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1.
Klin Onkol ; 32(Supplementum2): 109-117, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409086

RESUMO

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare variant of familial adenomatous polyposis. It is an autosomal-dominant cancer-predisposition syndrome with massive polyposis of the stomach and a significant risk of gastric adenocarcinoma. Li et al., 2016, described point mutations in the Ying Yang 1 binding site of the APC gene 1B promoter associated with GAPPS syndrome. The first GAPPS syndrome in a Czech family was described in 2016. At Masaryk Memorial Cancer Institute, GAPPS syndrome was diagnosed in eight families using Sanger sequencing. In all families, one mutation in promoter 1B of APC gene NM_001127511: c.-191T>C was detected. This mutation was not found in any patient with multiple colon polyposis without a detected classic mutation in the APC gene. In total, 24 carriers of this mutation in promoter 1B of the APC gene were detected. Out of those 24 carriers, 20 had massive gastric polyposis with more than 100 fundic glandular polyps diagnosed between the age of 22 and 65, 5 had already died of adenocarcinoma of the stomach (at the ages of 29, 40, 59, 60 and 64, respectively) and another woman was treated at the age of 29. Two female carriers do not yet have polyposis of the stomach at the ages of 31 and 65, respectively; one female carrier has incipient polyposis at the age of 58. A male carrier does not have any clinical symptoms, gastroscopy was not indicated because of his age. Prophylactic total gastrectomy with D2 lymphadenectomy has already been performed 6 times at Masaryk Memorial Cancer Institute, in 5 cases without adenocarcinoma at the ages of 27, 34, 44, 51 and 66, respectively; in one female carrier adenocarcinoma of the stomach was detected in a histology specimen. Two prophylactic gastrectomies with D1 lymphadenectomy were performed at University Hospital Brno at the ages of 42 and 50, respectively. In the Czech Republic point mutation c.-191T>C (rs879253783) in the 1B promoter of the APC gene is a frequent cause of gastric polyposis with a high risk of gastric adenocarcinoma, even at a young age. Positively tested individuals are recommended to high-risk oncology clinic. A necessary part of the discussion with the patient is information about a preventive gastrectomy.


Assuntos
Adenocarcinoma , Síndromes Neoplásicas Hereditárias , Neoplasias Gástricas , Adenocarcinoma/genética , Adenocarcinoma/prevenção & controle , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Institutos de Câncer , República Tcheca , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/prevenção & controle , Procedimentos Cirúrgicos Profiláticos , Neoplasias Gástricas/genética , Neoplasias Gástricas/prevenção & controle , Adulto Jovem
2.
World J Gastroenterol ; 25(24): 3069-3078, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31293342

RESUMO

BACKGROUND: Esophageal adenocarcinoma (EAC) and high-grade dysplasia (HGD) may appear in young patients with Barrett's esophagus (BE). However, characteristics of Barrett's-related neoplasia in this younger population remain unknown. AIM: To identify clinical characteristics that differ between young and old patients with early-stage Barrett's-related neoplasia. METHODS: We conducted a retrospective analysis of a prospectively maintained database comprised of consecutive patients with early-stage EAC (pT1) and HGD at a tertiary-referral center between 2001 and 2017. Baseline characteristics, drug and risk factor exposures, clinicopathological staging of EAC/HGD and treatment outcomes [complete eradication of neoplasia (CE-N), complete eradication of intestinal metaplasia (CE-IM), recurrence of neoplasia and recurrence of intestinal metaplasia] were retrieved. Multivariate analyses were performed to identify factors that differed significantly between older and younger (≤ 50 years) patients. RESULTS: We identified 450 patients with T1 EAC and HGD (74% and 26%, respectively); 45 (10%) were ≤ 50 years. Compared to the older group, young patients were more likely to present with ongoing gastroesophageal reflux disease (GERD) symptoms (55% vs 38%, P = 0.04) and to be obese (body mass index > 30, 48% vs 32%, P = 0.04). Multivariate logistic regression analysis showed that young patients were significantly more likely to have ongoing GERD symptoms [odds ratio (OR) 2.00, 95% confidence interval (CI) 1.04-3.85, P = 0.04] and to be obese (OR 2.06, 95%CI 1.07-3.98, P = 0.03) whereas the young group was less likely to have a smoking history (OR 0.39, 95%CI 0.20-0.75, P < 0.01) compared to the old group. However, there were no significant differences regarding tumor histology, CE-N, CE-IM, recurrence of neoplasia and recurrence of intestinal metaplasia (mean follow-up, 44.3 mo). CONCLUSION: While guidelines recommend BE screening in patients > 50 years of age, younger patients should be considered for screening endoscopy if they suffer from obesity and GERD symptoms.


