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Pancreatic Neoplasms: HELP
Articles by Carsten Jäger
Based on 15 articles published since 2010
(Why 15 articles?)
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Between 2010 and 2020, Carsten Jäger wrote the following 15 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Venous resection during pancreatectomy for pancreatic cancer: a systematic review. 2019

Wang, Xiaobo / Demir, Ihsan Ekin / Schorn, Stephan / Jäger, Carsten / Scheufele, Florian / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Department of General Surgery, School of Medicine, Acıbadem Mehmet Ali Aydınlar University, Istanbul, Turkey. ·Transl Gastroenterol Hepatol · Pubmed #31304423.

ABSTRACT: Pancreatic cancer is one of the most aggressive and lethal malignancies with a dismal prognosis and survival. The curative effects of venous resection (VR) in pancreatic cancer remain controversial. A systematic literature search was performed in PubMed, Embase and the Cochrane Library. The overall postoperative complications, perioperative mortality, histopathology, and long-term survival were compared between patients undergoing pancreatectomy combined with (VR+ group) or without (VR- group) VR. Forty-one studies were included in the systematic review. Pancreatectomy combined with VR required longer operation time and led to increased perioperative blood loss, whereas postoperative complications were similar. Patients in the VR+ group showed larger tumors and reduced R0 rates. Regarding long-term survival, patients with VR+ seemed to have impaired 1-, 3-, and 5-year survival. Based on our results, VR in pancreatic cancer is a safe and feasible procedure. Given the fact that patients have miserable outcomes and survival in the palliative setting alone, extended resection including VR is required for the purpose of achieving radical resection.

2 Review Preoperative biliary stenting versus operation first in jaundiced patients due to malignant lesions in the pancreatic head: A meta-analysis of current literature. 2017

Scheufele, Florian / Schorn, Stephan / Demir, Ihsan Ekin / Sargut, Mine / Tieftrunk, Elke / Calavrezos, Lenika / Jäger, Carsten / Friess, Helmut / Ceyhan, Güralp Onur. ·Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. Electronic address: gueralp.ceyhan@tum.de. ·Surgery · Pubmed #28043693.

ABSTRACT: BACKGROUND: Obstructive jaundice is a common presenting symptom among patients with pancreatic cancer. While benefits of preoperative biliary drainage have been suggested by previous studies, recent evidence has shown no significant improvements of preoperative biliary drainage on the postoperative outcome but rather an increase of complications. There is no clear consensus on whether to treat malignant obstructive jaundice with preoperative biliary drainage prior to operative intervention or to proceed directly to resection. Thus, our aim was to elucidate the impact of preoperative biliary drainage of obstructive jaundice due to malignant pancreatic head tumors on postoperative morbidity and mortality. METHODS: We conducted a meta-analysis in accordance with the PRISMA guidelines and carried out a systematic search of medical databases. The results were analyzed according to predefined criteria. We pooled the incidence of overall complications, wound infection, pancreatic fistula, intra-abdominal abscess, and death within the perioperative time period. RESULTS: We initially identified 1,816 studies, and 25 of these (22 retrospective studies, 3 randomized controlled trials) were finally included in the analysis with a total number of 6,214 patients. Analysis revealed an increased incidence of overall complications (odds ratio: 1.40; 95% confidence interval: 1.14-1.72; P = .002) and wound infections (odds ratio: 1.94; 95% confidence interval: 1.48-2.53; P < .00001) in patients receiving preoperative biliary drainage compared to operative intervention first. Mortality, incidence of pancreatic fistula, or intra-abdominal abscess formation were not affected by preoperative biliary drainage. CONCLUSION: Preoperative biliary drainage does not have a beneficial effect on postoperative outcome. The increase of postoperative overall complications and wound infections urges for precise indications for preoperative biliary drainage and against routine preoperative biliary decompression.

