Joaquín Cubiella

Colonoscopy versus Fecal Immunochemical Testing in Colorectal-Cancer Screening

BACKGROUND Colonoscopy and fecal immunochemical testing (FIT) are accepted strategies for colorectal-cancer screening in the average-risk population. METHODS In this randomized, controlled trial involving asymptomatic adults 50 to 69 years of age, we compared one-time colonoscopy in 26,703 subjects with FIT every 2 years in 26,599 subjects. The primary outcome was the rate of death from colorectal cancer at 10 years. This interim report describes rates of participation, diagnostic findings, and occurrence of major complications at completion of the baseline screening. Study outcomes were analyzed in both intention-to-screen and as-screened populations. RESULTS The rate of participation was higher in the FIT group than in the colonoscopy group (34.2% vs. 24.6%, P<0.001). Colorectal cancer was found in 30 subjects (0.1%) in the colonoscopy group and 33 subjects (0.1%) in the FIT group (odds ratio, 0.99; 95% confidence interval [CI], 0.61 to 1.64; P=0.99). Advanced adenomas were detected in 514 subjects (1.9%) in the colonoscopy group and 231 subjects (0.9%) in the FIT group (odds ratio, 2.30; 95% CI, 1.97 to 2.69; P<0.001), and nonadvanced adenomas were detected in 1109 subjects (4.2%) in the colonoscopy group and 119 subjects (0.4%) in the FIT group (odds ratio, 9.80; 95% CI, 8.10 to 11.85; P<0.001). CONCLUSIONS Subjects in the FIT group were more likely to participate in screening than were those in the colonoscopy group. On the baseline screening examination, the numbers of subjects in whom colorectal cancer was detected were similar in the two study groups, but more adenomas were identified in the colonoscopy group. (Funded by Instituto de Salud Carlos III and others; ClinicalTrials.gov number, NCT00906997.).

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.

5-Fluorouracil Adjuvant Chemotherapy Does Not Increase Survival in Patients With CpG Island Methylator Phenotype Colorectal Cancer

BACKGROUND & AIMS 5-Fluorouracil (5-FU)-based adjuvant chemotherapy does not increase survival times of patients with colorectal tumors with microsatellite instability. We determined the response of patients with colorectal tumors with the CpG island methylator phenotype (CIMP) to 5-FU-based therapy. METHODS We analyzed a population-based cohort of 302 patients with colorectal cancer (CRC) for a median follow-up time of 50.7 months. CIMP status was determined by analysis of the CACNAG1, SOCS1, RUNX3, NEUROG1, and MLH1 promoters; tumors were considered to be CIMP positive if at least 3 promoters were methylated. RESULTS Tumors from 29.5% of patients (89/302) were CIMP positive; CIMP status did not influence disease-free survival (DFS; log-rank = 0.3). Of tumors of TNM stages II-III (n = 196), 32.7% were CIMP positive. Among patients with stages II-III CRC who did not receive adjuvant 5-FU chemotherapy, those with CIMP-positive tumors had longest times of DFS (log-rank = 0.04); In patients who received chemotherapy, those with CIMP-positive tumors had shorter times of DFS (log-rank = 0.02). In patients with CIMP-negative tumors, adjuvant 5-FU chemotherapy significantly increased time of DFS (log-rank = 0.00001). However, in patients with CIMP-positive tumors, adjuvant 5-FU chemotherapy did not affect time of DFS (log-rank = 0.7). Multivariate analysis showed a significant, independent interaction between 5-FU treatment and CIMP status (hazard ratio [HR], 0.6; 95% confidence interval [CI], 0.5-0.8). Among patients with CIMP-positive tumors, adjuvant chemotherapy was not an independent predictor of outcome (HR, 0.8; 95% CI, 0.3-2.0). In patients who did not receive adjuvant 5-FU chemotherapy, CIMP status was the only independent predictor of survival (HR, 2.0; 95% CI, 1.1-3.8). CONCLUSIONS Patients with CIMP-positive colorectal tumors do not benefit from 5-FU-based adjuvant chemotherapy.

The efficacy of adjuvant chemotherapy with 5-fluorouracil in colorectal cancer depends on the mismatch repair status

AIMS The aim of this study is to evaluate if mismatch repair (MMR) defective colorectal cancer has a different response to adjuvant 5-fluorouracil (5-FU) chemotherapy in a cohort of patients prospectively followed during 5 years. METHODS The cohort included 754 surgically treated patients with colorectal cancer. MMR status was diagnosed by MLH1 and MSH2 immunohistochemistry and microsatellite instability analysis. Median follow-up was 49.2 months (range 1-73). At inclusion, 505 patients were diagnosed as TNM II or III stage, analysis of the efficacy of adjuvant chemotherapy was made on this population. Adjuvant chemotherapy was applied to 248 patients (98.2% 5-FU based). RESULTS MMR deficiency was found in 76 patients (10.1%). No differences were found in overall survival (log-rank p=0.3) or disease-free survival (log-rank p=0.3) regarding MMR status. Adjuvant chemotherapy improves survival in patients in the II or III stage, but this improvement is only evident in patients with MMR-competent tumours (log-rank p=0.00001). Survival of patients with MMR-defective tumours does not improve with adjuvant chemotherapy (log-rank p=0.7). A multivariate analysis showed an independent effect of the interaction between MMR status and adjuvant chemotherapy (Hazard ratio 2.04; 95% confidence interval: 1.42-2.93). CONCLUSION In a cohort of colorectal cancer patients, those with MMR-deficient tumours seem not to benefit from 5-FU-based chemotherapy.

