Andreas Raffel

Universitätsklinikum Düsseldorf, Düsseldorf, North Rhine-Westphalia, Germany

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Publications (74)163.06 Total impact

  • W T Knoefel, A Raffel
    DMW - Deutsche Medizinische Wochenschrift 04/2011; 136(17):896. · 0.65 Impact Factor
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    ABSTRACT: Currently, no effective treatment for malignant pheochromocytoma exists. The aim of our study was to investigate the role of chromogranin A (CgA) as a specific target molecule for immunotherapy in a murine model for pheochromocytoma. Six amino acid-modified and non-modified CgA peptides were used for dendritic cell vaccination. Altogether, 50 mice received two different CgA vaccination protocols; another 20 animals served as controls. In vitro tetramer analyses revealed large increases of CgA-specific cytotoxic T cells (CTL) in CgA-treated mice. Tumors of exogenous applied pheochromocytoma cells showed an extensive infiltration by CD8+ T cells. In vitro, CTL of CgA-treated mice exhibited strong MHC I restricted lysis capacities towards pheochromocytoma cells. Importantly, these mice showed strongly diminished outgrowth of liver tumors of applied pheochromocytoma cells. Our data clearly demonstrate that CgA peptide-based immunotherapy induces a cytotoxic immune response in experimental pheochromocytoma, indicating potential for therapeutic applications in patients with malignant pheochromocytoma.
    Molecular and Cellular Endocrinology 03/2011; 335(1):69-77. · 4.04 Impact Factor
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    ABSTRACT: Lymphatic infiltration is a well known phenomenon in different tumors including endocrine malignancies. However, little is known about the role of antigen-presenting cells and T cell activation in this context. The aim of our study was to investigate the quantity and function of CD14+/CD56+ monocytes in tumor patients including endocrine malignancies. First, these cells were characterized in peripheral blood of endocrine and non-endocrine cancer patients as well as in tumor tissue samples. Cancer patients had in mean 3.7 times more CD14+/CD56+ monocytes in the peripheral blood compared to healthy controls (p≤0.0001), while the highest frequencies were seen in patients with heavy tumor load. Importantly, these cells additionally expressed several NK cell markers. A proof of CD14+/CD56+ infiltrations into papillary thyroid carcinoma was shown by immunohistochemical analyses. Functional analyses revealed an apoptosis inducing capacity in vitro after IFN-α re-stimulation. Our data indicate the importance of tumor-lysing monocytes in antitumor immunity.
    Molecular and Cellular Endocrinology 02/2011; 337(1-2):52-61. · 4.04 Impact Factor
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    ABSTRACT: Neuroendokrine Neoplasien (NEN) sind eine morphologisch homogen erscheinende, biologisch und klinisch jedoch sehr heterogene Tumorgruppe. NEN können in jedem inneren Organ auftreten, am häufigsten sind sie jedoch in der Lunge und im gastroenteropankreatischen (GEP) System. Um die Diagnostik und Klassifikation der GEP-NEN zu vereinheitlichen und zu verbessern, wurden durch die European Neuroendocrine Tumor Society (ENETS) in den letzten 5 Jahren Leitlinien erarbeitet. Unter Berücksichtigung dieser Leitlinien wurde 2009 die TNM-Klassifikation der Union for International Cancer Control (UICC) vorgestellt. 2010 schließlich folgte eine neue Klassifikation der GEP-NEN durch die Weltgesundheitsorganisation (WHO). Diese Übersicht fasst die neue Klassifikation und morphologische Diagnostik der GEP-NEN zusammen. Auf dieser Basis ist eine ausgezeichnete Prognoseeinsschätzung der GEP-NEN möglich. Sie bestimmt die Auswahl der Bildgebung und der Behandlungsoptionen und sichert außerdem die Vergleichbarkeit von größeren Tumorkollektiven.
