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BACKGROUND: Robotic surgery has been developed with the aim of improving surgical quality and overcoming the limitations of conventional laparoscopy in the performance of complex mini-invasive procedures. The present study was designed to compare robotic and laparoscopic distal gastrectomy in the treatment of gastric cancer. METHODS: Between June 2008 and September 2015, 41 laparoscopic and 30 robotic distal gastrectomies were performed by a single surgeon at the same institution. Clinicopathological characteristics of the patients, surgical performance, postoperative morbidity/mortality and pathologic data were prospectively collected and compared between the laparoscopic and robotic groups by the Chi-square test and the Mann-Whitney test, as indicated. RESULTS: There were no significant differences in patient characteristics between the two groups. Mean tumor size was larger in the laparoscopic than in the robotic patients (5.3 ± 0.5 cm and 3.0 ± 0.4 cm, respectively; P = 0.02). However, tumor stage distribution was similar between the two groups. The mean number of dissected lymph nodes was higher in the robotic than in the laparoscopic patients (39.1 ± 3.7 and 30.5 ± 2.0, respectively; P = 0.02). The mean operative time was 262.6 ± 8.6 min in the laparoscopic group and 312.6 ± 15.7 min in the robotic group (P < 0.001). The incidences of surgery-related and surgery-unrelated complications were similar in the laparoscopic and in the robotic patients. There were no significant differences in short-term clinical outcomes between the two groups. CONCLUSIONS: Within the limitation of a small-sized, non-randomized analysis, our study confirms that robotic distal gastrectomy is a feasible and safe surgical procedure. When compared with conventional laparoscopy, robotic surgery shows evident benefits in the performance of lymphadenectomy with a higher number of retrieved and examined lymph nodes.
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Gastrectomia/métodos , Laparoscopia , Excisão de Linfonodo , Procedimentos Cirúrgicos Robóticos , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
INTRODUCTION: Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders with a 9 - 23% prevalence estimated in the general population. Patients can be subdivided into those who tend to have predominant diarrhea (IBS-D) or predominant constipation (IBS-C). Total annual productivity loss related to IBS in US is estimated at $205 million, with a significant impairment of health-related quality of life. A gold standard for the treatment of IBS is not established. Symptoms might improve with the use of few drugs and behavioral therapy, however, data concerning efficacy, safety and tolerability are limited. Therefore, development and validation of new therapies targeting at the molecular level are widely awaited. AREAS COVERED: We will specifically describe in this review Phase II and Phase III trials, with specific focus on treatment of IBS-D patients. Unfortunately, it is difficult to draw definite conclusions from Phase II and Phase III trials, because of the known high placebo effect. EXPERT OPINION: Drugs active on opioid receptor subtypes and neurokinin (NK) receptors seem to be the most promising, but substantial progress of information in this field is still needed. The achievement of more insights on the pathogenesis of IBS could surely better drive and target the therapy, but still strong efforts are awaited.
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Diarreia/tratamento farmacológico , Desenho de Fármacos , Síndrome do Intestino Irritável/tratamento farmacológico , Animais , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Diarreia/etiologia , Humanos , Síndrome do Intestino Irritável/fisiopatologia , Qualidade de VidaRESUMO
BACKGROUND: Some recent studies have suggested that laparoscopic surgery for colorectal cancer may provide a potential survival advantage when compared with open surgery. This study aimed to compare cancer-related survivals of patients who underwent laparoscopic or open resection of colon cancer in the same, high volume tertiary center. METHODS: Patients who had undergone elective open or laparoscopic surgery for colon cancer between January 2002 and December 2010 were analyzed. A clinical database was prospectively compiled. Survival analysis was calculated by using the Kaplan-Meier method. RESULTS: A total of 460 resections were performed. There were no significant differences between the laparoscopic (n = 227) and the open group (n = 233) apart from tumor stage: stage I tumors were more frequent in the laparoscopic group whereas stage II tumors were more frequent in the open group. The mean number of harvested lymph nodes was significantly higher in the laparoscopic than in the open group (20.0 ± 0.7 vs 14.2 ± 0.5, P < 0.01). The 5-year cancer-related survival for patients undergoing laparoscopic resection was significantly higher than that following open resections (83.1% vs 68.5%, P = 0.01). By performing a stage-to-stage comparison, we found that the improvement in survival in the laparoscopic group occurred mainly in patients with stage II tumors. CONCLUSIONS: Our study shows a survival advantage for patients who had undergone laparoscopic surgery for stage II colon cancer. This may be correlated with a higher number of harvested lymph nodes and thus a better stage stratification of these patients.
