Alexandra König

A pathogenic role for T cell–derived IL-22BP in inflammatory bowel disease

Interleukin-22 binding protein (IL-22BP) drives inflammatory bowel disease by sopping up the tissue-protective protein IL-22. Intestinal inflammation can impair mucosal healing, thereby establishing a vicious cycle leading to chronic inflammatory bowel disease (IBD). However, the signaling networks driving chronic inflammation remain unclear. Here we report that CD4+ T cells isolated from patients with IBD produce high levels of interleukin-22 binding protein (IL-22BP), the endogenous inhibitor of the tissue-protective cytokine IL-22. Using mouse models, we demonstrate that IBD development requires T cell–derived IL-22BP. Lastly, intestinal CD4+ T cells isolated from IBD patients responsive to treatment with antibodies against tumor necrosis factor–α (anti–TNF-α), the most effective known IBD therapy, exhibited reduced amounts of IL-22BP expression but still expressed IL-22. Our findings suggest that anti–TNF-α therapy may act at least in part by suppressing IL-22BP and point toward a more specific potential therapy for IBD.

Reduced Incidence of Nodal Micrometastasis after Major Response to Neoadjuvant Chemoradiation in Locally Advanced Esophageal Cancer

BackgroundNeoadjuvant treatment modalities for esophageal cancer were developed to improve local tumor control as well as to reduce lymph node metastases and distant metastases in patients with locally advanced esophageal cancer. The influence on nodal micrometastasis has not yet been evaluated.MethodsThis study includes 52 patients with localized (cT2-4, Nx, M0) esophageal cancers (21 adenocarcinomas, 31 squamous cell cancers) who received neoadjuvant chemoradiation (36Gy, 5-FU, cisplatin) followed by transthoracic en bloc esophagectomy with two field lymphadenectomy. The extent of histomorphologic regression was categorized into major (< 10%) and minor response (>10% vital residual tumor cells) as recently reported. A total of 1186 lymph nodes were diagnosed as negative for metastases by routine histopathological analysis and were further examined for the presence of isolated tumor cells with the monoclonal anti-epithelial antibody AE1/AE3.ResultsTwenty-two tumors (42.3%) showed a major histopathologic response whereas in 30 tumors (57.7%) only a minor response was present.Of 32 patients with a pN0 category, major response was present in 19 (59.4%) tumors, whereas 13 (40.6%) tumors showed minor response. Nine (69%) out of 13 patients with minor response had AE1/AE3-positive cells in their lymph nodes, whereas only four (21%) out of 19 pN0-patients with major response showed nodal micrometastasis (P = 0.013, χ2-test).ConclusionsIf tumors show a major histomorphologic response following neoadjuvant chemoradiation, the presence of nodal micrometastasis is significantly reduced compared to those with minor response.

Preoperative Pancreatic Resection (PREPARE) score: a prospective multicenter-based morbidity risk score.

Objectives:Development of a simple preoperative risk score to predict morbidity related to pancreatic surgery. Background:Pancreatic surgery is standardized with little technical diversity among institutions and unchanging morbidity and mortality rates in recent years. Preoperative identification of high-risk patients is potentially one of the rare avenues for improving the clinical course of patients undergoing pancreatic surgery. Methods:Using a prospectively collected multicenter database of patients undergoing pancreatic surgery (n = 703), surgical complications were classified according to the Clavien-Dindo classification. A new scoring system for preoperative identification of high-risk patients that included only objective preoperatively assessable variables was developed using a multivariate regression model. Subsequently, this scoring system was prospectively validated from 2011 to 2013 (n = 429) in a multicenter setting. Results:Eight independent preoperatively assessable variables were identified and included in the scoring system: systolic blood pressure, heart rate, hemoglobin level, albumin level, ASA (American Society of Anesthesiologists) score, surgical procedure, elective surgery or not, and disease of pancreatic origin or not. On the basis of 3 subgroups (low risk, intermediate risk, high risk), the proposed scoring system reached an accuracy of 75% for correctly predicting occurrence or nonoccurrence of major surgical complications in 80% of all analyzed patients within the validation cohort (c-statistic index = 0.709, P < 0.001, 95% confidence interval = 0.657–0.760). Conclusions:We present an easily applied scoring system with convincing accuracy for identifying low-risk and high-risk patients. In contrast to other systems, the score is exclusively based on objective preoperatively assessable characteristics and can be rapidly and easily calculated.

Expression of DIAPH1 is up-regulated in colorectal cancer and its down-regulation strongly reduces the metastatic capacity of colon carcinoma cells

In most cases, metastatic colorectal cancer is not curable, thus new approaches are necessary to identify novel targets for colorectal cancer therapy. Actin‐binding‐proteins (ABPs) directly regulate motility of metastasising tumor cells, and for cortactin an association with colon cancer metastasis has been already shown. However, as its depletion only incompletely inhibits metastasis, additional, more suitable cellular targets have to be identified. Here we analyzed expression of the ABPs, DIAPH1, VASP, N‐WASP, and fascin in comparison with cortactin and found that, besides cortactin, DIAPH1 was expressed with the highest frequency (63%) in colorectal cancer. As well as cortactin, DIAPH1 was not detectable in normal colon tissue and expression of both proteins was positively correlated with metastasis of colorectal cancer. To analyse the mechanistic role of DIAPH1 for metastasis of colon carcinoma cells in comparison with cortactin, expression of the proteins was stably down‐regulated in the human colon carcinoma cell lines HT‐29, HROC‐24 and HCT‐116. Analysis of metastasis of colon carcinoma cells in SCID mice revealed that depletion of DIAPH1 reduced metastasis 60‐fold and depletion of cortactin 16‐fold as compared with control cells. Most likely the stronger effect of DIAPH1 depletion on colon cancer metastasis is due to the fact that in vitro knock down of DIAPH1 impaired all steps of metastasis; adhesion, invasion and migration while down‐regulation of cortactin only reduced adhesion and invasion. This very strong reducing effect of DIAPH1 depletion on colon carcinoma cell metastasis makes the protein a promising therapeutic target for individualized colorectal cancer therapy.

