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Background: In 2003 Wein et al. published data after a short median follow up (23 months). Here we report on the long-term results., Material/methods: The patients (n=20) received a neoadjuvant treatment regimen comprising biweekly 85 mg/m2 oxaliplatin (L-OHP) (2h-infusion, d 1, 15, 29 qd 57) and 500 mg/m2 calcium folinic acid (FA) (1-2h-infusion, d 1, 8, 15, 22, 29, 36 qd 57) followed by 2600 mg/m2 5-Fluorouracil (5-FU) (24h-infusion, d 1, 8, 15, 22, 29, 36 qd 57). Two cycles of chemotherapy were administered, with a third being added when the treatment was well tolerated. Thereafter, curative resection of the liver metastases was attempted., Results: After neoadjuvant therapy, imaging procedures revealed complete remission in 2 patients (10%) and partial remission in 18 patients (90%). Diarrhea (Common Toxicity Criteria toxicity grade 3) was observed in 6 patients (30%) as main symptom of toxicity, followed by vomiting in 3 patients (15%). Higher grade sensomotoric neuropathy did not present. The curative resectability rate (R0) was 80%. In 9 out of 18 patients (50%) undergoing surgical intervention minor postoperative complications occurred. No postoperative mortality was observed. Over a median follow up of 45,5 months the median survival of all patients is 3.0 years and the 5-year overall survival rate is 40%. The 5-year disease-free survival rate is 25%., Conclusions: Neoadjuvant treatment with 5-FU combined with FA and L-OHP proved to be highly effective and well tolerated. Disease-free survival rates and median overall survival rates are promising.

Purpose: To asses if laser-induced thermotherapy (LITT) induces a specific cytotoxic T cell response in patients treated with LITT for colorectal cancer liver metastases., Methods: Eleven patients with liver metastases of colorectal cancer underwent LITT. Blood was sampled before and after LITT. Peripheral T cell activation was assessed by an interferon gamma (IFNg) secretion assay and flow cytometry. Test antigens were autologous liver and tumor lysate obtained from each patient by biopsy. T cells were stained for CD3/CD4/CD8 and IFNg to detect activated T cells. The ratio of IFNg positive to IFNg negative T cells was determined as the stimulation index (SI). To assess cytolytic activity, T cells were co-incubated with human colorectal cancer cells (CaCo) and cytosolic adenylate kinase release was measured by a luciferase assay., Results: IFNg secretion assay: before LITT SI was 12.73 (+/-4.83) for CD3+, 4.36 (+/-3.32) for CD4+ and 3.64 (+/-1.77) for CD8+ T cells against autologous tumor tissue. Four weeks after LITT SI had increased to 92.09 (+/-12.04) for CD3+ (P < 0.001), 42.92 (+/-16.68) for CD4+ (P < 0.001) and 47.54 (+/-15.68) for CD8+ T cells (P < 0.001) against autologous tumor tissue. No increased SI was observed with normal liver tissue at any time point. Cytotoxicity assay: before LITT activity against the respective cancer cells was low, with RLU = 1,493 (+/-1,954.68), whereas after LITT cytolytic activity had increased to RLU = 7,260 [+/-3,929.76 (P < 0.001)]., Conclusion: Patients with liver metastases of colorectal cancer show a tumor-specific cytotoxic T cell stimulation and a significantly increased cytolytic activity of CD3+, CD4+ and CD8+ T cells after LITT against an allogenic tumor (CaCo cell line).

Objective: Because of the high recurrence rates of colorectal adenomas, regular surveillance by colonoscopy has been recommended, but there is still a dearth of information on the long-term results of follow-up colonoscopy after polypectomy. The aims of this study were to determine the differences between initial adenomas and metachronous lesions, to evaluate the effect of long-term surveillance and to describe the hypothetical origin of the colorectal adenoma-carcinoma sequence., Material and Methods: Between 1978 and 2003 a total of 1091 patients undergoing periodic surveillance examinations were prospectively documented at the Erlangen Registry of Colorectal Polyps. Differences between initial and metachronous lesions found during long-term follow-up were studied. Statistical analysis using chi(2) testing of adenoma characteristics found in four subsequent recurrence periods was carried out, and the relative risk (RR) for the development of metachronous adenomas of advanced pathology was calculated., Results: In comparison with the initial findings, metachronous adenomas are generally significantly smaller lesions (p<0.00001), usually tubular in shape (p<0.00001) and bearing high-grade dysplasia less often (p<0.00001) and are usually located in the right colon (p<0.00001). These differences are found between the initial and four subsequent generations of metachronous adenomas. The number of synchronous adenomas is reduced only in the first recurrence (p<0.001); in the further generations equal proportions of multiplicity are found, as in the baseline examination. Patients with adenomas of advanced pathology, i.e. large, tubulovillous or villous adenomas at baseline, have a significantly higher risk for large (RR 2.73; 95% CI 1.77-4.20), tubulovillous or villous (RR 1.55; 95% CI 1.06-2.25) or multiple (RR 2.45; 95% CI 1.83-3.29) metachronous adenomas at the first recurrence., Conclusions: Metachronous adenomas show the uniform characteristics of being small tubular lesions rarely bearing high-grade dysplasia, usually located in the right colon. Thus regular follow-up colonoscopy can provide sufficient colorectal carcinoma prevention.

Background: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been strongly implicated in the pathogenesis of many types of human cancer. We wanted to specifically define their role in established colorectal cancer liver metastases., Patients and Methods: The MMP/TIMP expression profiles of N=9 colorectal primary tumour liver metastasis tissue pairs were determined using oligonucleotide-based arrays. Expression levels for the most relevant MMPs were confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR). Additionally, unsupervised clustering using the MMP/TIMP profile of N=25 colorectal cancer liver metastases was performed and the response to palliative 5-fluorouracil (5-FU)-based chemotherapy was assessed using radiological response criteria., Results: When comparing the primary tumors to their synchronous liver metastases, a statistically significant (p < 0.05) down-regulation of MMP1, -2, -3 and -12 was found in the metastases. Unsupervised clustering using the MMP/TIMP profiles of 25 liver metastases revealed two distinct subgroups with different responses to palliative, 5-FU-based chemotherapy (response rates: 22% vs. 56%, respectively). In particular, higher MMP7, TIMP1 and TIMP2 levels were found in the unfavourable group, while higher expression of MMP2, -9, -11 and -14 was associated with a more favourable response to chemotherapy., Conclusion: Colorectal cancer liver metastases show a distinctive MMP/TIMP profile with predictive implications.

