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1.
Medicine (Baltimore) ; 99(35): e21895, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871920

RESUMO

MicroRNAs (miRNAs) refers to a small, short non-coding RNA of endogenous class. They have shown to have an increasingly altered expression in many types of cancer, including colorectal cancer (CRC).In the present study, miRNA TaqManMGB and qRT-PCR was used to quantify the expression and clinical significance of 3 mature human miRNA in 82 pairs of colorectal adenocarcinoma tissues and normal adjacent tissue samples (NATS) collected from patients of the south-east part of Romania. Differences between CRC and NATS were analyzed using Wilcoxon test, while correlations between miRNAs expression levels and clinicopathological features were examined using non-parametric tests. In addition, the ability of selected miRNAs to function as biomarkers and, as potential indicators in CRC prognosis was also examined.When the miRNA expression was compared in CRC related NATS, miR-143, and miR-145 were significantly underexpressed (4.99 ±â€Š-1.02 vs -5.66 ±â€Š-1.66, P < .001; -4.85 ±â€Š-0.59 vs -9.27 ±â€Š-1.51, P < .001, respectively), while the pattern of miR-92a was significantly overexpressed (-5.55 ±â€Š-2.83 vs -4.92 ±â€Š-2.44, P < .001). Moreover, the expression levels of selected miRNAs were identified to be correlated with gradual increases in fold change expression with the depth of tumor invasion, lymph node invasion, and maximal increases with distant metastasis. Furthermore, the receiver operating characteristic analysis demonstrated that potential diagnostic of miR-143, miR-145, and miR-92a in discriminating CRC from NATS, with the area under the curve of 0.74, 0.85, and 0.84 respectively. The Kaplan-Meier and the log-rank test showed that a high level of miR-92a and low levels of miR-143 and miR-145 predicted poor survival rate in our cohorts.In conclusion, we can summarize that miR-145 and miR-143 are decreased, while miR-92 is increased in CRC compared to NATS, and associated with different stages of CRC pathogenesis. Thus, the expression of selected miRNAs can represent potential diagnostic and prognostic tools in patients with CRC from Romania.


Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , MicroRNAs/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Área Sob a Curva , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Romênia , Transcriptoma
2.
Anticancer Res ; 40(10): 5371-5378, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988856

RESUMO

BACKGROUND/AIM: 18 kDa Translocator protein (TSPO) is a mitochondrial protein up-regulated in colorectal carcinoma (CRC). Our purpose was to develop a TSPO-targeted doxorubicin prodrug (Dox-TSPO) which can be loaded onto drug-eluting beads for transarterial chemoembolization. Furthermore, we evaluated its loading and release kinetics and effects on cell viability. MATERIALS AND METHODS: N-Fmoc-DOX-14-O-hemiglutarate was coupled with a TSPO ligand, 6-TSPOmbb732, using classical N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate coupling to produce Dox-TSPO. Loading and elution studies were performed using DC beads™. Cell viability studies were performed using CellTiter-Glo® Luminescent Cell Viability Assay. RESULTS: Dox-TSPO was successfully synthesized and readily loaded onto and eluted from DC beads™, albeit at a slower rate than free doxorubicin. CRC cell lines expressing TSPO were 2- to 4- fold more sensitive to Dox-TSPO compared to free doxorubicin at 72 h. CONCLUSION: Dox-TSPO is a promising candidate for targeted and directed cancer treatment of CRC liver metastases.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/farmacologia , Pró-Fármacos/farmacologia , Receptores de GABA/genética , Proteínas de Transporte/química , Proteínas de Transporte/farmacologia , Linhagem Celular Tumoral , Quimioembolização Terapêutica/métodos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Humanos , Pró-Fármacos/química , Receptores de GABA/química
3.
Anticancer Res ; 40(10): 5411-5416, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988861