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Adenocarcinoma/cirurgia , Colectomia/métodos , Neoplasias do Colo/cirurgia , Laparoscopia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate radiological sacroiliac abnormalities in IBD patients without musculoskeletal symptoms and to determine the clinical and familiar differences between IBD patients with and without radiologic sacroiliac joint (SIJ) abnormalities. Subsequently, the patients with x-ray alterations were followed for 3 years in order to assess the onset of chronic inflammatory back pain (IBP). METHODS: 81 patients (55 Crohn-CD- and 26 ulcerative rettocolitis-UC) with remittent and low active IBD, from a tertiary referral centre of Gastroenterology Unit, were studied using SIJ x-rays. Differences in IBD clinical variables (activity and duration of CD and UC, extra-intestinal involvement, treatment with surgery and not, ESR and CRP levels), familiarity (for psoriasis, IBD, spondyloarthritis, coeliac syndrome), between patients with SIJ x-ray findings and without were investigated. Patients with radiological sacroiliac joint abnormalities were followed up clinically for 3 years and the onset of symptoms of chronic (higher than 3 consecutive months) IBP was investigated. RESULTS: 22/81 patients (27.1%) showed radiological SIJ abnormalities at baseline: isolated sclerosis in 17/22 (77.3%) and localised erosions in 12/22 (54.5%). Radiological SIJ involvement did not correlate with IBD clinical and familial variables. All patients were HLA B27 negative. At 3 years, 4/22 patients (18.1%) presented chronic IBP symptoms with bone oedema at MRI. CONCLUSIONS: In IBD, occult radiological SIJ alterations might precede the onset of axial symptoms but, in the absence of clinical signs, it is not possible to identify some IBD features or familiar predisposition that might be more frequent when SIJ abnormalities are involved. Clinical follow-up might be useful in these patients for a diagnosis of axial spondyloarthritis onset.
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Colite Ulcerativa/diagnóstico por imagem , Doença de Crohn/diagnóstico por imagem , Ílio/diagnóstico por imagem , Sacroileíte/etiologia , Sacro/diagnóstico por imagem , Espondilite/etiologia , Adolescente , Adulto , Idoso , Dor Crônica/diagnóstico , Dor Crônica/etiologia , Doença de Crohn/complicações , Edema/diagnóstico , Edema/etiologia , Feminino , Humanos , Itália , Dor Lombar/diagnóstico , Dor Lombar/etiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Medição da Dor , Valor Preditivo dos Testes , Radiografia , Fatores de Risco , Sacroileíte/diagnóstico , Espondilite/diagnóstico , Centros de Atenção Terciária , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND AND AIMS: Intestinal ultrasound [IUS] is widely accepted as a reliable tool to monitor Crohn's disease [CD]. Several IUS scores have been proposed, but none has been formally accepted by international organizations. Our aim here was to compare the available scores regarding their correlation with endoscopic activity. METHODS: Consenting CD patients undergoing ileocolonoscopy at our Unit between September 2021 and February 2023 were included. Endoscopic activity was defined as SES-CDâ ≥â 3 or Rutgeerts scoreâ ≥â i2b for operated patients. IUS was performed within 6 weeks of endoscopy and scored with IBUS-SAS, BUSS, Simple-US and SUS-CD scores. All correlations were performed using Spearman's rank coefficient [rho = ρ]. Receiver operating characteristic [ROC] curves were compared with the Hanley and McNeil method. RESULTS: Of 73 CD patients, 45 [61.6%] presented endoscopic activity, of whom 22 were severe [30.1%]. All IUS scores showed a significant positive correlation with endoscopy [pâ <â 0.0001], with IBUS-SAS ranking the highest [ρâ =â 0.87]. Similarly, IBUS-SAS was the most highly correlated with clinical activity [ρâ =â 0.58]. ROC analysis of IBUS-SAS for any endoscopic activity showed the highest area under the curve (0.95 [95% confidence interval 0.87-0.99]), with sensitivity of 82.2% and specificity of 100% for a cut-off value of 25.2. IBUS-SAS was statistically superior to all the other scores in detecting severe endoscopic activity [SES-CDâ ≥â 9 or Rutgeerts i4]. CONCLUSIONS: All IUS scores provided solid correlation with endoscopy and clinical symptoms. IBUS-SAS outperformed the others due to a more granular description that might help in stratifying different levels of disease activity. Therefore, the use of IBUS-SAS in centres with well-founded expertise in IUS can be suggested.
