Abstract: BACKGROUND: Inflammatory bowel disease is a premalignant condition for developing colorectal cancer. Since a correlation has been suggested between telomere length, chromosomal instability and neoplastic transformation in this setting, we sought to investigate whether telomerase expression in colorectal mucosa may constitute a biomarker for malignant transformation in patients with inflammatory bowel disease. PATIENTS AND METHODS: Forty-seven patients with inflammatory bowel disease with and without cancer or dysplasia were evaluated for human telomerase reverse transcriptase hTERT immunostaining in paraffin-embedded, formalin-fixed colorectal tissues. In addition, hTERT mRNA expression was assessed in fresh frozen specimens from a second set of 35 patients with inflammatory bowel disease at high or low risk for neoplastic transformation. RESULTS: Five out of 10 patients (50%) with colorectal cancer or high-grade dysplasia exhibited hTERT immunochemical detection in adjacent, non-transformed colonic mucosa. However, this phenomenon was also observed in non-affected mucosa of patients with either long-standing (13 out of 19 patients; 68%) or short duration (13 out of 18 patients; 72%) disease without cancer or dysplasia. On the other hand, hTERT mRNA expression in non-affected colorectal mucosa from patients at high risk for neoplastic transformation due to long-standing disease was higher than in those at low risk (7.42+/-6.43 vs. 2.87+/-1.47, respectively; p=0.006). CONCLUSIONS: Whereas hTERT immunostaining provides equivocal results, the observation that patients at high risk for colorectal cancer because of long-standing inflammatory bowel disease overexpress hTERT mRNA in non-affected colorectal mucosa suggests its potential usefulness as a biomarker of the risk of malignant transformation.
Abstract: OBJECTIVE: to analyse the association between rectal bleeding or a family history of colorectal cancer (CRC) and the results obtained in two rounds of a CRC screening pilot programme performed in L Hospitalet, Barcelona, Spain. SUBJECTS: males and females (50-69 years) were the target population. Together with the invitation letter, they received a questionnaire in which they were asked about rectal bleeding, family history of CRC and related neoplasms. The screening test was a guaiac-based faecal occult blood test (FOBT), and colonoscopy for positive tests. RESULTS: 25,829 FOBT were performed in 18,405 individuals. Information on rectal bleeding and a family history of CRC were obtained for 9,849 and 9,865 cases, respectively. Male sex (OR = 1.32), 60-69 years of age (OR = 1.48), rectal bleeding (OR = 1.84) and history of CRC (OR = 1.54) were independent predictors of positive FOBT. With regard to colonoscopy, a greater risk of diagnosing advanced neoplasm was observed among men (OR = 2.47) and subjects with a family history of CRC (OR = 1.98). CONCLUSIONS: CRC screening programmes must have instruments that make it possible to select the candidate population and the possibility of offering a study suited to the risk of individuals who are not susceptible to population screening by means of FOBT.
Abstract: BACKGROUND: Although colorectal cancer (CRC) screening strategies are quite common in the United States, their systematic introduction in Europe has been delayed until the year 2008. To estimate endoscopic requirements of four different CRC screening strategies (annual and biennial fecal occult blood testing (FOBT), flexible sigmoidoscopy every 5 years, and colonoscopy every 10 years) in an average-risk population. METHODS: A long-term Markov process model was designed combining three adherence rates for the four above-mentioned screening strategies in individuals aged from 50 to 74. Estimations included endoscopic procedures performed for both screening and surveillance purposes. Models were adjusted for age-related adenoma and CRC incidence rates, life expectancy, and cancer-related survival. RESULTS: The mean number of annual colonoscopies per 100,000 individuals aged 50-74 ranged from 100 to 271 for annual FOBT, from 75 to 203 for biennial FOBT, from 222 to 601 for sigmoidoscopy, and from 903 to 2,449 for colonoscopy-based strategies, depending on the adherence rate. According to these estimations, annual and biennial FOBT strategies would generate a slight decrease of current endoscopic activity (1.4-3.8% and 2.7-7.2%, respectively), whereas sigmoidoscopy and colonoscopy-based strategies would induce a 4.7-12.8% and 32-87% increase, respectively, with respect to a non-screening scenario. The model confirmed a 3-16% mean reduction of CRC incidence depending on the strategy and adherence rate. CONCLUSION: Whereas endoscopic capacity exists for widespread CRC screening with annual or biennial FOBT, implementation of potentially more effective strategies, such as flexible sigmoidoscopy or colonoscopy, would result in a significant increase of current endoscopic resources.
