Candidate predisposing germline copy number variants in early onset colorectal cancer patients

Purpose. A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called ‘missing heritability’. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset. Methods/patients. We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter. Results. We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis. Conclusions. These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC (AU)

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Candidate predisposing germline copy number variants in early onset colorectal cancer patients.

PURPOSE: A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called 'missing heritability'. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset. METHODS/PATIENTS: We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter. RESULTS: We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis. CONCLUSIONS: These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC.

High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families.

Lynch syndrome (LS) is caused by germline mutations in one of the four mismatch repair (MMR) genes. Defects in this pathway lead to microsatellite instability (MSI) in DNA tumors, which constitutes the molecular hallmark of this disease. Selection of patients for genetic testing in LS is usually based on fulfillment of diagnostic clinical criteria (i.e. Amsterdam criteria or the revised Bethesda guidelines). However, following these criteria PMS2 mutations have probably been underestimated as their penetrances appear to be lower than those of the other MMR genes. The use of universal MMR study-based strategies, using MSI testing and immunohistochemical (IHC) staining, is being one proposed alternative. Besides, germline mutation detection in PMS2 is complicated by the presence of highly homologous pseudogenes. Nevertheless, specific amplification of PMS2 by long-range polymerase chain reaction (PCR) and the improvement of the analysis of large deletions/duplications by multiplex ligation-dependent probe amplification (MLPA) overcome this difficulty. By using both approaches, we analyzed 19 PMS2-suspected carriers who have been selected by clinical or universal strategies and found five large deletions and one frameshift mutation in PMS2 in six patients (31%). Owing to the high incidence of large deletions found in our cohort, we recommend MLPA analysis as the first-line method for searching germline mutations in PMS2.

A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer.

Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility.

Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers.

Recent findings in colon cancer cells indicate that inhibition of the mitochondrial H(+)-adenosine triphosphate (ATP) synthase by the ATPase inhibitory factor 1 (IF1) promotes aerobic glycolysis and a reactive oxygen species (ROS)-mediated signal that enhances proliferation and cell survival. Herein, we have studied the expression, biological relevance, mechanism of regulation and potential clinical impact of IF1 in some prevalent human carcinomas. We show that IF1 is highly overexpressed in most (>90%) of the colon (n=64), lung (n=30), breast (n=129) and ovarian (n=10) carcinomas studied as assessed by different approaches in independent cohorts of cancer patients. The expression of IF1 in the corresponding normal tissues is negligible. By contrast, the endometrium, stomach and kidney show high expression of IF1 in the normal tissue revealing subtle differences by carcinogenesis. The overexpression of IF1 also promotes the activation of aerobic glycolysis and a concurrent ROS signal in mitochondria of the lung, breast and ovarian cancer cells mimicking the activity of oligomycin. IF1-mediated ROS signaling activates cell-type specific adaptive responses aimed at preventing death in these cell lines. Remarkably, regulation of IF1 expression in the colon, lung, breast and ovarian carcinomas is exerted at post-transcriptional levels. We demonstrate that IF1 is a short-lived protein (t1/2 ∼100 min) strongly implicating translation and/or protein stabilization as main drivers of metabolic reprogramming and cell survival in these human cancers. Analysis of tumor expression of IF1 in cohorts of breast and colon cancer patients revealed its relevance as a predictive marker for clinical outcome, emphasizing the high potential of IF1 as therapeutic target.

Leukocytapheresis for steroid-dependent ulcerative colitis in clinical practice: results of a nationwide Spanish registry.

