Publications by authors named "Francisco López-Kostner"

50 Publications

Immune System, Microbiota, and Microbial Metabolites: The Unresolved Triad in Colorectal Cancer Microenvironment.

Front Immunol 2021 26;12:612826. Epub 2021 Mar 26.

Research Core, Academic Department, Clínica Las Condes, Santiago, Chile.

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 or , 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.
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http://dx.doi.org/10.3389/fimmu.2021.612826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033001PMC
March 2021

Clinical, Pathological and Molecular Characteristics of Chilean Patients with Early-, Intermediate- and Late-Onset Colorectal Cancer.

Cells 2021 Mar 12;10(3). Epub 2021 Mar 12.

Oncology Center, Clinica Universidad de Los Andes, Santiago 7620157, Chile.

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.
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http://dx.doi.org/10.3390/cells10030631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999342PMC
March 2021

[The present situation of colorectal cancer in Chile].

Rev Med Chil 2020 Jun;148(6):858-867

Departamento de Manejo Integral de Cáncer y otros Tumores, Ministerio de Salud, Chile.

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.
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http://dx.doi.org/10.4067/S0034-98872020000600858DOI Listing
June 2020

Characterization of Chilean patients with sporadic colorectal cancer according to the three main carcinogenic pathways: Microsatellite instability, CpG island methylator phenotype and Chromosomal instability.

Tumour Biol 2020 Jul;42(7):1010428320938492

Coloproctology Unit, Clínica Las Condes, Santiago, Chile.

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.
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http://dx.doi.org/10.1177/1010428320938492DOI Listing
July 2020

Spectrum and Frequency of Tumors, Cancer Risk and Survival in Chilean Families with Lynch Syndrome: Experience of the Implementation of a Registry.

J Clin Med 2020 Jun 15;9(6). Epub 2020 Jun 15.

Oncology and Molecular Genetic Laboratory, Coloproctology Unit, Clínica Las Condes, Santiago 7591047, Chile.

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 , 23% , 12% and 6% 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 ( < 0.0001). The cumulative incidence of extracolonic cancers was higher in females than males ( = 0.001). variants are significantly more associated with the development of CRC than extracolonic tumors (59.5% vs. 40.5%) when compared to (47.5% vs. 52.5%) variants ( = 0.05018). The cumulative incidence of CRC was higher in / carriers compared to carriers ( = 0.03). In addition, carriers showed higher risk of extracolonic tumors ( = 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.
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http://dx.doi.org/10.3390/jcm9061861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356331PMC
June 2020

MLH1 intronic variants mapping to + 5 position of splice donor sites lead to deleterious effects on RNA splicing.

Fam Cancer 2020 10;19(4):323-336

Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB) [HIBA-IUHI-CONICET], C1199ABH, Buenos Aires, Argentina.

Germline pathogenic variants in the DNA mismatch repair genes (MMR): MLH1, MSH2, MSH6, and PMS2, are causative of Lynch syndrome (LS). However, many of the variants mapping outside the invariant splice site positions (IVS ± 1, IVS ± 2) are classified as variants of unknown significance (VUS). Three such variants (MLH1 c.588+5G>C, c.588+5G>T and c.677+5G>A) were identified in 8 unrelated LS families from Argentina, Brazil and Chile. Herein, we collected clinical information on these families and performed segregation analysis and RNA splicing studies to assess the implication of these VUS in LS etiology. Pedigrees showed a clear pattern of variant co-segregation with colorectal cancer and/or other LS-associated malignancies. Tumors presented deficient expression of MLH1-PMS2 proteins in 7/7 of the LS families, and MSI-high status in 3/3 cases. Moreover, RNA analyses revealed that c.588+5G>C and c.588+5G>T induce skipping of exon 7 whereas c.677+5G>A causes skipping of exon 8. In sum, we report that the combined clinical findings in the families and the molecular studies provided the evidences needed to demonstrate that the three MLH1 variants are causative of LS and to classify c.588+5G>C and c.677+5G>A as class 5 (pathogenic), and c.588+5G>T as class 4 (likely-pathogenic). Our findings underline the importance of performing clinical and family analyses, as well as RNA splicing assays in order to determine the clinical significance of intronic variants, and contribute to the genetic counseling and clinical management of patients and their relatives.
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http://dx.doi.org/10.1007/s10689-020-00182-5DOI Listing
October 2020

A snapshot of current genetic testing practice in Lynch syndrome: The results of a representative survey of 33 Latin American existing centres/registries.

Eur J Cancer 2019 09 20;119:112-121. Epub 2019 Aug 20.

