Frank Traub

Publications of Frank Traub

• Phosphoglycerate kinase 1 a promoting enzyme for peritoneal dissemination in gastric cancer.

  Authors: Derek Zieker, Ingmar Königsrainer, Isabel Tritschler, Markus Löffler, Stefan Beckert, Frank Traub, Kay Nieselt, Sarah Bühler, Michael Weller, Jochen Gaedcke, Russell S Taichman, Hinnak Northoff, Björn L D M Brücher, Alfred Königsrainer

  International journal of cancer. Journal international du cancer. 09/2009;

  Peritoneal carcinomatosis is a frequent finding in gastric cancer associated with a poor prognosis. The features that enable gastric tumors to disseminate are poorly understood until now. Previously,Peritoneal carcinomatosis is a frequent finding in gastric cancer associated with a poor prognosis. The features that enable gastric tumors to disseminate are poorly understood until now. Previously, we showed elevated mRNA levels of phosphoglycerate kinase 1 (PGK1), an ATP-generating enzyme in the glycolytic pathway, the chemokine receptor 4 (CXCR4), the corresponding chemokine ligand 12 (CXCL12) and beta-catenin in specimens from gastric cancer patients with peritoneal carcinomatosis. In this study the influence of PGK1 on CXCR4 and beta-catenin was assessed as well as the invasiveness of PGK1 overexpressing cancer cells. In this current study we found that PGK1 regulates the expression of CXCR4 and beta-catenin at the mRNA and protein levels. On the other hand, CXCR4 regulates the expression of PGK1. Plasmid-mediated overexpression of PGK1 dramatically increased the invasiveness of gastric cancer cells. Interestingly, inhibition of CXCR4 in cells overexpressing PGK1 produced only a moderate reduction of invasiveness, suggesting that PGK1 itself has a critical role in tumor invasiveness. Immunohistochemistry in specimens from diffuse gastric cancer patients also revealed an overexpression of PGK1 in patients with development of peritoneal carcinomatosis. Therefore, PGK1 may be a crucial enzyme in peritoneal dissemination. Together these findings suggest that the enhanced expression of PGK1 and its signaling targets CXCR4 and beta-catenin in gastric cancer cells promote peritoneal carcinomatosis. Thus, PGK1 may serve as prognostic marker and/or be a potential therapeutic target to prevent dissemination of gastric carcinoma cells into the peritoneum. (c) 2009 UICC.

• Everolimus Interferes with the Inflammatory Phase of Healing in Experimental Colonic Anastomoses.

  Authors: Markus A Küper, Nadja Schölzl, Frank Traub, Petra Mayer, Jürgen Weinreich, Stephan Coerper, Wolfgang Steurer, Alfred Königsrainer, Stefan Beckert

  The Journal of surgical research. 08/2009;

  BACKGROUND: Delayed wound healing is a serious side effect of mTOR inhibitor-based immunosuppression after solid organ transplantation. The aim of this study was to test the hypothesis that the mTORBACKGROUND: Delayed wound healing is a serious side effect of mTOR inhibitor-based immunosuppression after solid organ transplantation. The aim of this study was to test the hypothesis that the mTOR inhibitor everolimus interferes with the inflammatory phase of healing in experimental colonic anastomoses. MATERIALS AND METHODS: Thirty male Sprague-Dawley rats received a colonic anastomosis. Then, animals were randomized to three groups of daily treatment with either vehicle or everolimus in two different dosages (1.0mg/kg or 3.0mg/kg). After 7 d, rats were sacrificed, and mechanical, histologic, and biochemical parameters of intestinal healing were assessed. RESULTS: Anastomotic bursting pressure was significantly decreased by everolimus in both dosages, whereas hydroxyproline content was reduced only by the high everolimus dosage. Everolimus diminished cellular proliferation and new vessel growth. Furthermore, both quantity as well as quality of newly synthesized collagen fibers in the anastomotic granulation tissue was reduced. On the other hand, myeloperoxidase-positive (MPO) cells and interleukin-6 (IL-6) concentrations were increased, as was the activity of matrix-metalloproteinases MMP-2 and MMP-9. CONCLUSION: Everolimus interferes with the inflammatory phase of healing. However, it remains unclear whether this phenomenon is involved in everolimus impairment of experimental anastomotic repair.

