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BACKGROUND Increases in cardiac troponin (cTn) in coronavirus disease 2019 (COVID-19) have been associated with worse prognosis. Nonetheless, data about the significance of cTn in elderly subjects with COVID-19 are lacking. METHODS From a registry of consecutive patients with COVID-19 admitted to a hub hospital in Italy from 25/02/2020 to 03/07/2020, we selected those ≥ 60 year-old and with cTnI measured within three days from the molecular diagnosis of SARS-CoV-2 infection. When available, a second cTnI value within 48 h was also extracted. The relationship between increased cTnI and all-cause in-hospital mortality was evaluated by a Cox regression model and restricted cubic spline functions with three knots. RESULTS Of 343 included patients (median age: 75.0 (68.0−83.0) years, 34.7% men), 88 (25.7%) had cTnI above the upper-reference limit (0.046 µg/L). Patients with increased cTnI had more comorbidities, greater impaired respiratory exchange and higher inflammatory markers on admission than those with normal cTnI. Furthermore, they died more (73.9%vs. 37.3%, P < 0.001) over 15 (6−25) days of hospitalization. The association of elevated cTnI with mortality was confirmed by the adjusted Cox regression model (HR = 1.61, 95%CI: 1.06−2.52, P = 0.039) and was linear until 0.3 µg/L, with a subsequent plateau. Of 191 (55.7%) patients with a second cTnI measurement, 49 (25.7%) had an increasing trend, which was not associated with mortality (univariate HR = 1.39, 95%CI: 0.87−2.22, P = 0.265). CONCLUSIONS In elderly COVID-19 patients, an initial increase in cTn is common and predicts a higher risk of death. Serial cTn testing may not confer additional prognostic information.

The SARS-CoV-2 infection causes severe respiratory involvement (COVID-19) in 5–20% of patients through initial immune derangement, followed by intense cytokine production and vascular leakage. Evidence of immune involvement point to the participation of T, B, and NK cells in the lack of control of virus replication leading to COVID-19. NK cells contribute to early phases of virus control and to the regulation of adaptive responses. The precise mechanism of NK cell dysregulation is poorly understood, with little information on tissue margination or turnover. We investigated these aspects by multiparameter flow cytometry in a cohort of 28 patients hospitalized with early COVID-19. Relevant decreases in CD56brightCD16+/- NK subsets were detected, with a shift of circulating NK cells toward more mature CD56dimCD16+KIR+NKG2A+ and “memory” KIR+CD57+CD85j+ cells with increased inhibitory NKG2A and KIR molecules. Impaired cytotoxicity and IFN-γ production were associated with conserved expression of natural cytotoxicity receptors and perforin. Moreover, intense NK cell activation with increased HLA-DR and CD69 expression was associated with the circulation of CD69+CD103+ CXCR6+ tissue-resident NK cells and of CD34+DNAM-1brightCXCR4+ inflammatory precursors to mature functional NK cells. Severe disease trajectories were directly associated with the proportion of CD34+DNAM-1brightCXCR4+ precursors and inversely associated with the proportion of NKG2D+ and of CD103+ NK cells. Intense NK cell activation and trafficking to and from tissues occurs early in COVID-19, and is associated with subsequent disease progression, providing an insight into the mechanism of clinical deterioration. Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches., Author summary This is a detailed study of activating and inhibitory receptors in NK cells of COVID-19 patients when first admitted to the hospital for respiratory insufficiency. NK cells are known to be the first line of defense against invading viruses, and regulate downstream B and T cell responses, including antibody production. We observed intense NK cell activation with decreased functional activity, as well as intense circulation of putative tissue resident CD69+CD103+CXCR6+ NK cells, with a related surge in inflammatory CD34+ precursors from the bone marrow. The findings suggest that there is unprecedented trafficking of NK cells from peripheral tissues, their increased death with recruitment of emergency precursors from the bone marrow, and a relationship with the subsequent course of the disease of the patients. This in turn suggests possible areas of treatment and prevention.

As most erb-b2 receptor tyrosine kinase 2 (HER2)-positive breast cancer (BC) patients currently receive dual HER2-targeting added to neoadjuvant chemotherapy, improved methods for identifying individual response, and assisting post-surgical salvage therapy, are needed. Herein, we evaluated the 41-gene classifier trastuzumab advantage risk model (TRAR) as a predictive marker for patients enrolled in the NeoSphere trial. TRAR scores were computed from RNA of 350 pre- and 166 post-treatment tumor specimens. Overall, TRAR score was significantly associated with pathological complete response (pCR) rate independently of other predictive clinico-pathological variables. Separate analyses according to estrogen receptor (ER) status showed a significant association between TRAR score and pCR in ER-positive specimens but not in ER-negative counterparts. Among ER-positive BC patients not achieving a pCR, those with TRAR-low scores in surgical specimens showed a trend for lower distant event-free survival. In conclusion, in HER2-positive/ER-positive BC, TRAR is an independent predictor of pCR and represents a promising tool to select patients responsive to anti-HER2-based neoadjuvant therapy and to assist treatment escalation and de-escalation strategies in this setting. This article is protected by copyright. All rights reserved.

