56 research outputs found
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 âŒ99% of the euchromatic genome and is accurate to an error rate of âŒ1 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 fĂŒr klinische Fragestellungen zu Diagnostik, Therapie und Verlauf von
Patienten mit einer refraktÀren Sprue sowie intestinalen Lymphomen. In diesen
Arbeiten konnten wir zum einen zeigen, dass morphologische VerÀnderungen 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 extrazellulÀren Matrix hindeutet. Ein gestörter Metabolismus
der extrazellulĂ€ren Matrix lieĂ sich schlieĂlich 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
verstÀrkten Abbau der extrazellulÀren Matrix die Zottenatrophie bei der
Zöliakie erklÀren. 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 inadÀquat subepithelial gesteigerte Expression von Kollagen I-mRNS.
Diese markante Erhöhung der Synthese von extrazellulĂ€rer Matrix dĂŒrfte das
pathophysiologische Korrelat fĂŒr das subepithelial gelegene kollagene Band
darstellen. Die eben genannten Ergebnisse weisen auf eine wesentliche
Interaktion zwischen Immunsystem und extrazellulÀrer Matrix in Hinblick auf
die DĂŒnndarmmorphologie hin. Die Unterbrechung der Kaskade Immunsystem â
Aktivierung der Marixmetalloproteinasen bietet einen möglichen Therapieansatz
fĂŒr zukĂŒnftige Interventionsstrategien. Ein weiterer Schwerpunkt meiner Arbeit
waren diagnostische Fragestellungen bei Patienten mit einer refraktÀren Sprue.
Hier standen zunÀchst immunhistologische und molekularbiologische
Untersuchungen im Mittelpunkt. Der Ăbergang einer refraktĂ€ren Sprue in ein
intestinales T-Zelllymphom war lange Zeit bekannt. Jedoch existierten keine
differentialdiagnostischen Möglichkeiten zur Unterscheidung zwischen Patienten
mit einem hohen Risiko fĂŒr 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 fĂŒr
Pathologie entstanden, konnten wir zeigen, dass das Vorhandensein einer
dominanten klonalen Population von T-Zellen in Duodenalbiopsien von Patienten
mit einer refraktÀren Sprue mit einem hohen Risiko einhergeht eine ulzerative
Jejunitis oder ein intestinales T-Zelllymphom zu entwickeln (Abb. 8). Weniger
spezifisch, aber dafĂŒr sensitiver fĂŒr die Entwicklung einer refraktĂ€ren Sprue
Typ II sind ein sogenannter Antigenverlust von CD8 und des T-Zellrezeptors auf
intraepithelialen Lymphozyten in Duodenalbiopsien von Patienten mit einer
refraktÀren Sprue. Kontrollbiopsien von Patienten mit einer unkomplizierten
Zöliakie oder Duodenalniopsien von gesunden Kontrollen wiesen die Marker
Antigenverlust und KlonalitÀt nicht auf. Mit dem Hintergrund dieser Arbeiten
untersuchten wir den Erkenntniszugewinn des Einsatzes der Kapselendoskopie bei
Patienten mit einer refraktÀren 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 refraktÀren Sprue Typ I und lediglich in einem von sieben Patienten
mit einer refraktÀren Sprue Typ II einen wertvollen diagnostischen
Zusatzgewinn. In dem einen positiven Fall wurde eine durch die
Kapselendoskopie detektierte DĂŒnndarmstenose nicht mittels eines Enteroklysma-
CT gesehen. ErnĂŒchternd war die bei einem hohen Prozentsatz der Patienten nur
teilweise Einsicht des DĂŒnndarms 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 PhÀntotyp
intestinaler T-Zelllymphome. Hier lieĂen sich sehr spezifische zytotoxische
Marker auf intestinalen TZelllymphomen nachweisen, was auf eine homogene
EntitÀt der intestinalen T-Zelllymphome hinwies. Auch in Anlehnung an Arbeiten
anderer Gruppen, die zytotoxische Marker auf den intraepithelialen Lymphozyten
bei refraktĂ€rer Sprue nachwiesen, unterstĂŒtzen 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 hÀufiger CD56-positiv und
zeigen andere genetische Marker als Enteropathie-Typ T-Zelllymphome mit
Zöliakieassoziation (Deleeuw, Zettl et al. 2007). Therapeutische Optionen bei
der refraktÀren 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
refraktÀren 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 refraktÀren 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 refraktÀren Sprue oder verwandten
Erkrankungen, die auf Azathioprin nicht ansprechen oder eine Allergie
aufweisen, problematisch. Wir konnten in einem Fall ĂŒber ein gutes klinisches
und morphologisches Ansprechen eines Patienten mit einer Autoimmunenteropathie
auf einen oralen Calcineurin-Inhibitor (Tacrolimus) berichten. Diese Daten
zeigen eindrĂŒcklich die KomplexitĂ€t 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
groĂzelliges B-Zelllymphom, mit einer alleinigen Chemotherapie nach CHOP
ausreichend behandelt sind. Hier dĂŒrfte die zusĂ€tzliche Strahlentherapie keine
weitere Verbesserung des Ăberlebens erbringen. Bei Patienten mit einem
intestinalen T-Zelllymphom wurden die schlechten Daten aus vorausgegangenen
retrospektiven Untersuchungen trotz standardisierter Chemotherapie bestÀtigt.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—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 CancerâUpdate 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/ÎČ-catenin signaling pathway. The Food and Drug Administration (FDA)-approved anti-helminthic drug niclosamide is known to intervene in the Wnt/ÎČ-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 2Â 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 4Â 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
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