• Cellular liver regeneration after extended hepatic resection in pigs.

  Authors: Ruth Ladurner, Frank Traub, Martin Schenk, Alfred Königsrainer, Jörg Glatzle

  HPB surgery : a world journal of hepatic, pancreatic and biliary surgery. 02/2009; 2009:306740.

  BACKGROUND: The liver has an enormous capacity to regenerate itself. The aim of this study was to evaluate whether the regeneration is due to hypertrophy or hyperplasia of the remnant liver afterBACKGROUND: The liver has an enormous capacity to regenerate itself. The aim of this study was to evaluate whether the regeneration is due to hypertrophy or hyperplasia of the remnant liver after extended resection and whether a portosystemic shunt is beneficial. MATERIAL AND METHODS: An extended left hemihepatectomy was performed in 25 pigs, and in 14 after performing a portosystemic shunt. During follow up, liver regeneration was estimated by macroscopic markers such as liver volume and size of the portal fields [mm(2)] as well as the amount of hepatocytes per portal field and the amount of hepatocytes per mm(2). RESULTS: Regardless of the operation procedure, the volume of the remnant liver increased about 2.5 fold at the end of the first week after resection. The size of the portal fields increased significantly as well as the number of hepatocytes in the portal fields. Interestingly, the number of hepatocytes per mm(2) remained the same. CONCLUSION: After extended resection, liver regeneration was achieved by an extensive and significant hyperplasia of hepatocytes within the preexisting portal fields and not by de novo synthesis of new portal fields. However, there was no difference in liver regeneration regarding the operation procedure performed with or without portosystemic shunt.

• Feasibility study for secure closure of natural orifice transluminal endoscopic surgery gastrotomies by using over-the-scope clips.

  Authors: Thomas Kratt, Markus Küper, Frank Traub, Chi-Nghia Ho, Marc Oliver Schurr, Alfred Königsrainer, Frank Alexander Granderath, Andreas Kirschniak

  Gastrointestinal endoscopy. 12/2008; 68(5):993-6.

  BACKGROUND: The secure sealing of natural orifice transluminal endoscopic surgery (NOTES) approaches to the abdominal cavity is a problem that has not been solved. The feasibility of closingBACKGROUND: The secure sealing of natural orifice transluminal endoscopic surgery (NOTES) approaches to the abdominal cavity is a problem that has not been solved. The feasibility of closing iatrogenic endoscopic GI-tract perforations by using a new over-the-scope clip was recently described. OBJECTIVE: To demonstrate the feasibility of endoscopic closure of transgastric NOTES approaches with a novel clip system. DESIGN: Acute nonsurvival animal study (porcine model; n = 9). INTERVENTIONS: Transgastric approaches were performed by using a needle-knife and balloon dilation. After abdominopelvic exploration, the transgastric approaches were closed by using the OTSC clipping system with suction. The procedure was performed under laparoscopic visualization. RESULTS: Gastrotomy lesions could primarily be closed in 8 cases. However, the laparoscopic control indicated that the clip adaptation of the wound margins was not completely airtight under maximum insufflation of the stomach in 4 of 9 cases. LIMITATION: Nonsurvival animal study. CONCLUSIONS: Sufficient closure of transgastric NOTES approaches is feasible when using the OTSC system. When considering our clinical experience, the OTSC system was shown to be an uncomplicated and secure sealing technique in human beings.

• PGK1 a potential marker for peritoneal dissemination in gastric cancer.

  Authors: Derek Zieker, Ingmar Königsrainer, Frank Traub, Kay Nieselt, Bettina Knapp, Christian Schillinger, Christian Stirnkorb, Falko Fend, Hinnak Northoff, Susan Kupka, Björn L D M Brücher, Alfred Königsrainer

  Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 02/2008; 21(5-6):429-36.

