Three founder mutations in BRCA1 and BRCA2 account for about 10% of breast cancer occurring in Ashkenazi Jewish women diagnosed at 65 years of age or less (Karp et al, 1997). Other genes, such as ATM and RASH may play a role in breast cancer susceptibility, but their contribution to breast cancer incidence is presently unknown. The I1307K polymorphism in APC has recently been found to be associated with an increased risk of colorectal cancer: the odds ratio (OR) of colorectal cancer in association with this polymorphism was 1.78 for all cases and 2.86 for those diagnosed at under age 66 (Laken et al, 1997). Interestingly, in four of the eight pedigrees illustrated in that paper, possible I1307K-carrying women had been diagnosed with breast (three kindreds) or ovarian cancer (one kindred). We and others have shown that the I1307K polymorphism is over-represented in Ashkenazi Jewish women with breast cancer, compared with ethnically-matched controls (OR = 1.5, P = 0.003) . To further understand the way in which the I1307K allele might increase the risk of breast cancer, we used a historical cohort approach to compare the clinicopathological features of breast cancers occurring in those carrying the I1307K polymorphism in APC, with those seen in non-carriers. The effect of the I1307K allele on breast cancer survival was determined. MATERIALS AND METHODS CasesStudy subjects were identified in the medical records department of the Sir Mortimer B Davis Jewish-General Hospital (SMBD-JGH) and included women who self-reported as being Ashkenazi Jewish by birth and who were diagnosed with invasive breast cancer below 65 years of age between 1 January 1986 and 1 November 1995. Two hundred and nine breast cancer blocks from eligible women were identified. All but nine of these samples were used in the primary study . These samples were rendered anonymous after clinicopathological information was obtained from chart review, and therefore we have no family history available for any of these women. All pathological and molecular analyses of the samples were carried out blinded. The study was approved by the Research Ethics Committee of the SMBD-JGH. Specimens were reviewed by one pathologist (LB). Histological tumour type, grade (1-3) and axillary lymph node status (positive or negative for breast cancer metastases, with the number of positive lymph nodes recorded) was determined by specimen and chart review. The specimens were then coded and DNA was extracted from the paraffin wax-embedded blocks using standard techniques. We used tumour tissue as a source of DNA, and it is possible that I1307K polymorphisms detected could represent somatic mutations. However, loss of heterozygosity (LOH) is not common on 5q in breast cancer (Thompson et al, 1993;Devilee and Cornelisse, 1994;Medeiros et al, 1994) and no shortened forms of the APC protein were observed in cell lines Summary The I1307K polymorphism in APC has been found to predispose to colorectal cancer in Ashkenazi Jews, and has recently been associated with an increased risk...

The bronchiectasis severity index derived from these models was composed of prior hospitalisation (5 points), MRC dyspnoea score (0-3 points), FEV 1 (0-3 points), bacterial colonisation (0-3 points) Age (0-6 points) BMI <18.5 (2 points) Exacerbation frequency (0-2 points) and radiological extent (1 point). The AUC for mortality was 0.80 (0.74-0.86) and the AUC for hospitalisation was 0.88 (0.84-0.91). There was a clear difference in exacerbation frequency and quality of life using the St. Georges Respiratory Questionnaire between patients classified as low, intermediate and high risk by the score (p < 0.0001 for all comparisons).In the validation cohorts, the AUC for mortality ranged from 0.81-0.84 and for hospitalisation was AUC 0.80-0.88. Conclusions The bronchiectasis severity index identifies patients at risk of future mortality, hospital admissions and exacerbations. Background Primary ciliary dyskinesia (PCD) is an inherited disease related to ciliary dysfunction, with heterogeneity in clinical presentation, prognosis and ciliary ultrastructure. Our study aimed to comprehensively characterise a large cohort with respect to ciliary ultrastructure, beat frequency, sputum microbiology, mortality and lung function decline. Method A cohort of 100 adult PCD patients was identified at a tertiary respiratory centre. A retrospective analysis of clinical age at presentation and diagnosis alongside ciliary ultrastructure, nasal nitric oxide, beat frequency, sputum microbiology, lung function at diagnosis and follow-up and mortality were recorded. Non-parametric multi-parameter analysis of variance and Spearman rank correlation statistical analysis was performed to identify significant associations with decline in lung function (FEV1%/year). Median duration of follow-up was 7.5years (range 2-30years). Results Overall mortality was 4% (median age of death 55years). 