    Der Onkologe 01/2011; 17(7). · 0.13 Impact Factor
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    ABSTRACT: In den letzten 5Jahren wurden durch die European Neuroendocrine Tumor Society (ENETS) grundlegende Empfehlungen für eine standardisierte Pathologiediagnostik und Klassifikation neuroendokriner Neoplasien (NEN) des gastroenteropankreatischen Systems erarbeitet. Diese haben Eingang gefunden in die neue Klassifikation der Tumoren des Verdauungstraktes durch die Weltgesundheitsorganisation (WHO 2010) und teilweise auch in die TNM-Klassifikation der Union for International Cancer Control (UICC 2009). In dieser Übersicht wird die empfohlene Diagnostik hinsichtlich (1) Basisdiagnostik, (2) optionaler klinisch orientierter Diagnostik, (3) proliferationsbasiertem Grading, (4) Nomenklatur und (5) TNM-Klassifikation vorgestellt. Es wird auf die Notwendigkeit der standardisierten Pathologiediagnostik von NEN, erhoben am Biopsat oder Operationspräparat, in Zusammenschau mit den klinisch-bildgebenden Befunden für die optimale Einschätzung der Prognose und die Auswahl tumorspezifischer Behandlungsschemata hingewiesen. Eine enge interdisziplinäre Zusammenarbeit ist hierfür die Voraussetzung. During the last 5 years the European Neuroendocrine Tumor Society (ENETS) has developed basic recommendations for a standardized pathological diagnosis and classification of neuroendocrine neoplasms (NEN) of the gastroenteropancreatic system. These were included in the novel classification of tumors of the digestive system by the World Health Organization (WHO 2010) and the TNM classification of the union for international cancer control (2009). This review presents the pathology diagnosis regarding (1) basic diagnosis, (2) clinically relevant optional diagnosis, (3) proliferation-based grading, (4) nomenclature and (5) TNM classification. It is emphasized that a standardized diagnosis of NEN, together with clinical and radiological findings, is crucial for prognostic stratification and optimal therapy of patients with NEN. Therefore a close interdisciplinary collaboration is essential. SchlüsselwörterNeuroendokrine Tumoren–Pathologie–Grading–Klassifikation–Proliferation KeywordsNeuroendocrine tumors–Pathology–Grading–Classification–Proliferation
    Der Chirurg 01/2011; 82(7):567-573. · 0.52 Impact Factor
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    ABSTRACT: Pancreatic islet cell tumors (ICTs) occur as sporadic neoplasias or as a manifestation of multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau disease (VHL). Molecular classification of ICTs is mandatory for timely diagnosis and surveillance. Systematic comparison of VHL-ICTs and sporadic ICTs has been lacking. Our registry-based approaches used the German NET-Registry with 259 patients with neuroendocrine tumors (NETs), who were primarily diagnosed with NETs, and the German VHL-Registry with 485 molecular genetically confirmed patients who had undergone magnetic resonance imaging or computed tomography of the abdomen. All patients provided blood DNA for testing of the MEN1 and VHL genes for intragenic mutations and large deletions. In the NET-Registry, 9/101 patients (8.9%) with ICTs had germline mutations, 8 in MEN1 and 1 in VHL. In the VHL-Registry, prevalence of NETs was 52/487 (10.6%), and all were ICTs. Interestingly, of those with VHL p.R167W, 47% developed ICTs, compared to 2% of those with p.Y98H. In total, there were 92 truly sporadic, i.e. mutation-negative ICT patients. Comparing these with the 53 VHL-ICT patients, the statistically significant differences were predominance of female gender (P=0.01), multifocal ICTs (P=0.0029), and lower malignancy rate (P<0.001) in VHL-ICTs compared to sporadic cases. VHL was prevalent in <0.5% of NETs, while NETs occur in ∼10% of VHL, virtually exclusively as ICTs, which are rarely the first presentation. Patients with NETs should not be subjected to genetic testing of the VHL gene, unless they have multifocal ICTs, other VHL-associated tumors, and/or a family history for VHL.
    Endocrine Related Cancer 12/2010; 17(4):875-83. · 5.26 Impact Factor
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    ABSTRACT: Rectovaginal fistuale (RVF) are a serious and disabling problem for the patients and a surgical challenge for the treating physicians. The most common causes of RVF are postoperative complications, inflammatory bowel disease, complications of radiotherapy, obstetric complications, and neoplasia. Therapeutic options are diverse and results often unsatisfactory. This article presents the treatment of patients with rectovaginal fistulae in the general surgery department of University Hospital in Duesseldorf, Germany. The therapeutic strategy for treatment of RVF is divided according to aetiology, localisation, and comorbidity. A diverting ileostomy is particularly useful if acute inflammation exists. Secondary repair may then be a better option. An initial approach with a local repair by preanal repair is justified in low RVF. For failures muscle flaps are promising.