  BACKGROUND/AIMS: Peritoneal carcinomatosis, which is caused by the dissemination of cancer cells into the abdominal cavity is a frequent finding in patients with primary gastric cancer, and it isBACKGROUND/AIMS: Peritoneal carcinomatosis, which is caused by the dissemination of cancer cells into the abdominal cavity is a frequent finding in patients with primary gastric cancer, and it is associated with a poor prognosis. The mechanisms that mediate peritoneal carcinomatosis in diffuse primary gastric tumours require definition. METHODS: We therefore compared the gene expression profile in diffuse primary gastric cancer patients with and without peritoneal carcinomatosis (n=13). Human specimens from consecutive gastric cancer patients with and without peritoneal carcinomatosis were investigated using oligonucleotide microarrays. Differentially expressed genes of interest were further evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The results reveal a significant overexpression of phosphoglycerate kinase 1 (PGK1), the chemokine CXCR4 and its ligand CXCL12 in specimens from diffuse gastric cancer patients with peritoneal carcinomatosis. Overexpression of PGK1 is known to increase the expression of CXCR4. CXCR4 on its part can increase CXCL12 expression. Elevated levels of CXCR4 and CXCL12 are associated with an increase in the metastatic rate and play an important role in the metastatic homing of malignant cells. CONCLUSION: The overexpression of PGK1 and its signalling targets may be a expression-pathway in diffuse primary gastric carcinomas promoting peritoneal dissemination and may function as prognostic markers and/or be potential therapeutic targets to prevent the migration of gastric carcinoma cells into the peritoneum.

• Predominance of the basal type and HER-2/neu type in brain metastasis from breast cancer.

  Authors: Jochen Gaedcke, Frank Traub, Simone Milde, Ludwig Wilkens, Alexandru Stan, Helmut Ostertag, Mathias Christgen, Reinhard von Wasielewski, Hans H Kreipe

  Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 09/2007; 20(8):864-70.

  Although breast cancer is the second most common cause of central nervous system (CNS) metastases with a notable increase of incidence, only few studies on brain-metastasizing breast cancer areAlthough breast cancer is the second most common cause of central nervous system (CNS) metastases with a notable increase of incidence, only few studies on brain-metastasizing breast cancer are available. In this immunohistochemical and fluorescence in situ hybridization (FISH) study, metastases to the CNS (n=85) and primary breast cancers, with known involvement of the CNS (n=44) including paired primary and metastasized tumours (n=23), were investigated retrospectively for the expression of oestrogen- (ER) and progesterone- (PR) hormone receptors, Her-2/neu, epidermal growth factor receptor (EGFR), Ki-67, and cytokeratins (CKs) 5/14. The majority of brain metastases were steroid hormone receptor negative (ER 66%, PR 82%) corresponding to the findings in primary tumours with known involvement of the CNS (68% ER-negative, 75% PR-negative). The frequency of HER-2/neu-overexpressing or -amplified cancers was increased in both groups (34 and 32%, respectively). EGFR expression was more frequent in metastases (41%) than in primary tumours (16%). The proportions of cases with a basal phenotype were 26 and 30%, respectively. In paired primary tumours and metastases to the CNS, constancy of Her-2/neu status was observed in 87% of cases with only one sample turning Her-2/neu-negative and two samples acquiring overexpression/amplification in brain metastases. In contrast, steroid hormone receptors exhibited more frequently a loss of expression (17%) than a gain (9%) with 74% revealing a constant phenotype. We conclude that brain-metastasizing breast cancer belongs predominantly to the basal type or Her-2/neu type. Primary and metastatic tumours differ from each other only in a minority of cases, leading rather to a loss of steroid hormone receptors and to a gain of EGFR and Her-2/neu.

• Legumain expression as a prognostic factor in breast cancer patients.

  Authors: Jessica Gawenda, Frank Traub, Hans J Lück, Hans Kreipe, Reinhard von Wasielewski

  Breast cancer research and treatment. 03/2007; 102(1):1-6.

