Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entity

Immunohistochemical analysis of E-cadherin has changed the way lobular neoplasia is perceived. It has helped to classify difficult cases of carcinoma in situ with indeterminate features and led to the identification of new variants of lobular carcinoma. Pleomorphic lobular carcinoma (PLC) and pleomorphic lobular carcinoma in situ (PLCIS), recently described variants of invasive and in situ classic lobular carcinoma, are reported to be associated with more aggressive clinical behaviour. Although PLC/PLCIS show morphological features of classic lobular neoplasia and lack E-cadherin expression, it is still unclear whether these lesions evolve through the same genetic pathway as lobular carcinomas or are high-grade ductal neoplasms that have lost E-cadherin. Here we have analysed a case of extensive PLCIS and invasive PLC associated with areas of E-cadherin-negative carcinoma in situ with indeterminate features, using immunohistochemistry, chromogenic in situ hybridization, high-resolution comparative genomic hybridization (CGH) and array-based CGH. We observed that all lesions lacked E-cadherin and beta-catenin and showed gain of 1q and loss of 16q, features that are typical of lobular carcinomas but are not seen in high-grade ductal lesions. In addition, amplifications of c-myc and HER2 were detected in the pleomorphic components, which may account for the high-grade features in this case and the reported aggressive clinical behaviour of these lesions. Taken together, these data suggest that at least some PLCs may evolve from the same precursor or through the same genetic pathway as classic lobular carcinomas. Copyright (c) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Molecular evolution of breast cancer

Molecular analysis of invasive breast cancer and its precursors has furthered our understanding of breast cancer progression. In the past few years, new multi-step pathways of breast cancer progression have been delineated through genotypic-phenotypic correlations. Nuclear grade, more than any other pathological feature, is strongly associated with the number and pattern of molecular genetic abnormalities in breast cancer cells. Thus, there are two distinct major pathways to the evolution of low- and high-grade invasive carcinomas: whilst the former consistently show oestrogen receptor (ER) and progesterone receptor (PgR) positivity and 16q loss, the latter are usually ER/PgR-negative and show Her-2 over-expression/amplification and complex karyotypes. The boundaries between the evolutionary pathways of well-differentiated/low-grade ductal and lobular carcinomas have been blurred, with changes in E-cadherin expression being one of the few distinguishing features between the two. In addition, lesions long thought to be precursors of breast carcinomas, such as hyperplasia of usual type, are currently considered mere risk indicators, whilst columnar cell lesions are now implicated as non-obligate precursors of atypical ductal hyperplasia (ADH) and well-differentiated ductal carcinoma in situ (DCIS). However, only through the combination of comprehensive morphological analysis and cutting-edge molecular tools can this knowledge be translated into clinical practice and patient management. Copyright (C) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.

EGFR amplification and lack of activating mutations in metaplastic breast carcinomas

Metaplastic breast carcinomas are reported to harbour epidermal growth factor receptor (EGFR) overexpression in up to 80% of the cases, but EGFR gene amplification is the underlying genetic mechanism in around one-third of these. In this study, EGFR gene amplification as defined by chromogenic in situ hybridization and protein overexpression was examined in a cohort of 47 metaplastic breast carcinomas. Furthermore, the presence of activating EGFR mutations in exons 18, 19, 20, and 21 was investigated. Thirty-two cases showed EGFR overexpression and of these, 11 (34%) harboured EGFR gene amplification. In addition, EGFR amplification showed a statistically significant association with EGFR overexpression (p < 0.0094) and was restricted to carcinomas with homologous metaplasia. Ten cases, five with and five without EGFR amplification, were subjected to microarray-based CGH, which demonstrated that EGFR copy number gain may occur by amplification of a discrete genomic region or by gains of the short arm of chromosome 7 with a breakpoint near the EGFR gene locus, the minimal region of amplification mapping to EGFR, LANCL2, and SECOG. No activating EGFR mutations were identified, suggesting that this is unlikely to be a common alternative underlying genetic mechanism for EGFR expression in metaplastic breast carcinomas. Given that metaplastic breast carcinomas are resistant to conventional chemotherapy or hormone therapy regimens and that tumours with EGFR amplification are reported to be sensitive to EGFR tyrosine kinase inhibitors, these findings indicate that further studies are warranted to explore EGFR tyrosine kinase inhibitors as potential therapeutic agents for metaplastic breast carcinomas harbouring amplification of 7p11.2. Copyright (c) 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Characterization of tumour-infiltrating lymphocytes and apoptosis in colitis-associated neoplasia: comparison with sporadic colorectal cancer