RESUMO

BACKGROUND: Patients with inflammatory bowel disease have markedly increased risk for developing colitis-associated colorectal adenocarcinoma (CAC). There is no established prognostic biomarker for CAC. MATERIALS AND METHODS: A retrospective study was performed on a cohort of 57 CACs. Expression of caudal type homeobox transcription factor 2 (CDX2) and YES-associated protein 1 (YAP1) expression was correlated with clinicodemographic and histopathological features. RESULTS: Neither YAP1 nor CDX2 expression alone was significantly associated with tumor invasion beyond the muscularis propria or lymph node status. However, a subgroup of CAC with double negativity for expression of YAP1 and CDX2 was more frequently found in younger patients, and more frequently associated with higher pathological tumor stage and nodal metastasis. Furthermore, a positive correlation between CDX2 and YAP1 expression was identified in CAC and sporadic colorectal adenocarcinoma. CONCLUSION: Our study demonstrates that double negativity for expression of YAP1 and CDX2 defines a subgroup of CAC with early onset and aggressive clinical features.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Fator de Transcrição CDX2/genética , Colite/genética , Neoplasias Colorretais/genética , Fatores de Transcrição/genética , Adenocarcinoma/complicações , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Biomarcadores Tumorais/genética , Colite/complicações , Colite/patologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
4.
Anticancer Res ; 40(10): 5457-5462, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988867

RESUMO

BACKGROUND/AIM: Several studies have found elevated soluble CD40 Ligand (sCD40L) in the serum of patients with malignancies as well as those with inflammatory bowel disease (IBD). Our goal was to determine the possible causal role of sCD40L in colitis-associated colorectal cancer (CAC) by using the well-established azoxymethane/dextran sulfate sodium (AOM/DSS) protocol. MATERIALS AND METHODS: Twelve wild type (WT) and twelve TLR4 knock out (KO) female C57BL6 mice were divided into 4 experimental groups. Six WT and six TLR4 KO mice were treated with a single intraperitoneal dose (10 mg/kg of body weight) of AOM followed by three 7-day cycles of oral 2.5% DSS. The other two groups included 6 WT and 6 TLR4 KO mice that received only water and served as the control groups. The mice were sacrificed after 84 days. RESULTS: All mice in the AOM/DSS WT group developed CAC while all mice from the AOM/DSS TLR4 KO group were protected from CAC. We measured the serum and pathologic tissue levels of sCD40L with quantitative sandwich enzyme-linked immunoassay (ELISA) and found that serum sCD40L was significantly higher in wild-type mice that developed CAC compared to their healthy counterparts (wild-type and TLR-4 KO controls). In comparison, serum sCD40L levels were comparable between TLR-4 KO mice, which are protected from developing CAC, and their healthy counterparts (wild-type and TLR-4 KO controls). Of note, tissue levels of sCD40L were not affected by the development of CAC. CONCLUSION: Our findings point to the presence of an axis between TLR-4 and sCD40L, which may lead to decreased immunosurveillance and the subsequent development of colitis-associated cancer.


Assuntos
Ligante de CD40/genética , Colite/imunologia , Neoplasias Colorretais/induzido quimicamente , Receptor 4 Toll-Like/genética , Animais , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Imunidade Inata/genética , Camundongos , Camundongos Knockout
5.
Medicine (Baltimore) ; 99(36): e22060, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899071

RESUMO

The phase III West Japan Oncology Group (WJOG) 4407G study showed noninferiority of folinic acid, bolus/continuous fluorouracil, and irinotecan plus bevacizumab to modified folinic acid, bolus/continuous fluorouracil, and oxaliplatin 6 plus bevacizumab in progression-free survival (PFS) as first-line chemotherapy for patients with metastatic colorectal cancer. The aim of this study was to evaluate the predictive and prognostic value of morphologic response in patients with colorectal liver metastases (CLM) as a post hoc analysis of the WJOG4407G study.Morphologic response was assessed by comparing contrast-enhanced computed tomography (CT) images at baseline and week 8. Three blinded radiologists evaluated CT images and classified their response as optimal, incomplete, or no response according to the morphologic criteria. Response evaluation criteria in solid tumors (RECIST) response, early tumor shrinkage (ETS), and depth of response (DpR) were also evaluated.Among 395 patients who were eligible for efficacy analysis in the WJOG4407G study, 70 patients had liver-limited disease. We finally evaluated 55 of these patients. Optimal morphologic response was identified in 19 of 55 patients (34.5%). The median PFS was 10.7 months for patients with optimal response and 10.1 months in those with incomplete/no response (log-rank, P = .96). The median overall survival (OS) was 26.2 and 35.5 months, respectively (log-rank, P = .062). According to univariate analysis, morphologic response was not associated with PFS or OS, whereas RECIST response was significantly associated with both PFS and OS, with ETS and DpR being associated with significantly longer PFS.Morphologic response might be neither a predictive nor a prognostic factor in patients with CLM undergoing chemotherapy containing bevacizumab, whereas RECIST response was significantly associated with both PFS and OS.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Adulto , Idoso , Antimetabólitos Antineoplásicos , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Feminino , Fluoruracila/uso terapêutico , Humanos , Infusões Intravenosas/métodos , Irinotecano/uso terapêutico , Japão/epidemiologia , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Oxaliplatina/uso terapêutico , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos , Tomografia Computadorizada por Raios X/métodos , Inibidores da Topoisomerase I/uso terapêutico , Resultado do Tratamento , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/uso terapêutico
6.
Anticancer Res ; 40(9): 5301-5307, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878821