Abstract: Inflammatory bowel disease encompasses a group of diseases with poorly defined etiology that affect the digestive tract. These diseases are characterized by their chronic course and by periods of disease activity, of variable severity, that alternate with periods of clinical remission. In the last few years, inflammatory bowel disease has been the object of intense research, which has increased knowledge of the physiopathogenic mechanisms involved. This has enabled the development of a new generation of biotechnological drugs effective in patients previously considered to be refractory to medical treatment and has allowed the accumulated corticosteroid dose to be reduced and the indications for surgery and hospital admissions to be decreased, thus improving quality of life. In addition, some classical drugs have been demonstrated to be effective in recurrence prevention after surgery for Crohn's disease and in the prevention of dysplasia and colorectal cancer in inflammatory bowel disease.
Abstract: INTRODUCTION: Currently, the mechanisms that worsen the prognosis of complicated colon cancers are still not well known. Moreover, the possible effect of using sound oncological principles in emergency surgery on long-term prognosis has not been studied in detail. AIMS: The aim of the present study was to analyze the 5-year efficacy of curative oncological surgery for complicated colon cancer performed in an emergency setting in terms of tumor recurrence and survival compared with elective surgery of uncomplicated tumors. PATIENTS AND METHOD: We performed a prospective observational cohort study in patients who underwent emergency surgery for complicated colon cancer (group 1) and patients who underwent elective surgery (group 2). Exclusion criteria were tumors of less than 15 cm from the anal verge, palliative surgery, and distant metastases. RESULTS: During the study period, 646 patients underwent surgery: there were 165 (25.5%) emergency surgeries and 481 (74.5%) elective interventions. Surgery was considered curative in 456 (70.6%) patients: 102 (22.4%) emergency and 354 (77.6%) elective surgeries. Significant differences were found in disease stage between the 2 groups (P = 0.003). The postoperative mortality rate was 12.7% in group 1 and 3.4% in group 2 (P = 0.001). When patients were stratified by TNM stage, worse 5-year cancer-related and disease-free survival rates were observed in group 1 patients with stage II tumors. No differences were found in cancer-related survival rates in stage III patients (P = 0.178). There were no significant differences in overall survival, cancer-related survival or tumor recurrence rates when group 1 was compared with a subgroup of patients in group 2 with factors of poor prognosis. CONCLUSIONS: Complicated colon cancer presents in more advanced stages and had a worse overall long-term prognosis than uncomplicated tumour. These differences decrease when patients are subclassified by tumoral stage. Overall survival and cancer-related survival rates similar to those of elective surgery can be achieved in emergency surgery when curative oncological resection is performed.