Microarray analysis reaches increasing popularity during the investigation of prognostic gene clusters in oncology. The standardisation of technical procedures will be essential to compare various datasets produced by different research groups. In several projects the amount of available tissue is limited. In such cases the preamplification of RNA might be necessary prior to microarray hybridisation. To evaluate the comparability of microarray results generated either by amplified or non amplified RNA we isolated RNA from colorectal cancer samples (stage UICC IV) following tumour tissue enrichment by macroscopic manual dissection (CMD). One part of the RNA was directly labelled and hybridised to GeneChips (HG-U133A, Affymetrix), the other part of the RNA was amplified according to the "Eberwine" protocol and was then hybridised to the microarrays. During unsupervised hierarchical clustering the samples were divided in groups regarding the RNA pre-treatment and 5.726 differentially expressed genes were identified. Using independent microarray data of 31 amplified vs. 24 non amplified RNA samples from colon carcinomas (stage UICC III) in a set of 50 predictive genes we validated the amplification bias. In conclusion microarray data resulting from different pre-processing regarding RNA pre-amplification can not be compared within one analysis.

Background: According to the adenoma-carcinoma concept, all colorectal adenomas are to be removed and all patients have to undergo regular surveillance examinations. But there is still shortage on information on the long-term results of follow-up colonoscopy after polypectomy., Methods: Between 1978 and 2003, more than 20,000 polyps were prospectively documented at the Erlangen Registry of Colorectal Polyps. A total of 1,091 patients undergoing periodic surveillance examinations are studied for differences between initial and metachronous lesions of the colorectum. Statistical analysis using chi (2)-testing of adenoma characteristics found in four subsequent recurrence periods and calculation of the relative risk (RR) for the development of metachronous adenomas of advanced pathology was performed., Results: In comparison with the initial findings, metachronous adenomas are, in general, significantly smaller ones (p < 0.00001), more frequently tubular lesions (p < 0.00001) and bearing less often high-grade dysplasia (p < 0.00001). Adenomas of advanced pathology were significantly less often found during follow-up than at baseline examination (p < 0.0001). These differences are found between the initial and four subsequent generations of metachronous adenomas. Patients with adenomas of advanced pathology at baseline have a significantly higher risk for metachronous adenomas of advanced pathology (RR 1.51; 95%CI 1.04-1.93) at the first recurrence., Conclusions: Metachronous adenomas show uniform characteristics of being small tubular lesions rarely bearing high-grade dysplasia. Thus, regular surveillance examinations can provide sufficient colorectal carcinoma prevention.

Objective: For colorectal screening patients a mean gain of life time was previously calculated of about 30-50 days. Different recommendations for recognising at-risk groups and defining surveillance intervals after an initial finding of colorectal adenomas have been published. However, no benefit-risk analysis regarding to specific long-term effects of follow-up has been reported to date., Materials and Methods: A Markov model based on time-dependent transition possibilities was developed to perform a benefit-risk analysis of the risk-related surveillance recommendations based on the Erlangen Registry of Colorectal Polyps (ERCRP) in comparison with the recommendation of the German Society of Gastrointestinal Diseases and Nutrition (DGVS). The outcome was calculated for a 50-year-old patient with 30 years of follow-up after initial polypectomy. The data used in this model were taken from different sources, namely the ERCRP, the German Study Group of Colorectal Cancer, the German Statistical Yearbook, and from meta-analyses of studies reporting data on complications and sensitivity of colonoscopy., Results: Patients under surveillance have a mean lifetime gain of 98 (ERCRP) and 110 (DGVS) days compared with those who do not come for surveillance. 84% and 94% of deaths from colorectal carcinoma (CRC) could be prevented if patients were followed up according to the recommendations of the ERCRP and the DGVS, respectively. Less colonoscopies are needed to prevent one death from CRC following the recommendations of the ERCRP (221) than those of the DGVS (283). The risk of death due to colonoscopy for patients during follow-up is about 0.05% lifetime risk. Sensitivity analysis showed the stability of the results under a wide range of reasonable variations of relevant parameters. In a pessimistic one-way sensitivity analysis regarding compliance, effectiveness was reduced to one third., Conclusion: Surveillance using colonoscopy is an effective tool for preventing CRC after colorectal polypectomy, especially if a good compliance is assumed. The effectiveness is higher following the recommendations of the DGVS, but more colonoscopies are needed.

Aim: To assess the extent and reasons of non-compliance in surveillance for patients undergoing polypectomy of large (> or = 1 cm) colorectal adenomas., Methods: Between 1995 and 2002, colorectal adenomas > or = 1 cm were diagnosed in 210 patients and subsequently documented at the Erlangen Registry of Colorectal Polyps. One hundred and fifty-eight patients (75.2%) could be contacted by telephone and agreed to be interviewed. Additionally, records were obtained from the treating physicians., Results: Fifty-four out of 158 patients (34.2%) neglected any surveillance. Reasons for non-compliance included lack of knowledge concerning surveillance intervals (45.8%), no symptoms (29.2%), fear of examination (18.8%) or old age/severe illness (6.3%). In a multivariate analysis, the factors including female gender (P = 0.036) and age > 62 years (P = 0.016) proved to be significantly associated with non-compliance in surveillance., Conclusion: Efforts to increase compliance in surveillance are of utmost importance. This applies particularly to women's compliance. Effective strategies for avoiding metachronous colorectal adenoma and cancer should focus on both the improvement in awareness and knowledge of patients and information about physicians for surveillance.

Aim: To assess if a specific cytotoxic T cell response can be induced in patients with malignant liver tumors treated with radio-frequency ablation (RFA)., Methods: Six Patients with liver metastases of colorectal cancer and 6 with hepatocellular carcinoma (HCC) underwent RFA. Blood was sampled before, 4 and 8 wk after RFA. Test antigens were autologous liver and tumor lysate obtained from each patient by biopsy. Peripheral T cell activation was assessed by an interferon gamma (IFNgamma) secretion assay and flow cytometry. T cells were double-stained for CD4/CD8 and IFNgamma to detect cytotoxic T cells. The ratio of IFNgamma positive and IFNgamma negative T cells was determined as the stimulation index (SI). To assess cytolytic activity, T cells were co-incubated with human CaCo colorectal cancer and HepG2 HCC cells and release of cytosolic adenylate kinase was measured by a luciferase assay., Results: Before RFA SI was 0.021 (+/- 0.006) for CD4(+) and 0.022 (+/- 0.004) for CD8(+) T cells against nonmalignant liver tissue and 0.018 (+/- 0.005) for CD4(+) and 0.021 (+/- 0.004) for CD8(+) cells against autologous tumor tissue. Four weeks after RFA SI against tumor tissue increased to 0.109 (+/- 0.005) for CD4(+) and 0.11 (+/- 0.012) for CD8(+) T cells against HCC, and to 0.115 (+/- 0.031) for CD4(+) and 0.15 (+/- 0.02) for CD8(+) cells for colorectal metastases (P < 0.0001). No increased SI was observed with nonmalignant tumor tissue at all time points. Before RFA cytolytic activity against the respective cancer cells was low with 2.62 (+/- 0.37) relative luminescence units (RLU), but rose more than 100 fold 4 and 8 wk after RFA. Spontaneous release was < 2% of maximum release in all experiments., Conclusion: Patients with primary and secondary tumors of the liver show a significant tumor-specific cytotoxic T-cell stimulation with a dramatically increased tumor specific cytolytic activity of CD8(+) T cells after RFA.