    Zentralblatt für Chirurgie 08/2010; 135(4):307-11. · 0.69 Impact Factor
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    ABSTRACT: EpCAM (CD326) is overexpressed in progenitor cells of endocrine pancreatic islands of Langerhans during fetal development and was suggested to act as a morphoregulatory molecule in pancreatic island ontogeny. We tested whether EpCAM overexpression is reactivated in insulinomas, endocrine tumors arising in the pancreas. We used monoclonal anti-EpCAM antibody Ber-Ep4 for immunohistochemistry on formalin-fixed and paraffin-embedded tumor material. We analyzed 53 insulinomas: 40 benign (disease stage<IIa) and 13 malignant tumors (disease stage IIIb/IV). Disease stage disposition followed new TNM classification of the European Neuroendocrine Tumor Society (ENETS) for foregut neuroendocrine tumors (2006). Additionally, ten insulinoma metastases were analyzed. Clinical follow-up was available for overall survival analysis from 49 patients. The EpCAM expression of the islands of Langerhans was classified as 2+ in healthy pancreatic tissue. In 38% of the benign insulinomas (disease stage<IIa), we found strong (3+) EpCAM expression. In contrast, malignant insulinomas (disease stage IIIb/IV) and their metastases exhibited a strong (3+) EpCAM expression with 78 and 80% respectively, significantly more frequent (P<0.01). The malignant tissue was characterized by a significantly lower number of unstained cells and significantly higher number of 3+ stained cells. Quantitative PCR for EpCAM mRNA validated strong EpCAM expression in malignant insulinoma. Kaplan-Meier curves indicated survival disadvantage for EpCAM 3+ insulinomas, but this was not statistically significant (log-rank test). This first EpCAM expression study in benign/malignant insulinomas indicates that strong EpCAM expression could help to identify patients at risk for malignant disease and might be used as a therapeutic target for antibody-based therapies in patients with metastatic insulinoma.
    European Journal of Endocrinology 02/2010; 162(2):391-8. · 3.14 Impact Factor
  • Zentralblatt Fur Chirurgie - ZBL CHIR. 01/2010; 135(04):307-311.
  • Zentralblatt für Chirurgie 01/2010; 48(08). · 0.69 Impact Factor
  • Zeitschrift Fur Gastroenterologie - Z GASTROENTEROL. 01/2010; 48(08).
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    ABSTRACT: ZusammenfassungNeuroendokrine Tumoren des gastroenteropankreatischen Systems (GEP-NET) sind charakterisiert durch die Expression neuroendokriner Marker sowie die Synthese, Speicherung und Sekretion von Peptidhormonen und/ oder biogenen Aminen. Es handelt sich um mehr als 50 unterschiedliche Tumorentitäten mit klinisch sehr unterschiedlichem Verlauf. Sie können sporadisch oder familiär auftreten. Die hohe biologische und klinische Vielfalt äußert sich in unterschiedlichen genetischen Profilen auf DNA- und mRNA-Ebene, welche wie folgt zusammengefasst werden können: 1. NET unterscheiden sich genetisch von den häufigen nichtneuroendokrinen Karzinomen des Verdauungstraktes. 2. Die klinisch-pathologische Heterogenität der GEP-NET spiegelt sich auch auf genetischer Ebene wider. 3. Bei pankreatischen NET finden sich deutliche genetische Unterschiede zwischen Insulinomen und anderen Entitäten. 4. Die Tumorprogression geht bei pankreatischen NET mit einer Zunahme von genetischen Veränderungen einher. 5. Pankreatische NET unterscheiden sich genetisch von gastrointestinalen NET. 6. Sporadische GEP-NET unterscheiden sich genetisch von hereditären (familiären) GEP-NET.
    Viszeralmedizin. 01/2010; 26:283-288.
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    ABSTRACT: Obstructive jaundice caused by an intraductal hepatocellular carcinoma is a rare initial symptom. We report a rare case of an extrahepatic icteric type hepatocellular carcinoma. A 75-year-old patient was admitted to our hospital because of obstructive jaundice 3 months after resection of multilocular hepatocellular carcinoma. A postoperative bile leakage was treated by placement of a decompressing stent in the common bile duct. Endoscopic retrograde choledochoscopy showed extended blood clots filling the bile duct system and computed tomography revealed a local swelling in the common extrahepatic bile duct. The level of alpha-fetoprotein (AFP) was only slightly elevated but that of CA19-9 was dramatically increased. Cholangiography showed an intraductal filling defect typical of a cholangiocellular carcinoma. Bile duct brushing cytology showed no cholangiocellular carcinoma but hepatocellular carcinoma cells in the extrahepatic bile duct. An extrahepatic bile duct resection was performed. Histological examination confirmed the diagnosis of extrahepatic intraductal growth of hepatocellular carcinoma. Ectopic hepatocellular carcinoma is a rare but important differentially diagnosed of extrahepatic bile duct filling defect.
