RESUMO
BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive liver disease associated with inflammatory bowel disease (IBD). The percentage of PSC patients diagnosed with concomitant IBD varies considerably between studies. This raises the question whether all PSC patients would show intestinal inflammation if screened thoroughly, even in the absence of symptoms. METHODS: To address this question, we collected intestinal biopsies of healthy controls (n = 34), PSC (n = 25), PSC-IBD (n = 41), and IBD (n = 51) patients in a cross-sectional study and carried out cytokine expression profiling, 16S sequencing, in-depth histology, and endoscopy scoring. RESULTS: We found that the vast majority of PSC patients even without clinically manifest IBD showed infiltration of immune cells and increased expression of IL17A and IFNG in intestinal biopsies. However, expression of IL10 and FOXP3 were likewise increased, which may explain why these PSC patients have intestinal inflammation only on a molecular level. This subclinical inflammation in PSC patients was focused in the distal colon, whereas PSC-IBD patients showed inflammation either at the distal colon or on the right side of the colon and the terminal ileum. Furthermore, we observed that PSC patients without IBD showed signs of dysbiosis and exhibited a distinct microbial profile compared with healthy controls. CONCLUSIONS: We found a gradient of intestinal inflammation in the vast majority of PSC patients even in the absence of IBD. Thus, further studies evaluating the effect of anti-inflammatory therapies in PSC patients and their impact on the emergence of clinically manifest IBD and colorectal cancer development are needed.
RESUMO
INTRODUCTION: Carcinoid syndrome is the most frequent functional syndrome of neuroendocrine neoplasia. It is characterized by flushing, diarrhea, wheezing, hypotension, and exanthema and may cause carcinoid heart disease. METHODS: We assessed clinical characteristics and prognosis of patients with carcinoid syndrome and carcinoid heart disease in 276 patients from 3 referral centers. RESULTS: Carcinoid syndrome patients had a mean age of 57 years (range 21-84) and a normal BMI of 24.9 (SD 4.5; range 13.8-39.6). Most primaries were of small bowel or unknown primaries with distant metastasis in 94.6%. Flushing was the most frequent symptom in 74.3% of patients, followed by diarrhea in 68.8%, and wheezing in 40.9%. Pain was described by 45.3%, weakness by 23.5%, and weight loss of >10% in 6 months by 30.1% of patients. Carcinoid heart disease was diagnosed in 37.3% of patients (n = 104) by echocardiography and involved predominantly in the tricuspid valve. Combinations with other valve defects were common. Somatostatin analogs were taken by 80.4% of patients and 17% needed additional loperamide/opium tincture. Surgery and peptide receptor radiotherapy were most frequent treatments. The median survival of patients with carcinoid syndrome after diagnosis was 9 years. Prognosis was significantly impaired by male sex and diagnosis of carcinoid heart disease but surprisingly significantly increased by the presence of symptoms flushing and weakness. DISCUSSION/CONCLUSION: Carcinoid syndrome is associated with extensive disease and primaries in small bowels or of unknown primary. Weight loss, weakness, and pain are frequent, and carcinoid heart disease is diagnosed in more than one-third of patients.
Assuntos
Doença Cardíaca Carcinoide , Tumor Carcinoide , Síndrome do Carcinoide Maligno , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Cardíaca Carcinoide/complicações , Diarreia/complicações , Humanos , Masculino , Síndrome do Carcinoide Maligno/complicações , Síndrome do Carcinoide Maligno/diagnóstico , Pessoa de Meia-Idade , Dor , Prognóstico , Sons Respiratórios , Estudos Retrospectivos , Redução de Peso , Adulto JovemRESUMO
INTRODUCTION: Incidence of pancreatic neuroendocrine tumours (pNETs) is on the rise. The only curative treatment is surgical resection in localized or oligo-metastatic disease. However, patients may present with locally advanced or unresectable primary tumours. So far, no conversion therapy to achieve resectability has been established, which is partly due to lack of data on primary tumour response to therapies. Here, we specifically evaluate the primary tumour response to streptozocin/5-FU in a large cohort of metastatic pNET patients. METHODS: Five ENETS centres in Germany contributed 84 patients to the study cohort for retrospective analysis. RESULTS: Overall response rate (ORR) in primary tumours was 34% and disease control rate (DCR) 88%. ORR was different in metastases at 44% and DCR at 70%. Partial remission in primary tumours was more frequent among those located in pancreatic tail than that in pancreatic head (49% vs. 14%, p = 0.03). Correspondingly, metastases from tumours originating from pancreatic tail responded more frequently than metastases originating from pancreatic head (88.5% vs. 41.7%, p = 0.005). The median PFS of the primary tumours was longer than that in metastases (31 months vs. 16 months; p = 0.04). Considerable downsizing of the primary tumour was rare and occurred primarily in tumours located in the pancreatic tail. CONCLUSION: STZ/5-FU can achieve disease stabilization in a high proportion of metastatic pNET patients. In the majority of cases however it does not induce substantial downsizing of the primary tumour, thus possibly limiting its potential as conversion chemotherapy. Furthermore, the difference in response rate observed between different primary tumour locations warrants further exploration.
