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Screening programs for colorectal cancer (CRC) are standard in most developed countries because they reduce mortality and are cost-effective. Within them, colonoscopy allows to directly visualize the colon and remove neoplastic lesions. However, it is an expensive exam with low adherence in asymptomatic individuals. The fecal occult blood test (FOBT) is a low-cost and risk-free method for the user, which results in a high rate of adherence, explaining its use in most screening programs. This article analyzes the effectiveness of different fecal occult blood tests in screening programs. The main conclusions are that the sensitivity of the guaiac-based chemical test for the detection of colorectal cancer is lower than that observed with qualitative and quantitative immunological tests. Automated quantitative methods allow objective readings independent of the operator and the reaction reading time, necessary for the analysis of large numbers of samples. The participation rate with immunological FOBTs is higher than with chemical ones, which is why they are preferred by the different countries that have screening programs. The use of quantitative tests allows stratification of symptomatic and asymptomatic patients at higher risk, in the screening programs.

Colorectal (CRC) is one of the most common types of cancer worldwide. Most tumors develop from an adenoma in a period of 10 to 15 years, but some may appear without previous adenomatous lesions. Seventy-five percent of colorectal cancers are sporadic, 20% have a family component (first or second-degree relatives with CRC) and 5% have a hereditary predisposition with a Mendelian pattern. The epidemiological evolution in the recent years in Chile has a worrisome evolution and the treatment costs of advanced stages are a burden for the healthcare system. We herein highlight the main Chilean medical and scientific contributions on the pathogenesis, early diagnosis, and treatment of CRC, which lead to its better understanding, and therefore better management, based on local evidence.

In Chile, the mortality from colorectal cancer has been on the rise. A national screening program based on a fecal immunochemical test was started in 2012 as an international collaboration with Japan. This case-control study was designed to identify the risk factors for colorectal cancer, with a goal of increasing the participation rate for colorectal cancer screening. In accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines, we conducted a case-control study from 2012 to 2017; 23 845 asymptomatic participants were enrolled in the study. Participants who were fecal immunochemical test-positive or had a family history of colorectal cancer underwent a colonoscopy. We analyzed the odds ratio of the risk factors for colorectal cancer, including sex, age, family history, BMI, hypertension, diabetes, regular use of nonsteroidal anti-inflammatory drugs, alcohol consumption, smoking, physical activity, and daily intake of certain food items. For the screening program, 202 cases of colorectal cancer were detected, and 195 of them were evaluated pathologically after resection. Of these, 173 cases (88.7%) had colorectal cancer stage 0/1, 151 (77.4%) of which were treated with endoscopic resection. In the multivariate analysis, male sex, family history of colorectal cancer, and low intake of cereals or fibers were closely related to a high colorectal cancer incidence. Moreover, participants in their 60s and 70s had a higher incidence of colorectal cancer than those in their 50s. These results suggest that intensive screening of the high-risk population can help in improving the detection of colorectal cancer, whereas higher consumption of cereals or fibers can be effective in preventing its onset.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%–80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency. Radium Hospital Foundation (Oslo, Norway)

Colorectal cancer (CRC) is one of the most common cancers worldwide. As with other cancers, CRC is a multifactorial disease due to the combined effect of genetic and environmental factors. Most cases are sporadic, but a small proportion is hereditary, estimated at around 5-10%. In both, the tumor interacts with heterogeneous cell populations, such as endothelial, stromal, and immune cells, secreting different signals (cytokines, chemokines or growth factors) to generate a favorable tumor microenvironment for cancer cell invasion and metastasis. There is ample evidence that inflammatory processes have a role in carcinogenesis and tumor progression in CCR. Different profiles of cell activation of the tumor microenvironment can promote pro or anti-tumor pathways; hence they are studied as a key target for the control of cancer progression. Additionally, the intestinal mucosa is in close contact with a microorganism community, including bacteria, bacteriophages, viruses, archaea, and fungi composing the gut microbiota. Aberrant composition of this microbiota, together with alteration in the diet‐derived microbial metabolites content (such as butyrate and polyamines) and environmental compounds has been related to CRC. Some bacteria, such as pks+ Escherichia coli or Fusobacterium nucleatum, are involved in colorectal carcinogenesis through different pathomechanisms including the induction of genetic mutations in epithelial cells and modulation of tumor microenvironment. Epithelial and immune cells from intestinal mucosa have Pattern-recognition receptors and G-protein coupled receptors (receptor of butyrate), suggesting that their activation can be regulated by intestinal microbiota and metabolites. In this review, we discuss how dynamics in the gut microbiota, their metabolites, and tumor microenvironment interplays in sporadic and hereditary CRC, modulating tumor progression.

Colorectal cancer (CRC) is the second most frequent neoplasm in Chile and its mortality rate is rising in all ages. However, studies characterizing CRC according to the age of onset are still lacking. This study aimed to identify clinical, pathological, and molecular features of CRC in Chilean patients according to the age of diagnosis: early- (≤50 years, EOCRC), intermediate- (51–69 years, IOCRC), and late-onset (≥70 years, LOCRC). The study included 426 CRC patients from Clinica Las Condes, between 2007 and 2019. A chi-square test was applied to explore associations between age of onset and clinicopathological characteristics. Body Mass Index (BMI) differences according to age of diagnosis was evaluated through t-test. Overall (OS) and cancer-specific survival (CSS) were estimated by the Kaplan–Meier method. We found significant differences between the age of onset, and gender, BMI, family history of cancer, TNM Classification of Malignant Tumors stage, OS, and CSS. EOCRC category was characterized by a family history of cancer, left-sided tumors with a more advanced stage of the disease but better survival at 10 years, and lower microsatellite instability (MSI), with predominant germline mutations. IOCRC has shown clinical similarities with the EOCRC and molecular similarities to the LOCRC, which agrees with other reports.

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender.

Molecular classification of colorectal cancer is difficult to implement in clinical settings where hundreds of genes are involved, and resources are limited. This study aims to characterize the molecular subtypes of patients with sporadic colorectal cancer based on the three main carcinogenic pathways microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and chromosomal instability (CIN) in a Chilean population. Although several reports have characterized colorectal cancer, most do not represent Latin-American populations. Our study includes 103 colorectal cancer patients who underwent surgery, without neoadjuvant treatment, in a private hospital between 2008 and 2017. MSI, CIN, and CIMP status were assessed. Frequent mutations in KRAS, BRAF, and PIK3CA genes were analyzed by Sanger sequencing, and statistical analysis was performed by Fisher’s exact and/or chi-square test. Survival curves were estimated with Kaplan–Meier and log-rank test. Based on our observations, we can classify the tumors in four subgroups, Group 1: MSI-high tumors (15%) are located in the right colon, occur at older age, and 60% show a BRAF mutation; Group 2: CIN-high tumors (38%) are in the left colon, and 26% have KRAS mutations. Group 3: [MSI/CIN/CIMP]-low/negative tumors (30%) are left-sided, and 39% have KRAS mutations; Group 4: CIMP-high tumors (15%) were more frequent in men and left side colon, with 27% KRAS and 7% presented BRAF mutations. Three percent of patients could not be classified. We found that CIMP-high was associated with a worse prognosis, both in MSI-high and MSI stable patients (p = 0.0452). Group 3 (Low/negative tumors) tend to have better overall survival compared with MSI-high, CIMP-high, and CIN-high tumors. This study contributes to understanding the heterogeneity of tumors in the Chilean population being one of the few characterizations performed in Latin-America. Given the limited resources of these countries, these results allow to improve molecular characterization in Latin-American colorectal cancer populations and confirm the possibility of using the three main carcinogenic pathways to define therapeutic strategies.