    Hepatobiliary & pancreatic diseases international: HBPD INT 12/2009; 8(6):650-2. · 1.26 Impact Factor
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    ABSTRACT: Vascular leiomyosarcoma are rare tumors typically originating from the inferior vena cava (IVC). Due to nonspecific clinical signs most tumors are diagnosed at advanced stages. Complete surgical resection remains the only potential curative therapeutic option. Surgical strategy is particularly influenced by the level of the IVC affected. Due to the topographic relation to the renal veins level-II involvement of the IVC raises special surgical challenges with respect to the maintenance of venous outflow. We herein report two cases of leiomyosarcoma of the IVC with successful en bloc resection and individualized caval reconstruction. One patient presented with a large intramural and intraluminal mass and received a complete circumferential resection. Reconstruction was performed by graft replacement of the caval segment affected. The other patient displayed a predominantly extraluminal tumor growth and underwent semicircumferential resection of the IVC including the confluence of the left renal vein. In this case vascular reconstruction was performed by cavoplasty and reinsertion of the left renal vein into the proximal portion of the IVC. Resection margins of both patients were tumor free and no clinical signs of venous insufficiency of the lower extremity occurred. This paper presents two cases of successfully managed leiomyosarcomas of the vena cava and exemplifies two different options for vascular reconstruction in level II sarcomas and includes a thorough review of the literature.
    World Journal of Surgical Oncology 07/2009; 7:56. · 1.09 Impact Factor
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    ABSTRACT: Cholangiocarcinoma (CC), the most common biliary tract malignancy, is frequently seen in advanced unresectable stages and is typically localized extrahepatically. Early diagnosis is unusual because of nonspecific symptoms. Painless jaundice is usually the first sign of tumor. We present a patient with a CC (Klatskin tumor) with a complete biliary drainage by an aberrant bile duct without jaundice. A 67-year-old woman presented with persisting elevation of liver parameters. Diagnostic tests showed a Klatskin tumor type II. A curative right hepatic trisegmentectomy was performed after liver volume augmentation by preoperative vein embolization. A direct drainage of the right posterior bile duct into the common bile duct as an aberrant hepatic duct is a rare variation and is present in less than 5% of the population. In case of persistently perturbed liver function tests, an aberrant bile duct can cover up severe intrahepatic cholestasis and even obscure the diagnosis of a Klatskin tumor. Up to now it has not been described in the literature.
    Hepatobiliary & pancreatic diseases international: HBPD INT 03/2009; 8(1):103-5. · 1.26 Impact Factor
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    ABSTRACT: Fistulae between an ileal pouch and the vagina are an uncommon complication of ileal pouch-anal anastomosis following proctocolectomy and mucosectomy in patients with familial adenomatous polyposis coli. Several reports describe the successful use of muscle flaps to close recurrent pouch-vaginal-fistulae (PVF). However, series only contain small numbers and an optimal management has not yet been determined. We report the case of a 26-year old woman with a third recurrence of a PVF after proctocolectomy for treatment of familial adenomatous polyposis in October 2005. Because local approaches failed, definitive closure of the fistula was achieved by interposition of a gracilis muscle flap between the pouch-anal anastomosis and the vagina. The postoperative course was uneventful; the patient was discharged 7 days after surgery and remained free of recurrence and symptomatic complaints for 22 months now. The gracilis muscle flap proved to be an effective method in the treatment of recurrent PVF.
    Case Reports in Medicine 02/2009; 2009:676392.
  • Zentralblatt Fur Chirurgie - ZBL CHIR. 01/2009; 134(04).
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    ABSTRACT: Multicentric insulinoma disease was characterized with regard to its histopathology, multiple endocrine neoplasia type 1 (MEN1) status, precursor lesions, and the risk of hyperinsulinemic hypoglycemia recurrence. Fourteen patients with multicentric insulinoma disease were compared with 267 patients with sporadic and familial insulinomas. The tumors were classified according to the World Health Organization (WHO) criteria. The MEN1 status was defined clinically and by germline mutation analysis. Detection of the MEN1 gene locus was performed using fluorescence in situ hybridization. The surgical interventions and the duration of disease-free survival were recorded. Fourteen patients (5%) without evidence of MEN1 showed 53 macrotumors and 285 microtumors expressing exclusively insulin. In addition, they had small proliferative insulin-expressing monohormonal endocrine cell clusters (IMECCs). No allelic loss of the MEN1 locus was detected in 64 tumors. All but one patient had benign disease. Recurrent hypoglycemia occurred in 6/14 patients (11 recurrences; mean time to relapse 8.4 y). Thirteen patients with MEN1 (4.6%) showed 41 insulinomas and 133 tumors expressing islet hormones other than insulin. IMECCs were not detected. Allelic loss of the MEN1 locus was found in 17/19 insulinomas. Recurrent hypoglycemia occurred in 4/13 patients (4 recurrences; mean time to relapse 14.5 y). Solitary insulinomas were found in 254/281 patients (90.4%). IMECCs were absent. There was no recurrent hypoglycemia in 84 patients with benign insulinomas. Insulinomatosis is characterized by the synchronous and metachronous occurrence of insulinomas, multiple insulinoma precursor lesions, and rare development of metastases, but common recurrent hypoglycemia. This disease differs from solitary sporadic and MEN1-associated insulinomas.
