To assesses the safety and efficacy of Aspergillus niger prolyl endoprotease (AN-PEP) to mitigate the immunogenic effects of gluten in celiac patients.
Patients with initial diagnosis of celiac ...disease as confirmed by positive serology with subtotal or total villous atrophy on duodenal biopsies who adhere to a strict gluten-free diet (GFD) resulting in normalised antibodies and mucosal healing classified as Marsh 0 or I were included. In a randomised double-blind placebo-controlled pilot study, patients consumed toast (approximately 7 g/d gluten) with AN-PEP for 2 wk (safety phase). After a 2-wk washout period with adherence of the usual GFD, 14 patients were randomised to gluten intake with either AN-PEP or placebo for 2 wk (efficacy phase). Measurements at baseline included complaints, quality-of-life, serum antibodies, immunophenotyping of T-cells and duodenal mucosa immunohistology. Furthermore, serum and quality of life questionnaires were collected during and after the safety, washout and efficacy phase. Duodenal biopsies were collected after the safety phase and after the efficacy phase. A change in histological evaluation according to the modified Marsh classification was the primary endpoint.
In total, 16 adults were enrolled in the study. No serious adverse events occurred during the trial and no patients withdrew during the trial. The mean score for the gastrointestinal subcategory of the celiac disease quality (CDQ) was relatively high throughout the study, indicating that AN-PEP was well tolerated. In the efficacy phase, the CDQ scores of patients consuming gluten with placebo or gluten with AN-PEP did not significantly deteriorate and moreover no differences between the groups were observed. During the efficacy phase, neither the placebo nor the AN-PEP group developed significant antibody titers. The IgA-EM concentrations remained negative in both groups. Two patients were excluded from entering the efficacy phase as their mucosa showed an increase of two Marsh steps after the safety phase, yet with undetectable serum antibodies, while 14 patients were considered histologically stable on gluten with AN-PEP. Also after the efficacy phase, no significant deterioration was observed regarding immunohistological and flow cytometric evaluation in the group consuming placebo compared to the group receiving AN-PEP. Furthermore, IgA-tTG deposit staining increased after 2 wk of gluten compared to baseline in four out of seven patients on placebo. In the seven patients receiving AN-PEP, one patient showed increased and one showed decreased IgA-tTG deposits.
AN-PEP appears to be well tolerated. However, the primary endpoint was not met due to lack of clinical deterioration upon placebo, impeding an effect of AN-PEP.
Surgery in (pre)malignant celiac disease van de Water, Jolanda M W; Nijeboer, Petula; de Baaij, Laura R ...
World journal of gastroenterology : WJG,
11/2015, Letnik:
21, Številka:
43
Journal Article
Odprti dostop
AIM: To report the outcome of surgery in patients with(pre)malignant conditions of celiac disease(CD) and the impact on survival.METHODS: A total of 40 patients with(pre)malignant conditions of ...CD,ulcerative jejunitis(n = 5) and enteropathy associated T-cell lymphoma(EATL)(n = 35),who underwent surgery between 2002 and 2013 were retrospectively evaluated. Data on indications,operative procedure,post-operative morbidity and mortali ty,adjuvant therapy and overal l survival(OS) were collected. Eleven patients with EATL who underwent chemotherapy without resection were included as a control group for survival analysis. Patients were followed-up every three months during the first year and at 6-mo intervals thereafter.RESULTS: Mean age at resection was 62 years. The majority of patients(63%) underwent elective laparotomy. Functional stenosis(n = 1 3) and perforation(n = 12) were the major indications for surgery. In 70% of patients radical resection wasperformed. Early postoperative complications,mainly due to leakage or sepsis,occurred in 14/40(35%) of patients. Eight patients required reoperation. More patients who underwent resection in the acute setting(n = 3,20%) died compared to patients treated in the elective setting. With a median follow-up of 20 mo,seven patients(18%) required reoperation due to long-term complications. Significantly more patients who underwent acute surgery could not be treated with adjuvant chemotherapy. Patients who first underwent surgical resection showed significantly better OS than patients who received chemotherapy without resection.CONCLUSION: Although the complication rate is high,the preferred first step of treatment in(pre)malignant CD consists of local resection as early as possible to improve survival.
