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Background: Colorectal carcinoma (CRC) is one of the most frequently diagnosed forms of cancer worldwide. The RAS (KRAS, NRAS) and BRAF genes encode proteins that are important therapeutic targets for the treatment of CRC and, together with the mismatch repair (MMR) system, are closely related to patient prognosis and survival in advanced CRC. Here we evaluate the mutational profile and the frequency of mutations in the KRAS, NRAS and BRAF genes, along with the expression of MMR in advanced CRC, at a tertiary hospital in southern Brazil. Methods: A cross-sectional retrospective study was carried out, where molecular analysis of mutations in the KRAS, NRAS and BRAF genes was carried out, as well as immunohistochemistry for MMR proteins. Results: Next-generation sequencing (NGS) analysis of 310 tumors revealed that 202 patients (65.2%) had mutations. The KRAS gene (53.2%) was the most frequently mutated in our sample, with G12D being the most frequent, representing 30.5% of the mutations in this gene. The most frequent mutation found in BRAF was V600E (n=25; 89.3%) and differed significantly in women and in the right colon in patients with MMR deficiency. Among the 283 patients tested for MMR, the rate of loss of expression was 8.8% (25/283). Conclusions: Deficiency in the MMR system is associated with the presence of the BRAF V600E mutation, tumors located in the right colon, and the female sex. In our case series, more than 60% of patients had at least one mutation in KRAS, NRAS, or BRAF. The presence of mutations in these genes is closely related to CRC prognosis and helps define the best therapeutic approach in patients with metastatic CRC.
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Safer analgesic drugs remain a hard challenge because of cardiovascular and/or gastrointestinal toxicity, mainly. So, this study evaluated in vivo the antiproliferative actions of a fraction with casearins (FC) from Casearia sylvestris leaves against human colorectal carcinomas and antihyperalgesic effects on inflammatory- or opiate-based pain relief and oncologic pain in Sarcoma 180 (S180)-bearing mice. Moreover, docking investigations evaluated the binding among Casearin X and NMDA(N-methyl-D-aspartate)-type glutamate receptors. HCT-116 colorectal carcinoma-xenografted mice were treated with FC for 15 days. Antinociceptive assays included chemically induced algesia and investigated mechanisms by pharmacological blockade. Intraplantar region S180-bearing animals received a single dose of FC and were examined for mechanical allodynia and behavior alterations. AutoDock Vina determined molecular interactions among Cas X and NMDA receptor subunits. FC reduced tumor growth at i.p. (5 and 10 mg/kg) and oral (25 mg/kg/day) doses (31.12-39.27%). FC reduced abdominal pain, as confirmed by formalin and glutamate protocols, whose antinociception activity was blocked by naloxone and L-NAME (neurogenic phase) and naloxone, atropine, and flumazenil (inflammatory phase). Meanwhile, glibenclamide potentiated the FC analgesic effects. FC increased the paw withdrawal threshold without producing changes in exploratory parameters or motor coordination. Cas X generated a more stable complex with active sites of the NMDA receptor GluN2B subunits. FC is a promising antitumor agent against colorectal carcinomas, has peripheral analgesic effects by desensitizing secondary afferent neurons, and inhibits glutamate release from presynaptic neurons and/or their action on cognate receptors. These findings emphasize the use of clerodane diterpenes against cancer-related pain conditions.
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Medulloblastoma is the most common malignant pediatric brain tumor and has been linked to known cancer predisposition syndromes. We report a case of medulloblastoma of a 12-year-old Indo-Trinidadian female with a strong family history of colorectal carcinoma. In collaboration with the SickKids-Caribbean Initiative (SCI), her tumor was confirmed to be a WHO grade 4 medulloblastoma - Wnt subtype. Genetic testing further confirmed the presence of a pathogenic APC gene variant [c.3183_3187del (p.Gln1062*)] which led to a diagnosis of Turcot syndrome type 2. The index patient received multimodal therapy which included surgery, radiation and chemotherapy and is currently post end-of-treatment and in remission. This case report aims to highlight the complexity of diseases and the need for expertise in identifying them in low-and-middle income countries, the need for access to specialized testing and the benefits of collaborating between low-and-middle income and high-income countries when managing complex oncology patients.
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Tithonia diversifolia is a perennial bushy plant found in South America with significant ethnopharmacological importance as an antimalarial, antidiabetic, antibacterial, and anticancer agent. The aim of the present study was to determine the cytotoxicity of the ethanolic extract from leaves of T. diversifolia (TdE) on human cancer cell lines (HCT-116, SNB-19, NCIH-460 and MCF-7), as well as the mechanism of action involved in cell death and cellular modulation of oxidative stress. The TdE exhibited significant activity with IC50 values ranging from 7.12 to 38.41 µg/ml, with HCT-116 being the most sensitive cell line. Subsequent experiments were conducted with HCT-116 cell line. TdE decreased the number of viable cells, followed by induction of apoptotic events, increase in mitochondrial membrane permeabilization, and enhanced G2/M phase of the cell cycle. Pro-oxidative effects including elevated acidic vesicular organelle formation, lipid peroxidation, and nitric oxide by-products, as well as reduced levels of intracellular glutathione and reactive oxygen species production were also observed following incubation with TdE, which may lead to DNA damage followed by apoptotic cell death. These results demonstrate the potential of TdE ethanolic leaf extraction for biological activity and enhance the importance of continuing to study natural sources of plants for the development of anticancer agents.