BACKGROUND: Several small, prospective, open studies suggest that leukocytapheresis might be efficient in patients with steroid-dependent ulcerative colitis (UC). AIM: To evaluate the short- and long-term effectiveness of leukocytapheresis for the management of steroid-dependent UC in clinical practice. METHODS: A Web-based, nationwide database specifically designed to record the efficacy and safety data of leukocytapheresis therapy in UC was available from September 2007 in Spain. Clinical data were collected at treatment baseline, 1 month after the last apheresis session (initial efficacy), and 6 and 12 months thereafter (long-term efficacy). Remission was defined as a Mayo Clinic index ≤2 together with complete steroid withdrawal and response as a decrease of ≥3 from the baseline score. RESULTS: A total of 142 steroid-dependent UC patients were included in the registry, most of them treated with the Adacolumn™ system. In 69% of patients thiopurine therapy failed to achieve steroid-free clinical remission. Initial clinical remission was obtained in 37% of cases. The initial corticosteroid dose, the number and frequency of apheresis sessions, or the previous failure of thiopurines and/or infliximab did not influence the initial remission rate, but a greater decrease in CRP levels was associated with a higher probability to obtain initial remission. At 6 and 12 months, 41 and 36% of patients were in clinical remission, respectively. Only one serious adverse effect was recorded. CONCLUSIONS: In clinical practice, apheresis allows long-term steroid-free clinical remission in up to one third of steroid-dependent UC patients, even in those with prior failure of thiopurines.

Reverse phase protein microarrays quantify and validate the bioenergetic signature as biomarker in colorectal cancer.

A reverse phase protein microarray approach has been applied to quantify proteins of energy metabolism in normal and tumor biopsies of colorectal cancer (CRC) patients. The metabolic proteome of CRC specimens revealed a profound shift towards and enhanced glycolytic phenotype and concurrent mitochondrial alteration. The metabolic signature discriminated CRC patients with highly significant differences in overall and disease-free prognosis. The quantification of the bioenergetic signature of the tumor offers a relevant biomarker of CRC that could contribute in the handling of these patients.

A comparative study of two histological techniques for the identification of cytomegalovirus infection in colorectal biopsies from patients with chronic inflammatory bowel disease.

BACKGROUND: the role that cytomegalovirus (CMV) plays in inflammatory bowel disease (IBD) is controversial. The diagnosis of CMV infection in IBD depends on viral identification with hematoxylin-eosin (HE) or immunohistochemistry (IHC). Our aim was to compare the sensitivity of HE and IHC for this diagnosis in IBD patients. PATIENTS AND METHODS: a case-control study. Our database was searched for IBD patients with HE- or IHC-based CMV-positivity from 1997 to 2007. Controls were selected among IBD inpatients matched for age and year of diagnosis with CMV. Their clinical characteristics were analyzed. HE and IHC were performed on biopsies from cases and controls at 6 months before and after inclusion in the study. In the statistical analysis, p values below 0.05 were considered significant. RESULTS: ten IBD patients with CMV infection were identified. IBD-CMV patients were more steroid-resistant or steroid-dependent (p = 0.03), and underwent a higher number of colonic biopsies (p = 0.03). From 97 biopsies analyzed, 12 were HE-negative and IHC-positive, and 3 showed reversed results. The sensitivity of HE was 58.6%, 95% CI (38.9-78.3), and that of IHC was 89.7%, 95% CI (76.8-100). We did not find a good level of agreement between both techniques: kappa value 0.55, 95% CI (0.36-0.75). CMV positivity with IHC was associated with the use of more than one immunosuppressant drug, OR 13.5, 95%CI (1.2-152.2). Antiviral treatment was useful for CMV patients with steroid-dependent and steroid-refractory IBD. CONCLUSIONS: IHC shows a 30% higher sensitivity than HE for the diagnosis of CMV infection in IBD patients. There is no good level of agreement between both histological techniques.