    The American journal of surgical pathology 12/2008; 33(3):339-46. · 4.06 Impact Factor
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    ABSTRACT: Endothelial cells have been shown to induce adrenal steroidogenesis and to enhance aldosterone secretion via angiotensin II and endothelin 1-independent mechanisms. It has been demonstrated that endothelial cells and adrenocortical cells are capable of producing interleukin-6 (IL-6) and IL-6 is a factor known to stimulate adrenal cortisol secretion. We therefore asked whether endothelial cells have an effect on adrenal IL-6 generation and whether IL-6 mediates biosynthesis of aldosterone as is observed after exposure of adrenocortical cells to endothelial cell-conditioned medium (ECCM). Cells from the adrenocortical cancer cell line NCI-H295R were incubated with ECCM produced from human umbilical vein endothelial cells at increasing concentrations. As detected by an enzyme-linked immunosorbent assay, pure ECCM significantly increased IL-6 protein secretion by cultured adrenocortical cells in a dose-dependent fashion, to a 18.0+/-2.0 pg/mL (mean+/-SEM). This was paralleled by an enhanced IL-6 promoter activity as determined with the transfection of an IL-6-promoter-luciferase reporter gene construct. Pure ECCM also induced aldosterone secretion by adrenocortical cells more than three times that of controls with serum-free medium. ECCM PER SE contains significant amounts of IL-6 protein. However, blockade of IL-6 signal transduction did not interfere with aldosterone synthesis. These data suggest that endothelial cells secrete IL-6 and that endothelial cell-derived factors regulate adrenal IL-6 synthesis which does not alter adrenal aldosterone secretion. Our findings support the hypothesis that the endothelium and the adrenal gland may play a role in the development of some forms of hypertension and - more speculative - inflammation.
    Experimental and Clinical Endocrinology & Diabetes 09/2008; 116 Suppl 1:S70-4. · 1.56 Impact Factor
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    ABSTRACT: Somatostatin-producing neuroendocrine tumors (SOM-NETs) of the duodenum and pancreas appear to be heterogeneous. To determine their clinicopathological profiles, respective data were analyzed on a series of 82 duodenal and 541 pancreatic NETs. In addition, the clinical records of 821 patients with duodenal or pancreatic NETs were reviewed for evidence of a somatostatinoma syndrome. Predominant or exclusive expression of somatostatin was found in 21 (26%) duodenal and 21 (4%) pancreatic NETs. They were classified as sporadic (n=31) or neurofibromatosis type 1 (NF1)-associated duodenal NETs (n=3), gangliocytic paragangliomas (GCPGs; n=6), or poorly differentiated neuroendocrine carcinomas (pdNECs; n=2). In addition, five duodenal and four pancreatic SOM-NETs were found in five patients with multiple endocrine neoplasia type 1 (MEN1). Metastases occurred in 13 (43%) patients with sporadic or NF1-associated SOM-NETs, but in none of the duodenal or pancreatic MEN1-associated SOM-NETs or GCPGs. Sporadic advanced (stage IV) SOM-NETs were more commonly detected in the pancreas than in the duodenum. None of the patients (including the 821 patients for whom only the clinical records were reviewed) fulfilled the criteria of a somatostatinoma syndrome. Our data show that somatostatin expression is not only seen in sporadic NETs but may also occur in GCPGs, pdNECs, and hereditary NETs. Surgical treatment is effective in most duodenal and many pancreatic SOM-NETs. MEN1-associated SOM-NETs and GCPGs follow a benign course, while somatostatin-producing pdNECs are aggressive neoplasms. The occurrence of the so-called somatostatinoma syndrome appears to be extremely uncommon.
    Endocrine Related Cancer 04/2008; 15(1):229-41. · 5.26 Impact Factor

Publication Stats

540 Citations
163.06 Total Impact Points

Institutions

  • 2004–2013
    • Universitätsklinikum Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2001–2013
    • Heinrich-Heine-Universität Düsseldorf
      • • Institut für Neuropathologie
      • • Klinik für Unfall- und Handchirurgie
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2005–2008
    • Christian-Albrechts-Universität zu Kiel
      Kiel, Schleswig-Holstein, Germany
  • 2007
    • University of Zurich
      Zürich, Zurich, Switzerland