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The gene SASH1 (SAM-and SH3-domain containing 1) has originally been identified as a candidate tumour suppressor gene in breast cancer. SASH1 is a member of the SH3-domain containing expressed in lymphocytes (SLY1) gene family that encodes signal adapter proteins composed of several protein -protein interaction domains. The other members of this family are expressed mainly in haematopoietic cells, whereas SASH1 shows ubiquitous expression. We have used quantitative real-time PCR to investigate the expression of SASH1 in tissue samples from 113 patients with colon carcinoma, and compared the expression with 15 normal colon tissue samples. Moreover, nine benign adenomas and 10 liver metastases were analysed. Expression levels of SASH1 were strongly and significantly reduced in colon cancer of UICC stage II, III, and IV, as well as in liver metastases. Moreover, SASH1 was also found to be downregulated on protein levels by immunoblot analysis. However, SASH1 expression was not significantly deregulated in precancerous adenomas and in earlier stage lesions (UICC I). Overall, 48 out of 113 primary colon tumours showed SASH1 expression that was at least 10-fold lower than the levels found in normal colon tissue. Downregulation of SASH1 expression was correlated with the formation of metachronous distant metastasis, and multivariate analysis identified SASH1 downregulation as an independent negative prognostic parameter for patient survival. This study demonstrates for the first time that expression of a member of the SLY1-gene family has prognostic significance in human cancer.

Osteopontin (OPN) is a secreted phosphoprotein, which has been reported to be associated with tumor progression in numerous solid tumors. In a previous transcriptome study on colorectal cancer, we identified the gene OPN among the most strongly up-regulated transcripts. OPN has been suggested as a putative target of Wnt signaling, but the molecular mechanism responsible for its aberrant transcription is not fully understood. We analyzed 13 normal colon tissues, 9 adenomas, 120 primary colon tumors, and 10 liver metastases by quantitative reverse-transcription PCR. OPN expression was strongly elevated in primary colon cancer and liver metastasis, but not in pre-cancerous lesions and UICC stage I tumors. Multivariate analysis established OPN expression as an independent prognostic parameter for overall survival. Moreover, high OPN expression identified a subgroup of patients with bad prognosis. Next, we determined immunohistochemically a correlation of OPN expression with aberrant b-catenin staining, which is indicative of Wnt activation. Elevated expression of OPN was significantly correlated with increased cytoplasmic and nuclear b-catenin staining. The in vivo role of Wnt signaling for the expression of OPN was tested in genetically defined mouse models with (Apc 1638N ) or without (pvillin-KRAS V12G ) Wnt activating mutations. Mutation of the tumor suppressor APC was necessary for upregulation of OPN expression in the murine tumors on transcript and on protein levels. Thus, OPN is a transcriptional target of aberrant Wnt signaling, and OPN expression alone predicts survival in human colon cancer. ' 2007 Wiley-Liss, Inc.

Aneuploidy and genetic instability are a hallmark of colorectal cancer and other solid tumors, and they are thought to enhance tumor progression. The gene MAD2L2 (mitotic arrest deficient 2-like 2) encodes the spindle checkpoint protein MAD2L2 (or MAD2B), a key component of a surveillance system that delays anaphase until all chromosomes are correctly oriented. Defects in this mitotic checkpoint are known to contribute to genetic instability, i.e., numerical and structural aberrations of chromosomes. We have previously identified MAD2L2 as significantly upregulated in locally restricted colorectal tumors by gene expression profiling. So far, MAD2L2 has not been reported to play a major role in human cancer in contrast to its homologue MAD2. To address this question, 118 histologically confirmed colorectal lesions were analyzed by quantitative real-time PCR for expression of MAD2L2, and compared to normal colon tissue from 11 patients. Twenty-five out of 118 tumor samples (21%) showed MAD2L2 overexpression of 3-fold or more compared to normal colon, and the fraction of overexpressing tumors increased with tumor stage. Correspondingly, protein levels of MAD2L2 were found to be significantly upregulated in tumors as compared to matched normal tissue. Tumors with upregulated MAD2L2 expression had significantly higher numbers of aberrant mitotic figures (anaphase bridges), an indication of chromosomal instability. Elevated expression of MAD2L2 was significantly correlated with reduced patient survival. By multivariate analysis, MAD2L2 expression was retained as an independent prognostic parameter for patient survival. Thus, our results demonstrate that overexpression of MAD2L2 correlates with bad prognosis in colorectal cancer. ' 2006 Wiley-Liss, Inc.

