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B Dunne

Publications and source records attributed to B Dunne.

At least 19 recordsLinked to original sources
PubMed2006

Observer variation in immunohistochemical analysis of protein expression, time for a change?

AIM: Immunohistochemical analysis of protein expression is central to most clinical translational studies and defines patient treatment or selection criteria for novel drugs. Interobserver variation is rarely analysed despite recognition that this is a key area of potential inaccuracy. Therefore our aim was to examine observer variation and suggest the revision of current standards. METHODS AND RESULTS: We analysed inter- and intra-observer variation, by interclass correlation coefficient (ICCC) and kappa statistics, in 8661 samples. Intra-observer assessment of nuclear, cytoplasmic and membrane staining for seven proteins in 1323 samples resulted in an ICCC of 0.94 and a kappa-value of 0.787. Interobserver reproducibility, assessed on 28 proteins by seven observer pairs in 8661 carcinomas, gave an ICCC of 0.90 and a kappa-value of 0.70. No significant effect of either antibody or cellular compartmentalization was observed. CONCLUSION: We have demonstrated that ICCC is a consistent method to assess observer variation when a continuous scoring system is used, compared with kappa statistics, which depends on a categorical system. Given the importance of accurate assessment of protein expression in diagnostic and experimental medicine, we suggest raising thresholds for observer variation: ICCC of 0.7 should be regarded as the minimum acceptable standard, ICCC of 0.8 as good and ICCC of > or = 0.9 as excellent.

Biomarkers, Tumor↗
PubMed2005

IHC for Her2 with CBE356 antibody is a more accurate predictor of Her2 gene amplification by FISH than HercepTest in breast carcinoma.

BACKGROUND: Her2 (c-erbB-2/neu) overexpression in breast carcinoma predicts response to the anti-Her2 monoclonal antibody, trastuzumab, and is associated with a poor prognosis. When considering patients for trastuzumab treatment, Her2 protein expression is measured by imunohistochemistry (IHC) and, where staining is equivocal, by fluorescence in situ hybridisation (FISH) detection of Her2 gene amplification. AIMS: To compare IHC using CBE356 with IHC using the Food and Drug Administration approved HercepTesttrade mark. METHODS: CBE356 and HercepTest were analysed using 167 FISH characterised breast carcinomas. Immunohistochemical expression of Her2 was measured semiquantitatively. Sensitivity, specificity, predictive values, and overall accuracy were calculated for both IHC methods using gene amplification by FISH as the end point, and IHC and FISH assays were tested in Kaplan-Meier survival analysis. RESULTS: The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CBE356 positive (2+ and 3+) cases were 94%, 89%, 95%, 84%, and 97%, respectively, and of HercepTest positive (2+ and 3+) cases were 91%, 66%, 98%, 92%, and 91%, respectively. A positive result with CBE356, HercepTest, or FISH was associated with significantly decreased overall survival (log rank p = 0.005, p = 0.0017, and p = 0.0005, respectively). CONCLUSIONS: Positive IHC staining for Her2 using CBE356 is 3% more accurate and 23% more sensitive at predicting Her2 gene amplification by FISH than positive staining with HercepTest. Negative IHC using CBE356 antibody is 6% more likely to represent a truly negative result than negative staining with HercepTest. Overall, CBE356 was a more accurate predictor of Her2 gene amplification by FISH than HercepTest.

Adult↗
PubMed2004

Margin involvement and outcome in oesophageal carcinoma: a 10-year experience in a specialist unit.

