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1.
Genet Med ; 22(1): 15-25, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31337882

RESUMO

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.

3.
Eur J Cancer Prev ; 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31436751

RESUMO

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.

4.
Eur J Cancer ; 119: 112-121, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31442815

RESUMO

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.

5.
Front Immunol ; 10: 1394, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281317

RESUMO

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.

6.
Int J Cancer ; 145(2): 318-326, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30303536

RESUMO

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.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Detecção Precoce de Câncer , Feminino , Fidelidade a Diretrizes , Humanos , América Latina/epidemiologia , Masculino , Guias de Prática Clínica como Assunto , Medição de Risco
7.
Eur J Cancer Prev ; 28(4): 245-253, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29958195

RESUMO

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.

8.
Digestion ; 98(4): 270-274, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30130793

RESUMO

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.


Assuntos
Adenocarcinoma/diagnóstico , Adenoma/diagnóstico , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/métodos , Exossomos , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Adenoma/sangue , Adenoma/patologia , Idoso , Chile , Colo/diagnóstico por imagem , Colo/patologia , Colonoscopia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Feminino , Humanos , Cooperação Internacional , Japão , Masculino , Pessoa de Meia-Idade , Sangue Oculto , Projetos Piloto
9.
Rev Med Chil ; 146(6): 685-692, 2018 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-30148899

RESUMO

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.


Assuntos
Adenoma/diagnóstico , Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/métodos , Avaliação de Programas e Projetos de Saúde , Medição de Risco/métodos , Adenoma/patologia , Idoso , Análise de Variância , Chile , Colonoscopia/normas , Neoplasias Colorretais/patologia , Detecção Precoce de Câncer/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Sangue Oculto , Educação de Pacientes como Assunto , Projetos Piloto , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de Risco
10.
Rev. méd. Chile ; 146(6): 685-692, jun. 2018. tab, graf
Artigo em Espanhol | LILACS-Express | ID: biblio-961448

RESUMO

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.

11.
Genes Chromosomes Cancer ; 57(7): 350-358, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29520894

RESUMO

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.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença , Proteína 1 Homóloga a MutL/genética , Mutação , Neoplasias Colorretais Hereditárias sem Polipose/etnologia , Simulação por Computador , Células HEK293 , Humanos , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/química , Conformação Proteica , América do Sul
12.
Colorectal Dis ; 2018 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-29316139

RESUMO

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.

13.
BMC Cancer ; 17(1): 623, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28874130

RESUMO

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.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Biologia Computacional/métodos , Reparo de Erro de Pareamento de DNA , Feminino , Efeito Fundador , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Variação Genética , Mutação em Linhagem Germinativa , Humanos , América Latina/epidemiologia , Masculino , Pessoa de Meia-Idade , Vigilância da População , Processamento de RNA , Sistema de Registros , Fatores de Risco
14.
Tumour Biol ; 39(9): 1010428317724517, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28936923

RESUMO

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.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores ErbB/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Chile , Análise Mutacional de DNA , Feminino , Genes erbB-1 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Transdução de Sinais/genética , Análise Serial de Tecidos , Transcriptoma
15.
Rev Med Chil ; 145(4): 419-430, 2017 Apr.
Artigo em Espanhol | MEDLINE | ID: mdl-28748988

RESUMO

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.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Metilação de DNA/genética , DNA de Neoplasias/genética , Instabilidade de Microssatélites , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Chile , Neoplasias Colorretais/patologia , Consenso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Estudos Prospectivos
16.
Rev. méd. Chile ; 145(4): 419-430, abr. 2017. ilus, tab
Artigo em Espanhol | LILACS-Express | ID: biblio-902494

RESUMO

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.

17.
Rev. chil. cir ; 68(6): 417-421, dic. 2016. ilus, tab
Artigo em Espanhol | LILACS | ID: biblio-830094

RESUMO

Introducción: La filtración de anastomosis es una de las complicaciones de mayor impacto en cirugía colorrectal. Objetivo: Analizar la frecuencia e impacto de las filtraciones anastomóticas en cirugía laparoscópica colorrectal. Material y método: Estudio longitudinal de base de datos prospectiva de pacientes operados por cirugía colorrectal entre julio de 2007 y agosto de 2014. Resultados: De un total de 654 pacientes operados, 52,3% correspondían a hombres con una edad promedio de 57 años (42-72). La indicación más frecuente fue cáncer colorrectal con 244 pacientes, 159 (24,3%) operados por cáncer de colon y 85 (12,9%) por cáncer de recto, seguido por la enfermedad diverticular con 239 pacientes (36,5%) y 171 pacientes (26,1%) con otros diagnósticos. En 44 pacientes (6,7%) se objetivó filtración anastomótica, con una mediana de 4 días desde el postoperatorio para su diagnóstico. Como factores asociados a filtración se identificó al género masculino, riesgo anestesiológico según ASA, necesidad de conversión a laparotomía y la anastomosis ileoanal. En relación con el tratamiento, 15 pacientes (33,7%) fueron tratados de forma médica exitosa y 29 fue necesario reintervenirlos, de los cuales 23 (79,3%) requirieron una ostomía de protección. No hubo mortalidad asociada a la cirugía, y el promedio de hospitalización en los pacientes con filtración fue de 12 vs. 5 días para los pacientes sin filtración de la anastomosis. Conclusión: Este trabajo permite identificar a grupos de pacientes con mayor riesgo de filtraciones anastomóticas, quienes duplican su estadía hospitalaria y en un alto porcentaje deben ser reintervenidos. La sospecha y diagnostico precoz reducen la morbimortalidad.