Assuntos
Adenocarcinoma/epidemiologia , Esôfago de Barrett/diagnóstico por imagem , Neoplasias Esofágicas/epidemiologia , Esôfago/patologia , Lesões Pré-Cancerosas/diagnóstico por imagem , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Fatores Etários , Esôfago de Barrett/epidemiologia , Esôfago de Barrett/patologia , Comorbidade , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/normas , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/prevenção & controle , Esofagoscopia/normas , Esôfago/diagnóstico por imagem , Feminino , Seguimentos , Refluxo Gastroesofágico/epidemiologia , Humanos , Masculino , Programas de Rastreamento/métodos , Programas de Rastreamento/normas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Obesidade/epidemiologia , Guias de Prática Clínica como Assunto , Lesões Pré-Cancerosas/epidemiologia , Lesões Pré-Cancerosas/patologia , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco
4.
Medicina (Kaunas) ; 55(7)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31330954

RESUMO

Background and objectives: Human gastric adenocarcinoma (AGS) is one of the most common malignant cancers worldwide. The present study aimed to transfer oleuropein into cancer cells using synthetic paramagnetic nanoparticles and study their effect on the AGS (ATCC® CRL1739™) cell line. Materials and Methods: Paramagnetic nano-oleuropein was synthesized using four-stage co-precipitation by developing NH-connected bridges and was evaluated by EDS, SEM and FTIR methods. Different concentrations of magnetic oleuropein (0, 0.15, 0.45, 1.37, 4.12, 12.35, 37.04, 111.11, 333.33, 1000 µg/mL) were used to treat the AGS cell line in a completely randomized design using a statistical framework with three replicates. The relative expression rate of miR-200 and KRAS oncogenes was evaluated using real-time PCR. The inhibition rate of the AGS cells was assessed using the MTT test at 24, 48 and 72 h intervals. Results: The results showed that there was a significant difference between the inhibition rates of magnetic nano-oleuropein at IC50-24h (23.6 µg/mL), IC50-48h (15.2 µg/mL) and IC50-72h (9.2 µg/mL). Real-time PCR indicated that the relative expression of KRAS and miR-200 genes was highest at IC50 at these intervals. Conclusions: Magnetic nano-oleuropein can be subjected to objective testing and clinical evaluations as a natural antioxidant to prevent and treat gastric adenocarcinoma.


Assuntos
Adenocarcinoma/prevenção & controle , Expressão Gênica/efeitos dos fármacos , Iridoides/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/biossíntese , Neoplasias Gástricas/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Humanos , Iridoides/farmacologia , Nanopartículas/uso terapêutico , Olea/enzimologia , Olea/genética , Proteínas Proto-Oncogênicas p21(ras)/sangue , Espectrometria por Raios X/métodos
5.
BMC Gastroenterol ; 19(1): 109, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31248371

RESUMO

BACKGROUND: A key barrier to controlling esophageal adenocarcinoma (EAC) is identifying those most likely to benefit from screening and surveillance. We aimed to develop an online educational tool, termed IC-RISC™, for providers and patients to estimate more precisely their absolute risk of developing EAC, interpret this estimate in the context of risk of dying from other causes, and aid in decision-making. RESULTS: U.S. incidence and mortality data and published relative risk estimates from observational studies and clinical trials were used to calculate absolute risk of EAC over 10 years adjusting for competing risks. These input parameters varied depending on presence of the key precursor, Barrett's esophagus. The open source application works across common devices to gather risk factor data and graphically illustrate estimated risk on a single page. Changes to input data are immediately reflected in the colored graphs. We used the calculator to compare the risk distribution between EAC cases and controls from six population-based studies to gain insight into the discrimination metrics of current practice guidelines for screening, observing that current guidelines sacrifice a significant amount of specificity to identify 78-86% of eventual cases in the US population. CONCLUSIONS: This educational tool provides a simple and rapid means to graphically communicate risk of EAC in the context of other health risks, facilitates "what-if" scenarios regarding potential preventative actions, and can inform discussions regarding screening, surveillance and treatment options. Its generic architecture lends itself to being easily extended to other cancers with distinct pathways and/or intermediate stages, such as hepatocellular cancer. IC-RISC™ extends current qualitative clinical practice guidelines into a quantitative assessment, which brings the possibility of preventative actions being offered to persons not currently targeted for screening and, conversely, reducing unnecessary procedures in those at low risk. Prospective validation and application to existing well-characterized cohort studies are needed.


Assuntos
Adenocarcinoma/diagnóstico , Detecção Precoce de Câncer , Neoplasias Esofágicas/diagnóstico , Vigilância da População , Medição de Risco/métodos , Software , Adenocarcinoma/epidemiologia , Adenocarcinoma/prevenção & controle , Idoso , Estudos de Casos e Controles , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/prevenção & controle , Feminino , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Educação de Pacientes como Assunto , Fatores de Risco , Estados Unidos/epidemiologia
6.
Gastroenterology ; 157(3): 744-759.e4, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31154022