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OBJECTIVES: Inflammatory bowel disease (IBD) can affect young and reproductively active patients. Our aim was to analyze pregnancy outcomes in a large cohort of women with IBD. METHODS: All women with at least one pregnancy were given a questionnaire regarding the outcome of their pregnancy. They were divided into IBD pregnancies and controls depending on whether pregnancy occurred within or over 10 years prior to the diagnosis of IBD. RESULTS: Three hundred questionnaires were analyzed for a total of 478 pregnancies that led to live-born babies. Age at conception was older in IBD women than in the controls. Active smoking was more frequent in the control group. The risk of intrauterine growth restriction (IUGR) was higher in IBD pregnancies (odds ratio [OR] 3.028, 95% confidence interval [CI] 1.245-7.370, P = 0.013). The week of gestation at delivery was lower in the IBD population. And the risk of cesarean section was higher in IBD pregnancies (OR 1.963, 95% CI 1.274-3.028, P = 0.002). Among women with IBD pregnancy, the risk of preterm birth was higher in patients with active disease at the time of conception (OR 4.088, 95% CI 1.112-15.025, P = 0.030), but lower in patients who continued regular therapy during pregnancy. Similarly, the risk of urgent cesarean section was reduced in the case of disease remission, while the risk of a planned cesarean delivery was higher in patients with perianal disease (OR 11.314, 95% CI 3.550-36.058, P < 0.01). CONCLUSIONS: Our study shows a higher risk of IUGR, cesarean section, and poor blood pressure control in IBD pregnancies. We emphasize the importance of achieving disease remission before considering pregnancy.
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Doenças Inflamatórias Intestinais , Nascimento Prematuro , Lactente , Recém-Nascido , Humanos , Feminino , Gravidez , Resultado da Gravidez , Cesárea/efeitos adversos , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/epidemiologia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Few data are currently available about SB5 in inflammatory bowel diseases (IBD). The aim of this study was to assess the effectiveness and safety of SB5 in a cohort of patients with IBD in stable remission switched from the adalimumab (ADA) originator and in a cohort of patients with IBD naïve to ADA. METHODS: We prospectively enrolled patients with IBD who started ADA treatment with SB5 (naïve cohort) and those who underwent a nonmedical switch from the ADA originator to SB5 (switching cohort). Clinical remission and safety were assessed at baseline and at 3, 6, and 12 months. In addition, in a small cohort of patients who were switched, we assessed the ADA serum trough levels and antidrug antibodies at baseline, 3, and 6 months. RESULTS: In the naïve cohort, the overall remission rate at 12 months was 60.42%, whereas in the switching cohort it was 89.02%. Fifty-three (36.3%) patients experienced an adverse event, and injection site pain was the most common; it was significantly more frequent in the switching cohort (Pâ =â 0.001). No differences were found in terms of ADA serum trough levels at baseline, 3, and 6 months after switching. No patient developed antidrug antibodies after the switch. CONCLUSIONS: We found that SB5 seemed effective and safe in IBD, both in the naïve cohort and in the switching cohort. Further studies are needed to confirm these data in terms of mucosal healing.
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Medicamentos Biossimilares , Doenças Inflamatórias Intestinais , Adalimumab , Medicamentos Biossimilares/uso terapêutico , Seguimentos , Humanos , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Sistema de Registros , Comprimidos/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the presence of lower limb entheseal abnormalities in IBD patients without clinical signs and symptoms of SpA and their correlation with IBD clinical variables. METHODS: A total of 81 IBD patients [55 Crohn's disease (CD) and 26 ulcerative colitis (UC), 43 females and 38 males, mean age 41.3 (12.4) years, BMI 24 (2)] with low active (12) and inactive (67) disease were consecutively studied with US (LOGIQ5 General Electric 10-MHz linear array transducer) of lower limb entheses and compared with 40 healthy controls matched for sex, age and BMI. Quadriceps, patellar, Achilleon and plantar fascia entheses were scored according to the 0-36 Glasgow Ultrasound Enthesitis Scoring System (GUESS) and power Doppler (PD). Correlations of GUESS and PD with IBD features [duration, type (CD/UC) and activity (disease activity index for CD/Truelove score for UC)] were investigated. The intra- and inter-reader agreements for US were estimated in all images detected in patients and controls. RESULTS: Of the 81 patients, 71 (92.6%) presented almost one tendon alteration with mean GUESS 5.1 (3.5): 81.5% thickness (higher than controls P < 0.05), 67.9% enthesophytosis, 27.1% bursitis and 16.1% erosions. PD was positive in 13/81 (16%) patients. In controls, US showed only enthesophytes (5%) and no PD. GUESS and PD were independent of duration, activity or type (CD/UC) of IBD. The intra- and inter-reader agreements were high (>0.9 intra-class correlation variability). CONCLUSIONS: US entheseal abnormalities are present in IBD patients without clinical signs and symptoms of SpA. US enthesopathy is independent of activity, duration and type of gut disease.