Purpose: In locally advanced (uT 3 , N + ) adenocarcinomas of the esophagus, neoadjuvant chemotherapy improves patient outcome. However, only a subgroup of patients responds. Therefore, in the present study, we evaluated whether the response to neoadjuvant chemotherapy can be predicted by a pretreatment tumor biopsy analysis.Experimental Design: Biopsies of 47 patients with locally advanced (uT 3 , N + ) adenocarcinoma of the esophagus were obtained during primary staging. All patients underwent neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and leucovorin and subsequent resection of the esophagus. Biopsies were used for microarray analysis. The predominance of tumor cells within the specimens was >70%. Affymetrix U133 plus 2.0 gene chips with 54675 probe sets were used. A statistical comparison of patients responding to chemotherapy versus nonresponding patients was done. All patients were examined with immunohistology against Ephrin B3 receptor and Ki-67.Results: A total of 86 genes were at least 2-fold differentially regulated comparing responding with nonresponding adenocarcinomas of the esophagus. The predominant genes encoded for the regulation of the cell cycle, transduction, translation, cell-cell interaction, cytoskeleton, and the signal transduction. The strongest difference was seen for the Ephrin B3 receptor. This result could be confirmed by immunhistology. A statistical significant correlation between the Ephrin B3 receptor, chemotherapy response, pathologic staging, and grading could be shown.Conclusions: There were significant differences in the gene profile between patients with adenocarcinoma of the esophagus responding to neoadjuvant chemotherapy compared with nonresponding patients. This suggests that it could be possible to characterize patients responding to chemotherapy even before starting the treatment using customized microarray analysis. Clin Cancer Res; 16(1); 330-7. ©2010 AACR.

Zusammenfassung Hintergrund Moderne, individualisierte Therapien können das Überleben von Patienten mit kolorektalem Karzinom verbessern. Jedoch werden nicht alle Patienten zur Behandlung in ein zertifiziertes Darmkrebszentrum überwiesen, wo ihre Therapie, unterstützt durch ein Tumorboard, leitliniengerecht durchgeführt wird. Daher wird derzeit die Zweitmeinung bei Krebserkrankungen diskutiert. Diese Studie beschreibt Ergebnisse einer Pilotstudie hinsichtlich der Machbarkeit und des Bedarfs einer strukturierten, onlinebasierten, qualifizierten Zweitmeinung für Patienten mit kolorektalem Karzinom. Methoden Im Rahmen einer 15-monatigen Pilotphase zwischen 2009 und 2011 konnten Patienten mit kolorektalem Karzinom mittels einer onlinebasierten Elektronischen Patientenakte, unterstützt durch einen Case Manager, kostenfrei eine qualifizierte Zweitmeinung eines Tumorboards einholen. Ihre Zufriedenheit und ihre Lebensqualität (EORCT QLQ-C30) wurden über ein Jahr nachbeobachtet. Ergebnisse In 95 % der Fälle konnten eine vollständige Elektronische Patientenakte und eine Zweitmeinung erstellt werden. Weniger als die Hälfte der Teilnehmer erhielt die erste Therapieempfehlung aus einer Klinik mit Tumorboard. Die Erstmeinung konnte in 40 % der Fälle durch die Zweitmeinung bestätigt werden, in 33 % zeigte sich ein teilweises, in 27 % ein deutliches Abweichen. Bei Umsetzung der abweichenden Zweitmeinung verbesserte sich die Lebensqualität der Patienten. Schlussfolgerung Die Erstellung einer onlinebasierten, qualifizierten Zweitmeinung durch ein interdisziplinäres Tumorboard ist technisch und logistisch gut durchführbar. Die onlinebasierte Zweitmeinung könnte zukünftig die Qualität der Behandlung von Patienten mit kolorektalem Karzinom deutlich verbessern und damit ihre Lebensqualität erhöhen.

Acute acalculous cholecystitis (AAC) represents a severe disease in critically ill patients. The pathogenesis of acute necroinflammatory gallbladder disease is multifactorial and intensive care unit (ICU) patients show multiple risk factors. In addition AAC is difficult to diagnose because of the vague physical and non-specific technical findings. Only the combination of clinical and technical findings including the challenging physical examination of critically ill patients, laboratory results and ultrasound or computed tomography (CT) scan, will lead to the diagnosis. The condition of AAC has a rapid progress to gallbladder necrosis, gangrene and perforation and these complications are reflected in the high morbidity and mortality rates, therefore, therapy should be promptly initiated. If there are no clinical contraindications for an operative approach cholecystectomy is the definitive treatment and both open and laparoscopic procedures have been used. In unstable, critically ill patients percutaneous cholecystostomy should be immediately performed. In addition, transpapillary endoscopic drainage is also possible if there are contraindications for percutaneous cholecystostomy. Patients who fail to improve or deteriorate following interventional drainage should be reconsidered for cholecystectomy. Due to the fact that more than 90 % of patients treated with percutaneous cholecystostomy showed no recurrence of symptoms during a period of more than 1 year, it is still unclear if percutaneous cholecystostomy is the definitive treatment of AAC for unstable patients or if delayed cholecystectomy is still necessary.

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