RESUMO

BACKGROUND & AIMS: Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPARα in colon carcinogenesis. METHODS: Colon cancer was induced in mice with intestine-specific disruption of Ppara (PparaΔIE), Pparafl/fl (control), and mice with disruption of Ppara that express human PPARA (human PPARA transgenic mice), by administration of azoxymethane with or without dextran sulfate sodium (DSS). Colons were collected from mice and analyzed by immunoblots, quantitative polymerase chain reaction, and histopathology. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses were performed on urine and colons. We used molecular biology and biochemical approaches to study mechanisms in mouse colons, primary intestinal epithelial cells, and colon cancer cell lines. Gene expression data and clinical features of patients with colorectal tumors were obtained from Oncomine, and human colorectal-tumor specimens and adjacent normal tissues were collected and analyzed by immunohistochemistry. RESULTS: Levels of Ppara messenger RNA were reduced in colon tumors from mice. PparaΔIE mice developed more and larger colon tumors than control mice following administration of azoxymethane, with or without DSS. Metabolomic analyses revealed increases in methylation-related metabolites in urine and colons from PparaΔIE mice, compared with control mice, following administration of azoxymethane, with or without DSS. Levels of DNA methyltransferase 1 (DNMT1) and protein arginine methyltransferase 6 (PRMT6) were increased in colon tumors from PparaΔIE mice, compared with colon tumors from control mice. Depletion of PPARα reduced the expression of retinoblastoma protein, resulting in increased expression of DNMT1 and PRMT6. DNMT1 and PRMT6 decreased expression of the tumor suppressor genes Cdkn1a (P21) and Cdkn1b (p27) via DNA methylation and histone H3R2 dimethylation-mediated repression of transcription, respectively. Fenofibrate protected human PPARA transgenic mice from azoxymethane and DSS-induced colon cancer. Human colon adenocarcinoma specimens had lower levels of PPARA and retinoblastoma protein and higher levels of DNMT1 and PRMT6 than normal colon tissues. CONCLUSIONS: Loss of PPARα from the intestine promotes colon carcinogenesis by increasing DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of p27 in mice. Human colorectal tumors have lower levels of PPARA messenger RNA and protein than nontumor tissues. Agents that activate PPARα might be developed for chemoprevention or treatment of colon cancer.


Assuntos
Adenocarcinoma/prevenção & controle , Colo/enzimologia , Neoplasias do Colo/prevenção & controle , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Proteínas Nucleares/metabolismo , PPAR alfa/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Anticarcinógenos/farmacologia , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Colo/patologia , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA/efeitos dos fármacos , Bases de Dados Genéticas , Modelos Animais de Doenças , Fenofibrato/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/genética , PPAR alfa/agonistas , PPAR alfa/deficiência , PPAR alfa/genética , Proteína-Arginina N-Metiltransferases/genética , Transdução de Sinais
7.
Gastroenterology ; 157(2): 349-364.e1, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31082367

RESUMO

In patients with Barrett's esophagus (BE), metaplastic columnar mucosa containing epithelial cells with gastric and intestinal features replaces esophageal squamous mucosa damaged by gastroesophageal reflux disease. This condition is estimated to affect 5.6% of adults in the United States, and is a major risk factor for esophageal adenocarcinoma. Despite the prevalence and importance of BE, its pathogenesis is incompletely understood and there are disagreements over the cells of origin. We review mechanisms of BE pathogenesis, including transdifferentiation and transcommitment, and discuss potential cells of origin, including basal cells of the squamous epithelium, cells of esophageal submucosal glands and their ducts, cells of the proximal stomach, and specialized populations of cells at the esophagogastric junction (residual embryonic cells and transitional basal cells). We discuss the concept of metaplasia as a wound-healing response, and how cardiac mucosa might be the precursor of the intestinal metaplasia of BE. Finally, we discuss shortcomings in current diagnostic criteria for BE that have important clinical implications.


Assuntos
Esôfago de Barrett/patologia , Células Epiteliais/patologia , Mucosa Esofágica/patologia , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Esôfago de Barrett/diagnóstico , Esôfago de Barrett/epidemiologia , Cárdia/citologia , Cárdia/patologia , Transdiferenciação Celular , Progressão da Doença , Mucosa Esofágica/citologia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/prevenção & controle , Junção Esofagogástrica/citologia , Junção Esofagogástrica/patologia , Mucosa Gástrica/citologia , Mucosa Gástrica/patologia , Humanos , Metaplasia/patologia , Estados Unidos , Cicatrização/fisiologia
8.
Dig Dis ; 37(5): 381-393, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30970344

RESUMO

While the primary risk factor for oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO) is gastro-oesophageal reflux, the infection with Helicobacter pylori (H. pylori) is the dominant risk factor for gastric cancer. Reduction of reflux by dietary measures and proton pump inhibitors has some merits in OAC prevention, and the chemopreventive effect of Aspirin and statins is being widely investigated; however, improved outcome in OAC occurs primarily as the result of secondary prevention. Early detection of neoplastic lesions in Barrett's metaplasia can be achieved by surveillance endoscopies. Novel endoscopic imaging modalities carry similar importance as the endoscopic treatment techniques as without detection of early lesions, therapy cannot be applied. Minimally invasive approaches are currently being investigated to identify patients with BO who are at particular risk of neoplastic progression. While dietary factors also play an important role in the prevention of gastric cancer and chemoprevention seems to be promising, the most beneficial effect has been shown for the eradication of H. pylori infection, which results in at least a one third reduction of gastric cancer risk. This effect can be further improved if the eradication takes place prior to the development of pre-neoplastic gastric conditions such as mucosal atrophy or intestinal metaplasia (IM). The definition of the "point of no return", after which eradication is less effective, is of high importance, although H. pylori eradication can still be beneficial even at more advance stages of mucosal changes. For this reason, patients with advanced atrophy and IM should undergo endoscopic surveillance in the same way as patients with BO. There is also need for development of non-invasive tests to identify patients at high risk of progression to gastric cancer to improve outcome of these surveillance approaches.