Estudio comparativo entre dos técnicas histológicas para el diagnóstico de infección por citomegalovirus en biopsias colorrectales de pacientes con enfermedad inflamatoria intestinal crónica idiopática / A comparative study of two histological techniques for the identification of cytomegalovirus infection in colorectal biopsies from patients with chronic inflammatory bowel disease

Introducción: el papel que el citomegalovirus (CMV) juega enla enfermedad inflamatoria intestinal (EII) es controvertido. Eldiagnóstico de infección por CMV en estos pacientes reside en suidentificación en el tejido colónico mediante hematoxilina-eosina(HE) o inmunohistoquímica (IHC). Nuestro objetivo fue compararla sensibilidad de ambas técnicas histológicas para establecer estediagnóstico.Pacientes y métodos: estudio caso-control, identificando enel periodo 1997-2007 aquellos pacientes CMV positivos con HEo IHQ. Sus controles fueron apareados por edad y año de diagnósticode CMV en los casos. Se realizaron ambas técnicas en lasbiopsias de casos y controles obtenidas 6 meses antes y tras su inclusiónen el estudio. En el análisis estadístico consideramos significativoslos valores de p < 0,05.Resultados: encontramos infección por CMV en 10 pacientes.Estos sujetos presentaban más frecuentemente una EII resistenteo dependiente de esteroides (p = 0,03) y un mayor númerode biopsias de colon (p = 0,03). De 97 biopsias analizadas, 12fueron HE-negativas e IHC-positivas y 3 mostraron resultados inversos.La sensibilidad de HE fue 58,6% IC95 (38,9-78,3) y paraIHQ 89,7% IC95 (76,8-100). No encontramos una buena concordanciaentre ambas técnicas histológicas: kappa 0,55 IC95(0,36-0,75). La positividad para CMV se asoció al uso de más deun fármaco inmunosupresor, OR 13,5 IC95 (1,2-152,2). El tratamientoantiviral fue útil en la EII refractaria o dependiente de esteroides.Conclusiones: la IHQ posee una sensibilidad superior a HE(30%) para el diagnóstico de infección por CMV en la EII, no existiendobuena concordancia entre ambas técnicas histológicas(AU)

Background: the role that cytomegalovirus (CMV) plays in inflammatorybowel disease (IBD) is controversial. The diagnosis ofCMV infection in IBD depends on viral identification with hematoxylin-eosin (HE) or immunohistochemistry (IHC). Our aim wasto compare the sensitivity of HE and IHC for this diagnosis in IBDpatients.Patients and methods: a case-control study. Our databasewas searched for IBD patients with HE- or IHC-based CMV-positivityfrom 1997 to 2007. Controls were selected among IBD inpatientsmatched for age and year of diagnosis with CMV. Theirclinical characteristics were analyzed. HE and IHC were performedon biopsies from cases and controls at 6 months beforeand after inclusion in the study. In the statistical analysis, p valuesbelow 0.05 were considered significant.Results: ten IBD patients with CMV infection were identified.IBD-CMV patients were more steroid-resistant or steroid-dependent(p = 0.03), and underwent a higher number of colonic biopsies(p = 0.03). From 97 biopsies analyzed, 12 were HE-negativeand IHC-positive, and 3 showed reversed results. The sensitivityof HE was 58.6%, 95% CI (38.9-78.3), and that of IHC was89.7%, 95% CI (76.8-100). We did not find a good level of agreementbetween both techniques: kappa value 0.55, 95% CI (0.36-0.75). CMV positivity with IHC was associated with the use ofmore than one immunosuppressant drug, OR 13.5, 95%CI (1.2-152.2). Antiviral treatment was useful for CMV patients withsteroid-dependent and steroid-refractory IBD.Conclusions: IHC shows a 30% higher sensitivity than HEfor the diagnosis of CMV infection in IBD patients. There is nogood level of agreement between both histological techniques(AU)

Dysplasia and cancer in inflammatory bowel disease 10 years after diagnosis: results of a population-based European collaborative follow-up study.