Methylation of promoter regions and frameshift mutations in microsatellites of the coding sequence (CDS) of genes are frequently associated with loss of expression in microsatellite instable (MSI) colorectal carcinoma. In a panel of 40 MSI and 24 microsatellite stable (MSS) colorectal tumours as well as six cultured colorectal carcinoma cell lines hypermethylation of the TIMP3-promoter was found in 28% of MSI and 25% of MSS tumours, respectively. Additionally, three MSI tumours and one cell line displayed instability of a C7-repeat located in the CDS of the TIMP-3 gene. TIMP-3 fulfils all important criteria for being a target gene in the mutator pathway. Thus, TIMP-3 might be a factor of general importance for colorectal carcinogenesis.

Purpose: Desmoid tumors, also known as aggressive fibromatosis, occur with an incidence of 10 to 15 percent in patients affected by familial adenomatous polyposis, an autosomal inherited disease caused by germline mutations in the APC gene. However, sporadic forms with no hereditary background exist. The aim of this study was to find out whether there are APC germline mutations in apparently sporadic desmoid tumor patients without clinical or familial signs of familial adenomatous polyposis but with a family history of colorectal carcinoma in at least one family member., Methods: Genomic DNA and mRNA were isolated from peripheral blood leukocytes of index patients of eight nonrelated families. Mutation screening was performed using reverse transcriptase polymerase chain reaction-based protein truncation test for APC exons 1-14. The large APC exon 15 was scrutinized by the protein truncation test of four overlapping genomic fragments. Additionally, genomic DNA from five desmoid tumors was analyzed for loss of heterozygosity at D5S346 close to the APC locus., Results: No translational stop mutations typical for familial adenomatous polyposis could be found in the APC gene in any of the analyzed blood samples from the desmoid tumor patients. Additionally, no loss of heterozygosity at D5S346 was found in four of five desmoids; one tumor was not informative., Conclusions: These results may suggest that patients with sporadic desmoids and no clinical signs of familial adenomatous polyposis detected on careful examination, esophagogastroduodenoscopy, and complete colonoscopy do not need to be tested routinely for germline mutations of the APC gene. However, as large studies dealing with this problem are absent, it might be more time and cost effective to perform an APC mutational analysis instead.

Background and Aims: The aim of this work was to evaluate the efficacy and safety of second-line treatment with weekly high-dose 5-Fluorouracil (5-FU) as a 24-hour infusion (24-h inf.) and folinic acid (FA) (AIO-regimen) plus Oxaliplatin (L-OHP) after pre-treatment with the AIO regimen, focusing in particular on the efficacy of palliative first- and second-line treatment in colorectal carcinoma (CRC)., Patients and Methods: Patients with non-resectable distant CRC metastases were enrolled in a prospective phase II study for palliative second-line treatment after previous palliative first-line treatment in accordance with the AIO regimen. On an outpatient basis, the patients received a treatment regimen comprising biweekly 85 mg/m2 L-OHP in the form of a 2-hour intravenous (i.v.) infusion and 500 mg/m2 FA as a 1 to 2-hour i.v. infusion, followed by 2,600 mg/m2 5-FU administered as a 24-h inf. i.v. once weekly. A single treatment cycle comprised 6 weekly infusions followed by 2 weeks of rest., Results: During second-line treatment, a total of 26 patients received 340 chemotherapy applications. As the main symptom of toxicity, diarrhoea (NCI-CTC toxicity grade 3+4) presented in 5 patients (19%; 95% CI: 4-34), followed by nausea (CTC grade 3) in one patient (4%; 95% CI: 0-11). Twenty-three patients were evaluable for treatment response. The remission data can be summarised as follows: Complete remission (CR): n=1 (4%; 95% CI: 0-13); partial remission (PR): n=3 (13%; 95% CI: 0-27); stable disease (SD): n=11 (48%; 95% CI: 27-68) and progressive disease (PD): n=8 (35%; 95% CI: 15-54). The median progression-free survival (PFS) rate (n=26) was 3.3 months (range 0-11.5), the median survival time counted from the start of second-line treatment (n=26) 11.6 months (range 2.1-33.0) and the median survival time counted from the start of first-line treatment (n=26) 19.9 months (range 7.7-49.8)., Conclusion: Palliative second-line treatment according to the AIO regimen plus L-OHP is feasible in an outpatient setting and well tolerated by the patients. Tumour control (CR + PR + SD) was achieved in 65% of the patients, the median survival time being 11.6 months. The AIO regimen followed by the 'AIO regimen plus L-OHP' therapy sequence led to a promising median survival time of 19.9 months (range 7.7-49.8).

Chemotherapy of advanced stages of colorectal carcinoma is unsatisfactory. Retinoids inhibit cell growth and induce apoptosis in a variety of human malignancies. We compared the effect of the synthetic retinoid adapalene (ADA) and 9-cis-retinoic acid (CRA) on carcinoma cell lines in vitro. Colon carcinoma cell lines CC-531, HT-29 and LOVO as well as human foreskin fibroblasts were exposed to different concentrations of ADA and CRA for 3-72 hr. Proliferation was assessed by BrdU incorporation and apoptosis by FACS analysis. Breakdown of DeltaPsi(m) was determined by JC-1 staining and activity of caspases 3 and 8, by a colorimetric assay. Quantitative Western blots were performed to detect changes in bax, bcl-2 and caspase-3. Both retinoic derivatives suppressed DNA synthesis and induced apoptosis in all tested cell lines time- and dose-dependently. While the natural retinoid CRA showed moderate antiproliferative and proapoptotic effects only at the highest concentration (10(-4) M), the synthetic retinoic ADA was significantly more effective, showing remarkable effects even at 10(-5) M. ADA and CRA disrupt DeltaPsi(m) and induce caspase-3 activity in responsive tumor cells. Quantitative Western blots showed a shift of the bax:bcl-2 ratio toward proapoptotic bax in ADA-treated cells. Our results clearly indicate the superiority of ADA compared to CRA. Therefore, we suggest that ADA may be far more suitable as an adjunctive therapeutic agent for treatment of colon cancer in vivo., (Copyright 2003 Wiley-Liss, Inc.)