3 Article Borderline-resectable pancreatic adenocarcinoma: Contour irregularity of the venous confluence in pre-operative computed tomography predicts histopathological infiltration. 2019

Kaissis, Georgios A / Lohöfer, Fabian K / Ziegelmayer, Sebastian / Danner, Julia / Jäger, Carsten / Schirren, Rebekka / Ankerst, Donna / Ceyhan, Güralp O / Friess, Helmut / Rummeny, Ernst J / Weichert, Wilko / Braren, Rickmer F. ·Institute for diagnostic and interventional Radiology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. · Department of Surgery, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. · Department of Mathematics, Technische Universität München, Garching, Germany. · Department of General Pathology and Pathological Anatomy, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. ·PLoS One · Pubmed #30601813.

ABSTRACT: PURPOSE: The purpose of the current study was to compare CT-signs of portal venous confluence infiltration for actual histopathological infiltration of the vein or the tumor/vein interface (TVI) in borderline resectable pancreatic ductal adenocarcinoma (PDAC). METHODS AND MATERIALS: 101 patients with therapy-naïve, primarily resected PDAC of the pancreatic head without arterial involvement were evaluated. The portal venous confluence was assessed for contour irregularity (defined as infiltration) and degree of contact. The sensitivity and specificity of contour irregularity versus tumor to vein contact >180° as well as the combination of the signs for tumor cell infiltration of the vessel wall or TVI was calculated. Overall survival (OS) was compared between groups. RESULTS: Sensitivity and specificity of contour irregularity for identification of tumor infiltration of the portal venous confluence or the TVI was higher compared to tumor to vessel contact >180° for tumor cell infiltration (96%/79% vs. 91%/38% respectively, p<0.001). The combination of the signs increased specificity to 92% (sensitivity 88%). Patients with contour irregularity/ tumor to vein contact >180°/ both signs had significantly worse overall survival (16.2 vs. 26.5 months/ 17.9 vs. 37.4 months/ 18.5 vs. 26.5 months respectively, all p<0.05). CONCLUSION: Portal venous confluence contour irregularity is a strong predictor of actual tumor cell infiltration of the vessel wall or the TVI and should be noted as such in radiological reports.

4 Article Glycemic Variability Promotes Both Local Invasion and Metastatic Colonization by Pancreatic Ductal Adenocarcinoma. 2018

Jian, Ziying / Cheng, Tao / Zhang, Zhiheng / Raulefs, Susanne / Shi, Kuangyu / Steiger, Katja / Maeritz, Nadja / Kleigrewe, Karin / Hofmann, Thomas / Benitz, Simone / Bruns, Philipp / Lamp, Daniel / Jastroch, Martin / Akkan, Jan / Jäger, Carsten / Huang, Peilin / Nie, Shuang / Shen, Shanshan / Zou, Xiaoping / Ceyhan, Güralp O / Michalski, Christoph W / Friess, Helmut / Kleeff, Jörg / Kong, Bo. ·Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich (TUM), Munich, Germany. · Department of Nuclear Medicine, TUM, Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · Bavarian Center for Biomolecular Mass Spectrometry, Freising, Germany. · Medizinische Klinik und Poliklinik II, Klinikum der LMU, Munich, Germany. · Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany. · Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany. · German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany. · Division of Metabolic Diseases, TUM, Munich, Germany. · Department of Pathology, School of Medicine, Southeast University, Nanjing, China. · Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle, Germany. · German Cancer Consortium (DKTK) at the partner site Munich, Munich, Germany. ·Cell Mol Gastroenterol Hepatol · Pubmed #30258965.