Assuntos
Adenocarcinoma/prevenção & controle , Neoplasias Gastrointestinais/prevenção & controle , Prevenção Secundária , Trato Gastrointestinal Superior/patologia , Quimioprevenção , Neoplasias Esofágicas/prevenção & controle , Humanos , Neoplasias Gástricas/prevenção & controle
9.
Gastrointest Endosc ; 90(1): 55-63, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30926431

RESUMO

Recent breakthroughs in artificial intelligence (AI), specifically via its emerging sub-field "deep learning," have direct implications for computer-aided detection and diagnosis (CADe and/or CADx) for colonoscopy. AI is expected to have at least 2 major roles in colonoscopy practice-polyp detection (CADe) and polyp characterization (CADx). CADe has the potential to decrease the polyp miss rate, contributing to improving adenoma detection, whereas CADx can improve the accuracy of colorectal polyp optical diagnosis, leading to reduction of unnecessary polypectomy of non-neoplastic lesions, potential implementation of a resect-and-discard paradigm, and proper application of advanced resection techniques. A growing number of medical-engineering researchers are developing both CADe and CADx systems, some of which allow real-time recognition of polyps or in vivo identification of adenomas, with over 90% accuracy. However, the quality of the developed AI systems as well as that of the study designs vary significantly, hence raising some concerns regarding the generalization of the proposed AI systems. Initial studies were conducted in an exploratory or retrospective fashion by using stored images and likely overestimating the results. These drawbacks potentially hinder smooth implementation of this novel technology into colonoscopy practice. The aim of this article is to review both contributions and limitations in recent machine-learning-based CADe and/or CADx colonoscopy studies and propose some principles that should underlie system development and clinical testing.


Assuntos
Adenocarcinoma/diagnóstico , Adenoma/diagnóstico , Inteligência Artificial , Pólipos do Colo/diagnóstico , Colonoscopia , Neoplasias Colorretais/diagnóstico , Diagnóstico por Computador , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Adenocarcinoma/cirurgia , Adenoma/patologia , Adenoma/cirurgia , Pólipos do Colo/patologia , Pólipos do Colo/cirurgia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Aprendizado Profundo , Humanos , Pólipos Intestinais/diagnóstico , Pólipos Intestinais/patologia , Pólipos Intestinais/cirurgia , Garantia da Qualidade dos Cuidados de Saúde
10.
Gastric Cancer ; 22(4): 663-674, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30771119

RESUMO

BACKGROUND: Mediterranean diet (MD) adherence has been associated with reduced risks of esophageal and gastric cancer (subtypes) in a limited number of studies. We prospectively investigated associations between MD adherence and risks of esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA), and gastric non-cardia adenocarcinoma (GNCA) in a Dutch cohort. METHODS: Analyses were conducted using data from the 120852 participants of the Netherlands Cohort Study (NLCS), who were aged between 55 and 69 years at enrollment. Various MD scores, with and without alcohol, were calculated to estimate MD adherence. Using 20.3 years of follow-up, 133 ESCC, 200 EAC, 191 GCA, and 586 GNCA cases could be included in multivariable Cox regression analyses. RESULTS: Of the investigated scores, the alternate Mediterranean diet score without alcohol (aMEDr) performed best. aMEDr was inversely associated with risks of GCA and GNCA in men and women. However, statistical significance was only reached in men [ptrend: 0.019 (GCA), 0.016 (GNCA)]. Furthermore, higher aMEDr values were significantly associated with a reduced ESCC risk in men [HRper two-point increment (95% CI) = 0.57 (0.41-0.80), ptrend = 0.013], but not in women (pheterogeneity = 0.008). There was no evidence of an association between aMEDr and EAC risk. Educational level was a significant effect modifier for the association between aMEDr and GNCA risk (pheterogeneity = 0.0073). CONCLUSIONS: Higher MD adherence was associated with reduced risks of ESCC, GCA, and GNCA in the NLCS. However, the decreased ESCC risk might be limited to men.


