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OBJECTIVE: This study aimed to identify the oncogenes at 20q involved in colorectal adenoma to carcinoma progression by measuring the effect of 20q gain on mRNA expression of genes in this amplicon. METHODS: Segmentation of DNA copy number changes on 20q was performed by array CGH (comparative genomic hybridisation) in 34 non-progressed colorectal adenomas, 41 progressed adenomas (ie, adenomas that present a focus of cancer) and 33 adenocarcinomas. Moreover, a robust analysis of altered expression of genes in these segments was performed by microarray analysis in 37 adenomas and 31 adenocarcinomas. Protein expression was evaluated by immunohistochemistry on tissue microarrays. RESULTS: The genes C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5, mapping at 20q, were significantly overexpressed in carcinomas compared with adenomas as a consequence of copy number gain of 20q. CONCLUSION: This approach revealed C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5 genes to be important in chromosomal instability-related adenoma to carcinoma progression. These genes therefore may serve as highly specific biomarkers for colorectal cancer with potential clinical applications.

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BACKGROUND: Laparoscopic total mesorectal excision (TME) is being used in rectal cancer more frequently. The aim of this study was to analyze the differences in short-term outcomes between open and laparoscopic TME. METHODS: In this nonrandomized consecutive study, the short-term outcomes of 100 patients undergoing TME for proven rectal cancer were analyzed. RESULTS: Two groups of 50 patients underwent an open or laparoscopic TME for rectal cancer. Both groups were comparable. Laparoscopic surgery took longer to perform (250 vs. 197.5 min, p < 0.01), but was accompanied by less blood loss (350 vs. 800 ml, p < 0.01). Enteric function recovered sooner after laparoscopy. The numbers of major and minor complications were comparable between both groups, although fewer patients had major complications in the laparoscopic group (6 vs. 15 patients, p = 0.03). Hospital stay was shorter for patients who underwent a laparoscopic abdominoperineal resection (10 vs. 12 days, p = 0.04). Median follow-up was 17 months for the laparoscopic group and 22 months for the open group. Survival analyses between the groups showed no statistical difference in disease-free and overall survival. CONCLUSION: This study shows that laparoscopic TME for rectal cancer is a safe and feasible technique with some short-term benefits over open TME.

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BACKGROUND: Small bowel cancer (SBC) is one of the tumours associated with Lynch syndrome (LS). To advise on screening for this tumour it is paramount to be informed about the lifetime risk. The aim of this study was to calculate the lifetime risk of SBC in LS and to identify possible risk factors. METHODS: Clinical and pathological data were collected on 1496 proven or putative carriers of a mismatch repair gene mutation from 189 families. Kaplan-Meier survival analysis was used to calculate the lifetime risk and to assess potential risk factors. RESULTS: 28 (1.9%) of the 1496 (putative) mutation carriers were identified with SBC. The median age at diagnosis was 52 years (range 23-69 years). The lifetime risk of developing SBC was 4.2%. There was no difference in risk between males and females (log rank: p = 0.2470), or between MLH1 and MSH2 mutation carriers (log rank: p = 0.2754). SBC was not observed in MSH6 mutation carriers (n = 203). The previous occurrence of colorectal cancer and a family history of SBC did not increase the risk significantly. CONCLUSIONS: Approximately, one out of 25 mutation carriers will develop SBC during life. No specific risk factors were identified. The risk appeared to be too low to advise screening by means of an invasive burdensome procedure like double balloon enteroscopy. However, screening by a non-invasive procedure (videocapsule endoscopy) might be considered if future studies will show its cost effectiveness. In patients with unexplained abdominal complaints and/or unexplained iron deficiency anaemia SBC should be considered.

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BACKGROUND: Although it is now considered a standard treatment to irradiate an advanced mid or low rectal tumor before surgical total mesorectal excision (TME), the optimal time interval between radiation therapy and surgery remains controversial. MATERIALS AND METHODS: Between 1995 and 2005, patients undergoing preoperative radiation therapy and TME for locally advanced mid and low rectal tumors treated in the VU Medical Center or the Zaans Medical Center were entered into this study. All patients received identical radiation treatment in the VU Medical Center and were subsequently operated on within 2 weeks in the Zaans Medical Center (SI group) and after 6-8 weeks in the VU Medical Center (LI group). Preoperative tumor staging, operative data, postoperative complications, pathology results, and follow-up were compared. RESULTS: The SI group (N=57) underwent surgery after a median delay of 4 days and the LI group (N=51) after 45 days. Operative data and short-term morbidity were comparable for both groups. However, significantly higher numbers of complete remissions (12 vs 0%), tumor downstaging (55 vs 26%), and less lymph-node metastases (22 vs 44%) were found in the LI group. No significant differences were found regarding local control or long-term survival after a median follow-up of 34 months. CONCLUSION: Several advantages, such as complete remissions and downstaging in the LI group, do not appear to have expression in a better survival or less local recurrences after a median follow-up of 34 months. Although larger (randomized) studies will be needed for definite conclusions, this may indicate that patients can be operated on within 2 weeks after radiation therapy.