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Antineoplásicos , Tithonia , Humanos , Extractos Vegetales/farmacología , Células HCT116 , Estrés Oxidativo , Apoptosis , Especies Reactivas de Oxígeno/metabolismo , Etanol , Antineoplásicos/farmacología , Hojas de la PlantaRESUMEN
ABSTRACT Background: Colorectal carcinoma (CRC) is one of the common carcinomas with a rising incidence of metastasis due to its advanced stage of presentation. The existing biomarkers such as CEA (Carcinoembryonic antigen) etc., for prognosis, have low sensitivity and specificity. Hence a need for a newer definitive biomarker. Obesity is the leading cause of CRC. Leptin and adiponectin secreted by adipose tissue have been studied as potential biomarkers in the field of CRC. The present study helps to understand the association of leptin and adiponectin receptors with clinicopathological parameters. Objective: To correlate the various clinicopathological parameters with the tissue expression of leptin and adiponectin receptors in CRC. Methods: It is a cross-sectional prospective study conducted at a tertiary care hospital. Formalin fixed paraffin blocks of all radical resection CRC cases were collected and immunohistochemistry (IHC)was carried out on tumor tissue for leptin and adiponectin receptor. Tumor characteristics and clinical parameters were collected from the hospital medical records. Pearson's correlation coefficient test was used. Results: Immunohistochemistry was performed on 60 cases of CRC. Significant positive correlation of leptin was observed with size, lymph node metastasis, advanced stage, and grade of tumor (P<0.05). A significant correlation between adiponectin receptor and CRC was observed concerning age, stage, lymph node metastasis, distant metastasis and grade of tumor. Conclusion: Positive expression of leptin and negative expression of adiponectin receptors in CRC helps to predict the risk of metastasis.
RESUMO Contexto: O carcinoma colorretal (CCR) é um dos carcinomas comuns com incidência crescente de metástases devido ao seu estágio avançado de apresentação. Os biomarcadores existentes como CEA (antígeno carcinoembrionário) etc., para prognóstico, apresentam baixa sensibilidade e especificidade. Daí a necessidade de um biomarcador definitivo mais recente. A obesidade é a principal causa do CCR. A leptina e a adiponectina secretadas pelo tecido adiposo têm sido estudadas como potenciais biomarcadores na área do CCR. O presente estudo ajuda a compreender a associação dos receptores de leptina e adiponectina com parâmetros clinicopatológicos. Objetivo: Correlacionar os diversos parâmetros clinicopatológicos com a expressão tecidual dos receptores de leptina e adiponectina no CCR. Métodos: Trata-se de um estudo transversal, prospectivo, realizado em um hospital terciário. Blocos de parafina fixados em formalina de todos os casos de CCR de ressecção radical foram coletados e a imuno-histoquímica (IHQ) foi realizada no tecido tumoral para receptor de leptina e adiponectina. As características do tumor e os parâmetros clínicos foram coletados dos prontuários médicos do hospital. Foi utilizado o teste do coeficiente de correlação de Pearson. Resultados: A imunohistoquímica foi realizada em 60 casos de CCR. Correlação positiva significativa da leptina foi observada com tamanho e metástase linfonodal, estágio avançado e grau do tumor (P<0,01). Foi observada uma correlação significativa entre o receptor de adiponectina e o CCR em relação à idade, estágio, metástase linfonodal, metástase à distância e grau do tumor. Conclusão: A expressão positiva de leptina e a expressão negativa de receptores de adiponectina no CCR ajudam a prever o risco de metástase.
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Introdução: Lesões serrilhadas são consideradas precursoras dos adenocarcinomas colorretais. Estudá-las em suas fases iniciais é importante ao pensar na prevenção do câncer, quando, então, são lesões hiperplásicas, ou sésseis serrilhadas Objetivo: Realizar revisão integrativa da literatura para comparar as características endoscópicas e histopatológicas nas fases iniciais da doença, com a intenção de auxiliar no entendimento do câncer colorretal. Métodos: Revisão integrativa da literatura baseada em material de análise existente nas plataformas digitais SciELO Scientific Electronic Library Online, Google Scholar, Pubmed e Scopus. O início foi a busca com os seguintes descritores: "lesões sésseis serrilhadas, carcinoma colorretal, lesões superficiais", e seus equivalentes em inglês "serrated sessile lesions, colorectal carcinoma, superficial lesions" com busca AND ou OR, considerando o título e/ou resumo, e incluindo-se posteriormente somente aqueles com maior correlação para leitura dos textos completos. Resultados: Incluíram-se 39 artigos. Conclusão: A maioria das lesões serrilhadas superficialmente elevadas com mais de 5 mm e ressecadas por colonoscopias, são hiperplásicas. Elas ocorrem por todo o cólon e reto, enquanto as sésseis serrilhadas localizamse preferencialmente no cólon proximal. As hiperplásicas geralmente não apresentam displasias e as sésseis serrilhadas podem tê-las de forma intensa.
