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Pancreatic Neoplasms: HELP
Articles by Aurel Perren
Based on 42 articles published since 2008
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Between 2008 and 2019, A. Perren wrote the following 42 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas. 2016

Garcia-Carbonero, R / Sorbye, H / Baudin, E / Raymond, E / Wiedenmann, B / Niederle, B / Sedlackova, E / Toumpanakis, C / Anlauf, M / Cwikla, J B / Caplin, M / O'Toole, D / Perren, A / Anonymous6950853. ·Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain. ·Neuroendocrinology · Pubmed #26731334.

ABSTRACT: -- No abstract --

2 Guideline Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2012

Öberg, K / Knigge, U / Kwekkeboom, D / Perren, A / Anonymous3470737. ·Department of Endocrine Oncology, University Hospital, Uppsala University, Uppsala, Sweden. ·Ann Oncol · Pubmed #22997445.

ABSTRACT: -- No abstract --

3 Guideline ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification. 2009

Klöppel, Günter / Couvelard, Anne / Perren, Aurel / Komminoth, Paul / McNicol, Anne-Marie / Nilsson, Ola / Scarpa, Aldo / Scoazec, Jean-Yves / Wiedenmann, Bertram / Papotti, Mauro / Rindi, Guido / Plöckinger, Ursula / Anonymous1150617 / Anonymous1160617. ·Institut für Allgemeine Pathologie und Pathologische Anatomie, Universität Kiel, DE-24105 Kiel, Germany. guenterkloeppel@path.uni-kiel.de ·Neuroendocrinology · Pubmed #19060454.

ABSTRACT: -- No abstract --

4 Editorial The ENETS and AJCC/UICC TNM classifications of the neuroendocrine tumors of the gastrointestinal tract and the pancreas: a statement. 2010

Klöppel, Günter / Rindi, Guido / Perren, Aurel / Komminoth, Paul / Klimstra, David S. · ·Virchows Arch · Pubmed #20422210.

ABSTRACT: -- No abstract --

5 Review The Problem of High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms: Well-Differentiated Neuroendocrine Tumors, Neuroendocrine Carcinomas, and Beyond. 2018

Sorbye, Halfdan / Baudin, Eric / Perren, Aurel. ·Department of Oncology, Haukeland University Hospital, Jonas Lies vei 65, Bergen 5021, Norway; Department of Clinical Science, Haukeland University Hospital, Jonas Lies vei 65, Bergen 5021, Norway. Electronic address: halfdan.sorbye@helse-bergen.no. · Endocrine Oncology, Gustave Roussy, rue Édouard-Vaillant 114, Villejuif 94800, France. · Department of Pathology, University of Bern, Murtenstrasse 31, Bern 3008, Switzerland. ·Endocrinol Metab Clin North Am · Pubmed #30098724.

ABSTRACT: High-grade gastroenteropancreatic neuroendocrine neoplasms are well-differentiated neuroendocrine tumors or poorly differentiated small/large cell neuroendocrine carcinoma. Distinguishing these entities relies on different genetic backgrounds and resulting different biology. The new classification creates several problems. Almost all clinical treatment data on neuroendocrine neoplasms do not stratify between well and poorly differentiated, providing insufficient help in treatment selection. Treatment of gastroenteropancreatic neuroendocrine neoplasms should separate between well-differentiated neuroendocrine tumors and neuroendocrine carcinoma, and depends on primary tumor site, stage, proliferation rate, and clinical course. This article addresses how to diagnose and treat gastroenteropancreatic neuroendocrine neoplasms, focusing on well-differentiated neuroendocrine tumors versus neuroendocrine carcinomas.

6 Review Calcitonin-Producing Neuroendocrine Neoplasms of the Pancreas: Clinicopathological Study of 25 Cases and Review of the Literature. 2017

Uccella, Silvia / Blank, Annika / Maragliano, Roberta / Sessa, Fausto / Perren, Aurel / La Rosa, Stefano. ·Department of Medicine and Surgery, Unit of Pathology, University of Insubria, 21100, Varese, Italy. silvia.uccella@uninsubria.it. · Institute of Pathology, University of Bern, Bern, Switzerland. · Department of Medicine and Surgery, Unit of Pathology, University of Insubria, 21100, Varese, Italy. · Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland. ·Endocr Pathol · Pubmed #29063495.

ABSTRACT: Increased levels of circulating calcitonin are a clue in the diagnosis of medullary thyroid carcinoma. However, hypercalcitoninemia can also be related to other pathological conditions, including pancreatic neuroendocrine neoplasms (PanNENs). Ectopic hormonal production is not unusual in both functioning and non-functioning PanNENs; however, little is known about the frequency of calcitonin expression in these neoplasms. The aims of this study were to assess the frequency of calcitonin immunoreactivity in PanNENs, independently from serum calcitonin levels, and to evaluate the clinicopathological and prognostic features of calcitonin-immunoreactive (Cal-IR) PanNENs, including a comparison with cases already reported in the literature. We screened 229 PanNENs for the immunohistochemical expression of calcitonin, including both functioning and non-functioning neoplasms, as well as both well-differentiated and poorly differentiated PanNENs. Both the clinicopathological data and the follow-up information were available and were compared with the immunohistochemical results. In addition, we reviewed the features of the calcitonin-producing PanNENs previously reported in the literature. Calcitonin was expressed in 25 of our 229 PanNENs (10.9%). Examples of well- and poorly differentiated, as well as both functioning and non-functioning PanNENs, were found to be calcitonin immunoreactive. Cal-IR PanNENs did not show any significant difference with the whole series of neoplasms included in the study, when the clinicopathological parameters were considered, except for a younger age at diagnosis and for a larger size of the tumor in non-functioning Cal-IR PanNENs. Taken together, our results show that calcitonin immunoreactivity is not an exceptional event in PanNENs. Furthermore, calcitonin expression does not identify a separate clinical entity, in contrast to other PanNENs with ectopic hormone production, such as adrenocorticotropic hormone (ACTH)-producing PanNENs, which show a distinctively more aggressive behavior.

