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1.
Int J Nanomedicine ; 15: 8537-8552, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173291

RESUMO

Purpose: Assessment of inflammatory bowel disease (IBD) currently relies on aspecific clinical signs of bowel inflammation. Specific imaging of the diseased bowel regions is still lacking. Here, we investigate mucosal addressin cell adhesion molecule 1 (MAdCAM-1) as a reliable and specific endothelial target for engineered nanoparticles delivering imaging agents to obtain an exact mapping of diseased bowel foci. Materials and Methods: We generated a nanodevice composed of PLGA-PEG coupled with anti-MAdCAM-1 antibody half-chains and loaded with quantum dots (P@QD-MdC NPs). Bowel localization and systemic biodistribution of the nanoconjugate were analyzed upon injection in a murine model of chronic IBD obtained through repeated administration of dextran sulfate sodium salt. Specificity for diseased bowel regions was also assessed ex vivo in human specimens from patients with IBD. Potential for development as contrast agent in magnetic resonance imaging was assessed by preliminary study on animal model. Results: Synthesized nanoparticles revealed good stability and monodispersity. Molecular targeting properties were analyzed in vitro in a cell culture model. Upon intravenous injection, P@QD-MdC NPs were localized in the bowel of colitic mice, with enhanced accumulation at 24 h post-injection compared to untargeted nanoparticles (p<0.05). Nanoparticles injection did not induce histologic lesions in non-target organs. Ex vivo exposure of human bowel specimens to P@QD-MdC NPs revealed specific recognition of the diseased regions vs uninvolved tracts (p<0.0001). After loading with appropriate contrast agent, the nanoparticles enabled localized contrast enhancement of bowel mucosa in the rectum of treated mice. Conclusion: P@QD-MdC NPs efficiently detected bowel inflammation foci, accurately following the expression pattern of MAdCAM-1. Fine-tuning of this nanoconjugate with appropriate imaging agents offers a promising non-invasive tool for specific IBD diagnosis.


Assuntos
Moléculas de Adesão Celular/imunologia , Imunoconjugados/administração & dosagem , Doenças Inflamatórias Intestinais/diagnóstico por imagem , Mucoproteínas/imunologia , Pontos Quânticos/administração & dosagem , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Colite/induzido quimicamente , Colite/diagnóstico por imagem , Doença de Crohn/diagnóstico por imagem , Modelos Animais de Doenças , Feminino , Humanos , Imunoconjugados/farmacocinética , Injeções Intravenosas , Mucosa Intestinal/diagnóstico por imagem , Intestinos/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Distribuição Tecidual
4.
Aliment Pharmacol Ther ; 51(12): 1373-1383, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32383166

RESUMO

BACKGROUND: Transabdominal ultrasound is useful to assess inflammation in patients with ulcerative colitis (UC); however, the assessment of the rectum is challenging and a barrier for its widespread use. AIM: To evaluate if transperineal ultrasound is useful for predicting endoscopic and histological findings of the rectum in UC. METHODS: Fifty-three consecutive adults with UC who required colonoscopy were included and transperineal ultrasound was performed in combination with transabdominal ultrasound within a week before or after colonoscopy with rectal biopsy. Mayo endoscopic subscore (MES) ≤1 was defined as endoscopic healing and Geboes score <2.1, Robarts histopathology index ≤6, and Nancy index ≤1 were defined as histological healing. Limberg score and bowel wall thickness were recorded with transperineal ultrasound. Faecal calprotectin was also measured. RESULTS: Excellent correlation was confirmed between colonoscopy and transabdominal ultrasound in all segments except for the rectum. Rectal bowel wall thickness and Limberg score in transperineal ultrasound well correlated with rectal MES and histological indices. Bowel wall thickness ≤4 mm predicted endoscopic (Area under the curve [AUC] = 0.90) and histological (AUC = 0.87-0.89) healing. In multivariable logistic regression analysis, only bowel wall thickness in transperineal ultrasound was a significant independent predictor for rectal endoscopic and histologic healing (P < 0.05) and the predictability was better than faecal calprotectin. CONCLUSIONS: Transperineal ultrasound predicts endoscopic and histological healing of the rectum. The combination of transperineal ultrasound with transabdominal ultrasound visualises the entire colorectum and is an ideal modality for the treat-to-target strategy. Clinical Trials Registry number UMIN000033611 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000038323).