Background : Colorectal Cancer Screening Programs (CRCSP) are widely accepted in developed countries. Unfortunately, financial restrictions, low ad- herence rate and variability on colonoscopy standardization hamper the imple- mentation of CRCSP in developing countries. Aim : To analyze a multicentric pilot model of CRCSP in Chile. Material and Methods: A prospective model of CRCSP was carried out in three cities, from 2012 to 2015. The model was based on CRC risk assessment and patient education. Health care personnel were trained about logistics and protocols. The endoscopy team was trained about colonoscopy standards. A registered nurse was the coordinator in each center. We screened asymptomatic population aged between 50 and 75 years. Immunological fecal occult blood test (FIT) was offered to all participants. Subjects with positive FIT underwent colonoscopy. Results : A total of 12,668 individuals were enrolled, with a FIT compliance rate of 93.9% and 2,358 colonoscopies were performed. Two hundred and fifty high-risk adenomas and 110 cancer cases were diagnosed. One patient died before treatment due to car- diovascular disease, 74 patients (67%) underwent endoscopic resection and 35 had surgical treatment. Ninety one percent of patients had an early stage CRC (0-I-II). Among colonoscopy indicators, 80% of cases had an adequate bowel preparation (Boston > 6), cecal intubation rate was 97.7%, adenoma detection rate was 36.5%, and in 94.5% of colonoscopies, withdrawal time was adequate (> 8 min). Conclusions: This CRCS pilot model was associated to a high rate of FIT return and colonoscopy quality standards. Most CRCs detected with the program were treated by endoscopic resection

Background: Colorectal cancer (CRC) is an heterogeneous disease. Three carcinogenic pathways determine its molecular profile: microsatellite instability (MSI), chromosomal instability (CIN) and CpG island methylator phenotype (CIMP). Based on the new molecular classification, four consensus CRC molecular subtypes (CMS) are established, which are related to clinical, pathological and biological characteristics of the tumor. Aim: To classify Chilean patients with sporadic CRC according to the new consensus molecular subtypes of carcinogenic pathways. Material and Methods: Prospective analytical study of 53 patients with a mean age of 70 years (55% males) with CRC, operated at a private clinic, without neoadjuvant treatment. From normal and tumor tissue DNA of each patient, CIN, MSI and CIMP were analyzed. Combining these variables, tumors were classified as CMS1/MSI-immune, CMS2/canonical, CMS3/metabolic and CMS4/mesenchymal. Results: CMS1 tumors (19%) were located in the right colon, were in early stages, had MMR complex deficiencies and 67% had an activating mutation of the BRAF oncogene. CMS2 tumors (31%) were located in the left colon, had moderate differentiation, absence of vascular invasion, lymphatic and mucin. CMS3 tumors (29%) were also left-sided, with absence of vascular and lymphatic invasion, and 29% had an activating mutation of the KRAS oncogene. CMS4 tumors (21%) showed advanced stages and presence of metastases. Conclusions: This new molecular classification contributes to understanding the heterogeneity of tumors. It is possible to differentiate molecular subgroups of a single pathological diagnosis of adenocarcinoma, opening the door to personalized medicine.

High incidence of Rho Cdc42-GTPase overexpression has been found in Colorectal Cancer (CRC) samples, suggesting its potential role in tumor development. However, no conclusive studies have shown the lack of mutations and/or copy number of Cdc42 gene in this type of samples. To understand mutation/deletion and copy number status of Cdc42 gene, CRC patients were evaluated for both parameters. More than Cdc42 mutants, single-nucleotide variants were found. Analysis of regions flanking the Cdc42 gene showed allelic imbalance; 58.7% were loss of heterozygosity (LOH) positive and 14.8% presented microsatellite instability. The highest LOH percentage was located between microsatellite markers D1S199 and D1S2674, where the Cdc42 gene is located. No association between gender, age, and tumor stage was found. LOH validation through gene dosage analysis showed most CRC patients with allelic imbalance also presented a low gene dosage of Cdc42, although equal amounts of Cdc42 mRNA were detected in all samples. Although changes in Cdc42 expression were not found in any condition, Cdc42 activation was different between high and normal gene dosage samples, but not between samples with normal and low copy number. Low dosage of Cdc42 was also not related to changes in methylation status at the Cdc42 promoter region. Results suggest that low copy of Cdc42 gene is not associated with Cdc42 protein dysfunction in CRC patients.

We aimed to assess the current genetics practice to manage patients with Lynch syndrome (LS) across Latin America. A Latin American LS survey was sent out to 52 centres/registries, comprising a total of 12 countries from the region. Overall, 33 centres completed the survey, of which the oldest LS registry was established in 1992 in Sao Paulo (Brazil), and the youngest this year in San Jose (Costa Rica). In total, 87% (26/30) of the participating centres/registries belonging to the nine countries are performing genetic testing. Overall, 1352 suspected families were sequenced. Pathogenic variants were identified in 34% of the families, with slightly differing distribution of variants between females and males. Path_MLH1 variants were identified in 39% of females and 50% of males (p = 0.023), while path_MSH2 were identified in 37% of females and males, followed by path_PMS2 in 11% of females and 8% of males, path_MSH6 in 13% of females and 3% of males (p 0.001) and path_EPCAM in 0.3% of females and 2% of males. In Latin America, 9 of 12 (75%) participating countries had implemented healthcare for LS. LS screening is inconsistently applied within Latin America healthcare systems because of structural differences in the healthcare systems between the countries.

In colorectal cancer (CRC), cancer-associated fibroblasts (CAFs) are the most abundant component from the tumor microenvironment (TM). CAFs facilitate tumor progression by inducing angiogenesis, immune suppression and invasion, thus altering the organization/composition of the extracellular matrix (i.e., desmoplasia) and/or activating epithelial-mesenchymal transition (EMT). Soluble factors from the TM can also contribute to cell invasion through secretion of cytokines and recently, IL-33/ST2 pathway has gained huge interest as a protumor alarmin, promoting progression to metastasis by inducing changes in TM. Hence, we analyzed IL-33 and ST2 content in tumor and healthy tissue lysates and plasma from CRC patients. Tissue localization and distribution of these molecules was evaluated by immunohistochemistry (using localization reference markers α-smooth muscle actin or α-SMA and E-cadherin), and clinical/histopathological information was obtained from CRC patients. In vitro experiments were conducted in primary cultures of CAFs and normal fibroblasts (NFs) isolated from tumor and healthy tissue taken from CRC patients. Additionally, migration and proliferation analysis were performed in HT29 and HCT116 cell lines. It was found that IL-33 content increases in left-sided CRC patients with lymphatic metastasis, with localization in tumor epithelia associated with abundant desmoplasia. Although ST2 content showed similarities between tumor and healthy tissue, a decreased immunoreactivity was observed in left-sided tumor stroma, associated to metastasis related factors (advanced stages, abundant desmoplasia, and presence of tumor budding). A principal component analysis (including stromal and epithelial IL-33/ST2 and α-SMA immunoreactivity with extent of desmoplasia) allowed us to distinguish clusters of low, intermediate and abundant desmoplasia, with potential to develop a diagnostic signature with benefits for further therapeutic targets. IL-33 transcript levels from CAFs directly correlated with CRC cell line migration induced by CAFs conditioned media, with rhIL-33 inducing a mesenchymal phenotype in HT29 cells. These results indicate a role of IL-33/ST2 in tumor microenvironment, specifically in the interaction between CAFs and epithelial tumor cells, thus contributing to invasion and metastasis in left-sided CRC, most likely by activating desmoplasia.