Assuntos
Adenocarcinoma/prevenção & controle , Carcinoma de Células Escamosas/prevenção & controle , Dieta Mediterrânea , Neoplasias Esofágicas/prevenção & controle , Cooperação do Paciente , Neoplasias Gástricas/prevenção & controle , Adenocarcinoma/dietoterapia , Adenocarcinoma/patologia , Idoso , Carcinoma de Células Escamosas/dietoterapia , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/dietoterapia , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Prognóstico , Estudos Prospectivos , Fatores de Risco , Neoplasias Gástricas/dietoterapia , Neoplasias Gástricas/patologia , Inquéritos e Questionários
11.
Carcinogenesis ; 40(3): 403-411, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-30624620

RESUMO

Cigarette smoke (CS) contains hundreds of carcinogens and is a potent inducer of oxidative and bulky DNA damage, which when insufficiently repaired leads to activation of DNA damage response and possibly mutations. The DNA repair protein xeroderma pigmentosum group C (XPC) is primed to play an important role in CS-induced DNA damage because of its function in initiating repair of both bulky oxidative DNA damage. We hypothesized that loss of XPC function will increase susceptibility to developing CS- and carcinogen-induced lung cancer through impaired repair of oxidative DNA damage. Mice deficient in XPC (XPC-/-) exposed to chronic CS developed lung tumors whereas their wild-type littermates (XPC+/+) did not. XPC-/- mice treated with the CS-carcinogen urethane developed lung adenocarcinomas representing progressive stages of tumor development, with lung tumor number increased 17-fold compared with XPC+/+ mice. Mice heterozygous for XPC (XPC+/-) demonstrated a gene-dose effect, developing an intermediate number of lung tumors with urethane treatment. Treatment of XPC-/- mice with the carcinogen 3-methylcholanthrene followed by the proliferative agent butylated hydroxytoluene resulted in a 2-fold increase in lung adenocarcinoma development. Finally, tumor number decreased 7-fold in the lungs of XPC-/- mice by concurrent treatment with the antioxidant, N-acetylcysteine. Altogether, this supports a mechanism by which decreased XPC expression promotes lung adenocarcinoma development in response to CS-carcinogen exposure, due in part to impaired oxidative DNA damage repair.


Assuntos
Adenocarcinoma/induzido quimicamente , Adenocarcinoma/prevenção & controle , Carcinógenos/toxicidade , Fumar Cigarros/efeitos adversos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/prevenção & controle , Xeroderma Pigmentoso/metabolismo , Adenocarcinoma/metabolismo , Animais , Dano ao DNA , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Uretana/toxicidade
12.
Gut ; 68(8): 1379-1385, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30635408

RESUMO

OBJECTIVE: Surveillance interval protocols after complete remission of intestinal metaplasia (CRIM) post radiofrequency ablation (RFA) in Barrett's oesophagus (BE) are currently empiric and not based on substantial evidence. We aimed to assess the timeline, location and patterns of recurrence following CRIM to inform these guidelines. DESIGN: Data on patients undergoing RFA for BE were obtained from prospectively maintained databases of five (three USA and two UK) tertiary referral centres. RFA was performed until CRIM was confirmed on two consecutive endoscopies. RESULTS: 594 patients achieved CRIM as of 1 May 2017. 151 subjects developed recurrent BE over a median (IQR) follow-up of 2.8 (1.4-4.4) years. There was 19% cumulative recurrence risk of any BE within 2 years and an additional 49% risk over the next 8.6 years. There was no evidence of a clinically meaningful change in the recurrence hazard rate of any BE, dysplastic BE or high-grade dysplasia/cancer over the duration of follow-up, with an estimated 2% (95% CI -7% to 12%) change in recurrence rate of any BE in a doubling of follow-up time. 74% of BE recurrences developed at the gastro-oesophageal junction (GOJ) (24.1% were dysplastic) and 26% in the tubular oesophagus. The yield of random biopsies from the tubular oesophagus, in the absence of visible lesions, was 1% (BE) and 0.2% (dysplasia). CONCLUSIONS: BE recurrence risk following CRIM remained constant over time, suggesting that lengthening of follow-up intervals, at least in the first 5 years after CRIM, may not be advisable. Sampling the GOJ is critical to detecting recurrence. The requirement for random biopsies of the neosquamous epithelium in the absence of visible lesions may need to be re-evaluated.


Assuntos
Adenocarcinoma , Esôfago de Barrett , Ablação por Cateter , Neoplasias Esofágicas , Esofagoscopia , Medição de Risco , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Idoso , Esôfago de Barrett/epidemiologia , Esôfago de Barrett/patologia , Esôfago de Barrett/cirurgia , Biópsia/métodos , Biópsia/estatística & dados numéricos , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Ablação por Cateter/estatística & dados numéricos , Estudos de Coortes , Progressão da Doença , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/prevenção & controle , Junção Esofagogástrica/patologia , Esofagoscopia/métodos , Esofagoscopia/estatística & dados numéricos , Esôfago/patologia , Feminino , Humanos , Masculino , Metaplasia/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Lesões Pré-Cancerosas/patologia , Medição de Risco/métodos , Medição de Risco/normas , Reino Unido/epidemiologia , Estados Unidos/epidemiologia
13.
Gastroenterology ; 156(1): 63-74.e6, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30268788

