Javier de Oca

Large Bowel Obstruction: Predictive Factors for Postoperative Mortality

PURPOSEThe aims of this study were to assess the prognostic value for mortality of several factors in patients with colonic obstruction and to study the differences between proximal and distal obstruction.METHODSTwo-hundred and thirty-four consecutive patients who underwent emergency surgery for colonic obstruction were studied. Patients with an obstructive lesion distal to the splenic flexure were assessed as having a distal colonic obstruction. Resection and primary anastomosis was the operation of choice in selected patients. Alternative procedures were Hartmann’s procedure in high-risk patients, subtotal colectomy in cases of associated proximal colonic damage, and colostomy or intestinal bypass in the presence of irresectable lesions. Obstruction was considered proximal when the tumor was situated at the splenic flexure or proximally and a right or extended right colectomy was performed. A range of factors were investigated to estimate the probability of death: gender, age, American Society of Anesthesiologists score, nature of obstruction (benign vs. malign), location of the lesion (proximal vs. distal), associated proximal colonic damage and/or peritonitis, preoperative transfusion, preoperative renal failure, and laboratory data (hematocrit ≤30 percent, hemoglobin ≤10 g/dl, and leukocyte count >15,000/mm3). Univariate and multivariate forward steptwise logistic regression analysis was used to study the prognostic value of each significant variable in terms of mortality.RESULTSOne or more complications were detected in 109 patients (46.5 percent). Death occurred in 44 patients (18.8 percent). No differences were observed between proximal and distal obstruction. Age (>70 years), American Society of Anesthesiologists III–IV score, preoperative renal failure, and the presence of proximal colon damage with or without peritonitis were significantly associated with postoperative mortality in the univariate analysis. Only American Society of Anesthesiologists score, presence of proximal colon damage, and preoperative renal failure were significant predictors of outcome in multivariate logistic regression.CONCLUSIONLarge bowel obstruction still has a high of mortality rate. An accurate preoperative evaluation of severity factors might allow stratification of patients in terms of their mortality risk and help in the decision-making process for treatment. Such an evaluation would also enable better comparison between studies performed by different authors. Principles and stratification similar to those of distal lesions should be considered in patients with proximal colonic obstruction.

Prognostic factors for mortality in Left colonic peritonitis : A new scoring system

BACKGROUND Perforating lesions of the colon affect a heterogeneous group of patients, often elderly, and usually present as abdominal emergencies, with high morbidity and mortality. The aims of this study were to assess the prognostic value of specific factors in patients with left colonic peritonitis and to evaluate the utility of a scoring method that allows one to define groups of patients with different mortality risks. STUDY DESIGN Between January 1994 and December 1999, 156 patients (77 men and 79 women), with a mean (SD) age of 63.2 years (15.5 years) (range 22 to 87 years), underwent emergency operation for a distal colonic perforation. Intraoperative colonic lavage was the first choice operation and it was performed in 74 patients (47.4%). There were three alternative procedures: the Hartmann operation was performed in 69 patients (44.2%), subtotal colectomy in 9, and colostomy in 4 patients. We analyzed specific variables for their possible relation to death including gender, age, American Society of Anesthesiologists (ASA) score, immunocompromised status, etiology, and degree of peritonitis, preoperative organ failure, time (hours) between hospital admission and surgical intervention, and degree of temperature elevation (38 degrees C). Univariate relations between predictors and outcomes (death) were analyzed using logistic regression. Multivariate logistic regression analysis was used to assess the prognostic value of combinations of the variables. Significant factors identified in univariate and multivariate logistic regression analyses were used to define a left colonic Peritonitis Severity Score (PSS). Factors that were significant only in univariate analysis scored 2 points if present and 1 if not. Variables significant in multivariate analysis were scored from 1 to 3 points. Patients were randomly split into two groups, one to calculate the scoring system and the other to validate it. RESULTS Overall postoperative mortality rate was 22.4%. Septic-related mortality was observed in 24 patients (15.4%). Age, peritonitis grade, ASA score, immunocompromised status, and ischemic colitis were significant for postoperative death in univariate analysis. But only ASA score and preoperative organ failure were significantly associated with postoperative mortality in multivariate logistic regression analysis. The PSS, as defined in this study, was related to outcomes of patients. Mortality rate increased from 0%, when PSS was 6 points (minimum possible score), to 100% in patients with a PSS of 13 (maximum possible PSS = 14). CONCLUSIONS Left colonic peritonitis continues to have a persistently high mortality in patients with septic complications. ASA score and preoperative organ failure are the only factors that are significantly associated with mortality in the multivariate analysis. The PSS classification may help uniformly define the mortality risk of patients with distal large bowel peritonitis, and may help to increase the comparability of studies carried out at different centers.