ABSTRACT: Background & Aims: Although nearly half of pancreatic ductal adenocarcinoma (PDAC) patients have diabetes mellitus with episodes of hyperglycemia, its tumor microenvironment is hypoglycemic. Thus, it is crucial for PDAC cells to develop adaptive mechanisms dealing with oscillating glucose levels. So far, the biological impact of such glycemic variability on PDAC biology remains unknown. Methods: Murine PDAC cells were cultured in low- and high-glucose medium to investigate the molecular, biochemical, and metabolic influence of glycemic variability on tumor behavior. A set of in vivo functional assays including orthotopic implantation and portal and tail vein injection were used. Results were further confirmed on tissues from PDAC patients. Results: Glycemic variability has no significant effect on PDAC cell proliferation. Hypoglycemia is associated with local invasion and angiogenesis, whereas hyperglycemia promotes metastatic colonization. Increased metastatic colonization under hyperglycemia is due to increased expression of runt related transcription factor 3 (Runx3), which further activates expression of collagen, type VI, alpha 1 (Col6a1), forming a glycemic pro-metastatic pathway. Through epigenetic machinery, retinoic acid receptor beta (Rarb) expression fluctuates according to glycemic variability, acting as a critical sensor relaying the glycemic signal to Runx3/Col6a1. Moreover, the signal axis of Rarb/Runx3/Col6a1 is pharmaceutically accessible to a widely used antidiabetic substance, metformin, and Rar modulator. Finally, PDAC tissues from patients with diabetes show an increased expression of COL6A1. Conclusions: Glycemic variability promotes both local invasion and metastatic colonization of PDAC. A pro-metastatic signal axis Rarb/Runx3/Col6a1 whose activity is controlled by glycemic variability is identified. The therapeutic relevance of this pathway needs to be explored in PDAC patients, especially in those with diabetes.

5 Article Elevated systemic levels of the matrix metalloproteinase inhibitor TIMP-1 correlate with clinical markers of cachexia in patients with chronic pancreatitis and pancreatic cancer. 2018

Prokopchuk, Olga / Grünwald, Barbara / Nitsche, Ulrich / Jäger, Carsten / Prokopchuk, Oleksii L / Schubert, Elaine C / Friess, Helmut / Martignoni, Marc E / Krüger, Achim. ·Klinik und Poliklinik für Chirurgie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany. olga.prokopchuk@tum.de. · Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, Munich, Germany. · Klinik und Poliklinik für Chirurgie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany. · Medizinische Klinik II, Klinikum Obergöltzsch, Rodewisch, Germany. · Institut für Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. ·BMC Cancer · Pubmed #29394913.

ABSTRACT: BACKGROUND: Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a candidate diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC). Here, we determined the possible association of systemic TIMP-1 levels with cachexia and jaundice, two common PDAC-associated conditions. METHODS: Plasma TIMP-1 was measured by ELISA in patients diagnosed with PDAC (n = 36) and chronic pancreatitis (CP) (n = 25). Patients without pancreatic pathologies and known malignancies of other origin served as controls (n = 13). TIMP-1 levels in these patients were tested for asscociation with jaundice and chachexia, and furthermore correlated with cachexia-related clinical parameters such as weight loss and ferritin, parameters of lung function, hemoglobin and liver synthesis parameters. RESULTS: TIMP-1 plasma levels were mostly higher in CP and PDAC patients with concomitant jaundice or cachexia. Elevated plasma TIMP-1 levels were also associated with clinical cachexia markers, including absolute and relative values of weight loss and lung function, as well as ferritin, hemoglobin, and cholinesterase levels. TIMP-1 levels significantly correlated with cachexia only in patients without jaundice. Jaundice also impaired the use of TIMP-1 as a prognostic marker in cancer patients. Relating to cachexia status alone, a slightly improved association of TIMP-1 levels with survival of PDAC patients was observed. CONCLUSION: This retrospective study reports for the first time that plasma levels of TIMP-1 are associated with pancreatic lesion-induced cachexia in patients without jaundice. TIMP-1 is counterindicated as a survival marker in patients with jaundice.

6 Article R0 Versus R1 Resection Matters after Pancreaticoduodenectomy, and Less after Distal or Total Pancreatectomy for Pancreatic Cancer. 2018

Demir, Ihsan Ekin / Jäger, Carsten / Schlitter, A Melissa / Konukiewitz, Björn / Stecher, Lynne / Schorn, Stephan / Tieftrunk, Elke / Scheufele, Florian / Calavrezos, Lenika / Schirren, Rebekka / Esposito, Irene / Weichert, Wilko / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Institute for Pathology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Institute for Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany. · Institute of Pathology, Heinrich Heine University, Düsseldorf, Germany. ·Ann Surg · Pubmed #28692477.