Resumen Introducción: La resección anterior ultrabaja interesfintérica (RAUBIE), permite preservar la función esfinteriana en pacientes seleccionados con cáncer de recto (CR). No obstante, puede producir alteraciones en la función evacuatoria y esfinteriana. Objetivo: Analizar los resultados oncológicos y funcionales luego de una RAUBIE. Material y Método: Estudio observacional, analítico, transversal, durante el período 2007 a 2016. Criterios de inclusión: Pacientes sometidos a RAUBIE por CR con intención curativa. Todos los pacientes tuvieron un seguimiento el año 2017. Para la evaluación funcional se usó la escala de Jorge-Wexner, LARS y Kirwan. Análisis estadístico: Estadística descriptiva y método de Kaplan-Meier. Resultados: De 21 pacientes; catorce (67%) fueron varones, edad promedio: 59 años. Ubicación tumoral: 4 cm (2-6 cm) del margen anal. Dieciocho (85,7%) pacientes recibieron neoadyuvancia. Todos los márgenes quirúrgicos distales y radiales fueron negativos. Un paciente (4,8%) tuvo metástasis a distancia y no hubo recurrencia locorregional. Con una mediana de seguimiento de 76,3 (9,8-126,8) meses, la sobrevida global y libre de enfermedad a 5 años fue de: 100% y 95% (IC: 90,1-99,9%), respectivamente. Con una mediana de seguimiento de 90 meses (21,7-124,2); se realizó la evaluación funcional a 15/21 pacientes. El puntaje de Jorge-Wexner tuvo una mediana de 13 (4-17) puntos, la escala de LARS de 34 puntos y en la escala de Kirwan, cuatro pacientes (26,7%) mostraron una buena función (Kirwan I-II). Conclusión: Si bien los resultados oncológicos de los pacientes sometidos a una RAUBIE son satisfactorios, se debería tomar en cuenta los resultados funcionales al momento de proponer esta alternativa quirúrgica.

Objetivo: Analizar la frecuencia y tipo de tumores asociados en pacientes con poliposis adenomatosa familiar clásica (PAFc) sometidos a una colectomía profiláctica. Materiales y Métodos: Estudio de cohorte. Desde el registro de cáncer colorrectal (CCR) hereditario, se identificaron las familias con PAFc, y de estas a los pacientes que se les practicó una colectomía total con anastomosis íleorrectal (CT-AIR) o proctocolec-tomía restauradora (PCTR), desde 1999 al 2014. En el seguimiento se analizaron los tumores asociados y su mortalidad. Resultados: Se identificaron 27 pacientes, de los cuales 18 (66,7%) fueron sometidos a CT-AIR y 9 (33,3%) a PCTR. Al momento de la cirugía, 4 pacientes presentaban CCR (15%) y 5 tenían tumores extracolónicos (osteomas). En un seguimiento promedio de 49,4 meses (i: 2 y 178) se diagnosticaron: adenomas del tracto digestivo en 17 (63%) pacientes, de éstos 2 requirieron una proctectomía y 3 resecciones de adenomas duodenales. Ocho pacientes desarrollaron tumores desmoides (30%), y 3 de ellos fueron sometidos a una cirugía. Un paciente presentó un tumor extradigestivo (cáncer de tiroides) y sólo 8/27 (29,6%) pacientes no desarrollaron otros tumores. Un paciente falleció por progresión de su CCR. Discusión: En esta serie se confirma que la mayoría de los pacientes con PAFc seguirán desarrollando neoplasias después de su colectomía. conclusiones: La extirpación del colon y/o recto permitió evitar el desarrollo de CCR. Sin embargo, dos tercios de los pacientes presentaron otros tumores en quienes su seguimiento permitió una detección y tratamiento temprano.

Lynch syndrome (LS) is associated with the highest risk of colorectal (CRC) and several extracolonic cancers. In our effort to characterize LS families from Latin America, this study aimed to describe the spectrum of neoplasms and cancer risk by gender, age and gene, and survival in 34 Chilean LS families. Of them, 59% harbored path_MLH1, 23% path_MSH2, 12% path_PMS2 and 6% path_EPCAM variants. A total of 866 individuals at risk were identified, of which 213 (24.6%) developed 308 neoplasms. In males, CRC was the most common cancer (72.6%), while females showed a greater frequency of extracolonic cancers (58.4%), including uterus and breast (p &lt, 0.0001). The cumulative incidence of extracolonic cancers was higher in females than males (p = 0.001). Path_MLH1 variants are significantly more associated with the development of CRC than extracolonic tumors (59.5% vs. 40.5%) when compared to path_MSH2 (47.5% vs. 52.5%) variants (p = 0.05018). The cumulative incidence of CRC was higher in path_MLH1/path_MSH2 carriers compared to path_PMS2 carriers (p = 0.03). In addition, path_MSH2 carriers showed higher risk of extracolonic tumors (p = 0.002). In conclusion, this study provides a snapshot of the LS profile from Chile and the current LS-associated diagnostic practice and output in Chile. Categorizing cancer risks associated with each population is relevant in the genetic counselling of LS patients.

Background: In Chile, a national colorectal cancer (CRC) screening program using immunochemical fecal occult blood tests and colonoscopy was started in 2012 as an international collaboration between Chile and Japan. In the present study, we quantified exosomes in the peripheral blood and evaluated the implication of the results for CRC screening. Methods: A total of 25 peripheral plasma samples from the participants of CRC screening in Punta Arenas, Chile, were analyzed for exosomes. Results: Plasma exosomes were obtained from 5 participants with adenocarcinoma (4 pTis and 1 pT1), 8 with high-grade adenoma, 4 with low-grade adenoma, 4 with hyperplastic polyps, and 4 with normal findings. Participants with adenocarcinoma had significantly higher amounts of plasma exosomes (2.1–3.2 fold) than participants with normal findings, hyperplastic polyps, or low-grade adenoma (p = 0.016, p = 0.0034, and p = 0.0042 respectively; Tukey’s multiple comparisons test). The size of the representative lesion, the number of lesions, and the sum of those 2 factors in each participant correlated significantly with the exosome amounts (r = 0.56, r = 0.58, and r = 0.72, respectively; p < 0.01; Spearman’s correlation coefficient test). Conclusions: This pilot study demonstrated that quantification of plasma exosomes is a potential alternative screening method for detecting individuals with a high risk of colorectal malignancy.

Aim To describe the long-term outcomes of adipose-mesenchymal stem cells, platelet-rich plasma, and endorectal advancement flaps in patients with Perineal Crohn's Disease. Method This was a single-center, prospective, observational pilot study performed between March 2013 and December 2016. The study included adult patients diagnosed with Perianal Crohn's Disease (with complex perianal fistulas) refractory to previous surgical and/or biological treatment. Patients underwent surgical treatment in two stages. Stage 1: Fistula mapping, drainage, seton placement and lipoaspiration to obtain adipose-mesenchymal stem cells were performed. Stage 2: The setons were removed, and the fistula tract was debrided. A small endorectal advancement flap was created, with closure of the previous internal fistula opening. Then, 100-120 million adipose-mesenchymal stem cells mixed with platelet-rich plasma were injected into the internal fistula opening and fistula tract. Results The study included nine patients (seven females), with a median age of 36 years (r = 23-57). Eleven fistula tracks were treated, of which, two were pouch-vaginal fistulas. The median follow-up period was 31 months (r=21-37). At the end of the follow-up period, 10/11 (91%) fistulas were completely healed and 1/11 (9%) was partially healed. At the end of this period, there was no evidence of fistula relapse or adverse reactions in any patients. The Perianal Disease Activity Index and Inflammatory Bowel Disease Questionnaire scores significantly improved after the procedure. Conclusion Combined therapy with adipose-mesenchymal stem cells, platelet-rich plasma and endorectal advancement flaps yielded good results in patients with refractory Perineal Crohn's Disease. This article is protected by copyright. All rights reserved.

