reproducibility of DPI measurements were clinically acceptable.

Adult↗