Hospital de Especialidades Eugenio Espejo, Subproceso de Anatomía Patológica, Área de Genética Clínica, Quito, Ecuador.

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.
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http://dx.doi.org/10.1016/j.ejca.2019.07.017DOI Listing
September 2019

Colorectal cancer risk factors in asymptomatic Chilean population: a survey of international collaboration between Japan and Chile.

Eur J Cancer Prev 2020 03;29(2):127-133

Department of Comprehensive Pathology, Tokyo Medical and Dental University, Tokyo, Japan.

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.
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http://dx.doi.org/10.1097/CEJ.0000000000000531DOI Listing
March 2020

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

Genet Med 2020 01 24;22(1):15-25. Epub 2019 Jul 24.

Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.

Purpose: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer.

Methods: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years.

Results: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer.

Conclusion: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.
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http://dx.doi.org/10.1038/s41436-019-0596-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371626PMC
January 2020

Interleukin 33/ST2 Axis Components Are Associated to Desmoplasia, a Metastasis-Related Factor in Colorectal Cancer.

Front Immunol 2019 21;10:1394. Epub 2019 Jun 21.

Immunology Program, Innate Immunity Laboratory, Faculty of Medicine, Biomedical Sciences Institute, Universidad de Chile, Santiago, Chile.

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. 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.
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http://dx.doi.org/10.3389/fimmu.2019.01394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598075PMC
October 2020

From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America.

Int J Cancer 2019 07 5;145(2):318-326. Epub 2018 Dec 5.

AC Camargo Cancer Center, Sao Paulo, Brazil.

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.
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http://dx.doi.org/10.1002/ijc.31920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587543PMC
July 2019

[Results of a multicentric colorectal cancer screening program in Chile].

Rev Med Chil 2018 Jun;146(6):685-692

Hospital Eduardo Pereira, Valparaíso, Chile.

Background: Colorectal Cancer Screening Programs (CRCSP) are widely accepted in developed countries. Unfortunately, financial restrictions, low adherence rate and variability on colonoscopy standardization hamper the implementation 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 cardiovascular 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.
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http://dx.doi.org/10.4067/s0034-98872018000600685DOI Listing
June 2018

A Pilot Trial to Quantify Plasma Exosomes in Colorectal Cancer Screening from the International Collaborative Study between Chile and Japan.

Digestion 2018 21;98(4):270-274. Epub 2018 Aug 21.

Department of Human Pathology, Tokyo Medical and Dental University, Tokyo, Japan.

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.
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http://dx.doi.org/10.1159/000490559DOI Listing
March 2019

Histopathologic study from a colorectal cancer screening in Chile: results from the first 2 years of an international collaboration between Chile and Japan.

Eur J Cancer Prev 2019 07;28(4):245-253

Human Pathology, Tokyo Medical and Dental University, Tokyo, Japan.

A national colorectal cancer (CRC) screening program began in Chile in 2012, which is an international collaboration between Japan and Chile and is based on a standardized protocol supported by Tokyo Medical and Dental University. We describe the results from the first 2 years of screening at one public hospital in Punta Arenas, Chile. Of 4124 asymptomatic individuals aged between 50 and 75 years, 485 participants with immunological fecal occult blood test values of at least 100 ng/ml and/or those with family histories of CRC underwent colonoscopies. Lesions were found in 291 participants, and 642 histologic samples were obtained. Chilean pathologists made the initial histologic diagnoses, and a Japanese pathologist reviewed the histologic slides and analyzed the results. Of the 291 participants with lesions, 60 (20.6%) were diagnosed with adenocarcinomas, of which 50 (83.3%) were early-phase adenocarcinomas (pTis or pT1), and 163 (56.0%) were diagnosed with conventional adenomas, of which 96 (58.9%) were high-risk adenomas. The cancer prevalence within the screened population was 1.5% (60 of 4124). The colonoscopy cancer detection rate was 12.4% (60 of 485). Notably, we detected one flat-depressed (0-IIc) lesion that measured 5 mm and had invaded the submucosa. The findings from this screening program are the first to show the histopathologic distributions of consecutive lesions and the high incidence of CRC in Chile. The high detection rates for high-risk adenomas and cancer support the feasibility of early CRC screening and its potential to reduce the mortality associated with CRC.
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http://dx.doi.org/10.1097/CEJ.0000000000000454DOI Listing
July 2019

Evaluation of MLH1 variants of unclear significance.

Genes Chromosomes Cancer 2018 Jul 30;57(7):350-358. Epub 2018 Apr 30.

Biomedizinisches Forschungslabor, Medizinische Klinik 1, Universitätsklinik Frankfurt, Frankfurt, Germany.

