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Background: Determinants of adverse events for cirrhotic patients undergoing abdominal surgery have not been adequately assessed. Child-Turcotte-Pugh (CTP) and Model for End-Stage Liver Disease (MELD) have estimated perioperative outcomes with inconsistent results. Our study sought to combine novel serum markers with CTP and MELD to improve prognostication of 30-day postoperative mortality or liver transplant in cirrhotic patients undergoing abdominal surgery. Methods: A review was performed on 120 cirrhotic patients undergoing nonhepatic abdominal surgeries at Mount Sinai Medical Center from 2001-2011. Preoperative serum markers were evaluated by logistic regression and receiver-operator characteristics. Prognostic ability of scoring systems was assessed using Youden's J statistic ( J). Results: Albumin and hematocrit were independently predictive of 30-day mortality or transplant with optimal cutoff values of albumin at <3.05 mg/dl and hematocrit at <35.55 %. Adding these criteria to CTP>A, CTP>B, MELD ≥ 10, MELD ≥ 15, and MELD ≥ 20 improved sensitivity and specificity by an average of 6.1 and 32.1 %, respectively. The highest J values resulted from combining novel criteria with CTP>A (sensitivity, 80 %; specificity, 82 %; p < 0.01; J, 0.63) and MELD ≥ 10 (sensitivity, 63 %; specificity, 90 %; p < 0.01; J, 0.53). Conclusion: Augmenting CTP and MELD with albumin and hematocrit significantly improved the identification of cirrhotic patients at risk of 30-day mortality or transplantation following nonhepatic abdominal surgery. [ABSTRACT FROM AUTHOR]

Invasive species are an important driver of global biodiversity loss. Under international legislation, the UK has an obligation to eradicate or to control the alien, invasive American mink. Using a large-scale field experiment, we tested the effectiveness of a specified mink removal strategy, identified through earlier modelling work, in reducing the relative abundance of mink. We found that mink removal could be effective in reducing mink populations with four months or less of trapping per year, over only 2–3 years, but that for small sites (c. 20km) a flexible, reactive approach, coupled with continual monitoring for mink presence is necessary. Survival of reintroduced water voles at four sub-sites within our mink removal sites suggest that the reactive mink removal strategy adopted in this study was sufficient for water vole protection. We discuss the use of an adaptive management approach in local mink management, and consider the wider implications of our results for invasive species control on mainlands. [Copyright &y& Elsevier]

Background & Aims: Epigenetic silencing of tumor suppressor genes contributes to the pathogenesis of hepatocellular carcinoma (HCC). To identify clinically relevant tumor suppressor genes silenced by DNA methylation in HCC, we integrated DNA methylation data from human primary HCC samples with data on up-regulation of gene expression after epigenetic unmasking. Methods: We performed genome-wide methylation analysis of 71 human HCC samples using the Illumina HumanBeadchip27K array; data were combined with those from microarray analysis of gene re-expression in 4 liver cancer cell lines after their exposure to reagents that reverse DNA methylation (epigenetic unmasking). Results: Based on DNA methylation in primary HCC and gene re-expression in cell lines after epigenetic unmasking, we identified 13 candidate tumor suppressor genes. Subsequent validation led us to focus on functionally characterizing 2 candidates, sphingomyelin phosphodiesterase 3 (SMPD3) and neurofilament, heavy polypeptide (NEFH), which we found to behave as tumor suppressor genes in HCC. Overexpression of SMPD3 and NEFH by stable transfection of inducible constructs into an HCC cell line reduced cell proliferation by 50% and 20%, respectively (SMPD3, P = .003 and NEFH, P = .003). Conversely, knocking down expression of these genes with small hairpin RNA promoted cell invasion and migration in vitro (SMPD3, P = .0001 and NEFH, P = .022), and increased their ability to form tumors after subcutaneous injection or orthotopic transplantation into mice, confirming their role as tumor suppressor genes in HCC. Low levels of SMPD3 were associated with early recurrence of HCC after curative surgery in an independent patient cohort (P = .001; hazard ratio = 3.22; 95% confidence interval: 1.6−6.5 in multivariate analysis). Conclusions: Integrative genomic analysis identified SMPD3 and NEFH as tumor suppressor genes in HCC. We provide evidence that SMPD3 is a potent tumor suppressor gene that could affect tumor aggressiveness; a reduced level of SMPD3 is an independent prognostic factor for early recurrence of HCC. [Copyright &y& Elsevier]

Background & Aims According to the clonal model of tumor evolution, trunk alterations arise at early stages and are ubiquitous. Through the characterization of early stages of hepatocarcinogenesis, we aimed to identify trunk alterations in hepatocellular carcinoma (HCC) and study their intra- and inter-tumor distribution in advanced lesions. Methods A total of 151 samples representing the multistep process of hepatocarcinogenesis were analyzed by targeted-sequencing and a single nucleotide polymorphism array. Genes altered in early lesions (31 dysplastic nodules [DNs] and 38 small HCCs [sHCC]) were defined as trunk. Their distribution was explored in: a) different regions of large tumors (43 regions, 21 tumors), and b) different nodules of the same patient (39 tumors, 17 patients). Multinodular lesions were classified as intrahepatic metastases (IMs) or synchronous tumors based on chromosomal aberrations. Results TERT promoter mutations (10.5%) and broad copy-number aberrations in chromosomes 1 and 8 (3–7%) were identified as trunk gatekeepers in DNs and were maintained in sHCCs. Trunk drivers identified in sHCCs included TP53 (23%) and CTNNB1 (11%) mutations, and focal amplifications or deletions in known drivers (6%). Overall, TERT , TP53 and CTNNB1 mutations were the most frequent trunk events and at least one was present in 51% of sHCCs. Around 90% of mutations in these genes were ubiquitous among different regions of large tumors. In multinodular HCCs, 35% of patients harbored IMs; 85% of mutations in TERT , TP53 and/or CTNNB1 were retained in primary and metastatic tumors. Conclusions Trunk events in early stages ( TERT , TP53 , CTNNB1 mutations) were ubiquitous across different regions of the same tumor and between primary and metastatic nodules in >85% of cases. This concept supports the knowledge that single biopsies would suffice to capture trunk mutations in HCC. Lay summary Trunk alterations arise at early stages of cancer and are shared among all malignant cells of the tumor. In order to identify trunk alterations in HCC, we characterized early stages of hepatocarcinogenesis represented by dysplastic nodules and small lesions. Mutations in TERT , TP53 and CTNNB1 genes were the most frequent. Analyses in more advanced lesions showed that mutations in these same genes were shared between different regions of the same tumor and between primary and metastatic tumors, suggesting their trunk role in this disease. [ABSTRACT FROM AUTHOR]