ABSTRACT: OBJECTIVE: The aim of this study was to decipher the true importance of R0 versus R1 resection for survival in pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: PDAC is characterized by poor survival, even after curative resection. In many studies, R0 versus R1 does not result in different prognosis and does not affect the postoperative management. METHODS: Pubmed, Embase, and Cochrane databases were screened for prognostic studies on the association between resection status and survival. Hazard ratios (HRs) were pooled in a meta-analysis. Furthermore, our prospective database was retrospectively screened for curative PDAC resections according to inclusion criteria (n = 254 patients) between July 2007 and October 2014. RESULTS: In the meta-analysis, R1 was associated with a decreased overall survival [HR 1.45 (95% confidence interval, 95% CI 1.37-1.52)] and disease-free survival [HR 1.44 (1.30-1.59)] in PDAC when compared with R0. Importantly, this effect held true only for pancreatic head resection both in the meta-analysis [R0 ≥0 mm: HR 1.21 (1.05-1.39) vs R0 ≥1 mm: HR 1.66 (1.46-1.89)] and in our cohort (R0 ≥0 mm: 31.8 vs 14.5 months, P < 0.001; R0 ≥1 mm, 41.2 vs 16.8 months; P < 0.001). Moreover, R1 resections were associated with advanced tumor disease, that is, larger tumor size, lymph node metastases, and extended resections. Multivariable Cox proportional hazard model suggested G3, pN1, tumor size, and R1 (0 mm/1 mm) as independent predictors of overall survival. CONCLUSION: Resection margin is not a valid prognostic marker in publications before 2010 due to heterogeneity of cohorts and lack of standardized histopathological examination. Within standardized pathology protocols, R-status' prognostic validity may be primarily confined to pancreatic head cancers.

7 Article pT but not pN stage of the 8th TNM classification significantly improves prognostication in pancreatic ductal adenocarcinoma. 2017

Schlitter, Anna Melissa / Jesinghaus, Moritz / Jäger, Carsten / Konukiewitz, Björn / Muckenhuber, Alexander / Demir, Ihsan Ekin / Bahra, Marcus / Denkert, Carsten / Friess, Helmut / Kloeppel, Günter / Ceyhan, Güralp O / Weichert, Wilko. ·Institute of Pathology, Technical University Munich, Munich, Germany. Electronic address: melissa.schlitter@tum.de. · Institute of Pathology, Technical University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. · Department of Surgery, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Institute of Pathology, Technical University Munich, Munich, Germany. · Department of Surgery, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. · Department of Surgery, Charité University Hospital, Berlin, Germany. · Institute of Pathology, Charité University Hospital, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Germany. ·Eur J Cancer · Pubmed #28802189.

ABSTRACT: The UICC TNM (tumour-node-metastasis) staging system for pancreatic ductal adenocarcinoma (PDAC) has been a matter of debate over decades because survival prediction based on T stages was weak and unreliable. To improve staging, the recently published 8th TNM edition (2016) introduced a conceptually completely changed strictly size-based T staging system and a refined N stage for PDAC. To investigate the clinical value of the novel TNM classification, we compared the prognostic impact of pT and pN stage between the 7th and 8th edition in two well-characterised independent German PDAC cohorts from different decades, including a total number of 523 patients. Former UICC T staging (7th edition 2009) resulted in a clustering of pT3 cases (72% and 85% of cases per cohort, respectively) and failed to show significant prognostic differences between the four stages in one of the investigated cohorts (p = 0.074). Application of the novel size-based T stage system resulted in a more equal distribution of cases between the four T categories with a predominance of pT2 tumours (65% and 60% of cases). The novel pT staging algorithm showed greatly improved discriminative power with highly significant overall differences between the four pT stages in both investigated cohorts in univariate and multivariate analyses (p < 0.001, each). In contrast, no prognostic differences were observed between the recently introduced pN1 and pN2 categories in both cohorts (p = 0.970 and p = 0.061). pT stage of resected PDAC patients according to the novel UICC staging protocol (8th edition) significantly improves patient stratification, whereas introduction of an extended N stage protocol does not demonstrate high clinical relevance in our cohorts.