Assuntos
Segunda Neoplasia Primária , Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/uso terapêutico , Humanos , Tumores Neuroectodérmicos Primitivos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Estreptozocina/uso terapêuticoRESUMO
The prevalence of the chronic inflammatory bowel diseases (CIBD) Crohn's disease (CD) and ulcerative colitis (UC) is on the rise worldwide. In Germany CIBDs are also a significant healthcare problem. The pathogenesis is complex and involves genetic factors, environmental aspects and changes in the immunological constitution. Furthermore, the gut microbiota plays a role in the maintenance of intestinal inflammation. Fortunately, several new drugs, in particular biologicals, have been approved for the treatment of CIBDs. The treatment of UC is mainly based on 5aminosalicylic acid formulations, preferably as a topical form for distal colitis and proctitis as well as local budesonide formulations. In the case of extensive spread, high disease activity and refractory disease antibodies (biologicals) are successfully used, similar to CD. In addition to anti-tumor necrosis factor antibodies (infliximab, adalimumab, golimumab), vedolizumab, an anti-integrin antibody and the interleukin 12/23 antibody ustekinumab can be successfully used. The intravenous and also subcutaneous administration of antibodies are increasing in importance and are now available for all forms. Furthermore, the Janus kinase inhibitor tofacitinib is an orally administered option for UC. Clinical scores, endoscopy, ultrasound, laboratory parameters and calprotectin determination in stool are employed to evaluate treatment response (treat to target approach). Ultimately, the long-term goal is mucosal healing. Despite advances in the pharmaceutical treatment, a significant number of patients with CIBD still suffer from treatment refractory courses and need surgery at some time during the disease.
Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab , UstekinumabRESUMO
The ectoenzymes CD39 and CD73 play a major role in controlling tissue inflammation by regulating the balance between adenosine triphosphate (ATP) and adenosine. Still, little is known about the role of these two enzymes and ATP and its metabolites in the pathophysiology of inflammatory bowel disease (IBD). We isolated mononuclear cells from peripheral blood and lamina propria of the large intestine of patients diagnosed with IBD and of healthy volunteers. We then comprehensively analyzed the CD39 and CD73 expression patterns together with markers of activation (HLA-DR, CD38), differentiation (CCR7, CD45RA) and tissue-residency (CD69, CD103, CD49a) on CD4+, CD8+, γδ+ T cells and mucosa-associated invariant T cells using flow cytometry. CD39 expression levels of γδ+ and CD8+ T cells in lamina propria lymphocytes (LPL) were much higher compared to peripheral blood mononuclear cells. Moreover, the frequency of CD39+ CD4+ and CD8+, but not γδ+ LPL positively correlated with T-cell activation. The frequency of CD39+ cells among tissue-resident memory LPL (Trm) was higher compared to non-Trm for all subsets, confirming that CD39 is a marker for the tissue-resident memory phenotype. γδ+ Trm also showed a distinct cytokine profile upon stimulation - the frequency of IFN-γ+ and IL-17A+ cells was significantly lower in γδ+ Trm compared to non-Trm. Interestingly, we observed a decreased frequency of CD39+ γδ+ T cells in IBD patients compared to healthy controls (p = 0.0049). Prospective studies need to elucidate the exact role of this novel CD39+ γδ+ T-cell population with tissue-resident memory phenotype and its possible contribution to the pathogenesis of IBD and other inflammatory disorders.