Little is known on whether melanocortin 1 receptor (MC1R) associated cutaneous melanoma (CM) risk varies depending on histological subtype and body site, and whether tumour thickness at diagnosis (the most important prognostic factor for CM patients) differs between MC1R variant carriers and wild-type individuals. We studied the association between MC1R variants and CM risk by histological subtype, body site, and Breslow thickness, using the database of the M-SKIP project. We pooled individual data from 15 case-control studies conducted during 2005-2015 in Europe and the USA. Study-specific, multi-adjusted odds ratios were pooled into summary odds ratios (SOR) and 95% confidence intervals (CI) using random-effects models. Six thousand eight hundred ninety-one CM cases and 5555 controls were included. CM risk was increased among MC1R variant carriers vs. wild-type individuals. The increase in risk was comparable across histological subtypes (SOR for any variant vs. wild-type ranged between 1.57 and 1.70, always statistical significant) except acral lentiginous melanoma (ALM), for which no association emerged; and slightly greater on chronically (1.74, 95% CI 1.47-2.07) than intermittently (1.55, 95% CI 1.34-1.78) sun-exposed skin. CM risk was greater for those carrying 'R' vs. 'r' variants; correlated with the number of variants; and was more evident among individuals not showing the red hair colour phenotype. Breslow thickness was not associated with MC1R status. MC1R variants were associated with an increased risk of CM of any histological subtype (except ALM) and occurring on both chronically and intermittently sun-exposed skin. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Table of contents O1 Tumour heterogeneity: what does it mean? Dow-Mu Koh O2 Skeletal sequelae in adult survivors of childhood cancer Sue Creviston Kaste O3 Locoregional effects of breast cancer treatment Sarah J Vinnicombe O4 Imaging of cancer therapy-induced CNS toxicity Giovanni Morana, Andrea Rossi O5 Screening for lung cancer Christian J. Herold O6Risk stratification of lung nodules Theresa C. McLoud O7 PET imaging of pulmonary nodules Kirk A Frey O8 Transarterial tumour therapy Bernhard Gebauer O9 Interventional radiology in paediatric oncology Derek Roebuck O10 Image guided prostate interventions Jurgen J. Fütterer O11 Imaging cancer predisposition syndromes Alexander J. Towbin O12Chest and chest wall masses Thierry AG Huisman O13 Abdominal masses: good or bad? Anne MJB Smets O14 Hepatobiliary MR contrast: enhanced liver MRI for HCC diagnosis and management Giovanni Morana O15 Role of US elastography and multimodality fusion for managing patients with chronic liver disease and HCC Jeong Min Lee O16 Opportunities and challenges in imaging metastatic disease Hersh Chandarana O17 Diagnosis, treatment monitoring, and follow-up of lymphoma Marius E. Mayerhoefer, Markus Raderer, Alexander Haug O18 Managing high-risk and advanced prostate cancer Matthias Eiber O19 Immunotherapy: imaging challenges Bernhard Gebauer O20 RECIST and RECIST 1.1 Andrea Rockall O21 Challenges of RECIST in oncology imaging basics for the trainee and novice Aslam Sohaib O22 Lymphoma: PET for interim and end of treatment response assessment: a users’ guide to the Deauville Score Victoria S Warbey O23 Available resources Hebert Alberto Vargas O24 ICIS e-portal and the online learning community Dow-Mu Koh O25 Benign lesions that mimic pancreatic cancer Jay P Heiken O26 Staging and reporting pancreatic malignancies Isaac R Francis, Mahmoud, M Al-Hawary, Ravi K Kaza O27 Intraductal papillary mucinous neoplasm Giovanni Morana O28 Cystic pancreatic tumours Mirko D’Onofrio O29 Diffusion-weighted imaging of head and neck tumours Harriet C. Thoeny O30 Radiation injury in the head and neck Ann D King O31 PET/MR of paediatric brain tumours Giovanni Morana, Arnoldo Piccardo, Maria Luisa Garrè, Andrea Rossi O32 Structured reporting and beyond Hebert Alberto Vargas O33 Massachusetts General Hospital experience with structured reporting Theresa C. McLoud O34 The oncologist’s perspective: what the oncologist needs to know Nick Reed O35 Towards the cure of all children with cancer: global initiatives in pediatric oncology Carlos Rodriguez-Galindo O36 Multiparametric imaging of renal cancers Hersh Chandarana O37 Linking imaging features of renal disease and their impact on management strategies Hebert Alberto Vargas O38 Adrenals, retroperitoneum and peritoneum Isaac R Francis, Ashish P Wasnik O39 Lung and pleura Stefan Diederich O40 Advances in MRI Jurgen J. Fütterer O41 Advances in molecular imaging Wim J.G. Oyen O42 Incorporating advanced imaging, impact on treatment selection and patient outcome Cheng Lee Chaw, Nicholas van As S1 Combining ADC-histogram features improves performance of MR diffusion-weighted imaging for Lymph node characterisation in cervical cancer Igor Vieira, Frederik De Keyzer, Elleke Dresen, Sileny Han, Ignace Vergote, Philippe Moerman, Frederic Amant, Michel Koole, Vincent Vandecaveye S2 Whole-body diffusion-weighted MRI for surgical planning in patients with colorectal cancer and peritoneal metastases R Dresen, S De Vuysere, F De Keyzer, E Van Cutsem, A D’Hoore, A Wolthuis, V Vandecaveye S3 Role of apparent diffusion coefficient (ADC) diffusion-weighted MRI for predicting extra capsular extension of prostate cancer. P. Pricolo (paola.pricolo@ieo.it), S. Alessi, P. Summers, E. Tagliabue, G. Petralia S4 Generating evidence for clinical benefit of PET/CT – are management studies sufficient as surrogate for patient outcome? C. Pfannenberg, B. Gückel, SC Schüle, AC Müller, S. Kaufmann, N. Schwenzer, M. Reimold,C. la Fougere, K. Nikolaou, P. Martus S5 Heterogeneity of treatment response in skeletal metastases from breast cancer with 18F-fluoride and 18F-FDG PET GJ Cook, GK Azad, BP Taylor, M Siddique, J John, J Mansi, M Harries, V Goh S6 Accuracy of suspicious breast imaging—can we tell the patient? S Seth, R Burgul, A Seth S7 Measurement method of tumour volume changes during neoadjuvant chemotherapy affects ability to predict pathological response S Waugh, N Muhammad Gowdh, C Purdie, A Evans, E Crowe, A Thompson, S Vinnicombe S8 Diagnostic yield of CT IVU in haematuria screening F. Arfeen, T. Campion, E. Goldstraw S9 Percutaneous radiofrequency ablation of unresectable locally advanced pancreatic cancer: preliminary results D’Onofrio M, Ciaravino V, Crosara S, De Robertis R, Pozzi Mucelli R S10 Iodine maps from dual energy CT improve detection