Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Pancreatic Neoplasms: HELP
Articles by Irene Esposito
Based on 73 articles published since 2010
(Why 73 articles?)

Between 2010 and 2020, I. Esposito wrote the following 73 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline [Update of the S3 guidelines for pancreatic cancer. What is new for pathologists?]. 2014

Munding, J / Lüttges, J / Esposito, I / Tannapfel, A. ·Institut für Pathologie, Deutsches Mesotheliomregister, Ruhr-Universität Bochum, BG-Universitätsklinikum Bergmannsheil, Bürkle-de-la-Camp Platz 1, 44789, Bochum, Deutschland. ·Pathologe · Pubmed #24981895.

ABSTRACT: The S3 guidelines for pancreatic cancer were revised in 2013. Besides the oncological and palliative therapy modalities and surgical therapy, the guidelines for pathologists in topic 3 were updated. The modifications essentially concern the histopathological assessment of surgical specimens and in particular the circumferential resection margin and the R classification. In addition, the current recommendations were amended by recommendations concerning the pathohistological records, which should include the lymph node ratio in the future.

2 Guideline [S3-guideline exocrine pancreatic cancer]. 2013

Seufferlein, T / Porzner, M / Becker, T / Budach, V / Ceyhan, G / Esposito, I / Fietkau, R / Follmann, M / Friess, H / Galle, P / Geissler, M / Glanemann, M / Gress, T / Heinemann, V / Hohenberger, W / Hopt, U / Izbicki, J / Klar, E / Kleeff, J / Kopp, I / Kullmann, F / Langer, T / Langrehr, J / Lerch, M / Löhr, M / Lüttges, J / Lutz, M / Mayerle, J / Michl, P / Möller, P / Molls, M / Münter, M / Nothacker, M / Oettle, H / Post, S / Reinacher-Schick, A / Röcken, C / Roeb, E / Saeger, H / Schmid, R / Schmiegel, W / Schoenberg, M / Siveke, J / Stuschke, M / Tannapfel, A / Uhl, W / Unverzagt, S / van Oorschot, B / Vashist, Y / Werner, J / Yekebas, E / Anonymous260779 / Anonymous270779 / Anonymous280779. ·Klinik für Innere Medizin I, Universitätsklinikum Ulm. · Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Kiel. · Klinik für Radioonkologie und Strahlentherapie, Charité Universitätsmedizin Berlin. · Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, TU München. · Institut für Allgemeine Pathologie, Klinikum rechts der Isar, TU München. · Strahlenklinik, Universitätsklinikum Erlangen. · Leitlinienprogramm Onkologie, Deutsche Krebsgesellschaft e. V., Berlin. · I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz. · Klinik für Allgemeine Innere Medizin, Onkologie/Hämatologie, Gastroenterologie und Infektiologie, Klinikum Esslingen. · Klinik für Allgemeine Chirurgie, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes Homburg/Saar. · Klinik für Gastroenterologie, Endokrinologie und Stoffwechsel, Universitätsklinikum Gießen und Marburg. · Medizinischen Klinik und Poliklinik III, Klinikum der Universität München LMU. · Chirurgische Klinik, Universitätsklinikum Erlangen. · Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg. · Klinik für Allgemein-, Viszeral- und Thoraxchirurgie, Universitätsklinikum Hamburg-Eppendorf. · Klinik für Allgemeine Chirurgie, Thorax-, Gefäß- und Transplantationschirurgie, Universitätsmedizin Rostock. · AWMF-Institut für Medizinisches Wissensmanagement, Marburg. · Medizinische Klinik I, Klinikum Weiden. · Klinik für Allgemein-, Gefäß- und Viszeralchirurgie, Martin-Luther-Krankenhaus Berlin. · Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin Greifswald. · Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm. · Institut für Pathologie, Marienkrankenhaus Hamburg. · Medizinische Klinik - Schwerpunkt Gastroenterologie, Endokrinologie, Infektiologie, Caritasklinikum Saarbrücken. · Institut für Pathologie, Universitätsklinikum Ulm. · Klinik und Poliklinik für Strahlentherapie und Radiologische Onkologie, Klinikum rechts der Isar, TU München. · Klinik für Strahlentherapie und Radioonkologie, Klinikum Stuttgart. · AWMF-Institut für Medizinisches Wissensmanagement, Berlin. · Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Charité Universitätsmedizin Berlin. · Chirurgische Klinik, Universitätsmedizin Mannheim. · Abt. für Hämatologie und Onkologie, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum. · Institut für Pathologie, Universitätsklinikum Kiel. · Medizinische Klinik II, SP Gastroenterologie, Universitätsklinikum Gießen und Marburg. · Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Dresden. · II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, TU München. · Medizinische Klinik, Klinikum der Ruhr-Universität Bochum. · Klinik für Chirurgie, Rotkreuzklinikum München. · Klinik für Strahlentherapie, Universitätsklinikum Essen. · Institut für Pathologie, Ruhr-Universität Bochum. · Chirurgische Klinik, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum. · Institut für Medizinische Epidemiologie, Biometrie und Informatik, Martin-Luther-Universität Halle-Wittenberg. · Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum Würzburg. · Klinik für Allgemeine, Viszerale und Transplantationschirurgie, Universitätsklinikum Heidelberg. · Klinik für Allgemein-, Thorax- und Viszeralchirurgie, Klinikum Darmstadt. ·Z Gastroenterol · Pubmed #24338757.