RESUMO

BACKGROUND & AIMS: Colorectal cancer (CRC) deaths occur when patients do not receive screening or have inadequate follow-up of abnormal results or when the screening test fails. We have few data on the contribution of each to CRC-associated deaths or factors associated with these events. METHODS: We performed a retrospective cohort study of patients in the Kaiser Permanente Northern and Southern California systems (55-90 years old) who died of CRC from 2006 through 2012 and had ≥5 years of enrollment before diagnosis. We compared data from patients with those from a matched cohort of cancer-free patients in the same system. Receipt, results, indications, and follow-up of CRC tests in the 10-year period before diagnosis were obtained from electronic databases and chart audits. RESULTS: Of 1750 CRC deaths, 75.9% (n = 1328) occurred in patients who were not up to date in screening and 24.1% (n = 422) occurred in patients who were up to date. Failure to screen was associated with fewer visits to primary care physicians. Of 3486 cancer-free patients, 44.6% were up to date in their screening. Patients who were up to date in their screening had a lower risk of CRC death (odds ratio, 0.38; 95% confidence interval, 0.33-0.44). Failure to screen, or failure to screen at appropriate intervals, occurred in a 67.8% of patients who died of CRC vs 53.2% of cancer-free patients; failure to follow-up on abnormal results occurred in 8.1% of patients who died of CRC vs 2.2% of cancer-free patients. CRC death was associated with higher odds of failure to screen or failure to screen at appropriate intervals (odds ratio, 2.40; 95% confidence interval, 2.07-2.77) and failure to follow-up on abnormal results (odds ratio, 7.26; 95% confidence interval, 5.26-10.03). CONCLUSIONS: Being up to date on screening substantially decreases the risk of CRC death. In 2 health care systems with high rates of screening, most people who died of CRC had failures in the screening process that could be rectified, such as failure to follow-up on abnormal findings; these significantly increased the risk for CRC death.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Detecção Precoce de Câncer/mortalidade , Adenocarcinoma/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , California/epidemiologia , Causas de Morte , Neoplasias Colorretais/prevenção & controle , Detecção Precoce de Câncer/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Valor Preditivo dos Testes , Fatores de Proteção , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
14.
Life Sci ; 217: 141-147, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30528182

RESUMO

The use of genetically modified animals has been studied in scientific research over time as a way to discover new treatments or even a cure for various diseases. Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) is a model for prostate cancer (PCa) that develops lesions that range from preneoplastic to metastasis. Its similarity to human PCa brings essential knowledge about disease development as well as making possible to investigate different degrees of the tumor profile. We reviewed the literature regarding five important areas relating to PCa progression in the TRAMP model. We also present some useful PCa models comparing them to TRAMP. Furthermore, we investigated the effect of some therapies related to these areas highlighting the best approaches that can delay PCa progression. The revised studies showed that TRAMP cancer stages are well established from 8 to 30 weeks of age, which makes possible to interfere in specific times of PCa development. Moreover, inflammatory and angiogenic blockage before the appearance of malignant lesions retarded PCa progression and showed better results than therapeutical approaches in other phases in TRAMP mice. Reactive stroma is less studied than other areas, although it has been showing a particular relevance in PCa as a milestone in malignant transformation through the modulation of TGF-ß, vimentin, and αSMA. We concluded that even years after its creation, the TRAMP model is still one of the most essential tools for PCa study, as well as for the development of new strategies to prevent the disease.


Assuntos
Adenocarcinoma/patologia , Neovascularização Patológica/patologia , Próstata/patologia , Neoplasias da Próstata/patologia , Adenocarcinoma/complicações , Adenocarcinoma/prevenção & controle , Inibidores da Angiogênese/uso terapêutico , Animais , Anticarcinógenos/uso terapêutico , Quimioprevenção/métodos , Modelos Animais de Doenças , Progressão da Doença , Inflamação/complicações , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Transgênicos , Neovascularização Patológica/complicações , Neovascularização Patológica/prevenção & controle , Próstata/efeitos dos fármacos , Neoplasias da Próstata/complicações , Neoplasias da Próstata/prevenção & controle
15.
Nutrients ; 10(10)2018 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-30249054

RESUMO

The bioavailability of pollen bioactive compounds for humans is limited. In this study, our aim was to enhance the health-related benefits of pollen by fermentation with a Kombucha/SCOBY (symbiotic culture of bacteria and yeasts) consortium. We performed the fermentation of pollen suspended from the beginning with SCOBY on sweetened green tea or on Kombucha vinegar, by adding pollen after 20 days of Kombucha fermentation. We analyzed: formation of bioactive compounds (anti-oxidant polyphenols, soluble silicon, hydroxy-acids, short chain fatty acids-SCFA); parameters related to Kombucha fermentation (dynamics of lactic acid bacteria-LAB, formation of organic acids, soluble sugar evolution on Kombucha vinegar); the influence of Kombucha fermentation on pollen morphology and ultrastructure; in vitro cytotoxic and antitumoral effects of the Kombucha fermented pollen. The pollen addition increases LAB proportion in the total number of SCOBY microbial strains. SEM images highlight the adhesion of the SCOBY bacteria to pollen. Ultrastructural analysis reveals the release of the pollen content. The content of bioactive compounds (polyphenols, soluble silicon species and SCFA) is higher in the fermented pollen and the product shows a moderate antitumoral effect on Caco-2 cells. The health benefits of pollen are enhanced by fermentation with a Kombucha consortium.