Assuntos
Colite Ulcerativa/diagnóstico , Endoscopia Gastrointestinal/métodos , Períneo/diagnóstico por imagem , Ultrassonografia/métodos , Cicatrização , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colite Ulcerativa/fisiopatologia , Colonoscopia/métodos , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiopatologia , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Períneo/patologia , Períneo/fisiopatologia , Prognóstico , Reto/diagnóstico por imagem , Reto/patologia , Reto/fisiopatologia , Índice de Gravidade de Doença , Adulto Jovem
5.
Aliment Pharmacol Ther ; 52(1): 5-19, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32432797

RESUMO

INTRODUCTION: The prognosis of dysplasia in patients with IBD is largely determined from observational studies from the pre-videoendoscopic era (pre-1990s) that does not reflect recent advances in endoscopic imaging and resection. AIMS: To better understand the risk of synchronous colorectal cancer and metachronous advanced neoplasia (ie high-grade dysplasia or cancer) associated with dysplasia diagnosed in the videoendoscopic era, and to stratify risk according to a lesion's morphology, endoscopic resection status or whether it was incidentally detected on biopsy of macroscopically normal colonic mucosa (ie invisible). METHODS: A systematic search of original articles published between 1990 and February 2020 was performed. Eligible studies reported on incidence of advanced neoplasia at follow-up colectomy or colonoscopy for IBD-dysplasia patients. Quantitative and qualitative analyses were performed. RESULTS: Thirty-three studies were eligible for qualitative analysis (five for the meta-analysis). Pooled estimated proportions of incidental synchronous cancers found at colectomy performed for a pre-operative diagnosis of visible high-grade dysplasia, invisible high-grade dysplasia, visible low-grade dysplasia and invisible low-grade dysplasia were 13.7% (95% CI 0.0-54.1), 11.4% (95% CI 4.6-20.3), 2.7% (95% CI 0.0-7.1) and 2.4% (95% CI 0.0-8.5) respectively. The lowest incidences of metachronous advanced neoplasia, for dysplasia not managed with immediate colectomy but followed up with surveillance, tended to be reported by the studies where high definition imaging and/or chromoendoscopy was used and endoscopic resection of visible dysplasia was histologically confirmed. CONCLUSIONS: The prognosis of IBD-dysplasia diagnosed in the videoendoscopic era appears to have been improved but the quality of evidence remains low. Larger, prospective studies are needed to guide management. PROSPERO registration no: CRD42019105736.


Assuntos
Colo/diagnóstico por imagem , Colonoscopia/métodos , Doenças Inflamatórias Intestinais/complicações , Mucosa Intestinal/diagnóstico por imagem , Colo/patologia , Humanos , Hiperplasia/diagnóstico por imagem , Hiperplasia/etiologia , Hiperplasia/patologia , Doenças Inflamatórias Intestinais/diagnóstico por imagem , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
PLoS One ; 15(4): e0231796, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287314

RESUMO

BACKGROUND: Antimicrobial peptide expression is associated with disease activity in inflammatory bowel disease (IBD) patients. IBD patients have abnormal expression of elafin, a human elastase-specific protease inhibitor and antimicrobial peptide. We determined elafin expression in blood, intestine, and mesenteric fat of IBD and non-IBD patients. METHODS: Serum samples from normal and IBD patients were collected from two UCLA cohorts. Surgical resection samples of human colonic and mesenteric fat tissues from IBD and non-IBD (colon cancer) patients were collected from Cedars-Sinai Medical Center. RESULTS: High serum elafin levels were associated with a significantly elevated risk of intestinal stricture in Crohn's disease (CD) patients. Microsoft Azure Machine learning algorithm using serum elafin levels and clinical data identified stricturing CD patients with high accuracy. Serum elafin levels had weak positive correlations with clinical disease activity (Partial Mayo Score and Harvey Bradshaw Index), but not endoscopic disease activity (Mayo Endoscopic Subscore and Simple Endoscopic Index for CD) in IBD patients. Ulcerative colitis (UC) patients had high serum elafin levels. Colonic elafin mRNA and protein expression were not associated with clinical disease activity and histological injury in IBD patients, but stricturing CD patients had lower colonic elafin expression than non-stricturing CD patients. Mesenteric fat in stricturing CD patients had significantly increased elafin mRNA and protein expression, which may contribute to high circulating elafin levels. Human mesenteric fat adipocytes secrete elafin protein. CONCLUSIONS: High circulating elafin levels are associated with the presence of stricture in CD patients. Serum elafin levels may help identify intestinal strictures in CD patients.