OBJECTIVE: To determine dysplasia and cancer in the 1991-2004 European Collaborative Inflammatory Bowel Disease (EC-IBD) Study Group cohort. PATIENTS AND METHODS: A patient questionnaire and a physician per patient form were completed for each of the 1,141 inflammatory bowel disease patients (776 ulcerative colitis/365 Crohn's disease) from 9 centers (7 countries) derived from the EC-IBD cohort. Rates of detection of intestinal cancer and dysplasia as well as extra-intestinal neoplasms were computed. RESULTS: Patient follow-up time was 10.3 +/- 0.8 (range 9.4-11) years. The mean age of the whole group of IBD patients was 37.8 +/- 11.3 (range 16-76) years. Thirty-eight patients (3.3%; 26 with ulcerative colitis/12 with Crohn's disease, 21 males/17 females, aged 61.3 +/- 13.4, range 33-77 years), were diagnosed with 42 cancers. Cancers occurred 5.4 +/- 3.3 (range 0-11) years after inflammatory bowel disease diagnosis. Colorectal cancer was diagnosed in 8 (1 Crohn's disease and 7 ulcerative colitis patients--0.3 and 0.9% of the Crohn's disease and ulcerative colitis cohort, respectively) of 38 patients and 30 cancers were extra-intestinal. Four of 38 patients (10.5%) were diagnosed as having 2 cancers and they were younger compared to patients with one cancer (p = 0.0008). There was a trend for a higher prevalence of intestinal cancer in the northern centers (0.9%) compared to southern centers (0.3%, p = NS). Southern centers had more cases of extra-intestinal cancer compared to northern centers (2 vs. 3.8%, p = 0.08). Ten patients (0.9%; 8 with ulcerative colitis/2 with Crohn's disease, 8 males, aged 62.3 +/- 14.1 years) had colorectal dysplasia. CONCLUSIONS: In the first decade of the EC-IBD Study Group cohort follow-up study, the prevalence of cancer was as expected with most patients having a single neoplasm and an extra-intestinal neoplasm. In northern centers there was a trend for more intestinal cancers, while in southern centers there was a trend for more extra-intestinal cancers compared to northern centers.

Insuficiencia hepática fulminante secundaria a infiltración hepática difusa por melanoma coroideo / Acute liver failure secondary to malignant infiltration by melanoma

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[Acute cholestatic hepatitis after atorvastatin reintroduction]. / Hepatitis colestásica aguda tras la reintroducción de atorvastatina.

Consumption of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitors, known as statins, has been associated with elevated transaminase levels but rarely with acute hepatitis. Recently, several cases of acute hepatitis secondary to atorvastatin therapy have been published. We report the case of a 72-year-old man who developed acute cholestatic hepatitis after reinitiating treatment with atorvastatin at a higher dose than that previously prescribed. After treatment discontinuation, the patient made a full recovery, with normalization of clinical and laboratory findings.

Hepatitis colestásica aguda tras la reintroducción de atorvastatina / Acute cholestatic hepatitis after atorvastatin reintroduction

El consumo de los inhibidores de la 3-hidroxi-3-metilglutaril-coenzima A (HMG-CoA) reductasa, conocidos como estatinas, se ha asociado a la elevación de transaminasas y, menos frecuentemente, con cuadros de hepatotoxicidad. Recientemente se han comunicado varios casos de toxicidad hepática aguda por atorvastatina. Presentamos el caso de un varón de 72 años que desarrolló una hepatitis colestásica aguda tras la reintroducción de atorvastatina a una dosis superior a la previamente prescrita. La suspensión del fármaco permitió una total recuperación clínica y analítica

Consumption of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitors, known as statins, has been associated with elevated transaminase levels but rarely with acute hepatitis. Recently, several cases of acute hepatitis secondary to atorvastatin therapy have been published. We report the case of a 72-year-old man who developed acute cholestatic hepatitis after reinitiating treatment with atorvastatin at a higher dose than that previously prescribed. After treatment discontinuation, the patient made a full recovery, with normalization of clinical and laboratory findings

Hepatitis colestásica aguda tras la reintroducción de atorvastatina / Acute cholestatic hepatitis after atorvastatin reintroduction