Introduction: Anastomotic leak is the most important complication on colorectal surgery. Objective: Analyze the frequency and impact of anastomotic leaks in laparoscopic colorectal surgery. Material and methods: Longitudinal study of prospective database of patients undergoing colorectal surgery between July 2007 and August 2014. Results: 654 patients operated, 52.3% were men with an average age of 57 years (42-72). The most frequent indication was colorectal cancer in 244 patients, 159 (24.3%) operated for colon cancer and 85 (12.9%) for rectal cancer followed by diverticular disease in 239 patients (36.5%) and 171 patients (26.1%) with other diagnoses. In 44 patients (6.7%) anastomotic leakage was observed with a median of 4 days post surgery for diagnosis. As factors associated with filtration, we identified male gender, anesthesic risk according to ASA, need for conversion to laparotomy and ileoanal anastomosis. With regard to treatment, 15 (33.7%) were successfully treated with medical therapy alone and 29 required re-intervention, of which 23 (79.3%) required an ostomy protection. There was no mortality associated with surgery and average LOS was 12 vs. 5 days in patients with filtration compared with patients without anastomotic leakeage. Conclusion: This serie helps to identify patients groups with increased risk of anastomotic leakage who double their hospital LOS and in a higher percentage should need re-intervention. Suspicion and early diagnosis reduces morbidity and mortality.


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Fístula Anastomótica/epidemiologia , Cirurgia Colorretal/efeitos adversos , Laparoscopia/efeitos adversos , Fístula Anastomótica/terapia , Estudos Longitudinais , Complicações Pós-Operatórias/epidemiologia , Fatores de Risco
18.
DNA Cell Biol ; 35(12): 819-827, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27540769

RESUMO

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.


Assuntos
Neoplasias Colorretais/genética , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Perda de Heterozigosidade , Proteína cdc42 de Ligação ao GTP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Deleção de Sequência , Proteína cdc42 de Ligação ao GTP/deficiência
19.
Rev. chil. cir ; 68(2): 164-169, abr. 2016. tab
Artigo em Espanhol | LILACS | ID: lil-784847

RESUMO

phenotypic expression is the presence of múltiple colorectal adenomatous polyps (more than 100), with high probability developing colorrectal cancer (CRC) before the fifth decade of life. Prophylactic surgery (total colectomy or restorative proctocolectomy) reduces the risk of developing CRC. However, the risk of developing tumors in other organs remains present. Objetive: Analyze the frequency and type of tumors associated with classic familial adenomatous polyposis syndrome (FAPc) patients undergoing prophylactic colectomy. Material and Methods: Cohort study. From the registry of hereditary colorrectal cancer (CRC) at our institution, we identified patients with FAPc who underwent total colectomy with ileorrectal anastomosis (TC-IRA) or restorative proctocolectomy (RTPC), from 1999 to 2014. In the follow-up we analyzed related tumors and mortality. Results: 27 patients, of whom 18 (66.7%) underwent TC-IRA and 9 (33.3%) underwent RTPC. At the time of surgery, 4 patients had CRC (15%) and 5 had extracolonic tumors (osteomas). In a mean follow-up of 49, 4 months (i: 2 y 178) the following lesions were diagnosed: digestive tract adenomas in 17 (63%) patients, of these 2 required a proctectomy and 3 resection of duodenal adenomas. Eight patients developed desmoid tumors (30%), and 3 of them underwent surgery. One patient had an extradigestive tumor (thyroid cancer) and only 8/27 (29.6%) did not develop other tumors. One patient died due to progression of his CCR. Discussion: In this series it is confirmed that most patients will develop neoplasms FAPc after colectomy. conclusion: The removal of the colon and/or rectum is able to prevent the development of CRC. However, two thirds of the patients develop other tumors in which systematic surveillance allowed early detection and treatment.


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.


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Colectomia/efeitos adversos , Polipose Adenomatosa do Colo/cirurgia , Polipose Adenomatosa do Colo/complicações , Complicações Pós-Operatórias/epidemiologia , Seguimentos , Polipose Adenomatosa do Colo/patologia , Neoplasias Duodenais/etiologia , Neoplasias Duodenais/epidemiologia , Estadiamento de Neoplasias
20.
Fam Cancer ; 15(3): 437-45, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27007491

RESUMO

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.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Aconselhamento Genético/estatística & dados numéricos , Aconselhamento Genético/tendências , Predisposição Genética para Doença , Testes Genéticos , Sistema de Registros/estatística & dados numéricos , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Mutação em Linhagem Germinativa , América do Sul/epidemiologia
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