Colorectal cancer (CRC) is the second most common cause of all cancer deaths in Europe and the Western world with a lifetime risk of approximately 5%. Despite several improvements in the treatment of patients with unresectable CRC prognosis is poor and there is the need of developing new treatment strategies for patients with metastatic chemorefractory disease. The S100 calcium binding protein A4 (S100A4) predicts metastasis formation and reduced CRC patient survival. S100A4 was previously identified as transcriptional target of the Wnt/β-catenin signaling pathway. The Food and Drug Administration (FDA)-approved anti-helminthic drug niclosamide is known to intervene in the Wnt/β-catenin pathway signaling, leading to reduced expression of S100A4 linked to restricted in vivo metastasis formation. Thus, we aim at translation of our findings on restricting S100A4-driven metastasis into clinical practice for treating metastasized CRC patients progressing after standard therapy. NIKOLO is a phase II, single center, one-arm open-label clinical trial to investigate the safety and efficacy of niclosamide tablets in patients with metastasized CRC progressing under standard therapy. Eligible patients will receive 2 g of orally applied niclosamide once a day and will continue with the treatment once daily till disease progression or toxicity. Toxicities will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. The primary objective of this trial is to assess the progression free survival after 4 months, secondary objectives are overall survival, time to progression, disease control rate (remission + partial remission + stable disease), and safety. Furthermore, pharmacokinetic analysis will be conducted to evaluate niclosamide plasma concentration. This study is expected to provide evidence of the feasibility, toxicity and efficacy of niclosamide in the treatment of patients with metastasized CRC and could help to establish a new treatment option. The study is registered with ClinicalTrials.gov ( NCT02519582 ) and the European Clinical Trials Database (EudraCT 2014-005151-20).

Background and study aims: Patients with refractory celiac disease (RCD) are at risk of intestinal T-cell lymphoma, which is difficult to diagnose because it often develops in the small bowel. We therefore studied whether wireless capsule endoscopy was able to detect ulcerative jejunitis or intestinal T-cell lymphomas that were missed by standard endoscopic and imaging procedures in patients with RCD. Patients and methods: Detection of ulcerative jejunitis and overt T-cell lymphoma by capsule endoscopy or by upper and lower endoscopy, abdominal computed tomography (CT) or abdominal magnetic resonance tomography (MRT) was compared in 14 consecutive patients with RCD: in seven patients who showed loss of T-cell antigens on intraepithelial lymphocytes and/or clonality of the T-cell receptor gene (i. e. type II RCD) and in seven patients who did not have these features (i. e. type I RCD). Results: Complete evaluation of the small bowel by capsule endoscopy was achieved in 9/14 patients. Signs of ulcerative jejunitis or intestinal T-cell lymphoma, affecting further clinical management, were found in two patients with type II RCD: in one patient these signs were found only by capsule endoscopy (ulcerations and stenosis) and in another patient the abnormalities were identified by CT/MRT (mesenteric lymph nodes harboring lymphoma). No clinically relevant abnormalities were found in patients with type I RCD by lower endoscopy or by small-bowel imaging (capsule endoscopy, CT, or MRT). Conclusions: In patients with type II RCD, capsule endoscopy can detect additional cases with ulcerative jejunitis and could be included in the diagnostic armamentarium, subject to confirmation by larger series. In patients with type I RCD, our study confirmed the low diagnostic yield of imaging procedures, including wireless capsule endoscopy.

Refractory sprue (RS) is a rare malabsorption syndrome defined by persisting small bowel villous atrophy despite a strict gluten-free diet. The clinical picture and long-term outcome of RS is highly variable and is not well described. To define underlying and accompanying diseases and clinical outcome in consecutive patients with RS. Clinical and histological data from patients with RS at our department were analyzed retrospectively. RS was defined as villous atrophy and malabsorption despite a strict gluten-free diet persisting without improvement for more than 6 months or requiring earlier therapeutic intervention. Thirty-two patients with RS were identified (23 RS type I, nine RS type II). Follow-up period was 55 (12–372) months. Two patients progressed from RS type I into type II. Thrombembolic events occurred in nine cases, and additional autoimmune diseases were found in 17 patients. Overt intestinal T-cell lymphoma developed in four patients with RS type II. Three patients with RS type II died during the observation period owing to intestinal T-cell lymphoma and four with RS type I owing to infectious complications. Five-year cumulative survival was 90% (95% confidence interval 76–100) in patients with RS type I and higher than in patients with RS type II (53%, 12–94%; P<0.05). RS comprises a very heterogenous group of patients with long-term survival seen even in single patients with RS type II. Overall, survival is shorter in RS type II in comparison with RS type I. Patients with RS type I, however, show similar rates of disease-related complications as well as substantial mortality.

Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. ClinicalTrials.gov : NCT02047513, 08/13/2014.

Introduction: Refractory sprue (RS) is a rare malabsorption syndrome, which often requires long-term corticosteroid treatment. Locally acting budesonide could replace systemic corticosteroid therapy and reduce toxicity in patients with RS. Aims: To evaluate the efficacy and toxicity of budesonide in patients with RS. Patients and Methods: Clinical and histological data from patients with RS who received budesonide were analyzed. RS was defined as villous atrophy and malabsorption in spite of a strict gluten-free diet persisting for >6 months or requiring earlier therapeutic intervention. Results: We identified 9 patients (1 with autoimmune enteropathy, 4 with RS type I without and 3 with RS type II with signs of early T cell lymphoma and 1 with CD4-positive sprue-like intestinal T cell lymphoma), who received 9 mg/day of budesonide (range 6–12) for 24 months (1–60), and 7 of whom had an initial treatment with 40 mg/day of prednisolone (30–60) for 4 months (1–144). The initial body mass index was 18 (13.1–22.8) and increased similarly under prednisolone [21.5 (14.9–26.7), p < 0.05] and budesonide therapy [21 (18–27.2), p < 0.05]. The stool frequency per day also decreased similarly from 6 (2–8) to 2 (1–3) and 2 (1–5), each p < 0.05, under prednisolone and budesonide therapy, respectively. Two patients with RS type II did not respond and 7, including all 4 with RS type I, were clinically stable with budesonide therapy. Skin fragility in 1 patient was the only adverse effect of budesonide therapy. Conclusions: Budesonide may be an effective treatment option in patients with RS type I, which can stabilize the clinical condition similar to prednisolone.