BACKGROUND In Chile, mortality from colorectal cancer (CRC) has increased rapidly. To help address this issue, the Prevention Project for Neoplasia of the Colon and Rectum (PRENEC) program was initiated in 2012 with intensive support from Tokyo Medical and Dental University (TMDU) in Tokyo, Japan, as part of an international collaboration. METHODS From June 2012 to July 2014, a total of 10,575 asymptomatic participants were enrolled in PRENEC. Participants with positive immunochemical fecal occult blood test (iFOBT) results or a family history of CRC underwent colonoscopy. The colonoscopy results from a similar, previous project in Chile (PREVICOLON) were compared with those from PRENEC. Furthermore, the initial colonoscopies of 1562 participants in PRENEC were analyzed according to whether the colonoscopists were from TMDU or Chile. RESULTS The complete colonoscopy, adenoma detection, and cancer detection rates were 88.0%, 26.7%, and 1.1%, respectively, in PREVICOLON, while the corresponding values were 94.4%, 41.8%, and 6.0%, respectively, in PRENEC. In PRENEC, 107 cases of CRC were detected, amounting for 1.0% of all participants. Considering initial colonoscopies in PRENEC, the complete colonoscopy, adenoma detection, and cancer detection rates were 97.4%, 45.3%, and 9.3%, respectively, for physicians at TMDU and 93.3%, 41.5%, and 5.1%, respectively for Chilean physicians. The detection rates of intramucosal cancer were 7.3% and 3.7%, respectively, for TMDU and Chilean physicians. CONCLUSIONS Quality indicators of colonoscopy substantially improved from PREVICOLON to PRENEC. The assessments made by Chilean physicians alone were improved in PRENEC, but remained better in the TMDU group. Moreover, physicians from TMDU detected more CRCs than Chilean physicians, especially at earlier stages. Cancer 2016;122:71–77. © 2015 American Cancer Society.

Background: The molecular testing of KRAS mutation status in metastatic colorectal cancer patients is mandatory to identify patients eligible for anti- epidermal growth factor receptor monoclonal antibody therapy. Aim: To report the frequency of KRAS gene mutations in Chilean patients with colorectal cancer (CRC). Material and Methods: A cohort of 262 Chilean patients with CRC aged 26 to 90 years (53% males), was studied. KRAS mutation status was analyzed by real-time polymerase chain reaction and correlated with clinicopathological data. Results: Ninety-eight patients (37%) were positive for KRAS mutations. G12D was the most common mutation with a frequency of 36.7%, followed by G12V (25.5%), G13D (17.3%), G12A (7.1%), G12C (6.1%), G12S (5.1%) and G12R (2%). The frequency of the mutation in left, right colon and rectal tumors was 37.8, 32.6 and 44.9%, respectively. Among tumors with mutations, 86.7% were well or moderately differentiated tumors and the rest were poorly differentiated. No significant associations between KRAS gene mutations and other clinicopathological features of the tumor were observed. Conclusions: The frequencies of KRAS mutations reported in this study are similar to frequencies reported for European and North-American populations, lower than in a Spanish study and higher than in a Peruvian study. (Rev Med Chile 2014; 142: 1407-1414)

Background: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. Methods: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. Results: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. Conclusion: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries., Radium Hospital Foundation (Oslo, Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, Helse Sør-Øst (Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, the French Association Recherche contre le Cancer (ARC) in the analysis, and interpretation of data, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (Gefluc) in the analysis, and interpretation of data, the Association Nationale de la Recherche et de la Technologie (ANRT, CIFRE PhD fellowship to H.T.) in the analysis, and interpretation of data and by the OpenHealth Institute in the analysis, and interpretation of data. Barretos Cancer Hospital received financial support by FINEP-CT-INFRA (02/2010), info:eu-repo/semantics/publishedVersion

Background: The incidence and prevalence of Inflammatory Bowel Disease (IBD) has increased. Aim: To determine demographic and clinical characteristics of patients with IBD in a Chilean private hospital. Patients and methods: Review of a prospective registry of patients with IBD, started on 2012. It includes clinical, imaging, endoscopical and pathological information of patients. Results: Data of 316 patients with IBD, aged 16 to 86 years (56% females), were analyzed. Ulcerative Colitis (UC), Crohn´s and non-classifiable IBD were diagnosed in 230, 77 and 9 patients, respectively. The disease was diagnosed in 82% of patients in the period between 2002 and 2012. There was a peak in the diagnosis of both UC and CD between 20 and 39 years of age, without gender differences. The disease switched from UC to CD in six patients. In four, there was a change in disease behavior. Thirty eight patients were treated with biological therapy. The median lapse between the diagnosis and the use of biological therapy was 1 year in patients diagnosed after 2007, compared with 5.5 years among those patients diagnosed before 2007 (p=0.001). There was a trend towards a higher requirement of surgery until 2006. Posteriorly there was a stabilization of the requirement, concomitant with the incorporation of biological therapy. Conclusions: An adequate registry of IBD patients is necessary to improve demographic and clinical characteristics. A national registry is needed to assess the epidemiological changes of IBD in Chile.

Introduction Pelvic floor dyssynergia (PPD) is a common cause of outlet obstruction constipation. Treatment for this condition is based on pelvi-perineal re-education (PPR). The aim of this study was to evaluate the results of PPR on patients with PPD. Methods Patients with the diagnosis of PPD were included. The study was conducted between 2010 and 2011. PPR was performed by specialised kinesiologists. Prior and after treatment a constipation questionnaire was performed (KESS) (scale from 0 to 39 points, a higher score is associated with more symptom severity). KESS score before and after PPR were compared. Mann–Whitney–Wilcoxon rank sum test for paired samples was used for statistical analysis, P value Results Thirteen patients were included (11 women), and mean age was 44.3 years (range: 18–76). Mean total KESS score prior and after PPR were 19.6 (SD: 5.8) and 12.6 (SD: 6.3), respectively ( P =.002). Frequency of bowel movements, stool consistency, abdominal pain, and abdominal bloating did not present statistically significant changes before and after treatment. Use of laxatives, enemas and/or digitations, as well as unsuccessful evacuation, feelings of incomplete evacuation improved significantly. Total evacuation time (before 1.53 vs after 1; P =.012) and difficult evacuation causing painful efforts (before 2.08 vs after 1.07; P =.001) also decreased significantly. Conclusion PPR in patients with PPD significantly improves the symptoms of obstructive constipation, mainly with respect to mechanical assistance and difficult evacuation.

Resumen Introduccion La disinergia del piso pelviano (DPP) es una causa frecuente de estrenimiento por obstruccion defecatoria. El tratamiento de esta enfermedad esta basado en la rehabilitacion pelviperineal (RPP). El objetivo de este estudio es evaluar los resultados de la RPP en pacientes con DPP. Metodos Se incluye a pacientes con DPP a quienes se les realizo RPP entre el ano 2010 y el 2011. Se aplico previamente a las sesiones y al termino de ellas un cuestionario de estrenimiento (KESS) (escala de 0 a 39 puntos: a mayor puntuacion mayor sintomatologia). Se compararon los resultados del cuestionario KESS, de forma previa y posterior a la RPP. Analisis estadistico mediante Mann-Whitney-Wilcoxon para muestras pareadas; se considero significativo p Resultados Se incluyo a 13 pacientes (11 mujeres), edad promedio: 44,3 anos (r: 18-76). La puntuacion promedio del KESS previa y posterior al tratamiento fue de 19,6 (DE: 5,8) y de 12,6 puntos (DE: 6,3), respectivamente (p = 0,002). La frecuencia evacuatoria, consistencia de las deposiciones, dolor abdominal y distension abdominal no varian significativamente con el tratamiento. La necesidad del uso de enemas, laxantes o digitacion, asi como la evacuacion no exitosa o incompleta disminuyeron en forma significativa. Asimismo, el tiempo total de evacuacion (pre: 1,53 vs. post: 1; p = 0,012) y la percepcion de dificultad para evacuar (pre: 2,08 vs. post: 1,07; p = 0,001) mejoraron significativamente. Conclusiones La RPP en pacientes con DPP mejora significativamente los sintomas de la obstruccion defecatoria, principalmente con relacion a la asistencia mecanica y percepcion de dificultad defecatoria.