Assuntos
Colite Ulcerativa/sangue , Doença de Crohn/complicações , Elafina/sangue , Obstrução Intestinal/diagnóstico , Gordura Abdominal/citologia , Gordura Abdominal/metabolismo , Adipócitos/metabolismo , Adulto , Estudos de Casos e Controles , Linhagem Celular , Colite Ulcerativa/patologia , Colo/diagnóstico por imagem , Colo/patologia , Colonoscopia , Constrição Patológica/sangue , Constrição Patológica/diagnóstico , Constrição Patológica/etiologia , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Doença de Crohn/patologia , Elafina/metabolismo , Feminino , Fibroblastos , Voluntários Saudáveis , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Obstrução Intestinal/sangue , Obstrução Intestinal/etiologia , Obstrução Intestinal/patologia , Masculino , Cultura Primária de Células , Estudos Prospectivos , Índice de Gravidade de Doença
7.
Nat Commun ; 11(1): 1512, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32251296

RESUMO

Studies of inflammatory bowel disease (IBD) have been inconclusive in relating microbiota with distribution of inflammation. We report microbiota, host transcriptomics, epigenomics and genetics from matched inflamed and non-inflamed colonic mucosa [50 Crohn's disease (CD); 80 ulcerative colitis (UC); 31 controls]. Changes in community-wide and within-patient microbiota are linked with inflammation, but we find no evidence for a distinct microbial diagnostic signature, probably due to heterogeneous host-microbe interactions, and show only marginal microbiota associations with habitual diet. Epithelial DNA methylation improves disease classification and is associated with both inflammation and microbiota composition. Microbiota sub-groups are driven by dominant Enterbacteriaceae and Bacteroides species, representative strains of which are pro-inflammatory in vitro, are also associated with immune-related epigenetic markers. In conclusion, inflamed and non-inflamed colonic segments in both CD and UC differ in microbiota composition and epigenetic profiles.


Assuntos
Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Epigênese Genética/imunologia , Microbioma Gastrointestinal/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Adulto , Idoso , Bacteroides/genética , Bacteroides/imunologia , Bacteroides/isolamento & purificação , Biópsia , Células CACO-2 , Estudos de Casos e Controles , Estudos de Coortes , Colite Ulcerativa/genética , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Colo/diagnóstico por imagem , Colo/imunologia , Colo/microbiologia , Colo/patologia , Colonoscopia , Doença de Crohn/genética , Doença de Crohn/microbiologia , Doença de Crohn/patologia , DNA Bacteriano/isolamento & purificação , Enterobacteriaceae/genética , Enterobacteriaceae/imunologia , Enterobacteriaceae/isolamento & purificação , Epigenômica , Feminino , Microbioma Gastrointestinal/genética , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , RNA-Seq , Adulto Jovem
8.
Am J Surg Pathol ; 44(7): 955-961, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32235151