Inactivating mutations in the MLH1 gene cause the cancer predisposition Lynch syndrome, but for small coding genetic variants it is mostly unclear if they are inactivating or not. Nine such MLH1 variants have been identified in South American colorectal cancer (CRC) patients (p.Tyr97Asp, p.His112Gln, p.Pro141Ala, p.Arg265Pro, p.Asn338Ser, p.Ile501del, p.Arg575Lys, p.Lys618del, p.Leu676Pro), and evidence of pathogenicity or neutrality was not available for the majority of these variants. We therefore performed biochemical laboratory testing of the variant proteins and compared the results to protein in silico predictions on structure and conservation. Additionally, we collected all available clinical information of the families to come to a conclusion concerning their pathogenic potential and facilitate clinical diagnosis in the affected families. We provide evidence that four of the alterations are causative for Lynch syndrome, four are likely neutral and one shows compromised activity which can currently not be classified with respect to its pathogenic potential. The work demonstrates that biochemical testing, corroborated by congruent evolutionary and structural information, can serve to reliably classify uncertain variants when other data are insufficient.
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http://dx.doi.org/10.1002/gcc.22536DOI Listing
July 2018

Stem Cell Therapy in Refractory Perineal Crohn's Disease: Long-term Follow-up.

Colorectal Dis 2018 Jan 6. Epub 2018 Jan 6.

Colorectal Surgery Unit, Clínica Las Condes, Santiago, Chile.

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.
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http://dx.doi.org/10.1111/codi.14002DOI Listing
January 2018

EGFR pathway subgroups in Chilean colorectal cancer patients, detected by mutational and expression profiles, associated to different clinicopathological features.

Tumour Biol 2017 Sep;39(9):1010428317724517

1 Laboratorio de Oncología y Genética Molecular, Unidad de Coloproctología, Clínica Las Condes, Santiago, Chile.

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.
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http://dx.doi.org/10.1177/1010428317724517DOI Listing
September 2017

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.

BMC Cancer 2017 Sep 5;17(1):623. Epub 2017 Sep 5.

Hospital Sirio Libanes, Sao Paulo, Brazil.

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.
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http://dx.doi.org/10.1186/s12885-017-3599-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586063PMC
September 2017

[Characterization of patients with sporadic colorectal cancer following the new Consensus Molecular Subtypes (CMS)].

Rev Med Chil 2017 Apr;145(4):419-430

Unidad de Coloproctología, Clínica Las Condes, Santiago, Chile.

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.
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http://dx.doi.org/10.4067/S0034-98872017000400001DOI Listing
April 2017

Low Gene Dosage of Cdc42 Is Not Associated with Protein Dysfunction in Patients with Colorectal Cancer.

DNA Cell Biol 2016 Dec 19;35(12):819-827. Epub 2016 Aug 19.

1 Deparment of Pharmacy, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile .

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.
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http://dx.doi.org/10.1089/dna.2015.3098DOI Listing
December 2016

Lynch syndrome in South America: past, present and future.

Fam Cancer 2016 07;15(3):437-45

Cleveland Clinic Foundation, Cleveland, OH, USA.

After decades of unawareness about Lynch syndrome, the medical community in South America is increasingly interested and informed. The visits and support of mentors like H. T. Lynch had been crucial to this awakening. Several countries have at least one registry with skilled personnel in genetic counseling and research. However, this only represents a very restricted resource for the region. According to the GETH, there are 27 hereditary cancer care centers in South America (21 in Brazil, 3 in Argentina, 1 in Uruguay, 1 in Chile and 1 in Peru). These registries differ in fundamental aspects of function, capabilities and funding, but are able to conduct high quality clinical, research and educational activities due to the dedication and personal effort of their members, and organizational support. More support from the governments as well as the participation of the community would boost the initiatives of people leading these groups. Meantime, the collaboration among the South American registries and the involvement of registries and leaders from developed countries will allow to maximize the efficiency in caring for affected patients and their families. The aim of this article is to describe how the knowledge of LS began to be spread in South America, how the first registries were organized and to summarize the current state of progress. In addition, we will provide an update of the clinical and molecular findings in the region.
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http://dx.doi.org/10.1007/s10689-016-9903-7DOI Listing
July 2016

International collaboration between Japan and Chile to improve detection rates in colorectal cancer screening.

Cancer 2016 Jan 7;122(1):71-7. Epub 2015 Oct 7.

Department of Digestive and General Surgery, Tokyo Medical and Dental University, Tokyo, Japan.

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.
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http://dx.doi.org/10.1002/cncr.29715DOI Listing
January 2016

[Molecular analysis of sporadic colon cancer].