Background: Selection of patients with Lynch Syndrome (LS) for a genetic study involves the application of clinical criteria. To increase the rate of identification of mutations, the use of molecular studies as Microsatellite Instability (MSI) and Im- munohistochemistry (IHC) in the tumor has been proposed. Aim: To demonstrate the usefulness of MSI and IHC in the detection of mutations in patients with LS. Material and Methods : From our Familial Colorectal Cancer Registry, families suspected of LS were selected according to Amsterdam or Bethesda clinical criteria. Screening of germline mutations of MLH1, MSH2 and MSH6 genes was performed. In addition, analysis of MSI and IHC were performed in colorectal tumors. Results : A total of 35 families were studied (19 met Amsterdam and 16 met Bethesda criteria). Twenty one families harbored a germline alteration in MLH1, MSH2 or MSH6 (18 Amsterdam and 3 Bethesda). In these families, eighteen different alterations were found, 15 of which were mutations and 3 corresponded to variants of uncertain pathogenicity. On the other hand, 80% of the tumors showed positive microsatellite instability (27 MSI-high and 1 MSI-low), and immunohistochemical testing showed that 77% of tumors had the loss of a protein. Correlation between results of tumor molecular studies and the finding of germline nucleotide change showed that IHC and MSI predicted mutations in 81 and 100% of patients, respectively. Conclusions : MSI and IHC can efficiently select patients with a high probability of carrying a mutation in DNA repair genes

El cáncer rectal se define como el tumor ubicado entre el margen anal y los 15 cm hacia proximal. En el cáncer de recto, una precisa estadificación preoperatoria permite clasificar correctamente a los pacientes para las diversas terapias existentes, así como seleccionar el mejor tratamiento quirúrgico. La estadificación preoperatoria se realiza con el apoyo de métodos imagenológicos. Dentro de los métodos actualmente disponibles están la endosonografía rectal (EUS), tomografía computada (TC), resonancia magnética (RM), tomografía por emisión de positrones (PET/CT) y ultrasonido intraoperatorio (IOUS). La EUS es un método realizado por el cirujano colorrectal, que permite la evaluación de la invasión de la pared, así como también de los linfonodos, sin embargo, su principal limitación es la evaluación del compromiso de la fascia mesorrectal. La RM es, hasta el momento, el mejor método para evaluar el compromiso de la fascia mesorrectal, además de informar el compromiso de pared y una adecuada evaluación de linfonodos comprometidos. La TC es un método ampliamente disponible, cuya principal utilidad es la evaluación de metástasis a distancia. El PET/CT está cobrando actualmente mayor importancia, sin embargo, su uso en estadificación preoperatoria aún no es ampliamente aceptado. La IOUS permite evaluar el compromiso metastásico del hígado durante la cirugía y por lo tanto, determina conducta y pronóstico. Por lo anterior, es necesario un conocimiento actualizado del cirujano en cuanto a esta metodología, sus ventajas y limitaciones.

Introducción: En el cáncer colorrectal (CCR), se sugiere que un mejor pronóstico podría asociarse a una respuesta inmune antitumoral (del huésped) y/o a la presencia de una alta inestabilidad microsatelital (MSI). Objetivo: Determinar si los niveles de expresión de los marcadores de linfocitos T (CD3/CD4/CD8/ CD45RO/FoxP3) y el estado de MSI se asocian a estadios metastásicos en pacientes con CCR. Material y Método: Estudio prospectivo de 109 pacientes con diagnóstico de CCR. El análisis de expresión de los marcadores CD3/CD4/CD8/CD45RO/FoxP3 fue realizado por inmunohistoquímica; los tumores fueron clasificados en negativo, débil e intenso. La MSI fue evaluada con siete marcadores amplificados desde ADN normal y tumoral; los tumores fueron agrupados en: MSS (estable)/MSI-baja y MSI-alta. El análisis estadístico fue realizado con el test exacto de Fischer. Resultados: Una intensa expresión de los marcadores CD3+, CD4+, CD8+ y CD45RO+, fue observada en el 29%, 28%, 12% y 86% de los tumores, respectivamente. El 16% de los tumores presentó MSI-alta. Los tumores que presentan una alta densidad de linfocitos T (CD3+, CD4+ y CD45RO+) se asocian a estadios tempranos I-II (p = 0,023; p = 0,030 y p = 0,003, respectivamente). Adicionalmente, se identificó una asociación estadística significativa entre los tumores con MSS/MSI-baja y una menor capacidad de reclutar linfocitos T citotóxicos CD8+ (p = 0,037) y totales CD3+ (p = 0,064). Conclusión: Existe una asociación entre altas densidades de linfocitos T CD3+, CD4+ y CD45RO+ y tumores con estadios no metastásicos. Además, tumores con MSS/MSI-baja se asocian a un menor reclutamiento de linfocitos T CD8+ y CD3+.

Colorectal cancer is a multistep process affecting several signaling pathways including EGFR (epidermal growth factor receptor), a therapeutic target for metastatic disease. Our aim was to characterize the mutational and expression profiles of the EGFR pathway in colorectal tumors and to integrate these results according to five previously defined groups. We screened seven genes for mutations ( KRAS-BRAF-PIK3CA-PIK3R1-AKT1-MAP2K1-PTEN) and six proteins (EGFR-p110α-p85α-PTEN-phosphoAKT-phosphoMEK1) by immunohistochemistry, PTEN deletion, and MSI. At least one mutated gene was observed in 68% of tumors ( KRAS 45%, PIK3CA 21%, BRAF 14%, and PTEN 7%). PTEN deletion was observed in 10.7% of tumors and 19.6% were MSI-High. In all, 54% of tumors showed a high EGFR expression, 48% p110α, 4.4% phosphoAKT, and 22% phosphoMEK1; and 43% showed low PTEN expression and 22% p85α. In total, five groups of tumors were defined based on MSI, BRAF, and KRAS mutations. Three groups gather mainly early-stage tumors, whereas a fourth group is mostly conformed by advanced tumors. We described here that 71.4% of tumors from one group have a mutated PI3K/PTEN pathway, in comparison to other groups having 32%, 27%, and 25%. In addition, the five groups are differentiated by molecular features such as EGFR, p85α, p110α, and PTEN, showing variable expression among tumor groups. In conclusion, alterations on the EGFR pathway were found in a high percentage of colorectal cancer patients. Using the integration of diverse molecular markers, we ratified previous classification in an ethnic group having relevant genetic differences and living in a different environmental background, adding complementary molecular targets related to therapy.

Crohn’s disease (CD) is a multifactorial pathology associated with the presence of adherent-invasive Escherichia coli (AIEC) and NLRP3 polymorphic variants. The presence of intracellular E. coli in other intestinal pathologies (OIP) and the role of NLRP3-inflammasome in the immune response activated by these bacteria have not been investigated. In this study, we sought to characterize intracellular strains isolated from patients with CD, ulcerative colitis (UC) and OIP, and analyze NLRP3-inflammasome role in the immune response and bactericidal activity induced in macrophages exposed to invasive bacteria. For this, intracellular E. coli isolation from ileal biopsies, using gentamicin-protection assay, revealed a prevalence and CFU/biopsy of E. coli higher in biopsies from CD, UC and OIP patients than in controls. To characterization of bacterial isolates, pulsed-field gel electrophoresis (PFGE) patterns, virulence genes, serogroup and phylogenetic group were analyzed. We found out that bacteria isolated from a given patient were closely related and shared virulence factors; however, strains from different patients were genetically heterogeneous. AIEC characteristics in isolated strains, such as invasive and replicative properties, were assessed in epithelial cells and macrophages, respectively. Some strains from CD and UC demonstrated AIEC properties, but not strains from OIP. Furthermore, the role of NLRP3 in pro-inflammatory cytokines production and bacterial elimination was determined in macrophages. E. coli strains induced IL-1β through NLRP3-dependent mechanism; however, their elimination by macrophages was independent of NLRP3. Invasiveness of intracellular E. coli strains into the intestinal mucosa and IL-1β production may contribute to CD and UC pathogenesis.