Our objective was to evaluate the efficacy and safety of high-dose 5-fluorouracil (5-FU) as a 24-h infusion and folinic acid (FA) (AIO regimen) plus irinotecan (CPT-11) after pre-treatment with AIO plus oxaliplatin (L-OHP) in colorectal carcinoma (CRC). Twenty-six patients with non-resectable distant CRC metastases were analyzed for second- or third-line treatment with AIO plus CPT-11 after pre-treatment with AIO plus L-OHP. On an outpatient basis, the patients received a treatment regimen comprising weekly 80 mg/m2 CPT-11 in the form of a 1-h i.v. infusion and 500 mg/m2 FA as a 1- to 2-h i.v. infusion, followed by 2000 mg/m2 5-FU i.v. administered as a 24-h infusion once weekly. A single treatment cycle comprised six weekly infusions followed by 2 weeks of rest. A total of 26 patients received 344 chemotherapy applications with AIO plus CPT-11. The main symptom of toxicity was diarrhea (NCI-CTC toxicity grade 3+4) occurring in five patients (19%; 95% CI 7-39%). Nausea and vomiting presented in two patients (8%; 95% CI 1-25%). The response rate of 26 patients can be summarized as follows: partial remission: n=7 (27%; 95% CI 12-48%); stable disease: n=9 (35%; 95% CI 17-56%) and progressive disease: n=10 (38%; 95% CI 20-59%). The median progression-free survival (n=26) was 5.8 months (range 3-13), the median survival time counted from the treatment start with the AIO plus CPT-11 regimen was 10 months (range 2-24) and counted from the start of first-line treatment (n=26) was 23 months (range 10-66). We conclude that the AIO regimen plus CPT-11 is practicable in an outpatient setting and well tolerated by the patients. Tumor control was achieved in 62% of the patients. The median survival time was 10 months and the median survival time from the start of first-line treatment (n=26) was 23 months.

The prognosis of advanced colorectal carcinoma (CC) is poor. Established chemotherapy shows only limited efficacy but significant side effects. We investigated how far a combination of tamoxifen (TAM), 9-cis-retinoic acid (CRA) and the fluoroquinolone ciprofloxacin (CIP) synergize to inhibit proliferation and promote apoptosis of CC cells in vitro. The CC cell lines LOVO, CC-531 and SW-403 were incubated with TAM, CRA and CIP (10(minus;4)-10(minus;6) M) as single agents and in combination. Cell proliferation was assessed by bromodeoxyuridin incorporation. Apoptosis was quantified immunohistochemically and by FACS analysis after staining with propidium iodide. Changes in the expression of caspase 3, bax, bcl-2 and p21cip/waf were assessed by quantitative Western blotting. CRA and TAM monotherapy was moderately effective. Their combination enhanced apoptosis from 60% to more than 80% in all cell types. Apoptosis was paralleled by inhibition of proliferation and further potentiated by addition of CIP. The combination effectively up-regulated caspase 3 and bax and down-regulated bcl-2 and p21cip/waf. Combinations of biomodulaters act synergistically to inhibit proliferation and promote apoptosis in CC cells. Due to their known safety profile, this justifies clinical trials for colorectal cancer using combinations of these biological response modifiers.

Connective tissue turnover plays a prominent role in tumour growth and metastasis. We followed serum levels of seven connective tissue parameters in 37 patients with colorectal cancer metastatic to the liver prior to and during chemotherapy. Serum samples with episodes of tumour control (n=112) showed an increase of matrix metalloproteinase-2 (MMP-2) (P

To evaluate the new, bio-optical method of light-induced autofluorescence spectroscopy for the endoscopic in-vivo diagnosis of (pre)-cancerous lesions of the colorectum, 311 endogenous fluorescence spectra were obtained from normal, adenomatous and cancerous colorectal tissue in 11 patients with cancer, six patients with familial adenomatous polyposis, and six patients with multiple adenomatous polyps. A light source delivered either white or violet-blue light for excitation of tissue autofluorescence via a flexible endoscope. Endogenous fluorescence spectra emitted by the tissue were picked up with a fiberoptic probe and analysed with a spectrograph. Biopsies were taken for definitive classification of the spectra. Rectal cancer (n=11) as well as adenomas with severe dysplasia (n=19) showed specific differences between the emitted fluorescence spectra as compared with normal mucosa and hyperplastic polyps. Having applied a mathematical algorithm to the spectra, a sensitivity of 96% and a specificity of 93% were obtained for the diagnosis of rectal cancer. The equivalent values for the diagnosis of dysplastic ademomas were 98 and 89%, respectively. Light-induced autofluorescence spectroscopy is a new and promising bio-optical procedure for the endoscopic in-vivo diagnosis of colorectal cancer and dysplasia.

Background and Aims: The aim of this work was to investigate the relationship between microsatellite instability (MSI), treatment response and survival in palliative patients with colorectal cancer (CRC) undergoing first-line treatment with weekly 24-hour infusion (24-h inf.) of high-dose 5-fluorouracil (5-FU) and folinic acid (FA)., Patients and Methods: Tumour material from the colorectal primary carcinomas was analysed for 43 patients. MSI analysis was carried out and immunohistochemistry was performed with hMLH1 and hMSH2., Results: Tumours of 7 patients (16%) were highly instable (MSI-H). These patients had a better response rate (72% vs. 41%; p = 0.072) and a significantly better median survival (33 months, [95% CI 20-46] vs. 19 months, [95% CI 10-28]; p = 0.021) than microsatellite stable (MSS) patients (n = 36). Furthermore, MSI status was shown to be an independent predictive marker for survival (p = 0.037)., Conclusion: These data provide further support for the hypothesis that MSI-H CRC might have a better response and survival than (MSS) CRC in palliative first-line treatment.

Purpose: To evaluate the efficacy and safety of neoadjuvant treatment comprising weekly high-dose 5-fluorouracil (5-FU) as a 24-hour infusion, folinic acid (FA) and biweekly oxaliplatin (L-OHP), followed by metastatic resection in patients with primarily resectable liver metastases of colorectal cancer (CRC)., Patients and Methods: 20 patients with primarily resectable liver metastases of CRC were enrolled in a prospective phase II study. On an outpatient basis, the patients received a treatment regimen comprising biweekly 85 mg/m(2) L-OHP in the form of a 2-hour intravenous infusion and 500 mg/m(2) FA as a 1- to 2-hour intravenous infusion, followed by 2,600 mg/m(2 ) 5-FU administered as a 24-hour intravenous infusion once weekly. A single treatment cycle comprised one infusion per week during a period of 6 weeks followed by a 2-week rest. Two cycles were administered, with a third being added when the treatment was well tolerated. Thereafter, curative resection of the liver metastases was attempted, and the patients were followed up., Results: After neoadjuvant therapy, 2 of the original 20 patients showed complete remission (CR; 10%) and 18 patients partial remission (PR; 90%). As the main symptom of toxicity, diarrhea (CTC toxicity grade 3-4) was observed in 6 patients (30%), followed by vomiting in 3 patients (15%). The curative resectability rate was 80% (16 of 20). In 9 of 18 patients (50%) undergoing surgical intervention, mild postoperative complications, mainly wound healing disturbances (n = 5), occurred. No postoperative mortality was observed. Over a median follow-up of 23 months (12-38) 6 of 16 curatively resected patients developed distant metastases and 1 patient a local pelvic recurrence. The 2-year disease-free survival rate was 52% and the 2-year cancer-related survival rate 80%., Conclusion: The neoadjuvant treatment with weekly high-dose 5-FU in the form of a 24-hour infusion combined with FA and L-OHP is very effective and well tolerated. Surgical morbidity does not appear to be increased by the neoadjuvant treatment., (Copyright 2003 S. Karger AG, Basel)