ABSTRACT: -- No abstract --

3 Review Pathology assessment of pancreatic cancer following neoadjuvant treatment: Time to move on. 2018

Verbeke, Caroline / Häberle, Lena / Lenggenhager, Daniela / Esposito, Irene. ·Dept of Pathology, Institute of Clinical Medicine, University of Oslo, Norway; Dept of Pathology, Oslo University Hospital, Norway. Electronic address: c.s.verbeke@medisin.uio.no. · Institute of Pathology, Heinrich-Heine University and University Hospital of Düsseldorf, Germany. · Dept of Pathology, Institute of Clinical Medicine, University of Oslo, Norway; Dept of Pharmacology, Institute of Clinical Medicine, University of Oslo, Norway; Institute of Pathology and Molecular Pathology, University of Zürich and University Hospital Zürich, Switzerland. · Institute of Pathology, Heinrich-Heine University and University Hospital of Düsseldorf, Germany. Electronic address: irene.esposito@med.uni-duesseldorf.de. ·Pancreatology · Pubmed #29843972.

ABSTRACT: Neoadjuvant treatment has increasingly become an integral part of the multimodal management of patients with pancreatic cancer. In patients who are able to undergo surgery following preoperative therapy, tumour regression grading remains the diagnostic gold standard for the histomorphological assessment of the effect of neoadjuvant treatment. In recent years, however, there has been growing concern about inherent flaws of tumour regression grading systems as well as their imprecise and impractical criteria that result in divergence of practice and lack of interobserver agreement. Furthermore, existing tumour regression systems differ in their defining criteria and thresholds, leading to incomparability of data. In this review, the principles and limitations of the main existing tumour regression systems are discussed, and potential alternative assessment approaches and novel markers are presented.

4 Review Pathobiology of pancreatic cancer: implications on therapy. 2016

Regel, Ivonne / Hausmann, Simone / Benitz, Simone / Esposito, Irene / Kleeff, Jörg. ·a Institute of Pathology , Heinrich-Heine-University , Duesseldorf , Germany. · b Department of Surgery , Technical University , Munich , Germany. · c Department of Surgery , The Royal Liverpool and Broadgreen University Hospitals , Liverpool , UK. · d Department of Surgery , Heinrich-Heine-University , Duesseldorf , Germany. ·Expert Rev Anticancer Ther · Pubmed #26652651.

ABSTRACT: Although the concept of tumor heterogeneity was established several decades ago, the interest in this topic is still unbroken. With the identification of inter- and intratumoral genomic rearrangements and the detection of cancer stem cells (CSCs) through phenotypic variations of cancer cells there are increasing options for pancreatic cancer therapy. Indeed, some pre-clinical studies have shown promising results in the treatment of drug-resistant CSCs, whereby a few strategies were already tested in clinical trials. Basically, CSCs are influenced by the tumor microenvironment and an epigenetic reprogramming to gain stem cell-like characteristics. Targeting options inhibiting the epithelial-mesenchymal crosstalk or promoting epigenetic-driven differentiation of CSCs to a less aggressive phenotype raised the possibilities of further therapeutic applications, which will be discussed in this review.

5 Review [Metastasis of pancreatic tumors]. 2015

Häberle, L / Braren, R / Schlitter, A M / Esposito, I. ·Institut für Pathologie, Technische Universität München, München, Deutschland. · Institut für Radiologie, Klinikum rechts der Isar der Technischen Universität München, München, Deutschland. · Institut für Pathologie, Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Deutschland. irene.esposito@med.uni-duesseldorf.de. ·Pathologe · Pubmed #26391249.

ABSTRACT: With a 5-year survival rate that has remained stagnant at 6 % for decades, pancreatic ductal adenocarcinoma (PDAC) is still one of the most fatal malignancies. Despite intensive research, currently available therapy options are less than adequate. As more than half of the patients already show distant metastases at the time of diagnosis, metastatic disease should be a primary focus in the development of new therapeutic strategies. New findings from basic research provide various interesting approaches: molecular profiling of the primary tumor seems to be a possible method to gain knowledge about the prognosis, metastatic potential and therapy response of each individual case of PDAC. Certain subpopulations of cancer stem cells also seem to be of importance in metastasis of PDAC and could become potential therapeutic targets in the future. Interactions between tumor cells and their microenvironment are another crucial factor in the metastasis of pancreatic cancer and present various new starting points for potential therapies. As the number of cell types and signaling pathways that are found to play a role in PDAC metastasis continue to grow, the next big challenge will be to translate these findings into viable clinical applications.

6 Review Pathology, genetics and precursors of human and experimental pancreatic neoplasms: An update. 2015

Esposito, Irene / Segler, Angela / Steiger, Katja / Klöppel, Günter. ·Institute of Pathology, Heinrich-Heine-University of Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany. Electronic address: Irene.Esposito@med.uni-duesseldorf.de. · Institute of Pathology, Technische Universität München, Ismaningerstr. 22, 81675, Munich, Germany. ·Pancreatology · Pubmed #26365060.

ABSTRACT: Over the past decade, there have been substantial improvements in our knowledge of pancreatic neoplasms and their precursor lesions. Extensive genetic analyses, recently using high-throughput molecular techniques and next-generation sequencing methodologies, and the development of sophisticated genetically engineered mouse models closely recapitulating human disease, have improved our understanding of the genetic basis of pancreatic neoplasms. These advances are paving the way for refined, molecular-based classifications of pancreatic neoplasms with the potential to better predict prognosis and, possibly, response to therapy. Another major development resides in the identification of subsets of pancreatic exocrine and endocrine neoplasms which occur in the context of hereditary syndromes and whose genetic basis and tumor development have been at least partially defined. However, despite all molecular progress, correct and careful morphological characterization of tissue specimens both in the context of experimental and routine diagnostic pathology represents the basis for any further genetic investigation or clinical decision. This review focuses on the current and new concepts of classification and on the current models of tumor development, both in the field of exocrine and endocrine neoplasms, and underscores the importance of applying standardized terminology to allow adequate data interpretation and promote scientific exchange in the field of pancreas research.

