G Griffioen

Technische Universität München, München, Bavaria, Germany

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Publications (164)909.62 Total impact

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    ABSTRACT: Recently, complexes of matrix metalloproteinase matrix metalloproteinase-9 (MMP-9) with lipocalin-2 (neutrophil gelatinase-associated lipocalin) were found in the urine obtained from breast cancer patients, while these were completely absent in that obtained from healthy controls. In vitro data suggested a possible role for lipocalin-2 in the protection of MMP-9 against autolysis. To establish this effect in vivo, we determined the presence of MMP-9, lipocalin-2 and their complex in tumour tissue from 81 gastric cancer patients. The effect of the presence of the individual parameters, the complexes, and the inhibitors TIMP-1 and TIMP-2 on MMP-9 activity was evaluated with a bioactivity assay. Immuno-histochemical (double) staining identified epithelial cells as the most likely cellular source. Finally, evaluation of all these parameters with clinico-pathological scores revealed that tumour MMP-9/lipocalin-2 complexes were significantly related with the classifications of Laurén and WHO, and highly associated with worse survival in Cox's univariate (HR 2.087, P=0.006) and multivariate analyses (HR 2.095, P=0.025).
    European Journal of Cancer 09/2007; 43(12):1869-76. DOI:10.1016/j.ejca.2007.05.013 · 4.82 Impact Factor
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    ABSTRACT: Carcinogenesis in the human colon is associated with a marked increase in the tissue content of the urokinase-type plasmmogen activator (u-PA). This study was performed to determine the type of cells responsible for the u-PA increase in carcinomas of the colon and in their precursor lesions, the adenomas, by immunohistological evaluation applying monoclonal antibody 3689 directed to the β-chain of u-PA.Normal intestinal mucosa (n= 17) showed hardly any staining of u-PA, but some lamina propria cells were faintly positive. Carcinomas (n= 17) and adenomas (n= 16) showed a considerable and comparable staining intensity of u-PA in neoplastic columnar epithelial cells, and this staining was found to be diffuse and cytoplasmic. In a majority of the neoplastic tissues the u-PA staining was found to be patchy and not related to known risk markers of malignancy such as dysplasia in the adenomas, or to prognostic determinants such as Dukes' classification or differentiation in the carcinomas. The observation of strong u-PA positive lamina propria cells in adenomas but infrequently observed in normal mucosa and carcinomas was noteworthy. u-PA staining intensity of the tissue sections was found to correlate well with the u-PA antigen level in the tissue extracts determined by ELISA (r= 0.52, P= 0.0001) but poorly with the u-PA activity determined enzymatically (r= 0.28, P= 0.05).In conclusion, the u-PA increase in neoplasia of the human colon can be attributed to an increased diffuse cytoplasmic content of u-PA in neoplastic columnar epithelial cells.
    Histopathology 04/2007; 19(3):231 - 238. DOI:10.1111/j.1365-2559.1991.tb00027.x · 3.30 Impact Factor
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    ABSTRACT: The options for prevention of colorectal cancer in familial adenomatous polyposis are either a colectomy with ileorectal anastomosis (IRA) or a total proctocolectomy with ileal pouch-anal anastomosis (IPAA). Rectal cancer risk is eliminated by IPAA, but complication rate is higher than in IRA. Mutation analysis might predict severity of polyposis and be helpful in the surgical decision. Patients from the Dutch Polyposis Registry with an IRA were subdivided according to the site of adenomatous polyposis coli gene mutation into the attenuated (1), intermediate (2), and severe (3) genotype groups. Cumulative risks of secondary rectal excision and rectal cancer were calculated for each group. A total of 174 patients underwent an IRA: 26 patients from group 1, 121 from group 2, and 27 from group 3. Cumulative risks of rectal cancer 15 years after surgery were 6%, 3%, and 8% in groups 1, 2, and 3, respectively. Cumulative risks of rectal excision 20 years after IRA were 10%, 43%, and 74%, respectively. The risk of rectal excision was significantly higher in group 3 than in the other groups (P < .05). The risk of secondary rectal excision after IRA can be predicted on the basis of the adenomatous polyposis coli mutation site. An IRA appears to be the appropriate treatment in patients with the attenuated genotype. Patients with a severe genotype are good candidates for an IPAA.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 04/2007; 5(3):374-8. DOI:10.1016/j.cgh.2006.12.014 · 6.53 Impact Factor