of metastases in staging examinations of melanoma patients M. Uhrig, D. Simons, H. Schlemmer S11Can contrast enhanced CT predict pelvic nodal status in malignant melanoma of the lower limb? Kate Downey S12 Current practice in the investigation for suspected Paraneoplastic Neurological Syndromes (PNS) and positive malignancy yield. S Murdoch, AS Al-adhami, S Viswanathan P1 Technical success and efficacy of Pulmonary Radiofrequency ablation: an analysis of 207 ablations S Smith, P Jennings, D Bowers, R Soomal P2 Lesion control and patient outcome: prospective analysis of radiofrequency abaltion in pulmonary colorectal cancer metastatic disease S Smith, P Jennings, D Bowers, R Soomal P3 Hepatocellular carcinoma in a post-TB patient: case of tropical infections and oncologic imaging challenges TM Mutala, AO Odhiambo, N Harish P4 Role of apparent diffusion coefficient (ADC) diffusion-weighted MRI for predicting extracapsular extension of prostate cancer P. Pricolo, S. Alessi, P. Summers, E. Tagliabue, G. Petralia P5 What a difference a decade makes; comparison of lung biopsies in Glasgow 2005 and 2015 M. Hall, M. Sproule, S. Sheridan P6 Solid pseudopapillary tumour of pancreas: imaging features of a rare neoplasm KY Thein, CH Tan, YL Thian, CM Ho P7 MDCT - pathological correlation in colon adenocarcinoma staging: preliminary experience S De Luca, C Carrera, V Blanchet, L Alarcón, E Eyheremnedy P8 Image guided biopsy of thoracic masses and reduction of pneumothorax risk: 25 years experience B K Choudhury, K Bujarbarua, G Barman P9 Tumour heterogeneity analysis of 18F-FDG-PET for characterisation of malignant peripheral nerve sheath tumours in neurofibromatosis-1 GJ Cook, E Lovat, M Siddique, V Goh, R Ferner, VS Warbey P10 Impact of introduction of vacuum assisted excision (VAE) on screen detected high risk breast lesions L Potti, B Kaye, A Beattie, K Dutton P11 Can we reduce prevalent recall rate in breast screening? AA Seth, F Constantinidis, H Dobson P12 How to reduce prevalent recall rate? Identifying mammographic lesions with low Positive Predictive Value (PPV) AA Seth (archana.seth@nhs.net), F Constantinidis, H Dobson P13 Behaviour of untreated pulmonary thrombus in oncology patients diagnosed with incidental pulmonary embolism on CT R. Bradley, G. Bozas, G. Avery, A. Stephens, A. Maraveyas P14 A one-stop lymphoma biopsy service – is it possible? S Bhuva, CA Johnson, M Subesinghe, N Taylor P15 Changes in the new TNM classification for lung cancer (8th edition, effective January 2017) LE Quint, RM Reddy, GP Kalemkerian P16 Cancer immunotherapy: a review of adequate imaging assessment G González Zapico, E Gainza Jauregui, R Álvarez Francisco, S Ibáñez Alonso, I Tavera Bahillo, L Múgica Álvarez P17 Succinate dehydrogenase mutations and their associated tumours O Francies, R Wheeler, L Childs, A Adams, A Sahdev P18 Initial experience in the usefulness of dual energy technique in the abdomen SE De Luca, ME Casalini Vañek, MD Pascuzzi, T Gillanders, PM Ramos, EP Eyheremendy P19 Recognising the serious complication of Richter’s transformation in CLL patients C Stove, M Digby P20 Body diffusion-weighted MRI in oncologic practice: truths, tricks and tips M. Nazar, M. Wirtz, MD. Pascuzzi, F. Troncoso, F. Saguier, EP. Eyheremendy P21 Methotrexate-induced leukoencephalopathy in paediatric ALL Patients D.J. Quint, L. Dang, M. Carlson, S. Leber, F. Silverstein P22 Pitfalls in oncology CT reporting. A pictorial review R Rueben, S Viswanathan P23 Imaging of perineural extension in head and neck tumours B Nazir, TH Teo, JB Khoo P24 MRI findings of molecular subtypes of breast cancer: a pictorial primer K Sharma, N Gupta, B Mathew, T Jeyakumar, K Harkins P25 When cancer can’t wait! A pictorial review of oncological emergencies K Sharma, B Mathew, N Gupta, T Jeyakumar, S Joshua P26 MRI of pancreatic neuroendocrine tumours: an approach to interpretation D Christodoulou, S Gourtsoyianni, A Jacques, N Griffin, V Goh P27 Gynaecological cancers in pregnancy: a review of imaging CA Johnson, J Lee P28 Suspected paraneoplastic neurological syndromes - review of published recommendations to date, with proposed guideline/flowchart JA Goodfellow, AS Al-adhami, S Viswanathan P29 Multi-parametric MRI of the pelvis for suspected local recurrence of prostate cancer after radical prostatectomy R Bradley P30 Utilisation of PI-RADS version 2 in multi-parametric MRI of the prostate; 12-months experience R Bradley P31 Radiological assessment of the post-chemotherapy liver A Yong, S Jenkins, G Joseph P32 Skeletal staging with MRI in breast cancer – what the radiologist needs to know S Bhuva, K Partington P33 Perineural spread of lympoma: an educational review of an unusual distribution of disease CA Johnson, S Bhuva, M Subesinghe, N Taylor P34 Visually isoattenuating pancreatic adenocarcinoma. Diagnostic imaging tools. C Carrera, A Zanfardini, S De Luca, L Alarcón, V Blanchet, EP Eyheremendy P35 Imaging of larynx cancer: when is CT, MRI or FDG PET/CT the best test? K Cavanagh, E Lau

Tumor extracellular matrix (ECM) plays a pivotal role in outcome of breast cancer (BC) patients. Overespression of 58 genes, encoding 43 structural ECM proteins, has been identified to determine a specific cluster of BC with accelerated metastatic potential only in the undifferentiated (grade III) phenotype. The scope of this study was to characterize protein repertoire able to predict patient outcome in BC according to ECM gene expression pattern and histological grade. The differential proteomic analysis has been based on 2D-DIGE, MALDI-MS, bioinformatics and immunoblotting. Results suggested a relationship among ECM remodeling, signal mechanotransduction and metabolic rewiring in BCs characterized by a specific mRNA ECM signature and identified a set of dysregulated proteins characteristic of hormone receptors expression as fibrinogen beta chain (FGB), collagen alpha-1 (VI) chain (COL6A1) and alpha-1B-glycoprotein (A1BG). Furthermore, in triple negative tumors (TN) with ECM signature, the FGG and ?5?1/?v?3 integrins increased whereas detyrosinated alpha-tubulin, and mimecan (OGN) decreased leading to unorganized integrin presentation involving focal adhesion kinase (FAK), activation of Rho GTPases associated to epithelial mesenchymal transition. In hormone receptors negative BCs characterized by a specific ECM gene cluster, the differentially regulated proteins, identified in the present study,can be potentially relevant to predict patient's outcome.