RESUMO

Surveillance colonoscopies focused to detect dysplasia are recommended to prevent colorectal cancer in patients with long-standing colonic inflammatory bowel disease (IBD). To date, histologic diagnosis and gradation of IBD-related dysplasia has been challenged by a high variability among pathologists. We aimed to analyze the observer characteristics that are correlated with concordance deviations in this diagnosis. Eight pathologists evaluated a set of 125 endoscopic biopsy samples with a representative distribution of nondysplastic and dysplastic lesions from long-standing IBD patients. Two rounds of diagnosis were carried out during a period of 18 months. The κ test was applied to analyze concordance. Pathologists were grouped on the basis of their experience. A subanalysis was performed by eliminating the highly prevalent nondysplastic samples, as well as an analysis after observers' grouping. Overall interobserver agreement was good (κ=0.73), with an even higher pairwise value (κ=0.86) as well as the intraobserver agreement values (best κ=0.85). After eliminating the highly prevalent nondysplastic samples, the interobserver agreement was still moderate to good (best overall κ=0.50; best paired κ=0.72). Notable differences were seen between the pathologists with a high-volume and low-volume practice (best overall κ=0.61 and 0.41, respectively). The agreement in the diagnosis of dysplasia in IBD endoscopic biopsies may have been undervalued over time. This is the first study evaluating pathologists' diagnostic robustness in this field. The results suggest that examining a large volume of samples is the key factor to increase the consistency in the diagnosis and gradation of IBD-related dysplasia.


Assuntos
Colo/patologia , Colonoscopia , Neoplasias Colorretais/patologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia , Lesões Pré-Cancerosas/patologia , Biópsia , Colo/diagnóstico por imagem , Neoplasias Colorretais/diagnóstico por imagem , Consenso , Humanos , Doenças Inflamatórias Intestinais/diagnóstico por imagem , Mucosa Intestinal/diagnóstico por imagem , Variações Dependentes do Observador , Patologistas , Lesões Pré-Cancerosas/diagnóstico por imagem , Estudos Prospectivos
9.
Sci Rep ; 10(1): 2295, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041974

RESUMO

It is understood that colorectal adenomas progress to colonic adenocarcinoma. Adenoma detection rate (ADR) at endoscopy has been used as a key performance indicator at endoscopy and is inversely associated with diagnosis of interval colorectal cancer. As most endoscopy reporting systems do not routinely incorporate histological assessment, ADR reporting is a cumbersome task. Polyp Detection Rate (PDR) has therefore been adopted as a surrogate marker for ADR. A prospectively maintained database of colonoscopies performed between July 2015 and July 2017 was analysed. This was cross referenced with a histological database. Statistical analysis was performed using IBM SPSS, version 24. Inferential procedures employed included the Pearson's correlation coefficient (r) and Binomial logistic regression. Of 2964 procedures performed by 8 endoscopists, overall PDR was 27% and ADR was 19%. The PDR, ADR, adenoma to polyp detection rate quotient (APDRQ) and estimated ADR (PDR x APDRQ group average = 0.72) was calculated for each individual. There was a strong positive linear correlation between PDR and ADR,r(8) = 0.734, p = 0.038 and between PDR and estimated ADR, r(8) = 0.998, p < 0.001. Adenoma detection rate strongly correlated with estimated ADR, r(8) = 0.720, p = 0.044. With the exclusion of a moderate outlier, these correlations increased in both strength and significance. There was a stronger correlation between PDR and ADR,r(7) = 0.921, p = 0.003 and between ADR and estimated ADR, r(7) = 0.928, p = 0.003.


Assuntos
Adenocarcinoma/epidemiologia , Pólipos Adenomatosos/epidemiologia , Pólipos do Colo/epidemiologia , Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais/epidemiologia , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Colo/diagnóstico por imagem , Colo/patologia , Pólipos do Colo/diagnóstico , Pólipos do Colo/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Irlanda/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reto/diagnóstico por imagem , Reto/patologia , Estudos Retrospectivos , Adulto Jovem
10.
Gastroenterology ; 158(6): 1546-1547, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32017908