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    ABSTRACT: Matrix metalloproteinases (MMPs) are involved in tissue remodelling, tumour invasion and metastasis. High levels of gelatinases MMP-2 and MMP-9 in various types of cancer tissue are associated with worse survival of the patients. Complexes of MMP-9 with neutrophil gelatinase-associated lipocalin (NGAL, also known as lipocalin-2) were found in urine from breast cancer patients but were absent in healthy controls, suggesting a possible application as tumour marker. We analyzed the presence of MMP-9/NGAL complexes in tissue from gastric cancer patients and determined their possible clinical value. MMP-9, NGAL, and MMP-9/NGAL complexes were determined in 81 tissue homogenates from gastric cancer patients using quantitative zymography, ELISAs and a specific MMP-9 bioactivity assay. The tumour levels were examined for associations with established clinico-pathological parameters including classifications according to TNM, WHO, Laurén, and survival. Gastric carcinomas were found to have significantly increased MMP-9 (P Keywords: MMP-9; lipocalin; prognosis Document Type: Research Article DOI: http://dx.doi.org/10.1111/j.1538-7836.2006.00108.x Affiliations: 1: LUMC, Gastroenterology-Hepatology, Leiden, The Netherlands 2: University of Bieleveld, Germany 3: TNO Quality of Life, Biomedical Research, Leiden, The Netherlands Publication date: October 1, 2006 $(document).ready(function() { var shortdescription = $(".originaldescription").text().replace(/\\&/g, '&').replace(/\\, '<').replace(/\\>/g, '>').replace(/\\t/g, ' ').replace(/\\n/g, ''); if (shortdescription.length > 350){ shortdescription = "" + shortdescription.substring(0,250) + "... more"; } $(".descriptionitem").prepend(shortdescription); $(".shortdescription a").click(function() { $(".shortdescription").hide(); $(".originaldescription").slideDown(); return false; }); }); Related content In this: publication By this: publisher In this Subject: Allergy & Immunology By this author: Sier, C. ; Kubben, F. ; Hawinkels, L. ; Tschesche, H. ; van Duijn, W. ; Zuidwijk, K. ; van der Reijden, J. ; Hanemaaijer, R. ; Griffioen, G. ; Verspaget, H. GA_googleFillSlot("Horizontal_banner_bottom");
    Journal of Thrombosis and Haemostasis 10/2006; 4:127-127. DOI:10.1111/j.1538-7836.2006.00108.x · 5.55 Impact Factor
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    ABSTRACT: Enhanced antigen levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are associated with clinico-pathological parameters of the tumors and survival of patients with gastric cancer. Recently, Single Nucleotide Polymorphisms (SNPs) in MMP- and TIMP-genes have been associated with susceptibility for various diseases. In this study, we studied the genotype distribution and allele frequencies of SNPs of MMP-2, -7, -8 and -9 and TIMP-1 and -2 in gastric cancer patients in relation to tumor progression, patient survival, and tissue antigen expression. Genomic DNA was isolated from tissue of 81 Caucasian gastric cancer patients and from blood of 169 controls. Genotypes were analyzed by PCR based techniques. Antigen levels for MMPs and TIMPs were determined in tissue homogenates from the same patients using specific ELISAs. Genotype distribution and allele frequencies of MMP-2, -7, -8, -9, and TIMP-1 and -2 were similar in gastric cancer patients and controls, except for MMP-7-181 A>G. In addition, the genotype distribution of MMP-7-181 A>G was associated with H. pylori status (X2 7.8, P=0.005) and tumor-related survival of the patients (Log Rank 3.57, P=0.059). SNP TIMP-2303C>T correlated significantly with the WHO classification (X2 5.9, P=0.03) and strongly with tumor-related survival (Log Rank 11.74, P=0.0006). SNPs of MMP-2, -8, -9 and TIMP-1 were not associated with tumor-related survival. Only the MMP-2-1306 C>T polymorphism, located in the promoter of the gene, correlated significantly with the protein level within the tumors. First order dendrogram cluster analysis combined with Cox analysis identified the MMP-7-181 A>G and TIMP-2303C>T polymorphism combination to have a major impact on patients survival outcome. Conclusions: Determination of MMP-related SNPs, especially MMP-7-181 A>G and TIMP-2303C>T, might be a useful tool to stratify and select patients for primary resection and (neo)-adjuvant treatment of gastric cancer aiming at better outcome. In addition, upregulated protein level of MMP-2, associated with a promoter-located SNP, is a consistent independent prognostic factor in gastric cancer.
