Quality Improvement of Pancreatic Surgery by Centralization in the Western Part of the Netherlands

BACKGROUND: Centralization of pancreatic surgery in high-volume hospitals is under debate in many countries. In the western part of the Netherlands, the professional network of surgical oncologists agreed to centralize all pancreatic surgery from 2006 in two high-volume hospitals. Our aim is to evaluate whether centralization of pancreatic surgery has improved clinical outcomes and has changed referral patterns. MATERIALS AND METHODS: Data of the Comprehensive Cancer Centre West (CCCW) of all 249 patients who had a resection for suspected pancreatic cancer between 1996 and 2008 in the western part of the Netherlands were analyzed. Multivariable modeling was used to evaluate survival for 3 time periods; 1996–2000, 2001–2005 (introduction of quality standards), and 2006–2008 (after centralization). In addition, the differences in referral pattern were analyzed. RESULTS: From 2006, all pancreatic surgery was centralized in 2 hospitals. The 2-year survival rate increased after centralization from 39% to 55% (P = .09) for all patients who had a pancreatic resection for pancreatic cancer. After adjustment for age, tumor location, stage, histology, and adjuvant treatment, the latter period was significantly associated with improved survival (hazard ratio [HR] 0.50; 95% confidence interval [95% CI] 0.34–0.73). CONCLUSIONS: Centralization of pancreatic surgery was successful and has resulted in improved clinical outcomes in the western part of the Netherlands, demonstrating the effectiveness of centralization

Assessing PDL-1 and PD-1 in NoneSmall Cell Lung Cancer: A Novel Immunoscore Approach

Published version. Source at http://dx.doi.org/10.1016/j.cllc.2016.09.009 Novel immune biomarkers could complement the TNM classification for nonesmall cell cancer (NSCLC), improving the prognostic accuracy. The present study evaluated the prognostic significance of the immune checkpoint molecules programmed cell death protein 1 (PD-1) and PD-1 ligand (PD-L1) in 536 patients with stage I to IIIA NSCLC using an Immunoscore approach. Independently, and in combination, the infiltration of immune cells expressing PD-L1 and PD-1 predicted patient survival, supplementing the TNM classification in each stage. Introduction: Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or its ligand, PD-L1, have gained momentum in the treatment of nonesmall cell lung cancer (NSCLC). However, their prognostic significance remains controversial. The present study evaluated the expression of PD-L1 and PD-1 and their potential role in an Immunoscore, supplementing the TNM classification of NSCLC. Materials and Methods: Tissue microarrays constructed from tumor tissue samples from 2 cohorts of a total of 536 patients (University Hospital of North Norway, n ¼ 285; Nordland Hospital, n ¼ 251) with primary resected stage I to IIIA NSCLC. PD-L1 and PD-1 were evaluated by immunohistochemistry in the primary tumor and metastatic lymph node tissue. Results: In univariate analysis, a high density of PD-L1þ immune cells in the stromal compartment (S-PD-L1) and PD-1þ intraepithelial tumor infiltrating lymphocytes (T-PD-1) was associated with favorable disease-specific survival (DSS; S-PD-L1, P ¼ .004; T-PD-1, P ¼ .012), both limited to the squamous cell carcinoma histologic subgroup (S-PD-L1, P ¼ .002; T-PD-1, P ¼ .034). A combined low S-PD-L1 and T-PD-1 was associated with poor survival in all patients (DSS: hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.37-2.40; P < .001) at both centers and for all pathologic stages. In multivariate analysis, S-PD-L1 and T-PD-1 were independent positive prognostic factors, and combined low scores remained an independent prognosticator for poor survival (DSS: HR, 1.72; 95% CI, 1.29-2.28; P < .001; disease-free survival, P ¼ .001; overall survival, P ¼ .005). Conclusion: Our study identified S-PD-L1 and T-PD-1 as independent positive prognostic factors for NSCLC patients. Their combination added significant prognostic impact within each pathologic stage and hence are feasible to include in a TNM Immunoscore