Introduction: Serrated lesions are considered precursors of colorectal adenocarcinomas. Studying them in their initial phases is important when thinking about cancer prevention, when they are hyperplastic lesions, or sessile serrated lesions. Objective: To carry out an integrative review of the literature to compare the endoscopic and histopathological characteristics in the initial phases of the disease, with the intention to help understand colorectal cancer. Methods: Integrative literature review based on existing analysis material on the digital platforms SciELO Scientific Electronic Library Online, Google Scholar, Pubmed and Scopus. The beginning was the search with the following descriptors: "serrated sessile lesions, colorectal carcinoma, superficial lesions", with AND or OR search, considering the title and/or abstract , and subsequently including only those with the highest correlation for reading the full texts. Results: 39 articles were included. Conclusion: The majority of superficially elevated serrated lesions measuring more than 5 mm and resected by colonoscopies are hyperplastic. They occur throughout the colon and rectum, while the serrated sessiles are preferentially located in the proximal colon. Hyperplastic ones generally do not present dysplasias and sessile serrated ones can have them intensely.
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HumanosRESUMEN
Chloro(glycinato-N,O)(1,10-phenanthroline-N,N')copper(II) trihydrate complex was synthesized through the slow evaporation method. The crystal's structural, thermal, magnetic, and vibrational properties were obtained by X-ray powder diffraction (XRPD), thermal analyses, magnetization, Raman, and Fourier-transform infrared (FT-IR) spectroscopy. XRPD results showed that the crystalline complex belongs to a monoclinic system (P21/n). Thermal analyses revealed that around 333 K, the material undergoes a thermodynamically irreversible process. Magnetic data showed a paramagnetic behavior with weak ferromagnetic interactions. Moreover, all the Raman- and infrared-active bands were assigned from computational calculations based on the density functional theory (DFT) to analyze intra-molecular vibrational modes. In addition, the cytotoxic assay on colorectal cancer cells was performed to evaluate the antitumor activity of this ternary compound. Therefore, the antineoplastic activity of [Cu(1,10-phenanthroline)(glycine)Cl]â¢3H2O complex in HCT-116 cells was confirmed, showing a potent cytotoxic effect.
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Antineoplásicos , Neoplasias Colorrectales , Complejos de Coordinación , Cobre , Citotoxinas , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Cobre/química , Cobre/farmacología , Citotoxinas/química , Citotoxinas/farmacología , Células HCT116 , Humanos , Ratones , Células RAW 264.7RESUMEN
BACKGROUND: Mechanisms of resistance have been described during disease progression (PD) for patients under treatment with anti-EGFR plus chemotherapy (CT). The aim of our study was to evaluate efficacy of anti-EGFR rechallenge (ReCH) and reintroduction (ReIn) in metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: This is a retrospective analysis of patients with mCRC that previously received anti-EGFR + CT and interrupted therapy due to PD in the ReCH group and other reasons in the ReIn group. We aimed to describe progression-free survival (PFS), overall survival (OS) and response rate (RR) after re-exposure and to evaluate prognostic factors associated with PFS. RESULTS: Sixty-eight patients met the inclusion criteria. The median follow-up after re-exposure was 39.3 months. ReCH was adopted in 25% and ReIn in 75%. The median anti-EGFR free interval was at 10.5 months. At re-exposure, the main CT regimen was FOLFIRI in 58.8%. Cetuximab and Panitumumab were used in 59 and 9 patients, respectively. mPFS for ReCH and ReIn was 3.3 × 8.4 months, respectively (p 0.001). The objective response rate for ReCH and ReIn was 18% and 52%, respectively. In univariate analysis, adverse prognostic factors related to PFS were: stable disease or PD at first anti-EGFR exposure (HR: 2.12, CI:1.20-3.74; p = 0.009); ReCH (HR: 3.44, CI:1.88-6.29, p < 0.0001); rechallenge at fourth or later lines (HR: 2.51, CI:1.49-4.23, p = 0.001); panitumumab use (HR: 2.26 CI:1.18-5.54, p = 0.017). In the multivariate model, only ReCH remained statistically significant (HR = 2.63, CI: 1.14-6.03, p = 0.022). CONCLUSION: In our analysis, ReCH resulted in short PFS and low RR. However, reintroduction of anti-EGFR plus CT before complete resistance arose resulted in prolonged PFS. These data could be clinically useful to guide a treatment break due to side effects or patient decisions. Our data should be confirmed by larger and prospective trials.
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Abstract Introduction The study is aimed to outline the vector of colorectal cancer incidence in the industrial Aktobe province of western Kazakhstan through the first decade of the screening implementation, 2009-2018. Methods Rough incidence rates and annual percent changes were estimated for each age group at diagnosis, ethnicities, gender, residences, the disease stages and anatomic subsites (total N 1128) via regression analysis. Results Within 2009-2018 colorectal cancer rates increased from 14.74 to 23.19, with annual percent changes of 4.69%. The most significant growth was traced in men compared to women, up to 28.39 by 2018, with annual percent changes 6.64% vs. 2.64% (p = 0.0009). Annual percent changes in Kazakhs reached 8.7%, whereas Slavic groups showed decline in the incidence, annual percent changes −4.3% (p = 0.002). Declining in rates was also observed in urban population compared to rural one, annual percent changes −3.3% vs. 17.6%, respectively. Patients aged 60-69 made 31% of all cases and showed the largest annual percent changes 9.37% (p = 0.002). Patients at Stage II made 61% of all observations, but general trend evidenced sharp growth in the group of Stage I (annual percent changes 28.91%, p < 0.0001). Conclusion Overall, during the last decade colorectal cancer incidence increased 1.5 fold with expected further rise. However, the increment of Stage I portion by 2018 vs. advanced stages at diagnosis and the trend to decrease in rates among urban population inspire a definite assurance in potential efficiency of the screening program in long run. The next researches on colorectal cancer should include scenarios to reveal the role of disadvantaged environment in the region and consuming unhealthy ultra-processed food.