AIMS: Positive microscopic margins after major cancer surgery adversely affect prognosis. We questioned whether the benefit of a multimodal approach in oesophageal carcinoma is due to reduced resection margin involvement and whether multimodal therapy alters the disease course when margins are involved. METHODS: Pathology specimens of 212 patients, treated with either multimodal therapy or surgery alone, were re-reviewed to assess margin involvement by tumour. Margin status was compared with recurrence and survival data. RESULTS: Margin involvement was decreased with multimodal therapy (16 of 103 patients) vs surgery (33 of 109 patients), associated with reduced tumour recurrence and a significant survival advantage. However, even with involved margins, multimodal therapy had lower recurrence vs surgery and a small survival benefit. CONCLUSIONS: Multimodal therapy significantly reduces margin involvement. The benefit of multimodal therapy remains highly significant for patients with clear margins. This study confirms for oesophageal carcinoma the value of an aggressive surgical approach in achieving negative resection margins.

Adenocarcinoma↗
PubMed2004

Predictive power of cytomorphological features in equivocal (C3, C4) breast FNAC.

Definitive immediate diagnosis in breast fine needle aspiration cytology (FNAC) remains the aim for cytopathologists. We reviewed 72 consecutive equivocal (C3 and C4) aspirates with respect to 16 cytomorphological criteria. We assessed the power of each criterion at predicting either a malignant [positive predictive value (PPV)] or a benign [negative predictive value (NPV)] diagnosis by correlation with follow-up histology. Blind review led to 34% of cases being correctly definitively diagnosed. Eccentrically placed epithelial cell nuclei (PPV = 88%, sensitivity = 67%, specificity = 87%) and coarse nuclear chromatin (PPV = 81%, sensitivity = 72%, specificity = 83%) are the features that are most useful in predicting malignancy in this selected series. The presence of myoepithelial cells within epithelial groups is not a good indicator of a benign diagnosis (NPV = 24%, sensitivity = 80%, specificity = 53%).

Biopsy, Fine-Needle↗
PubMed2003

Spindle cell carcinoma of the breast: a case series of a rare histological subtype.

AIM: Spindle cell carcinoma (SpCC) represents <0.5% of breast cancers. We report the 15-year experience of SpCC at the Nottingham Breast Unit. METHODS: Histopathology and case notes of metaplastic carcinomas with predominant spindle cell differentiation were analysed for patient demographics, tumour pathology, c-erb B-2 oestrogen (ER) and progesterone (PR) receptor status and radiology. Treatment, recurrence and survival rates were also analysed. RESULTS: Nineteen patients with SpCC were identified. The median age was 68 years (range 27-92). Large ill-defined mass was the only consistent radiological features suggesting SpCC. Mean tumour size was 53 mm, (range 16-200 mm). Fifteen tumours were grade 3 and four were grade 2. Six out of 15 patients with axillary surgery had positive lymph nodes (40%). All tumours were oestrogen (ER) and progesterone (PR) negative. One tumour was focally c-erb B-2 positive in the non-spindle cell component. Median Nottingham Prognostic Index was 5.2 (range 3.6-6.6). Primary treatment was surgical in 89%. Adjuvant chemotherapy was given in four cases. The median disease free interval was 7 (range 2-109) months. Twelve cases recurred (63.2%). The main sites of metastasis were the lungs (9 cases), bone (6) and liver (1). Eleven cases have died of breast cancer (58%). Median survival was 18 months (range 4-109). CONCLUSION: SpCC is an aggressive histological type of carcinoma of the breast. Omitting node sampling may result in significant under-staging. Negative ER, PR and c-erb B-2 status limits treatment options.

Adult↗
PubMed2002

E7 proteins from oncogenic human papillomavirus types transactivate p73: role in cervical intraepithelial neoplasia.

In common with other E2F1 responsive genes such as p14(ARF) and B-myb, the promoter of p73 is shown to be positively regulated in cell lines and primary human keratinocytes by E7 proteins from oncogenic human papillomavirus (HPV) types 16, 18, 31 and 33, but not HPV 6. Mutational analysis revealed that transactivation of the p73 promoter by HPV 16E7 requires association with pRb. Expression of p73 in normal cervical epithelium is confined to the basal and supra-basal layers. In contrast, expression in neoplastic lesions is detected throughout the epithelium and increases with grade of neoplasia, being maximal in squamous cell cancers (SCC). Deregulation of expression of the N-terminal splice variant p73Delta2 was observed in a significant proportion of cancers, but not in normal epithelium. The frequent over-expression of p73Delta2, which has recognized transdominant properties, in malignant and pre-malignant lesions suggests a role in the oncogenic process in cervical epithelium.