Background. The goal of this study was to compare patterns of recurrence and long-term outcome after sphincter-saving procedures (SSPs) and abdominoperineal resection (APR) in patients with tumors located in the lower third of the rectum. Methods. We reviewed the charts of 1001 patients operated on for primary rectal adenocarcinoma between 1980 and 1991. All patients with tumors located between 5 and 7 cm from the anal verge and treated with curative intent were included. Results. Of the 261 patients who met our criteria, 162 had undergone SSP and 99 had undergone APR. The local recurrence rates for SSP and APR were 8% and 11%, respectively (p = 0.41), and the distant metastases rates were 23% and 28%, respectively (p = 0.35). Recurrence and distant metastases rates for SSP and APR, respectively, did not differ by TNM classification: stage I, 10% versus 9% (p = 0.9); stage II, 25% versus 43% (p = 0.13); and stage III, 56% versus 57% (p = 0.92). Five-year disease-free survival rates for SSP and APR patients were 70.5% and 62.3%, respectively (p = 0.2). Conclusions. Tumors in the lower third of the rectum can be treated with sphincter-saving procedures without compromising the chance of cure.

Laparoscopic colorectal surgery (LCRS) has several advantages over open surgery, but LCRS has been associated with a higher rate of postoperative complications (POCs) among obese patients [body mass index (BMI), ≥30 kg/m2]. The prevalence of obesity in Chile is increasing, up to 25.1 % in 2010, suggesting that a higher percentage of patients undergoing LCRS will be obese. This study compared POC rates between obese and nonobese patients undergoing LCRS. This study included case and control patients in a prospectively maintained LCRS database who underwent LCRS between July 2007 and June 2012 at Clinica Las Condes, Santiago, Chile. Obese and nonobese (BMI

Background: Genetic counselling and testing for Lynch syndrome have recently been introduced in several South American countries, though yet not available in the public health care system. Methods: We compiled data from publications and hereditary cancer registries to characterize the Lynch syndrome mutation spectrum in South America. In total, data from 267 families that fulfilled the Amsterdam criteria and/or the Bethesda guidelines from Argentina, Brazil, Chile, Colombia and Uruguay were included. Results: Disease-predisposing mutations were identified in 37% of the families and affected MLH1 in 60% and MSH2 in 40%. Half of the mutations have not previously been reported and potential founder effects were identified in Brazil and in Colombia. Conclusion: The South American Lynch syndrome mutation spectrum includes multiple new mutations, identifies potential founder effects and is useful for future development of genetic testing in this continent.

Recently, MUTYH mutations have been reported to predispose to the development of polyposis. However, polyposis caused by mutations in MUTYH has been characterized as an autosomal recessive hereditary disease, different from the autosomal dominant pattern observed in polyposis caused by APC mutations. We report a 41-year-old female consulting for anemia. Colonoscopy detected multiple sessile polyps and a cecal carcinoma. The patient was operated and in the surgical piece, the tumor invaded serosa and there was lymph node involvement. Approximately 100 polyps were found. The patient received 5-fluorouracil, as adjuvant therapy. The patient had a sister (of a total of 12 brothers) with a colorectal carcinoma. The genetic study identified a homozygous mutation of the MUTYH gene, called c.340T > C, that produces an amino acid change of tyrosine for histidine called p.Y114H. The sister with colorectal cancer was a heterozygous carrier of this mutation.

Introduction: Colorectal cancer (CRC) is the fourth leading cause of cancer death in Chile. Currently, treatment is surgical and adjuvance is based on chemotherapy mainly. One of the risk factors of CRC is obesity and metabolic syndrome. In search of factors that induce cell apoptosis, orexins were identified. Orexins are neuropeptides that regulate appetite, inhibit satiety and increase energy expenditure. The altered expression of orexin or its dysregulation has been associated with a wide range of human diseases such as narcolepsy, obesity, drug addiction and cancer. In rats and mice lacking orexin receptor, an increase in body mass index (BMI) was observed. Orexin Receptor 1 (OX1R) is overexpressed in CRC, but is not detected in normal colon tissue. Its activation by Orexin-A promotes apoptosis in cancer cell lines, and can be modulated by diet. Aim: To determine OX1R expression in the adenoma-carcinoma progression of CRC as possible therapeutic target, and its correlation with BMI. Material and Methods: Patients with neoplastic colorectal lesions undergoing surgical or endoscopic treatment between 2014 and 2015 were prospectively enrolled. Tissue samples of 29 patients were divided into 4 groups. Group A: control (n = 5), Group B: low-grade adenoma (n = 5), Group C: high-grade adenoma (n = 7), Group D: adenocarcinoma (n = 12). Formalin-fixed-paraffin-embedded samples were used to perform immunohistochemistry (IHC) of OX1R. Fresh tissues from Group D were used to assess protein and mRNA expression of OX1R by Western-blot and quantitative RT-PCR, respectively. Primary cultures were established from fresh tumor tissue of patients with adenocarcinoma. To compare OX1R expression levels we used the t-student test. Results: IHC expression of OX1R was detected both in the luminal membrane of colorectal epithelium and in the cytoplasm. We observed stained cells in 0-1% of the total area in Group A, B and C. In Group D, 7 samples showed staining 0-1%, 2 samples 1-10% and 3 samples 10-20%. High mRNA and protein expression was detected in stage III- IV adenocarcinoma samples compared to stage 0, I and II tumor samples. Normal adyacent tissue of CRC patients does not express OX1R. BMI is inversely associated with OX1R expression. Orexin A was able to induce apoptosis in primary cell cultures from advanced tumors in a dose dependent manner. Conclusions: OX1R is expressed scarcely in early stages of carcinogenesis. Its expression is induced significantly only in the most advanced adenocarcinomas, both at protein and mRNA levels, and is inversely associated with BMI. In primary cultures of patients with CRC, orexin A is able to induce apoptosis in a dose dependent manner. FONDECYT 1140012. Citation Format: Ana M. Wielandt, Cynthia Villarroel, Claudia Hurtado, Kento Inada, Hiroshi Kawachi, Daniela Simian, Maria T. Vial, Marcela Figueroa, Magdalena Castro, Udo Kronberg, Francisco Lopez-Kostner. Expression levels of orexin receptor 1 in different stages of colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5167.

A SCREENING PROGRAM FOR COLORECTAL CANCER IN CHILEAN SUBJECTS AGED FIFTY YEARS OR MORE Background: Mortality from colorectal cancer (CCR) in Chile has nearly doubled over the past 15 years. International studies have shown that CCR screening programs based on Fecal Occult Blood Test (FOBT) reduce CCR mortality. Aim: To analyze the results from a CCR screening model in people over 50 years. Material and methods: Between 2007 and 2009, a prospective multicenter study was performed in seven major Chilean cities. FOBT using an immunological method, was measured in asymptomatic subjects aged 50 years or more, without risk factors. In patients with a positive FOBT, with symptoms or with family risk factors, a colonoscopy was indicated. Results: A total of 6348 subjects were assessed, FOBT was performed in 4938 of them, with a compliance of 77%. The result was positive in 9.6%. A total of 2359 colonoscopies were ordered, with an overall compliance of 50.1%. Of the 1184 colonoscopies performed, adenomas and high risk adenomas were found in 304 (26%) and 75 (6%) patients, respectively. Thirteen patients were diagnosed with stage I and II CCR. Three of these lesions were excised endoscopically and 10 surgically. The detection rate of polyps, high risk adenomas and cancer was 75, 12 and 2 per 1000 screened individuals, respectively. Conclusions: This program allowed the early detection of an important number of high risk colon lesions, and all patients with CCR were diagnosed at early stages. Normal 0 21 false false false MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Tabla normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman"; mso-ansi-language:#0400; mso-fareast-language:#0400; mso-bidi-language:#0400;}