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Doenças Inflamatórias Intestinais/diagnóstico por imagem , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Reumáticas/diagnóstico por imagem , Espondiloartropatias/diagnóstico por imagem , Adulto , Distribuição por Idade , Estudos de Casos e Controles , Colite Ulcerativa/diagnóstico por imagem , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/fisiopatologia , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/epidemiologia , Doença de Crohn/fisiopatologia , Feminino , Humanos , Incidência , Doenças Inflamatórias Intestinais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Prognóstico , Valores de Referência , Doenças Reumáticas/epidemiologia , Doenças Reumáticas/fisiopatologia , Medição de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Espondiloartropatias/epidemiologia , Espondiloartropatias/fisiopatologia , UltrassonografiaRESUMO
BACKGROUND: Acute severe ulcerative colitis (ASUC) is a potentially life-threatening disease, and the best option in cases of steroid-refractory disease is still debated. We compared the early- and long-term efficacy and safety of the 2 available "rescue therapies", infliximab (IFX) and cyclosporine (CYS), in this setting. METHODS: We retrospectively evaluated patients admitted for ASUC and treated with "rescue therapy". The primary endpoint was early colectomy-free survival (30 days) and colectomy-free survival until the end of follow up. The secondary endpoints were predictors of colectomy and long-term maintenance of the treatment strategy over time. RESULTS: Of 129 patients admitted, 68 received rescue therapy (47 with IFX), whereas 7 underwent early colectomy (10.3%). At 30 days, fewer patients treated with IFX showed a need for colectomy (8.5% vs. 14.3%) compared to those in the CYS group, though the difference was non-significant (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.10-4.69; P=0.47). No severe side effects due to IFX and CYS were observed. During a mean follow up of 40 months, 23 additional patients (37.7%) underwent colectomy, and the rate was significantly lower in the IFX group (25.6%) than in the CYS group (66.7%) (hazard ratio 0.25, 95%CI 0.10-0.61; P=0.003). Colectomy-free survival was significantly higher in the IFX group than in the CYS group (P=0.018) at 12 months. CONCLUSIONS: In our setting, the early outcomes of IFX and CYS for ASUC were comparable. IFX was associated with significantly lower colectomy rates during the observation period and had a similar safety profile to CYS.
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BACKGROUND AND AIMS: Vedolizumab is a gut-selective anti-integrin (α4ß7) antibody for the treatment of inflammatory bowel disease with a well-known optimal safety profile. We aimed to compare its risk of infections with that of anti-TNF drugs and ustekinumab in patients with both ulcerative colitis and Crohn's disease. METHODS: All Crohn's disease and ulcerative colitis patients undergoing biological treatment at our centre between 2013 and 2019 were retrospectively included. All infectious complications were registered, considering both inpatient and outpatient events. A comparison of the exposure-adjusted infection rates of vedolizumab, anti-TNF drugs and ustekinumab was carried out, with a specific focus on the rate of gut infections. All infection rates were expressed in events per patient-years (PYs). RESULTS: The overall exposure-adjusted infection rate was 11.5/100 PYs. The most common infections were respiratory tract infections, cutaneous infections, HSV infections/reactivations and gut infections. The rate of serious infections was 1.3/100 PYs. The infection rate of vedolizumab was 17.5/100 PYs, with Crohn's disease patients having a lower infection risk compared with ulcerative colitis patients (P = 0.035). Gut infections were observed in 3.0% of the whole patient population (1.5/100 PYs) and were more common in the vedolizumab group (P = 0.0001). CONCLUSIONS: Our study confirms the good safety profile of vedolizumab. Among patients treated with vedolizumab, those with ulcerative colitis have a higher risk of developing infectious complications. Patients treated with vedolizumab have a higher risk of gut infections compared with patients treated with anti-TNF drugs or ustekinumab. Presumably, this is due to the gut-selective mechanism of action of vedolizumab.