Protective Effect of Ischemic Preconditioning on Cold Preservation and Reperfusion Injury Associated With Rat Intestinal Transplantation

ObjectiveTo define the protective effect of ischemic preconditioning on cold ischemia and reperfusion injury associated with intestinal transplantation, and the role of nitric oxide in this process. Summary Background DataIschemia/reperfusion injury continues to be a significant obstacle in small bowel transplantation. Preconditioning is a mechanism that protects against this injury. MethodsTo study the capacity of preconditioning to prevent cold ischemia-associated injury and the inflammatory response associated with intestinal transplantation, the authors studied a control group of animals, cold ischemia groups with or without previous preconditioning and with or without previous administration of L-NAME or NONOS, and intestinal transplantation groups with or without previous preconditioning and with or without previous administration of L-NAME or NONOS. ResultsHistologic findings and the release of lactate dehydrogenase into the preservation solution showed that preconditioning protects against cold ischemic preservation-associated injury. Preconditioning also prevented the inflammatory response associated with intestinal transplantation, measured by the above parameters and by neutrophil recruitment in the intestine. Inhibition of nitric oxide eliminates the protective effect. ConclusionsPreconditioning protects the intestinal grafts from cold preservation and reperfusion injury in the rat intestinal transplantation model. Nitric oxide is involved in this protection.

DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer

DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer (CRC) and precursor lesions have been extensively studied. Different panels have been reported attempting to improve current protocols in clinical practice, although no definite biomarkers have been established. In the present study, we have examined patient biopsies starting from a comprehensive analysis of DNA methylation differences between paired normal and tumor samples in known cancer-related genes aiming to select the best performing candidates informative for CRC diagnosis in stool samples. Five selected markers were considered for subsequent analyses in independent biologic cohorts and in silico data sets. Among the five selected genes, three of them (AGTR1, WNT2 and SLIT2) were validated in stool DNA of affected patients with a detection sensitivity of 78% [95% confidence interval (CI), 56%–89%]. As a reference, DNA methylation of VIM and SEPT9 was evaluated in a subset of stool samples yielding sensitivities of 55% and 20%, respectively. Moreover, our panel may complement histologic and endoscopic diagnosis of inflammatory bowel disease (IBD)-associated neoplasia, as it was also efficient detecting aberrant DNA methylation in non-neoplastic tissue samples from affected patients. This novel panel of specific methylation markers can be useful for early diagnosis of CRC using stool DNA and may help in the follow-up of high-risk patients with IBD. Cancer Prev Res; 6(7); 656–65. ©2013 AACR.

Novel Methylation Panel for the Early Detection of Colorectal Tumors in Stool DNA

BACKGROUND Previous studies showed that the assessment of promoter hypermethylation of a limited number of genes in tumor biopsies may identify the majority of colorectal tumors. This study aimed to assess the clinical usefulness of a panel of methylation biomarkers in stool DNA in the identification of colorectal tumors, using methylation-specific melting curve analysis (MS-MCA), a technique that simultaneously analyzes all cytosine-phosphate-guanine (CpG) residues within a promoter. MATERIALS AND METHODS The promoter methylation status of 4 tumor-related genes (RARB2, p16INK4a, MGMT, and APC) was analyzed in DNA stool samples and corresponding tissues in an initial set of 12 patients with newly diagnosed primary colorectal carcinomas and 20 patients with newly diagnosed colorectal adenomas, using methylation-specific polymerase chain reaction. Results were replicated in a set of 82 patients (20 healthy subjects, 16 patients with inflammatory bowel disease (IBD), 20 patients with adenomas, and 26 patients with carcinomas), using MS-MCA analyses. RESULTS In the initial set, >or= 1 positive methylation marker was detected in the stools of 9 of 12 patients (75%) with carcinomas and 12 of 20 patients (60%) with adenomas, with no false-positive results. Stool analyses missed 7 methylated lesions (25%). In the replication set, stool DNA testing detected 16 of 26 carcinomas (62%) and 8 of 20 adenomas (40%). The MS-MCAs missed 14 methylated tumors (37%). No aberrant methylation was evident in healthy subjects, but the RARB2 marker was positive in 2 of 15 stool samples (13%) of patients with IBD. CONCLUSION Analysis via MS-MCA of a panel of methylation markers in stool DNA may offer a good alternative in the early, noninvasive detection of colorectal tumors.