Carcinoma, Squamous Cell↗
PubMed2001

p73 is over-expressed in vulval cancer principally as the Delta 2 isoform.

p73 was studied in squamous cancers and precursor lesions of the vulva. Over-expression of p73 occurred commonly in both human papillomavirus (HPV)-positive and -negative squamous cell cancers (SCC) and high-grade premalignant lesions. Whereas expression in normal vulval epithelium was detected only in the basal and supra-basal layers, expression in neoplastic epithelium increased with grade of neoplasia, being maximal at both protein and RNA levels in SCC. p73 Delta 2 was the principal over-expressed isoform in the majority of cases of vulval SCC and often the sole form expressed in SCC. Over-expression of p73 was associated with expression of HPV-encoded E7 or with hypermethylation or mutation of p16(INK4a) in HPV-negative cases. There was a close correlation between expression of p73 and p14(ARF) in cancers with loss of p53 function. The frequent over-expression of p73 Delta 2 in neoplastic but not normal vulval epithelium, and its co-ordinate deregulation with other E2F-1 responsive genes suggests a role in the oncogenic process.

Cyclin-Dependent Kinase Inhibitor p16↗
PubMed2001

Scoring nuclear pleomorphism in breast cancer.

AIMS: Nuclear grade has equal weight with mitotic index and acinus formation in grading breast cancer, but criteria for its assessment are less well defined. This study examines consistency of nuclear grading in breast cancer and whether improved nuclear grading criteria are required. METHODS AND RESULTS: Photographic prints of haematoxylin-eosin sections of 100 unselected symptomatic breast cancers were circulated to histopathologists who assigned each carcinoma a nuclear pleomorphism score on a linear analogue scale 0-100 (0-33 equating to nuclear pleomorphism grade 1, 34-66 to grade 2, and 67-100 to grade 3). Seventeen histopathologists completed the exercise, including 11 breast specialists. While kappa scores for the implied nuclear grades indicated 'moderate' or 'good' agreement between individuals and the group as a whole, seven pathologists allocated analogue scores significantly lower than the median score allocated by the group to each case, while five allocated significantly higher scores. The range was from analogue scores 11.3 units lower on average than the median (assigning 27% of carcinomas nuclear grade 1, 60% grade 2, and 13% grade 3) to scores 7.5 units higher on average than the median (assigning only 2% carcinomas nuclear grade 1, 46% grade 2, and 52% grade 3). Five of six non-specialists allocated scores significantly lower than the group medians but only two of 11 specialists did so (P=0.018). CONCLUSIONS: Systematic differences between pathologists in scoring nuclear pleomorphism in breast cancer potentially contribute to differences in allocating overall grade and confirm the need for improved nuclear grading criteria. Specialists tend to allocate higher pleomorphism scores than non-specialists.

Breast Neoplasms↗
PubMed2001

A pathological study of tumour regression in oesophageal adenocarcinoma treated with preoperative chemoradiotherapy.