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Colite Ulcerativa , Doença de Crohn , Infecções , Doenças Inflamatórias Intestinais , Anticorpos Monoclonais Humanizados , Fatores Biológicos/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/epidemiologia , Doença de Crohn/induzido quimicamente , Doença de Crohn/tratamento farmacológico , Doença de Crohn/epidemiologia , Fármacos Gastrointestinais/efeitos adversos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/epidemiologia , Estudos Retrospectivos , Inibidores do Fator de Necrose Tumoral , Ustekinumab/efeitos adversosRESUMO
Intracellular adhesion molecules and matrix metalloproteinases (MMPs) are up-regulated in intestinal mucosa of patients with inflammatory bowel diseases (IBD), i.e. ulcerative colitis (UC) or Crohn's disease (CD). Our aim was to verify whether the vitamin D analogue ZK 156979 (ZK) down-regulates adhesion molecules, and decreases MMPs production by PBMC of IBD patients. ICAM-1 and LFA-1 levels increase, when PBMC were incubated with PHA or LPS or TNF-alpha, and decrease when these substances were used in combination with ZK. MMPs activity increases incubating the cells with PHA or LPS or TNF-alpha. MMP-9 decreases when ZK was used in association, while MMP-2 decreases only when ZK was used in combination with anti-TNF-alpha. Our results suggest that the down-regulation of ICAM-1 and LFA-1 on PBMC and the inhibition of MMP-9 activity by ZK could provide a potential role of this low calcemic vitamin D derivative in future strategies in IBD therapy.
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Moléculas de Adesão Celular/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Leucócitos Mononucleares/metabolismo , Metaloproteinases da Matriz/metabolismo , Vitamina D/análogos & derivados , Adulto , Idoso , Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Feminino , Humanos , Imunossupressores/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Fito-Hemaglutininas/farmacologia , Receptores de Calcitriol/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Vitamina D/farmacologiaRESUMO
BACKGROUND: Prevention and management of postoperative recurrence (POR) is a controversial field in Crohn's disease. The aim of this survey was to report common practice in real-life settings. METHODS: An 11-question survey was distributed among gastroenterologists attending the 14th European Crohn's and Colitis Organisation (ECCO) congress. RESULTS: Postoperative endoscopy to assess recurrence was routinely performed within 12 months by 87% of respondents. Forty-six percent of clinicians reported to maintain endoscopic assessment in routine follow-up even after first negative colonoscopy. Most respondents (60%) considered starting postoperative immunoprophylaxis in naïve patients if one or more known risk factors were present. The number of risk factors was an important driver for prescribing biologics over immunosuppressants for 60% of respondents.In case of fistulizing phenotype, perianal disease, or concomitant colonic involvement, the majority of physicians reported to start an immediate prophylaxis in 85, 98 and 88% of patients, respectively. A significant percentage of clinicians were more prone to an endoscopy-driven treatment in long-standing disease after failure of thiopurines (51%) and elderly (43%). CONCLUSION: Endoscopy within the first year after surgery to assess POR has become routine in most centres. The high rate of early prophylaxis with expensive biologics despite missing solid evidence highlights the need for more randomized trials.
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Doença de Crohn , Idoso , Colonoscopia , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Humanos , Período Pós-Operatório , Recidiva , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: The study aimed to evaluate the long-term efficacy and safety of vedolizumab in a real-life cohort of patients with inflammatory bowel diseases enrolled at a tertiary referral center. METHODS: Data were retrospectively collected from August 2016 to November 2018. The primary outcomes were clinical response and remission at 14, 24, and 52 weeks, and steroid-free remission rate (SFRR) at 52 weeks. Endoscopic response and remission rates at 52 weeks were the secondary outcomes. RESULTS: Altogether 49 patients (22 with ulcerating colitis [UC] and 27 with Crohn's Disease [CD]) were enrolled. The clinical response rate gradually dropped from 85% and 50% in CD and UC, respectively, at week 14 to 59% and 25% at week 52, with significantly a higher response in CD at week 14. The endoscopic response at week 52 was 55% in CD and 25% in UC (P = 0.21). CD group had a higher SFRR than UC group (41% vs 20%) at 52 weeks, although the difference was not statistically significant. Similar clinical and endoscopic rates were observed in biologic-naive and -experienced patients. We reported no discontinuation due to adverse drug reactions, and only mild to moderate events. CONCLUSIONS: In our cohort the clinical response in the induction phase was similar to those of registered trials, despite surprising better results for CD. During the maintenance phase we observed an higher drop out than in the reported literatures. Of note, its good safety profile makes vedolizumab a reliable choice in patients with contraindications to anti-tumor necrosis factor agents.