  Invasive tumor cells and their microenvironments are enriched with a broad spectrum of different proteases. Legumain, a novel asparaginyl endopeptidase, has been observed to be highly expressed inInvasive tumor cells and their microenvironments are enriched with a broad spectrum of different proteases. Legumain, a novel asparaginyl endopeptidase, has been observed to be highly expressed in several types of solid tumors. However, there is no data available identifying the relationship of legumain expression and clinicopathologic or biological variables in invasive breast cancer. For the first time, the prevalence of legumain expression in invasive breast cancer (n = 432) and non-neoplastic breast tissues (n = 128) was investigated by immunohistochemistry. Three staining patterns were observed in the cytoplasm: diffuse positivity, tiny dots and vesicles. Whereas vesicular positivity in the majority of tumor cells was significantly correlated to an adverse outcome, cytoplasmic and dot-like staining showed no prognostic effect. Vesicular positivity was observed in 24% of carcinomas, but only in one case of non-neoplastic breast tissue (<1%; proliferative mastopathy). This staining pattern was found to be independent of other factors analysed as grading, nodal status or HER2 expression. Besides being of prognostic value, legumain might prove to be an important predictive factor in breast cancer, since its unique cleavage specificity is already used in prodrug activation strategies.

• Prognostic impact of Skp2 and p27 in human breast cancer.

  Authors: Frank Traub, Michael Mengel, Hans J Lück, Hans H Kreipe, Reinhard von Wasielewski

  Breast cancer research and treatment. 10/2006; 99(2):185-91.

  PURPOSE: The cell cycle is controlled by cyclin-dependent kinases and one of the key players is the cyclin-dependent kinase inhibitor p27. The F-box protein Skp2 is a regulator of G1-S transition andPURPOSE: The cell cycle is controlled by cyclin-dependent kinases and one of the key players is the cyclin-dependent kinase inhibitor p27. The F-box protein Skp2 is a regulator of G1-S transition and promotes specifically the ubiquitin-mediated proteolysis of p27 via the proteasome pathway. In breast carcinomas, overexpression of Skp2 has been implicated in cell transformation and oncogenesis, but no data are available on the association of Skp2 and p27. The purpose was to evaluate the prevalence of Skp2 and p27 expression and determine whether a combined index has prognostic power in breast carcinomas. EXPERIMENTAL DESIGN: Three hundred and thirty-eight breast cancer specimens were analyzed for Skp2 and p27 expression by immunohistochemistry. Results were compared with classical histopathological criteria as well as other prognostic markers (ER, PR, HER2, p53, Ki-67) and correlated with the clinical outcome. RESULTS: Thirty-four percent of breast cancers analyzed showed both a high expression for Skp2 and a low expression for p27. In univariate Kaplan-Meier analysis, this combination was found to be significantly associated with a worse clinical course (p<0.0001). Including staging, grading and the other tested marker, the Skp2/p27 index proved to be of prognostic relevance in multivariate analysis. CONCLUSIONS: The combined assessment of Skp2 and p27 identifies aggressive breast cancer. In long-term follow-up, high Skp2 and low p27 indicate an unfavorable course. Beyond the prognostic importance of the Skp2/p27 index, it could serve as a predictive marker for new molecular targeted therapies aiming at Skp2.

• Peptidomic analysis of breast cancer reveals a putative surrogate marker for estrogen receptor-negative carcinomas.

  Authors: Frank Traub, Marco Jost, Rüdiger Hess, Karl Schorn, Christoph Menzel, Petra Budde, Peter Schulz-Knappe, Norbert Lamping, Andreas Pich, Hans Kreipe, Harald Tammen

  Laboratory investigation; a journal of technical methods and pathology. 04/2006; 86(3):246-53.