Assuntos
Síndrome de Imunodeficiência Adquirida/complicações , Coinfecção/diagnóstico , Granuloma/diagnóstico , Proctite/diagnóstico , Doenças Sexualmente Transmissíveis/diagnóstico , Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida/imunologia , Antibacterianos/administração & dosagem , Antivirais/administração & dosagem , Ceftriaxona/administração & dosagem , Chlamydia trachomatis/genética , Chlamydia trachomatis/isolamento & purificação , Coinfecção/tratamento farmacológico , Coinfecção/imunologia , Coinfecção/microbiologia , Colonoscopia , Citomegalovirus/isolamento & purificação , DNA Bacteriano/isolamento & purificação , Doxiciclina/administração & dosagem , Quimioterapia Combinada/métodos , Granuloma/tratamento farmacológico , Granuloma/imunologia , Granuloma/microbiologia , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Neisseria gonorrhoeae/genética , Neisseria gonorrhoeae/isolamento & purificação , Proctite/tratamento farmacológico , Proctite/imunologia , Proctite/microbiologia , Reto/diagnóstico por imagem , Reto/microbiologia , Reto/patologia , Doenças Sexualmente Transmissíveis/tratamento farmacológico , Doenças Sexualmente Transmissíveis/imunologia , Doenças Sexualmente Transmissíveis/microbiologia , Resultado do Tratamento , Valganciclovir/administração & dosagem
11.
PLoS One ; 15(1): e0227832, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945116

RESUMO

Here we characterized the development of the trypanosomatid Blastocrithidia raabei in the dock bug Coreus marginatus using light and electron microscopy. This parasite has been previously reported to occur in the host hemolymph, which is rather typical for dixenous trypanosomatids transmitted to a plant or vertebrate with insect's saliva. In addition, C. marginatus has an unusual organization of the intestine, which makes it refractory to microbial infections: two impassable segments isolate the anterior midgut portion responsible for digestion and absorption from the posterior one containing symbiotic bacteria. Our results refuted the possibility of hemolymph infection, but revealed that the refractory nature of the host provokes very aggressive behavior of the parasite and makes its life cycle more complex, reminiscent of that in some dixenous trypanosomatids. In the pre-barrier midgut portion, the epimastigotes of B. raabei attach to the epithelium and multiply similarly to regular insect trypanosomatids. However, when facing the impassable constricted region, the parasites rampage and either fiercely break through the isolating segments or attack the intestinal epithelium in front of the barrier. The cells of the latter group pass to the basal lamina and accumulate there, causing degradation of the epitheliocytes and thus helping the epimastigotes of the former group to advance posteriorly. In the symbiont-containing post-barrier midgut segment, the parasites either attach to bacterial cells and produce cyst-like amastigotes (CLAs) or infect enterocytes. In the rectum, all epimastigotes attach either to the cuticular lining or to each other and form CLAs. We argue that in addition to the specialized life cycle B. raabei possesses functional cell enhancements important either for the successful passage through the intestinal barriers (enlarged rostrum and well-developed Golgi complex) or as food reserves (vacuoles in the posterior end).


Assuntos
Infecções por Euglenozoa/veterinária , Heterópteros/imunologia , Interações Hospedeiro-Parasita/fisiologia , Estágios do Ciclo de Vida/fisiologia , Trypanosomatina/crescimento & desenvolvimento , Animais , Resistência à Doença , Infecções por Euglenozoa/imunologia , Infecções por Euglenozoa/parasitologia , Hemolinfa/parasitologia , Heterópteros/parasitologia , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/parasitologia , Mucosa Intestinal/ultraestrutura , Microscopia Eletrônica , Trypanosomatina/patogenicidade , Trypanosomatina/ultraestrutura
12.
Gastroenterol. hepatol. (Ed. impr.) ; 43(1): 57-61, ene. 2020. graf, tab
Artigo em Inglês | IBECS | ID: ibc-188295