RESUMO

BACKGROUND/AIM: The aim of this single center, non-randomized, open-label, uncontrolled, interventional trial was to determine the feasibility of continuous administration of low-dose human atrial natriuretic peptide (hANP) perioperatively during curative operation for colorectal cancer patients without history of acute heart failure. PATIENTS AND METHODS: The study included three males and two females ranging from 27 to 70 years old. Continuous intravenous injection of hANP solution was started before surgery. The primary endpoint was safety of hANP administration, and the secondary endpoints were perioperative changes in ANP, b-type natriuretic peptide, electrocardiogram (ECG), and lung function. RESULTS: The American Society of Anaesthesiologists physical status was 1, 2, and 3 in three, one, and one patient, respectively. Grade 2 hypotension was observed in one case. No marked changes were observed between pre- and post-operation in all cases. CONCLUSION: Perioperative low-dose hANP administration is feasible and safe in patients with curative colorectal cancer.


Assuntos
Fator Natriurético Atrial/administração & dosagem , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Insuficiência Cardíaca/prevenção & controle , Assistência Perioperatória , Complicações Pós-Operatórias/prevenção & controle , Adulto , Idoso , Biomarcadores , Neoplasias Colorretais/cirurgia , Eletrocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Avaliação de Sintomas , Resultado do Tratamento
7.
J Med Imaging Radiat Oncol ; 64(5): 671-673, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32945110

RESUMO

We report the case of who has been hospitalized complaining about fever in the last 4 days. Laboratory data revealed lymphocytopenia and leucopenia with an elevation of C-reactive protein and positive real-time reverse transcription-polymerase chain reaction (RT-PCR). Six days before this hospitalization, when the patient was asymptomatic, 18 F-FDG PET/CT images were performed for the therapeutic control of liver metastases of colorectal cancer. Lung abnormality findings at 18 F-FDG PET/CT images, unrelated to cancer metastases, but suspicious for viral infection, may suggest the presence of COVID-19 disease in its early phase before symptoms onset. Since PET/CT is more sensitive than CT scan in detecting host's reaction, the added value of this technique could be monitoring disease progression and could be used as a biomarker of lung disease activity and therefore as an important tool for a better understanding of the factors that contribute to the progression of lung disease.


Assuntos
Infecções por Coronavirus/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Pneumopatias/virologia , Pneumonia Viral/diagnóstico por imagem , Betacoronavirus , Neoplasias Colorretais/patologia , Progressão da Doença , Fluordesoxiglucose F18 , Humanos , Achados Incidentais , Neoplasias Hepáticas/secundário , Pandemias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos
8.
Medicine (Baltimore) ; 99(39): e22357, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991451

RESUMO

BACKGROUND: The incidence and mortality of colorectal cancer are high. Chemotherapy is currently the commonly used therapeutic scheme, but there are drug resistance and toxic and side effects. Kanglaite (KLT) injection is a broad-spectrum anticancer drug extracted from Semen Coicis (Yi Yi Ren), which has been widely used in the treatment of colorectal cancer. Clinical practice shows that KLT injection combined with chemotherapy has certain therapeutic advantages, but there is a lacking of evidence of evidence-based medicine. The purpose of this study is to systematically investigate the efficacy and safety of KLT injection combined with chemotherapy in the treatment of colorectal cancer. METHODS: Randomized controlled trials of KLT injection combined with chemotherapy in the treatment of colorectal cancer were retrieved from English databases (PubMed, Embase, Web of Science, the Cochrane Library) and Chinese databases (China National Knowledge Infrastructure, Wanfang, Chongqing VIP Chinese Science and Technology Periodical Database, Chinese Biological and Medical database), as well as searching Baidu academic and Google academic manually, and the retrieval time was from their establishment to August 2020. Two researchers independently conducted data extraction and literature quality evaluation on the quality of the included literatures, and meta-analysis was conducted on the included literatures using RevMan 5.3 (developed by the UK's International Cochrane Collaboration). RESULTS: This study assessed the efficacy and safety of KLT injection combined with chemotherapy in the treatment of colorectal cancer by effective rate, Karnofsky Performance Status, Carcinoemybryonic Angtigen remission rate, pain remission rate, and incidence of adverse reactions etc. CONCLUSIONS:: This study will provide reliable evidence-based evidence for the clinical application of KLT injection combined with chemotherapy in the treatment of colorectal cancer. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/EKVAF.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dor do Câncer/tratamento farmacológico , Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/patologia , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Avaliação de Estado de Karnofsky , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
9.
N Z Med J ; 133(1520): 15-26, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32994590