  Estrogen-receptor status provides a major biomarker in breast cancer classification and has an important impact on prognosis and treatment options. The aim of this study was to investigate peptideEstrogen-receptor status provides a major biomarker in breast cancer classification and has an important impact on prognosis and treatment options. The aim of this study was to investigate peptide profiles of invasive breast cancer with positive (n=39) and negative receptor status (n=41). Peptide profiles were generated by 'Differential Peptide Display', which is an offline-coupled combination of reversed-phase-HPLC and MALDI mass spectrometry. Mass spectrometric data were correlated with the immunohistochemically determined receptor state. Identification of peptides of interest was carried out by additional mass spectrometric methods (eg MALDI-TOF-TOF-MS-MS). Approximately 3000-7000 signals were detected per sample and thymosin alpha-1, an asparaginyl endopeptidase generated cleavage product of the ubiquitous acidic protein prothymosin-alpha, was found to differentiate the tumor samples according to their receptor status with the highest specificity. The concentration of Thymosin alpha-1 was found to be upregulated (n=37) in estrogen-negative cancer samples and downregulated (n=32) in estrogen-positive breast cancer samples. The expression of the precursor protein (Prothymosin-alpha) has been discussed previously as a prognostic factor in breast cancer. It is involved in the ER signal transduction pathway as an anti-coactivator-inhibitor. From our findings we conclude that Thymosin alpha-1 could serve as a surrogate marker in breast cancers and may indicate ER functionality.

• Nephroblastomatosis and loss of WT1 expression associated with trisomy 13.

  Authors: Frank Traub, Karin Sickmann, Mathewos Tessema, Ludwig Wilkens, Hans H Kreipe, Kenji Kamino

  Virchows Archiv : an international journal of pathology. 03/2006; 448(2):214-7.

  Trisomy 13 (Patau's syndrome) is a rare finding in newborns. The life span of babies affected by this chromosome abnormality is severely shortened, and multiple, partly severe malformations occur. InTrisomy 13 (Patau's syndrome) is a rare finding in newborns. The life span of babies affected by this chromosome abnormality is severely shortened, and multiple, partly severe malformations occur. In this study, we report on an unborn with trisomy 13 (artificially aborted on the 24th week) which showed, among other typical deformities, bilateral nephrogenic rests (nephroblastomatosis). Using molecular analysis, a loss of Wilms' tumor gene 1 (WT1) transcript and a biallelic expression of insulin growth factor 2 (IGF2) could be revealed. To our knowledge, this is the first reported case of trisomy 13 which showed this type of anomaly and gene expression findings.

• High-resolution genomic profiling reveals association of chromosomal aberrations on 1q and 16p with histologic and genetic subgroups of invasive breast cancer.

  Authors: Daniel E Stange, Bernhard Radlwimmer, Falk Schubert, Frank Traub, Andreas Pich, Grischa Toedt, Frank Mendrzyk, Ulrich Lehmann, Roland Eils, Hans Kreipe, Peter Lichter

  Clinical cancer research : an official journal of the American Association for Cancer Research. 02/2006; 12(2):345-52.

  PURPOSE: Invasive ductal carcinoma and invasive lobular carcinoma (ILC) represent the major histologic subtypes of invasive breast cancer. They differ with regard to presentation, metastatic spread,PURPOSE: Invasive ductal carcinoma and invasive lobular carcinoma (ILC) represent the major histologic subtypes of invasive breast cancer. They differ with regard to presentation, metastatic spread, and epidemiologic features. To elucidate the genetic basis of these differences, we analyzed copy number imbalances that differentiate the histologic subtypes.EXPERIMENTAL DESIGN: High-resolution genomic profiling of 40 invasive breast cancers using matrix-comparative genomic hybridization with an average resolution of 0.5 Mb was conducted on bacterial artificial chromosome microarrays. The data were subjected to classification and unsupervised hierarchical cluster analyses. Expression of candidate genes was analyzed in tumor samples.RESULTS: The highest discriminating power was achieved when combining the aberration patterns of chromosome arms 1q and 16p, which were significantly more often gained in ILC. These regions were further narrowed down to subregions 1q24.2-25.1, 1q25.3-q31.3, and 16p11.2. Located within the candidate gains on 1q are two genes, FMO2 and PTGS2, known to be overexpressed in ILC relative to invasive ductal carcinoma. Assessment of four candidate genes on 16p11.2 by real-time quantitative PCR revealed significant overexpression of FUS and ITGAX in ILC with 16p copy number gain. Unsupervised hierarchical cluster analysis identified three molecular subgroups that are characterized by different aberration patterns, in particular concerning gain of MYC (8q24) and the identified candidate regions on 1q24.2-25.1, 1q25.3-q31.3, and 16p11.2. These genetic subgroups differed with regard to histology, tumor grading, frequency of alterations, and estrogen receptor expression.CONCLUSIONS: Molecular profiling using bacterial artificial chromosome arrays identified DNA copy number imbalances on 1q and 16p as significant classifiers of histologic and molecular subgroups.