7 Review New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies. 2016

Schmitt, Anja M / Marinoni, Ilaria / Blank, Annika / Perren, Aurel. ·Institute of Pathology, University of Bern, Murtenstrasse 31, 3010, Bern, Switzerland. anja.schmitt@pathology.unibe.ch. · Institute of Pathology, University of Bern, Murtenstrasse 31, 3010, Bern, Switzerland. ·Endocr Pathol · Pubmed #27456058.

ABSTRACT: The recent findings on the roles of death-associated protein 6/α-thalassemia/mental retardation X-linked (DAXX/ATRX) in the development of pancreatic neuroendocrine tumors (PanNETs) have led to major advances in the molecular understanding of these rare tumors and open up completely new therapeutic windows. This overview aims at giving a simplified view on these findings and their possible therapeutic implications. The importance of epigenetic changes in PanNET is also underlined by recent findings of a cross-species study on microRNA (miRNA) and messenger RNA (mRNA) profiles in PanNETs.

8 Review [What is new in the pathology of pancreatic neuroendocrine tumors?]. 2015

Komminoth, P / Perren, A. ·Institut für Pathologie, Stadtspital Triemli, Birmensdorferstr. 497, 8063, Zürich, Schweiz, paul.komminoth@triemli.zuerich.ch. ·Pathologe · Pubmed #25941099.

ABSTRACT: The diagnostics of pancreatic neuroendocrine tumors (PanNEN) have changed in recent years especially concerning the World Health Organization (WHO) classification, TNM staging and grading. Furthermore, some new prognostic and predictive immunohistochemical markers have been introduced. Most progress, however, has been made in the molecular pathogenesis of these neoplasms. Using next generation sequencing techniques, the mammalian target of rapamycin (mTOR) pathway, hypoxia and epigenetic changes were identified as key players in tumorigenesis. In this article the most important developments of morphological as well as immunohistochemical diagnostics together with the molecular background of PanNEN are summarized.

9 Review Hyperplasia to neoplasia sequence of duodenal and pancreatic neuroendocrine diseases and pseudohyperplasia of the PP-cells in the pancreas. 2014

Klöppel, Günter / Anlauf, Martin / Perren, Aurel / Sipos, Bence. ·Department of Pathology, Technical University, Ismaningerstr. 22, 81675, München, Germany, guenter.kloeppel@alumni.uni-kiel.de. ·Endocr Pathol · Pubmed #24718881.

ABSTRACT: Hyperplastic changes of the neuroendocrine cell system may have the potential to evolve into neoplastic diseases. This is particularly the case in the setting of genetically determined and hereditary neuroendocrine tumor syndromes such as MEN1. The review discusses the MEN1-associated hyperplasia-neoplasia sequence in the development of gastrinomas in the duodenum and glucagon-producing tumors in the pancreas. It also presents other newly described diseases (e.g., glucagon cell adenomatosis and insulinomatosis) in which the tumors are (or most likely) also preceded by islet cell hyperplasia. Finally, the pseudohyperplasia of PP-rich islets in the pancreatic head is defined as a physiologic condition clearly differing from other hyperplastic-neoplastic neuroendocrine diseases.

10 Review Serotonin-producing enterochromaffin cell tumors of the pancreas: clinicopathologic study of 15 cases and comparison with intestinal enterochromaffin cell tumors. 2011

La Rosa, Stefano / Franzi, Francesca / Albarello, Luca / Schmitt, Anja / Bernasconi, Barbara / Tibiletti, Maria Grazia / Finzi, Giovanna / Placidi, Claudia / Perren, Aurel / Capella, Carlo. ·Department of Pathology, Ospedale di Circolo, Varese, Italy. stefano.larosa@ospedale.varese.it ·Pancreas · Pubmed #21705949.

ABSTRACT: OBJECTIVES: Serotonin-producing tumors of the pancreas are rare endocrine neoplasms composed of enterochromaffin (EC) cells that have been mainly described in the literature as case reports. This study analyzes the clinicopathologic features of a series of pancreatic EC cell neoplasms and their similarities to and differences from intestinal EC cell tumors. METHODS: The morphological, immunohistochemical, ultrastructural, and fluorescent in situ hybridization features of 15 pancreatic and 20 intestinal serotonin-producing neoplasms were compared. In addition, we reviewed the literature on pancreatic serotonin-producing tumors to better understand the clinicopathologic features of this rare tumor type. RESULTS: The lack of substance P and acidic fibroblast growth factor immunoreactivity; the low immunohistochemical expression of CDX2, vesicular monoamine transporter 1, connective tissue growth factor, and prostatic acid phosphatase; the lack of S100-positive sustentacular cells; the strong expression of vesicular monoamine transporter 2; and peculiar ultrastructural features characterize pancreatic EC cell tumors and differentiate them from intestinal ones, although both categories show similar chromosome 18 cytogenetic alterations. The review of the literature indicates that pancreatic functioning tumors associated with the carcinoid syndrome arise in younger patients and are larger, more frequently malignant, and more aggressive neoplasms than pancreatic nonfunctioning ones. CONCLUSIONS: Pancreatic EC cell tumors show several different morphological features compared with related intestinal tumors despite similar cytogenetic alterations on chromosome 18.