RESUMO

Introduction: Colonoscopy is currently considered to be the gold standard for evaluation of colonic mucosa inflammation in patients with ulcerative colitis (UC), but the procedure is invasive and cannot be repeated frequently, especially in the paediatric population. The aim of this study was to assess the role of faecal calprotectin (FC) as a predictor of endoscopic disease activity in paediatric patients with UC in clinical remission. Material and methods: Single-centre prospective study. Clinical remission was defined as Paediatric Ulcerative Colitis Activity Index <10. Endoscopic findings were assessed according to the Mayo Endoscopic Subscore (MES). MES≤1 was defined as endoscopic remission. All participants provided fresh faecal samples for measurement of FC. Results: A total of 34 visits of 24 children with UC were included in the study. There was a strong positive correlation between FC levels and endoscopic disease activity (n=34, r=0.83, p<0.001). The median FC levels in the subgroup with endoscopic activity (MES 2-3) were significantly higher than the median FC levels in the subgroup without endoscopic activity (MES≤1) (1000μg/g, IQR 575-1800μg/g vs. 100μg/g, IQR 80-223μg/g, p<0.001). At a cut-off of 298.5μg/g, FC had 92.3% sensitivity, 95.2% specificity and an AUROC 0.974 (SE 0.023, 95% CI 0.93-1, p<0.001) to predict endoscopic activity. Discussion: FC is an accurate surrogate marker of endoscopic activity in children with clinically quiescent UC


Introducción: Actualmente, la colonoscopia es considerada como el gold standard para la evaluación de la inflamación de la mucosa colónica en pacientes con colitis ulcerosa (CU), pero este procedimiento es invasivo y no se puede repetir frecuentemente, especialmente en la población pediátrica. El objetivo de este estudio es evaluar el papel de la calprotectina fecal (CF) como predictor de la actividad endoscópica de la enfermedad en pacientes pediátricos con CU en remisión clínica. Material y métodos: Estudio prospectivo monocéntrico. La remisión clínica se definió según el Índice de Actividad Pediátrico de Colitis Ulcerosa (Paediatric Ulcerative Colitis Activity Index) <10. Los hallazgos endoscópicos fueron evaluados según el Subscore Endoscópico de Mayo (SEM). SEM≤1 se definió como remisión endoscópica. En todos los participantes se obtuvo una muestra de heces para medición de la CF. Resultados: Un total de 34 visitas de 24 niños con CU se incluyeron en el estudio. Hubo una fuerte correlación positiva entre la CF y la actividad endoscópica de la enfermedad (n=34, r=0,83, p <0,001). La mediana de los niveles de CF en el subgrupo con actividad endoscópica (SEM 2-3) fue significativamente superior a la mediana de los niveles de CF en el subgrupo sin actividad endoscópica (MES≤1) (1.000 μg/g, IQR 575 μg/g-1.800 μg/g vs. 100 μg/g; IQR 80 μg/g-223 μg/g; p <0,001). Al nivel de corte de 298,5 μg/g la CF obtuvo una sensibilidad del 92,3%, una especificidad del 95,2% y un área bajo la curva de 0,974 (SE 0,023; IC del 95%, 0,93-1; p <0,001) para predecir actividad endoscópica. Discusión: La CF es un marcador indirecto preciso para actividad endoscópica en niños con CU clínicamente quiescente


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Colite Ulcerativa/diagnóstico , Endoscopia , Biomarcadores/análise , Fezes/química , Estudos Prospectivos , Mucosa Intestinal/patologia , Mucosa Intestinal/diagnóstico por imagem , Curva ROC
14.
Gastroenterology ; 158(3): 550-561, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31711921