Colorectal cancers (CRCs) are one of the most common forms of cancer in Poland and one of the leading causes of death. The tumors have been attributed to genetic, dietary, and other environmental factors, but recently growth factors such as gastrin have also been implicated in the carcinogenesis. The relationship between plasma amidated and nonamidated gastrin in CRCs is controversial. This study was designed (1) to determine the plasma levels of progastrin and amidated gastrin in 50 CRC patients before and 3-6 months after removal of the tumor, (2) to determine the tumor concentrations of these gastrin peptides and the level of expression for gastrin mRNA and gastrin/CCK(B) receptor mRNA, (3) to examine the expression of cyclooxygenase COX-1 and COX-2 mRNA in CRC tissue, and (4) to compare the prevalence of Hp and its cytotoxic protein, CagA, and cytokines (TNFalpha, IL-1beta, and IL-8) in CRCs, before and after removal of tumor. It was found that the CRC, its resection margin, and the plasma contained severalfold higher levels of progastrin than of amidated gastrins and that the removal of the CRC tumor resulted in a marked reduction in plasma progastrin level without a significant alteration in plasma levels of amidated gastrins. Both gastrin and CCK(B)-R mRNA were detected in the cancer tissue and resection margin by RT-PCR, and similarly, COX-1 and COX-2 mRNA were expressed in these tissues of most CRCs. The seroprevalence of Hp, especially that expressing CagA, and levels of IL-1beta, but not other cytokines, were significantly higher in CRC patients than in 100 age-, gender-, and profession-matched controls and did not change significantly about 3-6 months after tumor resection. We conclude that (1) the CRC and its margin contain large amounts of progastrin and show gene expression of gastrin, CCK(B)-R, and COX-2; (2) removal of the CRC markedly reduces the plasma concentrations of progastrin; (3) the Hp infection rate is higher in CRC, and this may contribute to colorectal cancerogenesis via enhancement of progastrin and gastrin release; and (4) plasma progastrin concentrations might serve as a biomarker of CRC.

Background: Patients who have had a colorectal adenoma are likely to develop a metachronous adenoma and therefore need to be kept under surveillance. It is essential to avoid unnecessary examinations by tailoring the frequency of follow up examinations to individual risk., Methods: A total of 3134 patients undergoing endoscopic removal of colorectal adenomas were prospectively recorded on the Erlangen Registry of Colorectal Polyps between 1978 and 1996. A multivariate analysis of 1159 patients on long term follow up was performed to identify risk factors determining surveillance intervals for patients with metachronous adenomas of advanced pathology-that is, adenomas >10 mm or with high grade dysplasia or invasive carcinoma., Results: Univariate analysis revealed that sex, parental history of colorectal carcinoma, and characteristics of the initial findings-that is, size, multiplicity, and amount of villous structure-were significant predictors of metachronous adenomas of advanced pathology. On the basis of multivariate analysis, two risk groups were identified: (1) patients with no parental history of colorectal carcinoma with only small (< or = 10 mm) tubular adenomas at the initial clearing examination have a very low risk, and we estimated that 10% will develop advanced metachronous adenomas after 10 years; (2) the high risk group contained all other patients, 10% of whom will show metachronous adenomas of advanced pathology at follow up after only three years., Conclusions: The risk of developing metachronous adenomas with advanced pathology can be stratified for various patient and adenoma characteristics. Surveillance intervals can be scheduled for low risk (10 years) and high risk (three years) patients. Risk related follow up thus helps to avoid unnecessary examinations.

Efficacy of chemotherapy in advanced stages of colorectal tumours is limited. The quinolone antibiotic ciprofloxacin was recently shown to inhibit growth and to induce apoptosis in human bladder carcinomas cells. We investigated the effect of ciprofloxacin on colon carcinoma lines in vitro. CC-531, SW-403 and HT-29 colon carcinoma and HepG2 hepatoma cells (control cells) were exposed to ciprofloxacin. Proliferation was assessed by bromodeoxyuridine-incorporation into DNA and apoptosis was measured by flow cytometry after propidium iodide or JC-1 staining. Expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax was analyzed by semiquantitative Western blot analysis and activity of caspases 3, 8 and 9 by substrate-cleavage assays. Ciprofloxacin suppressed DNA synthesis of all colon carcinoma cells time- and dose-dependently, whereas the hepatoma cells remained unaffected. Apoptosis reached its maximum between 200 and 500 microg ml(-1). This was accompanied by an upregulation of Bax and of the activity of caspases 3, 8 and 9, and paralleled by a decrease of the mitochondrial membrane potential. Ciprofloxacin decreases proliferation and induces apoptosis of colon carcinoma cells, possibly in part by blocking mitochondrial DNA synthesis. Therefore, qualification of ciprofloxacin as adjunctive agent for colorectal cancer should be evaluated., (Copyright 2002 The Cancer Research Campaign)

Background: In palliative first-line treatment of colorectal cancer, the secondary resection of distant metastases after downstaging has constantly gained in importance. The objective of this prospective study was to examine the tumor response rate, the toxicity, the median survival time and the prognostic impact of metastatic resection after downstaging of consecutively enrolled patients with primary nonresectable colorectal cancer treated with once weekly 24-hour (24-h) infusion of high-dose 5-fluorouracil (5-FU) and folinic acid., Patients and Methods: Between January 1995 and July 1997, 53 consecutive patients with primary nonresectable metastases were recruited for a prospective phase II study. The patients received in out-patient care 500 mg/m2 folinic acid in the form of a 1-2-hour infusion followed by 2600 mg/m2 5-FU administered as a 24-h infusion once weekly. One treatment cycle comprised six weekly infusions followed by a two week rest. Three cycles were administered, and in the event of complete remission (CR) or partial remission (PR) and good tolerability, a fourth cycle was undertaken. Thereafter, the possibility of performing a curative metastatic resection was investigated., Results: Of the 53 patients treated, 7 showed a CR (13%), 15 patients a PR (28%), 26 patients stable disease (SD) (49%), and 5 patients progressive disease (PD) (10%). As the main symptom of toxicity, diarrhea (CTC grade 3 + 4) was observed in 11 patients (21%), followed by leucocytopenia (CTC grade 3 + 4) in 2 patients (4%), and the hand-foot syndrome in 1 patient (2%). The median survival time was 17 months with a median follow-up of 41 months (range: 28-59 months). In 9 patients (17%), a secondary metastatic resection was considered; in 6 patients (11%) curative resection was performed, and 4 patients (8%) showed no evidence of disease for at least three years., Conclusion: In this phase II study, we have been able to show prospectively that, after downstaging by palliative treatment using a weekly 24-h infusion of high-dose 5-FU and folinic acid, secondary curative metastatic resection was technically feasible in 11% of the patients. For some of these patients, long-term survival is therefore possible. Secondary metastatic resection should be carried out in close interdisciplinary cooperation, and should be further investigated in prospective phase III studies.