11 Clinical Trial Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study. 2013

Christ, Emanuel / Wild, Damian / Ederer, Susanne / Béhé, Martin / Nicolas, Guillaume / Caplin, Martyn E / Brändle, Michael / Clerici, Thomas / Fischli, Stefan / Stettler, Christoph / Ell, Peter J / Seufert, Jochen / Gloor, Beat / Perren, Aurel / Reubi, Jean Claude / Forrer, Flavio. ·Division of Endocrinology, Diabetology and Clinical Nutrition, University Hospital of Berne, Inselspital, Berne, Switzerland. · Department of Radiology, Division of Nuclear Medicine, University of Basel Hospital, Switzerland; Department of Nuclear Medicine, University Hospital Freiburg, Germany; Institute of Nuclear Medicine, University College Hospital, London, UK. Electronic address: damian.wild@usb.ch. · Department of Radiology, Division of Nuclear Medicine, University of Basel Hospital, Switzerland. · Department of Nuclear Medicine, University Hospital Freiburg, Germany; Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, Villingen, Switzerland. · Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK. · Division of Endocrinology, Diabetes and Osteology, Kantonsspital, St Gallen, Switzerland. · Division of Visceral Surgery, Kantonsspital, St Gallen, Switzerland. · Division of Endocrinology, Diabetes and Osteology, Kantonsspital Luzern, Switzerland. · Institute of Nuclear Medicine, University College Hospital, London, UK. · Division of Endocrinology and Diabetology, University Hospital Freiburg, Germany. · Division of Visceral Surgery, University Hospital of Berne, Inselspital, Berne, Switzerland. · Institute of Pathology, University of Berne, Berne, Switzerland. ·Lancet Diabetes Endocrinol · Pubmed #24622317.

ABSTRACT: BACKGROUND: Small benign insulinomas are hard to localise, leading to difficulties in planning of surgical interventions. We aimed to prospectively assess the insulinoma detection rate of single-photon emission CT in combination with CT (SPECT/CT) with a glucagon-like peptide-1 receptor avid radiotracer, and compare detection rates with conventional CT/MRI techniques. METHODS: In our prospective imaging study, we enrolled adults aged 25-81 years at centres in Germany, Switzerland, and the UK. Eligible patients had proven clinical and biochemical endogenous hyperinsulinaemic hypoglycaemia and no evidence for metastatic disease on conventional imaging. CT/MRI imaging was done at referring centres according to standard protocols. At three tertiary nuclear medicine centres, we used whole body planar images and SPECT/CT of the abdomen up to 168 h after injection of (111)In-[Lys40(Ahx-DTPA-(111)In)NH2]-exendin-4 ((111)In-DTPA-exendin-4) to identify insulinomas. Consenting patients underwent surgery and imaging findings were confirmed histologically. FINDINGS: Between Oct 1, 2008, and Dec 31, 2011, we recruited 30 patients. All patients underwent (111)In-DTPA-exendin-4 imaging, 25 patients underwent surgery (with histological analysis), and 27 patients were assessed with CT/MRI. (111)In-DTPA-exendin-4 SPECT/CT correctly detected 19 insulinomas and four additional positive lesions (two islet-cell hyperplasia and two uncharacterised lesions) resulting in a positive predictive value of 83% (95% CI 62-94). One true negative (islet-cell hyperplasia) and one false negative (malignant insulinoma) result was identified in separate patients by (111)In-DTPA-exendin-4 SPECT/CT. Seven patients (23%) were referred to surgery on the basis of (111)In-DTPA-exendin-4 imaging alone. For 23 assessable patients, (111)In-DTPA-exendin-4 SPECT/CT had a higher sensitivity (95% [95% CI 74-100]) than did CT/MRI (47% [27-68]; p=0.011). INTERPRETATION: (111)In-DTPA-exendin-4 SPECT/CT could provide a good second-line imaging strategy for patients with negative results on initial imaging with CT/MRI. FUNDING: Oncosuisse, the Swiss National Science Foundation, and UK Department of Health.

12 Clinical Trial Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. 2011

Wild, Damian / Christ, Emanuel / Caplin, Martyn E / Kurzawinski, Tom R / Forrer, Flavio / Brändle, Michael / Seufert, Jochen / Weber, Wolfgang A / Bomanji, Jamshed / Perren, Aurel / Ell, Peter J / Reubi, Jean Claude. ·Institute of Nuclear Medicine, University College Hospital, London, United Kingdom. ·J Nucl Med · Pubmed #21680696.

ABSTRACT: METHODS: Eleven patients with malignant insulinoma were prospectively included. (111)In-[Lys(40)(Ahx-diethylenetriaminepentaacetic acid [DTPA])NH(2)]-exendin-4 SPECT/CT, (68)Ga- DOTATATE PET/CT, and in vitro receptor autoradiography were performed to assess the receptor status and to evaluate the detection rate. RESULTS: GLP-1 receptor targeting was positive in 4 of 11 patients, and sst(2) receptor expression was positive in 8 of 11. In only 1 patient were both receptors expressed. In 1 patient, GLP-1 receptor imaging was the only method that successfully localized the primary tumor in the pancreas. In 3 patients with sst(2)-expressing tumors, DOTATATE radiotherapy was effectively applied. CONCLUSION: As opposed to benign insulinomas, malignant insulinomas often lack GLP-1 receptors. Conversely, malignant insulinomas often express sst(2), which can be targeted therapeutically.

