Portal vein thrombosis; risk factors, clinical presentation and treatment

<p>Abstract</p> <p>Background</p> <p>Portal vein thrombosis (PVT) is increasingly frequently being diagnosed, but systematic descriptions of the natural history and clinical handling of the condition are sparse. The aim of this retrospective study was to describe risk factors, clinical presentation, complications and treatment of portal vein thrombosis in a single-centre.</p> <p>Methods</p> <p>Sixty-seven patients were identified in the electronic records from 1992 to 2005. All data were obtained from the patient records.</p> <p>Results</p> <p>One or more risk factors (e.g. prothrombotic disorder or abdominal inflammation) were present in 87%. Symptoms were abdominalia, splenomegaly, fever, ascites, haematemesis, and weight loss. Abdominalia and fever occurred more frequently in patients with acute PVT. Frequent complications were splenomegaly, oesophageal- and gastric varices with or without bleeding, portal hypertensive gastropathy and ascites. Varices and bleeding were more frequent in patients with chronic PVT. Patients who received anticoagulant therapy more frequently achieved partial/complete recanalization. Patients with varices who were treated endoscopically in combination with β-blockade had regression of the varices. The overall mortality was 13% in one year, and was dependent on underlying causes.</p> <p>Conclusion</p> <p>Most patients had a combination of local and systemic risk factors for PVT. We observed that partial/complete recanalization was more frequent in patients treated with anticoagulation therapy, and that regression of varices was more pronounced in patients who where treated with active endoscopy combined with pharmacological treatment.</p

Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy

How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor responders pass through bottlenecks, but re-grow by the time of surgical resection, suggesting a missed therapeutic opportunity. Cancers often show major changes in driver mutation presence or frequency after treatment, owing to outgrowth persistence or loss of sub-clones, copy number changes, polyclonality and/or spatial genetic heterogeneity. Post-therapy mutation spectrum shifts are also common, particularly C&gt;A and TT&gt;CT changes in good responders or bottleneckers. Post-treatment samples may also acquire mutations in known cancer driver genes (for example, SF3B1, TAF1 and CCND2) that are absent from the paired pre-treatment sample. Neo-adjuvant chemotherapy can rapidly and profoundly affect the oesophageal adenocarcinoma genome. Monitoring molecular changes during treatment may be clinically useful

Copy number signatures and mutational processes in ovarian carcinoma.

The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers. Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.NIHR, Ovarian Cancer Action, Cancer Research UK Cambridge Centre, Cambridge Experimental Cancer Medicine Centr

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Transdermal oestradiol as a method of androgen suppression for prostate cancer within the STAMPEDE trial platform

Androgen deprivation therapy (ADT) remains a cornerstone of the management of prostate cancer. The addition of ADT to radiotherapy improves disease-free and overall survival in the locally advanced setting and ADT forms the backbone onto which additional treatments may be added (either initially at first presentation or sequentially at disease progression). ADT is most commonly achieved with Gonadotrophin Releasing Hormone analogues (GnRHa) that act through the hypothalamic-pituitary-gonadal axis to prevent testicular production of testosterone. However, the therapeutic benefits of ADT are partially offset by its side-effects which include long-term This article is protected by copyright. All rights reserved

Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma

The incidence of esophageal adenocarcinoma (EAC) has risen significantly over recent decades. Although survival has improved, cure rates remain poor, with <20% of patients surviving 5 years. This is the first study to explore methylome, transcriptome and ENCODE data to characterize the role of methylation in EAC. We investigate the genome-wide methylation profile of 250 samples including 125 EAC, 19 Barrett's esophagus (BE), 85 squamous esophagus and 21 normal stomach. Transcriptome data of 70 samples (48 EAC, 4 BE and 18 squamous esophagus) were used to identify changes in methylation associated with gene expression. BE and EAC showed similar methylation profiles, which differed from squamous tissue. Hypermethylated sites in EAC and BE were mainly located in CpG-rich promoters. A total of 18575 CpG sites associated with 5538 genes were differentially methylated, 63% of these genes showed significant correlation between methylation and mRNA expression levels. Pathways involved in tumorigenesis including cell adhesion, TGF and WNT signaling showed enrichment for genes aberrantly methylated. Genes involved in chromosomal segregation and spindle formation were aberrantly methylated. Given the recent evidence that chromothripsis may be a driver mechanism in EAC, the role of epigenetic perturbation of these pathways should be further investigated. The methylation profiles revealed two EAC subtypes, one associated with widespread CpG island hypermethylation overlapping H3K27me3 marks and binding sites of the Polycomb proteins. These subtypes were supported by an independent set of 89 esophageal cancer samples. The most hypermethylated tumors showed worse patient survival