RESUMO

AIMS: To explore variations in the use of and timeliness of chemotherapy in patients diagnosed with colorectal cancer in New Zealand. METHODS: This study included patients diagnosed with colorectal cancer in New Zealand between 1 January 2006 and 31 December 2016. The first chemotherapy regime was identified from Pharmaceutical Collection dataset. Logistic regression model was used to estimate the adjusted odds ratio of having chemotherapy by subgroup after adjustment for other factors. RESULTS: 27.8% (6,737/24,217) of colon cancer patients and 43.8% (3,582/8,170) of rectal cancer patients received publicly funded chemotherapy. The uptake and timeliness of chemotherapy has been improving over time. Pacific people were the least likely to receive chemotherapy, followed by Maori and Asian. Younger patients, New Zealand European, patients with metastatic disease and patients in the Southern Cancer Network were more likely to have chemotherapy in less than 10 weeks post-diagnosis. Over half of the advanced colorectal cancer patients who did not receive chemotherapy were aged 80+ years or had a short life expectancy. CONCLUSIONS: Although the uptake and timeliness of chemotherapy for colorectal cancer has been improving, Maori, Pacific, Asian and older patients were less likely to receive chemotherapy and less likely to receive chemotherapy in a timely manner. There is a variation in use of chemotherapy by Region with patients in the Southern Cancer region appearing to be the most likely to receive chemotherapy and to receive it within a timely period.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Tratamento Farmacológico/métodos , Disparidades em Assistência à Saúde/etnologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Tratamento Farmacológico/economia , Grupos Étnicos , Feminino , Disparidades em Assistência à Saúde/estatística & dados numéricos , Humanos , Expectativa de Vida/etnologia , Expectativa de Vida/tendências , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Nova Zelândia/etnologia , Fatores de Tempo
10.
J Environ Pathol Toxicol Oncol ; 39(2): 101-111, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749120

RESUMO

Long noncoding RNAs (lncRNAs) have been reported to be involved in cancer initiation and evolution, including colorectal cancer (CRC). Nuclear-enriched abundant transcript 1 (NEAT1) exerts important functions in multiple cancers; however, the specific modulatory mechanism in CRC demands in-depth exploration. The expression levels of NEAT1, microRNA-195-5p (miR-195-5p), and centrosomal protein 55 (CEP55) were examined using quantitative real-time polymerase chain reaction (qRT-PCR), and protein expression of CEP55 was detected by Western blot assay. Cell proliferation and apoptosis were measured by 3-(4,5-dimethylthiazole-2-y1)-2,5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry. Transwell migration and invasion assays were applied to evaluate cell metastasis ability. Dual-luciferase reporter assay was used to analyze the correlation among NEAT1, miR-195-5p and CEP55. The expression of NEAT1 was up-regulated in CRC tissues and cells, and overall survival was lower with high expression of NEAT1. Knockdown of NEAT1 repressed cell proliferation, migration, and invasion, while inducing apoptosis in CRC cells. NEAT1 targeted miR-195-5p and inhibited the expression of miR-195-5p. Silence of NEAT1 inhibited CRC cell proliferation, migration, and invasion, and promoted apoptosis by up-regulating miR-195-5p. MiR-195-5p targeted and suppressed CEP55 expression, and CEP55 reverted the effects induced by miR-195-5p. NEAT1 regulated the expression of CEP55 through miR-195-5p. NEAT1 promotes colorectal cancer cellular processes by regulating CEP55 expression via the sponging of miR-195-5p. Therefore, NEAT1 might play a crucial role in CRC treatments.


