A case series in patients with enteropathy and granulomatous diseases

Background Although sarcoidosis and celiac disease are both chronic immunologic disorders involving multiple organ systems, reports about association of diseases in individual patients are sparse. While sarcoidosis is a chronic granulomatous disease presumably reflecting an exaggerated response to an unknown antigen, celiac disease is a T cell-driven disease triggered by ingestion of gluten, a protein composite found in wheat and related grains. Case presentation We present three cases with a longstanding history of sarcoidosis that have been additionally diagnosed with celiac-like enteropathy. In two cases, celiac disease was established applying celiac- specific serology and duodenal histology, while one case was revealed as an AIE-75-positive autoimmune enteropathy. The HLA-DR3/DQ2 haplotype was confirmed in both celiac patients, hence confirming previous data of linkage disequilibrium as a cause for disease association. Remarkably, one celiac patient presented with granulomatous nodulae in the ileum, thus reflecting an intestinal sarcoid manifestation. In contrast the patient with an autoimmune enteropathy, was HLA-DQ9/DQ6-positive, also arguing against CD. Conclusions Associations of sarcoidosis and celiac disease are rare but do occur. Determining the HLA status in patients with complex autoimmune associations might help classifying involved disease entities

Prognostic impact of Claudin 18.2 in gastric and esophageal adenocarcinomas

Introduction: The tight junction molecule Claudin 18.2 is selectively expressed in healthy and malignant gastric epithelial tissue and is a promising therapy target for high Claudin 18.2 expressing adenocarcinomas of the esophagogastric junction and stomach (AEG/S). Methods: This study analyzed the prevalence, characteristics and prognostic impact of Claudin 18.2 expression in primary tumor, lymph node and distant metastasis in a large Caucasian AGE/S cohort with 414 patients. Results: Claudin 18.2 was highly expressed in 17.1% of primary tumors, 26.7% of lymph node metastasis and 16.7% of distant metastasis. High Claudin 18.2 expression in lymph node metastasis and primary tumors correlated significantly (p < 0.001). High expression of Claudin 18.2 was neither associated with histomorphogical subtype, or tumor state, nor with overall survival. Conclusion: In Caucasian AEG/S patients, 17.1% appeared to be eligible for an anti-Claudin 18.2 therapy. Claudin 18.2 expression itself has no impact on prognosis and is not related to any tumor subtype

PuraStat in gastrointestinal bleeding: results of a prospective multicentre observational pilot study

Background: A recently developed haemostatic peptide gel for endoscopic application has been introduced to improve the management of gastrointestinal bleeding. The aim of this pilot study was to evaluate the feasibility, safety, efficacy and indication profiles of PuraStat in a clinical setting. Methods: In this prospective observational multicentre pilot study, patients with acute non-variceal gastrointestinal bleeding (upper and lower) were included. Primary and secondary application of PuraStat was evaluated. Haemoglobin, prothrombin time, platelets and transfusion behaviour were documented before and after haemostasis. The efficacy of PuraStat was assessed during the procedure, at 3 days and 1 week after application. Results: 111 patients with acute gastrointestinal bleeding were recruited into the study. 70 percent (78/111) of the patients had upper gastrointestinal bleeding and 30% (33/111) had lower gastrointestinal bleeding. After primary application of PuraStat, initial haemostatic success was achieved in 94% of patients (74/79, 95% CI 88-99%), and in 75% of the patients when used as a secondary haemostatic product, following failure of established techniques (24/32, 95% CI 59-91%). The therapeutic success rates (absence of rebleeding) after 3 and 7 days were 91% and 87% after primary use, and 87% and 81% in all study patients. Overall rebleeding rate at 30 day follow-up was 16% (18/111). In the 5 patients who finally required surgery (4.5%), PuraStat allowed temporary haemostasis and stabilisation. Conclusions: PuraStat expanded the therapeutic toolbox available for an effective treatment of gastrointestinal bleeding sources. It could be safely applied and administered without complications as a primary or secondary therapy. PuraStat may additionally serve as a bridge to surgery in order to achieve temporary haemostasis in case of refractory severe bleeding, possibly playing a role in preventing immediate emergency surgery

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

New pahtophysiologic, diagnostic and therapeutic aspects in celiac disease, refractory sprue and intestinal Non-Hodgkin-Lymphoma

