Carcinogenesis, Prediction, and Palliative Treatment of Gastrointestinal Cancer

The aim of this thesis was to gain better understanding of the etiology, the detection, and the palliative treatment of gastrointestinal cancer. We found HOX genes are mediators of (pre)malignant gastrointestinal lesions, vitamin D receptor polymorphisms and immunohistochemical biomarkers can be used to predict the risk of esophageal adenocarcinoma development, and palliative therapy modestly prolongs patient’s life and cost effectiveness of therapies can be assessed after phase II trials

Use of immunohistochemical biomarkers as independent predictor of neoplastic progression in Barrett's oesophagus surveillance

__Introduction:__ The low incidence of oesophageal adenocarcinoma (EAC) in Barrett's oesophagus (BE) patients reinforces the need for risk stratification tools to make BE surveillance more effective. Therefore, we have undertaken a systematic revi

Cost-effectiveness of cetuximab for advanced esophageal squamous cell carcinoma

Background Costly biologicals in palliative oncology are emerging at a rapid pace. For example, in patients with advanced esophageal squamous cell carcinoma addition of cetuximab to a palliative chemotherapy regimen appears to improve survival. However, it simultaneously results in higher costs. We aimed to determine the incremental cost-effectiveness ratio of adding c

Molecular Profile of Barrett's Esophagus and Gastroesophageal Reflux Disease in the Development of Translational Physiological and Pharmacological Studies

Barrett's esophagus (BE) is a premalignant condition caused by gastroesophageal reflux disease (GERD), where physiological squamous epithelium is replaced by columnar epithelium. Several in vivo and in vitro BE models were developed with questionable translational relevance when implemented separately. Therefore, we aimed to screen Gene Expression Omnibus 2R (GEO2R) databases to establish whether clinical BE molecular profile was comparable with animal and optimized human esophageal squamous cell lines-based in vitro models. The GEO2R tool and selected databases were used to establish human BE molecular profile. BE-specific mRNAs in human esophageal cell lines (Het-1A and EPC2) were determined after one, three and/or six-day treatment with acidified medium (pH 5.0) and/or 50 and 100 µM bile mixture (BM). Wistar rats underwent microsurgical procedures to generate esophagogastroduodenal anastomosis (EGDA) leading to BE. BE-specific genes (keratin (KRT)1, KRT4, KRT5, KRT6A, KRT13, KRT14, KRT15, KRT16, KRT23, KRT24, KRT7, KRT8, KRT18, KRT20, trefoil factor (TFF)1, TFF2, TFF3, villin (VIL)1, mucin (MUC)2, MUC3A/B, MUC5B, MUC6 and MUC13) mRNA expression was assessed by real-time PCR. Pro/anti-inflammatory factors (interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, tumor necrosis factor α, interferon γ, granulocyte-macrophage colony-stimulating factor) serum concentration was assessed by a Luminex assay. Expression profile in vivo reflected about 45% of clinical BE with accompanied inflammatory response. Six-day treatment with 100 µM BM (pH 5.0) altered gene expression in vitro reflecting in 73% human BE profile and making this the most reliable in vitro tool taking into account two tested cell lines. Our optimized and established combined in vitro and in vivo BE models can improve further physiological and pharmacological studies testing pathomechanisms and novel therapeutic targets of this disorder

Development of a national medical leadership competency framework: The Dutch approach

Background: The concept of medical leadership (ML) can enhance physicians' inclusion in efforts for higher quality healthcare. Despite ML's spiking popularity, only a few countries have built a national taxonomy to facilitate ML competency education and training. In this paper we discuss the development of the Dutch ML competency framework with two objectives: to account for the framework's making and to complement to known approaches of developing such frameworks. Methods: We designed a research approach and analyzed data from multiple sources based on Grounded Theory. Facilitated by the Royal Dutch Medical Association, a group of 14 volunteer researchers met over a period of 2.5 years to perform: 1) literature review; 2) individual interviews; 3) focus groups; 4) online surveys; 5) international framework comparison; and 6) comprehensive data synthesis. Results: The developmental processes that led to the framework provided a taxonomic depiction of ML in Dutch perspective. It can be seen as a canonical 'knowledge artefact' created by a community of practice and comprises of a contemporary definition of ML and 12 domains, each entailing four distinct ML competencies. Conclusions: This paper demonstrates how a new language for ML can be created in a healthcare system. The success of our approach to capture insights, expectations and demands relating leadership by Dutch physicians depended on close involvement of the Dutch national medical associations and a nationally active community of practice; voluntary work of diverse researchers and medical practitioners and an appropriate research design that used multiple methods and strategies to circumvent reverberation of established opinions and conventionalisms. Implications: The experiences reported here may provide inspiration and guidance for those anticipating similar work in other countries to develop a tailored approach to create a ML framework

DNA integrity as biomarker in pancreatic cyst fluid

Identification of pancreatic cysts with malignant potential is important to prevent pancreatic cancer development. Integrity of cell free DNA (cfDNA) has been described as tumor biomarker, but its potential for pancreatic cancer is unclear. While normal apoptotic cells release uniformly truncated DNA, malignant tissues release long fragments of cell free DNA (cfDNA). We measured 247 base pair (bp) and 115 bp DNA fragments of ALU repeats by qPCR in serum from healthy controls and pancreatic cancer patients, and in cyst fluid from pancreatic cyst patients. No differences in total cfDNA (ALU115) and cfDNA integrity (ALU247/115) were observed between sera from healthy controls (n=19) and pancreatic cancer patients (n=19). Although elevated as compared to serum, but no differences in cfDNA were found in cyst fluid from high risk (n=10) and low risk (n=20) cyst patients. We conclude that cfDNA integrity is not a useful marker to identify (pre)malignant pancreatic lesions

Vitamin D receptor polymorphisms are associated with reduced esophageal vitamin D receptor expression and reduced esophageal adenocarcinoma risk

Epidemiological studies indicate that vitamin D exerts a protective effect on the development of various solid cancers. However, concerns have been raised regarding the potential deleterious role of high vitamin D levels in the development of esophageal adenocarcinoma (EAC). This study investigated genetic variation in the vitamin D receptor (VDR) in relation to its expression and risk of Barrett esophagus (BE) and EAC. VDR gene regulation was investigated by immunohistochemistry, reverse transcriptase–polymerase chain reaction (RT-PCR) and gel shift assays. Fifteen haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene were analyzed in 858 patients with reflux esophagitis (RE), BE or EAC and 202 healthy controls. VDR mRNA expression was higher in BE compared with squamous epithelium. VDR protein was located in the nucleus in BE. An rs1989969T/rs2238135G haplotype was identified in the 5’ regulatory region of the VDR gene. It was associated with an approximately two-fold reduced risk of RE, BE and EAC. Analysis of a replication cohort was done for BE that confirmed this. The rs1989969T allele causes a GATA-1 transcription factor binding site to appear. The signaling of GATA-1, which is regarded as a negative transcriptional regulator, could explain the findings for rs1989969. The rs2238135G allele was associated with a significantly reduced VDR expression in BE; for the rs1989969T allele, a trend in reduced VDR expression was observed. We identified a VDR haplotype associated with reduced esophageal VDR expression and a reduced incidence of RE, BE and EAC. This VDR haplotype could be useful in identifying individuals who benefit most from vitamin D chemoprevention