AIMS: To measure residual tumour in oesophageal adenocarcinoma treated with preoperative chemoradiotherapy, to correlate specific pathological variables with survival, and to describe morphological changes in tumour and non-neoplastic tissue resulting from preoperative treatment. METHODS: Resection specimens from 47 cases of oesophageal adenocarcinoma treated with preoperative 5-fluorouracil/cisplatin and radiotherapy were reviewed. Residual tumour was assessed in terms of tumour regression grade (TRG), pTNM stage, lymphovascular space invasion, and resection margin involvement. Survival analysis was performed using the Kaplan-Meier method and log rank test. Cox's proportional hazard model was used for multivariate analysis. RESULTS: A complete pathological response (TRG1) was present in eight cases. The absence of residual tumour was confirmed by negative immunohistochemical staining for MNF116. Tumour corresponding to TRG2 was present in five cases, to TRG3 in nine, to TRG4 in 22, and to TRG5 in three. By multivariate analysis, pN0 status (n = 35) had a positive effect on survival (p = 0.04) and TRG had no significant effect on survival (p = 0.06). Patients with pN0 tumours had a median survival of 48 months versus eight months for those with pN1 tumours (log rank test, p < 0.0001). We found that giant fibroblasts were discernible from single large residual tumour cells on haematoxylin and eosin alone. CONCLUSION: Response to preoperative chemoradiotherapy in oesophageal adenocarcinoma is variable. Although there are as yet no reliable predictors of response to treatment, patients who are identified at diagnosis as having negative loco-regional lymph nodes should benefit considerably from this treatment approach.

Adenocarcinoma↗
PubMed2000

Partial hepatectomy and laparoscopic-guided liver biopsy in rhesus macaques (Macaca mulatta): novel approach for study of liver regeneration.

BACKGROUND AND PURPOSE: Although valuable information has been gained using a rodent partial hepatectomy model to assess liver regeneration, the ability to apply this research to humans remains uncertain. Thus, liver regeneration was assessed in a non-human primate, the rhesus macaque (Macaca mulatta). METHODS: One animal underwent 60% hepatectomy, a second animal underwent 30% hepatectomy, and control surgery (cholecystectomy) was performed on two separate animals. Laparoscopic-guided liver biopsy was performed on days 1, 2, 7, 14, and 30 after surgery. Changes in hemoglobin concentration and alanine transaminase activity were assessed, and liver regeneration was evaluated by measuring the expression of Ki-67. RESULTS: All animals survived surgery and laparoscopy. Substantial liver regeneration was induced in the animal that underwent 60% hepatectomy. Excellent tissue specimens were obtained via laparoscopic-assisted liver biopsy. CONCLUSIONS: Sixty percent partial hepatectomy in rhesus macaques appears to be an excellent model for the study of hepatocellular regeneration. The procedure was safe, and effectively induced liver regeneration. In addition, laparoscopic-guided liver biopsy allows observation of changes in the liver remnant as regeneration develops, and provides excellent tissue specimens for analysis. Thus, this rhesus macaque partial hepatectomy model will allow further characterization of liver regeneration in a species closer to humans.

Animals↗
PubMed1999

Detection and treatment of depression in a VA primary care clinic.

The Veterans Health Administration clinical guideline for major depressive disorder was used in screening 574 male veterans treated in primary care settings in the Department of Veterans Affairs health care system. Thirteen percent (N=73) screened positive for depression, and 33 percent of those patients showed evidence of a major depressive episode. Pre- and posttreatment assessment of a sample of 16 patients treated for depression in a primary care setting revealed statistically significant improvement with treatment.

Adult↗
PubMed1997

Malignant chondroid syringoma presenting as multiple pulmonary nodules.

Malignant chondroid syringoma, a very rare tumour, presenting with multiple pulmonary metastases in a 50 year old woman is described. Initial diagnostic confusion with pulmonary hamartoma occurred due to histopathological similarities. However, re-examination of a skin biopsy specimen taken 17 years previously from a hand lesion yielded the necessary information to identify the pulmonary lesions definitively as metastases from the original skin lesion. The features of this very rare indolent tumour are described.

Adenoma, Pleomorphic↗
PubMed1996

Multidrug resistance in ocular melanoma.