7 Review [Classification and malignant potential of pancreatic cystic tumors]. 2015

Esposito, I / Schlitter, A M / Sipos, B / Klöppel, G. ·Institut für Pathologie und Pathologische Anatomie, Technische Universität München, Ismaningerstr. 22, 81675, München, Deutschland, esposito@lrz.tum.de. ·Pathologe · Pubmed #25663186.

ABSTRACT: Cystic lesions of the pancreas are increasingly diagnosed with a reported prevalence of 10 % in 70-year-old individuals. Despite their broad spectrum, most resected cystic lesions can be attributed to one of the following entities: intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), serous cystic neoplasms (SCN), neuroendocrine cystic tumors (NECT), and solid pseudopapillary neoplasms (SPN). Among them, IPMN and MCN represent precursors of ductal adenocarcinoma, NECT and SPN are low-grade, potentially malignant lesions, and SCN are usually benign. Due to the not negligible morbidity and mortality rates in pancreatic surgery, even in highly specialized centers, an interdisciplinary preoperative stratification of pancreatic cystic lesions into high- and low-risk tumors is necessary in order to accurately select those cases that need to undergo immediate resection. The role of the pathologist is fundamental in both the preoperative assessment and in the postoperative classification, which determines prognosis, further treatment, and follow-up.

8 Review Update on surgical treatment of pancreatic neuroendocrine neoplasms. 2014

D'Haese, Jan G / Tosolini, Chiara / Ceyhan, Güralp O / Kong, Bo / Esposito, Irene / Michalski, Christoph W / Kleeff, Jörg. ·Jan G D'Haese, Chiara Tosolini, Güralp O Ceyhan, Bo Kong, Christoph W Michalski, Jörg Kleeff, Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. ·World J Gastroenterol · Pubmed #25320524.

ABSTRACT: Pancreatic neuroendocrine neoplasms (PNENs) are rare and account for only 2%-4% of all pancreatic neoplasms. All PNENs are potential (neurendocrine tumors PNETs) or overt (neuroendocrine carcinomas PNECs) malignant, but a subset of PNETs is low-risk. Even in case of low-risk PNETs surgical resection is frequently required to treat hormone-related symptoms and to obtain an appropriate pathological diagnosis. Low-risk PNETs in the body and the tail are ideal for minimally-invasive approaches which should be tailored to the individual patient. Generally, surgeons must aim for parenchyma sparing in these cases. In high-risk and malignant PNENs, indications for tumor resection are much wider than for pancreatic adenocarcinoma, in many cases due to the relatively benign tumor biology. Thus, patients with locally advanced and metastatic PNETs may benefit from extensive resection. In experienced hands, even multi-organ resections are accomplished with acceptable perioperative morbidity and mortality rates and are associated with excellent long term survival. However, poorly differentiated neoplasms with high proliferation rates are associated with a dismal prognosis and may frequently only be treated with chemotherapy. The evidence on surgical treatment of PNENs stems from reviews of mostly single-center series and some analyses of nation-wide tumor registries. No randomized trial has been performed to compare surgical and non-surgical therapies in potentially resectable PNEN. Though such a trial would principally be desirable, ethical considerations and the heterogeneity of PNENs preclude realization of such a study. In the current review, we summarize recent advances in the surgical treatment of PNENs.

9 Review Pathology of pancreatic ductal adenocarcinoma: facts, challenges and future developments. 2014

Esposito, Irene / Konukiewitz, Björn / Schlitter, Anna Melissa / Klöppel, Günter. ·Irene Esposito, Björn Konukiewitz, Anna Melissa Schlitter, Günter Klöppel, Institute of Pathology, Technische Universität München, 81675 Munich, Germany. ·World J Gastroenterol · Pubmed #25320520.

ABSTRACT: Despite major improvements concerning its diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease with an extremely poor prognosis. Pathology, as interface discipline between basic and clinical medicine, has substantially contributed to the recent developments and has laid the basis for further progress. The definition and classification of precursor lesions of PDAC and their molecular characterization is a fundamental step for the potential identification of biomarkers and the development of imaging methods for early detection. In addition, by integrating findings in humans with the knowledge acquired through the investigation of transgenic mouse models for PDAC, a new model for pancreatic carcinogenesis has been proposed and partially validated in individuals with genetic predisposition for PDAC. The introduction and validation of a standardized system for pathology reporting based on the axial slicing technique has shown that most pancreatic cancer resections are R1 resections and that this is due to inherent anatomical and biological properties of PDAC. This standardized assessment of prognostic relevant parameters represents the basis for the successful conduction of multicentric studies and for the interpretation of their results. Finally, recent studies have shown that distinct molecular subtypes of PDAC exist and are associated with different prognosis and therapy response. The prospective validation of these results and the integration of molecular analyses in a comprehensive pathology report in the context of individualised cancer therapy represent a major challenge for the future.

10 Review Intraductal neoplasms of the pancreas. 2014

Klöppel, Günter / Basturk, Olca / Schlitter, Anna Melissa / Konukiewitz, Björn / Esposito, Irene. ·Institute of Pathology, Technische Universität München, Munich, Germany. Electronic address: guenter.kloeppel@lrz.tum.de. · Memorial Sloan-Kettering Cancer Center, New York, New York. · Institute of Pathology, Technische Universität München, Munich, Germany. ·Semin Diagn Pathol · Pubmed #25282472.