Assuntos
Antioxidantes/metabolismo , Ácidos Graxos Voláteis/metabolismo , Chá de Kombucha , Lactobacillaceae/metabolismo , Pólen , Silício/metabolismo , Chá , Adenocarcinoma/prevenção & controle , Animais , Antineoplásicos/metabolismo , Aderência Bacteriana , Células CACO-2 , Linhagem Celular Tumoral , Neoplasias do Colo/prevenção & controle , Meios de Cultura , Composição de Medicamentos/métodos , Fermentação , Microbiologia de Alimentos , Humanos , Chá de Kombucha/microbiologia , Camundongos , Extratos Vegetais/metabolismo , Extratos Vegetais/uso terapêutico , Pólen/microbiologia , Pólen/ultraestrutura , Polifenóis/metabolismo , Açúcares/metabolismo , Chá/metabolismo , Chá/microbiologia , Leveduras/metabolismo
16.
Arch Gynecol Obstet ; 298(5): 981-989, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30242499

RESUMO

PURPOSE: The present study investigated the preventive effect of the cyclooxygenase (COX)-2 inhibitor, celecoxib, in 7,12-dimethylbenz[a]anthracene (DMBA)-induced ovarian cancer in a rat model. METHODS: A diet containing celecoxib (1500 ppm) was started 2 weeks before the introduction of DMBA. DMBA-soaked cotton threads were surgically applied to induce ovarian cancer in female Wistar rats. Tumor growth and survival were observed for 24 weeks. RESULTS: During the study period, an overall tumor incidence of 97.5% was observed and 65% of tumors were ovarian adenocarcinoma. The celecoxib diet significantly reduced the incidence and size of DMBA-induced ovarian cancers and significantly improved survival of tumor-bearing rats. The preventive effect of celecoxib was associated with increased apoptosis. CONCLUSION: DMBA-induced ovarian cancer in rats recapitulates many pathophysiological features of the human counterpart. Our results provide supportive evidence that celecoxib has a preventive effect on development of ovarian cancer in a rat model.


Assuntos
9,10-Dimetil-1,2-benzantraceno/administração & dosagem , Celecoxib/administração & dosagem , Inibidores de Ciclo-Oxigenase , Neoplasias Ovarianas/induzido quimicamente , Neoplasias Ovarianas/prevenção & controle , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Animais , Apoptose , Carcinossarcoma/induzido quimicamente , Carcinossarcoma/patologia , Carcinossarcoma/prevenção & controle , Ciclo Celular , Dieta , Feminino , Neoplasias Ovarianas/patologia , Ratos , Ratos Wistar , Sarcoma/induzido quimicamente , Sarcoma/patologia , Sarcoma/prevenção & controle
17.
Surg Oncol ; 27(3): 479-484, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30217305

RESUMO

BACKGROUND AND OBJECTIVES: Surgical trauma in patients undergoing colorectal cancer resection generates local and systemic inflammatory responses that can affect oncological outcomes. Post-operative peritoneal fluids of patients undergoing colorectal surgery increase the pro-malignant effect of cancer cells in vitro with correlation to elevated TNFα in these fluids. This study evaluated whether inhibiting TNFα in patients' postoperative fluid biopsies would attenuate this effect. METHODS: Peritoneal fluids from 53 patients undergoing colorectal surgery were sampled before and daily after surgery via intra-abdominal drains. Fluid biopsies were evaluated for their impact on the migration capacity of colon cancer cells and for cytokine levels. TNFα was inhibited using infliximab and cell migration was reevaluated. RESULTS: Colon cancer migration capacity was increased in postoperative fluid biopsies from all patients (P < 0.005) and was elevated compared to pre-resection levels. Infliximab attenuated this effect in >90%, decreasing migration capacity by 30% (p < 0.001). CONCLUSIONS: Inhibition of TNFα in postoperative peritoneal fluids attenuates the increase in cancer cell migration capacity generated following colorectal resection. These findings correlate with other studies suggesting that attenuation of the post-operative inflammatory response may have oncological benefit. Clinical studies are needed to evaluate the effect of peri-operative TNFα inhibition in clinical settings.


Assuntos
Adenocarcinoma/prevenção & controle , Líquido Ascítico/metabolismo , Movimento Celular , Neoplasias Colorretais/prevenção & controle , Complicações Pós-Operatórias , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Líquido Ascítico/patologia , Proliferação de Células , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Células Tumorais Cultivadas
18.
Gastroenterol Hepatol ; 41(9): 585-596, 2018 Nov.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30245076

RESUMO

This document updates the recommendations made by the Spanish Society of Family and Community Medicine and the Spanish Association of Gastroenterology for the diagnosis and prevention of colorectal cancer (CRC). In order to evaluate the quality of the evidence and determine the recommendation levels of the interventions, we used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. This document establishes optimal delay intervals based on symptoms and the faecal immunochemical test (FIT) and recommends reducing the barriers for diagnostic confirmation in symptomatic subjects. With regard to CRC screening in the average-risk population, we propose strategies to achieve the universal implementation of organised CRC screening programmes based on biennial FIT and to increase the participation of the target population, including the involvement of Primary Healthcare. This Clinical Practice Guideline recommends universal screening for Lynch syndrome with mismatch repair proteins immunohistochemistry or microsatellite instability in incident CRCs and the use of gene panels in patients with adenomatous polyposis. It also updates the strategies to reduce the incidence and mortality of both CRC and other tumours associated with hereditary syndromes. Regarding non-hereditary familial CRC and surveillance after resection of adenomas, serrated lesions or CRC, we established the recommendations based on the attributable risk and the risk reduction of the proposed intervention. Finally, the document includes recommendations regarding surveillance intervals in inflammatory bowel disease and the attitude towards dysplasia.


