Allogeneic Blood Transfusion Does Not Affect Outcome After Curative Resection for Advanced Cholangiocarcinoma

Purpose: To assess the impact of perioperative blood transfusion on overall and disease-free survival in patients undergoing curative resection for cholangiocarcinoma. Methods: In a single-center study, 128 patients undergoing curative resection for cholangiocarcinoma between 2001 and 2010 were assessed. The median follow-up period was 19months. Transfused and nontransfused patients were compared by Cox regression and propensity score analyses. Results: Overall, 38 patients (29.7%) received blood transfusions. The patient characteristics were highly biased with respect to receiving transfusions (propensity score 0.69±0.22 vs. 0.11±0.16, p<0.001). In the unadjusted analysis, blood transfusion was associated with a 105% increased risk of mortality [hazard ratio (HR) 2.05, 95% CI 1.19-3.51, p=0.010]. In the multivariate (HR 1.14, 95% CI 0.52-2.48, p=0.745) and the propensity score-adjusted Cox regression (HR 1.02, 95% CI 0.39-2.62, p=0.974), blood transfusion had no influence on overall survival. Similarly, in the propensity score-adjusted Cox regression (HR 0.62, 95% CI 0.24-1.58, p=0.295), no relevant effect of blood transfusion on disease-free survival was observed. Conclusions: To our knowledge, this is the first propensity score-based analysis providing compelling evidence that the worse oncological outcome after curative resection for advanced cholangiocarcinoma in patients receiving perioperative blood transfusions is caused by the clinical circumstances requiring the transfusions, not by the blood transfusions themselves

Double-blind, placebo-controlled first in human study to investigate an oral vaccine aimed to elicit an immune reaction against the VEGF-Receptor 2 in patients with stage IV and locally advanced pancreatic cancer

BACKGROUND: The investigational oral DNA vaccine VXM01 targets the vascular endothelial growth factor receptor 2 (VEGFR-2) and uses Salmonella typhi Ty21a as a vector. The immune reaction elicited by VXM01 is expected to disrupt the tumor neovasculature and, consequently, inhibit tumor growth. VXM01 potentially combines the advantages of anti-angiogenic therapy and active immunotherapy. METHODS/DESIGN: This phase I trial examines the safety, tolerability, and immunological and clinical responses to VXM01. The randomized, placebo-controlled, double blind dose-escalation study includes up to 45 patients with locally advanced and stage IV pancreatic cancer. The patients will receive four doses of VXM01 or placebo in addition to gemcitabine as standard of care. Doses from 10(6) cfu up to 10(10) cfu of VXM01 will be evaluated in the study. An independent data safety monitoring board (DSMB) will be involved in the dose-escalation decisions. In addition to safety as primary endpoint, the VXM01-specific immune reaction, as well as clinical response parameters will be evaluated. DISCUSSION: The results of this study shall provide the first data regarding the safety and immunogenicity of the oral anti-VEGFR-2 vaccine VXM01 in cancer patients. They will also define the recommended dose for phase II and provide the basis for further clinical evaluation, which may also include additional cancer indications. TRIAL REGISTRATION: EudraCT No.: 2011-000222-29, NCT01486329, ISRCTN6880927

Initiation of an Inflammatory Response in Resident Intestinal Lamina Propria Cells -Use of a Human Organ Culture Model

<div><p>Resident human lamina propria immune cells serve as powerful effectors in host defense. Molecular events associated with the initiation of an intestinal inflammatory response in these cells are largely unknown. Here, we aimed to characterize phenotypic and functional changes induced in these cells at the onset of intestinal inflammation using a human intestinal organ culture model. In this model, healthy human colonic mucosa was depleted of epithelial cells by EDTA treatment. Following loss of the epithelial layer, expression of the inflammatory mediators <i>IL1B, IL6, IL8, IL23A, TNFA, CXCL2</i>, and the surface receptors CD14, TLR2, CD86, CD54 was rapidly induced in resident lamina propria cells <i>in situ</i> as determined by qRT-PCR and immunohistology. Gene microarray analysis of lamina propria cells obtained by laser-capture microdissection provided an overview of global changes in gene expression occurring during the initiation of an intestinal inflammatory response in these cells. Bioinformatic analysis gave insight into signalling pathways mediating this inflammatory response. Furthermore, comparison with published microarray datasets of inflamed mucosa <i>in vivo</i> (ulcerative colitis) revealed a significant overlap of differentially regulated genes underlining the <i>in vivo</i> relevance of the organ culture model. Furthermore, genes never been previously associated with intestinal inflammation were identified using this model. The organ culture model characterized may be useful to study molecular mechanisms underlying the initiation of an intestinal inflammatory response in normal mucosa as well as potential alterations of this response in inflammatory bowel disease.</p></div

Over-representation of GO terms in dataset of upregulated genes in the LEL model.

1<p>P value of hypergeometric test for over-representation (conditional on GO structure).</p>2<p>Count: number of GO term associated genes in the dataset of upregulated genes.</p>3<p>Size: total number of GO term associated genes.</p

Induction of inflammatory gene expression in resident lamina propria cells following loss of the epithelial layer.

<p>(<b>A</b>) Time scheme of the LEL model. Arrows indicate time points of tissue collection. Tissue samples were collected prior to culturing (TM t = 0 h), after washing (TM t = 2 h), as well during and after completion of epithelial cell release by EDTA treatment (LEL-M t = 3/4/5 h). As a control, tissue samples were collected from TM cultured for 5 h (TM t = 5 h). (<b>B</b>) LEL induces gene expression of <i>IL1B</i>, <i>IL6</i>, <i>IL8</i>, <i>IL23A</i>, <i>TNFA, IFNG</i>, and <i>CCL2</i> in resident lamina propria cells. Transcript levels of cytokines/chemokines were determined by qRT-PCR in tissue samples collected as described in (A). Shown are the mean normalized transcript numbers ± SEM of at least 4 independent experiments. Gray bars represent transcript levels of TM (t = 0/2/5 h), black bars represent transcript levels of LEL-M (t = 3/4/5h). (<b>C</b>) EDTA treatment does not induce inflammatory cytokines in PBMC or LPMC. PBMC and LPMC, respectively, were exposed to 0.7 mM EDTA/HBSS or medium (RPMI/2% FCS) for 3 h. Subsequently, transcript levels of <i>IL6</i>, <i>IL8</i>, <i>IL1B</i>, and <i>IL23A</i> were determined by qRT-PCR (<i>IL8</i> and <i>IL23A</i> not tested for LPMC). The results of two independent experiments are shown.</p