ABSTRACT: There are three types of pancreatic neoplasms that predominantly have an intraductal growth pattern: the common, usually cystic, intraductal papillary mucinous neoplasms (IPMNs); the rare, usually solid intraductal tubulopapillary neoplasms (ITPNs); and the rare intraductal tubular pyloric gland-type adenoma. In addition to these three tumor types, pancreatic neoplasms with a usually solid growth pattern such as acinar cell carcinomas, neuroendocrine tumors, and undifferentiated carcinomas may present, though very rarely, as predominantly intraductally growing neoplasms. IPMNs can be subclassified into main duct and branch duct tumors; into low- and high-grade dysplasia groups; and into tumors with intestinal, pancreatobiliary, oncocytic, or gastric cellular differentiation. The intestinal-, pancreatobiliary-, and oncocytic-type IPMNs occur predominantly in the main duct of the head of the pancreas and more commonly progress to invasive adenocarcinomas. The gastric-type IPMNs are frequently multifocal, occur predominantly in the branch ducts of the uncinate process, and have a low risk of progressing to invasive carcinoma. The prognosis for patients with an IPMN depends largely on the subtype and the presence and the stage of an invasive carcinoma. ITPNs are nodular tumors, often in the pancreatic head, and composed of densely packed tubular glands. Molecular genetics reveal KRAS, GNAS, and RNF43 as the most frequently mutated genes in IPMNs, while ITPNs show wild-type KRAS. Recent progress in genetic sequencing of pancreatic neoplasms and the identification of specific genetic mutations also holds promise for the future development of novel gene-based diagnostic tests in intraductal neoplasms of the pancreas that might even be used in preoperative conditions.

11 Review [Intraductal papillary neoplasms of the bile duct (IPNB). Diagnostic criteria, carcinogenesis and differential diagnostics]. 2013

Schlitter, A M / Klöppel, G / Esposito, I. ·Institut für Allgemeine Pathologie und pathologische Anatomie, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675, München, Deutschland. ·Pathologe · Pubmed #24196621.

ABSTRACT: Intraductal papillary neoplasms of the bile duct (IPNB) are rare precursor lesions of intrahepatic and extrahepatic cholangiocarcinoma that follow an adenoma-carcinoma sequence. According to the histomorphology and the distinct immunohistochemical mucin pattern, four different subtypes are recognized: pancreatobiliary, intestinal, gastric and oncocytic. Differential diagnoses include micropapillary lesions (biliary intraepithelial neoplasms), papillary cystic lesions (intraductal tubulopapillary neoplasms) and cystic lesions (mucinous cystic neoplasms).

12 Review [New insights into the origin of pancreatic cancer. Role of atypical flat lesions in pancreatic carcinogenesis]. 2012

Esposito, I / Konukiewitz, B / Schlitter, A M / Klöppel, G. ·Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Trogerstr. 18, 81675 München. Esposito@lrz.tum.de ·Pathologe · Pubmed #23011021.

ABSTRACT: The identification and characterization of precursor lesions is fundamental to develop screening programs for early diagnosis and treatment, aiming at reducing cancer-related mortality. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that becomes clinical apparent only in advanced stages. In order to enable screening procedures for early detection of PDAC, an exact characterization of precursor lesions is of utmost importance. Pancreatic intraepithelial neoplasias (PanIN) are the most frequent and best characterized precursors of PDAC and are lesions with a ductal phenotype thus indicating a ductal cell origin of PDAC. However, evidence from genetically engineered mouse models suggests that tubular complexes (TC) originating through a process of acinar-ductal metaplasia (ADM) form atypical flat lesions (AFL) that may represent an alternative pathway of pancreatic carcinogenesis. Based on a thorough morphological and genetic analysis of murine TC, AFL and PanIN and their human counterparts, a new dual model of pancreatic carcinogenesis is proposed taking into account the role of AFL as possible new precursors of PDAC.

13 Review The impact of the activated stroma on pancreatic ductal adenocarcinoma biology and therapy resistance. 2012

Erkan, Mert / Reiser-Erkan, Carolin / Michalski, Christoph W / Kong, Bo / Esposito, Irene / Friess, Helmut / Kleeff, Jorg. ·Department of General Surgery, Klinikum rechts der Isar, Technische Universität München, Germany. m.mert.erkan@googlemail.com ·Curr Mol Med · Pubmed #22272725.

ABSTRACT: Around 95% of patients diagnosed with pancreatic cancer will die of their disease within 5 years, three quarters within a year. The major hurdle in improving prognosis is the lack of a therapeutic time window. Early cancerous lesions are far beneath our threshold of detection. Therefore, at the time of diagnosis even early (T1) tumors can be metastatic and resistant to conventional treatments. Several therapies targeting epithelial tumor cells-all showing impressive results in vitro and in animal experiments-have failed to show relevant effects in clinical trials. This discrepancy between experimental data and clinical reality results mostly from the inefficiency of our current experimental setups in recreating the tumor microenvironment. Forming more than 80% of the tumor mass, the fibrotic stroma of pancreatic ductal adenocarcinoma is not a passive scaffold for the malignant cells but an active player in carcinogenesis. This component is mostly missing in the xeno-/allograft- mouse models. Although tumors are bigger if stellate cells are co-implanted, due to the disproportionate cancer/stromal cell ratio and -possibly- too rapid tumor growth, the stromal reaction is much smaller than in human pancreatic cancer. One the other hand, desmoplasia is present only in some of the genetically engineered mouse models. Clinically, stromal activity of the pancreatic ductal adenocarcinoma has as great an impact on patient prognosis as the lymph node status of the tumor. The exact molecular mechanisms behind this observation remain obscure. However, one possible fundamental biologic explanation could be that selective pressure applied by the stroma leads to the evolution of cancer cells. Consequently, somatic evolution of invasive cancer could be viewed as a sequence of phenotypical adaptations to this barrier, highlighting the importance of the fibrotic tumor microenvironment in the behavior of pancreatic cancer. In this review, the interaction of the epithelial tumor cells with the stroma in humans and in various animal models is scrutinized, and novel therapeutic options for uncoupling cancer-stroma interactions are discussed.

14 Review [Pathology and classification of intraductal papillary mucinous neoplasms of the pancreas]. 2012

Schlitter, A M / Esposito, I. ·Institut für Pathologie, Technische Universität München, Ismaninger Strasse 22, Munich, Germany. ·Chirurg · Pubmed #22271052.