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BACKGROUND: Future colorectal cancer (CRC) screening programmes should not (greatly) interfere with regular health care. Hence, we analysed the Dutch endoscopic practice to provide a clear insight into endoscopic workload and manpower with a special emphasis on the current ability to facilitate a successful implementation of a faecal occult blood test (FOBT)-based nationwide CRC screening programme. METHODS: A questionnaire was sent to all Dutch endoscopy units (n = 100) in the spring of 2005. The questionnaire included topics ranging from the numbers and specifications of endoscopies performed in 2004 and the numbers of endoscopists per unit to expected vacancies for gastroenterologists and waiting times. RESULTS: The response rate was 98%, representing a total of 49,253 hospital beds. overall, a 26% increase in the number of endoscopies from 325,000 in 1999 to almost 410,000 in 2004 was found, accompanied by a 25% increase in manpower. The total number of endoscopists was 598. regional differences were observed in the number of endoscopists, the total number of endoscopies and colonoscopies, and the number of endoscopies per endoscopist. A biannual FOBT-based screening programme would yield an additional workload of 25,385 colonoscopies a year amounting to a 22% increase in the total number of colonoscopies performed. However, the workload per unit would only have to increase by five extra colonoscopies a week. CONCLUSION: Whereas an FOBT-based CRC screening programme is currently feasible without strongly interfering with regular health care, future plans regarding the scale and preferred mode of screening should incorporate solid data on the (regional) endoscopic capacity and manpower needed for a successful implementation.

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AIM: To find out whether there are differences in attitudes about colorectal cancer (CRC) screening among gastrointestinal (GI) specialists and general practitioners (GPs) and which method is preferred in a national screening program. METHODS: Four hundred and twenty Dutch GI specialists in the Netherlands and 400 GPs in Amsterdam were questioned in 2004. Questions included demographics, affiliation, attitude towards screening both for the general population and themselves, methods of screening, family history and individual risk. RESULTS: Eighty-four percent of the GI specialists returned the questionnaire in comparison to 32% of the GPs (P < 0.001). Among the GI specialists, 92% favoured population screening whereas 51% of GPs supported population screening (P < 0.001). Of the GI specialists 95% planned to be screened themselves, while 30% of GPs intended to do so (P < 0.001). Regarding the general population, 72% of the GI specialists preferred colonoscopy as the screening method compared to 27% of the GPs (P < 0.001). The method preferred for personal screening was colonoscopy in 97% of the GI specialists, while 29% of the GPs favoured colonoscopy (P < 0.001). CONCLUSION: Screening for CRC is strongly supported by Dutch GI specialists and less by GPs. The major health issue is possibly misjudged by GPs. Since GPs play a crucial role in a successful national screening program, CRC awareness should be realized by increasing knowledge about the incidence and mortality, thus increasing awareness of the need for screening among GPs.

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BACKGROUND: To determine at what stage during gastric carcinogenesis Epstein-Barr virus (EBV) enters the gastric epithelial cells, the presence of EBV was investigated in two pathogenetically related but distinct forms of adenocarcinoma of the stomach-gastric carcinoma of the intact stomach (GCIS) and gastric stump carcinoma (GSC)-and their presumed precursor lesions. PATIENTS AND METHODS: Eleven patients with EBV positive GCIS and eight patients with EBV positive GSC, demonstrated by the highly sensitive EBV encoded RNA 1/2 (EBER1/2) RNA in situ hybridisation (RISH) technique, were studied. Paraffin wax embedded tissue available from preoperative gastric biopsies and tumour adjacent tissue from the resection specimens containing normal gastric mucosa, inflamed gastric mucosa, and preneoplastic lesions (intestinal metaplasia and dysplasia) was investigated by EBER1/2 RISH, in addition to EBV nuclear antigen 1 (EBNA-1) and latent membrane protein 1 (LMP-1) immunohistochemistry (IHC). RESULTS: In both GCIS and GSC and their precursor lesions EBER1/2 transcripts were restricted to the carcinoma cells. In addition, positivity of EBNA-1 IHC was also restricted to the tumour cells. IHC for LMP-1 was negative in all cases tested. CONCLUSIONS: The absence of EBER1/2 transcripts in preneoplastic gastric lesions (intestinal metaplasia and dysplasia) and their presence in two distinct types of gastric carcinoma strongly suggest that EBV can only infect neoplastic gastric cells and thus is a late event in gastric carcinogenesis.