Resumo Introdução O objetivo do estudo é delinear o vetor da incidência do câncer colorretal na província industrial de Aktobe, no oeste do Cazaquistão, durante a primeira década da implementação do rastreamento, 2009‒2018. Métodos Taxas de incidência brutas e alterações percentuais anuais foram estimadas para cada faixa etária ao diagnóstico, etnias, sexo, residências, estágios da doença e localizações anatômicas (N total de 1.128) através da análise de regressão. Resultados Entre 2009‒2018, as taxas de câncer colorretal aumentaram de 14,74 para 23,19, com alteração percentual anual de 4,69%. O crescimento mais significativo foi evidenciado em homens em comparação com as mulheres, até 28,39 em 2018, com alterações percentuais anuais de 6,64% contra 2,64% (p = 0,0009). Alterações percentuais anuais nos cazaques atingiu 8,7%, enquanto os grupos eslavos mostraram declínio na incidência, alterações percentuais anuais -4,3% (p = 0.002). O declínio nas taxas também foi observado na população urbana em comparação com a rural, alterações percentuais anuais -3,3% vs. 17,6%, respectivamente. Pacientes com idade entre 60‒69 anos eram 31% de todos os casos e apresentaram as maiores alterações percentuais anuais 9,37% (p = 0,002). Os pacientes no Estágio II eram 61% de todas as observações, mas a tendência geral evidenciou crescimento acentuado no grupo do Estágio I (alterações percentuais anuais 28.91%; p < 0,0001). Conclusão No geral, durante a última década, a incidência de câncer colorretal aumentou 1,5 vezes com expectativa de maior aumento. No entanto, o incremento da porção do Estágio I em 2018 em comparação com os estágios avançados no momento do diagnóstico e a tendência de diminuição nas taxas entre a população urbana inspira uma garantia definitiva de eficiência potencial do programa de rastreamento em longo prazo. As próximas pesquisas sobre o câncer colorretal devem incluir cenários para revelar o papel do ambiente desfavorecido na região e o consumo de alimentos ultraprocessados não saudáveis.
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adulto Joven , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/epidemiología , Incidencia , Estudios RetrospectivosRESUMEN
Hyaluronan is a glycosaminoglycan normally present in the extracellular matrix in most tissues. Hyaluronan is a crucial player in many processes associated with cancer, such as angiogenesis, invasion, and metastasis. However, little has been reported regarding the action of hyaluronan on monocytes/macrophages (Mo/MØ) in tumor angiogenesis and its consequences on tumor development. In the present study, we investigated the effects of hyaluronan of different sizes on human Mo/MØ angiogenic behavior in colorectal and breast carcinoma. In vitro, the treatment of Mo/MØ with lysates and conditioned media from a breast but not from colorectal carcinoma cell line plus high-molecular weight hyaluronan induced: (a) an increased expression of angiogenic factors VEGF, IL-8, FGF-2, and MMP-2, (b) an increased endothelial cell migration, and (c) a differential expression of hyaluronan-binding protein TSG-6. Similar results were observed in Mo/MØ derived from breast cancer patients treated with tumor lysates. Besides, macrophages primed with high-molecular weight hyaluronan and inoculated in human breast cancer xenograft tumor increased blood vessel formation and diminished TSG-6 levels. In contrast, the effects triggered by high-molecular weight hyaluronan on Mo/MØ in breast cancer context were not observed in the context of colorectal carcinoma. Taken together, these results indicate that the effect of high-molecular weight hyaluronan as an inductor of the angiogenic behavior of macrophages in breast tumor context is in part consequence of the presence of TSG-6.
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Neoplasias de la Mama/metabolismo , Carcinoma/metabolismo , Moléculas de Adhesión Celular/genética , Neoplasias Colorrectales/metabolismo , Ácido Hialurónico/farmacología , Células Precursoras de Monocitos y Macrófagos/efectos de los fármacos , Neovascularización Patológica/metabolismo , Animales , Neoplasias de la Mama/patología , Carcinoma/patología , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Medios de Cultivo Condicionados/farmacología , Femenino , Factor 2 de Crecimiento de Fibroblastos/genética , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Células Precursoras de Monocitos y Macrófagos/citología , Células Precursoras de Monocitos y Macrófagos/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
ABSTRACT Introduction: Colorectal carcinoma is commonest cancer of gastrointestinal tract. It is represent third cancer in man worldwide beyond lung and prostate cancers. It is fourth cancer in woman beyond breast, lung and uterus cancers. Deaths from colorectal cancer are more in compare with other GIT cancers. Objective: The aim is prove epidemiological and clinical data of colorectal cancer. Method: Our study conducted in Misan Province, Iraq. The data collected from 2013 to 2016. Seventy one patients that found have colorectal cancer. Gender, age, residency, site of cancer, family history, past history, year of onset, smoking history, alcohol intake, presentation, staging and histopathology pattern are get. Results: Prevalence of colon and rectum carcinoma is 3.75%. The most age group affected was 51-60 years as 30.99%. The gender and residency of patients have no effect on cancer percent. Obesity, Family history, cigarette smoking and alcohol consumption risk factors. In 42.25% of patients had family history of cancer. Conclusion: Most common site of colorectal carcinoma left colon, which present in 61.97%. There is increase in new cases detection of colorectal carcinoma from 2013 to 2016. Advanced stages cancer were most common stages description as IIIA, IIIB, IIIC and IV in 12.67%, 16.90%, 19.72% and 15.49%. The common histopathological pattern is differentiated adenocarcinoma as 53.52%.
