RESUMO
BACKGROUND: Data regarding the effectiveness of adalimumab (ADA) in the treatment of perianal fistula in patients with Crohn's disease (CD) naive to antitumor necrosis factor (TNF) therapy are scarce. AIM: : To assess the effectiveness of ADA in the treatment of perianal fistulas in CD patients naive to anti-TNF therapy. METHODS: A retrospective multicenter study was designed. The Fistula Drainage Assessment Index was used to assess the clinical response, and the Van Assche and Ng indexes to classify radiologic response (magnetic resonance imaging). RESULTS: A total of 46 patients (83% women, 83% complex fistula) were included. At 6 months, 72% of patients responded to ADA (54% remission, 18% partial response) and at 12 months 49% responded (41% remission, 8% partial response). Among patients with complex fistula, the response rate was 66% at 6 months and 39% at 12 months. Nine patients escalated the ADA dose to 40 mg weekly, 6 for partial response and 3 for absence of response. Thirty-three percent of these patients achieved remission after dose escalation. There was a good correlation between clinical and radiologic assessment of response (κ=0.68). In the multivariate analysis, complex fistula was the only predictor of a worse response (hazard ratio 0.083; 95% confidence interval, 0.0009-0.764; P=0.028). Adverse effects were recorded in 11% of patients. CONCLUSIONS: ADA was effective for the treatment of perianal fistulas in CD patients naive to anti-TNF drugs. We found a good correlation between clinical and radiologic assessment of therapy response.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Doença de Crohn/tratamento farmacológico , Fístula Cutânea/tratamento farmacológico , Fístula Retal/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Doença de Crohn/complicações , Doença de Crohn/cirurgia , Fístula Cutânea/etiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fístula Retal/etiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
The clinical evidence of dietary polyphenols as colorectal cancer (CRC) chemopreventive compounds is very weak. Verification in humans of tissue-specific molecular regulation by the intake of polyphenols requires complex clinical trials that allow for the procurement of sufficient pre- and postsupplementation tissue samples. Ellagitannins (ETs), ellagic acid (EA) and their gut microbiota-derived metabolites, the urolithins, modify gene expression in colon normal and cancer cultured cells. We conducted here the first clinical trial with 35 CRC patients daily supplemented with 900 mg of an ET-containing pomegranate extract (PE) and evaluated the expression of various CRC-related genes in normal and cancerous colon tissues before (biopsies) and after (surgical specimens) 5-35 days of supplementation. Tissues were also obtained from 10 control patients (no supplementation) that confirmed a large, gene- and tissue-specific interindividual variability and impact of the experimental protocol on gene expression, with some genes induced (MYC, CD44, CDKN1A, CTNNB1), some repressed (CASP3) and others not affected (KRAS). Despite these issues, the consumption of the PE was significantly associated with a counterbalance effect in the expression of CD44, CTNNB1, CDKN1A, EGFR and TYMs, suggesting that the intake of this PE modulated the impact of the protocol on gene expression in a gene- and tissue-specific manner. These effects were not associated with the individuals' capacity to produce specific urolithins (i.e., metabotypes) or the levels of urolithins and EA in the colon tissues and did not reproduce in vitro effects evidencing the difficulty of demonstrating in vivo the in vitro results.
Assuntos
Neoplasias Colorretais/dietoterapia , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Taninos Hidrolisáveis/farmacologia , Lythraceae/química , Extratos Vegetais/farmacologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Extratos Vegetais/química , Reprodutibilidade dos TestesRESUMO
SCOPE: MicroRNAs (miRs) are proposed as colorectal cancer (CRC) biomarkers. Pomegranate ellagic acid and their microbiota metabolites urolithins exert anticancer effects in preclinical CRC models, and target normal and malignant colon tissues in CRC patients. Herein, we investigated whether the intake of pomegranate extract (PE) modified miRs expression in surgical colon tissues versus biopsies from CRC patients. METHODS AND RESULTS: We conducted a randomized, double-blind, controlled trial. Thirty-five CRC patients consumed 900 mg PE daily before surgery. Control CRC patients (no PE intake, n = 10) were included. Our results revealed: (1) significant differences for specific miRs between malignant and normal tissues modifiable by the surgical protocols; (2) opposed trends between -5p and -3p isomolecules; (3) general induction of miRs attributable to the surgery; (4) moderate modulation of various miRs following the PE intake, and (5) no association between tissue urolithins and the observed miRs changes. CONCLUSION: PE consumption appears to affect specific colon tissue miRs but surgery critically alters miRs levels hindering the discrimination of significant changes caused by dietary factors and the establishment of genuine differences between malignant and normal tissues as biomarkers. The components responsible for the PE effects and the clinical relevance of these observations deserve further research.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Lythraceae , MicroRNAs/genética , Extratos Vegetais/farmacologia , Idoso , Idoso de 80 Anos ou mais , Colo/efeitos dos fármacos , Colo/fisiologia , Neoplasias Colorretais/dietoterapia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Método Duplo-Cego , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pré-OperatóriosRESUMO
SCOPE: Urolithins are bioactive metabolites produced by the gut microbiota from ellagitannins (ETs) and ellagic acid (EA). We investigated whether urolithins could be detected in colon tissues from colorectal cancer (CRC) patients after pomegranate extract (PE) intake. METHODS AND RESULTS: CRC patients (n = 52) were divided into controls and PEs consumers (900 mg/day for 15 days) before surgical resection. PEs with low (PE-1) and high (PE-2) punicalagin:EA ratio were administered. Twenty-three metabolites, but no ellagitannins, were detected in urine, plasma, normal (NT) or malignant (MT) colon tissues using UPLC-ESI-QTOF-MS/MS (UPLC, ultra performance liquid chromatography; QTOF, quadrupole TOF). Free EA, five EA conjugates, gallic acid and 12 urolithin derivatives were found in colon tissues. Individual and total metabolites levels were higher in NT than in MT, independently of the PE consumed. The maximal mean concentration (1671 ± 367 ng/g) was found in NT after consumption of PE-1 and the lowest concentration (42.4 ± 10.2 ng/g) in MT with PE-2. Urolithin A or isourolithin A were the main urolithins produced (54 and 46% patients with urolithin A or isourolithin A phenotype, respectively). High punicalagin content (PE-2) hampered urolithins formation. CONCLUSION: Significant levels of EA derivatives and urolithins are found in human colon tissues from CRC patients after consumption of pomegranate. Further studies are warranted to elucidate their biological activity.