High expression of miR-17-5p in tumor epithelium is a predictor for poor prognosis for prostate cancer patients

MicroRNAs (miRs) are small non-coding RNA molecules, which are involved in the development of various malignancies, including prostate cancer (PCa). miR-17-5p is considered the most prominent member of the miR-17-92 cluster, with an essential regulatory function of fundamental cellular processes. In many malignancies, up-regulation of miR-17-5p is associated with worse outcome. In PCa, miR-17-5p has been reported to increase cell proliferation and the risk of metastasis. In this study, prostatectomy specimens from 535 patients were collected. Tissue microarrays were constructed and in situ hybridization was performed, followed by scoring of miR-17-5p expression on different tumor compartments. High expression of miR-17-5p in tumor epithelium was associated with biochemical failure (BF, p p = 0.019). In multivariate analyses, high miR-17-5p expression in tumor epithelial cells was an independent negative prognostic factor for BF (HR 1.87, 95% CI 1.32–2.67, p < 0.001). In vitro analyses confirmed association between overexpression of miR-17-5p and proliferation, migration and invasion in prostate cancer cell lines (PC3 and DU145). In conclusion, our study suggests that a high cancer cell expression of miR-17-5p was an independent negative prognostic factor in PCa

Visualization and analysis of RNA-Seq assembly graphs.

RNA-Seq is a powerful transcriptome profiling technology enabling transcript discovery and quantification. Whilst most commonly used for gene-level quantification, the data can be used for the analysis of transcript isoforms. However, when the underlying transcript assemblies are complex, current visualization approaches can be limiting, with splicing events a challenge to interpret. Here, we report on the development of a graph-based visualization method as a complementary approach to understanding transcript diversity from short-read RNA-Seq data. Following the mapping of reads to a reference genome, a read-to-read comparison is performed on all reads mapping to a given gene, producing a weighted similarity matrix between reads. This is used to produce an RNA assembly graph, where nodes represent reads and edges similarity scores between them. The resulting graphs are visualized in 3D space to better appreciate their sometimes large and complex topology, with other information being overlaid on to nodes, e.g. transcript models. Here we demonstrate the utility of this approach, including the unusual structure of these graphs and how they can be used to identify issues in assembly, repetitive sequences within transcripts and splice variants. We believe this approach has the potential to significantly improve our understanding of transcript complexity

Acute cholecystitis in high risk surgical patients: percutaneous cholecystostomy versus laparoscopic cholecystectomy (CHOCOLATE trial): Study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Laparoscopic cholecystectomy in acute calculous cholecystitis in high risk patients can lead to significant morbidity and mortality. Percutaneous cholecystostomy may be an alternative treatment option but the current literature does not provide the surgical community with evidence based advice.</p> <p>Methods/Design</p> <p>The CHOCOLATE trial is a randomised controlled, parallel-group, superiority multicenter trial. High risk patients, defined as APACHE-II score 7-14, with acute calculous cholecystitis will be randomised to laparoscopic cholecystectomy or percutaneous cholecystostomy. During a two year period 284 patients will be enrolled from 30 high volume teaching hospitals. The primary endpoint is a composite endpoint of major complications within three months following randomization and need for re-intervention and mortality during the follow-up period of one year. Secondary endpoints include all other complications, duration of hospital admission, difficulty of procedures and total costs.</p> <p>Discussion</p> <p>The CHOCOLATE trial is designed to provide the surgical community with an evidence based guideline in the treatment of acute calculous cholecystitis in high risk patients.</p> <p>Trial Registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2666">NTR2666</a></p

DIRECT trial. Diverticulitis recurrences or continuing symptoms: Operative versus conservative Treatment. A MULTICENTER RANDOMISED CLINICAL TRIAL