Pathobiology of dysplasia in chronic inflammatory bowel disease: Current recommendations for surveillance of dysplasia. Patients with ulcerative colitis and Crohn's disease bear an about 10- and 4-fold increased risk, respectively, for developing colorectal carcinoma. Apart from typical locations of colorectal carcinoma in the sigmoid colon and rectum other locations were also often observed, e. g. right hemicolon or multifocal distribution. Histologically colorectal neoplasms frequently present as mucinous adenocarcinoma (signet-ring cell carcinoma). The risk for neoplasm depends on extension, severity, duration and therapeutic responsiveness of chronic colonic inflammation, and it seems pathogenetically to be similar in ulcerative colitis and Crohn's disease. Colorectal carcinoma in inflammatory bowel disease arises from epithelial dysplasia. Since there are no reliable biological markers available to date, surveillance-programs continue to rely on the discovery of dysplasia (unequivocal intraepithelial neoplasia). Detection of dysplasia by colonoscopy achieves 70-85 % sensitivity.Endoscopic surveillance should start after 8 years of disease's duration in pancolitis, after 10-12 years in left- sided colitis and after 12 years in Crohn's disease of the colon, with regular intervals every 1-2 years. 3-5 biopsies should be done every 10 cm from mucosa free of inflammation. Additionally, every fine or discrete alteration of the mucosal surface should be recorded. Multiple biosies should also be taken from such minimal lesions as well as from more macroscopically suspicious areas like plaques, nodular lesions or stenosis. The clinical consequence of a positive screening for dysplasia is colectomy because of an assumed risk of cancer of about 40-70 %. Dysplasia in macroscopically suspect areas bear the highest risk of cancer (non-adenoma like dysplasia), followed by multiple high-grade lesions without a macroscopic lesion, and multiple low-grade dysplasias. Detection of single dysplastic lesions in flat mucosa should be followed by a control endoscopy after 2-6 months, and if dysplasia is seen again, colectomy is recommended.

Helicobacter pylori (HP) infection is usually accompanied by an increased plasma level of gastrin, a potent mitogen able to induce cyclooxygenase (COX)-2. This study examined (a) the seroprevalence of HP, its cytotoxic protein, CagA, and cytokines (tumor necrosis factor alpha, interleukins 1beta and 8) in 80 patients with colorectal cancers, before and after the removal of tumor, compared with 160 age- and gender-matched controls; (b) the gene expression of gastrin and its receptors (CCKB-R) in the cancer tissue, (c) the plasma levels and tumor tissue contents of gastrin, and (d) the mRNA expression of COX-1, COX-2, and apoptotic proteins (Bax and Bcl2) in cancer tissue and intact colonic mucosa. Anti-HP IgG, anti-CagA IgG seroprevalence, and cytokine levels were analyzed by enzyme-linked immunosorbent assay tests; gene expressions of gastrin, CCKB-R, COX-1, COX-2, Bax, and Bcl2 by reverse transcriptase polymerase chain reaction; and gastrin by radioimmunoassay. The seroprevalence of HP, especially that expressing CagA, was significantly higher in cancer patients than in controls and did not change 1 week after tumor resection while plasma cytokines were significantly reduced after this operation. Both gastrin and CCKB-R mRNA were detected in the cancer tissue and the resection margin; similarly, COX-2 mRNA was expressed in most of cancers and their resection margin but not in intact colonic mucosa, where only COX-1 was detected. The colorectal cancer tissue contained several folds more immunoreactive gastrin than cancer resection margin and many folds more than the intact colonic mucosa. We conclude that colon adenocarcinoma and its resection margin overexpress gastrin, its receptors, CCKB-R, and COX-2, and that HP infection may contribute to colonic cancerogenesis via overexpression of gastrin and COX-2, which may account for the stimulation of the tumor growth and the reduction in apoptosis as documented by enhanced mRNA expression of anti-apoptotic Bcl2 over proapoptotic Bax proteins.

Background and Study Aims: Patients who have had a colorectal adenoma are likely to develop a metachronous adenoma, and therefore need to be kept under surveillance. The question is whether metachronous adenomas will be found at the same anatomical site as the preceding adenomas, thus prompting us to focus surveillance examinations on this region, using flexible sigmoidoscopy or total colonoscopy., Patients and Methods: Between 1978 and 1996 a long-term follow up of 1091 patients was prospectively documented at the Erlangen Registry of Colorectal Polyps. The anatomical sites--distal (rectosigmoid) and proximal colon--of two subsequent generations of metachronous adenomas were analysed using logistic regression analysis., Results: In 556 (51%) patients metachronous adenomas were found during follow up. In 211 (37.9%) of these patients a right-sided shift in the first generation of metachronous adenomas in comparison with initial lesions (P<0.0001) was found. Some 305 patients underwent further follow up, and 51 (27.1%) out of 188 patients with metachronous lesions demonstrated a right-sided shift in their second generation (vs. first generation) of metachronous adenomas. Proximally located first generation metachronous adenomas would be missed by flexible sigmoidoscopy in 50.8% of patients with only distal adenomas at baseline colonoscopy, and in 58.7% of patients with second-generation lesions. Multivariate analysis revealed that multiplicity (odds ratio 2.64, 95% CI 1.49-4.66) and size of initial adenomas (>5 mm) (odds ratio 3.60, 95% CI 1.96-6.66) were significantly associated with a right-sided shift in metachronous adenomas, while female gender was associated with a significantly lower tendency to manifest a right-sided shift (odds ratio of 0.64. 95% CI 0.43-0.94)., Conclusions: Metachronous adenomas are found significantly more often in the right colon than would be expected assuming clustering at the same anatomical site as the preceding lesions. Total colonoscopy is thus needed for surveillance, regardless of the initial adenoma site.

Background: There have been contradictory reports on the benefit of CEA and CA 19-9 measurements in patients with metastatic colorectal cancer using palliative chemotherapy. The object of this study was to examine the diagnostic accuracy of monitoring of palliative chemotherapy by means of CEA and CA 19-9., Patients and Methods: The tumour markers CEA and CA 19-9 were subjected to serial measurement in patients with metastatic colorectal cancer (n = 90) using palliative first-line chemotherapy with weekly 24-hour infusion of high-dose 5-FU with FA and were compared with objective response according to WHO criteria. 85 patients could be evaluated. 43 patients (51%) initially had elevated CEA (> or = 10 ng/ml) and 33 patients (39%) elevated CA19-9 (> or = 50 IE/ml). In 24 patients (28%), both markers were initially increased. With CEA positive patients, 143 cycles of chemotherapy were carried out, which showed the following response in the various cycles: 21 episodes with progressions (ePD), 69 episodes with no change (eNC), 53 episodes with partial/complete remission (ePR/eCR). With CA 19-9 positive patients, 100 cycles of chemotherapy were carried out with the following results: 21 episodes with progressions (ePD), 48 episodes with eNC, and 31 episodes with ePR/eCR., Results: A CEA rise by at least 50% differentiated between ePD versus eNC/ePR/eCR with a sensitivity of 76% and specificity of 90%. With CEA decreases of at least 30% in 99% of these patient episodes (78 of 79), a tumour progression could be excluded. Patients with an initial drop in CEA after the first cycle of chemotherapy of at least 50% of the initial level had a significantly higher probability of achieving an ePR/eCR in further therapy (relative risk 2.9; P = 0.002). With an CA 19-9 increase of at least 30%, a sensitivity progression of 62% and a specifity of 90% could be calculated. A CA 19-9 decrease of at least 60% excludes a progression in 95% of the patient episodes., Conclusions: A CEA or CA 19-9 rise is only conditionally appropriate for recording progressions. A progression however, can be excluded with falling levels with high diagnostic accuracy, in which CEA offers a greater degree of certainty than CA 19-9. With a drop in CEA 79 of 143 (= 55%) of the CT scans could be saved, in which case 78 of 79 patient episodes (99%) were correctly assessed as 'no progression'. In patients with an increased CEA and CA 19-9 the CEA determination is sufficient for the further monitoring. A confirmation of these results by multicenter trials can result in a considerable decrease of monitoring costs for palliative treatment.