Risk of Cancer in Cases of Suspected Lynch Syndrome Without Germline Mutation

BACKGROUND & AIMS Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS. METHODS We studied a population-based cohort of 1705 consecutive patients, performing MSI tests and immunohistochemical analyses of MMR proteins. Patients were diagnosed with Lynch syndrome when they were found to have pathogenic germline mutations. Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylation, and no pathogenic mutation were considered to have LLS. The clinical characteristics of patients and the age- and sex-adjusted standardized incidence ratios (SIRs) of cancer in families were compared between groups. RESULTS The incidence of CRC was significantly lower in families of patients with LLS than in families with confirmed cases of Lynch syndrome (SIR for Lynch syndrome, 6.04; 95% confidence interval [CI], 3.58-9.54; SIR for LLS, 2.12; 95% CI, 1.16-3.56; P < .001). However, the incidence of CRC was higher in families of patients with LLS than in families with sporadic CRC (SIR for sporadic CRC, 0.48; 95% CI, 0.27-0.79; P < .001). CONCLUSIONS The risk of cancer in families with LLS is lower that of families with Lynch syndrome but higher than that of families with sporadic CRC. These results confirm the need for special screening and surveillance strategies for these patients and their relatives.

Modifiable endoscopic factors that influence the adenoma detection rate in colorectal cancer screening colonoscopies

BACKGROUND Adenoma detection rate (ADR) has become the most important quality indicator for colonoscopy. OBJECTIVE The aim of this study was to investigate which modifiable factors, directly related to the endoscopic procedure, influenced the ADR in screening colonoscopies. DESIGN Observational, nested study. SETTING Multicenter, randomized, controlled trials. PATIENTS Asymptomatic people aged 50 to 69 years were eligible for a multicenter, randomized, controlled trial designed to compare colonoscopy and fecal immunochemical testing in colorectal cancer screening. A total of 4539 individuals undergoing a direct screening colonoscopy were included in this study. INTERVENTION Colonoscopy. MAIN OUTCOME MEASUREMENTS Bowel cleansing, sedation, withdrawal time in normal colonoscopies, and cecal intubation were analyzed as possible predictors of adenoma detection by using logistic regression analysis, adjusted for age and sex. RESULTS In multivariate analysis, after adjustment for age and sex, factors independently related to the ADR were a mean withdrawal time longer than 8 minutes (odds ratio [OR] 1.51; 95% CI, 1.17-1.96) in normal colonoscopies and split preparation (OR 1.26; 95% CI, 1.01-1.57). For advanced adenomas, only withdrawal time maintained statistical significance in the multivariate analysis. For proximal adenomas, withdrawal time and cecal intubation maintained independent statistical significance, whereas only withdrawal time longer than 8 minutes and a <10-hour period between the end of preparation and colonoscopy showed independent associations for distal adenomas. LIMITATIONS Only endoscopic variables have been analyzed. CONCLUSION Withdrawal time was the only modifiable factor related to the ADR in colorectal cancer screening colonoscopies associated with an increased detection rate of overall, advanced, proximal, and distal adenomas.

Prognostic factors in nonresectable pancreatic adenocarcinoma: a rationale to design therapeutic trials.

Objective:Most patients with pancreatic cancer show an advanced tumor at the time of diagnosis. In recent years, new therapies have been developed in such patients, thus forcing the analysis of factors that influence their survival. The present study was aimed at determining the prognostic factors in a series of 134 consecutive patients with pancreatic carcinoma not suitable for surgical resection, due to either locally advanced tumors or metastatic spread.Methods:First, 34 epidemiological, clinical, analytical, and tumor-related parameters recruited at admission were included in a univariate analysis of survival by using the Kaplan-Meier method. Those significant variables in the previous step were thereafter introduced in a Cox regression procedure. A prognostic index for calculating the relative risk of death of each patient was also proposed.Results:The median survival time in the whole series was 3.11 months, the 3, 6, and 12 months probability of survival being 51%, 28%, and 8%, respectively. Eight of 34 variables (jaundice and toxic syndrome at admission, serum cholesterol, iron and alanine aminotransferase concentrations, leukocyte count, baseline performance status, and the presence of distant metastases) were selected in the univariate analysis. Of these eight parameters, the Cox regression analysis identified a preserved baseline performance status (OR = 2.14, 95% CI = 1.49–3.04) and the absence of metastases (OR = 1.34, 95% CI = 1.03–1.73) as the only variables independently associated with a longer survival. Therefore, a prognostic index was constructed allowing the division of patients in three different groups according to their relative risk of death (RRD) = exp (performance status × 0.7589 + presence of metastases × 0.2891).Conclusions:The results of the present investigation suggest that baseline performance status and distant metastases should be considered in designing and evaluating any therapeutic trial in patients with nonresectable pancreatic carcinoma.