ABSTRACT: Intraductal papillary mucinous neoplasms (IPMN) are precursor lesions of ductal adenocarcinoma of the pancreas and one of the most common cystic entities in this organ. Branch and main duct types are further distinguished based on the tumor localization. An additional classification is based on the predominant architecture and immunohistochemical profile with four prognostic relevant subtypes, gastric, intestinal, pancreato-biliary and oncocytic. This review provides an overview about the malignant potential of the different subtypes and the prognosis of associated invasive tumors and gives recommendations for the pathological assessment of resection specimens with IPMNs.

15 Clinical Trial pERK, pAKT and p53 as tissue biomarkers in erlotinib-treated patients with advanced pancreatic cancer: a translational subgroup analysis from AIO-PK0104. 2014

Ormanns, Steffen / Siveke, Jens T / Heinemann, Volker / Haas, Michael / Sipos, Bence / Schlitter, Anna Melissa / Esposito, Irene / Jung, Andreas / Laubender, Rüdiger P / Kruger, Stephan / Vehling-Kaiser, Ursula / Winkelmann, Cornelia / Fischer von Weikersthal, Ludwig / Clemens, Michael R / Gauler, Thomas C / Märten, Angela / Geissler, Michael / Greten, Tim F / Kirchner, Thomas / Boeck, Stefan. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, München, Germany. stefan.boeck@med.uni-muenchen.de. ·BMC Cancer · Pubmed #25164437.

ABSTRACT: BACKGROUND: The role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not yet been defined. METHODS: Within the phase III study AIO-PK0104 281 patients with advanced pancreatic cancer received an erlotinib-based 1st-line regimen. Archival tissue from 153 patients was available for central immunohistochemistry staining for pERK, pAKT and p53. Within a subgroup analysis, biomarker data were correlated with efficacy endpoints and skin rash using a Cox regression model. RESULTS: Fifty-five out of 153 patients were classified as pERKlow and 98 patients as pERKhigh; median overall survival (OS) was 6.2 months and 5.7 months, respectively (HR 1.29, p = 0.16). When analysing pERK as continuous variable, the pERK score was significantly associated with OS (HR 1.06, 95% CI 1.0-1.12, p = 0.05). Twenty-one of 35 patients were pAKTlow and 14/35 pAKThigh with a corresponding median OS of 6.4 months and 6.8 months, respectively (HR 1.03, p = 0.93). Four out of 50 patients had a complete loss of p53 expression, 20 patients a regular expression and 26 patients had tumors with p53 overexpression. The p53 status had no impact on OS (p = 0.91); however, a significant improvement in progression-free survival (PFS) (6.0 vs 1.8 months, HR 0.24, p = 0.02) and a higher rate of skin rash (84% vs 25%, p = 0.02) was observed for patients with a regular p53 expression compared to patients with a complete loss of p53. CONCLUSION: pERK expression may have an impact on OS in erlotinib-treated patients with advanced pancreatic cancer; p53 should be further investigated for its potential role as a predictive marker for PFS and skin rash. TRIAL REGISTRATION: NCT00440167 (registration date: February 22, 2007).

16 Article Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis. 2019

Benitz, Simone / Straub, Tobias / Mahajan, Ujjwal Mukund / Mutter, Jurik / Czemmel, Stefan / Unruh, Tatjana / Wingerath, Britta / Deubler, Sabrina / Fahr, Lisa / Cheng, Tao / Nahnsen, Sven / Bruns, Philipp / Kong, Bo / Raulefs, Susanne / Ceyhan, Güralp O / Mayerle, Julia / Steiger, Katja / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W / Regel, Ivonne. ·Department of Medicine II, University Hospital, LMU Munich, Munich, Germany. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA. · Bioinformatic Unit, Biomedical Center, Faculty of Medicine, LMU Munich, Munich, Germany. · Quantitative Biology Center, University of Tuebingen, Tuebingen, Germany. · Institute of Pathology, Heinrich-Heine University and University Hospital, Duesseldorf, Germany. · Department of Surgery, Technical University Munich, Munich, Germany. · Institute of Pathology, Technical University Munich, Munich, Germany. · Institute of Pathology, Heinrich-Heine-Universitat Dusseldorf, Dusseldorf, Germany. · Department of Surgery, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany. ·Gut · Pubmed #30954952.

ABSTRACT: BACKGROUND AND AIMS: Besides well-defined genetic alterations, the dedifferentiation of mature acinar cells is an important prerequisite for pancreatic carcinogenesis. Acinar-specific genes controlling cell homeostasis are extensively downregulated during cancer development; however, the underlying mechanisms are poorly understood. Now, we devised a novel in vitro strategy to determine genome-wide dynamics in the epigenetic landscape in pancreatic carcinogenesis. DESIGN: With our in vitro carcinogenic sequence, we performed global gene expression analysis and ChIP sequencing for the histone modifications H3K4me3, H3K27me3 and H2AK119ub. Followed by a comprehensive bioinformatic approach, we captured gene clusters with extensive epigenetic and transcriptional remodelling. Relevance of Ring1b-catalysed H2AK119ub in acinar cell reprogramming was studied in an inducible Ring1b knockout mouse model. CRISPR/Cas9-mediated Ring1b ablation as well as drug-induced Ring1b inhibition were functionally characterised in pancreatic cancer cells. RESULTS: The epigenome is vigorously modified during pancreatic carcinogenesis, defining cellular identity. Particularly, regulatory acinar cell transcription factors are epigenetically silenced by the Ring1b-catalysed histone modification H2AK119ub in acinar-to-ductal metaplasia and pancreatic cancer cells. Ring1b knockout mice showed greatly impaired acinar cell dedifferentiation and pancreatic tumour formation due to a retained expression of acinar differentiation genes. Depletion or drug-induced inhibition of Ring1b promoted tumour cell reprogramming towards a less aggressive phenotype. CONCLUSIONS: Our data provide substantial evidence that the epigenetic silencing of acinar cell fate genes is a mandatory event in the development and progression of pancreatic cancer. Targeting the epigenetic repressor Ring1b could offer new therapeutic options.