RESUMO

BACKGROUND & AIMS: Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC). METHODS: In a phase 2, proof-of-concept, double-blind, parallel-group study, adult outpatients with modified Mayo Clinic scores (MCSs) (stool frequency, rectal bleeding, and endoscopy findings) of 4-9, endoscopic subscores of 2 or more, and rectal bleeding subscores of 1 or more were randomly assigned to groups given once-daily etrasimod 1 mg (n = 52), etrasimod 2 mg (n = 50), or placebo (n = 54) for 12 weeks. The study was performed from October 15, 2015, through February 14, 2018, at 87 centers in 17 countries. The primary endpoint was an increase in the mean improvement in modified MCS from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement (subscores of 1 or less) from baseline to week 12. Exploratory endpoints, including clinical remission, are reported in the article, although the study was statistically powered to draw conclusions only on the primary endpoint. RESULTS: At week 12, the etrasimod 2 mg group met the primary and all secondary endpoints. Etrasimod 2 mg led to a significantly greater increase in mean improvement in modified MCS from baseline than placebo (difference from placebo, 0.99 points; 90% confidence interval, 0.30-1.68; P = .009), and etrasimod 1 mg led to an increase in mean improvement from baseline in modified MCS of 0.43 points more than placebo (90% confidence interval, reduction of 0.24 to increase of 1.11; nominal P = .15). Endoscopic improvement occurred in 41.8% of patients receiving etrasimod 2 mg vs 17.8% receiving placebo (P = .003). Most adverse events were mild to moderate. Three patients had a transient, asymptomatic, low-grade atrioventricular block that resolved spontaneously all patients had evidence of atrioventricular block before etrasimod exposure. CONCLUSIONS: In patients with moderately to severely active ulcerative colitis, etrasimod 2 mg was more effective than placebo in producing clinical and endoscopic improvements. Further clinical development is warranted. Clinicaltrials.gov, Number: NCT02447302.


Assuntos
Acetatos/administração & dosagem , Bloqueio Atrioventricular/epidemiologia , Colite Ulcerativa/tratamento farmacológico , Hemorragia Gastrointestinal/prevenção & controle , Indóis/administração & dosagem , Acetatos/efeitos adversos , Adulto , Doenças Assintomáticas/epidemiologia , Bloqueio Atrioventricular/induzido quimicamente , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Colo/patologia , Colonoscopia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/epidemiologia , Hemorragia Gastrointestinal/etiologia , Humanos , Indóis/efeitos adversos , Quimioterapia de Indução/efeitos adversos , Quimioterapia de Indução/métodos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Estudo de Prova de Conceito , Reto , Índice de Gravidade de Doença , Receptores de Esfingosina-1-Fosfato/imunologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Resultado do Tratamento
15.
Gastroenterology ; 158(3): 515-526.e10, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31711925

RESUMO

BACKGROUND & AIMS: Noninvasive tests to measure endoscopic activity in patients with Crohn's disease (CD) have limitations. We aimed to develop a test to identify patients in remission, based on endoscopic analysis, and monitor CD activity based on serum levels of proteins. METHODS: We developed a test to measure 13 proteins in blood (ANG1, ANG2, CRP, SAA1, IL7, EMMPRIN, MMP1, MMP2, MMP3, MMP9, TGFA, CEACAM1, and VCAM1), called the endoscopic healing index [EHI], using samples from 278 patients with CD from a multinational training cohort. We validated the test using 2 independent cohorts of patients with CD: 116 biologic-naive patients with early-stage CD (validation cohort 1) and 195 biologic-exposed patients with chronic CD (validation cohort 2). The ability of the test to identify patients with active disease vs patients in remission (defined as a simple endoscopic score for CD of ≤2 and ≤1 in each segment, or a total CD endoscopic index of severity score <3) was assessed by using area under receiver operating characteristic curve (AUROC) analysis. The diagnostic accuracy of the test was compared with that of measurement of serum C-reactive protein (CRP) and fecal calprotectin. RESULTS: The EHI scores range from 0 to 100 units; higher scores indicate more severe CD activity, based on endoscopy findings. The EHI identified patients in remission with an AUROC of 0.962 in validation cohort 1 (95% confidence interval, 0.942-0.982) and an AUROC of 0.693 in validation cohort 2 (95% confidence interval, 0.619-0.767), regardless of CD location or phenotype. A cutoff value of 20 points identified patients in remission with the highest level of sensitivity (97.1% in validation cohort 1 and 83.2% in validation cohort 2), with specificity values of 69.0% and 36.6%, respectively. A cutoff value of 50 points identified patients in remission with the highest level of specificity (100% in validation cohort 1 and 87.8% in validation cohort 2), with sensitivity values of 37.3% and 30.0%, respectively. The EHI identified patients in remission with a significantly higher AUROC value than the test for CRP (0.876, P < .001 in validation cohort 1 and 0.624, P = .109 in validation cohort 2). In analysis of patients with available FC measurements, the AUROC value for the EHI did not differ significantly from that of measurement of FC (AUROC, 0.950 for EHI vs AUROC, 0.923 for FC; P = .147 in validation cohort 1 and AUROC, 0.803 for EHI vs AUROC, 0.854 for FC; P = .298 in validation cohort 2). CONCLUSIONS: We developed an index called the EHI to identify patients with CD in endoscopic remission based on blood levels of 13 proteins. The EHI identified patients with resolution of endoscopic disease activity, with good overall accuracy, although with variation between the 2 cohorts assessed. The EHI AUROC values were comparable to measurement of FC and higher than measurement of serum CRP. The test might be used in practice to assess endoscopic activity in patients with CD.