Ausgehend von der Frage nach lokalen Mechanismen der Zottenatrophie bei der Zöliakie sowie experimentellen Untersuchungen am Tiermodell, interessierten wir uns für klinische Fragestellungen zu Diagnostik, Therapie und Verlauf von Patienten mit einer refraktären Sprue sowie intestinalen Lymphomen. In diesen Arbeiten konnten wir zum einen zeigen, dass morphologische Veränderungen der Zotten und Krypten einhergehen mit einer Erhöhung der CD4/CD8 T-Zellratio und einer erhöhten Kollagen I-mRNS Expression, was auf eine Immunmodulation des Metabolismus der extrazellulären Matrix hindeutet. Ein gestörter Metabolismus der extrazellulären Matrix ließ sich schließlich auch bei der unbehandelten Zöliakie und einer Unterform, der kollagenen Sprue detektieren. Im Unterschied zur kollagenen Sprue, zeigt sich bei der unkomplizierten Zöliakie eine normale Kollagen I-mRNS Synthese, jedoch eine erhöhte Matrixmetalloproteinase-1 und Matrixmetalloproteinase-3 mRNS Expression. Diese könnte durch einen verstärkten Abbau der extrazellulären Matrix die Zottenatrophie bei der Zöliakie erklären. Bei der kollagenen Sprue, einer schwer behandelbaren Erkrankung mit einer Verdickung des subepithelialen kollagenen Bandes, fand sich dagegen zwar eine ebenfalls zu Normalpersonen erhöhte Expression von Matrixmetalloproteinase-1 und Matrixmetalloproteinase-3 mRNS, jedoch eine hierzu inadäquat subepithelial gesteigerte Expression von Kollagen I-mRNS. Diese markante Erhöhung der Synthese von extrazellulärer Matrix dürfte das pathophysiologische Korrelat für das subepithelial gelegene kollagene Band darstellen. Die eben genannten Ergebnisse weisen auf eine wesentliche Interaktion zwischen Immunsystem und extrazellulärer Matrix in Hinblick auf die Dünndarmmorphologie hin. Die Unterbrechung der Kaskade Immunsystem – Aktivierung der Marixmetalloproteinasen bietet einen möglichen Therapieansatz für zukünftige Interventionsstrategien. Ein weiterer Schwerpunkt meiner Arbeit waren diagnostische Fragestellungen bei Patienten mit einer refraktären Sprue. Hier standen zunächst immunhistologische und molekularbiologische Untersuchungen im Mittelpunkt. Der Übergang einer refraktären Sprue in ein intestinales T-Zelllymphom war lange Zeit bekannt. Jedoch existierten keine differentialdiagnostischen Möglichkeiten zur Unterscheidung zwischen Patienten mit einem hohen Risiko für die Entwicklung eines intestinalen T-Zelllymphoms und Patienten mit einem niedrigen Risiko. In diesen Arbeiten, die in Kooperation mit Prof. H.-D. Foss und PD Dr. M. Hummel aus der Abteilung für Pathologie entstanden, konnten wir zeigen, dass das Vorhandensein einer dominanten klonalen Population von T-Zellen in Duodenalbiopsien von Patienten mit einer refraktären Sprue mit einem hohen Risiko einhergeht eine ulzerative Jejunitis oder ein intestinales T-Zelllymphom zu entwickeln (Abb. 8). Weniger spezifisch, aber dafür sensitiver für die Entwicklung einer refraktären Sprue Typ II sind ein sogenannter Antigenverlust von CD8 und des T-Zellrezeptors auf intraepithelialen Lymphozyten in Duodenalbiopsien von Patienten mit einer refraktären Sprue. Kontrollbiopsien von Patienten mit einer unkomplizierten Zöliakie oder Duodenalniopsien von gesunden Kontrollen wiesen die Marker Antigenverlust und Klonalität nicht auf. Mit dem Hintergrund dieser Arbeiten untersuchten wir den Erkenntniszugewinn des Einsatzes der Kapselendoskopie bei Patienten mit einer refraktären Sprue im Vergleich zu konventionellen Techniken wie der radiologischen Bildgebung und der Standardendoskopie. In dieser Arbeit erbrachte die Kapselendoskopie in keinem von sieben Patienten mit einer refraktären Sprue Typ I und lediglich in einem von sieben Patienten mit einer refraktären Sprue Typ II einen wertvollen diagnostischen Zusatzgewinn. In dem einen positiven Fall wurde eine durch die Kapselendoskopie detektierte Dünndarmstenose nicht mittels eines Enteroklysma- CT gesehen. Ernüchternd war die bei einem hohen Prozentsatz der Patienten nur teilweise Einsicht des Dünndarms durch die Kapsel. Ausgehend von diesem Ergebnis sind Untersuchungen zur Wertigkeit der Doppelballonenteroskopie im Vergleich mit der Kapselendoskopie und radiologischer Bildgebung wie auch dem PET-CT im Gange (Hadithi, Mallant et al. 2006). Ausgehend von der durch Professor Dr. E.