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Obesity is an increasing public health problem. As a consequence, many people attempt to lose weight by dieting or participation in weight loss programmes. Weight loss is associated with an increased risk of symptomatic gallstones. Preventive measures include keeping the rate of weight loss below 1.5 kg per week, and providing a fat intake of at least 7 g a day. If it is expected that the rate of weight loss will be faster or difficult to control, for example after bariatric surgery, prophylaxis with ursodeoxycholic acid may be considered.

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BACKGROUND: Current recommendations are for endoscopic surveillance of patients with Barrett's oesophagus to detect dysplasia and to diagnose carcinoma at an early and possibly treatable stage. However, observations suggest that these current practice guidelines are thwarted by many factors often not taken into account. These observations stem from general surveillance aspects as well from specific data on Barrett's oesophagus. This review therefore aims at discussing data on the current surveillance strategy in conjunction with general surveillance aspects relevant for their interpretation. METHODS: Literature survey of published articles. RESULTS: A critical reappraisal of the literature shows that the current surveillance strategy is hampered by multiple problems with the marker dysplasia, cost-ineffectiveness, an overrated cancer risk and an astonishing lack of prospective, randomized data showing a clear benefit in terms of a greater life expectancy. Moreover, the decisive study is unlikely ever to be performed because of the large number of patients needed and the required length of follow-up. As a result, protocols are being carried out that have never been critically tested prior to large-scale clinical implementation. CONCLUSIONS: Although these findings should not lead to therapeutic nihilism, the data raise the issue of whether or not surveillance protocols should be restricted to specialized referral centres with particular research efforts aimed at improving existing and developing new techniques that lack most of the described pitfalls and problems. Since it is foreseen that matters will not change rapidly in the (near) future, the clinician has no other choice than to rely on individually tailored arguments to survey taking into account for example family history, age and anxiety about potential long-term effects.

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Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatch-repair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer.

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The c-met proto-oncogene, encoding the hepatocyte growth factor receptor, can be activated by various mechanisms. These include, among others, gene amplification with concomitant overexpression and the tpr-met oncogenic rearrangement. In the case of gastric cancer, contradictory results on the presence of the tpr-met oncogenic rearrangement have been published. The current study aimed therefore to assess the prevalence of tpr-met expression in Caucasian gastric adenocarcinomas, to evaluate the importance of this oncogene in their carcinogenesis. In addition, the level of c-met expression was determined, to evaluate the role of this alternative mode of activation of the proto-oncogene. A series of Caucasian gastric adenocarcinomas (n=43) and normal gastric mucosal samples (n=14) was analysed for tpr-met and c-met expression. Expression of tpr-met mRNA in the samples was performed by two reverse transcriptase polymerase chain reaction (RT-PCR) assays, with excellent correlation. The specificity of both methods was confirmed by direct sequencing of the PCR products of the MNNG-HOS cell line, which is known to contain the rearrangement. The level of c-met expression was assessed using semi-quantitative RT-PCR assays and immunohistochemistry (IHC). None of the normal gastric mucosal or gastric adenocarcinoma samples expressed tpr-met mRNA, as determined by both RT-PCR assays. Seventy per cent of the adenocarcinomas showed overexpression of c-met, according to elevated c-met mRNA levels, compared with the expression level of normal gastric mucosa. A significant correlation was found between the level of c-met mRNA and protein expression. In conclusion, these results strongly suggest that tpr-met activation does not play a role in Caucasian gastric carcinogenesis, while overexpression of the c-met gene occurs in the majority of Caucasian gastric adenocarcinomas.

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Application of recombinant adenoviral vectors for cancer gene therapy is currently limited due to lack of specificity for tumor cells. For gastric and esophageal adenocarcinoma, we present here that the relative abundant expression of the primary adenovirus receptor, coxsackie/adenovirus receptor (CAR), on normal epithelium compared to carcinoma favors the transduction of the epithelium. As such, to achieve specific transduction of cancer cells, targeting approaches are required that ablate the binding of the virus to CAR and redirect the virus to tumor-specific receptors. By immunohistochemistry and reverse transcriptase polymerase chain reaction assays, we demonstrate a marked difference in expression of the human epithelial cell adhesion molecule (EpCAM) between normal and (pre)malignant lesions of the stomach and esophagus. Based on this, we explored the feasibility of using EpCAM to achieve gastric and esophageal adenocarcinoma selective gene transfer. Adenoviral vectors redirected to EpCAM using bispecific antibodies against the adenovirus fiber-knob protein and EpCAM specifically infected gastric and esophageal cancer cell lines. Using primary human cells, an improved ratio of tumor transduction over normal epithelium transduction was accomplished by the EpCAM-targeted vectors. This study thus indicates that EpCAM-targeted adenoviral vectors may be useful for gastric and esophageal cancer-specific gene therapy in patients.