Although esophagectomy with or without (neo)adjuvant chemoradiation therapy is the current standard of care for patients with early esophageal adenocarcinoma with high-risk features or after ...nonradical endoscopic resection of an early esophageal adenocarcinoma, not all patients are eligible for surgery due to varying reasons. In these patients, cryoballoon ablation may serve as an alternative treatment option considering the potential of deeper tissue ablation as compared to heat-based ablation techniques. We report the first case in which cryoballoon ablation was successfully performed as salvage therapy with a curative intent for positive deep resection margins after an incomplete endoscopic resection of a recurrent early esophageal adenocarcinoma.
Enteropathy Associated T-cell Lymphoma (EATL) is an intestinal tumour of intra-epithelial lymphocytes. Based on morphology, immunohistochemistry and genetic profile EATL can be divided into two ...groups. EATL type I is a large cell lymphoma which is highly associated with Coeliac Disease (CD) and mostly presents with malabsorption, weight loss and CD-related symptoms. EATL type II consists of small to medium-sized cells and presents often with obstruction or perforation of the small bowel. This type of EATL has no known association with CD. When EATL has been diagnosed a thorough diagnostic work-up is needed. This work-up preferably includes video capsule enteroscopy (VCE), double-balloon enteroscopy (DBE), computed tomography (CT) combined with 18F-fluorodeoxyglucose positron emission tomography scan (18F-FDG-PET scan) if possible and magnetic resonance enteroclysis (MRE). Nowadays, most EATL patients are treated with chemotherapy mostly preceded by resection of the tumour and followed by stem cell transplantation. Despite these therapies outcome of EATL remains very poor with a 5-year survival of 8–20%. In order to improve survival prospective multicentre trials, studying new therapies are needed. The combination of chemotherapy, monoclonal antibodies and/or apoptosis inducing small molecules might be a potential treatment for EATL in the (nearby) future.
Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal non-Hodgkin lymphoma with a poor, though variable prognosis. The International Prognostic Index (IPI) and the prognostic index for ...peripheral T-cell lymphoma (PIT) have limited predictive value for outcome of EATL. The purpose of this study was to develop and validate a prognostic model for EATL, which can identify high-risk patients who need more aggressive therapy.
This retrospective multicenter study was based on 92 patients and included 45 patients diagnosed with EATL between 1999 and 2009 from the Netherlands and 47 patients from England and Scotland, diagnosed with EATL between 1994 and 1998. A new EATL prognostic index (EPI) was constructed using the RPART (recursive partitioning and regression trees) procedure. Validation was performed applying the bootstrap method.
Three risk groups were distinguished (P < 0.0001): a high-risk group, characterized by the presence of B-symptoms median overall survival (OS) of 2 months; an intermediate-risk group, comprising patients without B-symptoms and an IPI score ≥ 2 (7 months); and a low-risk group, representing patients without B-symptoms and an IPI score of 0 to 1 (34 months). Internal validation showed stability of statistical significance and prognostic discrimination. In contrast with the IPI and PIT, the EPI better classified patients in risk groups according to their clinical outcome.
Our new, validated, prognostic model EPI accurately predicts survival outcome in EATL and may be used for patient selection for new therapeutic strategies and evaluation of clinical trials.
Celiac disease: Assessment of quality of life van de Water, Jolanda M W; Mulder, Chris J J
Nature reviews. Gastroenterology & hepatology,
04/2009, Letnik:
6, Številka:
4
Journal Article
Objective
Magnesium treatment in patients with subarachnoid hemorrhage (SAH) can result in hypocalcemia; this hypocalcemia increases the risk of delayed cerebral ischemia (DCI) and poor outcome. We ...assessed whether low serum levels of total calcium in patients with SAH treated with magnesium is mediated by parathyroid hormone (PTH) or calcitriol, and whether increased PTH or low serum levels of ionized calcium are associated with an increased risk of DCI and poor outcome.
Patients and Methods
We studied 167 patients included in a randomized, placebo controlled trial on magnesium in SAH. Mean serum magnesium during treatment was related to mean serum levels of ionized calcium, PTH and calcitriol with linear regression. Hypocalcemia (Ca
2+
) and high serum PTH were related to the occurrence of DCI by means of the Cox proportional hazards model and to poor outcome by logistic regression.
Results
Serum magnesium was inversely related to ionized calcium (
B
= −0.1; 95% CI −0.12 to −0.06), but not to PTH or calcitriol. Neither hypocalcemia nor high serum PTH was related to DCI. Hypocalcemia did not increased the risk for poor outcome (OR 1.2; 95% CI 0.6–2.3). In the subgroup of patients with known PTH (
n
= 67), high serum PTH increased the risk for poor outcome (OR 5.4; 1.6–18.9).