Assuntos
Neoplasias Colorretais/genética , RNA Longo não Codificante/genética , Apoptose/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Mucosa Gástrica/citologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HCT116 , Humanos , Estimativa de Kaplan-Meier , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo
12.
Medicine (Baltimore) ; 99(30): e21368, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791745

RESUMO

Pulmonary metastasectomy is considered to be a feasible method for selected colorectal cancer (CRC) patients. This study aimed to optimize the individualized surgical strategy of pulmonary metastasectomy, especially in choice of surgery extent and systematic mediastinal lymph nodes dissection.Data of 267 CRC patients who underwent pulmonary metastasectomy from July 2011 to July 2017 in Shanghai Cancer Center Fudan University were reviewed. Recurrence-free survival (RFS), overall survival (OS) and other clinical characteristics were compared between patients who accepted different surgical strategy.A total of 93 (34.8%) patients underwent lobectomy, 162 (60.7%) wedge resection, and 12 (4.5%) segmentectomy. Mediastinal lymph nodes dissection or sampling was performed in 106 (39.7%) patients. The median follow-up phase was 32.5 months (range 7.2-104.7 months). Patients were divided into 2 groups according to the surgical extent, lobectomy group and sublobar resection group. The median RFS and OS were 46.4 and 76.5 months for patients underwent, respectively. In the patients whose tumor diameter was ≥ 1.5 cm, RFS (5-year; 44.9% vs 29.8%, log-rank P = .03; hazard ratio, 0.71; 95% CI 0.52-0.89, P = .026) was better in the lobectomy group; however, no difference was found in OS. Meanwhile, in the patients whose tumor size was <1.5 cm, no difference was observed in RFS, as well as in OS. In the patients with metastatic lesion size ≥1.5 cm, a trend towards better RFS was found in patients received lymph nodes dissection, but it did not reach statistical significance.Lobectomy has more curative significance for CRC patients with single pulmonary metastatic lesion ≥1.5 cm. Systematic mediastinal lymph nodes dissection did not improve clinical outcome for CRC patients occurred pulmonary metastasis.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Pulmonares/cirurgia , Pulmão/cirurgia , Pneumonectomia/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Pulmão/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
PLoS Genet ; 16(8): e1008947, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32833970

RESUMO

Genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with various phenotypes, but together they explain only a fraction of heritability, suggesting many variants have yet to be discovered. Recently it has been recognized that incorporating functional information of genetic variants can improve power for identifying novel loci. For example, S-PrediXcan and TWAS tested the association of predicted gene expression with phenotypes based on GWAS summary statistics by leveraging the information on genetic regulation of gene expression and found many novel loci. However, as genetic variants may have effects on more than one gene and through different mechanisms, these methods likely only capture part of the total effects of these variants. In this paper, we propose a summary statistics-based mixed effects score test (sMiST) that tests for the total effect of both the effect of the mediator by imputing genetically predicted gene expression, like S-PrediXcan and TWAS, and the direct effects of individual variants. It allows for multiple functional annotations and multiple genetically predicted mediators. It can also perform conditional association analysis while adjusting for other genetic variants (e.g., known loci for the phenotype). Extensive simulation and real data analyses demonstrate that sMiST yields p-values that agree well with those obtained from individual level data but with substantively improved computational speed. Importantly, a broad application of sMiST to GWAS is possible, as only summary statistics of genetic variant associations are required. We apply sMiST to a large-scale GWAS of colorectal cancer using summary statistics from ∼120, 000 study participants and gene expression data from the Genotype-Tissue Expression (GTEx) project. We identify several novel and secondary independent genetic loci.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Neoplasias Colorretais/patologia , Biologia Computacional , Regulação Neoplásica da Expressão Gênica/genética , Variação Genética/genética , Genótipo , Humanos , Modelos Estatísticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
15.
PLoS One ; 15(8): e0236569, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756596