-O. Riecken initiierten multizentrischen, klinischen Studie zu intestinalen Non-Hodgkin Lymphomen, untersuchten wir den Phäntotyp intestinaler T-Zelllymphome. Hier ließen sich sehr spezifische zytotoxische Marker auf intestinalen TZelllymphomen nachweisen, was auf eine homogene Entität der intestinalen T-Zelllymphome hinwies. Auch in Anlehnung an Arbeiten anderer Gruppen, die zytotoxische Marker auf den intraepithelialen Lymphozyten bei refraktärer Sprue nachwiesen, unterstützen unsere Daten eine einheitliche klonale Abstammung der intestinalen T-Zelllymphome von intraepithelialen zytotoxischen T-Lymphozyten (de Bruin, Connolly et al. 1997). Aktuelle genetische Untersuchungen einer multinationalen Arbeitsgruppe konnten eine weitere Unterteilung vornehmen: monomorphe Lymphome scheinen eher keine Assoziation mit einer Zöliakie aufzuweisen, sind häufiger CD56-positiv und zeigen andere genetische Marker als Enteropathie-Typ T-Zelllymphome mit Zöliakieassoziation (Deleeuw, Zettl et al. 2007). Therapeutische Optionen bei der refraktären Sprue beinhalten eine Immunsuppression, systemisch wirksame Steroide oder die Einleitung einer Chemotherapie. Da diese Therapien mit hohen Nebenwirkungsraten vergesellschaftet sind, untersuchten wir die Wirksamkeit eines lokal wirksamen oralen Steroids (Budesonid) bei Patienten mit einer refraktären Sprue. In dieser Arbeit konnten wir eine gute Wirksamkeit von Budesonid bei fast allen Patienten bei einer insgesamt geringen Nebenwirkungsrate nachweisen. Trotzdem bleibt diese Therapie bei Patienten mit einer refraktären Sprue Typ II rein symptomatisch. In den parallel gewonnenen Duodenalhistologien kam es unter Budesonid zu keiner signifikanten Verbesserung der Zottenatrophie. Die Anwendung oral gut resorbierbarer Immunsuppressiva ist bei Patienten mit einer refraktären Sprue oder verwandten Erkrankungen, die auf Azathioprin nicht ansprechen oder eine Allergie aufweisen, problematisch. Wir konnten in einem Fall über ein gutes klinisches und morphologisches Ansprechen eines Patienten mit einer Autoimmunenteropathie auf einen oralen Calcineurin-Inhibitor (Tacrolimus) berichten. Diese Daten zeigen eindrücklich die Komplexität der Spruesyndrome und legen eine differenzierte Diagnostik und Therapie nahe. In der ersten prospektiven Multizenterstudie zu intestinalen Non-Hodgkin Lymphomen konnten wir zeigen, dass Patienten mit einem intestinalen B-Zelllymphom, hier zumeist diffus großzelliges B-Zelllymphom, mit einer alleinigen Chemotherapie nach CHOP ausreichend behandelt sind. Hier dürfte die zusätzliche Strahlentherapie keine weitere Verbesserung des Überlebens erbringen. Bei Patienten mit einem intestinalen T-Zelllymphom wurden die schlechten Daten aus vorausgegangenen retrospektiven Untersuchungen trotz standardisierter Chemotherapie bestätigt.We showed in this work that extracellular matrix turn-over is essential in villus atrophy. We also analyzed loss of antigen and clonality in T-cell receptor PCR as markers for development of intestinal T-cell lymphoma. We found that clonality is highly suspicious and loss of antigen highly sensitive for refractory sprue type II, which is a high risk for development of refractory sprue type II. Clinically we show retrospectively that budesonide is effective in treatment for refractory sprue type I as well type II. In the single existing prospective study on intestinal T- and B-cell lymphoma, we could show that intestinal T-cell lymphoma has a much worse prognosis in comparison to other peripheral T-cell lymphoma

