Breast cancer is stratified into four distinct clinical subtypes, using three key biomarkers (Her2/Neu gene status, Estrogen and Progesterone receptor status). However, each subtype is a heterogeneous group, displaying significant variation in survival rates and treatment response. New biomarkers are required to provide more precise stratification of breast cancer cohorts to inform personalised treatment options/predict outcomes. Tip60 is a member of the MYST sub-family of histone acetyltransferases (HATs), and is directly involved in genome maintenance, gene regulation and DNA damage response/repair pathways (key chemotherapeutic influencing mechanisms). We aimed to determine if quantifying Tip60 staining patterns improved breast cancer stratification. We defined Tip60 protein in vivo, quantifying location (cytoplasmic, nuclear), percent of cells and staining intensity in a breast cancer tissue microarray (n = 337). A significant association of specific Tip60 staining patterns with breast cancer subtype, ER or PR status and Tumour grade was found. Importantly, low Tip60 mRNA expression correlated with poor overall survival and relapse free survival. We found Tip60 is a biomarker able to stratify breast cancer patients, and low Tip60 expression is a significant risk factor indicating a higher chance of disease reoccurrence. This work highlights Tip60 regulation as a key factor influencing the development of breast cancer.

BACKGROUND:Argonaute-2 (Ago2) is an essential component of microRNA biogenesis implicated in tumourigenesis. However Ago2 expression and localisation in breast cancer remains undetermined. The aim was to define Ago2 expression (mRNA and protein) and localisation in breast cancer, and investigate associations with clinicopathological details.METHODS:Ago2 protein was stained in breast cancer cell lines and tissue microarrays (TMAs), with intensity and localization assessed. Staining intensity was correlated with clinicopathological details. Using independent databases, Ago2 mRNA expression and gene alterations in breast cancer were investigated.RESULTS:In the breast cancer TMAs, 4 distinct staining intensities were observed (Negative, Weak, Moderate, Strong), with 64.2% of samples stained weak or negatively for Ago2 protein. An association was found between strong Ago2 staining and, the Her2 positive or basal subtypes, and between Ago2 intensity and receptor status (Estrogen or Progesterone). In tumours Ago2 mRNA expression correlated with reduced relapse free survival. Conversely, Ago2 mRNA was expressed significantly lower in SK-BR-3 (HER2 positive) and BT-20 (Basal/Triple negative) cell lines. Interestingly, high levels of Ago2 gene amplification (10-27%) were observed in breast cancer across multiple patient datasets. Importantly, knowledge of Ago2 expression improves predictions of breast cancer subtype by 20%, ER status by 15.7% and PR status by 17.5%.CONCLUSIONS:Quantification of Ago2 improves the stratification of breast cancer and suggests a differential role for Ago2 in breast cancer subtypes, based on levels and cellular localisation. Further investigation of the mechanisms affecting Ago2 dysregulation will reveal insights into the molecular differences underpinning breast cancer subtypes.

Objectives: Minimally-Invasive Parathyroidectomy (MIP) is the gold standard treatment of primary hyperparathyroidism in single-gland disease with adequate pre-operative localization. The study aim was to evaluate the effect of concomitant thyroid pathology on the accuracy of pre-operative localization for primary hyperparathyroidism and impact on the surgical approach. Methods: A retrospective cohort analysis of patients undergoing surgical intervention for parathyroid disease in a tertiary referral center from 1999 to June 2014 was conducted. Results: Of 429 parathyroidectomies performed on 424 patients, coexistent thyroid pathology was identified in 68 patients (16%). The sensitivity of pre-operative localization of parathyroid pathology in these patients was considerably lower than in patients without concurrent thyroid disease: ultrasonography 55% vs 63%, 99mTc-sestamibi scintigraphy 50% vs 60% and CT 47% vs 49%. Single-gland disease was present in 58 patients (85%), but correctly identified on pre-operative imaging in only 43%. Of these 58 patients, 45 (66%) required Bilateral Neck Exploration (BNE), with MIP in 23 (34%) with a conversion rate of 13%. All conversions resulted from intra-operative identification of thyroid disease. Of the remaining open procedures, 40 (88%) were conducted with simultaneous thyroid lobectomy/total thyroidectomy, 2 (4%) due to multi-nodular goitre, and 3 to thyroiditis and thyroid nodules/cysts. The biochemical cure rate was 100%. In 84 months median follow-up, no patient experienced persistent or recurrent hypercalcemia, or required re-intervention. Conclusion: Concurrent thyroid pathology reduces the sensitivity of pre-operative localization of parathyroid pathology and results in higher rates of open parathyroidectomy in single-gland disease.

Jennifer Ferguson2, Guy Stevens1, Robert Hills2, Kate Gower Thomas1 1Breast Test Wales, Cardiff, UK; 2Cardiff University School of Medicine, Cardiff, UK Correspondence: Jennifer Ferguson Introduction To determine the rate and classification of interval breast cancer (IC) in the two years preceeding and following the introduction of digital mammography in 2011 in a national screening programme. Methods Two 2-year bands were used to ensure completed data for pre and post digital groups. Retrospective analysis of a prospectively collected database of IC was undertaken, identifying women who had undergone screening in the two years prior to and after the introduction of digital screening mammography (1.1.10 until 31.12.11 and 1.1.12 until 31.12.13). Chi squared analysis was used to compare the rate between the two groups and the rate of false negative (FN) and minimal signs (MS) categories considered together. Results Of 87,868 screened before digital between 1.1.10 and 31.12.11, 103 developed IC (0.12%) and of 100,672 screened with digital between 1.1.12 and 31.12.13, 145 developed IC (0.14%) (p = 0.12). Those women with FN and MS interval cancer numbered 17 (16.5%) predigital and 41 (28.3%) with digital; (p = 0.04). The number of true IC was similar in the pre (49.5%) and post (46.9%) groups. Conclusion The rate if IC is similar to the NHSBSP standard (1.2 per 1000 women screened). Despite earlier groups indicating that digital technology will lessen the number of IC, especially those ‘missed’ (FN and MS groups) which are often asymmetric densities and poorly defined masses, this has not been found in our study. The reasons for this will be discussed and examples will be shown.

Background. Every new scientific field can be traced back to a single, seminal publication. Therefore, a bibliometric analysis can yield significant insights into the history and potential future of a research field. This year marks 21 years since that first ground-breaking microRNA (miRNA) publication. Here, we make the case that the miRNA field is mature, utilising bibliometrics.Methods. Utilising the Web of Science™ (WoS) database publication and citation information, we charted the history of miRNA-related publications, describing and dissecting contributions by publication type (plus category, pay-per-view or open access), journal (highlighting dominant journals), by country, citations and languages.Results. We found that the United States of America (USA) publishes the most miRNA papers, followed by China and Germany. Significantly, publications attributed to the USA also receive the most citations per publication, followed by a close grouping of England, Germany and France. We also describe the relevance and acceptance of the miRNA field to different research areas, through its uptake in areas from oncology to plant sciences. Exploring the recent momentous change in publishing, we find that although pay-per view articles vastly out-number open-access articles, the citation rate of pay-per-view articles is currently less than double that of open-access.Conclusions. We believe the trends described here represent the typical evolution of a research field. By analysing publications, citations and distribution patterns, key moments in the evolution of this research area are recognised, indicating the maturation of the miRNA field and providing guidance for future research endeavours.