17 Article Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas. 2019

Amato, Eliana / Mafficini, Andrea / Hirabayashi, Kenichi / Lawlor, Rita T / Fassan, Matteo / Vicentini, Caterina / Barbi, Stefano / Delfino, Pietro / Sikora, Katarzyna / Rusev, Borislav / Simbolo, Michele / Esposito, Irene / Antonello, Davide / Pea, Antonio / Sereni, Elisabetta / Ballotta, Maria / Maggino, Laura / Marchegiani, Giovanni / Ohike, Nobuyuki / Wood, Laura D / Salvia, Roberto / Klöppel, Günter / Zamboni, Giuseppe / Scarpa, Aldo / Corbo, Vincenzo. ·ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy. · Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy. · Department of Pathology, Tokai University School of Medicine, Isehara, Japan. · Institute of Pathology, Heinrich-Heine-University and University Hospital of Düsseldorf, Düsseldorf, Germany. · Department of Surgery, General Surgery B, University of Verona, Verona, Italy. · Section of Anatomic Pathology, Azienda Ospedaliera Rovigo, Rovigo, Italy. · Department of Pathology and Laboratory Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, Technical University Munich, Munich, Germany. · Division of Pathology, Sacro Cuore-Don Calabria Hospital, Negrar, Italy. ·J Pathol · Pubmed #30306561.

ABSTRACT: Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low-grade malignant neoplasms that metastasise to the liver or peritoneum in 10-15% of cases. They almost invariably present somatic activating mutations of CTNNB1. No comprehensive molecular characterisation of metastatic disease has been conducted to date. We performed whole-exome sequencing and copy-number variation (CNV) analysis of 10 primary SPN and comparative sequencing of five matched primary/metastatic tumour specimens by high-coverage targeted sequencing of 409 genes. In addition to CTNNB1-activating mutations, we found inactivating mutations of epigenetic regulators (KDM6A, TET1, BAP1) associated with metastatic disease. Most of these alterations were shared between primary and metastatic lesions, suggesting that they occurred before dissemination. Differently from mutations, the majority of CNVs were not shared among lesions from the same patients and affected genes involved in metabolic and pro-proliferative pathways. Immunostaining of 27 SPNs showed that loss or reduction of KDM6A and BAP1 expression was significantly enriched in metastatic SPNs. Consistent with an increased transcriptional response to hypoxia in pancreatic adenocarcinomas bearing KDM6A inactivation, we showed that mutation or reduced KDM6A expression in SPNs is associated with increased expression of the HIF1α-regulated protein GLUT1 at both primary and metastatic sites. Our results suggest that BAP1 and KDM6A function is a barrier to the development of metastasis in a subset of SPNs, which might open novel avenues for the treatment of this disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

18 Article BRAF 2019

Dizdar, Levent / Werner, Thomas A / Drusenheimer, Jasmin C / Möhlendick, Birte / Raba, Katharina / Boeck, Inga / Anlauf, Martin / Schott, Matthias / Göring, Wolfgang / Esposito, Irene / Stoecklein, Nikolas H / Knoefel, Wolfram T / Krieg, Andreas. ·Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany. · Institute of Pathology, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany. · Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany. · Institute of Pathology and Cytology, St. Vincenz Hospital Limburg, Limburg, Germany. · Division for Specific Endocrinology, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany. ·Int J Cancer · Pubmed #30144031.

ABSTRACT: To determine the role of BRAF

19 Article Serotonin uptake is required for Rac1 activation in Kras-induced acinar-to-ductal metaplasia in the pancreas. 2018

Saponara, Enrica / Visentin, Michele / Baschieri, Francesco / Seleznik, Gitta / Martinelli, Paola / Esposito, Irene / Buschmann, Johanna / Chen, Rong / Parrotta, Rossella / Borgeaud, Nathalie / Bombardo, Marta / Malagola, Ermanno / Caflisch, Amedeo / Farhan, Hesso / Graf, Rolf / Sonda, Sabrina. ·Department of Visceral and Transplant Surgery, University Hospital of Zurich, Zurich, Switzerland. · Department of Clinical Pharmacology and Toxicology, University Hospital of Zurich, Zurich, Switzerland. · Institute Gustave Roussy, Institut National de la Santé et de la Recherche Médicale (INSERM), Villejuif, France. · Institute for Cancer Research, Medical University, Wien, Austria. · Institut für Pathologie, University Hospital of Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany. · Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland. · Laboratory of Molecular Oncology, Thorax und Lungen Tumor Zentrum, University Hospital of Zurich, Zurich, Switzerland. · Department of Biochemistry, University of Zurich, Zurich, Switzerland. · Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. · Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland. ·J Pathol · Pubmed #30058725.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), which is the primary cause of pancreatic cancer mortality, is poorly responsive to currently available interventions. Identifying new targets that drive PDAC formation and progression is critical for developing alternative therapeutic strategies to treat this lethal malignancy. Using genetic and pharmacological approaches, we investigated in vivo and in vitro whether uptake of the monoamine serotonin [5-hydroxytryptamine (5-HT)] is required for PDAC development. We demonstrated that pancreatic acinar cells have the ability to readily take up 5-HT in a transport-mediated manner. 5-HT uptake promoted activation of the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1), which is required for transdifferentiation of acinar cells into acinar-to-ductal metaplasia (ADM), a key determinant in PDAC development. Consistent with the central role played by Rac1 in ADM formation, inhibition of the 5-HT transporter Sert (Slc6a4) with fluoxetine reduced ADM formation both in vitro and in vivo in a cell-autonomous manner. In addition, fluoxetine treatment profoundly compromised the stromal reaction and affected the proliferation and lipid metabolism of malignant PDAC cells. We propose that Sert is a promising therapeutic target to counteract the early event of ADM, with the potential to stall the initiation and progression of pancreatic carcinogenesis. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