Histone deacetylases (HDAC) extensively contribute to the c-Myc oncogenic program, pointing to their inhibition as an effective strategy against c-Myc-overexpressing cancers. We, thus, studied the therapeutic activity of the new-generation pan-HDAC inhibitor ITF2357 (Givinostat®) against c-Myc-overexpressing human B-cell non-Hodgkin lymphomas (B-NHLs). ITF2357 anti-proliferative and pro-apoptotic effects were analyzed in B-NHL cell lines with c-Myc translocations (Namalwa, Raji and DOHH-2), stabilizing mutations (Raji) or post-transcriptional alterations (SU-DHL-4) in relationship to c-Myc modulation. ITF2357 significantly delayed the in vitro growth of all B-NHL cell lines by inducing G1 cell-cycle arrest, eventually followed by cell death. These events correlated with the extent of c-Myc protein, but not mRNA, downregulation, indicating the involvement of post-transcriptional mechanisms. Accordingly, c-Myc-targeting microRNAs let-7a and miR-26a were induced in all treated lymphomas and the cap-dependent translation machinery components 4E-BP1, eIF4E and eIF4G, as well as their upstream regulators, Akt and PIM kinases, were inhibited in function of the cell sensitivity to ITF2357, and, in turn, c-Myc downregulation. In vivo, ITF2357 significantly hampered the growth of Namalwa and Raji xenografts in immunodeficient mice. Noteworthy, its combination with suboptimal cyclophosphamide, achieved complete remissions in most animals and equaled or even exceeded the activity of optimal cyclophosphamide. Collectively, our findings provide the rationale for testing the clinical advantages of adding ITF2357 to current therapies for the still very ominous c-Myc-overexpressing lymphomas. They equally provide the proof-of-concept for its clinical evaluation in rational combination with the promising inhibitors of B-cell receptor and PI3K/Akt/mTOR axis currently in the process of development.

O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder A. K. Srivastava, Y. Wang, R. Huang, C. Skinner, T. Thompson, L. Pollard, T. Wood, F. Luo, R. Stevenson O2 Phenome-wide association study for smoking- and drinking-associated genes in 26,394 American women with African, Asian, European, and Hispanic descents R. Polimanti, J. Gelernter O3 Effects of prenatal environment, genotype and DNA methylation on birth weight and subsequent postnatal outcomes: findings from GUSTO, an Asian birth cohort X. Lin, I. Y. Lim, Y. Wu, A. L. Teh, L. Chen, I. M. Aris, S. E. Soh, M. T. Tint, J. L. MacIsaac, F. Yap, K. Kwek, S. M. Saw, M. S. Kobor, M. J. Meaney, K. M. Godfrey, Y. S. Chong, J. D. Holbrook, Y. S. Lee, P. D. Gluckman, N. Karnani, GUSTO study group O4 High-throughput identification of specific qt interval modulating enhancers at the SCN5A locus A. Kapoor, D. Lee, A. Chakravarti O5 Identification of extracellular matrix components inducing cancer cell migration in the supernatant of cultivated mesenchymal stem cells C. Maercker, F. Graf, M. Boutros O6 Single cell allele specific expression (ASE) IN T21 and common trisomies: a novel approach to understand DOWN syndrome and other aneuploidies G. Stamoulis, F. Santoni, P. Makrythanasis, A. Letourneau, M. Guipponi, N. Panousis, M. Garieri, P. Ribaux, E. Falconnet, C. Borel, S. E. Antonarakis O7 Role of microRNA in LCL to IPSC reprogramming S. Kumar, J. Curran, J. Blangero O8 Multiple enhancer variants disrupt gene regulatory network in Hirschsprung disease S. Chatterjee, A. Kapoor, J. Akiyama, D. Auer, C. Berrios, L. Pennacchio, A. Chakravarti O9 Metabolomic profiling for the diagnosis of neurometabolic disorders T. R. Donti, G. Cappuccio, M. Miller, P. Atwal, A. Kennedy, A. Cardon, C. Bacino, L. Emrick, J. Hertecant, F. Baumer, B. Porter, M. Bainbridge, P. Bonnen, B. Graham, R. Sutton, Q. Sun, S. Elsea O10 A novel causal methylation network approach to Alzheimer’s disease Z. Hu, P. Wang, Y. Zhu, J. Zhao, M. Xiong, David A Bennett O11 A microRNA signature identifies subtypes of triple-negative breast cancer and reveals MIR-342-3P as regulator of a lactate metabolic pathway A. Hidalgo-Miranda, S. Romero-Cordoba, S. Rodriguez-Cuevas, R. Rebollar-Vega, E. Tagliabue, M. Iorio, E. D’Ippolito, S. Baroni O12 Transcriptome analysis identifies genes, enhancer RNAs and repetitive elements that are recurrently deregulated across multiple cancer types B. Kaczkowski, Y. Tanaka, H. Kawaji, A. Sandelin, R. Andersson, M. Itoh, T. Lassmann, the FANTOM5 consortium, Y. Hayashizaki, P. Carninci, A. R. R. Forrest O13 Elevated mutation and widespread loss of constraint at regulatory and architectural binding sites across 11 tumour types C. A. Semple O14 Exome sequencing provides evidence of pathogenicity for genes implicated in colorectal cancer E. A. Rosenthal, B. Shirts, L. Amendola, C. Gallego, M. Horike-Pyne, A. Burt, P. Robertson, P. Beyers, C. Nefcy, D. Veenstra, F. Hisama, R. Bennett, M. Dorschner, D. Nickerson, J. Smith, K. Patterson, D. Crosslin, R. Nassir, N. Zubair, T. Harrison, U. Peters, G. Jarvik, NHLBI GO Exome Sequencing Project O15 The tandem duplicator phenotype as a distinct genomic configuration in cancer F. Menghi, K. Inaki, X. Woo, P. Kumar, K. Grzeda, A. Malhotra, H. Kim, D. Ucar, P. Shreckengast, K. Karuturi, J. Keck, J. Chuang, E. T. Liu O16 Modeling genetic interactions associated with molecular subtypes of breast cancer B. Ji, A. Tyler, G. Ananda, G. Carter O17 Recurrent somatic mutation in the MYC associated factor X in brain tumors H. Nikbakht, M. Montagne, M. Zeinieh, A. Harutyunyan, M. Mcconechy, N. Jabado, P. Lavigne, J. Majewski O18 Predictive biomarkers to metastatic pancreatic cancer treatment J. B. Goldstein, M. Overman, G. Varadhachary, R. Shroff, R. Wolff, M. Javle, A. Futreal, D. Fogelman O19 DDIT4 gene expression as a prognostic