12% of patients had a central pair/transposition defect, 37% missing outer dynein arms, 15% missing inner dynein arms, 28% no arms, and 3% had normal ultrastructure. There was no significant correlation between ciliary ultrastructure, beat frequency (range 0-13.9Hz) and nasal nitric oxide with clinical age at presentation (range 1-26 years) and diagnosis (range 1-72 years) or lung function at presentation and decline with followup. There was additionally no significant association between sputum isolation including Pseudomonas aeruginosa with lung function decline. 44% of patients had Pseudomonas aeruginosa chronic infection. The incidence of NTM colonisation was low (4%). Aspergillus species colonisation was additionally low (5%). The average lung function decline in the cohort was 1.45% FEV1/year. Conclusions Comprehensive characterisation of an adult PCD cohort with ciliary ultrastructure, light microscopy, clinical presentation and follow-up data shows a relatively favourable outcome with optimum care. Ciliary ultrastructure, beat frequency and nasal nitric oxide does not predict prognosis. Contrary to parallel diagnoses such as cystic fibrosis and adult...

of secondary prevention on discharge were then sequentially added to models to assess the extent to which they explained the mortality difference. Results 300,146 patients with a first MI were identified. 34,027 (11.3%) had COPD. In-hospital mortality was greater for COPD patients after a STEMI (see Table 1), this difference was reduced after adjusting for in-hospital factors. Mortality was also greater for COPD patients at 180 days; this was not reduced after adjustment for in-hospital factors, but was reduced after adjusting for use of secondary prevention. In-hospital mortality was also greater for COPD patients after a non-STEMI, this was reduced after adjusting for in-hospital factors. Mortality at 180-days after a non-STEMI was greater for COPD patients, this was reduced after adjusting for in-hospital factors, but not after adjusting for use of secondary prevention. Conclusions Improved recognition and timely use of reperfusion treatments after a STEMI may significantly reduce the in-hospital mortality for COPD patients. Longer term mortality in COPD patients after a STEMI may be improved by increased use of secondary prevention drugs. Increased use of timely angiography may improve mortality for COPD patients after a non-STEMI. Mesenchymal stromal cells (MSCs) are inherently tumour-homing and can be isolated, expanded and transduced, making them viable candidates for cell therapy. This tumour-tropism has been used to deliver anti-cancer therapies to various tumour models in several organs. In a previous study we have shown that MIF is the key director of MSC migration and infiltration towards tumour cells. We have shown this major role for MIF (mainly via CXCR4), using in vitro migration and invasion assays, in presence of different receptor inhibitors and achieving a drastic decrease in both processes using MIF inhibitor. Importantly we show that knock down of either CXCR4 or MIF abrogates MSC homing to tumours in an in vivo pulmonary metastasis model, confirming the in vitro 2D and 3D assays. In this study we define the mechanism behind MIF stimulation of MSC homing to tumours. We show that MIF upregulates other cytokines involved in chemotaxis, such as IL6, IL8 and CCL2 and upregulates MIF as well, amplifying the initial trigger and generating a positive feedback loop. However when inhibiting those cytokines individually, we never achieved a decrease in migration as drastic as for MIF inhibition. This suggests that the up-regulation of this set of cytokines would lead to chemoattraction of leucocytes to the site of the tumour, which was observed in a 3D model. Therefore, MIF trigger is amplified by its own upregulation in MSCs via a positive feedback loop, confirming again our previous findings and its key role as a regulator of MSC homing to tumours. This improved understanding of MSC tumour tropism will further enable development of novel cellular therapies for cancers. S109 MESENCHYMAL STEM CELLS EXPRESSING FULL LENGTH TRAIL -A PROMISING THERAPY FOR CANCERZQ Yuan, KK Kolluri, SM Janes. University ...