Background: Hereditary non-polyposis colorectal cancer (HNPCC) patients frequently develop synchronous colorectal cancer (SCRC) which also occurs sporadically in other patients. Recent studies on microsatellite instability (MSI) in sporadic SCRC diverge completely in their findings (0%-100%). In the present study MSI and mismatch repair (MMR) proteins were evaluated according to standardised criteria (exclusion of a family history, MSI analysed according to NCI recommendations), Methods: Paraffin embedded sections of SCRC of 30 patients were evaluated for MSI and the loss of protein expression of hMLH1 and hMSH2., Results: 3 out of 30 (10%) patients exhibited MSI-H which 5 out of 30 (17%) showed MSI-L. Loss of protein expression of either hMLH1 or hMSH2 was found in all cases of MSI-H and none of the MSI-L cancers., Conclusion: MSI is found in sporadic cases of SCRC to about the same extent as it is mentioned in the literature on sporadic single colorectal cancers. Immunohistochemistry with mismatch repair proteins could be used as a pre-screening for MMR deficiency in sporadic SCRC.

Helicobacter pylori, infecting more than 50% of the world population, results in gastritis, usually located in the antral portion of the stomach, accompanied by hypergastrinemia, the key factor in gastric and colorectal carcinogenesis. Excessive mucosal cell proliferation for many years may eventually result in gastric atrophy, cell mutation and transformation of gastric mucosal cells into gastrin-producing cells, which also express gastrin receptors serving to stimulate cell proliferation and tumor growth. These processes may be completed by the expression of cyclooxygenase-2 (COX-2) as an inflammation enzyme to release excessive amounts of PGE(2), leading to further proliferation, reduction in apoptosis, angiogenesis and tumor growth. H. pylori eradication results in complete regression of MALT lymphoma and subsequent normalisation of excessive gastrin release and COX-2 expression. Reduction of gastrin by active immunisation (gastrimmune), blocking of gastrin receptors with specific blockers and suppression of COX-2 might be helpful in inhibiting tumor growth and invasion.

A number of investigations have recently been published on the role of microsatellite instability (MSI) in the process of colorectal carcinogenesis. The data concerning colorectal adenomas are difficult to compare (due to differences in the tumor collection, selection and number of analyzed loci, definition of high and low instability and histological types), and this review therefore examines the significance of the results of these publications. We then discuss the extent to which MSI and its effects on the integrity of the genome are early or late events in the malignant transformation, and which clinicopathological features are presented by MSI-positive adenomas. Finally, we consider the clinical importance of microsatellite status for the diagnosis of hereditary nonpolyposis colorectal cancer and the possibility of preventing adenomas and carcinomas by nonsteroidal anti-inflammatory drugs.

Background: Anthranoid laxatives are the most commonly used purgatives in the therapy of acute and chronic constipation. Recent experimental data and a prospective cohort study provide evidence of a possible risk of anthranoid use for the development of colorectal neoplasms., Materials and Methods: We performed a prospective case control study at the University of Erlangen to investigate the risk of anthranoid laxative use for the development of colorectal adenomas or carcinomas. A total of 202 patients with newly diagnosed colorectal carcinomas, 114 patients with adenomatous polyps, and 238 patients (controls) with no colorectal neoplasms who had been referred for total colonoscopy were studied. The use of anthranoid preparations was assessed by standardised interview, and endoscopically visible or microscopic melanosis coli was studied by histopathological examination., Results: There was no statistically significant risk of anthranoid use for the development of colorectal adenomas (unadjusted odds ratio 1.0; 95% CI 0.5-1.9) or carcinomas (unadjusted odds ratio 1.0; 95% CI 0.6-1.8). Even after adjustment for the risk factors age, sex, and blood in the stools by logistic regression analysis the odds ratio for adenomas was 0.84 (95% CI 0. 4-1.7) and for carcinomas 0.93 (95% CI 0.5-1.7). Also, there were no differences between the patient and control groups for duration of intake. Macroscopic and high grade microscopic melanosis coli were not significant risk factors for the development of adenomas or carcinomas., Conclusion: Neither anthranoid laxative use, even in the long term, nor macroscopic or marked microscopic melanosis coli were associated with any significant risk for the development of colorectal adenoma or carcinoma.

Background: Percutaneous ethanol injection (PEI) and radio-frequency (RF) ablation are possible palliative treatment modalities for patients with non-resectable liver metastases of colorectal carcinomas. The different techniques are explained and reviewed., Results: PEI did not show promising results for the treatment of liver metastases. RF results were more encouraging; some studies showed improved mean survival times for patients when a complete necrosis of the metastases could be achieved. The maximum diameter of the necrotic area possible in a single session is about 5 cm., Conclusion: PEI and RF are palliative last-line treatment strategies for patients with non-resectable liver metastases and should only be applied if chemotherapy is not sufficient or not possible. The long-term efficacy of RF ablation in this group of patients has to be evaluated.