8 Article Molecular, morphological and survival analysis of 177 resected pancreatic ductal adenocarcinomas (PDACs): Identification of prognostic subtypes. 2017

Schlitter, Anna Melissa / Segler, Angela / Steiger, Katja / Michalski, Christoph W / Jäger, Carsten / Konukiewitz, Björn / Pfarr, Nicole / Endris, Volker / Bettstetter, Markus / Kong, Bo / Regel, Ivonne / Kleeff, Jörg / Klöppel, Günter / Esposito, Irene. ·Institute of Pathology, Technische Universität München, Munich, Germany. · Department of Surgery, University Hospital Heidelberg, Germany. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany. · Molecular Pathology South-Bavaria, Munich, Germany. · Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany. · The Royal Liverpool and Broadgreen University Hospitals, Prescot Street, Liverpool L7 8XP, United Kingdom. · Department of General-, Visceral- and Pediatric Surgery, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany. ·Sci Rep · Pubmed #28145465.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has generally a poor prognosis, but recent data suggest that there are molecular subtypes differing in clinical outcome. This study examines the association between histopathologic heterogeneity, genetic profile, and survival. Tumor histology from 177 resected PDAC patients with follow-up data was subclassified according to predominant growth pattern, and four key genes were analyzed. PDACs were classified as conventional (51%), combined with a predominant component (41%), variants and special carcinomas (8%). Patients with combined PDACs and a dominant cribriform component survived longer than patients with conventional or other combined PDACs. Genetic alterations in at least two out of four genes were found in 95% of the patients (KRAS 93%, TP53 79%, CDKN2A/p16 75%, SMAD4 37%). Patients with less than four mutations survived significantly longer (p = 0.04) than those with alterations in all four genes. Patients with either wildtype KRAS or CDKN2A/p16 lived significantly longer than those with alterations in these genes (p = 0.018 and p = 0.006, respectively). Our data suggest that the number of altered genes, the mutational status of KRAS and certain morphological subtypes correlate with the outcome of patients with PDAC. Future pathology reporting of PDAC should therefore include the KRAS status and a detailed morphological description.

9 Article Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer. 2017

Heid, Irina / Steiger, Katja / Trajkovic-Arsic, Marija / Settles, Marcus / Eßwein, Manuela R / Erkan, Mert / Kleeff, Jörg / Jäger, Carsten / Friess, Helmut / Haller, Bernhard / Steingötter, Andreas / Schmid, Roland M / Schwaiger, Markus / Rummeny, Ernst J / Esposito, Irene / Siveke, Jens T / Braren, Rickmer F. ·Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Germany. · Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Germany. · 2nd Medical Department, Klinikum rechts der Isar, Technische Universität München, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), partner site Essen, University Hospital Essen, Essen, Germany. · Department of Surgery, Koc University School of Medicine, Istanbul, Turkey. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Germany. · Institute of Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technische Universität München, Germany. · Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland. · Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Germany. · Institute of Pathology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany. rbraren@tum.de j.siveke@dkfz-heidelberg.de Irene.Esposito@med.uni-duesseldorf.de. · 2nd Medical Department, Klinikum rechts der Isar, Technische Universität München, Germany. rbraren@tum.de j.siveke@dkfz-heidelberg.de Irene.Esposito@med.uni-duesseldorf.de. · Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Germany. rbraren@tum.de j.siveke@dkfz-heidelberg.de Irene.Esposito@med.uni-duesseldorf.de. ·Clin Cancer Res · Pubmed #27663591.

ABSTRACT:

10 Article A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling. 2016

Kong, Bo / Wu, Weiwei / Cheng, Tao / Schlitter, Anna Melissa / Qian, Chengjia / Bruns, Philipp / Jian, Ziying / Jäger, Carsten / Regel, Ivonne / Raulefs, Susanne / Behler, Nora / Irmler, Martin / Beckers, Johannes / Friess, Helmut / Erkan, Mert / Siveke, Jens T / Tannapfel, Andrea / Hahn, Stephan A / Theis, Fabian J / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · Department of Surgery, Technische Universität München (TUM), Munich, Germany Institute of Computational Biology, Helmholtz-Zentrum München, Munich, Germany. · Institute of Experimental Genetics (IEG), Helmholtz-Zentrum München, Munich, Germany. · Institute of Experimental Genetics (IEG), Helmholtz-Zentrum München, Munich, Germany Technische Universität München, Chair of Experimental Genetics, Freising, Germany Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Germany. · Department of Surgery, Koc University School of Medicine, Istanbul, Turkey. · Department of Gastroenterology, TUM, Munich, Germany. · Institute of Pathology, Ruhr-University Bochum, Bochum, Germany. · Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany. · Institute of Computational Biology, Helmholtz-Zentrum München, Munich, Germany. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·Gut · Pubmed #25601637.