RESUMO Introdução: O carcinoma colorretal é o câncer mais comum do trato gastrointestinal. É o terceiro tipo de câncer mais observado no sexo masculino mundialmente, atrás dos cânceres de pulmão e próstata. É o quarto câncer mais observado no sexo feminino, atrás dos cânceres de mama, pulmão e útero. As mortes por câncer colorretal são mais comuns comparadas a outros cânceres do TGI. Objetivo: O objetivo do estudo é comprovar dados epidemiológicos e clínicos do câncer colorretal. Métodos: Nosso estudo foi conduzido na província de Misan, no Iraque. Os dados foram coletados de 2013 a 2016. Setenta e um pacientes apresentaram câncer colorretal. Sexo, idade, local de residência, local do câncer, história familiar, história pregressa, ano de início, história de tabagismo, etilismo, apresentação, estadiamento e padrão histopatológico foram obtidos. Resultados: A prevalência de carcinoma de cólon e reto é de 3,75%. A faixa etária mais afetada foi de 51 a 60 anos, com 30,99%. O gênero e o local de residência dos pacientes não afetam a porcentagem de ocorrência do câncer. Obesidade, antecedentes familiares, tabagismo e consumo de álcool são fatores de risco. 42,25% dos pacientes tinha história familiar de câncer. Conclusão: O local mais comum de carcinoma colorretal é o cólon esquerdo, com 61,97%. Houve aumento na detecção de novos casos de carcinoma colorretal de 2013 a 2016. Os estágios avançados de câncer mais comuns foram IIIA, IIIB, IIIC e IV em 12,67%, 16,90%, 19,72% e 15,49% dos casos. O padrão histopatológico comum é o adenocarcinoma diferenciado, em 53,52% dos casos.
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Humanos , Neoplasias Colorrectales/epidemiología , Enfermedades del Colon , Factores de Riesgo , IrakRESUMEN
For most cancers, the treatment of choice is still chemotherapy despite its severe adverse effects, systemic toxicity and limited efficacy due to the development of multidrug resistance (MDR). MDR leads to chemotherapy failure generally associated with a decrease in drug concentration inside cancer cells, frequently due to the overexpression of ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2), which limits the efficacy of chemotherapeutic drugs. The aim of this review is to compile information about transcriptional and post-transcriptional regulation of ABC transporters and discuss their role in mediating MDR in cancer cells. This review also focuses on drug resistance by ABC efflux transporters in cancer cells, particularly hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) cells. Some aspects of the chemotherapy failure and future directions to overcome this problem are also discussed.
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Transportadoras de Casetes de Unión a ATP/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Colorrectales/metabolismo , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Hepáticas/metabolismo , Humanos , Proteína 2 Asociada a Resistencia a Múltiples MedicamentosRESUMEN
Resumen Introducción: la hepatitis autoinmune idiopática (HAI) es una enfermedad crónica que predomina en mujeres, con episodios de actividad y remisión, favoreciendo la fibrosis hepática. El 40% de los pacientes presenta historia familiar de enfermedades autoinmunes. Al parecer, es mediada por la interacción antígeno-anticuerpo; sin embargo, su causa es desconocida. Se conoce la asociación frecuente de HAI con cáncer hepatobiliar; menos frecuente con linfomas, cáncer de piel y cáncer de colon; y casi inexistente con síndromes hereditarios de cáncer de colon. Este caso debutó con HAI y sangrado rectal causado por poliposis adenomatosa familiar (PAF) y adenocarcinoma de colon sigmoide. Caso clínico: mujer de 51 años con HAI de 1 año de evolución manejada con prednisolona y azatioprina. Se realizó una colonoscopia total por anemia en la que se encontraron múltiples pólipos entre 5 y 10 mm y 1 de 30 mm sésil, ulcerado, en colon sigmoide. Se realizó una polipectomía endoscópica múltiple que reportó un adenoma tubulovelloso con displasia de alto y bajo grado en varios pólipos y un adenocarcinoma de bajo grado en el pólipo del sigmoide. Los estudios de extensión fueron negativos para metástasis. Se realizó una repleción nutricional prequirúrgica, luego una colectomía subtotal y una procto-ileoanastomosis con ileostomía de protección. La patología de pieza quirúrgica mostró un adenocarcinoma de colon de bajo grado y adenomas tubulares y tubulovellosos con displasias de alto y bajo grado. Discusión y conclusiones: La asociación de HAI con PAF y cáncer colorrectal (CC) es infrecuente. Es conocida la correlación de HAI con cáncer hepatobiliar (asociado con cirrosis), linfomas, cáncer de piel y otros desórdenes autoinmunes. El pronóstico es malo y no puede establecerse una correlación clara con moduladores inmunes.