13 Article Intertumor heterogeneity in 60 pancreatic neuroendocrine tumors associated with multiple endocrine neoplasia type 1. 2019

Selberherr, Andreas / Koperek, Oskar / Riss, Philipp / Scheuba, Christian / Niederle, Martin B / Kaderli, Reto / Perren, Aurel / Niederle, Bruno. ·Section "Endocrine Surgery", Division of General Surgery, Department of Surgery, Medical University, Währinger Gürtel 18-20, A-1090, Vienna, Austria. andreas.selberherr@meduniwien.ac.at. · Department of Pathology, Medical University, Währinger Gürtel 18-20, A-1090, Vienna, Austria. · Section "Endocrine Surgery", Division of General Surgery, Department of Surgery, Medical University, Währinger Gürtel 18-20, A-1090, Vienna, Austria. · Department of Anesthesiology, Medical University, Währinger Gürtel 18-20, A-1090, Vienna, Austria. · Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3012, Bern, Switzerland. ·Orphanet J Rare Dis · Pubmed #30795813.

ABSTRACT: BACKGROUND: Patients with multiple endocrine neoplasia type 1 (MEN-1) develop multiple pancreatic neuroendocrine neoplasias (PNENs). Size at diagnosis and growth during follow-up are crucial parameters. According to the WHO 2017, grading is another important parameter. The impact of grading compared to size (WHO 2000) on the clinical course needs to be evaluated. METHODS: Sixty PNENs of six patients with MEN-1 were retrospectively evaluated. RESULTS: Fifty-one tumors with a diameter of < 20 mm were graded as G1. Two of 9 tumors with diameters of ≥20 mm were graded as G2. Tumor size of ≥20 mm correlated significantly with higher proliferation (p = 0.000617). Lymph node metastases were documented in two patients with a total of 19 tumors. In one patient, all 13 tumors (diameter: 0.4 to 100 mm) were classified as G1. However, metastases were documented in 9/29 lymph nodes. In the other patient, 5 tumors (3.5 to 20 mm) were classified as G1. The sixth tumor (30 mm) was classified as G2 (Ki-67: 8%). Metastases were revealed in 2/20 lymph nodes. CONCLUSIONS: Tumor size of ≥20 mm seems to correlate with more aggressive MEN-1 related pancreatic disease, regardless of individual proliferation. Tumors ≥20 mm and tumors graded as G2 should be treated surgically regardless of their size.

14 Article Development of a Class Prediction Model to Discriminate Pancreatic Ductal Adenocarcinoma from Pancreatic Neuroendocrine Tumor by MALDI Mass Spectrometry Imaging. 2019

Casadonte, Rita / Kriegsmann, Mark / Perren, Aurel / Baretton, Gustavo / Deininger, Sören-Oliver / Kriegsmann, Katharina / Welsch, Thilo / Pilarsky, Christian / Kriegsmann, Jörg. ·Proteopath GmbH, Trier, 54296, Germany. · Institute of Pathology, University of Heidelberg, Heidelberg, 69120, Germany. · Institute of Pathology, University of Bern, Bern, 3012, Switzerland. · Institute of Pathology, University Hospital Carl Gustav Carus at the Technical University of Dresden, Dresden, 01307, Germany. · Bruker Daltonik, Bremen, 28359, Germany. · Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, 69120, Germany. · MVZ for Histology, Cytology and Molecular Diagnostics, Trier, 54296, Germany. ·Proteomics Clin Appl · Pubmed #30548962.

ABSTRACT: PURPOSE: To define proteomic differences between pancreatic ductal adenocarcinoma (pDAC) and pancreatic neuroendocrine tumor (pNET) by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). EXPERIMENTAL DESIGN: Ninety-three pDAC and 126 pNET individual tissues are assembled in tissue microarrays and analyzed by MALDI MSI. The cohort is separated in a training (52 pDAC and 83 pNET) and validation set (41 pDAC and 43 pNET). Subsequently, a linear discriminant analysis (LDA) model based on 46 peptide ions is performed on the training set and evaluated on the validation cohort. Additionally, two liver metastases and a whole slide of pDAC are analyzed by the same LDA algorithm. RESULTS: Classification of pDAC and pNET by the LDA model is correct in 95% (39/41) and 100% (43/43) of patients in the validation cohort, respectively. The two liver metastases and the whole slide of pDAC are also correctly classified in agreement with the histopathological diagnosis. CONCLUSION AND CLINICAL RELEVANCE: In the present study, a large dataset of pDAC and pNET by MALDI MSI is investigated, a class prediction model that allowed separation of both entities with high accuracy is developed, and differential peptide peaks with potential diagnostic, prognostic, and predictive values are highlighted.

15 Article Therapeutic targeting of tumor-associated macrophages in pancreatic neuroendocrine tumors. 2018

Krug, Sebastian / Abbassi, Rami / Griesmann, Heidi / Sipos, Bence / Wiese, Dominik / Rexin, Peter / Blank, Annika / Perren, Aurel / Haybaeck, Johannes / Hüttelmaier, Stefan / Rinke, Anja / Gress, Thomas M / Michl, Patrick. ·Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany. · Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany. · Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany. · Department of Visceral, Thoracic and Vascular Surgery, Philipps-University, Marburg, Germany. · Institute of Pathology, Philipps-University, Marburg, Germany. · Institute of Pathology, University of Bern, Bern, Switzerland. · Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany. · Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany. ·Int J Cancer · Pubmed #29696624.