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Esquema de Medicação , Quimioterapia Combinada , Feminino , Fármacos Gastrointestinais/efeitos adversos , Glucocorticoides/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Centros de Atenção Terciária , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Lymphocytes are crucial in the pathogenesis of inflammatory bowel disease (IBD) and are an important target for drug development. Our aim was to verify whether 2 vitamin D derivatives, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and EB 1089, could induce cell apoptosis and affect cell-cell interaction by regulating adhesion molecule levels. METHODS: Peripheral blood mononuclear cell (PBMC) proliferation was studied by [3H]thymidine incorporation and apoptosis was determined using an enzyme-linked immunosorbent assay (ELISA) kit. (Poly(ADP-ribose)polymerase (PARP) cleavage, caspase-3, and ICAM-1 protein levels were determined by Western blot analysis. RESULTS: Our results indicate that 1,25(OH)2D3 or EB 1089 or anti-TNF-alpha (infliximab) induce apoptosis in PBMC obtained from healthy subjects. In IBD patients apoptosis is induced by vitamin D derivatives and by anti-TNF-alpha only in CD patients. Caspase-3 activation and PARP cleavage are registered when PBMC were treated with vitamin D derivatives. ICAM-1 levels remarkably increase when PBMC was incubated with lipopolysaccharide (LPS) or TNF-alpha. The treatment with the vitamin D derivatives, alone or in combination with LPS or TNF-alpha, significantly decreases ICAM-1 levels both in healthy subjects and IBD patients. In HUVEC cocultured with PBMC, previously incubated with LPS or TNF-alpha associated with 1,25(OH)2D3, ICAM-1 levels decrease both in healthy subjects and IBD patients. CONCLUSIONS: 1,25(OH)2D3 and EB 1089 inhibit PBMC proliferation, induce apoptosis in PBMC of healthy subjects and IBD patients, and affect ICAM-1 expression on PBMC and on HUVEC cocultured with PBMC, suggesting that the ICAM-1 downregulation could provide a new target for controlling the recruitment of leukocytes at the sites of inflammation in IBD.
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Apoptose/genética , DNA/genética , Regulação para Baixo/genética , Doenças Inflamatórias Intestinais/genética , Molécula 1 de Adesão Intercelular/genética , Leucócitos Mononucleares/metabolismo , Vitamina D/administração & dosagem , Adulto , Idoso , Apoptose/efeitos dos fármacos , Western Blotting , Calcitriol/análogos & derivados , Calcitriol/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fragmentação do DNA , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/tratamento farmacológico , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Prognóstico , Vitamina D/agonistas , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico , Vitaminas/uso terapêuticoRESUMO
OBJECTIVE: Pathological evidence supports a potential role of the pro- and anti-inflammatory cytokine network in the pathogenesis of inflammatory bowel disease (IBD). Moreover, associated studies suggest a possible involvement of cytokine-related genes in IBD susceptibility. In this study, we evaluated the effect of the anti-inflammatory interleukin-10 (IL10) gene on ulcerative colitis (UC). MATERIAL AND METHODS: Two functional single nucleotide polymorphisms (-1082 G/A, -819 T/C) in the IL10 promoter in 203 Italian sporadic UC patients and 391 controls were determined using high-resolution melting analysis. RESULTS: The frequency of the -1082A allele was significantly higher in the UC patients than in controls (p=0.00003); -1082 genotype frequencies were also significantly different between UC patients and controls (p=0.0001). Allele and genotype frequencies of -819 T/C were not significantly associated with UC. Furthermore, the frequencies of haplotypes -1082A/-819C and -1082A/-819T, which have been reported to have a lower promoter activity, were significantly higher in UC patients than in controls (p=0.0004). After gender stratification, we found a significant difference in the -1082A allele (p=0.00004) and genotype (p=0.0002) frequencies only between female UC patients and controls; the same result was obtained for the -1082A/-819C and -1082A/-819T haplotypes (p=0.0006). CONCLUSIONS: A gender effect is observed, with women of AG/AA IL10 genotypes and AC/AT haplotypes having a higher risk of developing UC at a younger age. This finding could be related to the previously documented lower IL10 production associated with the -1082A allele and to the IL10 down-regulating effect of estrogens.