Conclusions
Magnesium treatment in patients with SAH leads to hypocalcemia without effect on outcome. PTH is related to poor outcome, but this is independent of magnesium therapy.
Abstract 2722
Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal lymphoma that arises from intraepithelial lymphocytes. Clinical outcome of patients with EATL is very poor, due to ...chemotherapy-resistance and high relapse rates. Therefore, new therapeutic options for EATL are urgently needed. Studies in other types of lymphoma have shown that inhibition of apoptosis may cause chemotherapy-resistance and that restoration of defective apoptosis can induce cell death in these lymphomas. Preliminary data in EATL samples have demonstrated an increased expression of a fraction of NF-κB target genes, suggesting upregulation of NF-κB activity in EATL tumor cells. NF-κB activity can be inhibited by the proteasome inhibitor bortezomib resulting in induction of apoptosis. In the present study, we evaluated if apoptosis is inhibited in EATL cells and if Bortezomib can restore apoptosis in EATL cells.
Laser-capture microdissection was applied to 16 fresh frozen EATL samples to obtain purified tumor cells for RNA isolation. Intraepithelial lymphocytes (IEL) of healthy controls were obtained from fresh duodenal biopsies and isolated by cell sorting. RT-MLPA analysis revealed that the pro-apoptotic BH3-only gene Noxa was significantly downregulated in most EATL samples compared to healthy donor IEL. Induction with etoposide resulted in caspase-9 mediated apoptosis in EATL cells with relatively high Noxa expression, whereas in EATL cells with low Noxa expression no apoptosis was induced, suggesting an inhibition in the intrinsic apoptosis pathway. Treatment with Bortezomib resulted in induction of apoptosis in EATL cells. The lethal dose (LD50) varied between 7.5 nM and 15 nM. Bortezomib induced cell death in EATL cells was caspase-9 mediated. mRNA and protein expression analysis showed upregulation of Noxa after incubation with bortezomib.
In conclusion, our study showed that bortezomib induces apoptosis by upregulation of Noxa in EATL cells. Bortezomib therefore may be a potential drug in the treatment of patients with EATL.
No relevant conflicts of interest to declare.
Abstract 3092
Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal lymphoma that arises from intraepithelial lymphocytes. In Western countries EATL accounts for 5% of all ...gastrointestinal lymphomas and in 80–90% of all cases this lymphoma is associated with celiac disease (CD). Based on clinical presentation, EATL can be divided into two subtypes: primary and secondary EATL. Primary EATL develops without a preceding history of CD. The first presentation is often perforation or obstruction, which leads to diagnosis of both EATL and CD. Secondary EATL is diagnosed in patients with well-established CD or refractory CD. These patients deteriorate and eventually develop EATL. The current standard treatment for both types of EATL consists of surgery and chemotherapy, but overall survival (OS) is poor and new therapeutic strategies are urgently needed. For risk-based selection of patients for new therapies and clinical trials, prognostic models as the International Prognostic Index (IPI) are generally used. Since IPI is not predictive for EATL, we determined a prognostic model specifically for EATL, which can identify high-risk patients who need more aggressive therapy.
Forty-one patients were diagnosed with EATL and retrospectively analyzed. Two- and 5-years OS were 18% and 10% respectively (range: 0 – 97 months). In multivariate analysis, 3 risk factors were predictive for survival: serum LDH > normal (P < 0.001; RR 6.65; 95% CI 1.96 to 9.89), presence of B-symptoms (P < 0.001; RR 4.41; 95% CI 2.73 to 16.18) and subtype secondary EATL (P = 0.036; RR 2.33; 95% CI 1.06 to 5.13). A weighted point score was assigned to each of these 3 factors and a prognostic model was constructed. Four risk groups were identified (P < 0.0001). Group I showed most favorable outcome: 2- and 5-years OS were 55% and 30% respectively. Although survival rates in groups II, III and IV were significantly different, in none of these groups 2-years survival was achieved. Therefore, the model was simplified to a low risk and a high risk group (P < 0.0001, Figure 1). The low risk group represented patients with no risk factors, i.e. primary EATL with no B-symptoms and normal LDH. In the high risk group, patients had 1 or more of the risk factors elevated serum LDH, B-symptoms or subtype secondary EATL. The new prognostic model showed superior predictive capacity as compared to IPI.
In conclusion, our new prognostic model clearly identifies a high and a low risk group. Patients with one or more of the risk factors serum LDH > normal, B-symptoms or subtype secondary EATL are at high risk, and therefore new therapies for this group are urgently needed.
Display omitted
No relevant conflicts of interest to declare.
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