Background: Persisting abdominal complaints are common after an episode of diverticulitis treated conservatively. Furthermore, some patients develop frequent recurrences. These two groups of patients suffer greatly from their disease, as shown by impaired health related quality of life and increased costs due to multiple specialist consultations, pain medication and productivity losses. Both conservative and operative management of patients with persisting abdominal complaints after an episode of diverticulitis and/or frequently recurring diverticulitis are applied. However, direct comparison by a randomised controlled trial is necessary to determine which is superior in relieving symptoms, optimising health related quality of life, minimising costs and preventing diverticulitis recurrences against acceptable morbidity and mortality associated with surgery or the occurrence of a complicated recurrence after conservative management. We, therefore, constructed a randomised clinical trial comparing these two treatment strategies. Methods/design: The DIRECT trial is a multicenter randomised clinical trial. Patients (18-75 years) presenting themselves with persisting abdominal complaints after an episode of diverticulitis and/or three or more recurrences within 2 years will be included and randomised. Patients randomised for conservative treatment are treated according to the current daily practice (antibiotics, analgetics and/or expectant management). Patients randomised for elective resection will undergo an elective resection of the affected colon segment. Preferably, a laparoscopic approach is used. The primary outcome is health related quality of life measured by the Gastro-intestinal Quality of Life Index, Short-Form 36, EQ-5D and a visual analogue scale for pain quantification. Secondary endpoints are morbidity, mortality and total costs. The total follow-u

Integrating chromosomal aberrations and gene expression profiles to dissect rectal tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Accurate staging of rectal tumors is essential for making the correct treatment choice. In a previous study, we found that loss of 17p, 18q and gain of 8q, 13q and 20q could distinguish adenoma from carcinoma tissue and that gain of 1q was related to lymph node metastasis. In order to find markers for tumor staging, we searched for candidate genes on these specific chromosomes.</p> <p>Methods</p> <p>We performed gene expression microarray analysis on 79 rectal tumors and integrated these data with genomic data from the same sample series. We performed supervised analysis to find candidate genes on affected chromosomes and validated the results with qRT-PCR and immunohistochemistry.</p> <p>Results</p> <p>Integration of gene expression and chromosomal instability data revealed similarity between these two data types. Supervised analysis identified up-regulation of <it>EFNA1 </it>in cases with 1q gain, and <it>EFNA1 </it>expression was correlated with the expression of a target gene (<it>VEGF</it>). The <it>BOP1 </it>gene, involved in ribosome biogenesis and related to chromosomal instability, was over-expressed in cases with 8q gain. <it>SMAD2 </it>was the most down-regulated gene on 18q, and on 20q, <it>STMN3 </it>and <it>TGIF2 </it>were highly up-regulated. Immunohistochemistry for SMAD4 correlated with <it>SMAD2 </it>gene expression and 18q loss.</p> <p>Conclusion</p> <p>On basis of integrative analysis this study identified one well known CRC gene (<it>SMAD2</it>) and several other genes (<it>EFNA1, BOP1, TGIF2 </it>and <it>STMN3</it>) that possibly could be used for rectal cancer characterization.</p

Body Fat Free Mass Is Associated with the Serum Metabolite Profile in a Population-Based Study

To characterise the influence of the fat free mass on the metabolite profile in serum samples from participants of the population-based KORA (Cooperative Health Research in the Region of Augsburg) S4 study. Analyses were based on metabolite profile from 965 participants of the S4 and 890 weight-stable subjects of its seven-year follow-up study (KORA F4). 190 different serum metabolites were quantified in a targeted approach including amino acids, acylcarnitines, phosphatidylcholines (PCs), sphingomyelins and hexose. Associations between metabolite concentrations and the fat free mass index (FFMI) were analysed using adjusted linear regression models. To draw conclusions on enzymatic reactions, intra-metabolite class ratios were explored. Pairwise relationships among metabolites were investigated and illustrated by means of Gaussian graphical models (GGMs). We found 339 significant associations between FFMI and various metabolites in KORA S4. Among the most prominent associations (p-values 4.75 × 10(-16)-8.95 × 10(-06)) with higher FFMI were increasing concentrations of the branched chained amino acids (BCAAs), ratios of BCAAs to glucogenic amino acids, and carnitine concentrations. For various PCs, a decrease in chain length or in saturation of the fatty acid moieties could be observed with increasing FFMI, as well as an overall shift from acyl-alkyl PCs to diacyl PCs. These findings were reproduced in KORA F4. The established GGMs supported the regression results and provided a comprehensive picture of the relationships between metabolites. In a sub-analysis, most of the discovered associations did not exist in obese subjects in contrast to non-obese subjects, possibly indicating derangements in skeletal muscle metabolism. A set of serum metabolites strongly associated with FFMI was identified and a network explaining the relationships among metabolites was established. These results offer a novel and more complete picture of the FFMI effects on serum metabolites in a data-driven network