    Journal of Thrombosis and Haemostasis 10/2006; 4:128-128. DOI:10.1111/j.1538-7836.2006.00110.x · 5.55 Impact Factor
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    ABSTRACT: Gastric cancers express enhanced levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes may be associated with disease susceptibility and might also affect their antigen expression. We studied the genotype distribution and allele frequencies of SNPs of MMP-2, -7, -8 and -9 and TIMP-1 and -2 in gastric cancer patients in relation to tumour progression, patient survival and tissue antigen expression. The genotype distribution and allele frequencies were similar in gastric cancer patients and controls, except for MMP-7(-181A>G). In addition, the genotype distribution of MMP-7(-181A>G) was associated with Helicobacter pylori status (chi(2) 7.8, P=0.005) and tumour-related survival of the patients. Single-nucleotide polymorphism TIMP-2(303C>T) correlated significantly with the WHO classification (chi(2) 5.9, P=0.03) and also strongly with tumour-related survival (log rank 11.74, P=0.0006). Single-nucleotide polymorphisms of MMP-2, -8, -9 and TIMP-1 were not associated with tumour-related survival. Only the gene promoter MMP-2(-1306C>T) polymorphism correlated significantly with the protein level within the tumours. First-order dendrogram cluster analysis combined with Cox analysis identified the MMP-7(-181A>G) and TIMP-2(303C>T) polymorphism combination to have a major impact on patients survival outcome. We conclude that MMP-related SNPs, especially MMP-7(-181A>G) and TIMP-2(303C>T), may be helpful in identifying gastric cancer patients with a poor clinical outcome.
    British Journal of Cancer 09/2006; 95(6):744-51. DOI:10.1038/sj.bjc.6603307 · 4.82 Impact Factor
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    ABSTRACT: In a pioneer study, we showed 10 years ago that enhanced tissue levels of the matrix metalloproteinases (MMPs) MMP-2 and MMP-9 in gastric cancers, as determined by zymography, were related with worse overall survival of the patients. To corroborate these observations, we now assessed MMP-2 and MMP-9 with new techniques in an expanded group of gastric cancer patients (n = 81) and included for comparison MMP-7, MMP-8 and the tissue inhibitors of MMPs, TIMP-1 and -2. All MMPs and TIMP-1 were significantly increased in tumour tissue compared to normal gastric mucosa. Matrix metalloproteinase-7, -8 and -9, and the TIMPs showed some correlations with the clinicopathologic parameters TNM, WHO and Laurén classification, but their levels were not related with survival. Regardless of the determination method used, that is, enzyme-linked immunosorbent assay or bioactivity assay, an enhanced tumour MMP-2 level did not show a significant correlation with any of the clinicopathological parameters, but was confirmed to be an independent prognostic factor in gastric cancer.