20 Article Stromal heterogeneity in pancreatic cancer and chronic pancreatitis. 2018

Haeberle, Lena / Steiger, Katja / Schlitter, Anna Melissa / Safi, Sami Alexander / Knoefel, Wolfram Trudo / Erkan, Mert / Esposito, Irene. ·Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Duesseldorf, Germany. · Institute of Pathology, Technische Universitaet Muenchen, Munich, Germany. · Department of Surgery, University Hospital of Duesseldorf, Duesseldorf, Germany. · Department of Surgery, Koc University Hospital, Istanbul, Turkey. · Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Duesseldorf, Germany. Electronic address: irene.esposito@med.uni-duesseldorf.de. ·Pancreatology · Pubmed #29778400.

ABSTRACT: BACKGROUND/OBJECTIVES: An abundant stromal reaction is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). The cells mainly responsible for the stromal reaction are activated pancreatic stellate cells (PSCs). Despite their crucial role, PSCs are not well characterized. PSCs share characteristics with the better-known hepatic stellate cells (HSCs). The aim of this study was a detailed analysis of PSCs in PDAC and CP. METHODS: Whole-slide specimens of CP (n = 12) and PDAC (n = 10) were studied by histochemistry and immunohistochemistry. The stroma was evaluated using Movat's pentachrome stain. PSCs were tested by immunohistochemistry for PSC markers (α-SMA, CD34, desmin, NGFR, SPARC and tenascin C) and HSC markers (α-crystallin B, CD56, NGF, NT-3, synaptophysin and TrkC). Alpha-SMA, tenascin C, SPARC and NT-3 staining were verified on tissue micro arrays (TMAs) from a well-characterized cohort of 223 PDAC patients. PSCs isolated from human PDAC and CP tissue samples as well as HSCs were evaluated by immunofluorescence. RESULTS: While the stroma of CP cases was characterized by a collagen-rich fibrosis, PDAC stroma displayed higher mucin content (p = 0.0002). PSCs showed variable expression of tested markers. In PDAC samples, staining of most markers was found around tumor complexes, while CP samples showed a greater variety of localizations. Alpha-SMA staining correlated with collagen-rich fibrosis (p = 0.012), while NT-3 staining correlated with mucin-rich stroma (p = 0.008). A peritumoral staining was confirmed for α-SMA, tenascin C, SPARC and NT-3 in the PDAC TMA cohort (n = 223). In a subgroup of patients with pancreatic head tumors and UICC 2009 IIB (n = 144), α-SMA staining intensity was a prognostic factor for overall survival at uni- and multivariate analysis (p = 0.036 and p = 0.002). CONCLUSIONS: The close similarities between PSCs and HSCs were confirmed. Heterogeneous expression patterns of the tested markers might reflect different levels of activation or differentiation, or even multiple subpopulations of PSCs. Survival analysis suggests an impact of stromal composition on survival.

21 Article Pancreatic Ductal Adenocarcinoma Subtyping Using the Biomarkers Hepatocyte Nuclear Factor-1A and Cytokeratin-81 Correlates with Outcome and Treatment Response. 2018

Muckenhuber, Alexander / Berger, Anne Katrin / Schlitter, Anna Melissa / Steiger, Katja / Konukiewitz, Björn / Trumpp, Andreas / Eils, Roland / Werner, Jens / Friess, Helmut / Esposito, Irene / Klöppel, Günter / Ceyhan, Güralp O / Jesinghaus, Moritz / Denkert, Carsten / Bahra, Marcus / Stenzinger, Albrecht / Sprick, Martin R / Jäger, Dirk / Springfeld, Christoph / Weichert, Wilko. ·Institute of Pathology, Technical University Munich and German Cancer Consortium (DKTK; partner site Munich), Munich, Germany. · Department of Medical Oncology, Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, Germany. · Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany. · Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH, Heidelberg, Germany. · German Cancer Consortium (DKTK), Heidelberg, Germany. · Division of Theoretical Bioinformatics and Heidelberg Center for Personalised Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany. · Department of Surgery, University Hospital of the Ludwig-Maximilian University, Munich, Germany. · Department of Surgery, University Hospital of the Technical University Munich, Munich, Germany. · Institute of Pathology, University Hospital Düsseldorf, Düsseldorf, Germany. · Institute of Pathology, Charité University Medicine Berlin and German Cancer Consortium (DKTK; partner site Berlin), Berlin, Germany. · Department of Surgery, Charité University Medicine Berlin, Berlin, Germany. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Pathology, Technical University Munich and German Cancer Consortium (DKTK; partner site Munich), Munich, Germany. wilko.weichert@tum.de. ·Clin Cancer Res · Pubmed #29101303.


22 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.

23 Article Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy. 2018

Kong, Bo / Bruns, Philipp / Behler, Nora A / Chang, Ligong / Schlitter, Anna Melissa / Cao, Jing / Gewies, Andreas / Ruland, Jürgen / Fritzsche, Sina / Valkovskaya, Nataliya / Jian, Ziying / Regel, Ivonne / Raulefs, Susanne / Irmler, Martin / Beckers, Johannes / Friess, Helmut / Erkan, Mert / Mueller, Nikola S / Roth, Susanne / Hackert, Thilo / Esposito, Irene / Theis, Fabian J / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China. · Institute of Computational Biology, Helmholtz-Zentrum München GmbH, Neuherberg, Germany. · Institute of Pathology, TUM, Munich, Germany. · Institute für Klinische Chemie und Pathobiochemie, TUM, Munich, Germany. · Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany. · German Cancer Consortium (DKTK) at the partner site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany. · German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany. · Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany. · Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany. · Chair of Experimental Genetics, Technische Universität München, Freising, Germany. · Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany. · Department of Surgery, Koc University, Istanbul, Turkey. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Mathematics, TUM, Munich, Germany. · NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. ·Gut · Pubmed #27646934.

