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BACKGROUND Currently approved Poly ADP-Ribose Polymerase (PARP) inhibitors (PARPi) selectively inhibit and trap both PARP1 and PARP2 (PARP1/2) at sites of single strand (ss) deoxyribonucleic acid (DNA) (ssDNA) damage, preventing ssDNA repair and leading to replication-dependent DNA double strand breaks. Recent data suggest that only inhibition of PARP1 is required for anti-proliferative effects, while PARP2 functions in the survival of haematopoietic stem and progenitor cells. These observations suggest that the inhibition and trapping of PARP 2 is not needed for anti-cancer effects, and may be a major driver of haematological toxicity observed. AZD9574 is a novel brain-penetrant PARPi that potently and selectively inhibits and traps PARP1, with the goal of delivering efficacious, less toxic, and more combinable PARPi. Furthermore, owing to its central nervous system penetration capability, AZD9574 may provide a new treatment option for patients with CNS malignancies or patients with brain metastases characterized by homologous recombination deficiency (HRD). METHODS This is a first-in-human modular study primarily designed to evaluate the safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents at increasing dose levels in patients with advanced solid malignancies, followed by expansion cohorts in specific indications. The study will also characterize the pharmacokinetics of AZD9574 and explore potential biological activity by assessing pharmacodynamic and exploratory biomarkers and anti-tumour activity. Module 1 will enrol patients with advanced breast, ovarian, pancreatic or prostate tumours harbouring homologous recombination deficiencies. Module 2 will enrol patients with isocitrate dehydrogenase (IDH)1/2 mutated glioma.

Inhibition of the mammalian target of rapamycin (mTOR) pathway extends life span in all species studied to date, and in mice delays the onset of age-related diseases and comorbidities. However, it is unknown if mTOR inhibition affects aging or its consequences in humans. To begin to assess the effects of mTOR inhibition on human aging-related conditions, we evaluated whether the mTOR inhibitor RAD001 ameliorated immunosenescence (the decline in immune function during aging) in elderly volunteers, as assessed by their response to influenza vaccination. RAD001 enhanced the response to the influenza vaccine by about 20% at doses that were relatively well tolerated. RAD001 also reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age. These results raise the possibility that mTOR inhibition may have beneficial effects on immunosenescence in the elderly.

Multi-detector row CT (MDCT) has been widely used to detect primary lesions and to evaluate TNM staging. In this study we evaluated the accuracy of dynamic MDCT in the preoperative determination of the resectability of gastric cancer. MDCT was used to image 350 cases of gastric cancer diagnosed by biopsy before surgery. MDCT findings regarding TNM staging and resectability were correlated with surgical and pathological findings. The accuracy of MDCT for staging gastric cancer was high, especially for tumour stage T1 (94.3%), lymph node stage N2 (87.3%), and for predicting distant metastases (>96.6%). When resectability was considered to be the outcome, the total accuracy of MDCT was 87.4%, sensitivity was 89.7% and specificity was 76.7%. Results showed high sensitivity for identifying peritoneal seeding (90.0%) and for predicting liver metastasis (80.0%). Dynamic enhanced MDCT is useful for TNM staging of gastric cancers and for predicting tumour respectability preoperatively.

Comment in J Clin Invest. 2008 Mar;118(3):839-841, Although cystic fibrosis (CF) is a monogenic disease, its clinical manifestations are influenced in a complex manner. Severity of lung disease, the main cause of mortality among CF patients, is likely modulated by several genes. The mannose-binding lectin 2 (MBL2) gene encodes an innate immune response protein and has been implicated as a pulmonary modifier in CF. However, reports have been conflicting, and interactions with other modifiers have not been investigated. We therefore evaluated the association of MBL2 with CF pulmonary phenotype in a cohort of 1,019 Canadian pediatric CF patients. MBL2 genotypes were combined into low-, intermediate-, and high-expression groups based on MBL2 levels in plasma. Analysis of age at first infection with Pseudomonas aeruginosa demonstrated that MBL2 deficiency was significantly associated with earlier onset of infection. This MBL2 effect was amplified in patients with high-producing genotypes of transforming growth factor beta 1 (TGFB1). Similarly, MBL2 deficiency was associated with more rapid decline of pulmonary function, most significantly in those carrying the high-producing TGFB1 genotype. These findings provide evidence of gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGF-β1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function., published_or_final_version

In this report, we focused on the multiplicity issue in Problem 1 of Genetic Analysis Workshop 15. We investigated and compared the performance of the stratified false-discovery rate control method with the traditional aggregated approach, in an application to genome-wide linkage analyses of single-nucleotide polymorphism-to-gene expression data. We showed the importance of utilizing the available map information and demonstrated the power gained by conducting false-discovery rate control separately for cis and trans regulators under three different frameworks: fixed rejection region, fixed false-discovery rate, and fixed number of rejections.

Recent advances in molecular technologies have resulted in the ability to screen hundreds of thousands of single nucleotide polymorphisms and tens of thousands of gene expression profiles. While these data have the potential to inform investigations into disease etiologies and advance medicine, the question of how to adequately control both type I and type II error rates remains. Genetic Analysis Workshop 15 datasets provided a unique opportunity for participants to evaluate multiple testing strategies applicable to microarray and single nucleotide polymorphism data. The Genetic Analysis Workshop 15 multiple testing and false discovery rate group (Group 15) investigated three general categories for multiple testing corrections, which are summarized in this review: statistical independence, error rate adjustment, and data reduction. We show that while each approach may have certain advantages, adequate error control is largely dependent upon the question under consideration and often requires the use of multiple analytic strategies.

4033 Background: HCC is a major health problem across the world. The global HCC BRIDGE study is the first global, large-scale, observational study to document the real-world experience of HCC patients from diagnosis to death. Methods: This longitudinal cohort study (started March 2009) includes HCC patients newly diagnosed between January 2005 and June 2011 and treated at major medical centers, with data collected retrospectively and prospectively as recorded in patient charts. Full patient enrollment is expected at the end of January 2012. Results: At the time of the first interim analysis (July 2011), 12,442 treated HCC patients were enrolled at 42 sites in Asia (n=8909, 72% [China: n=6295, 71%; Japan: n=295, 3%]), Europe (n=2040, 16%) and North America 1493 (n=1493, 12%). Mean age was 57 years; 82% were male. The predominant risk factor was HBV in Asia (76%) and HCV in Europe (48%), North America (45%) and Japan (69%). Most patients were diagnosed without surveillance (Asia, 82%; Europe, 73%; North America, 69%; Japan, 64%). In Asia, Europe and North America, the predominant BCLC stage at diagnosis was C (48%, 46%, 46%) followed by A (34%, 28%, 26%). First recorded treatments in Asia, Europe and North America were resection (31%, 15%, 21%), transplantation (1%, 3%, 1%), TACE (49%, 30%, 36%), other locoregional therapy (12%, 35%, 23%) and systemic therapy (3%, 10%, 8%). Treatments ever used (2005–2011) in Asia, Europe and North America were resection (33%, 17%, 24%), transplantation (2%, 6%, 12%), TACE (57%, 35%, 48%), other locoregional therapy (20%, 42%, 37%) and systemic therapy (9%, 20%, 21%). These results will be updated with data from the full study population (approx. 19,000 patients), and preliminary survival data will be presented. Conclusions: As the largest study of its type, in 19,000 patients worldwide, the HCC BRIDGE study provides valuable insights into global HCC disease characteristics and patient management. Based on prior analyses, differences in risk factors among regions confirm well-known trends, while other observed differences (e.g., treatment variations) may be related to country- and site-specific practices and patient characteristics.