The development of colorectal cancer is a major complication for patients with chronic idiopathic colitis. Colitis-associated tumours tend to occur at a younger age and be more aggressive than sporadic colorectal cancers. While we have previously associated the presence of tumour-infiltrating lymphocytes (TILs) and increased apoptosis in sporadic colorectal cancer with high-level microsatellite instability and improved prognosis, little is known of the relationship between these variables in colitis-associated colorectal cancer. The aim of this study was to correlate TILs and tumour cell apoptosis in colitis-associated neoplasms stratified according to microsatellite instability. Twenty tumour and 11 dysplastic samples resected from 21 patients with long-standing colitis were analysed for microsatellite instability at 10 microsatellite markers. TIL distribution (CD3, CD8) and function (granzyme B) were quantified by immunohistochemistry. Neoplastic cell apoptosis was assessed using the M30 CytoDEATH antibody. These findings were compared with 40 microsatellite stable (MSS) sporadic colorectal cancers previously evaluated for TILs and neoplastic apoptosis. Low-level microsatellite instability was found in 1/20 colitis-associated tumours. All other colitis-associated lesions were designated MSS. CD3(+) and CD8(+) TIL counts were significantly higher in colitis-associated lesions compared with NISS sporadic colorectal cancer (p < 0.0001, p = 0.001 respectively). Despite their higher TIL density, colitis-associated tumours were more likely to present late (Dukes' stage C or D) (P = 0.02). Functionally, colitis-associated TILs demonstrated significantly less granzyme B expression compared to sporadic cancers (p = 0.002). The level of tumour cell apoptosis was similar between the two groups (sporadic, 1.53%; colitis cancers, 1.45%). In conclusion, NISS colitis-associated tumours have a higher prevalence of CD3(+)/CD8(+) TILs but no associated increase in tumour cell killing by apoptosis. Unlike cytotoxic T cells in sporadic colorectal cancer, TILs do not appear to enhance the prognosis of colitis-associated colorectal cancer. This may be related to an impairment of granzyme B expression within these lesions. Copyright (c) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Developing the public health function of locum pharmacists under the auspices of the new pharmacy contract