Toll-like receptor 2 (TLR2) is a type I pattern recognition receptor that has been shown to participate in intestinal homeostasis. Its increased expression in the lamina propria has been associated with the pathogenesis in inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD). Recently, soluble TLR2 (sTLR2) variants have been shown to counteract inflammatory responses driven by the cognate receptor. Despite the evident roles of TLR2 in intestinal immunity, no study has elucidated the production and cellular source of sTLR2 in IBD. Furthermore, an increase in the population of activated macrophages expressing TLR2 that infiltrates the intestine in IBD has been reported. We aimed first to assess the production of the sTLR2 by UC and CD organ culture biopsies and lamina propria mononuclear cells (LPMCs) as well as the levels of sTLR2 in serum, and then characterize the cell population from lamina propria producing the soluble protein. Mucosa explants, LPMCs and serum were obtained from UC, CD patients and control subjects. The level of sTLR2 was higher in conditioned media from organ culture biopsies and LPMCs from UC patients in comparison to CD and controls. Moreover, an inverse correlation between the content of intestinal and serum sTLR2 levels was observed in UC patients. Additionally, when characterizing the cellular source of the increased sTLR2 by LPMCs from UC patients, an increase in TLR2(+)/CD33(+) cell population was found. Also, these cells expressed CX3CR1, which was related to the increased levels of intestinal FKN in UC patients, suggesting that a higher proportion of TLR2(+) mononuclear cells infiltrate the lamina propria. The increased production of sTLR2 suggests that a differential regulating factor of the innate immune system is present in the intestinal mucosa of UC patients.

PURPOSE: Lynch syndrome is the most common inherited syndrome of colorectal cancer, caused principally by germline mutations in MLHI and MSH2. We report our experience with genetic screening in the diagnosis of Lynch syndrome in Chile, a country previously underserved in the capacity to diagnose hereditary colorectal cancer. METHODS: Families from our Familial Colorectal Cancer Registry were selected for this study if they fulfilled either Amsterdam I/II or Bethesda criteria for classification of Lynch syndrome. Analysis of colorectal tumors from probands included a microsatellite instability study and immunohistochemical evaluation for MLHI and MSH2. Screening of germline mutations was performed by single-strand conformation polymorphism analysis and DNA sequencing. RESULTS: A total of 21 families were evaluated, 14 meeting Amsterdam criteria and 7 meeting Bethesda criteria. Tumors in 20 families (95%) showed microsatellite instability (19 high and 1 low) and 9 of these 20 families (45%) harbored a germline mutation (7 of 13 Amsterdam and 2 of 7 Bethesda families). Of the 9 mutations identified, 6 were in MLH1 and 3 in MSH2. Two of the mutations were novel, 3 were previously found in 1 to 2 European populations, and 4 were previously found in various ethnic populations worldwide. Only 2 mutations were previously found in another Latin American population (Colombia). In our probands, colorectal cancer was located mainly (57%) in the right or transverse colon. Pedigree information from 104 family affected members of 21 studied families showed endometrial cancer to be the most frequent primary extracolonic tumor, accounting for 15.1% of total cases, followed by stomach (13.2%) and breast cancer (11.3%). Analysis of mitochondrial DNA haplotypes showed a strong Amerindian genetic component in 15 (71.4%) of the 21 families analyzed. CONCLUSION: The study of Lynch syndrome in families of different ethnic origins contributes to the definition of genetic and clinical differences among populations. Wide distribution in other ethnic populations strongly suggests varying origins of 4 the mutations found. Although cancer phenotype was consistent with those from other Latin American populations, only 2 of 9 mutations were shared with other South American populations and 2 novel mutations were found. The Chilean population is considered to be an admixture of Amerindian and European—mainly Spanish—populations, producing an ethnic group with significant genetic differences from populations previously studied.

Background: Fecal and urinary incontinence (FI and UI) are psychologically and socially debilitating and embarrassing conditions. Aim: To determine the prevalence of FI and associated factors in patients assessed in health centers (HC) and nursing home (NH) residents. Material and Methods: Prospective, multicentric survey carried out in 3 HC and 16 NH of Santiago. Patients and residents of NH were interrogated about FI between March and July, 2004. Results: The questionnaire was answered by 618 patients attending health centers aged 18 to 87 years (75% females) and 128 nursing home residents aged 40 to 103 years (80% females). The prevalence of liquid or solid FI in HC and NH was 2.7 and 45%, respectively. Among the latter, the incontinence for liquids and solids was 19% and 42%, respectively. The prevalence of UI was 30.1 and 62.7% in HC patients and NH residents, respectively. Among patients attending HC, multivariable analysis showed a relation between older age and urinary incontinence with liquid or solid FI. Among NH residents, multivariate analysis showed a relation between urinary incontinence and motor disabilities with liquid or solid FI. Conclusions: The prevalence of liquid or solid FI among patients assessed in health center is 2.7%. This figure increases in older people, those with UI and in NH residents (Rev Med Chile 2008; 136: 867-72). (Key words: Fecal incontinence; Health centers, ambulatory; Nursing homes)

Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch Syndrome is an autosomic dominant syndrome involving 596-1096 of colorectal cancer patients. Mutations in MLH1 and MSH2 genes account for most cases. These two genes participate in the DNA mismatch repair pathway. Therefore mutation carriers show microsatellite instability (MSI) in tumors. This syndrome is characterized by the early development of colorectal cancer (before 50 years) and an increased incidence of cancer in other organs. We report four siblings from a family diagnosed with HNPCC. All of them were subjected to colonic surgery for colorectal cancer Moreover, one patient developed an ampulloma after her colon surgery. The molecular-genetic analysis revealed three brothers with microsatellite instability in the tumor tissue, the absence of the MLH1 protein, and the presence of a germ Une mutation localized in introm 15 ofthe MLH1 gene

The laparoscopic approach is an alternative for the elective treatment of diverticular colon disease (DCD). Aim: To analyze the results of patients electively operated for DCD using a laparoscopic technique. Material and Methods: Data of patients with DCD operated using laparoscopy at the Catholic University of Chile Clinical Hospital were prospectively recorded from January 1999 to August 2006. Indications for surgery were repetitive crises of acute diverticulitis, the persistence of the symptoms or anatomic deformity after the first crisis and complicated diverticulitis (Hinchey 1-2) that responded to the medical treatment. The laparoscopic technique used five ports and the surgical specimen was extracted through a suprapubic approach. Results: One hundred and six patients aged 32 to 82 years (49% females) were operated in the study period. Fifty five percent had a previous abdominal surgery. The mean operative time was 213 minutes (range: 135-360). Four patients were converted to open surgery (3.7%). One or more early post-operative complications were observed in five patients (4.7%). The mean time for passing gases and reinitiate liquid diet was 1.7 and 2.4 days respectively. The median post operative stay after surgery was 4 days. There was no operative mortality. Mean follow-up time was 27 months and only one patient (0.9%) had a new episode of acute diverticular disease, with a satisfactory response to medical treatment. No patient has developed bowel obstruction. Conclusions: The laparoscopic approach is a safe alternative in the elective surgical treatment of DCD

Background: Colon perforation is an uncommon but feared complication of colonoscopy. The treatment is usually surgical but occasionally it does not require an operation. Aim: To report our experience in the diagnosis and management of colon perforation after colonoscopy. Material and methods: Retrospective review of the database of 11,720 colonoscopies. The medical records of those patients that had a perforation were reviewed. Results: Twelve perforations in patients aged 26 to 92 years (six women), were identified with a global perforation rate of 0.1%. Five occurred during diagnostic and seven during therapeutic procedures. All perforations were confirmed by a plain X ray or CT scan of the abdomen. Four patients, without signs of initial diffuse peritoneal irritation, were medically treated. One of these, finally required surgery. Among operated patients, a primary suture was done in five, a primary excision without colostomy in three and a Hartmann procedure due to a severe peritoneal contamination in one. No patient died. Conclusions: There is a higher risk of colon perforation during therapeutic colonoscopies. Selected cases may be safely treated without surgery