ABSTRACT: Pancreatic neuroendocrine tumors (PNETs) represent a heterogeneous group of neuroendocrine neoplasms with varying biological behavior and response to treatment. Although targeted therapies have been shown to improve the survival for patients at advanced stage, resistance to current therapies frequently occurs during the course of therapy. Previous reports indicate that the infiltration of tumor-associated macrophages (TAMs) in PNETs might correlate with tumor progression and metastasis formation. We aimed to evaluate the prognostic and functional impact of TAMs in human PNETs in vitro and in vivo and to investigate the effect of therapeutic targeting TAMs in a genetic PNET mouse model. TAM expression pattern was assessed immunohistochemically in human PNET tissue sections and a tissue-micro-array of PNET tumors with different functionality, stage, and grading. The effect of liposomal clodronate on TAM cell viability was analyzed in myeloid cell lines and isolated murine bone macrophages (mBMM). In vivo, RIP1Tag2 mice developing insulinomas were treated with liposomal clodronate or PBS-Liposomes. Tumor progression, angiogenesis and immune cell infiltration were assessed by immunohistochemistry. In human, insulinomas TAM density was correlated with invasiveness and malignant behavior. Moreover, TAM infiltration in liver metastases was significantly increased compared to primary tumors. In vitro, Liposomal clodronate selectively inhibited the viability of myeloid cells and murine bone macrophages, leaving PNET tumor cell lines largely unaffected. In vivo, repeated application of liposomal clodronate to RIP1Tag2 mice significantly diminished the malignant transformation of insulinomas, which was accompanied by a reduced infiltration of F4/80-positive TAM cells and simultaneously by a decreased microvessel density, suggesting a pronounced effect of clodronate-induced myeloid depletion on tumor angiogenesis. Concomitant treatment with the antiangiogenic TKI sunitinib, however, did not show any synergistic effects with liposomal clodronate. TAMs are crucial for malignant transformation in human PNET and correlate with metastatic behavior. Pharmacological targeting of TAMs via liposomal clodronate disrupts tumor progression in the RIP1Tag2 neuroendocrine tumor model and was associated with reduced tumor angiogenesis. Based on these results, using liposomal clodronate to target proangiogenic myeloid cells could be employed as novel therapeutic avenue in highly angiogenic tumors such as PNET.

16 Article GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth. 2018

Li, Leanne / Zeng, Qiqun / Bhutkar, Arjun / Galván, José A / Karamitopoulou, Eva / Noordermeer, Daan / Peng, Mei-Wen / Piersigilli, Alessandra / Perren, Aurel / Zlobec, Inti / Robinson, Hugh / Iruela-Arispe, M Luisa / Hanahan, Douglas. ·Swiss Institute of Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland. · David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. · Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland. · Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland; School of Life Science, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland. · Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK. · Department of Molecular, Cell and Developmental Biology, Jonsson Comprehensive Cancer Center and Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA. · Swiss Institute of Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: douglas.hanahan@epfl.ch. ·Cancer Cell · Pubmed #29606348.

ABSTRACT: Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). Here, we establish that GKAP governs invasive growth and treatment response to NMDAR inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells. Furthermore, we distilled genome-wide expression profiles orchestrated by the NMDAR-GKAP signaling axis, identifying transcriptome signatures in tumors with low/inhibited NMDAR activity that significantly associate with favorable patient prognosis in several cancer types.

17 Article Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism. 2017

Wiedmer, Tabea / Blank, Annika / Pantasis, Sophia / Normand, Lea / Bill, Ruben / Krebs, Philippe / Tschan, Mario P / Marinoni, Ilaria / Perren, Aurel. ·Institute of Pathology, University of Bern, Bern, Switzerland. · Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland. · Department of Internal Medicine, Regional Hospital Emmental Burgdorf, Burgdorf, Switzerland. · Institute of Pathology, University of Bern, Bern, Switzerland. aurel.perren@pathology.unibe.ch ilaria.marinoni@pathology.unibe.ch. ·Mol Cancer Ther · Pubmed #28729403.

ABSTRACT: Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in primary cells isolated from PanNET patients. The same treatment combination reduced tumor burden in the Rip1Tag2 transgenic PanNET mouse model. The combination of sunitinib and chloroquine reduced recovery and induced apoptosis

18 Article Results after surgical treatment of liver metastases in patients with high-grade gastroenteropancreatic neuroendocrine carcinomas. 2017

Galleberg, R B / Knigge, U / Tiensuu Janson, E / Vestermark, L W / Haugvik, S-P / Ladekarl, M / Langer, S W / Grønbæk, H / Österlund, P / Hjortland, G O / Assmus, J / Tang, L / Perren, A / Sorbye, H. ·Department of Oncology, Haukeland University Hospital, Bergen, Norway. Electronic address: renate.berget.galleberg@helse-bergen.no. · Departments of Surgery C and Endocrinology PE, Rigshospitalet, University of Copenhagen, Denmark. Electronic address: rxs484@ku.dk. · Department of Medical Sciences, Uppsala University, Sweden. Electronic address: eva.tiensuu_janson@medsci.uu.se. · Department of Oncology, Odense University Hospital, Denmark. Electronic address: lene.vestermark@syd.dk. · Department of Hepato-Pancreato-Biliary Surgery, Rikshospitalet, Oslo University Hospital, Norway. Electronic address: sphaugvik@yahoo.de. · Department of Oncology, Aarhus University Hospital, Denmark. Electronic address: mortlade@rm.dk. · Department of Oncology, Rigshospitalet, University of Copenhagen, Denmark. Electronic address: swlanger@dadlnet.dk. · Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark. Electronic address: henning.gronbaek@aarhus.rm.dk. · Department of Oncology, Helsinki University Central Hospital, Finland. Electronic address: pia.osterlund@pshp.fi. · Department of Oncology, Oslo University Hospital, Norway. Electronic address: goo@ous-hf.no. · Center for Clinical Research, Haukeland University Hospital, Bergen, Norway. Electronic address: jorg.assmus@helse-bergen.no. · Department of Pathology, MSKCC, New York, USA. Electronic address: tangl@MSKCC.ORG. · Department of Pathology, University of Bern, Switzerland. Electronic address: aurel.perren@pathology.unibe.ch. · Department of Oncology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Norway. Electronic address: Halfdan.sorbye@helse-bergen.no. ·Eur J Surg Oncol · Pubmed #28522174.