Assuntos
Colite Ulcerativa/genética , Predisposição Genética para Doença , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Identidade de Gênero , Frequência do Gene , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
OBJECTIVE: To evaluate the efficacy and safety of golimumab in biological naive and experienced patients with moderately to severely active ulcerative colitis (UC) treated at two Italian IBD centers. METHODS: We retrospectively reviewed our prospectively maintained UC database from March 2015 to March 2017. Patients received golimumab 200 mg at week 0, 100 mg at week 2, then 50 mg or 100 mg every 4 weeks. Follow-up was recorded at 12 and 24 weeks and in March 2017, with a median follow-up of 64 weeks. The main outcomes evaluated were clinical remission (CR) and adverse event rates. RESULTS: Of the 59 patients (44% naive and 56% experienced), CR rate was 47% at 12-week follow-up, 55% (among the 49 patients on treatment) at 24-week follow-up and 49% (among 35 patients on treatment) at the last follow-up visit. Median treatment duration was 52 weeks (interquartile range 30-64 weeks) among patients treated for >6 months. Overall, 10 (17%) patients experienced adverse events, of whom 50% discontinued treatment. The most frequent adverse events were infections. Biological naive and experienced patients did not differ in terms of CR and adverse event rates. CONCLUSIONS: Our real-life experience showed that CR decreased over time and was achieved by almost one-third of the cohort at the last follow-up visit. Golimumab showed an overall favorable safety profile and the results were not different between biological naive and experienced patients. Future research is needed to confirm our results and to identify criteria to select patients most likely to respond.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Adulto , Anticorpos Monoclonais/efeitos adversos , Feminino , Fármacos Gastrointestinais/efeitos adversos , Herpes Simples/induzido quimicamente , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Retratamento , Estudos Retrospectivos , Infecções Urinárias/induzido quimicamenteRESUMO
BACKGROUND: Hypersensitivity reactions (HRs) and loss of response (LOR) to infliximab (IFX) are related to drug immunogenicity characterized by antidrug antibodies (ADAs). OBJECTIVE: To analyze the timing of ADA appearance and its relationship with drug levels and clinical outcomes in IFX-treated patients with different diseases. METHODS: Samples were longitudinally collected before each infusion from 91 IFX-treated patients and were assayed for ADA and drug levels by enzyme-linked immunosorbent assay and for IgE by ImmunoCAP system. Clinical data regarding efficacy and safety of therapy were also monitored. RESULTS: The ADA onset occured quite early, irrespective of the type of disease, during the first year and more frequently and earlier during the second cycle of therapy. Patients with HR were more frequently ADA-positive and with higher ADA titers compared with other patient groups. ADA onset tends to precede HRs and LOR; all HRs that occur after a period of drug interruption are preceded by ADA development. Before ADA detection, a progressive decline in IFX levels until a complete disappearance was observed. The ADA titer was maintained for years both in patients with ongoing therapy and in those who interrupted it. IgE ADAs are more frequently developed in patients with higher ADA levels and earlier ADA onset, but their rate of negativization is faster. CONCLUSION: The present data suggest that most IFX-exposed patients develop ADAs within the first year of treatment irrespective of disease type. The clinical outcome to the treatment is preceded by ADA development, which in turn is associated with the reduction in drug serum levels. Both ADA evaluation and therapeutic drug monitoring may have a relevant impact on clinical practice, giving new insights to predict LOR and HRs.
Assuntos
Antirreumáticos/imunologia , Hipersensibilidade a Drogas/imunologia , Doenças do Sistema Imunitário/imunologia , Imunoglobulina E/sangue , Infliximab/imunologia , Adulto , Idoso , Antirreumáticos/sangue , Hipersensibilidade a Drogas/diagnóstico , Monitoramento de Medicamentos , Feminino , Humanos , Doenças do Sistema Imunitário/diagnóstico , Imunidade Humoral , Infliximab/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do TratamentoRESUMO
Crohn's disease (CD) is an inflammatory disease characterized by the activation of the immune system in the gut. Since tumor necrosis factor (TNF-alpha) plays an important role in the initiation and perpetuation of intestinal inflammation in CD, we investigated whether TX 527 [19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)], a Vitamin D analogue, could affect peripheral blood mononuclear cells (PBMC) proliferation and exert an immunosuppressive effect on TNF-alpha production in CD patients, and whether this immunosuppressive action could be mediated by NF-kappaB down-regulation. TX 527 significantly decreased cell proliferation and TNF-alpha levels. On activation, NF-kappaB, rapidly released from its cytoplasmatic inhibitor (IKB-alpha), transmigrates into the nucleus and binds to DNA response elements in gene promoter regions. The activation of NF-kappaB, stimulated by TNF-alpha, and its nuclear translocation together with the degradation of IKB-alpha were blocked by TX 527. At the same time, NF-kappaB protein levels present in cytoplasmic extracts decreased in the presence of TNF-alpha and increased when PBMC were incubated with TX 527. The results of our studies indicate that TX 527 inhibits TNF-alpha mediated effects on PBMC and the activation of NF-kappaB and that its action is mediated by Vitamin D receptor (VDR), which is activated when the cells are stimulated with TX 527.