Focal Point - There are reduced opportunities for locum pharmacists to access training and education that meets their needs and enables them to play a full role under the new pharmacy contract - Eighty-six per cent of locums consider themselves to be more health professional than business person, compared to just 48% of pharmacy owners - Forty per cent of locums believe that a lack of access to training is a major barrier to the development of their public health function - While locum pharmacists are arguably more likely to embrace 'professionalising', patient-care-based roles, they are also the group least likely to be able to access the necessary training to fulfill such roles Introduction It has been suggested that locum pharmacists do not want the business-based responsibilities (e.g. staff management, meeting targets, etc) that come with pharmacy management.1 Research also suggests that locums derive great satisfaction from the health-professional aspects of the pharmacists’ role (e.g. patient contact, the provision of advice, etc).1 However, upon the introduction of the new pharmacy contract (April 2005), concerns were expressed that it was becoming increasingly difficult for locum pharmacists to access training and education that would meet their needs and enable them to play a full role under the new framework.2,3 Method After piloting, in August 2006 a self-completion postal questionnaire was sent to a random sample of practising community pharmacists, stratified for country and sex, within Great Britain (n = 1998), with a follow-up to non-responders 4 weeks later. Data were analysed using SPSS (v12.0). A final response rate of 51% (n = 1023/1998) was achieved. Respondents were asked ‘indicate how you view yourself as a pharmacist’ – in terms of their relative focus on the health-professional and business aspects of their role. Respondents were also asked ‘do you consider a lack of training opportunities to be a barrier to the development of the public health role of community pharmacists?’. Results Locums were significantly more likely than owners or employees to consider each factor a major barrier. Discussion Four in 10 locums consider a lack of training opportunities to constitute a major barrier to the development of their public health function. Pharmacy may not be able to provide the services required of it by the policy agenda if pharmacists are unable to be involved in extended role activities through a lack of training opportunities. Therefore, the paradox that needs to be addressed is that while locum pharmacists are arguably more likely to embrace ‘professionalising’, patient-care-based roles, they are also the group least likely to be able to access training to fulfil such roles. The training needs of this large subset of the pharmacist population need to be assessed and met if the whole community pharmacy workforce is going to maximise its contribution to public health under the new contractual framework. References 1 Shann P, Hassell K. An exploration of the diversity and complexity of the pharmacy locum workforce. London: Royal Pharmaceutical Society of Great Britain; 2004. 2 Almond M. Locums – key players in workforce – cast adrift as contract launched. Pharm J 2005;274:420. 3 Bishop DH. A lack of appreciation of what really happens. Pharm J 2005;274:451.

Blastocyst environment and its influence on offspring cardiovascular health:the heart of the matter

The development of adult-onset diseases such as type II diabetes, obesity and cardiovascular disease is traditionally attributed to adult lifestyle characteristics such as a lack of physical exercise, poor diet and smoking. However, evidence from both human and animal model studies has demonstrated that environmental factors such as an imbalance or reduction in maternal nutrition during gestation can have adverse effects on offspring metabolism and cardiovascular health. The severity and nature of the phenotypic changes induced in offspring is influenced by the period of gestation manipulated. In particular, the mammalian preimplantation embryo in different animal models displays particular sensitivity to environmental factors, either in vivo (maternal diet) or in vitro (embryo culture) that is associated with the onset of cardiovascular dysfunction in adult life. The detailed mechanisms by which environmental conditions can alter postnatal cardiovascular physiology are poorly understood. However, various factors including endothelial function, vascular responsiveness, the renin-angiotensin system, kidney structure and early postnatal growth dynamics have all been recognize as potential contributors. Here, we review the relationship between preimplantation embryo environment and postnatal cardiovascular disease risk, and consider biochemical, molecular, genetic and physiological pathways implicated in this association. © 2009 The Authors Journal compilation © 2009 Anatomical Society of Great Britain and Ireland.

Impact of electric vehicles on GB electricity demand and associated benefits for system control

This paper investigates the impact that electric vehicle uptake will have on the national electricity demand of Great Britain. Data from the National Travel Survey, and the Coventry and Birmingham Low Emissions Demonstration (CABLED) are used to model an electrical demand profile in a future scenario of significant electric vehicle market penetration. These two methods allow comparison of how conventional cars are currently used, and the resulting electrical demand with simple substitution of energy source, with data showing how electric vehicles are actually being used at present. The report finds that electric vehicles are unlikely to significantly impact electricity demand in GB. The paper also aims to determine whether electric vehicles have the potential to provide ancillary services to the grid operator, and if so, the capacity for such services that would be available. Demand side management, frequency response and Short term Operating Reserve (STOR) are the services considered. The report finds that electric cars are unlikely to provide enough moveable demand peak shedding to be worthwhile. However, it is found that controlling vehicle charging would provide sufficient power control to viably act as frequency response for dispatch by the transmission system operator. This paper concludes that electric vehicles have technical potential to aid management of the transmission network without adding a significant demand burden. © 2013 IEEE.