ABSTRACT: BACKGROUND: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are generally characterized by synchronous metastases, high aggressiveness and a dismal prognosis. Current international guidelines do not recommend surgical treatment of liver metastases, however the existing data are scarce. The aim of this study was to evaluate the results of curatively intended resection/radiofrequency ablation (RFA) of liver metastases in patients with metastatic GEP-NEC. METHODS: 32 patients with a diagnosis of high-grade gastroenteropancreatic neuroendocrine neoplasm (Ki-67 > 20%) and with intended curative resection/RFA of liver metastases, were identified among 840 patients from two Nordic GEP-NEC registries. Tumor morphology (well vs poor differentiation) was reassessed. Overall survival (OS) and progression-free survival (PFS) was assessed by Kaplan-Meier analyses for the entire cohort and for subgroups. RESULTS: Median OS after resection/RFA of liver metastases was 35.9 months (95%-CI: 20.6-51.3) with a five-year OS of 43%. The median PFS was 8.4 months (95%-CI: 3.9-13). Four patients (13%) were disease-free after 5 years. Two patients had well-differentiated morphology (NET G3) and 20 patients (63%) had Ki-67 ≥ 55%. A Ki-67 < 55% and receiving adjuvant chemotherapy were statistically significant factors of improved OS after liver resection/RFA. CONCLUSION: This study shows a long median and long term survival after liver surgery/RFA for these selected metastatic GEP-NEC patients, particularly for the group with a Ki-67 in the relatively lower G3 range. Our findings indicate a possible role for surgical treatment of liver metastases in the management of this patient population.

19 Article Hypo-methylation mediates chromosomal instability in pancreatic NET. 2017

Marinoni, I / Wiederkeher, A / Wiedmer, T / Pantasis, S / Di Domenico, A / Frank, R / Vassella, E / Schmitt, A / Perren, A. ·Institute of PathologyUniversity of Bern, Bern, Switzerland Ilaria.marinoni@pathology.unibe.ch. · Institute of PathologyUniversity of Bern, Bern, Switzerland. · GCB Graduate School BernBern, Switzerland. ·Endocr Relat Cancer · Pubmed #28115389.

ABSTRACT: DAXX and or ATRX loss occur in 40% of pancreatic neuroendocrine tumors (PanNETs). PanNETs negative for DAXX or ATRX show an increased risk of relapse. The tumor-associated pathways activated upon DAXX or ATRX loss and how this event may induce chromosomal instability (CIN) and alternative lengthening telomeres (ALT) are still unknown. Both DAXX and ATRX are involved in DNA methylation regulation. DNA methylation of heterochromatin and of non-coding sequences is extremely important for the maintenance of genomic stability. We analyzed the association of DAXX and/or ATRX loss and CIN with global DNA methylation in human PanNET samples and the effect of DAXX knock-down on methylation and cell proliferation. We assessed

20 Article The prognostic and predictive value of sstr 2017

Brunner, Philippe / Jörg, Ann-Catherine / Glatz, Katharina / Bubendorf, Lukas / Radojewski, Piotr / Umlauft, Maria / Marincek, Nicolas / Spanjol, Petar-Marko / Krause, Thomas / Dumont, Rebecca A / Maecke, Helmut R / Müller-Brand, Jan / Briel, Matthias / Schmitt, Anja / Perren, Aurel / Walter, Martin A. ·Institute of Pathology, University Hospital Basel, CH, Basel, Switzerland. · Institute of Nuclear Medicine, University Hospital Basel, CH, Basel, Switzerland. · Institute of Nuclear Medicine, University Hospital Bern, CH, 3010, Bern, Switzerland. · Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland. · Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, CH, Switzerland. · Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada. · Institute of Pathology, University Bern, Bern, Switzerland. · Institute of Nuclear Medicine, University Hospital Bern, CH, 3010, Bern, Switzerland. m.a.walter@gmx.net. ·Eur J Nucl Med Mol Imaging · Pubmed #27539020.

ABSTRACT: PURPOSE: Our aim was to assess the prognostic and predictive value of somatostatin receptor 2 (sstr METHODS: We established a tissue microarray and imaging database from NET patients that received sstr RESULTS: We included a total of 279 patients. In these patients, sstr CONCLUSIONS: Our results suggest sstr

21 Article mTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors. 2016

Falletta, Simona / Partelli, Stefano / Rubini, Corrado / Nann, Dominik / Doria, Andrea / Marinoni, Ilaria / Polenta, Vanessa / Di Pasquale, Carmelina / Degli Uberti, Ettore / Perren, Aurel / Falconi, Massimo / Zatelli, Maria Chiara. ·Department of Medical ScienceSection of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy. · Pancreatic Surgery UnitPancreas Translational and Research Institute, San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy. · Department of Biomedical Sciences and Public HealthPolytechnic University of Marche, Ancona, Italy. · Institut fur PathologieUniversity of Bern, Bern, Switzerland. · Department of Medical ScienceSection of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy ztlmch@unife.it. ·Endocr Relat Cancer · Pubmed #27697900.