marker in several malignant tumors L. Bravo, W. Fajardo, H. Gomez, C. Castaneda, C. Rolfo, J. A. Pinto O20 Spatial organization of the genome and genomic alterations in human cancers K. C. Akdemir, L. Chin, A. Futreal, ICGC PCAWG Structural Alterations Group O21 Landscape of targeted therapies in solid tumors S. Patterson, C. Statz, S. Mockus O22 Genomic analysis reveals novel drivers and progression pathways in skin basal cell carcinoma S. N. Nikolaev, X. I. Bonilla, L. Parmentier, B. King, F. Bezrukov, G. Kaya, V. Zoete, V. Seplyarskiy, H. Sharpe, T. McKee, A. Letourneau, P. Ribaux, K. Popadin, N. Basset-Seguin, R. Ben Chaabene, F. Santoni, M. Andrianova, M. Guipponi, M. Garieri, C. Verdan, K. Grosdemange, O. Sumara, M. Eilers, I. Aifantis, O. Michielin, F. de Sauvage, S. Antonarakis O23 Identification of differential biomarkers of hepatocellular carcinoma and cholangiocarcinoma via transcriptome microarray meta-analysis S. Likhitrattanapisal O24 Clinical validity and actionability of multigene tests for hereditary cancers in a large multi-center study S. Lincoln, A. Kurian, A. Desmond, S. Yang, Y. Kobayashi, J. Ford, L. Ellisen O25 Correlation with tumor ploidy status is essential for correct determination of genome-wide copy number changes by SNP array T. L. Peters, K. R. Alvarez, E. F. Hollingsworth, D. H. Lopez-Terrada O26 Nanochannel based next-generation mapping for interrogation of clinically relevant structural variation A. Hastie, Z. Dzakula, A. W. Pang, E. T. Lam, T. Anantharaman, M. Saghbini, H. Cao, BioNano Genomics O27 Mutation spectrum in a pulmonary arterial hypertension (PAH) cohort and identification of associated truncating mutations in TBX4 C. Gonzaga-Jauregui, L. Ma, A. King, E. Berman Rosenzweig, U. Krishnan, J. G. Reid, J. D. Overton, F. Dewey, W. K. Chung O28 NORTH CAROLINA macular dystrophy (MCDR1): mutations found affecting PRDM13 K. Small, A. DeLuca, F. Cremers, R. A. Lewis, V. Puech, B. Bakall, R. Silva-Garcia, K. Rohrschneider, M. Leys, F. S. Shaya, E. Stone O29 PhenoDB and genematcher, solving unsolved whole exome sequencing data N. L. Sobreira, F. Schiettecatte, H. Ling, E. Pugh, D. Witmer, K. Hetrick, P. Zhang, K. Doheny, D. Valle, A. Hamosh O30 Baylor-Johns Hopkins Center for Mendelian genomics: a four year review S. N. Jhangiani, Z. Coban Akdemir, M. N. Bainbridge, W. Charng, W. Wiszniewski, T. Gambin, E. Karaca, Y. Bayram, M. K. Eldomery, J. Posey, H. Doddapaneni, J. Hu, V. R. Sutton, D. M. Muzny, E. A. Boerwinkle, D. Valle, J. R. Lupski, R. A. Gibbs O31 Using read overlap assembly to accurately identify structural genetic differences in an ashkenazi jewish trio S. Shekar, W. Salerno, A. English, A. Mangubat, J. Bruestle O32 Legal interoperability: a sine qua non for international data sharing A. Thorogood, B. M. Knoppers, Global Alliance for Genomics and Health - Regulatory and Ethics Working Group O33 High throughput screening platform of competent sineups: that can enhance translation activities of therapeutic target H. Takahashi, K. R. Nitta, A. Kozhuharova, A. M. Suzuki, H. Sharma, D. Cotella, C. Santoro, S. Zucchelli, S. Gustincich, P. Carninci O34 The undiagnosed diseases network international (UDNI): clinical and laboratory research to meet patient needs J. J. Mulvihill, G. Baynam, W. Gahl, S. C. Groft, K. Kosaki, P. Lasko, B. Melegh, D. Taruscio O36 Performance of computational algorithms in pathogenicity predictions for activating variants in oncogenes versus loss of function mutations in tumor suppressor genes R. Ghosh, S. Plon O37 Identification and electronic health record incorporation of clinically actionable pharmacogenomic variants using prospective targeted sequencing S. Scherer, X. Qin, R. Sanghvi, K. Walker, T. Chiang, D. Muzny, L. Wang, J. Black, E. Boerwinkle, R. Weinshilboum, R. Gibbs O38 Melanoma reprogramming state correlates with response to CTLA-4 blockade in metastatic melanoma T. Karpinets, T. Calderone, K. Wani, X. Yu, C. Creasy, C. Haymaker, M. Forget, V. Nanda, J. Roszik, J. Wargo, L. Haydu, X. Song, A. Lazar, J. Gershenwald, M. Davies, C. Bernatchez, J. Zhang, A. Futreal, S. Woodman O39 Data-driven refinement of complex disease classification from integration of heterogeneous functional genomics data in GeneWeaver E. J. Chesler, T. Reynolds, J. A. Bubier, C. Phillips, M. A. Langston, E. J. Baker O40 A general statistic framework for genome-based disease risk prediction M. Xiong, L. Ma, N. Lin, C. Amos O41 Integrative large-scale causal network analysis of imaging and genomic data and its application in schizophrenia studies N. Lin, P. Wang, Y. Zhu, J. Zhao, V. Calhoun, M. Xiong O42 Big data and NGS data analysis: the cloud to the rescue O. Dobretsberger, M. Egger, F. Leimgruber O43 Cpipe: a convergent clinical exome pipeline specialised for targeted sequencing S. Sadedin, A. Oshlack, Melbourne Genomics Health Alliance O44 A Bayesian classification of biomedical images using feature extraction from deep neural networks implemented on lung cancer data V. A. A. Antonio, N. Ono, Clark Kendrick C. Go O45 MAV-SEQ: an interactive platform for the Management, Analysis, and Visualization of sequence data Z. Ahmed, M. Bolisetty, S. Zeeshan, E. Anguiano, D. Ucar O47 Allele specific enhancer in EPAS1 intronic regions may contribute to high altitude adaptation of Tibetans C. Zeng, J. Shao O48 Nanochannel based next-generation mapping for structural variation detection and comparison in trios and populations H. Cao, A. Hastie, A. W. Pang, E. T. Lam, T. Liang, K. Pham, M. Saghbini, Z. Dzakula O49 Archaic introgression in indigenous populations of Malaysia revealed by whole genome sequencing Y. Chee-Wei, L. Dongsheng, W. Lai-Ping, D. Lian, R. O. Twee Hee, Y. Yunus, F. Aghakhanian, S. S. Mokhtar, C. V. Lok-Yung, J. Bhak, M. Phipps, X. Shuhua, T. Yik-Ying, V. Kumar, H. Boon-Peng O50 Breast and ovarian cancer prevention: is it time for population-based mutation screening of high risk genes? I. Campbell, M.