Abstract: BACKGROUND: Cyclooxygenase 2 (COX-2) overexpression is a frequent but not universal event in colorectal cancer. It has been suggested that COX-2 protein expression is reduced in colorectal cancer with a defective mismatch repair (MMR) system, a phenomenon commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC) but also present in up to 15% of sporadic tumors. Aim: To assess COX-2 expression in a large series of fully characterized colorectal cancer patients with respect to the MMR system and to dissect the mechanisms responsible for altered COX-2 expression in this setting. PATIENTS AND METHODS: MMR-deficient colorectal cancer were identified in a nationwide, prospective, multicenter study (EPICOLON project). Control MMR-proficient colorectal cancer patients were randomly selected. COX-2 expression was evaluated by immunohistochemistry. Personal and familial characteristics, as well as MSH2/MLH1 expression and germ line mutations, were evaluated. RESULTS: One hundred fifty-three patients, 46 with MMR deficiency and 107 with MMR proficiency, were included in the analysis. Overall, tumor COX-2 overexpression was observed in 107 patients (70%). COX-2 overexpression was observed in 85 patients (79%) with a MMR-proficient system, but only in 22 patients (48%) with a MMR-deficient colorectal cancer (P < 0.001). The lack of COX-2 overexpression was independently associated with a MMR-deficient system (odds ratio, 3.89; 95% confidence interval, 1.78-8.51; P = 0.001) and a poor degree of differentiation (OR, 3.83; 95% CI, 1.30-11.31; P = 0.015). In the subset of patients with a MMR-deficient colorectal cancer, lack of COX-2 overexpression correlated with a poor degree of differentiation, no fulfillment of Amsterdam II criteria, absence of MSH2/MLH1 germ line mutations, presence of tumor MSH2 expression, and lack of tumor MLH1 expression. CpG island promoter hypermethylation of COX2 was observed in 6 of 18 (33%) tumors lacking COX-2 expression in comparison with 2 of 28 (7%) tumors expressing this protein (P = 0.04). CONCLUSIONS: Up to half of MMR-deficient colorectal cancer do not show COX-2 overexpression, a fact observed almost exclusively in patients with sporadic forms. COX2 hypermethylation seems to be responsible for gene silencing in one third of them. These results suggest the potential utility of nonsteroidal anti-inflammatory drugs in HNPCC chemoprevention and may explain the lack of response of this approach in some sporadic tumors.
Abstract: PURPOSE: Although systematic postoperative surveillance of patients with colorectal cancer has been demonstrated to improve survival, it remains unknown whether a more intensive strategy provides any significant advantage. This prospective, multicenter, randomized, controlled trial was aimed at comparing the efficacy of two different surveillance strategies in terms of both survival and recurrence resectability. PATIENTS AND METHODS: Patients with stage II or III colorectal cancer were allocated randomly to either a simple surveillance strategy including clinical evaluation and serum carcinoembryonic antigen monitoring, or an intensive strategy in which abdominal computed tomography or ultrasonography, chest radiograph, and colonoscopy were added. RESULTS: A total of 259 patients were included: 132 were observed according to the simple strategy and 127 were observed according to the intensive strategy. Both groups were similar with respect to baseline characteristics and rate and type of tumor recurrence. After a median follow-up of 48 months, there was no difference in the probability of overall survival in the whole series (hazard ratio [HR] = 0.87; 95% CI, 0.49 to 1.54; P = .62). However, the intensive strategy was associated with higher overall survival in patients with stage II tumors (HR = 0.34; 95% CI, 0.12 to 0.98; P = .045) and in those with rectal lesions (HR = 0.09; 95% CI, 0.01 to 0.81; P = .03), mainly due to higher rate of resectability for recurrent tumors. Colonoscopy was responsible for the detection of the highest proportion (44%) of resectable tumor recurrence in the intensive arm. CONCLUSION: A more intensive surveillance strategy improves the prognosis of patients with stage II colorectal cancer or those with rectal tumors. Inclusion of regular performance of colonoscopy seems justified up to the fifth year of follow-up, at least.
Abstract: Identification of individuals who should undergo hereditary nonpolyposis colorectal cancer (HNPCC) genetic testing is a critical and difficult issue. For this purpose, the National Cancer Institute outlined a set of recommendations, the Bethesda guidelines, which have recently been revised. OBJECTIVE: To compare the clinical performance of original and revised Bethesda guidelines for the detection of MSH2/MLH1 gene carriers in patients with colorectal cancer. METHODS: A total of 1,222 patients with newly diagnosed colorectal cancer were included in the EPICOLON study, a prospective, multicenter, nationwide epidemiology survey aimed at establishing the incidence of HNPCC in Spain (JAMA 2005; 293:1986-1994). Performance characteristics of the original and revised Bethesda guidelines were assessed with respect to the presence of MSH2/MLH1 germline mutations. Logistic regression analysis was performed to establish the most effective strategy. RESULTS: Original or revised Bethesda guidelines were equivalent strategies in terms of sensitivity (100%vs 100%; ns), specificity (98.1%vs 97.9%; ns), and overall accuracy (98.1%vs 97.9%; ns), as well as positive (25.8%vs 24.2%) and negative predictive values (100%vs 100%). The most discriminating individual variables were criteria number 1 (i.e., fulfillment of the Amsterdam criteria; RR = 34.14; 95% CI = 6.85-170.16; p < 0.001) and number 2 (i.e., individuals with two HNPCC-related neoplasms; RR = 35.63; 95% CI = 4.83-262.6; p < 0.001) of the original guidelines, and criterion number 1 of the revised guidelines (i.e., colorectal cancer diagnosed under 50 yr of age; RR = 29.34; 95% CI = 3.81-225.96; p= 0.001). The aggregation of these three criteria was equivalent to both Bethesda guidelines in terms of sensitivity (100%) and negative predictive value (100%), but superior to the revised criteria regarding specificity (98.5%; p < 0.05), overall accuracy (98.5%; p < 0.05), and positive predictive value (30.8%). CONCLUSIONS: Original and revised Bethesda guidelines are equivalent, highly effective criteria for the identification of MSH2/MLH1 gene mutation carriers in patients with newly diagnosed colorectal cancer. A new set of recommendations, based on a combination of some of their individual criteria, may provide additional advantages in terms of effectiveness.