AIMS/BACKGROUND: Metastatic disease in patients with ocular melanoma is resistant to chemotherapy. One of the main mechanisms of modulating multidrug resistance is the expression of the multidrug resistance gene 1 (MDR1) product (p-glycoprotein) by tumour cells. The purpose of this study was to evaluate the frequency of expression of the MDR1 gene in ocular melanoma whose primary treatment was surgical excision or enucleation. METHODS: Twelve recent ocular melanomas were received fresh, snap frozen and cryostat sections of tumour were analysed for expression of MDR1 by immunohistochemistry using a well characterised monoclonal antibody to MDR1. Tumour explants were established in short term tissue culture from four tumours and cell blocks were examined by immunohistochemistry. RESULTS: MDR1 expression was present in five of 12 ocular melanomas. Upregulation of protein expression was found in four cell lines established in short term culture from tumour explants. A recurrent tumour, initially treated by local excision and radioactive plaque, showed overexpression of MDR1 mRNA. CONCLUSIONS: These results suggest that significant level of MDR1 may be intrinsically present in ocular melanomas before exposure to drugs involved in multidrug resistance, and indicate the possible importance of MDR1 in modulating chemoresistance in ocular melanoma. Chemosensitisation may be of potential value in planning adjuvant chemotherapy for patients with metastatic disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Twenty-four hour blood pressure effect of once-daily lisinopril, enalapril, and placebo in patients with mild to moderate hypertension.

This multicentre, double-blind, parallel-group, placebo-controlled study compared the antihypertensive effects of equal doses of two long-acting angiotensin converting enzyme (ACE) inhibitors. After a two-week, placebo run-in phase, 110 patients with mild to moderate hypertension were randomised to receive 10 mg lisinopril or enalapril, or placebo for 4 weeks. Office BPs were measured at regular intervals throughout the study. Twenty-four hour ambulatory blood pressure (ABP) was measured at baseline and after the first and final doses of study drug. Serum ACE activity and aldosterone were obtained concomitantly with each ABP monitoring. Office BP differences from placebo reached (P less than 0.05) or approached (P less than 0.10) statistical significance at all observations for the lisinopril group but were not significant for any observation in the enalapril group and approached significance on two occasions. After four weeks of treatment, ABP analysis revealed that the lisinopril and enalapril groups, when compared with placebo, had similar and significant systolic and diastolic AUC reductions (P less than 0.01) from baseline over the 24 h dosing interval. During the second half of the dosing interval, 13-24 h post drug administration, the lisinopril group was significantly different from placebo (systolic BP, P = 0.002; diastolic BP, P = 0.005) while the enalapril group was not. Both drugs were well tolerated. The results indicate that monotherapy with 10 mg of lisinopril is as effective as with 10 mg of enalapril, and that ABP monitoring is useful in more precisely depicting the clinical effect of the known pharmacokinetic properties of these two agents.

Adult↗
PubMed1990

Once-daily lisinopril compared with twice-daily captopril in the treatment of mild to moderate hypertension: assessment of office and ambulatory blood pressures.

This multicenter, double-blind, parallel-group study compared the antihypertensive effects of two angiotensin-converting enzyme inhibitors, lisinopril and captopril, in 70 patients (35 lisinopril, 35 captopril) with mild-to-moderate essential hypertension. Doses of 10, 20, and 40 mg once-daily lisinopril or 25, 50, and 100 mg bid captopril were increased at biweekly intervals until patients responded to treatment, as defined by a decrease in office diastolic pressure to less than 90 mm Hg or at least a 10 mm Hg decrease from baseline. Patients who responded to a 2-week titration dose remained at that dose for another 2 weeks. Blood pressure assessments were made using both office and ambulatory blood pressure monitoring. Area under the curve analysis of ambulatory blood pressure reductions showed significant differences between treatment groups for both systolic (P = .023) and diastolic (P = .007) blood pressures, with lisinopril-treated patients showing the most significant reduction in pressure. Greater reductions (P less than .05) were also noted in patients receiving lisinopril at hours 10 to 12, suggesting two blood pressure troughs for those receiving captopril. Both drugs were well tolerated, and no patients withdrew from either treatment group. The authors concluded that after at least 4 weeks of therapy, once-daily lisinopril administration was more effective than twice-daily captopril administration in reducing blood pressure, when measured by 24-hour ambulatory blood pressure monitoring.

Ambulatory Care↗