ABSTRACT: OBJECTIVE: The initial steps of pancreatic regeneration versus carcinogenesis are insufficiently understood. Although a combination of oncogenic Kras and inflammation has been shown to induce malignancy, molecular networks of early carcinogenesis remain poorly defined. DESIGN: We compared early events during inflammation, regeneration and carcinogenesis on histological and transcriptional levels with a high temporal resolution using a well-established mouse model of pancreatitis and of inflammation-accelerated Kras RESULTS: We defined three distinctive phases-termed inflammation, regeneration and refinement-following induction of moderate acute pancreatitis in wild-type mice. These corresponded to different waves of proliferation of mesenchymal, progenitor-like and acinar cells. Pancreas regeneration required a coordinated transition of proliferation between progenitor-like and acinar cells. In mice harbouring an oncogenic Kras mutation and challenged with pancreatitis, there was an extended inflammatory phase and a parallel, continuous proliferation of mesenchymal, progenitor-like and acinar cells. Analysis of high-resolution transcriptional data from wild-type animals revealed that organ regeneration relied on a complex interaction of a gene network that normally governs acinar cell homeostasis, exocrine specification and intercellular signalling. In mice with oncogenic Kras, a specific carcinogenic signature was found, which was preserved in full-blown mouse pancreas cancer. CONCLUSIONS: These data define a transcriptional signature of early pancreatic carcinogenesis and a molecular network driving formation of preneoplastic lesions, which allows for more targeted biomarker development in order to detect cancer earlier in patients with pancreatitis.

24 Article Apparent Diffusion Coefficient (ADC) predicts therapy response in pancreatic ductal adenocarcinoma. 2017

Trajkovic-Arsic, M / Heid, I / Steiger, K / Gupta, A / Fingerle, A / Wörner, C / Teichmann, N / Sengkwawoh-Lueong, S / Wenzel, P / Beer, A J / Esposito, I / Braren, R / Siveke, J T. ·Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Institute of Radiology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. · Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany. · 2. Medizinische Klinik, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. · Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. · Department of Nuclear Medicine, University Hospital of Ulm, Ulm, Germany. · Institute of Pathology, University Clinic Duesseldorf, Heinrich-Heine University, Duesseldorf, Germany. · Institute of Radiology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. rbraren@tum.de. · Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. j.siveke@dkfz.de. · German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center (DKFZ), Heidelberg, Germany. j.siveke@dkfz.de. · 2. Medizinische Klinik, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. j.siveke@dkfz.de. ·Sci Rep · Pubmed #29213099.

ABSTRACT: Recent advances in molecular subtyping of Pancreatic Ductal Adenocarcinoma (PDAC) support individualization of therapeutic strategies in this most aggressive disease. With the emergence of various novel therapeutic strategies and neoadjuvant approaches in this quickly deteriorating disease, robust approaches for fast evaluation of therapy response are urgently needed. To this aim, we designed a preclinical imaging-guided therapy trial where genetically engineered mice harboring endogenous aggressive PDAC were treated with the MEK targeting drug refametinib, which induces rapid and profound tumor regression in this model system. Multi-parametric non-invasive imaging was used for therapy response monitoring. A significant increase in the Diffusion-Weighted Magnetic Resonance Imaging derived Apparent Diffusion Coefficient (ADC) was noted already 24 hours after treatment onset. Histopathological analyses showed increased apoptosis and matrix remodeling at this time point. Our findings suggest the ADC parameter as an early predictor of therapy response in PDAC.

25 Article Isolation of circulating tumor cells from pancreatic cancer by automated filtration. 2017

Brychta, Nora / Drosch, Michael / Driemel, Christiane / Fischer, Johannes C / Neves, Rui P / Esposito, Irene / Knoefel, Wolfram / Möhlendick, Birte / Hille, Claudia / Stresemann, Antje / Krahn, Thomas / Kassack, Matthias U / Stoecklein, Nikolas H / von Ahsen, Oliver. ·Bayer AG, Biomarker Research, 13353 Berlin, Germany. · Current/Present address: JPT Peptide Technologies GmbH, 12489 Berlin, Germany. · Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany. · Institute of Pathology, Heinrich-Heine-University of Duesseldorf, 40225 Duesseldorf, Germany. · Current/Present address: University Medical Center Hamburg-Eppendorf, Department of Tumor Biology, 20246 Hamburg, Germany. · Institute of Pharmaceutical & Medicinal Chemistry, University of Duesseldorf, 40225 Duesseldorf, Germany. ·Oncotarget · Pubmed #29156783.

ABSTRACT: It is now widely recognized that the isolation of circulating tumor cells based on cell surface markers might be hindered by variability in their protein expression. Especially in pancreatic cancer, isolation based only on EpCAM expression has produced very diverse results. Methods that are independent of surface markers and therefore independent of phenotypical changes in the circulating cells might increase CTC recovery also in pancreatic cancer. We compared an EpCAM-dependent (IsoFlux) and a size-dependent (automated Siemens Healthineers filtration device) isolation method for the enrichment of pancreatic cancer CTCs. The recovery rate of the filtration based approach is dramatically superior to the EpCAM-dependent approach especially for cells with low EpCAM-expression (filtration: 52%, EpCAM-dependent: 1%). As storage and shipment of clinical samples is important for centralized analyses, we also evaluated the use of frozen diagnostic leukapheresis (DLA) as source for isolating CTCs and subsequent genetic analysis such as