A framework for ensemble modelling of climate change impacts on lakes worldwide : the ISIMIP Lake Sector

Empirical evidence demonstrates that lakes and reservoirs are warming across the globe. Consequently, there is an increased need to project future changes in lake thermal structure and resulting changes in lake biogeochemistry in order to plan for the likely impacts. Previous studies of the impacts of climate change on lakes have often relied on a single model forced with limited scenario-driven projections of future climate for a relatively small number of lakes. As a result, our understanding of the effects of climate change on lakes is fragmentary, based on scattered studies using different data sources and modelling protocols, and mainly focused on individual lakes or lake regions. This has precluded identification of the main impacts of climate change on lakes at global and regional scales and has likely contributed to the lack of lake water quality considerations in policy-relevant documents, such as the Assessment Reports of the Intergovernmental Panel on Climate Change (IPCC). Here, we describe a simulation protocol developed by the Lake Sector of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP) for simulating climate change impacts on lakes using an ensemble of lake models and climate change scenarios for ISIMIP phases 2 and 3. The protocol prescribes lake simulations driven by climate forcing from gridded observations and different Earth system models under various representative greenhouse gas concentration pathways (RCPs), all consistently bias-corrected on a 0.5 degrees x 0.5 degrees global grid. In ISIMIP phase 2, 11 lake models were forced with these data to project the thermal structure of 62 well-studied lakes where data were available for calibration under historical conditions, and using uncalibrated models for 17 500 lakes defined for all global grid cells containing lakes. In ISIMIP phase 3, this approach was expanded to consider more lakes, more models, and more processes. The ISIMIP Lake Sector is the largest international effort to project future water temperature, thermal structure, and ice phenology of lakes at local and global scales and paves the way for future simulations of the impacts of climate change on water quality and biogeochemistry in lakes.Peer reviewe

Border Insecurity: Reading Transnational Environments in Jim Lynch’s Border Songs

This article applies an eco-critical approach to contemporary American fiction about the Canada-US border, examining Jim Lynch’s portrayal of the British Columbia-Washington borderlands in his 2009 novel Border Songs. It argues that studying transnational environmental actors in border texts—in this case, marijuana, human migrants, and migratory birds—helps illuminate the contingency of political boundaries, problems of scale, and discourses of risk and security in cross-border regions after 9/11. Further, it suggests that widening the analysis of trans-border activity to include environmental phenomena productively troubles concepts of nature and regional belonging in an era of climate change and economic globalization. Cet article propose une lecture écocritique de la fiction étatsunienne contemporaine portant sur la frontière entre le Canada et les États-Unis, en étudiant le portrait donné par Jim Lynch de la région frontalière entre la Colombie-Britannique et Washington dans son roman Border Songs, paru en 2009. L’article soutient que l’étude, dans les textes sur la frontière, des acteurs environnementaux transnationaux – dans ce cas-ci, la marijuana, les migrants humains et les oiseaux migratoires – jette un jour nouveau sur la contingence des limites territoriales politiques, des problèmes d’échelle et des discours sur le risque et la sécurité des régions transfrontalières après les évènements du 11 septembre 2001. Il suggère également qu’en élargissant l’analyse de l’activité transfrontalière pour y inclure les phénomènes environnementaux, on brouille de façon productive les concepts de nature et d’appartenance régionale d’une époque marquée par les changements climatiques et la mondialisation de l’économie