In-vitro and in-vivo antivenin activity of 2-[2-(5,5,8a-trimethyl-2- methylene-decahydro-naphthalen-1-yl)-ethylidene]-succinaldehyde against Ophiophagus hannah venom

Objectives Curcuma zedoaroides A. Chaveerach & T. Tanee, locally known as Wan-Paya-Ngoo-Tua-Mia, is commonly used in the North-Eastern part of Thailand as a 'snakebite antidote'. The aim of this study was to isolate the active compound from the rhizome of C. zedoaroides, to determine its structure and to assess its antagonistic activity in vitro and in vivo against King cobra venom. Methods The active compound was obtained from C. zedoaroides by extraction with acetone followed by purification using column chromatography; its X-ray structure was determined. Its inhibition of venom lethality was studied in vitro in rat phrenic nerve-hemidiaphragms and in vivo in mice. Key findings The acetone extract of the Curcuma rhizomes contained a C20 dialdehyde, [2-(5,5,8a-trimethyl-2-methylene-decahydro-naphthalen-1-yl)-ethylidene] -succinaldehyde, as the major component. The isolated curcuma dialdehyde was found active in vitro and in vivo for antivenin activity against the King cobra venom. Using isolated rat phrenic nerve-hemidiaphragm preparations, a significant antagonistic effect on the inhibition of neuromuscular transmission was observed in vitro. Inhibition on muscle contraction, produced by the 4 μg/ml venom, was reversed by 2-16 μg/ml of Curcuma dialdehyde in organ bath preparations over a period of 2 h. Mice intraperitoneally injected with 0.75 mg/kg venom and dialdehyde at 100 mg/kg had a significantly increased survival time. Injection of Curcuma dialdehyde (100 mg/kg) 30 min before the subcutaneous injection of the venom resulted in a 100% survival time after 2 h compared with 0% for the control group. Conclusions The in vitro and in vivo evaluation confirmed the medicinal use of traditional snake plants against snakebites. The bioactivity is linked to an isolated molecule and not a result of synergistic effects of a mixture. The active compound was isolated and the structure fully elucidated, including its stereochemistry. This dialdehyde is a versatile chemical building block and can be easily obtained from this plant source. © 2010 Royal Pharmaceutical Society of Great Britain.

Comparative physical, mechanical and crystallographic properties of a series of gemfibrozil salts

Objectives Understanding the impact of the counterion on the properties of an acidic or basic drug may influence the choice of salt form, especially for less potent drugs with a high drug load per unit dose. The aim of this work was to determine the influence of the hydrogen bonding potential of the counterion on the crystal structure of salts of the poorly soluble, poorly compressible, acidic drug gemfibrozil and to correlate these with mechanical properties. Methods Compacts of the parent drug and the salts were used to determine Young's modulus of elasticity using beam bending tests. Crystal structures were determined previously from X-ray powder diffraction data. Key findings The free acid, tert-butylamine, 2-amino-2-methylpropan-1-ol and 2-amino-2-methylpropan-1, 3-diol salts had a common crystal packing motif of infinite hydrogen-bonded chains with cross-linking between pairs of adjacent chains. The tromethamine (trsi) salt, with different mechanical properties, had a two-dimensional sheet-like network of hydrogen bonds, with slip planes, forming a stiffer compact. Conclusions The type of counter ion is important in determining mechanical properties and could be selected to afford slip and plastic deformation. © 2010 Royal Pharmaceutical Society of Great Britain.

ImageLearn - Decoding Britain's Landscape

Abstract Ordnance Survey, our national mapping organisation, collects vast amounts of high-resolution aerial imagery covering the entirety of the country. Currently, photogrammetrists and surveyors use this to manually capture real-world objects and characteristics for a relatively small number of features. Arguably, the vast archive of imagery that we have obtained portraying the whole of Great Britain is highly underutilised and could be ‘mined’ for much more information. Over the last year the ImageLearn project has investigated the potential of "representation learning" to automatically extract relevant features from aerial imagery. Representation learning is a form of data-mining in which the feature-extractors are learned using machine-learning techniques, rather than being manually defined. At the beginning of the project we conjectured that representations learned could help with processes such as object detection and identification, change detection and social landscape regionalisation of Britain. This seminar will give an overview of the project and highlight some of our research results.