Abstract Introduction: Idiopathic autoimmune hepatitis (IAH) is a chronic disease that occurs predominately in women, has episodic activity and remission, and favors hepatic fibrosis. Forty percent of patients have family histories of autoimmune diseases. It is apparently mediated by antigen-antibody interaction, but its causes are unknown. IAH is frequently associated with hepatobiliary cancer, less frequently with lymphomas, skin cancer and colon cancer and very rarely with hereditary colon cancer syndrome. This case debuted IAH and rectal bleeding caused by familial adenomatous polyposis (FAP) and adenocarcinoma of the sigmoid colon. Clinical case: The patient was a 51-year-old woman who had had IAH for one year which had been managed with prednisolone and azathioprine. A total colonoscopy, performed because of anemia, found multiple polyps that measured 5 and 10 mm and one ulcerated 30 mm sessile polyp in the sigmoid colon. A multiple endoscopic polypectomy revealed a tubulovillous adenoma with high and low grade dysplasia in several polyps and a low grade adenocarcinoma in the sigmoid polyp. Tests and examinations for metastasis were negative. Following presurgical nutritional repletion, a subtotal colectomy was performed and an ileal pouch-anal anastomosis with protective ileostomy was created. The pathology of the surgical specimen showed low grade adenocarcinoma of the colon and tubular and tubulovillous adenomas with high and low grade dysplasia. Discussion and conclusions: Association of IAH with familial adenomatous polyposis (FAP) and colorectal cancer (CC) occurs infrequently although associations of IAH with hepatobiliary cancer associated with cirrhosis, lymphomas, skin cancer and other autoimmune disorders are well-known. The prognosis is bad and no clear correlation with immune modulators can be established.
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Humanos , Femenino , Persona de Mediana Edad , Asociación , Neoplasias Colorrectales , Neoplasias del Colon , Hepatitis Autoinmune , Pacientes , LiteraturaRESUMEN
Abstract Hotspot mutations (c.-124bp G > A and c.-146bp G > A) in the promoter region of the TERT gene have been recently described in several types of solid tumors, including glioma, bladder, thyroid, liver and skin neoplasms. However, knowledge with respect to colorectal precursor lesions and cancer is scarce. In the present study we aimed to determine the frequency of hotspot TERT promoter mutations in 145 Brazilian patients, including 103 subjects with precursor lesions and 42 with colorectal carcinomas, and we associated the presence of such mutations with the patients clinical-pathological features. The mutation analysis was conclusive in 123 cases, and none of the precursor and colorectal carcinoma cases showed TERT promoter mutations. We conclude that TERT mutations are not a driving factor in colorectal carcinogenesis.
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PURPOSE: Presence of cancer stem cells (CSCs) contributes to tumor outgrowth, chemo-resistance and relapse in some cancers including colorectal carcinoma (CRC). The current characterization methods of CSCs in CRC only allows enrichment of CSCs but not their purification. Recent reports showed that ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6Gal-I) plays an essential role in protecting tumor cells against harsh environment like oxidative stress and nutrient deprivation. Therefore, whether ST6Gal-I may be highly expressed in CSCs or whether it may enhance resistance of tumor cells to chemotherapy deserves exploration. METHOD: ST6Gal-I levels were determined in CRC specimens, compared to paired normal colorectal tissue, and examined in CD133+ vs CD133- CRC cells, and CD44+ vs CD44- CRC cells. ST6Gal-I levels and their association with patient survival were examined. In vivo, 2 CRC cell lines Caco-2 and SW48 were transduced with two lentiviruses, one lentivirus carrying a green fluorescent protein reporter and a luciferase reporter under a cytomegalovirus promoter to allow tracing tumor cells by both fluorescence and luciferase activity, and one lentivirus carrying a nuclear red fluorescent protein under the control of ST6Gal-I promoter to allow separation of ST6Gal-I+ vs ST6Gal-I- CRC cells. Tumor sphere formation, resistance to fluorouracil-induced apoptosis, and frequency of tumor formation after serial adoptive transplantation were done on ST6Gal-I+ vs ST6Gal-I- CRC cells. RESULT: ST6Gal-I levels were significantly upregulated in clinically obtained CRC specimens, compared to paired normal colorectal tissue. Poorer patient survival was detected in ST6Gal-I-high CRC, compared to ST6Gal-I-low subjects. Higher levels of ST6Gal-I were detected in CD133+ CRC cells than CD133- CRC cells, and in CD44+ CRC cells than in CD44- CRC cells. Compared to ST6Gal-I- CRC cells, ST6Gal-I+ CRC cells generated significantly more tumor spheres in culture, were more resistant to fluorouracil-induced apoptosis likely through upregulating cell autophagy, and generated tumor more frequently after serial adoptive transplantation. CONCLUSION: ST6Gal-I may be highly expressed in the cancer stem-like cells in CRC and enhances cancer cell resistance to chemotherapy.