-A. Young, P. James, Lifepool O53 Comprehensive coverage from low DNA input using novel NGS library preparation methods for WGS and WGBS C. Schumacher, S. Sandhu, T. Harkins, V. Makarov O54 Methods for large scale construction of robust PCR-free libraries for sequencing on Illumina HiSeqX platform H. DoddapaneniR. Glenn, Z. Momin, B. Dilrukshi, H. Chao, Q. Meng, B. Gudenkauf, R. Kshitij, J. Jayaseelan, C. Nessner, S. Lee, K. Blankenberg, L. Lewis, J. Hu, Y. Han, H. Dinh, S. Jireh, K. Walker, E. Boerwinkle, D. Muzny, R. Gibbs O55 Rapid capture methods for clinical sequencing J. Hu, K. Walker, C. Buhay, X. Liu, Q. Wang, R. Sanghvi, H. Doddapaneni, Y. Ding, N. Veeraraghavan, Y. Yang, E. Boerwinkle, A. L. Beaudet, C. M. Eng, D. M. Muzny, R. A. Gibbs O56 A diploid personal human genome model for better genomes from diverse sequence data K. C. C. Worley, Y. Liu, D. S. T. Hughes, S. C. Murali, R. A. Harris, A. C. English, X. Qin, O. A. Hampton, P. Larsen, C. Beck, Y. Han, M. Wang, H. Doddapaneni, C. L. Kovar, W. J. Salerno, A. Yoder, S. Richards, J. Rogers, J. R. Lupski, D. M. Muzny, R. A. Gibbs O57 Development of PacBio long range capture for detection of pathogenic structural variants Q. Meng, M. Bainbridge, M. Wang, H. Doddapaneni, Y. Han, D. Muzny, R. Gibbs O58 Rhesus macaques exhibit more non-synonymous variation but greater impact of purifying selection than humans R. A. Harris, M. Raveenedran, C. Xue, M. Dahdouli, L. Cox, G. Fan, B. Ferguson, J. Hovarth, Z. Johnson, S. Kanthaswamy, M. Kubisch, M. Platt, D. Smith, E. Vallender, R. Wiseman, X. Liu, J. Below, D. Muzny, R. Gibbs, F. Yu, J. Rogers O59 Assessing RNA structure disruption induced by single-nucleotide variation J. Lin, Y. Zhang, Z. Ouyang P1 A meta-analysis of genome-wide association studies of mitochondrial dna copy number A. Moore, Z. Wang, J. Hofmann, M. Purdue, R. Stolzenberg-Solomon, S. Weinstein, D. Albanes, C.-S. Liu, W.-L. Cheng, T.-T. Lin, Q. Lan, N. Rothman, S. Berndt P2 Missense polymorphic genetic combinations underlying down syndrome susceptibility E. S. Chen P4 The evaluation of alteration of ELAM-1 expression in the endometriosis patients H. Bahrami, A. Khoshzaban, S. Heidari Keshal P5 Obesity and the incidence of apolipoprotein E polymorphisms in an assorted population from Saudi Arabia population K. K. R. Alharbi P6 Genome-associated personalized antithrombotical therapy for patients with high risk of thrombosis and bleeding M. Zhalbinova, A. Akilzhanova, S. Rakhimova, M. Bekbosynova, S. Myrzakhmetova P7 Frequency of Xmn1 polymorphism among sickle cell carrier cases in UAE population M. Matar P8 Differentiating inflammatory bowel diseases by using genomic data: dimension of the problem and network organization N. Mili, R. Molinari, Y. Ma, S. Guerrier P9 Vulnerability of genetic variants to the risk of autism among Saudi children N. Elhawary, M. Tayeb, N. Bogari, N. Qotb P10 Chromatin profiles from ex vivo purified dopaminergic neurons establish a promising model to support studies of neurological function and dysfunction S. A. McClymont, P. W. Hook, L. A. Goff, A. McCallion P11 Utilization of a sensitized chemical mutagenesis screen to identify genetic modifiers of retinal dysplasia in homozygous Nr2e3rd7 mice Y. Kong, J. R. Charette, W. L. Hicks, J. K. Naggert, L. Zhao, P. M. Nishina P12 Ion torrent next generation sequencing of recessive polycystic kidney disease in Saudi patients B. M. Edrees, M. Athar, F. A. Al-Allaf, M. M. Taher, W. Khan, A. Bouazzaoui, N. A. Harbi, R. Safar, H. Al-Edressi, A. Anazi, N. Altayeb, M. A. Ahmed, K. Alansary, Z. Abduljaleel P13 Digital expression profiling of Purkinje neurons and dendrites in different subcellular compartments A. Kratz, P. Beguin, S. Poulain, M. Kaneko, C. Takahiko, A. Matsunaga, S. Kato, A. M. Suzuki, N. Bertin, T. Lassmann, R. Vigot, P. Carninci, C. Plessy, T. Launey P14 The evolution of imperfection and imperfection of evolution: the functional and functionless fractions of the human genome D. Graur P16 Species-independent identification of known and novel recurrent genomic entities in multiple cancer patients J. Friis-Nielsen, J. M. Izarzugaza, S. Brunak P18 Discovery of active gene modules which are densely conserved across multiple cancer types reveal their prognostic power and mutually exclusive mutation patterns B. S. Soibam P19 Whole exome sequencing of dysplastic leukoplakia tissue indicates sequential accumulation of somatic mutations from oral precancer to cancer D. Das, N. Biswas, S. Das, S. Sarkar, A. Maitra, C. Panda, P. Majumder P21 Epigenetic mechanisms of carcinogensis by hereditary breast cancer genes J. J. Gruber, N. Jaeger, M. Snyder P22 RNA direct: a novel RNA enrichment strategy applied to transcripts associated with solid tumors K. Patel, S. Bowman, T. Davis, D. Kraushaar, A. Emerman, S. Russello, N. Henig, C. Hendrickson P23 RNA sequencing identifies gene mutations for neuroblastoma K. Zhang P24 Participation of SFRP1 in the modulation of TMPRSS2-ERG fusion gene in prostate cancer cell lines M. Rodriguez-Dorantes, C. D. Cruz-Hernandez, C. D. P. Garcia-Tobilla, S. Solorzano-Rosales P25 Targeted Methylation Sequencing of Prostate Cancer N. Jäger, J. Chen, R. Haile, M. Hitchins, J. D. Brooks, M. Snyder P26 Mutant TPMT alleles in children with acute lymphoblastic leukemia from México City and Yucatán, Mexico S. Jiménez-Morales, M. Ramírez, J. Nuñez, V. Bekker, Y. Leal, E. Jiménez, A. Medina, A. Hidalgo, J. Mejía P28 Genetic modifiers of Alström syndrome J. Naggert, G. B. Collin, K. DeMauro, R. Hanusek, P. M. Nishina P31 Association