Susceptibility Genetic Variants Associated With Colorectal Cancer Risk Correlate With Cancer Phenotype

BACKGROUND & AIMS Ten common low-penetrant genetic variants have been consistently associated with colorectal cancer (CRC) risk; little is known about the correlation between these variants and CRC phenotype. Characterization of such a correlation would improve CRC management and prevention programs. We assessed the association between these genetic variants and CRC phenotype in patients and modeled pairwise combinations to detect epistasis. METHODS The validation population corresponded to a prospective, multicenter, population-based cohort (EPICOLON I) of 1096 patients with newly diagnosed CRC. The replication set was an independent, prospective, multicenter Spanish cohort (EPICOLON II) of 895 patients with newly diagnosed CRC. For individual single nucleotide polymorphism (SNP) association analyses, a multivariate method using logistic regression was applied in EPICOLON I and subsequently prospectively validated in EPICOLON II. Interactions between SNPs were assessed using the likelihood ratio test. RESULTS Validated results confirmed that the C allele on 8q23.3 (rs16892766) was significantly associated with advanced-stage tumors (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.15-1.90; P value = 4.9 x 10(-3)). The G allele on 8q24.21 (rs6983267) was more common in patients with a familial history of CRC (OR, 2.02; 95% CI, 1.35-3.03; P value = 3.9 x 10(-4)). The combination of rs6983267 on 8q24.21 and rs9929218 on 16q22.2 was associated with a history of colorectal adenoma (carriers of GG and AA, respectively; OR, 2.28; 95% CI, 1.32-3.93; P = 5.0 x 10(-4)). CONCLUSIONS CRC susceptibility variants at 8q23.3, 8q24.21, and 16q22.2 appear to be associated with cancer phenotype. These findings might be used to develop screening and surveillance strategies.

Clinical Performance of Original and Revised Bethesda Guidelines for the Identification of MSH2/MLH1 Gene Carriers in Patients with Newly Diagnosed Colorectal Cancer: Proposal of a New and Simpler Set of Recommendations

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.

Análisis del curso clínico de la pancreatitis aguda hipertrigliceridémica y su comparación con el de la litiásica

Fundamento y objetivo La hipertrigliceridemia es una causa aceptada de pancreatitis aguda, pero su curso clinico no esta bien definido. Ademas, la presencia de suero lipemico puede interferir en la determinacion de las enzimas pancreaticas y dificultar el diagnostico. El objetivo fue analizar el comportamiento clinico de las pancreatitis agudas por hipertrigliceridemia y el valor diagnostico de la determinacion serica de las enzimas pancreaticas en esta enfermedad. Pacientes y metodo Se analizaron retrospectivamente 31 datos demograficos, clinicos y analiticos de 19 pancreatitis agudas por hipertrigliceridemia y se compararon con los de 19 pancreatitis agudas de etiologia litiasica sin hipertrigliceridemia. El diagnostico de pancreatitis aguda se realizo cuando existian un cuadro clinico y datos radiologicos y/o laparotomicos compatibles. Se considero que habia pancreatitis aguda por hipertrigliceridemia cuando la cifra de trigliceridos era superior a 1.000 mg/dl y se excluian otras etiologias. Se considero que habia pancreatitis aguda litiasica cuando los calculos eran identificados por ultrasonografia, la cifra de trigliceridos era inferior a 200 mg/dl y no existia consumo de alcohol. Resultados Las pancreatitis agudas por hipertrigliceridemia presentaban, respecto a las pan creatitis agudas litiasicas, antecedentes familiares y personales de hipertrigliceridemia (9 frente a 0), mas episodios previos de pancreatitis (13 frente a 2), mayor numero de complicaciones (29 frente a 5) y de pancreatitis graves (13 frente a 5). No hubo mortalidad en ningun grupo. Las cifras de amilasa y lipasa apoyaron el diagnostico en el 26 y el 58% de las pancreatitis agudas por hipertrigliceridemia, frente al 58 y el 79% de las pancreatitis agudas litiasicas, respectivamente. Las pancreatitis agudas por hipertrigliceridemia precisaron de un mayor tiempo de hospitalizacion (24 [45] frente a 7,6 [3,1] dias; p = NS). No se han identificado factores demograficos ni analiticos que permitan predecir la gravedad de las pancreatitis agudas por hipertrigliceridemia. Conclusiones Las pancreatitis agudas por hipertrigliceridemia suelen ser recidivantes y su curso clinico es mas grave que el de las pancreatitis agudas litiasicas. Las cifras de amilasa y lipasa son menos utiles para el diagnostico de pancreatitis agudas hipertrigliceridemicas que en el de las litiasicas.