ABSTRACT: OBJECTIVE: Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity. DESIGN: We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material. RESULTS: Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype. CONCLUSIONS: These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.

11 Article Outcomes of resections for pancreatic adenocarcinoma with suspected venous involvement: a single center experience. 2015

Michalski, Christoph W / Kong, Bo / Jäger, Carsten / Kloe, Silke / Beier, Barbara / Braren, Rickmer / Esposito, Irene / Erkan, Mert / Friess, Helmut / Kleeff, Jorg. ·Department of Surgery, Technische Universität München, Ismaningerstrasse 22, 81675, Munich, Germany. · Current address: Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Institute of Radiology, Technische Universität München, Munich, Germany. · Institute of Pathology, Technische Universität München, Munich, Germany. · Current address: Institute of Pathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. · Current address: Department of Surgery, Koc University School of Medicine, Istanbul, Turkey. · Department of Surgery, Technische Universität München, Ismaningerstrasse 22, 81675, Munich, Germany. kleeff@tum.de. ·BMC Surg · Pubmed #26296752.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) patients frequently present with borderline resectable disease, which can be due to invasion of the portal/superior mesenteric vein (PV/SMV). Here, we analyzed this group of patients, with emphasis on short and long-term outcomes. METHODS: 156 patients who underwent a resection for PDAC were included in the analysis and sub-stratified into a cohort of patients with PV/SMV resection (n = 54) versus those with standard surgeries (n = 102). RESULTS: While venous resections could be performed safely, there was a trend towards shorter median survival in the PV/SMV resection group (22.7 vs. 15.8 months, p = 0.157). These tumors were significantly larger (3.5 vs. 4.3 cm; p = 0.026) and margin-positivity was more frequent (30.4% vs. 44.4%, p = 0.046). CONCLUSION: Venous resection was associated with a higher rate of margin positivity and a trend towards shorter survival. However, compared to non-surgical treatment, resection offers the best chance for long term survival.

12 Article Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer. 2015

Müller, Sören / Raulefs, Susanne / Bruns, Philipp / Afonso-Grunz, Fabian / Plötner, Anne / Thermann, Rolf / Jäger, Carsten / Schlitter, Anna Melissa / Kong, Bo / Regel, Ivonne / Roth, W Kurt / Rotter, Björn / Hoffmeier, Klaus / Kahl, Günter / Koch, Ina / Theis, Fabian J / Kleeff, Jörg / Winter, Peter / Michalski, Christoph W. ·Molecular BioSciences, Goethe University, Frankfurt am Main, Germany. s.mueller@bio.uni-frankfurt.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. s.mueller@bio.uni-frankfurt.de. · Molecular Bioinformatics Group, Institute of Computer Science, Cluster of Excellence Frankfurt 'Macromolecular Complexes' Faculty of Computer Science and Mathematics, Frankfurt am Main, Germany. s.mueller@bio.uni-frankfurt.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. susanne.raulefs@tum.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. philipp.bruns@helmholtz-muenchen.de. · Molecular BioSciences, Goethe University, Frankfurt am Main, Germany. fgrunz@stud.uni-frankfurt.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. fgrunz@stud.uni-frankfurt.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. ploetner@genxpro.de. · GFE Blut mbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. rolf.thermann@gfeblut.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. Carsten.Jaeger@lrz.tu-muenchen.de. · Department of Pathology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. melissa.schlitter@lrz.tu-muenchen.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. kongbo81@hotmail.com. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. ivonne.regel@lrz.tum.de. · GFE Blut mbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. kurt.roth@gfeblut.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. rotter@genxpro.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. hoffmeier@genxpro.de. · Molecular BioSciences, Goethe University, Frankfurt am Main, Germany. kahl@em.uni-frankfurt.de. · Molecular Bioinformatics Group, Institute of Computer Science, Cluster of Excellence Frankfurt 'Macromolecular Complexes' Faculty of Computer Science and Mathematics, Frankfurt am Main, Germany. ina.koch@bioinformatik.uni-frankfurt.de. · Institute of Computational Biology, Helmholtz Zentrum Munich, Neuherberg, Germany. fabian.theis@helmholtz-muenchen.de. · Department of Mathematics, TU Munich, Boltzmannstrasse 3, Garching, Germany. fabian.theis@helmholtz-muenchen.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. kleeff@tum.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. pwinter@genxpro.de. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. cwmichalski@gmail.com. ·Mol Cancer · Pubmed #25910082.