Abstract: BACKGROUND: The demand for gastrointestinal endoscopy is increasing in most developed countries, resulting in an important rise in overall costs and waiting lists for endoscopic procedures. Therefore, adherence to appropriate indications for these procedures is essential for the rational use of finite resources in an open-access system. AIM: To assess indications and appropriateness of colonoscopy according to the European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE) criteria. METHODS: From May to June 2004, all consecutive patients referred to our Unit for open-access colonoscopy were considered for inclusion in this prospective study. Appropriateness of each colonoscopy was established according to the EPAGE criteria. In order to evaluate whether appropriateness of use correlated with the diagnostic yield of colonoscopy, relevant endoscopic findings were also recorded. RESULTS: A total of 350 consecutive patients were included in the study. In 38 of them, the colonoscopy indication was not listed in the EPAGE guidelines and, consequently, they were not evaluated. In the remaining 312 patients, the indication for the procedure was considered inappropriate in 73 (23%) patients. Both referring doctor characteristics (specialty and health care setting) and patient data (age) correlated with appropriateness of endoscopy. The diagnostic yield was significantly higher for appropriate colonoscopies (42%) than in those judged inappropriate (21%) (P = 0.001). CONCLUSIONS: A noteworthy proportion of patients referred for colonoscopy to an open-access endoscopy unit are considered inappropriate because of their indication, with significant differences among specialties. These results suggest that implementation of validated guidelines for its appropriate use could improve this situation and, considering the correlation between appropriateness and diagnostic yield, even contribute to improve the prognosis of patients with colorectal diseases.
Abstract: CONTEXT: The selection of individuals for hereditary nonpolyposis colorectal cancer (HNPCC) genetic testing is challenging. Recently, the National Cancer Institute outlined a new set of recommendations, the revised Bethesda guidelines, for the identification of individuals with HNPCC who should be tested for microsatellite instability. OBJECTIVE: To establish the most effective and efficient strategy for the detection of MSH2/MLH1 gene carriers.DESIGN, SETTING, AND PATIENTS: A prospective, multicenter, nationwide study (the EPICOLON study) in 20 hospitals in the general community in Spain of 1222 patients with newly diagnosed colorectal cancer between November 1, 2000, and October 31, 2001. INTERVENTIONS: Microsatellite instability testing and MSH2/MLH1 immunostaining in all patients regardless of age, personal or family history, and tumor characteristics. Patients whose tumors exhibited microsatellite instability and/or lack of protein expression underwent MSH2/MLH1 germline testing. MAIN OUTCOME MEASURES: Effectiveness and efficiency of both microsatellite instability testing and immunostaining, either directly or previous selection of patients according to the revised Bethesda guidelines, were evaluated with respect to the presence of MSH2/MLH1 germline mutations. RESULTS: Two hundred eighty-seven patients (23.5%) fulfilled the revised Bethesda guidelines. Ninety-one patients (7.4%) had a mismatch repair deficiency, with tumors exhibiting either microsatellite instability (n = 83) or loss of protein expression (n = 81). Germline testing identified 11 mutations (0.9%) in either MSH2 (7 cases) or MLH1 (4 cases) genes. Strategies based on either microsatellite instability testing or immunostaining previous selection of patients according to the revised Bethesda guidelines were the most effective (sensitivity, 81.8% and 81.8%; specificity, 98.0% and 98.2%; positive predictive value, 27.3% and 29.0%, respectively) to identify MSH2/MLH1 gene carriers. Logistic regression analysis confirmed the revised Bethesda guidelines as the most discriminating set of clinical parameters (odds ratio, 33.3; 95% confidence interval, 4.3-250; P = .001). CONCLUSION: The revised Bethesda guidelines constitute a useful approach to identify patients at risk for HNPCC. In patients fulfilling these criteria, both microsatellite instability testing and immunostaining are equivalent and highly effective strategies to further select those patients who should be tested for MSH2/MLH1 germline mutations.
