Clinical and economic impact of a switch from high- to low-volume renal replacement therapy in patients with acute kidney injury.

High-intensity renal replacement therapy protocols in intensive care patients with acute kidney injury have failed to translate to improved patient outcomes when compared with lower-intensity protocols. This retrospective study explored the clinical and economic impacts of switching from a 30-35 ml.kg(-1) .h(-1) (high-volume) to a 20 ml.kg(-1) .h(-1) (low-volume) protocol. Patients (n = 366) admitted 12 months before (n = 187) and after (n = 179) the switch were included in the study. There was no difference in in-hospital mortality (77/187 (41%) vs 75/179 (42%), respectively, p = 0.92), intensive care unit mortality (55/187 (29%) vs 61/179 (34%), respectively, p = 0.40), duration of organ support or extent of renal recovery between the high- and low-volume cohorts. A 25% reduction in daily replacement fluid usage was observed, equating to a cost saving of over £27 000 per annum. In conclusion, a switch from high- to low-volume continuous haemodiafiltration had minimal effects on clinical outcomes and resulted in marked cost savings.

Prostatic biopsies in selected men aged 75 years and older guide key clinical management decisions.

PURPOSE: Increasing life expectancy and PSA testing has increased the number of men over the age of seventy-five presenting for investigation of potential prostate malignancies. Prostatic biopsies provide diagnostic information; however, they are invasive and may not alter management decisions. Therefore, this study aimed to investigate whether prostate biopsies in this age group were justified. MATERIALS AND METHODS: All men aged 75 years and older who underwent prostatic biopsies between January 2010 and November 2011 at Bedford Hospital were identified and the indication for the biopsies, histopathological results and subsequent management plan investigated. RESULTS: One hundred and thirty-eight (138) prostatic biopsies were undertaken and malignancies identified in 60/138 (43 %) cases. Prebiopsy PSA and examination findings had a poor positive predictive value of 54 %. Fifty-five out of sixty (92 %) cancers were classified as high or medium risk disease with 30/60 (50 %) patients commencing radiotherapy treatment with curative intent. CONCLUSION: In selected patients aged 75 years or over, prostatic biopsies provide important diagnostic information which directly impacts on clinical decisions, supporting their use in this age group.

Integrative analysis of array-comparative genomic hybridisation and matched gene expression profiling data reveals novel genes with prognostic significance in oesophageal adenocarcinoma.

BACKGROUND AND AIMS: The incidence of oesophageal adenocarcinoma (OAC) has been increasing rapidly with a dismal survival rate of less than 20%. Understanding the genomic aberrations and biology of this cancer may enhance disease interventions. This study aimed to use genome-wide genomic and expression data to enhance the understanding of OAC pathogenesis and identify groups with differential outcomes. METHODS: Array-comparative genomic hybridisation (aCGH) analysis was carried out on 56 fresh frozen OAC resection samples with long-term clinical follow-up data. Samples with aberrations were further analysed with whole-genome single-nucleotide polymorphism arrays to confirm aCGH findings. Matched gene expression microarray data were used to identify genes with high copy number-expression correlations. Nested-multiplex PCR on DNA from microdissected specimens and fluorescence in situ hybridisation assays were used for target validation. Immunohistochemistry on the same cohort and independent samples (n=371) was used for subsequent validation. Kaplan-Meier survival analyses were performed based on aCGH data after unsupervised K-means clustering (K=5, 50 iterations) and immunohistochemistry data. RESULTS: aCGH identified 17 common regions (>5% samples) of gains and 11 common regions of losses, including novel regions in OAC (loci 11p13 and 21q21.2). Integration of aCGH data with matched gene expression microarray data highlighted genes with high copy number-expression correlations: two deletions (p16/CDKN2A, MBNL1) and four gains (EGFR, WT1, NEIL2, MTMR9). Immunohistochemistry demonstrated protein over-expression of targets with gains: EGFR (10%), WT1 (20%), NEIL2 (14%) and MTMR9 (25%). These targets individually (p<0.060) and in combination had prognostic significance (p=0.008). On the genomic level, K-means clustering identified a cluster (32% of cohort) with differential log(2) ratios of 16 CGH probes (p<4×10(-7)) and a worse prognosis (median survival=1.37 years; p=0.015). CONCLUSIONS: Integration of aCGH and gene expression data identified copy number aberrations and novel genes with prognostic potential in OAC.

Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer.

Around 25-40% of cases of hereditary diffuse gastric cancer (HDGC) are caused by heterozygous E-cadherin (CDH1) germline mutations. The mechanisms for loss of the second allele still remain unclear. The aims of this study were to elucidate mechanisms for somatic inactivation of the wild-type CDH1 allele and to seek evidence for cadherin switching. Archival tumour material was analysed from 16 patients with CDH1 germline mutations and seven patients fulfilling HDGC criteria without CDH1 germline mutations. The 16 CDH1 exons were sequenced. E-cadherin promoter methylation was analysed by bisulphite sequencing and pyrosequencing and allele specificity was determined using polymorphic loci. Loss of heterozygosity was analysed using microsatellite markers. Cadherin expression levels were determined by real-time RT-PCR and immunohistochemistry. Six of 16 individuals with germline mutations had at least one second hit mechanism. Two exonic mutations (exon 9 truncating, exon 3 missense) and four intronic mutations which may affect splicing were identified. Tumours from 4/16 individuals had promoter hypermethylation that was restricted to the A allele haplotype in three cases. E-cadherin loss (mRNA and protein) generally correlated with identification of a second hit. In cases without germline E-cadherin mutations there was no evidence for somatic mutation or significant promoter methylation. P-cadherin (>25% cells) was expressed in 7/13 (54%) and 4/5 (80%) with and without germline CDH1 mutations, respectively, independent of complete E-cadherin loss. Overall, inactivation of the second CDH1 allele occurs by mutation and methylation events. Methylation is commonly allele-specific and is uncommon without germline mutations. P-cadherin over-expression commonly occurs in individuals with diffuse type gastric cancer.