RESUMO

BACKGROUND: The inflammatory biomarkers, YKL-40 and interleukin-6 (IL-6), are elevated in patients with metastatic colorectal cancer. We examined their associations with relapse-free survival and overall survival in combination with serum C-reactive protein (CRP), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) in patients with colorectal liver metastases. METHODS: Altogether 441 consecutive patients undergoing liver resection at Helsinki University Hospital between 1998 and 2013 were included in the study. Pre- and postoperative YKL-40 and IL-6 were determined from serum samples with commercially available enzyme-linked immunosorbent assay (ELISA) kits, and CRP, CEA, and CA19-9 by routine methods. Associations between these biomarkers and relapse-free and overall survival were examined using Cox regression analysis. RESULTS: Patients with 2-5 elevated biomarkers were at an increased risk of relapse compared to those with 0-1 elevated biomarkers, preoperatively (HR 1.37, 95% CI 1.1-1.72) or postoperatively (HR 1.54, 95% CI 1.23-1.92). Patients with 2-5 elevated biomarkers were also at an increased risk of death compared to those with 0-1 elevated biomarkers, preoperatively (HR 1.76, 95% CI 1.39-2.24) or postoperatively (HR 1.83, 95% CI 1.44-2.33). CONCLUSION: The results suggest that a protein panel of the inflammatory biomarkers YKL-40, IL-6, and CRP, and the cancer biomarkers CEA and CA19-9 might identify patients that benefit from more aggressive treatment and surveillance, although the additional value of IL-6 and CRP in this aspect is limited.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Neoplasias Hepáticas/sangue , Recidiva Local de Neoplasia/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Glicosídicos Associados a Tumores/sangue , Antígeno Carcinoembrionário/sangue , Proteína 1 Semelhante à Quitinase-3/sangue , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Hepatectomia , Humanos , Interleucina-6/sangue , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Intervalo Livre de Progressão
16.
J Cancer Res Clin Oncol ; 146(11): 2861-2870, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32772171

RESUMO

PURPOSE: IGF-1Ec is an isoform of Insulin-like growth factor 1 (IGF-1) and has recently been identified to be overexpressed in cancers including prostate and neuroendocrine tumours. The aim of this paper is to investigate the expression of IGF-1Ec in colorectal cancer and polyps compared to normal colon tissues and its association with recurrent disease using semi-quantitative immunohistochemistry. METHODS: Immunohistochemistry for IGF-1Ec expression was performed for colorectal cancer, colorectal polyps and normal colonic tissues. The quantification of IGF-1Ec expression was performed with the use of Image J software and the IHC profiler plugin. Following ethics approval from the National Research Ethics Service (Reference 11/LO/1521), clinical information including recurrent disease on follow-up was collected for patients with colorectal cancer. RESULTS: Immunohistochemistry was performed in 16 patients with colorectal cancer and 11 patients with colonic polyps and compared to normal colon tissues and prostate adenocarcinoma (positive control) tissues. Significantly increased expression of IGF-1Ec was demonstrated in colorectal cancer (p < 0.001) and colorectal polyps (p < 0.05) compared to normal colonic tissues. Colonic adenomas with high-grade dysplasia had significantly higher expression of IGF-1Ec compared to low-grade dysplastic adenomas (p < 0.001). Colorectal cancers without lymph node metastases at the time of presentation had significantly higher IGF-1Ec expression compared to lymph node-positive disease (p < 0.05). No correlation with recurrent disease was identified with IGF-1Ec expression. CONCLUSION: IGF-1Ec is significantly overexpressed in colorectal cancer and polyps compared to normal colon tissues offering a potential target to improve colonoscopic identification of colorectal polyps and cancer and intraoperative identification of colorectal tumours.


Assuntos
Pólipos Adenomatosos/diagnóstico , Pólipos do Colo/diagnóstico , Neoplasias Colorretais/diagnóstico , Fator de Crescimento Insulin-Like I/metabolismo , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Pólipos do Colo/metabolismo , Pólipos do Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Fator de Crescimento Insulin-Like I/análise , Masculino
17.
PLoS One ; 15(8): e0236799, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756574

RESUMO

INTRODUCTION: Numerous prior studies, even from countries with free access to care, have associated long travel time to care with poor survival in patients with colorectal cancer. METHODS: This is a data-linkage study of all 3718 patients with colorectal cancer, diagnosed between 2007 and 2013 in Northern Sweden, one of the most sparsely populated areas in Europe. Travel time to nearest hospital was calculated based on GPS coordinates and multivariable Cox regression was used to analyse possible associations between travel time and cause-specific survival. RESULTS: No association between travel time and survival was observed, either in univariable analysis (colon HR 1.00 [95% CI 0.998-1.003]; rectal HR 0.998; [95% CI 0.995-1.002]) or in multivariable Cox regression analysis (colon HR 0.999 [95% CI 0.997-1.002]; rectal HR 0.997 [95% CI 0.992-1.002]). CONCLUSIONS: In contrast to most other studies, no association between travel time and colorectal cancer survival was found; despite that longer travel time was associated with known risk factors for poorer outcome. In the Swedish health care setting, travel time does not appear to represent a barrier to care or to negatively influence outcomes.