of genomic variants with the occurrence of angiotensin-converting-enzyme inhibitor (ACEI)-induced coughing among Filipinos E. M. Cutiongco De La Paz, R. Sy, J. Nevado, P. Reganit, L. Santos, J. D. Magno, F. E. Punzalan , D. Ona , E. Llanes, R. L. Santos-Cortes , R. Tiongco, J. Aherrera, L. Abrahan, P. Pagauitan-Alan; Philippine Cardiogenomics Study Group P32 The use of “humanized” mouse models to validate disease association of a de novo GARS variant and to test a novel gene therapy strategy for Charcot-Marie-Tooth disease type 2D K. H. Morelli, J. S. Domire, N. Pyne, S. Harper, R. Burgess P34 Molecular regulation of chondrogenic human induced pluripotent stem cells M. A. Gari, A. Dallol, H. Alsehli, A. Gari, M. Gari, A. Abuzenadah P35 Molecular profiling of hematologic malignancies: implementation of a variant assessment algorithm for next generation sequencing data analysis and clinical reporting M. Thomas, M. Sukhai, S. Garg, M. Misyura, T. Zhang, A. Schuh, T. Stockley, S. Kamel-Reid P36 Accessing genomic evidence for clinical variants at NCBI S. Sherry, C. Xiao, D. Slotta, K. Rodarmer, M. Feolo, M. Kimelman, G. Godynskiy, C. O’Sullivan, E. Yaschenko P37 NGS-SWIFT: a cloud-based variant analysis framework using control-accessed sequencing data from DBGAP/SRA C. Xiao, E. Yaschenko, S. Sherry P38 Computational assessment of drug induced hepatotoxicity through gene expression profiling C. Rangel-Escareño, H. Rueda-Zarate P40 Flowr: robust and efficient pipelines using a simple language-agnostic approach;ultraseq; fast modular pipeline for somatic variation calling using flowr S. Seth, S. Amin, X. Song, X. Mao, H. Sun, R. G. Verhaak, A. Futreal, J. Zhang P41 Applying “Big data” technologies to the rapid analysis of heterogenous large cohort data S. J. Whiite, T. Chiang, A. English, J. Farek, Z. Kahn, W. Salerno, N. Veeraraghavan, E. Boerwinkle, R. Gibbs P42 FANTOM5 web resource for the large-scale genome-wide transcription start site activity profiles of wide-range of mammalian cells T. Kasukawa, M. Lizio, J. Harshbarger, S. Hisashi, J. Severin, A. Imad, S. Sahin, T. C. Freeman, K. Baillie, A. Sandelin, P. Carninci, A. R. R. Forrest, H. Kawaji, The FANTOM Consortium P43 Rapid and scalable typing of structural variants for disease cohorts W. Salerno, A. English, S. N. Shekar, A. Mangubat, J. Bruestle, E. Boerwinkle, R. A. Gibbs P44 Polymorphism of glutathione S-transferases and sulphotransferases genes in an Arab population A. H. Salem, M. Ali, A. Ibrahim, M. Ibrahim P46 Genetic divergence of CYP3A5*3 pharmacogenomic marker for native and admixed Mexican populations J. C. Fernandez-Lopez, V. Bonifaz-Peña, C. Rangel-Escareño, A. Hidalgo-Miranda, A. V. Contreras P47 Whole exome sequence meta-analysis of 13 white blood cell, red blood cell, and platelet traits L. Polfus, CHARGE and NHLBI Exome Sequence Project Working Groups P48 Association of adipoq gene with type 2 diabetes and related phenotypes in african american men and women: The jackson heart study S. Davis, R. Xu, S. Gebeab, P Riestra, A Gaye, R. Khan, J. Wilson, A. Bidulescu P49 Common variants in casr gene are associated with serum calcium levels in koreans S. H. Jung, N. Vinayagamoorthy, S. H. Yim, Y. J. Chung P50 Inference of multiple-wave population admixture by modeling decay of linkage disequilibrium with multiple exponential functions Y. Zhou, S. Xu P51 A Bayesian framework for generalized linear mixed models in genome-wide association studies X. Wang, V. Philip, G. Carter P52 Targeted sequencing approach for the identification of the genetic causes of hereditary hearing impairment A. A. Abuzenadah, M. Gari, R. Turki, A. Dallol P53 Identification of enhancer sequences by ATAC-seq open chromatin profiling A. Uyar, A. Kaygun, S. Zaman, E. Marquez, J. George, D. Ucar P54 Direct enrichment for the rapid preparation of targeted NGS libraries C. L. Hendrickson, A. Emerman, D. Kraushaar, S. Bowman, N. Henig, T. Davis, S. Russello, K. Patel P56 Performance of the Agilent D5000 and High Sensitivity D5000 ScreenTape assays for the Agilent 4200 Tapestation System R. Nitsche, L. Prieto-Lafuente P57 ClinVar: a multi-source archive for variant interpretation M. Landrum, J. Lee, W. Rubinstein, D. Maglott P59 Association of functional variants and protein physical interactions of human MUTY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome Z. Abduljaleel, W. Khan, F. A. Al-Allaf, M. Athar , M. M. Taher, N. Shahzad P60 Modification of the microbiom constitution in the gut using chicken IgY antibodies resulted in a reduction of acute graft-versus-host disease after experimental bone marrow transplantation A. Bouazzaoui, E. Huber, A. Dan, F. A. Al-Allaf, W. Herr, G. Sprotte, J. Köstler, A. Hiergeist, A. Gessner, R. Andreesen, E. Holler P61 Compound heterozygous mutation in the LDLR gene in Saudi patients suffering severe hypercholesterolemia F. Al-Allaf, A. Alashwal, Z. Abduljaleel, M. Taher, A. Bouazzaoui, H. Abalkhail, A. Al-Allaf, R. Bamardadh, M. Athar