    British Journal of Cancer 05/2006; 94(7):1035-40. DOI:10.1038/sj.bjc.6603041 · 4.82 Impact Factor
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    ABSTRACT: Crohn's disease is associated with a host of factors potentially increasing the risk for osteoporosis and fractures. The aim of our study was to identify the most predictive factors for skeletal pathology in this patients. Using a cross-sectional study design, 146 randomly selected patients with Crohn's disease of variable disease activity who were given standard therapy to control disease activity, including glucocorticoids, and who attended the outpatient clinic of the Gastroenterology Unit on regular follow-up visits were studied. Bone mineral density (BMD) measurements and lateral X-rays of the spine were performed, and biochemical parameters of bone turnover, gonadal hormones and C-reactive protein (CRP) as markers of disease activity were measured in all patients. There were 61 men and 85 women, with a mean age of 43 years and mean disease duration of 20 years. The majority of patients (86%) had been treated with glucocorticoids at some stage during their illness at a median dose of 7.5 mg/day, 43% were currently using these agents and 66% had undergone an intestinal resection. Twenty-one percent of patients had below-normal 25-hydroxy vitamin D levels. Osteoporosis was documented in 26% of patients, predominantly at the femoral neck, but also at the lumbar spine or at both sites; osteopenia was documented in 45% of patients. Prevalence of vertebral and non-vertebral fractures was, respectively, 6% and 12%. Ileum resection was the most predictive factor for osteoporosis: RR 3.84 (CI 1.24-9.77, p=0.018), followed by age: RR 1.05 (CI 1.02-1.08, p<0.001) and current or past glucocorticoid use: RR 1.94 (CI 0.92-4.10, p=0.08). Our data suggest that in patients with Crohn's disease, the risk of osteoporosis is best predicted by a history of ileum resection.
    Osteoporosis International 04/2006; 17(4):535-42. DOI:10.1007/s00198-005-0016-7 · 4.17 Impact Factor
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    ABSTRACT: Lynch syndrome family members have a high risk of developing colorectal (CRC), endometrial (EC), and other cancers. A large-scale surveillance program was introduced in The Netherlands in the late 1980s. The aims of the study were to evaluate the effectiveness of this program by assessing mortality because of CRC and EC before and after 1990 and to compare mortality because of all cancers (except CRC/EC) with mortality in the general population. Family members with at least 50% probability of being a carrier were selected for the study. The standardized mortality ratio (SMR) because of cancer and the absolute excess risk of death (AER) were calculated. In the total cohort (N = 2788), 445 subjects had died because of cancer. The 3 most frequent causes of cancer-related deaths were CRC (50.3%), EC (6.7%), and brain tumors (6.7%). A significant decrease (70%) in SMR for CRC over time was observed (P < .001); the SMR for EC showed no decreasing trend over time. A significantly increased SMR was found for cancer of the small bowel (SMR = 18.3), brain (SMR = 9.1), kidney/ureter (SMR = 5.9), ovarium (SMR = 2.3), pancreas (SMR = 2.2), and stomach (SMR = 2.1). The AER was significantly increased for brain tumors only. Since the introduction of surveillance, the mortality because of CRC has decreased. Except for brain tumors, we did not find a significantly increased AER for tumors other than CRC/EC.
    Gastroenterology 04/2006; 130(3):665-71. DOI:10.1053/j.gastro.2005.11.032 · 13.93 Impact Factor
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    ABSTRACT: Lynch syndrome families have a substantial risk of developing colorectal cancer (CRC). The recommended surveillance protocol includes colonoscopy every 2 years from age 20-25 years. It is yet unknown whether annual screening of patients aged 40-60 years is more effective than bi-annual screening, whether patients who had an adenoma removed should be re-examined after a year and whether surveillance of second-degree relatives is indicated. The aim of this study was to address these issues. All carriers of a mismatch repair gene mutation who participated in the surveillance program were selected from the Dutch Lynch syndrome registry. The results of colonoscopy were prospectively collected. A total of 666 mutation carriers were identified in 110 families. Fourty-one CRCs were detected during endoscopic follow-up, of which 34 (83%) were diagnosed between age 40 and 60 years. In five of 34 patients, CRC was diagnosed within 1 year after colonoscopy, eight cancers were diagnosed between 1 and 2 years and the remaining tumors more than 2 years after colonoscopy. All eight CRCs detected between 1 and 2 years were at local stage. At least one adenoma was diagnosed at 141 examinations. The risk of developing CRC during follow-up in carriers with an adenoma was similar as in carriers without an adenoma at the previous colonoscopy. 280 parent-child couples with at least one Lynch syndrome-related carcinoma were identified in 110 families. In only 19 (6.8%) of these couples, CRC developed earlier in the child than an Lynch syndrome-associated cancer in the parent. The current surveillance protocol, i.e., bi-annual colonoscopy in first-degree relatives independent of age and endoscopic findings, appears to be appropriate.