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In the chapter, an analysis of the literature on the relationship between Helicobacter pylori, the use of proton pump inhibitors and the development of atrophic gastritis is presented, and the difficulties of classifying gastritis and the new possibilities of quantifying chronic inflammation by morphometric analysis are discussed. The issue surrounding the necessity of eradicating H. pylori in H. pylori-positive patients has still not been solved. Most studies have now accepted that proton pump inhibitors indeed accelerate the onset of atrophic gastritis in H. pylori-positive patients, but evidence against such an association was published in one recent (Scandinavian) study; conclusions from this study have, however, been challenged by several groups. Some data are available on the efficacy of H. pylori eradication with regard to the prevention of atrophy. The limited significance of the development of parietal cell protrusions and fundic gland cysts is better understood, but much less is known of the development and long-term consequence of H. pylori-induced autoimmune gastritis. Finally, recent studies in H. pylori-positive patients indicate that treatment with proton pump inhibitors may promote bacterial N-nitrosation formation. These data taken together suggest that the eradication of H. pylori may be based not only on morphological arguments, but also on bacterial alterations in the gastric milieu.

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Despite improvements in diagnostic and therapeutic modalities, the prognosis of patients with gastrointestinal malignancies has remained poor. In essence, this poor outcome is related to the majority of patients presenting at an already advanced stage of disease at the time of diagnosis. Unfortunately, however, mass screening and surveillance programmes aimed at early detection and treatment in the population at large are in most countries considered to be cost-ineffective. Moreover, even with regard to established risk groups, there is considerable debate over whether current surveillance strategies are beneficial to these patients in terms of a reduction in cancer-related mortality. This chapter addresses various aspects of screening and surveillance. In the first part, general issues are discussed, whereas the second part focuses particularly on disease entities frequently encountered in gastrointestinal practice.

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Gastric carcinogenesis is strongly associated with Helicobacter pylori infection, but the underlying genetic mechanisms are largely unknown. The aim of this study was to correlate chromosomal aberrations in gastric cancer to H. pylori status and its different strains, as well as to histological type and other clinico-pathological variables. DNA from 46 gastric cancers (male/female 35/11, age 27-85 years) was extracted from formaldehyde-fixed, paraffin-embedded material and tested for chromosomal gains and losses by comparative genomic hybridization (CGH). Chromosomal aberrations with frequencies of 20% or higher were considered to be non-random changes associated with gastric cancer. The mean number of chromosomal events per tumour was 9.7 (range 0-27), with a mean of 3.2 gains (range 0-16) and 6.5 losses (range 0-15). Gains were most frequently found at chromosomes 8q and 13q (24% and 26%, respectively). Losses were predominantly found on chromosome arms 2q, 9p, 12q, 14q, 15q, 16p, 16q, 17p, 17q, 19p, 19q, and 22q (22%, 30%, 43%, 22%, 33%, 50%, 28%, 50%, 39%, 33%, 39%, and 37%, respectively). Common regions of overlap narrowed down to 2q11-14, 8q23, 9p21, 12q24, 13q21-22, 14q24 and 15q11-15. The mean number of gains was higher in tumours with metastases than in localized tumours (4.1 vs. 1.9, p=0.04). Tumours with a loss at 17p showed a higher number of losses than tumours without a 17p loss (9. 5 vs. 4.7 on average, p<0.001). Neither H. pylori status (+, n=25; -, n=21) nor H. pylori strain was correlated to the total number of events or to any specific chromosomal aberration, nor were there differences between intestinal (n=30) and diffuse (n=15) cancers or any other clinico-pathological variable tested. In conclusion, a complex of chromosomal aberrations is involved in gastric cancer, but their pattern does not depend on H. pylori status or strain, nor on the histological type of the tumour. The exact biological meaning of these aberrations in carcinogenesis needs further clarification.