Studies in preclinical models have demonstrated the superior anti-tumor effect of CpG oligodeoxynucleotides (CpG-ODN) when administered at the tumor site rather than systemically. We evaluated the effect of aerosolized CpG-ODN on lung metastases in mice injected with immunogenic N202.1A mammary carcinoma cells or weakly immunogenic B16 melanoma cells. Upon reaching the bronchoalveolar space, aerosolized CpG-ODN activated a local immune response, as indicated by production of IL-12p40, IFN-γ and IL-1β and by recruitment and maturation of DC cells in bronchoalveolar lavage fluid of mice. Treatment with aerosolized CpG-ODN induced an expansion of CD4+ cells in lung and was more efficacious than systemic i.p. administration against experimental lung metastases of immunogenic N202.1A mammary carcinoma cells, whereas only i.p. delivery of CpG-ODN provided anti-tumor activity, which correlated with NK cell expansion in the lung, against lung metastases of the poorly immunogenic B16 melanoma. The inefficacy of aerosol therapy to induce NK expansion was related to the presence of immunosuppressive macrophages in B16 tumor-bearing lungs, as mice depleted of these cells by clodronate treatment responded to aerosol CpG-ODN through expansion of the NK cell population and significantly reduced numbers of lung metastases. Our results indicate that tumor immunogenicity and the tumor-induced immunosuppressive environment are critical factors to the success of CpG therapy in the lung, and point to the value of routine sampling of the lung immune environment in defining an optimal immunotherapeutic strategy.

International audience; Recent studies have reported the potential clinical utility for metastatic breast cancer (MBC) patients of continuing trastuzumab beyond progression. Based on those results, here the authors have examined the benefits of trastuzumab-continuation by specifically evaluating RECIST responses upon first line trastuzumab-treatment as a potential predictive marker for therapeutic effect of trastuzumab-continuation beyond metastatic disease progression. The authors carried out a retrospective analysis of 272 HER2 positive MBC patients under trastuzumab treatment at 22 different oncology Italian centers during the years of 2000 and 2001 who progressed under first line trastuzumab-treatment. The primary end point of the study was the survival from the date of first documented progression upon first line trastuzumab treatment of disease. Data analysis involved the use of matching on propensity score to balance variables between treated and untreated subjects and to reduce bias. Of the 272 HER2-positive MBC patients, 154 (56.6%) continued treatment. 79 (51.3%) of those 154 patients showed responses based on RECIST criteria during first-line trastuzumab-treatment. Of the 118 patients that suspended trastuzumab, RECIST responses had been observed in 44 (37.3%). Cox proportional hazards analysis of progressed patients, matched using propensity score, showed that discontinuation of trastuzumab at metastatic disease progression was a risk factor for significantly reduced overall survival in both responder (HR = 2.23; 95% CI = 1.03-4.82) and non-responder groups (HR = 3.53, 95% CI = 1.73-7.21), with no significant differences in the two estimated HRs (-value of the likelihood-ratio test = 0.690). Continued trastuzumab treatment after disease progression has clinically and statistically significant effects in both RECIST responder and non-responder MBC patients.

Background The standardization of the HER2 score and recent changes in therapeutic modalities points to the need for a reevaluation of the role of HER2 in recently diagnosed breast carcinoma. Patients and methods A multicenter, retrospective study of 1794 primary breast carcinomas diagnosed in Italy in 2000/2001 and scored in HER2 four categories according to immunohistochemistry was conducted. Results Ductal histotype, vascular invasion, grade, MIB1 positivity, estrogen and progesterone receptor expression differed significantly in HER2 3+ tumors compared with the other categories. HER2 2+ tumors almost showed values intermediate between those of the negative and the 3+ subgroups. The characteristics of HER2 1+ tumors were found to be in between those of HER2 0 and 2+ tumors. With a median follow-up of 54 months, HER2 3+ status was associated with higher relapse rates in node-positive and node-negative subgroups, while HER2 2+ only in node positive. Analysis of relapses according to type of therapy provided evidence of responsiveness of HER2-positive tumors to chemotherapy, especially taxanes. Conclusions The present prognostic significance of HER2 is correlated to receptor expression level and points to the need to consider HER2 2+ and HER2 3+ tumors as distinct diseases with different outcomes and specific features.

Background Trials have shown a beneficial effect of n-3 polyunsaturated fatty acids in patients with a previous myocardial infarction or heart failure. We evaluated the potential benefit of such therapy in patients with multiple cardiovascular risk factors or atherosclerotic vascular disease who had not had a myocardial infarction. Methods In this double-blind, placebo-controlled clinical trial, we enrolled a cohort of patients who were followed by a network of 860 general practitioners in Italy. Eligible patients were men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction. Patients were randomly assigned to n-3 fatty acids (1 g daily) or placebo (olive oil). The initially specified primary end point was the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after the event rate was found to be lower than anticipated, the primary end point was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes. Results Of the 12,513 patients enrolled, 6244 were randomly assigned to n-3 fatty acids and 6269 to placebo. With a median of 5 years of follow-up, the primary end point occurred in 1478 of 12,505 patients included in the analysis (11.8%), of whom 733 of 6239 (11.7%) had received n-3 fatty acids and 745 of 6266 (11.9%) had received placebo (adjusted hazard ratio with n-3 fatty acids, 0.97; 95% confidence interval, 0.88 to 1.08; P=0.58). The same null results were observed for all the secondary end points. Conclusions In a large general-practice cohort of patients with multiple cardiovascular risk factors, daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity. (Funded by Societa Prodotti Antibiotici and others; ClinicalTrials.gov number, NCT00317707.).