Assuntos
Adenocarcinoma/prevenção & controle , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/prevenção & controle , Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiologia , Polipose Adenomatosa do Colo , Quimioprevenção , Colectomia , Colonoscopia , Neoplasias Colorretais/epidemiologia , Dieta , Detecção Precoce de Câncer/normas , Humanos , Doenças Inflamatórias Intestinais , Estilo de Vida , Síndromes Neoplásicas Hereditárias/diagnóstico , Sangue Oculto , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/cirurgia , Fatores de Risco
19.
Int J Mol Sci ; 19(7)2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30011784

RESUMO

Melatonin is a tryptophan-derived molecule with pleiotropic activities which is produced in all living organisms. This "sleep" hormone is a free radical scavenger, which activates several anti-oxidative enzymes and mechanisms. Melatonin, a highly lipophilic hormone, can reach body target cells rapidly, acting as the circadian signal to alter numerous physiological functions in the body. This indoleamine can protect the organs against a variety of damaging agents via multiple signaling. This review focused on the role played by melatonin in the mechanism of esophagoprotection, starting with its short-term protection against acute reflux esophagitis and then investigating the long-term prevention of chronic inflammation that leads to gastroesophageal reflux disease (GERD) and Barrett's esophagus. Since both of these condition are also identified as major risk factors for esophageal carcinoma, we provide some experimental and clinical evidence that supplementation therapy with melatonin could be useful in esophageal injury by protecting various animal models and patients with GERD from erosions, Barrett's esophagus and neoplasia. The physiological aspects of the synthesis and release of this indoleamine in the gut, including its release into portal circulation and liver uptake is examined. The beneficial influence of melatonin in preventing esophageal injury from acid-pepsin and acid-pepsin-bile exposure in animals as well as the usefulness of melatonin and its precursor, L-tryptophan in prophylactic and supplementary therapy against esophageal disorders in humans, are also discussed.


Assuntos
Adenocarcinoma/prevenção & controle , Esôfago de Barrett/prevenção & controle , Neoplasias Esofágicas/prevenção & controle , Esofagite Péptica/prevenção & controle , Melatonina/uso terapêutico , Animais , Esôfago/efeitos dos fármacos , Esôfago/metabolismo , Esôfago/patologia , Humanos , Melatonina/metabolismo , Melatonina/farmacologia , Modelos Biológicos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico
20.
Oncol Rep ; 40(3): 1761-1768, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30015929

RESUMO

The need for effective treatment of KRAS­mutant lung cancer is an emerging issue. Rho GTPase­activating protein 35 (ARHGAP35) is reported to be a possible molecular target for lung adenocarcinoma. We investigated the effect of long­term ARHGAP35 suppression on the proliferation, migration and molecular dynamics of lung adenocarcinomas harboring KRAS and EGFR gene mutations. Lung adenocarcinoma cell lines A549 (KRAS­mutant) and PC9 and H1975 (EGFR­mutants) were used, and ARHGAP35 knockdown was carried out using puromycin. Cell viability, migration and molecular dynamics were assayed 1 month after introducing small hairpin RNA. The compensatory upregulated mechanism was screened by western blotting and confirmed by a specific inhibitor. Finally, we tested the effects of cosuppression of the SRC/ARHGAP35 axis and the identified pathway in vitro. ARHGAP35 suppression was attenuated by long­term knockdown of the target genes. Compensatory mechanisms by SRC and STAT3 caused attenuation in A549 cells. After long­term ARHGAP35 knockdown, both A549 and PC9 cells were more sensitive to treatment with a STAT3 inhibitor. The suppressive effect of ARHGAP35 knockdown on migration was sustained, but only modest, in all cell lines. Synergistic and strong growth inhibition was observed with concomitant use of an SRC inhibitor and a STAT3 inhibitor in A549 cells. STAT3 activation compensated for ARHGAP35 knockdown in lung adenocarcinoma with the KRAS mutation. Moreover, cosuppression of the STAT3 pathway and SRC/ARHGAP35 axis may be an effective strategy for treating lung adenocarcinoma, especially in the presence of a KRAS mutation.


Assuntos
Receptores ErbB/genética , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Neoplasias Pulmonares/prevenção & controle , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas pp60(c-src)/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas pp60(c-src)/genética , Proteínas Repressoras/genética , Fator de Transcrição STAT3/genética , Células Tumorais Cultivadas
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