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For advanced irresectible gastric cancer, sequential high-dose methotrexate and 5-fluorouracil (both on day 1) combined with adriamycin on day 15 (FAMTX regimen), cycled every 28 days, is a fairly effective but toxic treatment, with a high incidence of neutropenic fever, dose reductions and dose delays. In order to improve FAMTX toxicity, we studied the feasibility of two modified FAMTX regimens with lenograstim support. Seven advanced gastric cancer patients were treated with all three FAMTX drugs on day 1 followed by lenograstim 150 microgm(-2)for 10 days, in 21-day cycles (FUMA regimen). The next seven patients were treated with the same drugs at the same doses, but with adriamycin 1 day prior to methotrexate and 5-fluorouracil administration (AFUM regimen). Patients were monitored for toxicity, response, and survival. The total number of courses was 27 for FUMA and 35 for AFUM with a median of four courses per patient in each cohort. In the FUMA regimen, considerable toxicity consisting of mucositis and fatigue as well as grade 4 neutropenia occurred, and forced four out of seven patients to stop treatment. The consecutive AFUM regimen showed only mild toxicity, and all patients could finish treatment without dose reductions or delays. We found unanticipated and probably sequence-dependent toxicity profiles in two investigational, modified FAMTX schedules with lenograstim support, leading to high rates of dose-limiting toxicity in the FUMA regimen as opposed to mild toxicity in the AFUM regimen, even though the same total drug doses and treatment cycle length (dose intensity) were employed.

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Approximately 10% of gastric adenocarcinomas worldwide are associated with human EBV. These carcinomas generally do not express the latent membrane protein 1 (LMP1), the major known EBV oncogene. Recently, another EBV gene [ie., BARF1 (BamHI A rightward open reading frame)] was shown to have transforming and immortalizing capacities. Therefore, in this study, we investigated the expression of BARF1 in EBV-carrying gastric adenocarcinomas in relation to the expression of other latent EBV transcripts. In the present study, 10 of 132 gastric adenocarcinomas tested positive for EBV using EBER1/2-RNA in situ hybridization. We demonstrate BARF1 gene transcription in nine EBV-carrying gastric adenocarcinomas (with sufficient RNA quality) using the BARF1-specific nucleic acid sequence-based amplification assay. In addition, we also detected other latent EBV transcripts (ie., BARF0-, LMP2A-, and Q/K-driven EBNA1 transcripts in these carcinomas using reverse transcription-PCR analysis. No expression of LMP1, EBNA2, and ZEBRA (either at transcription or protein level) was found. In addition, two cases were positive for BHRF1 transcripts, the viral bcl-2 homologue. Thus, together with BARF1 transcription, a unique and distinct EBV latency type has been found in EBV-associated gastric adenocarcinomas. Because BARF1 exerts immortalizing effects on human epithelial cells in vitro and EBV-carrying gastric adenocarcinomas lack the expression of LMP1, the BARF1 gene might act as the viral oncogene in EBV-carrying gastric carcinomas. The BARF1 gene offers an alternative way for EBV-mediated oncogenesis other than LMP1.

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AIMS: Cyclin D1 overexpression was examined in early gastric carcinomas and precursor lesions with the following aims; (1) to assess the chronology of cyclin D1 overexpression in various stages of gastric carcinogenesis, (2) to correlate cyclin D1 overexpression with the Lauren type, the grade of differentiation and the type of growth pattern of the tumours and (3) to correlate cyclin D1 overexpression with clinical parameters, in particular lymph node metastasis and overall prognosis. METHODS AND RESULTS: Forty-five paraffin-embedded gastrectomy specimens from early carcinomas were examined for the presence of various precursor lesions. The Lauren type, the grade of differentiation and the type of growth pattern were reassessed for all early carcinomas. Cyclin D1 overexpression was examined using the monoclonal antibody DCS-6. Cyclin D1 overexpression was absent from all precursor lesions. Ten early carcinomas (22%) were cyclin D1 positive without significant differences when stratified according to Lauren type, grade of differentiation, type of growth pattern or lymph node status. Univariate analysis failed to show a significant difference in 5-year surival rate between cyclin D1 positive and negative early carcinomas (90% vs. 94%). CONCLUSIONS: Cyclin D1 protein overexpression does not play a role in the progression from normal to neoplastic gastric mucosa and does not discriminate between intestinal and diffuse type early gastric carcinomas of Caucasian origin. Moreover, mechanisms other than cyclin D1 protein overexpression underlie the reported difference in biological behaviour of early gastric carcinomas with different types of growth pattern. Finally, although it appears that cyclin D1 does not have prognostic significance, studies on larger numbers, including advanced carcinomas, are warranted.

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