Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT)

Polymeric cytotoxic conjugates are being developed with the aim of preferential delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I inhibitor camptothecin linked to a water-soluble polymeric backbone methacryloylglycynamide ( average molecular weight 18 kDa, 10% CPT by weight). It was administered as a 30-min infusion once every 4 weeks to patients with advanced solid malignancies. The objectives of our study were to determine the maximum tolerated dose, dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document responses to this treatment. The starting dose was 30 mgm(-2) (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mgm(-2). Dose-limiting toxicities were myelosuppression, neutropaenic sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum dose. The maximum tolerated dose and dose recommended for further clinical study was 200 mgm(-2). The half-lives of both MAG-CPT and released CPT were prolonged (46 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4 weeks after treatment. However, subsequent pharmacodynamic studies of this agent have led to its withdrawal from clinical development

The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.

The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome

Optimising corticosteroid injection for lateral epicondylalgia with the addition of physiotherapy: A protocol for a randomised control trial with placebo comparison

<p>Abstract</p> <p>Background</p> <p>Corticosteroid injection and physiotherapy are two commonly prescribed interventions for management of lateral epicondylalgia. Corticosteroid injections are the most clinically efficacious in the short term but are associated with high recurrence rates and delayed recovery, while physiotherapy is similar to injections at 6 weeks but with significantly lower recurrence rates. Whilst practitioners frequently recommend combining physiotherapy and injection to overcome harmful effects and improve outcomes, study of the benefits of this combination of treatments is lacking. Clinicians are also faced with the paradox that the powerful anti-inflammatory corticosteroid injections work well, albeit in the short term, for a non-inflammatory condition like lateral epicondylalgia. Surprisingly, these injections have not been rigorously tested against placebo injections. This study primarily addresses both of these issues.</p> <p>Methods</p> <p>A randomised placebo-controlled clinical trial with a 2 × 2 factorial design will evaluate the clinical efficacy, cost-effectiveness and recurrence rates of adding physiotherapy to an injection. In addition, the clinical efficacy and adverse effects of corticosteroid injection beyond that of a placebo saline injection will be studied. 132 participants with a diagnosis of lateral epicondylalgia will be randomly assigned by concealed allocation to one of four treatment groups – corticosteroid injection, saline injection, corticosteroid injection with physiotherapy or saline injection with physiotherapy. Physiotherapy will comprise 8 sessions of elbow manipulation and exercise over an 8 week period. Blinded follow-up assessments will be conducted at baseline, 4, 8, 12, 26 and 52 weeks after randomisation. The primary outcome will be a participant rating of global improvement, from which measures of success and recurrence will be derived. Analyses will be conducted on an intention-to-treat basis using linear mixed and logistic regression models. Healthcare costs will be collected from a societal perspective, and along with willingness-to-pay and quality of life data will facilitate cost-effectiveness and cost-benefit analyses.</p> <p>Conclusion</p> <p>This trial will utilise high quality trial methodologies in accordance with CONSORT guidelines. Findings from this study will assist in the development of evidence based practice recommendations and potentially the optimisation of resource allocation for rehabilitating lateral epicondylalgia.</p> <p>Trial registration</p> <p>Australian New Zealand Clinical Trials Register ACTRN12609000051246</p

Identification of Candidate Growth Promoting Genes in Ovarian Cancer through Integrated Copy Number and Expression Analysis

Ovarian cancer is a disease characterised by complex genomic rearrangements but the majority of the genes that are the target of these alterations remain unidentified. Cataloguing these target genes will provide useful insights into the disease etiology and may provide an opportunity to develop novel diagnostic and therapeutic interventions. High resolution genome wide copy number and matching expression data from 68 primary epithelial ovarian carcinomas of various histotypes was integrated to identify genes in regions of most frequent amplification with the strongest correlation with expression and copy number. Regions on chromosomes 3, 7, 8, and 20 were most frequently increased in copy number (>40% of samples). Within these regions, 703/1370 (51%) unique gene expression probesets were differentially expressed when samples with gain were compared to samples without gain. 30% of these differentially expressed probesets also showed a strong positive correlation (r≥0.6) between expression and copy number. We also identified 21 regions of high amplitude copy number gain, in which 32 known protein coding genes showed a strong positive correlation between expression and copy number. Overall, our data validates previously known ovarian cancer genes, such as ERBB2, and also identified novel potential drivers such as MYNN, PUF60 and TPX2

Italian guidelines for primary headaches: 2012 revised version

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105–190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version

Genome-wide association of multiple complex traits in outbred mice by ultra low-coverage sequencing

The authors wish to acknowledge excellent technical assistance from A. Kurioka, L. Swadling, C. de Lara, J. Ussher, R. Townsend, S. Lionikaite, A.S. Lionikiene, R. Wolswinkel and I. van der Made. We would like to thank T.M. Keane and A.G. Doran for their help in annotating variants and adding the FVB/NJ strain to the MGP. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics and the Wellcome Trust Sanger Institute for the generation of the sequencing data. This work was funded by Wellcome Trust grant 090532/Z/09/Z (J.F.). Primary phenotyping of the mice was supported by the Mary Lyon Centre and Mammalian Genetics Unit (Medical Research Council, UK Hub grant G0900747 91070 and Medical Research Council, UK grant MC U142684172). D.A.B. acknowledges support from NIH R01AR056280. The sleep work was supported by the state of Vaud (Switzerland) and the Swiss National Science Foundation (SNF 14694 and 136201 to P.F.). The ECG work was supported by the Netherlands CardioVascular Research Initiative (Dutch Heart Foundation, Dutch Federation of University Medical Centres, Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences) PREDICT project, InterUniversity Cardiology Institute of the Netherlands (ICIN; 061.02; C.A.R. and C.R.B.). N.C. is supported by the Agency of Science, Technology and Research (A*STAR) Graduate Academy. R.W.D. is supported by a grant from the Wellcome Trust (097308/Z/11/Z).Peer reviewedPostprin