Emergency operations for nondiverticular perforation of the left colon

OBJECTIVE Although diverticulitis is the most common cause of large bowel perforation, other disease may result in left colonic peritonitis. The aim of this study was to evaluate and compare the incidence, management, and outcome of patients with different causes of nondiverticular left colonic perforations. PATIENTS AND METHODS From January 1992 to September 2000, 212 surgical patients underwent emergency operation for distal colonic peritonitis. Perforations were caused by diverticulitis in 133 patients (63%) and by a nondiverticular process in 79 (37%). Mortality and morbidity in patients with nondiverticular perforation of the distal large bowel its relationship with the general conditions, the grade and the cause of peritonitis were analysed. Four types of surgical procedures were used. Hartmanns procedure was performed in 40 patients (51%); intraoperative colonic lavage, resection, and primary anastomosis (ICL) in 27 patients (34%); colostomy in 7 (9%); and subtotal colectomy in 5 (6%). RESULTS Perforated neoplasm, the most common cause of peritonitis, was observed in 30 patients, colonic ischemia in 20, iatrogenia in 13, and other causes in 16 patients. One or more complications were observed in 57 patients (72%); among causes of perforation, colonic ischemia was significantly associated with the longest hospital stay and highest mortality. Eighteen patients (23%) died. CONCLUSIONS Left large bowel perforation by nondiverticular disease is associated with high mortality and morbidity. The prognosis of patients is determined by the development of septic shock and colonic ischemia, as underlying disease, may influence patient survival.

Long-term results of ileal pouch–anal anastomosis in Crohn's disease

The unexpected diagnosis of Crohns disease (CD) after restorative proctocolectomy is a relatively frequent occurrence. We report a retrospective analysis of the long-term development of patients with an ileal pouch–anal anastomosis (IPAA) in whom the definitive anatomopathological diagnosis was CD, and compare their development with that of patients in whom the diagnosis of ulcerative colitis (UC) was confirmed. We reviewed the clinical data of 112 patients with an IPAA. The definitive diagnosis was CD in 12, and UC in the rest. The mean follow-up period was 76 months (range 12 to 192). We analyzed and compared the epidemiologic and clinical data, postoperative complications, functional results, anxiety, and quality of life in the two groups. Postoperative morbidity and the degree of satisfaction were similar in the two groups. The test showed a lower level of anxiety and higher quality of life in patients with CD. Of all the functional parameters studied, only urgency of defecation presented a higher risk in the CD group (HR: 4.13, CI: 1.41–12.04, p = 0.027). Despite the fact that a diagnosis of CD is currently considered a contraindication for an IPAA, some patients with secondary diagnosis of CD have good functional outcome and quality of life after restorative proctocolectomy. Closure of the temporary ileostomy may be justified in these patients.

Aberrant gene expression in mucosa adjacent to tumor reveals a molecular crosstalk in colon cancer

BackgroundA colorectal tumor is not an isolated entity growing in a restricted location of the body. The patient’s gut environment constitutes the framework where the tumor evolves and this relationship promotes and includes a complex and tight correlation of the tumor with inflammation, blood vessels formation, nutrition, and gut microbiome composition. The tumor influence in the environment could both promote an anti-tumor or a pro-tumor response.MethodsA set of 98 paired adjacent mucosa and tumor tissues from colorectal cancer (CRC) patients and 50 colon mucosa from healthy donors (246 samples in total) were included in this work. RNA extracted from each sample was hybridized in Affymetrix chips Human Genome U219. Functional relationships between genes were inferred by means of systems biology using both transcriptional regulation networks (ARACNe algorithm) and protein-protein interaction networks (BIANA software).ResultsHere we report a transcriptomic analysis revealing a number of genes activated in adjacent mucosa from CRC patients, not activated in mucosa from healthy donors. A functional analysis of these genes suggested that this active reaction of the adjacent mucosa was related to the presence of the tumor. Transcriptional and protein-interaction networks were used to further elucidate this response of normal gut in front of the tumor, revealing a crosstalk between proteins secreted by the tumor and receptors activated in the adjacent colon tissue; and vice versa. Remarkably, Slit family of proteins activated ROBO receptors in tumor whereas tumor-secreted proteins transduced a cellular signal finally activating AP-1 in adjacent tissue.ConclusionsThe systems-level approach provides new insights into the micro-ecology of colorectal tumorogenesis. Disrupting this intricate molecular network of cell-cell communication and pro-inflammatory microenvironment could be a therapeutic target in CRC patients.