Assuntos
Colonoscopia , Doença de Crohn/diagnóstico , Fármacos Gastrointestinais/administração & dosagem , Infliximab/administração & dosagem , Índice de Gravidade de Doença , Adulto , Biomarcadores/sangue , Proteína C-Reativa/análise , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Colo/patologia , Doença de Crohn/sangue , Doença de Crohn/tratamento farmacológico , Fezes/química , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Complexo Antígeno L1 Leucocitário/análise , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Recidiva , Indução de Remissão/métodos , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
19.
Gastroenterology ; 158(4): 862-874.e8, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31376388

RESUMO

BACKGROUND & AIMS: Few studies have evaluated long-term outcomes of ongoing colonoscopic screening and surveillance in a screening population. We aimed to determine the 10-year risk for advanced neoplasia (defined as adenomas ≥10mm, adenomas with villous histology or high-grade dysplasia, or colorectal cancer [CRC]) and assessed whether baseline colonoscopy findings were associated with long-term outcomes. METHODS: We collected data from the Department of Veterans Affairs Cooperative Studies Program Study on 3121 asymptomatic veterans (50-75 years old) who underwent a screening colonoscopy from 1994 through 1997 at 13 medical centers and were then followed for 10 years or until death. We included 1915 subjects with at least 1 surveillance colonoscopy and estimated cumulative incidence of advanced neoplasia by Kaplan-Meier curves. We then fit a longitudinal joint model to estimate risk of advanced neoplasia at each subsequent examination after baseline, adjusting for multiple colonoscopies within individuals. RESULTS: Through 10 years of follow-up, there were 146 individuals among all baseline colonoscopy groups found to have at least 1 incident advanced neoplasia. The cumulative 10-year incidence of advanced neoplasia was highest among those with baseline CRC (43.7%; 95% CI 13.0%-74.4%), followed by those with baseline advanced adenoma (AA) (21.9%; 95% CI 15.7-28.1). The cumulative 10-year incidence of advanced neoplasia was 6.3% (95% CI 4.1%-8.5%) and 4.1% (95% CI 2.7%-5.4%) for baseline 1 to 2 small adenomas (<1cm, and without villous histology or high-grade dysplasia) and no neoplasia, respectively (log-rank P = .10). After adjusting for prior surveillance, the risk of advanced neoplasia at each subsequent examination was not significantly increased in veterans with 1 or 2 small adenomas at baseline (odds ratio 0.96; 95% CI 0.67-1.41) compared with veterans with no baseline neoplasia. CONCLUSIONS: Baseline screening colonoscopy findings associate with advanced neoplasia within 10 years. Individuals with only 1 or 2 small adenomas at baseline have a low risk of advanced neoplasia over 10 years. Alternative surveillance strategies, could be considered for these individuals.


Assuntos
Adenoma/patologia , Pólipos do Colo/patologia , Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais/epidemiologia , Detecção Precoce de Câncer/estatística & dados numéricos , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Idoso , Colo/diagnóstico por imagem , Colo/patologia , Colo/cirurgia , Pólipos do Colo/diagnóstico por imagem , Pólipos do Colo/cirurgia , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Incidência , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Mucosa Intestinal/cirurgia , Estudos Longitudinais , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia , United States Department of Veterans Affairs/estatística & dados numéricos , Veteranos/estatística & dados numéricos
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