    Familial Cancer 02/2006; 5(4):373-8. DOI:10.1007/s10689-006-0008-6 · 1.62 Impact Factor
  • European Journal of Gastroenterology & Hepatology 01/2006; 18(1). DOI:10.1097/00042737-200601000-00203 · 2.15 Impact Factor
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    ABSTRACT: We evaluated the prevalence and characteristics of adenomas in a young population not genetically predisposed for the development of colorectal cancer (CRC). The databases of the Dutch Hereditary Colorectal Cancer Registry were used. The study population included patients (n = 444) who had regular endoscopy until mutation analysis revealed they did not carry the (Adenomatous Polyposis Coli (APC)/Mismatch Repair) gene defect identified in their family. At first colonoscopy (n = 342; 50% males, mean age 37 yr) a total of 19 adenomas (10 males, mean age 50 yr, range 24-91 yr) and two CRCs (2 males, age 49 and 72 yr) were identified, and at first sigmoidoscopy (n = 102; 53% males, mean age 29 yr) three adenomas (2 males, age 8, 40, and 41 yr) were found. A second colonoscopy was performed in 14 patients with, and in 162 patients without an adenoma. Three of 14 patients (21%) developed a new adenoma (all >50 yr) and 8 of 162 (5%) patients developed their first adenoma during follow-up. In the colonoscopy group, the cumulative proportion of patients free of adenomas at age 50 yr was 86%. Of all adenomas diagnosed during colonoscopy (n = 49), 65% were located distal from the flexura lienalis. Of the adenomas detected during all endoscopies (n = 53), 9.8% were > or =7 mm, 7.5% showed high-grade dysplasia, and 7.5% showed tubulovillous features. On the basis of our findings during colonoscopy we conclude that the risk of developing adenomas/CRC in young individuals without genetic risk factors is low. Adenoma surveillance programs should focus on young individuals with a positive family (or personal) history for adenomas/CRC, or on individuals >50 yr.
    The American Journal of Gastroenterology 02/2005; 100(1):139-43. DOI:10.1111/j.1572-0241.2005.41000.x · 9.21 Impact Factor
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    ABSTRACT: In vitro studies suggest that a deficient mismatch repair (MMR) system reduces 5-Fluorouracil cytotoxicity. Colon cancer (CC) in hereditary nonpolyposis colorectal cancer (HNPCC) is due to a dysfunctioning MMR gene that leads to microsatellite instability (MSI). Clinical studies on the efficacy of 5-Fluorouracil (5-FU) in MSI high tumours are contradictory. In a retrospective study, we compared the survival of subjects with stage III CC from HNPCC families that were treated with and without adjuvant 5-FU. The Dutch HNPCC family registry was used. Information on adjuvant chemotherapy for stage III CC was obtained from subjects of families with a mutation and/or who fulfilled the AMS criteria or who were strongly suspicious for HNPCC. CC specific survival was calculated. Observation time was measured either until the date of death, date of a second primary CC or until the closing date of the study, i.e., June 1, 2001. Statistical analysis was done by Kaplan-Meier survival analysis. A total of 92 subjects with stage III CC were included. Twenty-eight of them (17 males) had adjuvant treatment with 5-FU. The median follow-up was 4 (range: 1-17) years; 8 subjects died of CC. The 5-year survival was 70% (95% Cl: 49-90). Sixty-four subjects (36 males) did not have adjuvant therapy. Their median follow-up was 6 (range: 0-23) years. Twenty of them died of CC. The 5-year survival in this group was also 70% (95% Cl: 59-83). To date, the selection of patients with CC for 5-FU treatment is based on the stage rather than the biology of the tumour. In our study, the 5-year survival of subjects treated with and without adjuvant 5-FU did not differ. Further studies are necessary to elucidate the role of MSI in 5-FU treatment of MSI-H tumours in HNPCC.