Rev Med Chil 2015 Mar;143(3):310-9

Background: In Chile, colorectal cancer (CRC) is often diagnosed in late stages. Thus, surgical treatment must be complemented with chemotherapy. KRAS mutations and microsatellite instability have been detected in these tumors. However, the response to treatment in patients without KRAS mutations varies and requires a better understanding.

Aim: To determine the frequency and distribution of somatic point mutations in KRAS, BRAF and PIK3CA genes and microsatellite instability status (MSI) in patients with colon cancer (CC).

Material And Methods: A prospective observational study of patients undergoing surgery for colon cancer. Tumor-derived DNA was analyzed by polymerase chain reaction (PCR) for the most frequent mutations of KRAS, BRAF and PIK3CA. PCR was also used to analyze MSI.

Results: Fifty-eight patients with sporadic CC were analyzed, 16 showed KRAS mutations (G12R, G12D, G12V, G13D) and out of the 42 patients that did not show any mutation, 10 had mutations in BRAF (V600E) and PIK3CA (E542K, E545D, E545K, Q546E, H1047R). BRAF mutations alone or in combination with PIK3CA mutations were observed in 27% of high MSI tumors and in 2% of tumors without instability (p < 0.049). A higher percentage of high MSI tumors were located in the right colon (p < 0.001), and showed BRAF mutation (p < 0.020).

Conclusions: The highest percentage of high MSI and BRAF mutations was observed in the right colon. Therefore, this study suggests the presence of different molecular features between right and left colon tumors that should be considered when defining the therapeutic management.
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http://dx.doi.org/10.4067/S0034-98872015000300005DOI Listing
March 2015

Mesenchymal stem cells and platelet-rich plasma in the treatment of patients with perineal Crohn's disease.

Int J Colorectal Dis 2016 Mar 28;31(3):725-6. Epub 2015 Apr 28.

Colorectal Surgery Unit, Clínica Las Condes, Lo Fontecilla 441, Las Condes, Santiago, Chile.

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http://dx.doi.org/10.1007/s00384-015-2221-yDOI Listing
March 2016

[KRAS gene somatic mutations in Chilean patients with colorectal cancer].

Rev Med Chil 2014 Nov;142(11):1407-14

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.
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http://dx.doi.org/10.4067/S0034-98872014001100007DOI Listing
November 2014

[Inflammatory bowel disease. Experience in 316 patients].

Rev Med Chil 2014 Aug;142(8):1006-13

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. Subsequently 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.
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http://dx.doi.org/10.4067/S0034-98872014000800008DOI Listing
August 2014

Escherichia coli isolates from inflammatory bowel diseases patients survive in macrophages and activate NLRP3 inflammasome.

Int J Med Microbiol 2014 May 6;304(3-4):384-92. Epub 2014 Feb 6.

Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, CL 8380453, Chile. Electronic address:

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 characterize 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.
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http://dx.doi.org/10.1016/j.ijmm.2014.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075040PMC
May 2014

Does obesity increase early postoperative complications after laparoscopic colorectal surgery? Results from a single center.

Surg Endosc 2014 Jul 1;28(7):2090-6. Epub 2014 Feb 1.

Colorectal Unit, Surgery Department, Clinica Las Condes, Lo Fontecilla 441, 7550000, Santiago, Chile,

Background: 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/m(2)]. 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.

Methods: 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 <30 kg/m(2)) patients were paired by gender, age, American Society of Anesthesiologists class, preoperative diagnosis, and type of surgery. Intraoperative complications and POCs were documented up to 30 days. The severity of each POC was classified by Clavien-Dindo score.

Results: In this study, 449 patients who underwent LCRS during the study period were identified. The study paired 53 obese patients (mean BMI 33.1 kg/m(2)) with 53 nonobese patients (mean BMI 25.9 kg/m(2)). The median age was 55 years in the obese group and 57 years in the nonobese group, and 60% of the patients in both groups were men. The findings showed POCs in 13 obese (24.5%) and 15 nonobese (28.3%) patients (p = 0.66). Stratified by severity of POCs, the two groups were similar (p = 0.62). The two groups did not differ in terms of the median time to the first feeding (1 day each) or the hospital length of stay (4 days each). Similar percentages of patients in the two groups required reoperation (p = 0.4), intensive care unit (ICU) admission (p = 0.77), and readmission to the hospital (p = 0.65) because of POCs.

Conclusion: The frequency of POCs after LCRS was no higher among the obese patients than among the nonobese patients.
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http://dx.doi.org/10.1007/s00464-014-3440-yDOI Listing
July 2014