Abstract: Colorectal cancer is the most common cancer in Western countries and the second leading cause of cancer-related death. Sporadic lesions represent 75-80% of all colorectal cancer, whereas 20-25% are in younger individuals or in patients with a family history of cancer, suggesting a heritable susceptibility. Persons with germline alterations in cancer-promoting genes, such as those with familial adenomatous polyposis and hereditary non-polyposis colorectal cancer, stand to benefit significantly from chemopreventive interventions, along with those who had already developed any colorectal neoplasia (either adenoma or carcinoma). Among the most promising approaches to chemoprevention is the use of non-steroidal anti-inflammatory drugs, including both selective and non-selective cyclooxigenase-2 inhibitors. Although the present article is mainly focused on these drugs and their mechanisms of action, other strategies with potential involvement in colorectal cancer chemoprevention such as peroxisome proliferator activated receptor ligands, epithelial growth factor receptor blockers, calcium, vitamin D, folate, and DNA methyltransferase inhibitors are also reviewed.
Abstract: Colorectal cancer (CRC) is one of the most common neoplasms and a leading cause of death related to cancer worldwide. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent autosomal dominant predisposition to the development of CRC, accounting for approximately 2.5% of the total CRC burden in Spain. Genomic rearrangements in the MSH2 and MLH1 genes have been reported to account for an important proportion of the mutation spectrum in HNPCC, and DNA dosage techniques have been developed facilitating molecular screening of such deletions/duplications. We screened for MSH2 and MLH1 genomic rearrangements by multiplex ligation-dependent probe amplification (MLPA) in 142 Spanish patients at risk for HNPCC prior to the exon-by-exon mutation scanning and found a deletion encompassing exons 9-16 of MSH2 and a duplication encompassing exons 11-16 of MSH2, both only in one case. These results showed that MSH2/MLH1 rearrangements in Spanish patients at risk for HNPCC seem to be a less frequent mutational event than in other populations.
Abstract: AIM: To establish the usefulness of KRAS mutational analysis in the diagnosis of pancreatic adenocarcinoma by comparing this technique with conventional cytology in aspirates obtained by endosonography-guided fine-needle aspiration. METHODS: All consecutive patients with pancreatic focal lesions undergoing endosonography-guided fine-needle aspiration were included. Samples were obtained with the concurrence of an attendant cytopathologist. Detection of codon-12 KRAS mutations was performed by the restriction fragment length polymorphism-polymerase chain reaction method. The effectiveness of conventional cytology, KRAS mutational analysis and their combination was established with respect to the definitive diagnosis. A cost-effectiveness analysis was also performed. RESULTS: Thirty-three patients had pancreatic adenocarcinoma and 24 patients had other lesions. A total of 136 samples was obtained. In patients in whom specimens were adequate (93% for cytology; 100% for mutational analysis), the specificity of both techniques was 100%, whereas the sensitivity favoured cytology (97% vs. 73%). When inadequate samples were considered as misdiagnosed, a combination of both techniques reached the highest overall accuracy (cytology, 91%; mutational analysis, 84%; combination of both, 98%). CONCLUSIONS: Cytology from aspirates obtained by endosonography-guided fine-needle aspiration is the most precise single technique for the diagnosis of pancreatic adenocarcinoma. However, when adequate specimens are not available to reach a cytological diagnosis, the addition of KRAS mutational analysis represents the best strategy.