Hereditary Diffuse Gastric Cancer&mdash;Update Based on the Current Consort Recommendations

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant inherited cancer syndrome that has been associated with a mutation of the CDH1, and rarely the CTNNA1 gene, respectively. HDGC is characterized histologically by multifocal growth and signet ring cells in the gastric mucosa and lobular type breast cancer. In cases of a proven pathogenic CDH1 mutation, a prophylactic gastrectomy, or alternatively, an annual surveillance gastroscopy in expert centers is recommended. Additionally, MR imaging of the breast should be performed annually starting from the age of 30, to detect lobular breast cancer. In 2020, the International Gastric Cancer Linkage Consortium (IGCLC) additionally defined new clinical groups with specific recommendations: (1) the group of patients with a proven mutation in the CDH1 gene, but exclusive manifestation as lobular breast cancer, was defined as hereditary lobular breast cancer (HLBC); (2) the group, which clinically fulfills familial HDGC criteria, in the absence of a relevant mutation, was designated as HDGC-like. This update summarizes relevant aspects of hereditary gastric cancer and the current recommendation criteria of the IGCLC published in 2020

Hereditary Diffuse Gastric Cancer—Update Based on the Current Consort Recommendations

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant inherited cancer syndrome that has been associated with a mutation of the CDH1, and rarely the CTNNA1 gene, respectively. HDGC is characterized histologically by multifocal growth and signet ring cells in the gastric mucosa and lobular type breast cancer. In cases of a proven pathogenic CDH1 mutation, a prophylactic gastrectomy, or alternatively, an annual surveillance gastroscopy in expert centers is recommended. Additionally, MR imaging of the breast should be performed annually starting from the age of 30, to detect lobular breast cancer. In 2020, the International Gastric Cancer Linkage Consortium (IGCLC) additionally defined new clinical groups with specific recommendations: (1) the group of patients with a proven mutation in the CDH1 gene, but exclusive manifestation as lobular breast cancer, was defined as hereditary lobular breast cancer (HLBC); (2) the group, which clinically fulfills familial HDGC criteria, in the absence of a relevant mutation, was designated as HDGC-like. This update summarizes relevant aspects of hereditary gastric cancer and the current recommendation criteria of the IGCLC published in 2020

Phase II trial to investigate the safety and efficacy of orally applied niclosamide in patients with metachronous or sychronous metastases of a colorectal cancer progressing after therapy: the NIKOLO trial

Abstract Background 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. Methods/Design 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. Discussion 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. Trial registration The study is registered with ClinicalTrials.gov (NCT02519582) and the European Clinical Trials Database (EudraCT 2014-005151-20)

Unintentional Long-Term Esophageal Stenting due to a Complete Response in a Patient with Stage UICC IV Adenocarcinoma of the Gastroesophageal Junction

Endoscopic stent implantation is a common short-treatment option in palliative settings in patients with esophageal cancer. Advanced disease is associated with low survival rates; therefore, data on the long-term outcome are limited. So far, cases of long-term remission or even cure of metastasized adenocarcinoma of the gastroesophageal junction or stomach (AGS) have only been reported from Asia. A 51-year-old male patient primarily diagnosed with metastasized adenocarcinoma of the gastroesophageal junction (GEJ) [type I, cT3cN+cM1 (hep), CEA positive, UICC stage IV] received palliative esophageal stenting with a self-expandable metal stent. As disease progressed after four cycles with epirubicin, oxaliplatin, and capecitabin, treatment was changed to 5-FU and Irinotecan. The patient did not return after 5 cycles of FOLFIRI, but presented 4 years later with mild dysphagia. Endoscopy surprisingly revealed no relevant stenosis or stent migration. Repeated histological analyses of a residual mass at the GEJ did not detect malignancy. Since the initially diagnosed hepatic metastases were no longer detectable by computed tomography, cure from esophageal cancer was assumed. Dysphagia was ascribed to esophageal motility disorder by a narrowed esophageal lumen after long-term stenting. Thus, endoscopic stent implantation is an important method in palliative treatment of dysphagia related to AGS. New systemic treatment strategies like trastuzumab in Her2neu positive cases or new VEGF-inhibitors like ramucirumab will lead to more long-time survivors with AGS. In conclusion, future endoscopic treatment strategies in AGS represent a challenge for the development of new stent techniques in either extraction or programmed complete dissolution