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Neoplasias Colorrectales/tratamiento farmacológico , Células Madre Neoplásicas/enzimología , Sialiltransferasas/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos , Humanos , beta-D-Galactósido alfa 2-6-SialiltransferasaRESUMEN
Introducción: El riesgo de desarrollar neoplasias colónicas en pacientes acromegálicos y su relación directa con los niveles elevados de GH/IGF-1 no están bien establecidos y continúan siendo motivo de controversia en la literatura mundial. El objetivo de este trabajo fue evaluar el riesgo de desarrollar lesiones neoplásicas avanzadas (LNA) (adenomas mayores a 1 cm, componente velloso mayor del 75% y/o displasia de alto grado), en pacientes con acromegalia, comparado con un grupo control. Materiales y métodos: Estudio multicéntrico caso-control retrospectivo. Ciento treinta y siete pacientes con acromegalia que realizaron videocolonoscopia (VCC) fueron incluidos inicialmente, aunque solo 69 cumplieron criterios de inclusión. Sesenta y dos controles fueron obtenidos: por cada caso (paciente con acromegalia) 2 «controles¼ fueron seleccionados aleatorizadamente e igualados por edad y sexo. El riesgo se expresó en odds ratio (OR) y su correspondiente intervalo de confianza (IC) del 95%. La significación estadística fue considerada una p < 0,05. Resultados: De los 69 pacientes con VCC completa y datos adecuados para su análisis, 28 presentaron VCC positiva con hallazgos de pólipos (40%) y 41 VCC negativa o normal (60%). Dentro del grupo con VCC positiva, 14 presentaron LNA (20%) y solo un paciente presentó diagnóstico de cáncer colorrectal. Para el análisis caso-control se incluyó a 31 pacientes frente al grupo control (n = 62) que cumplieron con los criterios de inclusión. La presencia de pólipos colónicos, adenomas y LNA en los pacientes con acromegalia fue de 19/31 (61,9%), 14/31 (45,16%) y 10/31 (32,25%), y en el grupo control de 18/62 (29,03%), 11/62 (17,74%) y 4/62 (6,45%), respectivamente. El riesgo de adenomas y LNA fue mayor en el grupo de acromegalia en comparación con el grupo control, siendo ambos resultados estadísticamente significativos: adenomas OR 2,54 (IC 1,22-5,25) p = 0,005, LNA OR: 7,3 (2,4-25), p = 0,00. Conclusión: La acromegalia se asocia a un mayor riesgo de lesiones colónicas preneoplásicas. Este hallazgo justifica el cribado con VCC al diagnóstico en pacientes con acromegalia.
Background: The risk of developing cancerous lesions in the colon of acromegaly patients and their direct relationship with elevated growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels is not well established, and is still controversial in the international literature. The objective of this study was to evaluate the risk of developing advanced neoplastic lesions (ALN: greater than 1 cm adenomas, villous component greater than 75% and/or high grade dysplasia) in patients with acromegaly compared to a control group. Materials and methods: A multicentre, retrospective case-control study was conducted initially on 137 patients with acromegaly (cases) who underwent videocolonoscopy (VCC), although only 69 met inclusion criteria. Sixty-two controls were obtained, and for each case two "controls" were randomly selected and matched by age and gender. Risk was expressed as odds ratio (OR) and its corresponding 95% con"dence interval (CI). P values < .05 were considered statistical significantly. Results: Of the 69 acromegaly patients with a completed VCC and adequate data for their analysis, 28 had a positive VCC with findings of polyps (40%), and 41 VCC negative with no lesions (60%). Within the group with positive VCC, 14 were ALN (20%) and one a colorectal cancer. In the case-control analysis, 31 cases were to be analysed against the control group (n = 62). The presence of colonic polyps, adenomas, and ALN in patients with acromegaly was 19/31 (61.9%), 14/31 (45.16%), and 10/31 (32.25%), respectively, and in the control group, it was 18/62 (29.03%), 11/62 (17.74%), and 4/62 (6.45%), respectively. The risk of adenomas and ALN was higher in the acromegaly group compared to the control group: adenomas OR: 2.54 (95% CI 1.22-5.25) P=.005, ALN OR: 7.3 (2.4-25) P=.00. Conclusion: This preliminary case control study showed an increased risk of pre-cancerous colprectal lesions in patients with acromegaly, supporting the VCC screening at diagnosis.
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Lesiones Precancerosas/complicaciones , Acromegalia/complicaciones , Lesiones Precancerosas/diagnóstico , Neoplasias Colorrectales/prevención & control , Factores de Riesgo , Colonoscopía , Ajuste de RiesgoRESUMEN
Gastrointestinal cancer is a group of tumors that affect multiple sites of the digestive system, including the stomach, liver, colon and pancreas. These cancers are very aggressive and rapidly metastasize, thus identifying effective targets is crucial for treatment. Galectin-1 (Gal-1) belongs to a family of glycan-binding proteins, or lectins, with the ability to cross-link specific glycoconjugates. A variety of biological activities have been attributed to Gal-1 at different steps of tumor progression. Herein, we summarize the current literature regarding the roles of Gal-1 in gastrointestinal malignancies. Accumulating evidence shows that Gal-1 is drastically up-regulated in human gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic ductal adenocarcinoma tissues, both in tumor epithelial and tumor-associated stromal cells. Moreover, Gal-1 makes a crucial contribution to the pathogenesis of gastrointestinal malignancies, favoring tumor development, aggressiveness, metastasis, immunosuppression and angiogenesis. We also highlight that alterations in Gal-1-specific glycoepitopes may be relevant for gastrointestinal cancer progression. Despite the findings obtained so far, further functional studies are still required. Elucidating the precise molecular mechanisms modulated by Gal-1 underlying gastrointestinal tumor progression, might lead to the development of novel Gal-1-based diagnostic methods and/or therapies.