El consumo de los inhibidores de la 3-hidroxi-3-metilglutaril-coenzima A (HMG-CoA) reductasa, conocidos como estatinas, se ha asociado a la elevación de transaminasas y, menos frecuentemente, con cuadros de hepatotoxicidad. Recientemente se han comunicado varios casos de toxicidad hepática aguda por atorvastatina. Presentamos el caso de un varón de 72 años que desarrolló una hepatitis colestásica aguda tras la reintroducción de atorvastatina a una dosis superior a la previamente prescrita. La suspensión del fármaco permitió una total recuperación clínica y analítica

Consumption of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitors, known as statins, has been associated with elevated transaminase levels but rarely with acute hepatitis. Recently, several cases of acute hepatitis secondary to atorvastatin therapy have been published. We report the case of a 72-year-old man who developed acute cholestatic hepatitis after reinitiating treatment with atorvastatin at a higher dose than that previously prescribed. After treatment discontinuation, the patient made a full recovery, with normalization of clinical and laboratory findings

Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer.

AIM: Some retrospective studies have shown a lack of benefit of 5-fluorouracil (5-FU) adjuvant chemotherapy in patients with mismatch repair (MMR) deficient colorectal cancer. Our aim was to assess if this molecular marker can predict benefit from 5-FU adjuvant chemotherapy. A second objective was to determine if MMR status influences short term survival. METHODS: We included 754 patients with a median follow up of 728.5 days (range 1-1097). A total of 260 patients with stage II or III tumours received 5-FU adjuvant chemotherapy, according to standard clinical criteria and irrespective of their MMR status. A tumour was considered MMR deficient when either BAT-26 showed instability or there was loss of MLH1 or MSH2 protein expression. RESULTS: At the end of the follow up period, 206 patients died and 120 presented with tumour recurrence. Sixty six (8.8%) patients had MMR deficient tumours. There were no significant differences in overall survival (MMR competent 72.1%; MMR deficient 78.8%; p = 0.3) or disease free survival (MMR competent 61.3%; MMR deficient 72.3%; p = 0.08). In patients with stage II and III tumours, benefit from 5-FU adjuvant chemotherapy was restricted to patients with MMR competent tumours (overall survival: chemotherapy 87.1%; non-chemotherapy 73.5%; log rank, p = 0.00001). Patients with MMR deficient tumours did not benefit from adjuvant chemotherapy (overall survival: chemotherapy 89.5%; non-chemotherapy 82.4%; log rank, p = 0.4). CONCLUSIONS: Benefit from 5-FU adjuvant chemotherapy depends on the MMR status of tumours in patients with colorectal cancer. 5-FU adjuvant chemotherapy improves survival in patients with MMR competent tumours but this benefit from chemotherapy cannot be extended to patients with MMR deficient tumours.

[Intestinal metaplasia at the esophagogastric junction. Prevelence and association in patients undergoing endoscopy]. / Metaplasia intestinal en la unión esofagogástrica. Prevalencia y asociaciones en una población sometida a endoscopia.

AIM: Short segments of intestinal metaplasia (IM) at the esophagogastric junction is an unclear entity. Several studies have reported wide variations in its prevalence and in the factors associated with its development. Recently, this entity has been divided into esophageal IM and cardiac IM, as two different lesions in etiopathogenesis and prognosis. We studied the prevalence of these conditions and their association with gastroesophageal reflux disease (GERD) and Helicobacter pylori infection. METHODS: In 161 patients, biopsies were obtained from the distal esophagus (2), just below the Z line (3), and in the gastric antrum (4). IM was diagnosed on the basis of staining of goblet cells with Alcian blue and was classified as esophageal if ILZ < IEG or cardiac ILZ = IEG. H. pylori was determined by rapid urease (CLO-test) and histology. Diagnosis of GERD was based on typical symptoms, endoscopy, and histology. In 54 patients with IM (73%) esophageal manometry and 24-hour pH-metry was also performed. RESULTS: IM was detected in 74 patients (46%); IM was esophageal in 33 patients (20.5%) and cardiac in 41 patients (25.4%). Patients with IM were significantly older than those without (p = 0.007) and took proton pump inhibitors more frequently (p = 0.004). No correlation was found between reflux symptoms, esophageal lesions or histological changes with either type of IM. No differences between esophageal or cardiac IM were detected by esophageal pH-metry. H. pylori infection was unrelated to cardiac IM, but these patients had a lower frequency of endoscopic and histological changes in the distal esophagus. CONCLUSIONS: Intestinal metaplasia is a common finding in patients sent for gastroscopy and is probably an acquired lesion that increases in prevalence with age. We found no associations between esophageal IM and GERD, evaluated by typical symptoms, endoscopic and histological changes and pH-metry. H. pylori infection showed no relation to cardiac IM.