Assuntos
Alcinos/sangue , Colecalciferol/sangue , Doença de Crohn/sangue , NF-kappa B/sangue , Vitamina D/análogos & derivados , Adulto , Idoso , Alcinos/uso terapêutico , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Colecalciferol/uso terapêutico , Doença de Crohn/tratamento farmacológico , Interações Medicamentosas , Feminino , Humanos , Proteínas I-kappa B/sangue , Terapia de Imunossupressão , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Receptores de Calcitriol/sangue , Fator de Necrose Tumoral alfa/farmacologia , VitaminasRESUMO
BACKGROUND: The active form of vitamin D, 1,25(OH)(2)D(3), exerts important effects on proliferation and differentiation of many cell types, and immunoregulatory activities in particular on T cell-mediated immunity. AIM: The aim of this study was to investigate whether KH 1060, a vitamin D analogue, could decrease tumor necrosis factor-alpha (TNF-alpha) levels in patients with inflammatory bowel disease (IBD). METHODS: PBMC proliferation was determined by [(3)H]thymidine incorporation. TNF-alpha levels were measured by ELISA kit; VDR, Bcl-2 and Bax protein levels with Western blot analysis. RESULTS: KH 1060 inhibited PBMC proliferation and decreased TNF-alpha levels in IBD patients and this effect was synergistic with anti-TNF-alpha. VDR protein levels were significantly increased by PBMC treatment with KH 1060 or anti-TNF-alpha or their combination in ulcerative colitis (UC) patients, and decreased in Crohn's disease (CD) patients, treating the cells with KH 1060. In UC patients an increase in Bcl-2 and Bax levels was observed incubating, PBMC with KH 1060 or anti-TNF-alpha or their combination. In CD patients a slight decrease in Bcl-2 levels was registered when anti-TNF alone or in association with KH 1060 was used. Bax protein levels were slightly increased in the presence of KH 1060 alone or in combination with anti-TNF. CONCLUSION: This study shows that KH 1060 acts as an immunomodulator on PBMC, acting as TNF-alpha inhibitor. This finding provides strong evidence that vitamin D status could be an important regulator of immunity IBD.
Assuntos
Calcitriol/análogos & derivados , Imunossupressores/farmacologia , Doenças Inflamatórias Intestinais/sangue , Leucócitos Mononucleares/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais/farmacologia , Calcitriol/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Infliximab , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Calcitriol/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
BACKGROUND: The disease course and colectomy rate of ulcerative colitis (UC) vary largely in population-based and referral center cohorts. We retrospectively evaluated our cohort to determine the disease course and risk factors for colectomy. METHODS: A cohort of 1723 ulcerative colitis patients (986 males; mean age, 34.8 ± 15.4 yrs) were identified and followed since 1960s for a mean of 11 ± 9 years (range, 1-49 yrs). RESULTS: The disease extension was classified as E1, E2, and E3 on diagnosis at 19.7%, 54.2%, and 26.1% of patients, respectively. At the final follow-up, the disease extension increased in 20% of the cases. Extraintestinal manifestations (EIMs) were reported by 11% of the patients, whereas systemic corticosteroids (CS), IM or anti-TNFα agents were used by 68.6%, 20.4%, and 6.4% of patients, respectively. The crude colectomy rate was 7% (120 pts), with a 1.2% rate (n = 21) at 1 year from diagnosis (95% CI, 0.7-1.7) and a Kaplan-Meyer estimation of up to 18.2% after 30 years of follow-up. The 1-year colectomy rate showed no significant difference through the decades, whereas the 5-year and 10-year absolute value of colectomy was halved in the last 2 decades compared with the period from 1960 to 1990 (P = 0.01), with a general trend of a reduced colectomy rate at survival curves (P = 0.056). CONCLUSIONS: The colectomy rate was low in our cohort and further reduced in the last 2 decades. However, despite the availability of anti-TNFα agents, no further significant reduction of colectomies was observed in the last decade.