Nanofluidic Digital PCR for KRAS Mutation Detection and Quantification in Gastrointestinal Cancer

BACKGROUND Concomitant quantification of multiple mutant KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) alleles may provide information in addition to that provided by standard mutation-detection procedures. We assessed the feasibility of a nanofluidic digital PCR array platform to detect and quantify KRAS mutations simultaneously in clinically relevant samples. METHODS We assessed 2 groups of patients (colorectal and pancreatic disease): Group 1 consisted of 27 patients with colorectal carcinomas, 14 patients with adenomas, and 5 control individuals; group 2 consisted of 42 patients with pancreatic carcinoma, 4 with adenocarcinomas of the ampulla, and 6 with chronic pancreatitis). Digital PCR was performed with the Digital Array Chip (Fluidigm). RESULTS Nanofluidic digital PCR detected mutant alleles at 0.05% to 0.1%, depending on the variant analyzed. For the colorectal disease group, conventional PCR detected 9 (64%) of 14 adenomas that were positive for KRAS mutants, whereas digital PCR increased this number to 11 (79%) of 14. Sixteen (59%) of 27 carcinomas showed KRAS mutation with conventional PCR. Two additional cases were detected with digital PCR. In 5 cases (3 adenomas, 2 carcinomas), the total number of mutant alleles changed. For the pancreatic disease group, digital PCR increased the number of positive cases from 26 to 34 (81%) and identified ≥ 2 mutant alleles in 25 cases, compared with conventional PCR, which identified multiple KRAS mutant alleles in only 12 cases. A good correlation was observed between results obtained with tumor biopsies and those obtained with pancreatic juice. CONCLUSIONS Digital PCR provides a robust, quantitative measure of the proportion of KRAS mutant alleles in routinely obtained samples. It also allows a better classification of tumors, with potential clinical relevance.

Novel methylation panel for the early detection of neoplasia in high-risk ulcerative colitis and Crohn's colitis patients†

Background:Patients with ulcerative colitis and Crohns colonic disease are at increased risk of developing colorectal cancer (CRC). The aim of the study was to analyze the methylation status of selected genes as a risk marker for CRC in inflammatory bowel disease (IBD) patients. Methods:We evaluated the methylation status of four genes (TGFB2, SLIT2, HS3ST2, and TMEFF2) in biopsies of four groups of patients: 60 patients with sporadic CRC, 32 patients with IBD-associated neoplasia, 85 patients with IBD without associated neoplasia (20 at high risk and 65 at low risk), and 28 healthy controls. Methylation-specific melting curve analysis (MS-MCA) was used. Methylation status of these genes was also assessed in stool DNA from 60 IBD patients without neoplasia. Results:Methylation of the panel of genes analyzed was a very common phenomenon (78%) in IBD-associated neoplasia. The prevalence of methylation in adjacent nonneoplastic mucosa was also high (12/30). This prevalence was higher than in mucosa from healthy controls (2/28;7.1%; P < 0.05). Methylation of SLIT2 and TMEFF2 was more frequently detected in the mucosa of IBD patients at high risk of dysplasia or cancer (15/20) than patients at low risk (32/63) (P = 0.05 and P = 0.03, respectively). When stool samples were assessed, only SLIT2 gene methylation was more frequently methylated in the group of patients at high risk of dysplasia or cancer (4/16) compared to low risk (0/37) (P = 0.006). Conclusions:Analysis of a panel of methylation markers may help in the early identification of colorectal dysplasia or cancer in high-risk IBD patients.