    International Journal of Cancer 05/2004; 109(3):468-71. DOI:10.1002/ijc.11712 · 5.01 Impact Factor
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    Journal of Medical Genetics 04/2004; 41(3):e31. · 5.64 Impact Factor
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    ABSTRACT: Barrett's oesophagus develops as a consequence of severe gastro-oesophageal reflux. The importance of Barrett's oesophagus lies in the small risk of developing high-grade dysplasia and subsequent adenocarcinoma. Because of poor treatment results in patients with advanced adenocarcinoma, surveillance of patients with Barrett's oesophagus for the development of dysplasia, although not uncontroversial, is widely practised in the gastroenterological community. The aim of surveillance is to detect adenocarcinoma in an early stadium where surgical cure is possible. In recent years several endoscopic treatments for both high-grade dysplasia and intramucosal adenocarcinoma have been developed. In this review some basic aspects of Barrett's oesophagus are discussed together with endoscopic treatments such as endoscopic mucosal resection, local thermal treatments and photodynamic therapy. Although surgical resection is probably the treatment of choice in fit patients, local endoscopic treatments should be considered in patients with high-grade dysplasia or intramucosal carcinoma who are unfit or unwilling to have surgery.
    Scandinavian journal of gastroenterology. Supplement 02/2004; DOI:10.1080/00855920410010979
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    ABSTRACT: In view of the high risk of developing a new primary colorectal carcinoma (CRC), subtotal colectomy rather than segmental resection or hemicolectomy is the preferred treatment in hereditary non-polyposis colorectal cancer (HNPCC) patients. Subtotal colectomy however implies a substantial decrease in quality of life. To date, colonoscopic surveillance has been shown to reduce CRC occurrence. To compare the potential health effects in terms of life expectancy (LE) for patients undergoing subtotal colectomy or hemicolectomy for CRC. A decision analysis (Markov) model was created. Information on the 10 year risk of CRC after subtotal colectomy (4%) and hemicolectomy (16%) and stages of CRCs detected within a two year surveillance interval (32% Dukes' A, 54% Dukes' B, and 14% Dukes' C) were derived from two cohort studies. Five year survival rates used for the different Dukes stages (A, B, and C) were 98%, 80%, and 60%, respectively. Remaining LE values were calculated for hypothetical cohorts with an age at CRC diagnosis of 27, 47, and 67 years, respectively. Remaining LE values were also calculated for patients with CRC of Dukes' stage A. The overall LE gain of subtotal colectomy compared with hemicolectomy at ages 27, 47, and 67 was 2.3, 1, and 0.3 years, respectively. Specifically for Dukes' stage A, this would be 3.4, 1.5, and 0.4 years. Unless surveillance results improve, subtotal colectomy still seems the preferred treatment for CRC in HNPCC in view of the difference in LE. For older patients, hemicolectomy may be an option as there is no appreciable difference in LE.
    Gut 01/2004; 52(12):1752-5. · 13.32 Impact Factor
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    ABSTRACT: The adenoma-carcinoma sequence in hereditary nonpolyposis colorectal cancer (HNPCC) is accelerated. It remains unknown whether the mismatch repair (MMR) defect also promotes the development of adenomas. The aim of this study was to compare the risk of developing colorectal adenoma and carcinoma in HNPCC carriers and noncarriers (controls) and to compare the features of adenomas in both groups. Eighty-six families with a known MMR gene mutation from the Dutch HNPCC Registry were analyzed. Subjects with known mutation status with colonoscopies performed for the purpose of surveillance were selected for this study. Information on the surveillance examinations was obtained from medical reports. The histology of all adenomas was confirmed. Immunohistochemistry was performed in a subgroup of adenomas. We identified 249 carriers and 247 controls. The proportion of subjects free of an adenoma at the age of 60 years was 29.7% for carriers and 70.8% for controls (P < 0.05). The adenomas in carriers were larger, and a higher proportion had villous components and/or high-grade dysplasia (P < 0.05, all analyses). The adenomas and carcinomas of the carriers were located predominantly in the proximal colon. Most adenomas showed absent staining of the MMR proteins. This study indicates that the MMR defect is involved in the early stages of development of adenomas. We recommend immunohistochemical staining of large adenomas with high-grade dysplasia in young patients (younger than 50 years) to identify patients with suspected HNPCC.
