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Sydney, Australia
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Zardawi S.J.,St. Vincent's Institute | Zardawi I.,John Hunter Hospital | McNeil C.M.,St. Vincent's Institute | McNeil C.M.,University of Sydney | And 23 more authors.
Histopathology | Year: 2010

Aims: Activation of Notch signalling results in hyperplasia and tumorigenesis in murine mammary epithelium. However, there is little information regarding the expression of Notch1 in premalignant lesions and early breast cancer. We investigated expression of Notch1 in breast cancer development and its association with molecular subtypes. Methods and results: Immunohistochemical expression of Notch1 was determined in a murine model of mammary carcinogenesis and in breast tissue from two cohorts of breast cancer patients, the first (n = 222) comprising a histological progression series and the second an outcome series of 228 patients with operable invasive ductal carcinoma. Enhanced expression of Notch1 protein was an early event in both murine and human breast cancer development with progressive increases in expression with the development of hyperplasia and malignancy. High Notch1 was not prognostic in the outcome cohort. There was, however, a highly significant association of high Notch1 protein with the HER-2 molecular subtype of breast cancer (P = 0.008). Conclusions: These data demonstrate that aberrant Notch regulation is an early event in mammary carcinogenesis and is associated with the HER-2 molecular subtype of breast cancer, and suggest the Notch signalling pathway may be a potential therapeutic target worthy of further investigation. © 2010 Blackwell Publishing Limited.


Bullock M.,Kolling Institute of Medical Research | O'Neill C.,Royal North Shore Hospital | Chou A.,SYDPATH | Clarkson A.,Royal North Shore Hospital | And 19 more authors.
Endocrine-Related Cancer | Year: 2012

Identification of BRAFV600E in thyroid neoplasia may be useful because it is specific for malignancy, connotes a worse prognosis, and is the target of novel therapies currently under investigation. Sanger sequencing is the 'gold standard' for mutation detection but is subject to sampling error and requires resources beyond many diagnostic pathology laboratories. In this study, we compared immunohistochemistry (IHC) using a BRAFV600E mutation-specific MAB to Sanger sequencing on DNA from formalin-fixed paraffin-embedded tissue, in a well-characterized cohort of 101 papillary thyroid carcinoma (PTC) patients. For all cases, an IHC result was available; however, five cases failed Sanger sequencing. Of the 96 cases with molecular data, 68 (71%) were BRAFV600E positive by IHC and 59 (61%) were BRAFV600E positive by sequencing. Eleven cases were discordant. One case was negative by IHC and initially positive by sequencing. Repeat sequencing of that sample and sequencing of a macrodissected sample were negative for BRAFV600E. Of ten cases positive by IHC but negative by sequencing on whole sections, repeat sequencing on macrodissected tissue confirmed the IHC result in seven cases (suggesting that these were false negatives of sequencing on whole sections). In three cases, repeat sequencing on recut tissue remained negative (including using massive parallel sequencing), but these cases demonstrated relatively low neoplastic cellularity. We conclude that IHC for BRAFV600E is more sensitive and specific than Sanger sequencing in the routine diagnostic setting and may represent the new gold standard for detection of BRAFV600E mutation in PTC. © 2012 Society for Endocrinology.


Stone E.,St Vincents Hospital Sydney | Stone E.,Kinghorn Cancer Center | Allen H.A.,St Vincents Hospital Sydney | Allen H.A.,Kinghorn Cancer Center | And 8 more authors.
Internal Medicine Journal | Year: 2014

Background: Epidermal growth factor receptor (EGFR) mutation positivity in primary non-small-cell lung cancer (NSCLC) may confer increased sensitivity to EGFR tyrosine kinase inhibitor (TKI) therapy with improved progression-free survival over EGFR wild-type tumours. Some mutation subtypes may not confer such TKI sensitivity. The incidence of rare and compound subtypes in the Australian lung cancer population is not fully defined. Aims: The aim of the study was to audit the incidence of EGFR mutation in serial cases of primary non-squamous NSCLC presenting to two multidisciplinary team meetings in metropolitan Sydney for incidence, type of mutation and phenotypic association with mutation positivity. Methods: Serially presenting cases of primary non-squamous NSCLC were tested for EGFR mutation. The cases presented to either of two multidisciplinary team meetings in metropolitan Sydney and were referred for EGFR mutation testing on the basis of non-squamous NSCLC histopathology. Samples from the two sites were analysed for EGFR mutation at one of three different laboratories, each using a slightly different assay. Data on phenotypic characteristics, smoking history and clinicopathological features of the tumour were collected. Results: There is a relatively high incidence of EGFR mutation in non-squamous NSCLC in a series of patients drawn from two metropolitan multidisciplinary team meetings in Sydney at a rate of 23.8%. A high proportion of rare and compound EGFR mutations were identified (6/32 mutation positive cases, 18.8%). Conclusions: The incidence of EGFR mutation may be higher in Australian populations than in other populations of predominantly European origin. Rare and compound EGFR mutations may occur and may have implications for treatment that differ from classically activating mutations. © 2014 Royal Australasian College of Physicians.


Jabbour J.,The University of Notre Dame Australia | Earls P.,SydPath | Biggs N.,St Vincents Clinic | Gracie G.,SydPath | And 2 more authors.
Journal of Laryngology and Otology | Year: 2016

Background: Vestibular schwannomas in younger patients have been observed to be larger in size and grow more quickly. Objective: This study aimed to evaluate the expression of three important cell cycle proteins, cyclin D1, cyclin D3 and Ki-67, in vestibular schwannoma patients separated into two age groups: ≤40 years or >40 years. Method: Immunohistochemical detection of cyclin D1, cyclin D3 and Ki-67 was undertaken in 180 surgically resected vestibular schwannomas. Results: The proliferation index of vestibular schwannomas was statistically higher in the ≤40 years age group compared to that in the >40 years age group (mean of 4.52 vs 3.27, respectively; p = 0.01). Overexpression of cyclin D1 and cyclin D3 was found in 68 per cent and 44 per cent of tumours, respectively. Conclusion: There was an increased Ki-67 proliferation index in the younger age group that appears to correlate with clinical behaviour. Vestibular schwannomas in both age groups show increased expression of cyclin D1 and cyclin D3. Copyright © JLO (1984) Limited 2015.

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