Chromosomal Aberrations Associated with Sequential Steps of the Metastatic Cascade in Colorectal Cancer Patients

BACKGROUND Genomic information can help to identify colorectal tumors with high and low metastatic potential, thereby improving prediction of benefit of local and/or systemic treatment. Here we investigated chromosomal aberrations in relation to the different stages of the metastatic cascade: dissemination of tumor cells into the mesenteric vein, metastatic outgrowth in the liver, intravasation of the peripheral blood circulation, and development of further distant metastasis. METHODS Peripheral and mesenteric blood from colorectal cancer patients (n = 72) were investigated for circulating tumor cells, and DNA extracted from their primary tumors was subjected to array comparative genomic hybridization profiling. The results were validated with an independent set of primary colorectal tumors (n = 53) by quantitative reverse transcription PCR. RESULTS Mesenteric intravasation and liver metastasis were correlated with losses of chromosomes 16p (72%), 16q (27%), and 19 (54%), gain along 1q31 (45%) and 20q (60%), tumor cell infiltration into the peripheral blood circulation, and further distant metastasis with gain of chromosome 8q (59%) and 12 (47%, P < 0.01). Chromosome 12 gain was associated with poor overall survival in the initial (2.8 vs >7 years) and validation cohort (3.3 vs >6 years). The prospective study presented here is a hypothesis-generating study and confirmation with larger cohorts is required. CONCLUSIONS This is the first study that investigated colorectal cancer in its different stages of metastasis in correlation with copy number changes of the primary tumor. This information might be helpful to identify patients with limited metastatic spread who may profit from liver metastasis resection and may lead to the discovery of new therapeutic targets.Microarray data have been deposited in NCBIs Gene Expression Omnibus and are accessible through GEO Series accession number GSE82228.

Operation for GERD: Conventional Approach

In 1956, Rudolph Nissen introduced the antireflux effect of wrapping the gastric fundus around the distal esophagus. The “open Nissen fundoplication” and its modifications have since been used to treat moderate-to-severe gastroesophageal reflux disease (GERD) in situations in which medical therapy has failed. Laparoscopic antireflux procedures have, since the first reports in 1991, become the method of choice in dealing with surgical options for symptoms of GERD. As has been the case for several other laparoscopic procedures, questions have arisen about the limitations of these procedures in comparison with the traditional open techniques. An open approach may be preferable in patients who have undergone previous open upper abdominal surgery or in cases of recurrent or re-recurrent GERD when revisional laparoscopy may not seem sufficient to definitely treat the disease.

Ösophagus-Frühkarzinome: pro Chirurgie

Ösophagus-Frühkarzinome sind Karzinome, die nur auf die Mukosa oder Submukosa beschränkt sind, ohne Hinweis auf die Größe, Längenausdehnung oder den regionalen Lymphknotenbefall. Es stehen zwei verschiedene Behandlungsmethoden in der Therapie der Ösophagus-Frühkarzinome zur Verfügung: die klassischen chirurgischen Methoden bzw. die endoskopischen Methoden. Mit den chirurgischen Techniken kann man nicht nur den befallenen Abschnitt des Ösophagus, sondern auch die potentiell befallenen Lymphknoten entfernen. Weitere Vorteile sind: die «High grade»-Dysplasien sind häufig multifokal; 33–50% der Patienten mit hochgradiger Dysplasie in der Biopsie zeigen in der endgültigen Histologie Karzinome; 50% aller Patienten mit Beschränkung des Tumors auf die Submukosa haben Lymphknotenmetastasen; ein exaktes Tumor-Staging ist nur nach chirurgischer Resektion möglich; die Lokalrezidivrate nach chirurgischen Eingriffen liegt deutlich unter 5%, die Rezidivrate nach endoskopischer Therapie bei bis zu 25%. Allerdings weisen die chirurgischen Methoden ein Morbiditätsrisiko von 18–50% auf und zeigen sogar in ‘High volume’-Zentren eine Mortalitätsrate von 3–7%. In Japan ist die endoskopische Resektion der ‘Goldstandard’ bei gastrointestinalen Frühkarzinomen, sofern die spezifischen Indikationen erfüllt sind. In Anbetracht der niedrigen Morbiditäts- und Mortalitätsraten bei Patienten, die endoskopisch behandelt wurden, bleibt jedoch weiterhin offen: Für welche Patienten ist die endoskopische Mukosaresektion die Methode der Wahl? Mit welcher Rezidivrate muss gerechnet werden? Wann sollte ein Patient, der primär endoskopisch behandelt worden ist, der chirurgischen Therapie zugeführt werden? Unter Berücksichtigung der sinkenden perioperativen Morbidität und Mortalität (nahe 0%) bei Patienten, die einer limitierten Ösophagusresektion zugeführt wurden, bleiben folgende Fragen offen: Welche Patienten sollen nicht operiert werden? Welche Patienten müssen primär chirurgisch behandelt werden, um von einer aggressiveren Therapie mit einer ausgedehnten Lymphadenektomie zu profitieren?