Disease outcome in inflammatory bowel disease: mortality, morbidity and therapeutic management of a 796-person inception cohort in the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD).

BACKGROUND: The course of inflammatory bowel diseases (IBD) has mainly been studied using different methods in single patient cohorts. The aim of the present study was to assess clinical aspects of disease outcome in a population-based cohort of IBD patients over a 4-year period in multiple centres across Europe. METHODS: A total of 796 patients with IBD diagnosed in 10 centres between October 1991 and October 1993, registered at the EC IBD study centre (98% of the original cohort), participated in the study. Investigators filled out a standard follow-up form containing questions on the method of follow-up, vital status of the patient, change in diagnosis, extraintestinal manifestations, medical and surgical treatment, and physician's global assessment of disease activity. RESULTS: Complete relief of the complaints was reported in 255 (48%) patients with ulcerative colitis (UC), 9 (50%) with indeterminate colitis (IC), but only in 87 (35%) of patients with Crohn disease (CD). Improvement was reported in 195 (37%) patients with UC, 113 (45%) with CD and 6 (33%) with IC. During the 4-year follow-up period, 23 patients died (14 UC, 8 CD. and 1 IC). The mean age at death was 69.3 years (s, 14.9 years). The deaths of three patients were recorded as directly due to IBD. CONCLUSIONS: With the present approach to therapeutic management the short-term outcome of patients with IBD seems to be favourable in 10 medical centres in the north and south of Europe. However, more detailed studies including both objective and subjective measures are necessary.

[Epidemiological study on the incidence of inflammatory bowel disease in 4 Spanish areas. Spanish Group on the Epidemiological Study of Inflammatory Bowel Disease]. / Estudio epidemiológico sobre la incidencia de enfermedad inflamatoria intestinal en cuatro áreas españolas. Grupo Español para el Estudio Epidemiológico de la Enfermedad Inflamatoria Intestinal.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) shows marked geographical variations. The aim of this study was to determine and compare the incidence of IBD in four Spanish areas: Sabadell (Northeast), Vigo (Northwest), Mallorca island and Motril (South). PATIENTS AND METHODS: Prospective survey based on inception cohorts over a two-years period (1 October 1991 to September 1993). Subjects were the patients resident in these areas and diagnosed of IBD according to a standard protocol for case ascertainment and definition. RESULTS: Altogether 328 cases were identified, of whom 191 were diagnosed as ulcerative colitis (UC), 135 as Crohn's disease (CD) and 2 as indeterminate colitis. The overall adjusted incidence rate per 100,000 persons between ages 15-64 years of UC and CD were respectively 9.8 and 5.2 in Sabadell, 7.7 and 5.0 in Vigo, 7.8 and 5.8 in Mallorca and 4.3 and 6.5 in Motril. The Incidence rate ratio showed no significant differences for either conditions among these areas. The global adjusted incidence rate of UC in Spanish areas (8.0; IC 95%: 6.3-9.7) was significantly lower to that of Northern European countries while that of CD (5.5; IC 95%: 4.1-6.9) was between that of Northern and Southern Europe with no significant differences. CONCLUSIONS: The incidence of IBD did not show differences among the Spanish areas, and rates are between 2 and 6 times higher than those previously reported. The incidence of UC is significantly lower than that observed in the North of Europe, while for CD the incidence is between that of Northern and Southern Europe.