ABSTRACT: Medical therapy of pancreatic neuroendocrine tumors (P-NET) may take advantage of Everolimus treatment. However, the extent of therapeutic response cannot be predicted. This study was aimed to identify the possible predictive markers of response to Everolimus in P-NET. We found that Everolimus reduced the cell viability and induced apoptosis in primary cultures of 6 P-NET (P-NET-R), where the proliferative and antiapoptotic effects of IGF1 were blocked by Everolimus. On the contrary, 14 P-NET primary cultures (P-NET-NR) were resistant to Everolimus and IGF1, suggesting an involvement of PI3K/AKT/mTOR pathway in the mechanism of resistance. The response to Everolimus in vitro was associated with an active AKT/mTOR pathway and seemed to be associated with a greater clinical aggressiveness. In addition, a patient sensitive to Everolimus in vitro was sensitive to this drug in vivo also and showed a positive p-AKT immunohistochemistry (IHC) at tissue level. Similarly, a patient resistant to Everolimus treatment after surgery was not sensitive to the drug in vitro and had a negative p-AKT IHC staining. Therefore, present data confirm that P-NET primary cultures may be considered a model for testing medical treatment efficacy and that IHC characterization of p-AKT might help in identifying human P-NET who can benefit from Everolimus treatment. These data encourage conducting a prospective multicenter study involving different groups of P-NET patients treated with Everolimus.

22 Article PTEN alterations of the stromal cells characterise an aggressive subpopulation of pancreatic cancer with enhanced metastatic potential. 2016

Wartenberg, Martin / Centeno, Irene / Haemmig, Stefan / Vassella, Erik / Zlobec, Inti / Galván, José A / Neuenschwander, Maja / Schlup, Cornelia / Gloor, Beat / Lugli, Alessandro / Perren, Aurel / Karamitopoulou, Eva. ·Clinical Pathology Division, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland; Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland. · Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland. · Molecular Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland. · Department of Visceral Surgery, Insel University Hospital, Freiburgstrasse 4, CH-3010, Bern, Switzerland. · Clinical Pathology Division, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland; Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland. Electronic address: eva.diamantis@pathology.unibe.ch. ·Eur J Cancer · Pubmed #27475963.

ABSTRACT: BACKGROUND: Neoplastic stroma is believed to influence tumour progression. Here, we examine phosphatase and tensin homolog deleted on chromosome ten (PTEN) status in the tumour microenvironment of pancreatic ductal adenocarcinoma (PDAC) focussing especially at the stromal cells. METHODS: We asses PTEN at protein, messenger RNA and DNA level using a well-characterised PDAC cohort (n = 117). miR-21, known to target PTEN, is assessed after RNA extraction from different laser-capture-microdissected cell populations, including cancer cells and juxta-tumoural and tumour-remote stroma. RESULTS: PTEN deletion was the most frequent cause of PTEN protein loss in PDAC cells (71%) and correlated with vascular invasion (p = 0.0176) and decreased overall survival (p = 0.0127). Concomitant PTEN protein loss in tumour and juxta-tumoural stroma, found in 21.4% of PDACs, correlated with increased distant metastasis (p = 0.0045). Stromal cells with PTEN protein loss frequently showed PTEN genetic aberrations, including hemizygous PTEN deletion (46.6%) or chromosome 10 monosomy (40%). No alterations were found in the tumour-remote stroma. miR-21 was overexpressed by cancer- and juxta-tumoural stromal cells, in some cases without simultaneous PTEN gene alterations. No PTEN mutations or promoter methylation were detected. CONCLUSIONS: We find various mechanisms of PTEN protein loss in the different tumour cell populations, including allelic PTEN deletions, gross chromosomal 10 aberrations and altered miR-21 expression. PTEN deletion is a major cause of PTEN protein loss in PDAC and correlates with aggressive characteristics and worse outcome. PTEN protein loss in juxta-tumoural stromal cells is mostly due to PTEN haplo-insufficiency and characterises a subgroup of PDACs with enhanced metastatic potential. In the tumour microenvironment of the invasive front, PTEN silencing by miR-21 in cancer and surrounding stromal cells acts not only cooperatively but also independently of the genetic aberrations to precipitate PTEN protein loss and promote further tumour growth.

23 Article Interlaboratory variability of MIB1 staining in well-differentiated pancreatic neuroendocrine tumors. 2015

Blank, Annika / Wehweck, Laura / Marinoni, Ilaria / Boos, Laura Amanda / Bergmann, Frank / Schmitt, Anja Maria / Perren, Aurel. ·University of Bern, Institute of Pathology, Murtenstr. 31, CH-3012, Bern, Switzerland. annika.blank@pathology.unibe.ch. · Department of Cardiology, Pneumology and Internal Intensive Care Medicine, Klinikum Neuperlach, Städtisches Klinikum München GmbH, Oskar-Maria-Graf-Ring 5, 83575, Munich, Germany. · University of Bern, Institute of Pathology, Murtenstr. 31, CH-3012, Bern, Switzerland. · University of Heidelberg, Institute of Pathology, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. ·Virchows Arch · Pubmed #26384025.

ABSTRACT: Neuroendocrine tumors (NET) are routinely graded and staged to judge prognosis. Proliferation index using MIB1 staining has been introduced to assess grading. There are vivid discussions on cutoff definitions, automated counting, and interobserver variability. However, no data exist regarding interlaboratory reproducibility for low proliferation indices which are of importance to discriminate between G1 and G2 NET. We performed MIB1 staining in three different university hospital-based pathology laboratories on a tissue micro array (TMA) of a well-characterized patient cohort, containing pancreatic NET of 61 patients. To calculate the proliferation index, number of positive tumor nuclei was divided by the total number of tumor nuclei. Labeling index was compared to mitotic counts in whole tissue sections and to clinical outcome. Linear regression analysis, intraclass comparison, and log-rank analysis were performed. Intraclass correlation showed moderate-to-fair agreement. Especially low proliferating tumors were affected by interlaboratory differences. Log-rank analysis was performed for each lab and resulted in three different cutoffs (5.0, 3.0, and 0.5 %). Every calculated cutoff stratified the patient cohort to a significant extent for the underlying stain (p < 0.001, <0.001, and <0.001) but showed no or lesser significance when applied to the other stains. Significant and relevant interlab differences for MIB1 exist. Since the MIB1 proliferation index influences grading, local cutoffs or external standardization should urgently be introduced to achieve reliability and reproducibility.