ABSTRACT: BACKGROUND: Previous studies identified microRNAs (miRNAs) and messenger RNAs with significantly different expression between normal pancreas and pancreatic cancer (PDAC) tissues. Due to technological limitations of microarrays and real-time PCR systems these studies focused on a fixed set of targets. Expression of other RNA classes such as long intergenic non-coding RNAs or sno-derived RNAs has rarely been examined in pancreatic cancer. Here, we analysed the coding and non-coding transcriptome of six PDAC and five control tissues using next-generation sequencing. RESULTS: Besides the confirmation of several deregulated mRNAs and miRNAs, miRNAs without previous implication in PDAC were detected: miR-802, miR-2114 or miR-561. SnoRNA-derived RNAs (e.g. sno-HBII-296B) and piR-017061, a piwi-interacting RNA, were found to be differentially expressed between PDAC and control tissues. In silico target analysis of miR-802 revealed potential binding sites in the 3' UTR of TCF4, encoding a transcription factor that controls Wnt signalling genes. Overexpression of miR-802 in MiaPaCa pancreatic cancer cells reduced TCF4 protein levels. Using Massive Analysis of cDNA Ends (MACE) we identified differential expression of 43 lincRNAs, long intergenic non-coding RNAs, e.g. LINC00261 and LINC00152 as well as several natural antisense transcripts like HNF1A-AS1 and AFAP1-AS1. Differential expression was confirmed by qPCR on the mRNA/miRNA/lincRNA level and by immunohistochemistry on the protein level. CONCLUSIONS: Here, we report a novel lncRNA, sncRNA and mRNA signature of PDAC. In silico prediction of ncRNA targets allowed for assigning potential functions to differentially regulated RNAs.

13 Article A common genetic variation of melanoma inhibitory activity-2 labels a subtype of pancreatic adenocarcinoma with high endoplasmic reticulum stress levels. 2015

Kong, Bo / Wu, Weiwei / Valkovska, Nataliya / Jäger, Carsten / Hong, Xin / Nitsche, Ulrich / Friess, Helmut / Esposito, Irene / Erkan, Mert / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München, Munich, Germany. · Institute of Pathology, Technische Universität München, Munich, Germany. · Department of Surgery, Koc School of Medicine, Istanbul, Turkey. · Department of Surgery, University of Heidelberg, Germany. ·Sci Rep · Pubmed #25657029.

ABSTRACT: HNF1 homeobox A (HNF1A)-mediated gene expression constitutes an essential component of the secretory pathway in the exocrine pancreas. Melanoma inhibitory activity 2 (MIA2), a protein facilitating protein secretion, is an HNF1A target. Protein secretion is precisely coordinated by the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) system. Here, we demonstrate that HNFA and MIA2 are expressed in a subset of human PDAC tissues and that HNF1A induced MIA2 in vitro. We identified a common germline variant of MIA2 (c.A617G: p.I141M) associated with a secretory defect of the MIA2 protein in PDAC cells. Patients carrying MIA2(I141M) survived longer after tumor resection but the survival benefit was restricted to those patients who received adjuvant chemotherapy. The MIA2(I141M) variant was associated with high expression of ER stress/UPR genes--in particular those of the ERN1/XBP arm--in human PDAC samples. Accordingly, PDAC cell lines expressing the MIA2(I141M) variant expressed high levels of ERN1 and were more sensitive to gemcitabine. These findings define an interaction between the common MIA2(I141M) variant and the ER stress/UPR system and specify a subgroup of PDAC patients who are more likely to benefit from adjuvant chemotherapy.