    Gastroenterology 01/2004; 126(1):42-8. DOI:10.1053/j.gastro.2003.10.043 · 13.93 Impact Factor
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    ABSTRACT: The purpose is to document the clinical, pathological, and genetic features of pancreatic carcinoma (PC) in carriers of a specific p16-Leiden mutation (a 19-bp deletion in exon 2 of the CDKN2A gene). Clinical data and paraffin embedded tissue were obtained from 12 patients of p16-Leiden-positive families with PC. Because of the known 19-bp germ-line deletion, we could specifically analyze the genotype of the wild-type allele for loss of heterozygosity. K-ras codon 12 mutations were determined and immunohistochemical testing for p16, Tp53, Smad4, and cyclooxygenase 2 was performed. The average age of subjects that developed PC (8 males) was 58 years (range, 43-74 years). Histology was considered as conventional ductal adenocarcinoma in 11 of 12 and neuroendocrine carcinoma (1 of 12). The carcinomas were located in the head (10 of 12), corpus (1 of 12), and tail (1 of 12) of the pancreas. The specific p16-Leiden mutation was confirmed in the tissue of all subjects. Loss of heterozygosity of the wild-type allele was present in 2 of 7 tumors analyzed. Immunostaining for p16 was negative in 10 of 10. Tp53 mutations were detected in 5 of 12. Smad4 was negative in 5 of 12 and cyclooxygenase 2 was overexpressed in 11 of 12. K-ras codon 12 mutations were present in 9 of 10 and in three precursor lesions even before abrogation of p16 protein expression was seen (one of three). The p16-Leiden deletion was associated with progression toward conventional ductal adenocarcinomas in all cases but one. Our observations might support the feasibility of early diagnosis of PC in p16-Leiden mutation carriers and might also indicate that chemoprevention needs consideration.
    Clinical Cancer Research 10/2003; 9(10 Pt 1):3598-605. · 8.19 Impact Factor
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    ABSTRACT: The lifetime risk of developing duodenal cancer in familial adenomatous polyposis (FAP) is about 5 per cent. When and to what extent surgical intervention should be undertaken to prevent death from invasive carcinoma is controversial. The aim of this study was to determine the effectiveness of various surgical treatments for cancer and severe duodenal adenomatosis. A questionnaire was mailed to the members of the Leeds Castle Polyposis Group to obtain data on patients with FAP, treated for duodenal cancer or severe duodenal adenomatosis after 1990. Sixty-nine patients were included. The indication for surgery was invasive cancer in 13 patients, of whom six died from metastatic disease. Fifty-six patients were initially treated for severe duodenal adenomatosis, five (9 per cent) of whom died from metastatic disease (P = 0.002). In surviving patients, adenomas recurred after ampullectomy (six of eight, at mean follow-up of 11 months), after duodenotomy with polypectomy (17 of 21, at mean 29 months) and after pancreatoduodenectomy (six of 25, at mean 47 months). None of six patients who underwent a pancreas-sparing duodenectomy had recurrence of adenoma (mean follow-up 11 months). Surgery for duodenal adenomatosis should take place before endoscopic biopsy reveals invasive cancer. Even after extensive surgical procedures, small bowel adenomas may occur, emphasizing the need for chemoprevention.
    British Journal of Surgery 07/2003; 90(6):705-10. DOI:10.1002/bjs.4094 · 5.21 Impact Factor
  • Gastroenterology 04/2003; 124(4). DOI:10.1016/S0016-5085(03)81191-5 · 13.93 Impact Factor

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5k Citations
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  • 2007
    • Technische Universität München
      München, Bavaria, Germany
  • 1987–2007
    • Leiden University Medical Centre
      • Department of Gastroenterology and Hepatology
      Leyden, South Holland, Netherlands
  • 2006
    • University of Groningen
      Groningen, Groningen, Netherlands
  • 1988–2006
    • Leiden University
      • Molecular Cell Biology Group
      Leyden, South Holland, Netherlands
  • 1998
    • Bielefeld University
      Bielefeld, North Rhine-Westphalia, Germany
  • 1989
    • Maastricht University
      • Department of Pathology
      Maestricht, Limburg, Netherlands