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Galectina 1/metabolismo , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Regulación Neoplásica de la Expresión Génica , Neovascularización Patológica/patología , Transducción de Señal , Adhesión Celular , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Galectina 1/genética , Neoplasias Gastrointestinales/tratamiento farmacológico , Glicosilación , Humanos , Tolerancia Inmunológica , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Neovascularización Patológica/genética , Regulación hacia ArribaRESUMEN
BACKGROUND: Treatment of metastatic colorectal adenocarcinoma (mCRC) has evolved, and survival is over 30 months in contemporary trials. Nevertheless, there is a paucity of effective regimes after the first or second-line treatment. Thus, reexposure to previously used drugs has become a treatment strategy for some patients. We aimed to evaluate the efficacy of retreatment with an oxaliplatin-containing regimen in mCRC and correlate this with clinicopathologic features. PATIENTS AND METHODS: We retrospectively analyzed 83 patients with mCRC who underwent reexposure to oxaliplatin (REOX). REOX was defined as a second trial of an oxaliplatin-containing regimen after a previous failure. Primary endpoint was time to treatment failure (TTF). RESULTS: The median age was 53.5 years, and the female/male ratio was 51.8%/48.2%. The site of the primary tumor was colon (67.5%) and rectal (32.5%). KRAS was mutated in 39.8%. Liver-limited metastasis was found in 19.3% of patients. The main regimen was 5-fluorouracil, levoleucovorin, and oxaliplatin (mFOLFOX6) (84.3%). Bevacizumab and cetuximab were used in 42.2% and 6% of patients, respectively. REOX was used in the third and fourth lines in 48.2% and 25.3% of patients, respectively. The median TTF after REOX was 6.04 months. Overall survival (OS) was 10.04 months. Disease control (complete response + partial response + stable disease) was observed in 56.6%, whereas 42.2% had progressive disease. Partial response + complete response to previous oxaliplatin was predictive of prolonged OS. Patients who attained disease control had better median OS compared with those with progressive disease (14.5 vs. 6.24 months; P < .0001). CONCLUSION: In the setting of heavily pretreated patients with mCRC, REOX was an effective treatment, with mTTF of 6.04 months in our cohort. Selection of patients with the longest time since previous oxaliplatin can translate in better outcome. Further studies should be conducted to confirm our data.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Mutación , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Selección de Paciente , Proteínas Proto-Oncogénicas p21(ras)/genética , Retratamiento , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Molecular pathology is playing an increasingly important role in the treatment and overall management of patients with colorectal carcinoma. Three distinct genetic pathways have been identified that play a role in carcinogenesis: the chromosomal instability pathway, the microsatellite instability pathway, and the CpG island methylator phenotype pathway. Certain genetic mutations, some of which overlap with the aforementioned pathways, can also indicate that a carcinoma patient has a genetic predisposition syndrome, such as familial adenomatous polyposis, Lynch syndrome, and hamartomatous polyposis syndromes. A variety of advanced methods, including next-generation sequencing, are available to test for these and other mutations, such as targetable mutations that may allow tailoring of a treatment regimen to a patient's specific cancer (e.g., KRAS and BRAF mutations). The possible future role of testing circulating tumor cells is also addressed. New mutations and syndromes continue to be discovered, ensuring that our knowledge of colorectal carcinoma and our ability to treat it will advance in the future (AU)
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Síndromes Neoplásicos Hereditarios , Neoplasias Colorrectales/genética , Inestabilidad Cromosómica , Patología Molecular , CarcinogénesisRESUMEN
Reduced CDX2 and cytokeratin 20 (CK20) expression in colorectal carcinoma with BRAF mutation and high-level microsatellite instability (MSI-H) has been well documented. The immunophenotype of BRAF-mutated microsatellite stable (MSS) colorectal carcinoma has not been reported. We analyzed 205 colorectal carcinomas including 28 BRAF-mutated MSS, 53 BRAF-mutated MSI-H, and 124 BRAF wild-type MSS tumors for CDX2, cytokeratin 7 (CK7), and CK20 immunohistochemical expression. CDX2 was scored semiquantitatively for both staining intensity and percent of tumor cells staining and a modified CDX2 H-score was calculated. Patients with BRAF-mutated MSS colorectal carcinomas were more frequently stage IV at presentation compared to patients with BRAF-mutated MSI-H colorectal carcinomas and BRAF wild-type MSS colorectal carcinomas (32% versus 8% versus 15%, P < .001). BRAF-mutated MSS colorectal carcinoma displayed reduced CDX2 expression compared to BRAF wild-type MSS colorectal carcinoma (75% versus 94%; mean CDX2 H-score 98 versus 150, P < .001). CK7 expression was more often identified in BRAF-mutated MSS colorectal carcinoma compared to both BRAF-mutated MSI-H colorectal carcinoma and BRAF wild-type MSS colorectal carcinoma (39% versus 6% versus 6%, P = .0001). BRAF-mutated MSI-H colorectal carcinomas were less often CK20 positive compared to BRAF-mutated MSS and BRAF wild-type MSS tumors (70% versus 93% versus 90%, P = 0.001). In summary, BRAF-mutated MSS colorectal carcinoma often displays reduced CDX2 and increased CK7 expression. Knowledge of this altered immunophenotype is important as patients with BRAF-mutated MSS colorectal carcinoma often present with metastatic disease and the altered tumor immunophenotype may lead to the erroneous assumption that origin from the colon/rectum is unlikely.