Assuntos
Neoplasias Colorretais/mortalidade , Idoso , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Bases de Dados Factuais , Escolaridade , Feminino , Humanos , Armazenamento e Recuperação da Informação , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Sistema de Registros , Fatores de Risco , Fatores de Tempo
18.
APMIS ; 128(10): 543-551, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32794608

RESUMO

The Hippo pathway is a tumor suppressive pathway regulating Yes-associated protein-TEA domain-containing sequence-specific transcription factor (YAP-TEAD) complex. VGLL (Vestigial-like) proteins are transcriptional cofactors competing with YAP for TEAD binding and interfering oncogenic activity of YAP-TEAD complex. We evaluated the expression of VGLL4, YAP, and TEAD4 and assessed their correlations with clinicopathologic factors and prognostic effects in 295 colorectal cancers. VGLL4 was positive in 164 (55.6%) cases and correlated with small tumor size, low pT classification, and absence of lymph node metastasis. YAP and TEAD4 were highly expressed in 138 (46.8%) cases and 144 (48.8%) cases, respectively, and high expressions were associated with presence of lymphovascular invasion and lymph node metastasis, or distant metastasis. VGLL4 expression was significantly correlated with low YAP expression (p < 0.001) and had significantly better overall survival than negative expression (p < 0.001). High YAP (HR, 2.108; 95% confidence interval, 1.239-3.584; p = 0.006) and TEAD4 (1.724; 1.021-2.912; p = 0.042) expressions were associated with poor overall survivals. The combined VGLL4pos YAPlow expression showed the best overall survival than other groups (p < 0.001). VGLL4 expression (0.381; 0.212-0.683; p = 0.001) and combined VGLL4pos YAPlow expression (0.227; 0.108-0.475; p < 0.001) were independent good prognostic factors in colorectal cancers. The expressions of VGLL4, YAP, and TEAD4 can be used as prognostic markers in colorectal cancer patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Fatores de Transcrição/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Proteínas de Ligação a DNA/biossíntese , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/biossíntese , Prognóstico , Análise de Sobrevida
19.
PLoS One ; 15(8): e0235319, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810173

RESUMO

Aberrant activation of the Wnt signalling pathway is required for tumour initiation and survival in the majority of colorectal cancers. The development of inhibitors of Wnt signalling has been the focus of multiple drug discovery programs targeting colorectal cancer and other malignancies associated with aberrant pathway activation. However, progression of new clinical entities targeting the Wnt pathway has been slow. One challenge lies with the limited predictive power of 2D cancer cell lines because they fail to fully recapitulate intratumoural phenotypic heterogeneity. In particular, the relationship between 2D cancer cell biology and cancer stem cell function is poorly understood. By contrast, 3D tumour organoids provide a platform in which complex cell-cell interactions can be studied. However, complex 3D models provide a challenging platform for the quantitative analysis of drug responses of therapies that have differential effects on tumour cell subpopulations. Here, we generated tumour organoids from colorectal cancer patients and tested their responses to inhibitors of Tankyrase (TNKSi) which are known to modulate Wnt signalling. Using compounds with 3 orders of magnitude difference in cellular mechanistic potency together with image-based assays, we demonstrate that morphometric analyses can capture subtle alterations in organoid responses to Wnt inhibitors that are consistent with activity against a cancer stem cell subpopulation. Overall our study highlights the value of phenotypic readouts as a quantitative method to asses drug-induced effects in a relevant preclinical model.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Organoides/efeitos dos fármacos , Tanquirases/antagonistas & inibidores , Adulto , Animais , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/patologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Imageamento Tridimensional , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Organoides/patologia
20.
Am J Surg Pathol ; 44(9): 1224-1234, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32804454

RESUMO

This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.


Assuntos
Adenocarcinoma/genética , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Fusão Gênica , Rearranjo Gênico , Adenocarcinoma/química , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Idoso , Biomarcadores Tumorais/análise , Neoplasias Colorretais/química , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Análise Mutacional de DNA , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Japão , Metástase Linfática , Masculino , Mutação , Estadiamento de Neoplasias , Fenótipo , Resultado do Tratamento , Estados Unidos
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