14 Article Comparative analysis of the revenues of pylorus-preserving pancreatic head resections and laparoscopic cholecystectomies as prototypic surgical procedures in the German health-care system. 2013

Stellwag, Tina / Michalski, Christoph W / Kong, Bo / Erkan, Mert / Reiser-Erkan, Carolin / Jäger, Carsten / Meinl, Christian / Friess, Helmut / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Ismaningerstrasse 22, Munich 81675, Germany. ·Langenbecks Arch Surg · Pubmed #23778973.

ABSTRACT: BACKGROUND: Although centralization of complex surgical procedures such as pancreaticoduodenectomies is associated with a reduction in morbidity and mortality rates, it is unclear whether such surgeries are adequately represented in the German disease-related group (DRG) system. PATIENTS AND METHODS: Out of all patients who underwent pancreatic resections (n = 450) at our institution between January 2008 and November 2011, 76 patients who underwent a pylorus-preserving pancreatic head resection due to pancreatic head adenocarcinoma were selected for analysis. The revenues generated by these surgical procedures were compared with those of 144 patients who had undergone elective laparoscopic cholecystectomies for symptomatic gallstone disease between January 2009 and September 2010 in our hospital. RESULTS: In patients undergoing pylorus-preserving pancreaticoduodenectomy, revenues per case were 1,585.55 Euros, with an average length of hospital stay (ALOS) of 19.9 days (range 7-55 days) and an average postoperative hospital stay of 16 days; however, if the ALOS was exceeded, expenditures increasingly exceeded returns. Analysis of the cohort of patients with pylorus-preserving pancreaticoduodenectomies demonstrated average revenues per day of 79.27 Euros. In contrast, for laparoscopic cholecystectomy, which was treated with high surgical standardization and stringent case management, the ALOS was only 2.8 days, producing average revenues of 288.80 Euros per day and total revenues of 817.53 Euros per case. CONCLUSION: At university hospitals, cost-effective realization of major pancreatic surgery is difficult, while highly standardized surgeries such as laparoscopic cholecystectomies can be performed at a favorable balance. This may be due to, firstly, an underrepresentation of university hospitals in the German DRG calculation basis and, secondly, to a relatively long preoperative hospital stay as a result of extensive diagnostic measures. We consider this kind of preoperative assessment paramount for an academic pancreatic center and thus argue for an increased reimbursement for these procedures.

15 Article The actin binding protein destrin is associated with growth and perineural invasion of pancreatic cancer. 2012

Klose, Theresa / Abiatari, Ivane / Samkharadze, Tamar / De Oliveira, Tiago / Jäger, Carsten / Kiladze, Merab / Valkovskaya, Nataliya / Friess, Helmut / Michalski, Christoph W / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Munich, Germany. ·Pancreatology · Pubmed #22898637.

ABSTRACT: BACKGROUND/OBJECTIVES: The small actin-binding protein destrin is one of the key regulators involved in remodeling of the actin cytoskeleton, a process crucial for cytokinesis, cell migration and polarized cell growth as well as for cancer cell migration and invasion. METHODS: A novel ex vivo nerve invasion model mirroring perineural cancer cell invasion as a key feature of pancreatic ductal adenocarcinoma has been previously established. Using this model, highly nerve-invasive clones of human pancreatic cancer cell lines have been obtained. Genome-wide transcriptional analyses of these cells revealed up-regulation of destrin in highly versus lowly nerve-invasive pancreatic cancer cells. RESULTS: Increased expression of destrin in these nerve-invasive cells was validated using quantitative RT-PCR and immunoblotting; concomitant changes in cell morphology were demonstrated using immunofluorescence analysis. Silencing of destrin by two specific siRNA oligonucleotides in Panc-1 pancreatic cancer cells decreased invasiveness and migration, and reduced proliferation of these cells. CONCLUSIONS: Destrin is upregulated in nerve-invasive pancreatic cancer cells and its expression might be related to perineural invasiveness.