24 Article Expression of E-cadherin repressors SNAIL, ZEB1 and ZEB2 by tumour and stromal cells influences tumour-budding phenotype and suggests heterogeneity of stromal cells in pancreatic cancer. 2015

Galván, J A / Zlobec, I / Wartenberg, M / Lugli, A / Gloor, B / Perren, A / Karamitopoulou, E. ·Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern CH-3010, Switzerland. · 1] Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern CH-3010, Switzerland [2] Division of Clinical Pathology, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern CH-3010, Switzerland. · Department of Visceral Surgery, Insel University Hospital, Freiburgstrasse 4, CH-3010 Bern, Switzerland. ·Br J Cancer · Pubmed #25989272.

ABSTRACT: BACKGROUND: There is evidence that tumour-stroma interactions have a major role in the neoplastic progression of pancreatic ductal adenocarcinoma (PDAC). Tumour budding is thought to reflect the process of epithelial-mesenchymal transition (EMT); however, the relationship between tumour buds and EMT remains unclear. Here we characterize the tumour-budding- and stromal cells in PDAC at protein and mRNA levels concerning factors involved in EMT. METHODS: mRNA in situ hybridisation and immunostaining for E-cadherin, β-catenin, SNAIL1, ZEB1, ZEB2, N-cadherin and TWIST1 were assessed in the main tumour, tumour buds and tumour stroma on multipunch tissue microarrays from 120 well-characterised PDACs and associated with the clinicopathological features, including peritumoural (PTB) and intratumoural (ITB) budding. RESULTS: Tumour-budding cells showed increased levels of ZEB1 (P<0.0001) and ZEB2 (P=0.0119) and reduced E-cadherin and β-catenin (P<0.0001, each) compared with the main tumour. Loss of membranous β-catenin in the main tumour (P=0.0009) and tumour buds (P=0.0053), without nuclear translocation, as well as increased SNAIL1 in tumour and stromal cells (P=0.0002, each) correlated with high PTB. ZEB1 overexpression in the main tumour-budding and stromal cells was associated with high ITB (P=0.0084; 0.0250 and 0.0029, respectively) and high PTB (P=0.0005; 0.0392 and 0.0007, respectively). ZEB2 overexpression in stromal cells correlated with higher pT stage (P=0.03), lymphatic invasion (P=0.0172) and lymph node metastasis (P=0.0152). CONCLUSIONS: In the tumour microenvironment of phenotypically aggressive PDAC, tumour-budding cells express EMT hallmarks at protein and mRNA levels underlining their EMT-type character and are surrounded by stromal cells expressing high levels of the E-cadherin repressors ZEB1, ZEB2 and SNAIL1, this being strongly associated with the tumour-budding phenotype. Moreover, our findings suggest the existence of subtypes of stromal cells in PDAC with phenotypical and functional heterogeneity.

25 Article Accumulation of FOXP3+T-cells in the tumor microenvironment is associated with an epithelial-mesenchymal-transition-type tumor budding phenotype and is an independent prognostic factor in surgically resected pancreatic ductal adenocarcinoma. 2015

Wartenberg, Martin / Zlobec, Inti / Perren, Aurel / Koelzer, Viktor Hendrik / Gloor, Beat / Lugli, Alessandro / Karamitopoulou, Eva. ·Clinical Pathology Division, University of Bern, Bern, CH-3010, Switzerland. · Translational Research Unit, Institute of Pathology, University of Bern, Bern, CH-3010, Switzerland. · Department of Visceral Surgery, Insel University Hospital, Bern, CH-3010, Switzerland. ·Oncotarget · Pubmed #25669968.

ABSTRACT: Here we explore the role of the interplay between host immune response and epithelial-mesenchymal-transition (EMT)-Type tumor-budding on the outcome of pancreatic adenocarcinoma (PDAC). CD4+, CD8+, and FOXP3+T-cells as well as iNOS+ (M1) and CD163+-macrophages (M2) were assessed on multipunch tissue-microarrays containing 120 well-characterized PDACs, precursor lesions (PanINs) and corresponding normal tissue. Counts were normalized for the percentage of tumor/spot and associated with the clinico-pathological features, including peritumoral (PTB) and intratumoral (ITB) EMT-Type tumor-budding and outcome. Increased FOXP3+T-cell-counts and CD163-macrophages and decreased CD8+T-cell-counts were observed in PDACs compared with normal tissues and PanINs (p < 0.0001). Increased peritumoral FOXP3+T-cell-counts correlated significantly with venous invasion, distant metastasis, R1-status, high-grade ITB, PTB and independently with reduced survival. Increased intratumoral FOXP3+T-cells correlated with lymphatic invasion, N1-stage, PTB and marginally with adverse outcome. High peritumoral CD163-counts correlated with venous invasion, PTB and ITB. High intratumoral CD163-counts correlated with higher T-stage and PTB. PDAC-microenvironment displays a tumor-favoring immune-cell composition especially in the immediate environment of the tumor-buds that promotes further growth and indicates a close interaction of the immune response with the EMT-process. Increased peritumoral FOXP3+T-cell density is identified as an independent adverse prognostic factor in PDAC. Patients with phenotypically aggressive PDACs may profit from targeted immunotherapy against FOXP3.

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