Background: Mutations of K-RAS-2 gene and tumour suppressor genes have been found in both colorectal adenomas and carcinomas. The aim of this study was to investigate the prognostic value of K-RAS-2 gene mutations found in initial colorectal adenomas for predicting the risk of metachronous adenomas., Methods: Genomic DNA was extracted from formalin-fixed and paraffin-embedded adenomas larger than 5 mm in diameter removed at the initial total colonoscopy between 1980 and 1982. All patients underwent colonoscopic follow-up for at least 10 years. The sequence of exon 1 of the K-RAS-2 oncogene was amplified with the polymerase chain reaction technique and screened for mutation by single-strand conformation polymorphism analysis. All suspected mutations were confirmed by direct DNA sequencing. The predictive value of K-RAS-2 gene mutations for the risk of metachronous adenomas was assessed by chi-square testing and logistic regression analysis., Results: Of 54 patients 39 (72%) were male and 15 (28%) female. At the time the initial adenoma was removed, 31 (57%) patients were younger than 60, whereas 23 (43%) were 60 years or older. Point mutations of the K-RAS-2 oncogene were found in the index adenomas of 15 (27.7%) patients. Mutations were found more frequently in large (> or = 20 mm) adenomas and in adenomas with severe dysplasia (P = 0.0011 and P = 0.0310, respectively). There were no significant associations between K-RAS-2 mutations and anatomic location, histologic type, or number of synchronous initial lesions. Mutations were found predominantly at codon 12 with transversions from GGT to GTT (57%), from GGT to GAT (36%), and from GGT to TTT (one patient). The single mutation found at codon 13 showed a transversion from GGC to GAC. There were significant associations between size (> or = 20 mm) and K-RAS-2 mutation of the initial adenomas and the size (> 5 mm) of metachronous adenomas (P = 0.0259 and P = 0.0265, respectively). However, multivariate analysis showed that K-RAS-2 mutations did not provide a significant additional contribution to the prognostic value of the size of the initial adenoma (odds ratio, 7.62; 95% confidence interval (CI), 1.68-34.48) and the amount of villous structure (odds ratio, 0.22; 95% CI, 0.05-0.90) it contained., Conclusions: Patients with large (> or = 20 mm) adenomas and adenomas with K-RAS-2 mutations found at the initial examination have a significantly higher risk of developing large (> 5 mm) metachronous adenomas during surveillance. Multivariate analysis of initial adenoma characteristics showed that the risk of metachronous colorectal adenomas can be adequately estimated by the size and the histologic type of the largest initial adenoma and that K-RAS-2 mutations are of secondary importance only. Further studies based on a larger series will have to identify the adenoma characteristics that will help to improve follow-up strategies.

Background/aims: To date, risk factors for severe dysplasia in colorectal adenomas have been studied mainly in endoscopically removed material. The aim of this study was to determine whether there are any differences between adenomas removed endoscopically and surgically in terms of patient and polyp characteristics., Methodology: Between 1978 and 1993, 5092 consecutive patients with 9874 colorectal adenomas attending the Medical and Surgical Departments of the University of Erlangen were prospectively documented in the Erlangen Registry of Colorectal Polyps, and statistically examined using regression analysis., Results: 5995 adenomas were removed endoscopically from 3343 patients. 3879 adenomas were surgically resected in 1749 patients. 313 (9.4%) of the former, and 218 (12.5%) of the latter, patients harboured adenomas with severe dysplasia. The size of the adenoma and the tubulovillous or villous structure were the leading risk factors, both in endoscopically and surgically removed adenomas. Adenomas located in the right colon were at a lower risk in both endoscopic and surgical specimens. The risk factors in endoscopically removed adenomas can be described by a model of independent variables. However, the risk of severe dysplasia in surgically resected adenomas needs to be described in an interactive model. Villous structure act as a confounder which modifies the risk profile by increasing the risk associated with multiplicity and right-sided location., Conclusions: The risk of severe dysplasia in colorectal adenomas needs to be described in different models, depending on the method of adenoma removal-either endoscopic or surgical. A global model describing the colorectal dysplasia-carcinoma sequence will depend on the composition of the endoscopically or surgically removed adenomas and will be a more complex model than the clear and simple description applicable to purely endoscopic studies.

Unlabelled: Melanosis coli has long been considered as a harmless pigmentation of the colorectum associated with the use of laxatives containing anthraquinone. Recent experimental and clinical studies, however, have provided some evidence of a possible association between melanosis coli/laxative use and colorectal cancer., Methods: In 2.229 consecutive patients we retrospectively analyzed the association of melanosis coli and laxative use with colorectal neoplasia. All the patients had undergone total colonoscopy, and the colorectal neoplasias had been examined histopathologically in accordance with the WHO classification. Information concerning laxative use, bowel habits and family history of colorectal cancer was obtained from the medical records. The statistical analysis was done using the Mantel-Haenszel-test for linear association., Results: The presence of colorectal cancer was not associated with melanosis coli or laxative use. However, colorectal adenomas were found significantly more frequently in patients with melanosis coli than in those without melanosis (p = 0.0002). But adenomas associated with melanosis coli were significantly smaller than those not associated with melanosis (p < 0.0001), and were located predominantly in the proximal colon (p = 0.0002). In the patients with melanosis coli the relative risk was significantly higher for tubular (1.80; 95% CI: 1.26-2.56) and tubulovillous adenomas (2.03; 95% CI: 1.09-3.76), but not for villous adenomas. No significant differences were found in the grade of dysplasia of adenomas in patients with, and those without, melanosis coli., Conclusion: There appears to be no association between colorectal cancer and melanosis coli or laxative use. Colorectal adenomas are more frequently found in patients with melanosis coli. Colorectal adenomas do not contain the melanin-like pigmentation. The association of adenomas with melanosis coli can be explained by the ease of detection of even tiny polyps as white spots within a dark-colored colonic mucosa.

Background: The risk of invasive carcinoma developing in colorectal adenomas is influenced by a number of characteristics of both patients and adenomas, and the composition of the sample analysed., Patients and Methods: Between 1978 and 1993 more than 20,000 polyps were prospectively documented at the Erlangen Registry of Colorectal Polyps, and analysed statistically by logistic regression., Results: The size of the adenomas proved to be the most important factor for adenomas equal to or larger than 15 mm as compared with smaller lesions. In 5,137 diminutive adenomas (< or = 5 mm) invasive carcinoma was never found. Adenomas in the right-sided colon had a lower risk than those in the left colon or rectum, but with increasing adenoma size, the malignancy rate showed a right-sided shift. In adenomas of up to 36 mm in diameter, invasive carcinoma was found more often when they were located in the rectum or left colon while adenomas larger than 36 mm were more likely to harbour invasive carcinoma when located in the right or left colon rather than in the rectum., Conclusions: A multivariate analysis of 11,380 adenomas detected at the first total colonoscopy showed that the factors size and site, both of which can be assessed by endoscopic inspection alone, were found to enable a statistically and clinically adequate assessment of the malignancy risk.

In a retrospective study a cohort of 2,277 patients was defined by colonoscopy. Among other factors it was tested whether in these patients laxative use or the endoscopically diagnosed presence of melanosis coli were risk factors related to colorectal neoplasma. In comparison to patients taking no laxatives there was no significant increase in colorectal cancer rate either in laxative users or in patients with melanosis coli. However, there was a statistically significant association between the occurrence of colorectal adenomas and laxative use (relative risk of all patients exposed to laxatives = 1.72; of patients exposed to laxatives without melanosis coli = 1.47). The relative risk of adenoma development in patients with melanosis coli was 2.19. Taking into account that polyps can be diagnosed in the dark mucosa of melanosis coli patients more easily, even this relative risk of 2.19 seems to be related to a generally enhanced risk of laxative intake rather than to a special group of (anthranoid containing) laxatives.