• SELDI-MS-based expression profiling of ductal invasive and lobular invasive human breast carcinomas.

  Authors: Frank Traub, Henning Feist, Hans H Kreipe, Andreas Pich

  Pathology, research and practice. 02/2005; 201(12):763-70.

  Expression profiling using proteomic techniques has a great potential to identify new biomarkers that might help to better diagnose and treat diseases such as breast cancer, which is one of theExpression profiling using proteomic techniques has a great potential to identify new biomarkers that might help to better diagnose and treat diseases such as breast cancer, which is one of the leading causes of cancer death in women. Surface-enhanced laser desorption ionization mass spectrometry (SELDI-MS) combines chromatographic separation of peptides and proteins with mass spectrometry and is a fast, user-friendly tool to analyze protein and peptide profiles. SELDI-MS was employed for a comparative analysis of lobular invasive versus ductal invasive breast tumors to find differentially expressed proteins and peptides, and to validate this technique for biomarker identification using complex samples such as tissue. After optimization of sample preparation using HMEC and MCF-7 cell lines, 20 breast tumors were analyzed, and about 550 mass signals corresponding to an estimated 140 native peptides and proteins were detected in each tumor. Only 14% of the mass signals were present in more than six tumors of one subgroup or in more than 12 tumors of both groups showing a great overall heterogeneity of the peptide and protein profiles obtained. Peptide mass signals specific for each of the analyzed groups were identified. In addition, we detected peptides from laser-microdissected ductal invasive and intraductal tumor parts corresponding to peptides present in whole tumors. The low amount of identified peptides and proteins and the observed heterogeneity suggest that SELDI-MS is not well suited for biomarker identification of and profiling experiments on complex samples such as tumor tissue.

• Feasibility study for secure closure of natural orifice transluminal endoscopic surgery gastrotomies by using over-the-scope clips

  Authors: Thomas Kratt, Markus Küper, Frank Traub, Chi-Nghia Ho, Marc-Oliver Schurr, Alfred Königsrainer, Frank Alexander Granderath, Andreas Kirschniak

  Gastrointestinal Endoscopy.

  BackgroundThe secure sealing of natural orifice transluminal endoscopic surgery (NOTES) approaches to the abdominal cavity is a problem that has not been solved. The feasibility of closing iatrogenicBackgroundThe secure sealing of natural orifice transluminal endoscopic surgery (NOTES) approaches to the abdominal cavity is a problem that has not been solved. The feasibility of closing iatrogenic endoscopic GI-tract perforations by using a new over-the-scope clip was recently described.ObjectiveTo demonstrate the feasibility of endoscopic closure of transgastric NOTES approaches with a novel clip system.DesignAcute nonsurvival animal study (porcine model; n = 9).InterventionsTransgastric approaches were performed by using a needle-knife and balloon dilation. After abdominopelvic exploration, the transgastric approaches were closed by using the OTSC clipping system with suction. The procedure was performed under laparoscopic visualization.ResultsGastrotomy lesions could primarily be closed in 8 cases. However, the laparoscopic control indicated that the clip adaptation of the wound margins was not completely airtight under maximum insufflation of the stomach in 4 of 9 cases.LimitationNonsurvival animal study.ConclusionsSufficient closure of transgastric NOTES approaches is feasible when using the OTSC system. When considering our clinical experience, the OTSC system was shown to be an uncomplicated and secure sealing technique in human beings.