Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS)

<p>Abstract</p> <p>Background</p> <p>Radical surgery is the cornerstone in the treatment of resectable gastric cancer. The Intergroup 0116 and MAGIC trials have shown benefit of postoperative chemoradiation and perioperative chemotherapy, respectively. Since these trials cannot be compared directly, both regimens are evaluated prospectively in the CRITICS trial. This study aims to obtain an improved overall survival for patients treated with preoperative chemotherapy and surgery by incorporating radiotherapy concurrently with chemotherapy postoperatively.</p> <p>Methods/design</p> <p>In this phase III multicentre study, patients with resectable gastric cancer are treated with three cycles of preoperative ECC (epirubicin, cisplatin and capecitabine), followed by surgery with adequate lymph node dissection, and then either another three cycles of ECC or concurrent chemoradiation (45 Gy, cisplatin and capecitabine). Surgical, pathological, and radiotherapeutic quality control is performed. The primary endpoint is overall survival, secondary endpoints are disease-free survival (DFS), toxicity, health-related quality of life (HRQL), prediction of response, and recurrence risk assessed by genomic and expression profiling. Accrual for the CRITICS trial is from the Netherlands, Sweden, and Denmark, and more countries are invited to participate.</p> <p>Conclusion</p> <p>Results of this study will demonstrate whether the combination of preoperative chemotherapy and postoperative chemoradiotherapy will improve the clinical outcome of the current European standard of perioperative chemotherapy, and will therefore play a key role in the future management of patients with resectable gastric cancer.</p> <p>Trial registration</p> <p>clinicaltrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00407186">NCT00407186</a></p

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

Guilds in the transition to modernity: the cases of Germany, United Kingdom, and the Netherlands

One important aspect of the transition to modernity is the survival of elements of the Old Regime beyond the French Revolution. It has been claimed that this can explain why in the late 19th and early 20th centuries some Western countries adopted national corporatist structures while others transformed into liberal market economies. One of those elements is the persistence or absence of guild traditions. This is usually analyzed in a national context. This paper aims to contribute to the debate by investigating the development of separate trades in Germany, the United Kingdom and the Netherlands throughout the 19th century. We distinguish six scenarios of what might have happened to crafts and investigate how the prevalence of each of these scenarios in the three countries impacted on the emerging national political economies. By focusing on trades, rather than on the national political economy, our analysis demonstrates that in each country the formation of national political economies and citizenship rights was not the result of a national pattern of guild survival. Rather, the pattern that emerged by the end of the 19th century was determined by the balance between old and new industries, and between national and regional or local government

Spray impingement in the early direct injection premixed charge compression ignition regime

The main goal of this paper is to acquire more insight into the relationship between wall and piston impingement of liquid fuel and unburnt hydrocarbon emissions (UHC) emissions, under early direct injection (EDI) premixed charge compression ignition (PCCI) operating conditions. To this end, the vaporization process is modeled for various operating conditions using a commercial CFD code (StarCD). Predicted values for liquid core penetration, or liquid length LL, have been successfully checked against experimental data from literature over a wide range of operating conditions. Next, the correlation between the CFD results for wall and piston impingement and measured UHC emissions is studied. The diesel fuel used in the experiments is modeled as n-dodecane and n-heptadecane, representing the low and high end of the diesel boiling range, respectively. A distinction is made between liquid spray impingement on the piston surface and cylinder liner. For a conventional DI diesel nozzle, the high UHC emissions in the EDI PCCI regime correlate well with modeled cylinder wall impingement. Conversely, piston impingement is negligible in this regime. Accordingly, it may be assumed that the primary cause for high UHC emissions in the EDI PCCI regime, using conventional DI nozzles, is caused by liquid spray impingement against the cylinder liner. In this regime it was found that a higher intake and fuel temperature, as well as an elevated intake pressure have a positive effect on both UHC emissions and the spray impingement against the cylinder wall. This provides additional evidence that the two parameters (i.e., UHC and wall impingement) are linked. Lastly, the impact of nozzle cone angle is investigated. When adopting a narrow cone angle nozzle in the EDI PCCI regime, wall impingement is negligible and piston wetting becomes the dominant source of UHC emissions

Optimization of operating conditions in the early direct injection premixed charge compression ignition regime

Early Direct Injection Premixed Charge Compression Ignition (EDI PCCI) is a widely researched combustion concept, which promises soot and CO2 emission levels of a spark-ignition (SI) and compression-ignition (CI) engine, respectively. Application of this concept to a conventional CI engine using a conventional CI fuel faces a number of challenges. First, EDI has the intrinsic risk of wall-wetting, i.e. collision of fuel against the combustion chamber periphery. Second, engine operation in the EDI regime is difficult to control as auto-ignition timing is largely decoupled from fuel injection timing. In dual-mode PCCI engines (i.e. conventional DI at high loads) wall-wetting should be prevented by selecting appropriate (most favorable) operating conditions (EGR level, intake temperature, injection timing-strategy etc.) rather than by redesign of the engine (combustion chamber shape, injector replacement etc.). This paper presents the effects of EGR concentration, intake temperature, intake pressure, injection timing, injection pressure and fuel temperature on engine performance and emission behavior in EDI PCCI mode. In addition, several minor adjustments to the conventional injector nozzle are investigated. Wall-wetting and engine performance are characterized by the measured emissions (smoke and unburned hydrocarbons) and in-cylinder pressure (CA50 and IMEP). The main contribution of this paper is to investigate the cumulative effects on engine performance and emissions, unburnt hydrocarbons (HC) in particular, of various known measures designed to address wall-wetting. All experiments have been performed at low load (~ 3-4 bar IMEP) and at an engine speed of 1200 RPM, using a modified 6-cylinder 12.6 liter heavy-duty DI DAF XE 355 C engine. Experiments are conducted in one dedicated cylinder, which is equipped with a stand-alone fuel injection system, EGR circuit and air compressor, fuelled with commercial diesel fuel (EN590)