El objetivo de este trabajo es presentar el resultado de la primera proctocolectomía laparoscópica con reservorio íleo-anal, sin ileostomía de protección, practicada en el Hospital Clínico de la Pontificia Universidad Católica de Chile. La operación se realizó en un paciente de 34 años con poliposis adenomatosa familiar. El paciente tuvo un cuadro clínico de un mes y medio de evolución, caracterizado por dolor abdominal y cambio del hábito intestinal. El estudio colonoscópico reveló la presencia de múltiples pólipos en colon (>100 pólipos), así como también, compromiso rectal. Dado los hallazgos intraoperatorios se decidió efectuar una proctocolectomía laparoscópica más un reservorio ileal en J, sin ileostomía de protección; la pieza operatoria se extrajo mediante una incisión de Pfannenstiel. La cirugía se realizó sin dificultades en un tiempo de 340 minutos. El paciente se realimentó con líquidos al 5º día y se dio de alta al 9º día postoperatorio, sin complicaciones. No se registraron complicaciones en el seguimiento temprano a 30 días del alta hospitalaria. Luego de 6 meses desde su operación, el paciente presenta 4-6 deposiciones diarias, sin urgencia y utiliza loperamida® en forma esporádica

Background: First degree relatives of patients with colorectal carcinoma are at a higher risk of having the disease than the general population. Therefore, they should be subjected to screening colonoscopy. Aim: To assess the effectiveness of colonoscopy among first degree relatives of patients with colorectal carcinoma. Material and methods: A free colonoscopy was offered to first degree relatives of patients operated on for colorectal cancer between 1998 and 2000. As inclusion criteria, subjects had to be asymptomatic, older than 40 years or less than 10 years younger than the index case. Each subject was contacted twice, inviting him/her to have a colonoscopy performed. Results: Two hundred forty three relatives were contacted for the study and in 76, a colonoscopy was performed. Among the latter, a neoplasm was found in 13 (17%): One adenocarcinoma and 12 adenomas. Three of these lesions were located in the right colon. The main reason given by the 176 subjects that did not agree to have a colonoscopy was lack of interest. Conclusions: Screening colonoscopy is effective to detect adenoma and adenocarcinomaamong first degree relatives of patients with colorectal carcinoma, however only 31% of all potential relatives agreed to undergo a colonoscopy (Rev Med Chile 2006; 134: 997-1001). (Key words: Colonic neoplasms; Colonoscopy; Rectal neoplasms)

Background: Among colorectal cancer hereditary variants, two syndromes show a predisposition to the disease based on germline mutations: Familial Adenomatous Polyposis (FAP) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Aim: To screen mutations in FAP and HNPCC families in Chile. Materials and Methods: Two FAP and one HNPCC families were studied. The APC gene (for FAP patients) and the MLH1 gene (for HNPCC patients), were screened for mutations on genomic DNA. The molecular analysis was performed through polymerase chain reaction, Single Strand Conformer Polymorphism (SSCP) and DNA sequencing. Mutations were defined as changes in the DNA sequence leading into a stop codon and a truncated protein. Results: In the two FAP families the analysis revealed a mutation consisting in the deletion of five nucleotides named c.3927_3931delAAAGA. The genetic study of the HNPCC family demonstrated the insertion of one adenine in codon 168 of exon 6, named c.504insA. Discussion: Germ-line mutations were identified in the three families. The relevance of these studies in a better knowledge of cancer susceptibility, and the possibility of identifying in relatives in risk by molecular diagnosis

Han pasado 15 años desde la primera publicación de una cirugía laparoscópica por cáncer colorrectal (CLCC) y finalmente parece ser que la evidencia la apoya, e incluso para algunos autores es indiscutible que se obtendrían mejores resultados. En nuestra institución, el año 1998 se dio inicio a un protocolo en cirugía laparoscópica de colon, para abordar los casos oncológicos en forma progresiva y de acuerdo al avance en la curva de aprendizaje. El objetivo de este trabajo es analizar los resultados inmediatos y la seguridad de la resección oncológica en pacientes sometidos a una CLCC. Material y Método: Este es un trabajo prospectivo que incluye a todos los pacientes operados por cáncer colorrectal en el marco de un protocolo de desarrollo de la cirugía laparoscópica. Resultados: Entre septiembre de 1998 y agosto de 2004 se efectuaron 131 cirugías laparoscópicas colorrectales; en 32 (24%) de ellos el motivo de la intervención fue un cáncer colorrectal. La edad promedio fue 64 años (i: 26-88) y el 47% correspondió al sexo femenino. El tumor se encontraba localizado en el recto en 9 pacientes y en los 23 restantes en el colon (derecho 6, izquierdo 7 y sigmoides 10). La resección del tumor fue realizada con intención curativa en 29 pacientes. Las operaciones practicadas fueron: resección de colon sigmoides en 10 pacientes, hemicolectomía izquierda en 7, hemicolectomía derecha en 6, resección anterior baja en 4, resección abdóminoperineal en 3 y proctocolectomía más reservorio ileal en 2 pacientes. En 4 pacientes fue necesario convertir a cirugía convencional (12%) por dificultad anatómica. Una o más complicaciones se observaron en 8 pacientes (morbilidad de 25%) y un paciente fallece en la serie. El promedio de ganglios recuperados en la pieza operatoria fue 23 (4-86) y en ningún paciente se observó un margen microscópico positivo. De acuerdo a la etapificación TNM, los pacientes fueron clasificados como etapa I, II, III y IV el 31%, 28%, 28% y 13% respectivamente. La mediana del restablecimiento del tránsito a gases, realimentación con sólidos y estadía hospitalaria fue 2 días, 3 días y 5 días. Todos los pacientes han acudidos a controles postoperatorios regulares (promedio de seguimiento 16.4 meses) sin observar implantes en sitios de trocares en ninguno de ellos. No se ha observado progresión tumoral en ninguno de los pacientes etapa I y II. Conclusión: El trabajo en el marco de un protocolo permite obtener resultados seguros y similares a los publicados después de cirugía convencional. Considerando los resultados en las piezas operatorias y un seguimiento a corto plazo, se sugiere que la CLCC mantiene los criterios de seguridad oncológica de la cirugía convencional The first laparoscopic surgery for colorectal cancer was reported fifteen years ago. After a long period, the evidence seems to support this technique as a safety treatment for oncologic cases and for some authors there is no doubt that better result can be obtained. At our institution, a protocol in laparoscopic colorectal surgery was started in 1998, the main aim was to progress in oncologic cases according to complexity and advances in the learning curve. The aim of this paper is to analize early results and the safety of oncologic resection in patients who underwent laparoscopic surgery for colorectal cancer. Material and Method: This is a prospective study which include all patients operated on for colorectal cancer by laparoscopy between 1998 and 2004. Results: During this period, 131 patients underwent laparoscopic colorectal surgery and colorectal cancer was the indication for surgery in 32 patients (24%). The mean age was 64 year old (r: 26-88) and 47% of patients were female. The tumor location was rectum in 9 patients and colon in 23 patients (rigth 6, left 7 and sigmoid 10). The tumor resection was performed with curative intent in 29 patients. The surgical technique was sigmoid resection in 10 patients, left hemicolectomy in 7, right hemicolectomy in 6, low anterior resection in 4, abdominoperineal resection in 3 and restorative proctocolectomy with J pouch in two cases. Four patients were converted to open surgery (12%) due to anatomic dificulty. One or more complications were observed in 8 patients (25%) and one patient died after surgery. The mean number of lymph nodes retrieved was 23 (r: 4-86) and a positive histopathologic margin was not observed at any patient. According to TNM clasification, stage I, II, III and IV was observed in 31%, 28% 28% and 13% of patients respectively. The median time of passing flatus, solid oral feeding and hospital stay was 2 days, 3 days and 5 days respectively. All patients have been followed up (mean time 16.4 months) and no tumor trocar implants have been observed. No tumor progression have been observed in any stage I or II patients. Conclusion: Working under a protocol allows to obtain satisfactory surgical results. Considering results obtained from the surgical specimens and a short follow-up, looks like colorectal cancer can be treated by laparoscopy whitout compromising the oncologic standard observed after open surgery