A Raffel

Heinrich-Heine-Universität Düsseldorf, Düsseldorf, North Rhine-Westphalia, Germany

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Publications (79)187.38 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Here we tested whether global histone modifications predict survival in organic hyperinsulinism and whether global histone modification pattern can be used to distinguish benign from malignant primary insulinoma. A tissue microarray (TMA) was built, using samples from 63 patients with organic hyperinsulinism. The TMA was classified according to the WHO classification of 2004 [WHO 1A: benign insulinoma (wdPET); WHO 1B: unknown behavior (wdPETub); WHO 2/3: malignant insulinoma (wdPEC/pdPEC)]. The TMA consisted of tissue cores from islands of Langerhans, primary insulinomas, lymph node metastases, and hepatic metastases. Immunohistochemistry was performed on consecutive TMA slides with antibodies against H3K9Ac, H3K18Ac, H4K12Ac, H3K4diMe, and H4R3diMe. The Remmele immunoreactive scoring system was used to classify the staining. The IHC staining results were correlated to the WHO-classification of 2004 as well as to clinical follow-up data (mean: 107 months; range: 1-312 months). A nuclear staining pattern was observed for all antibodies directed against histone H3 and H4 acetylation/methylation sites. We observed significant differences in the distribution of the medians across all investigated tissue types (H3K9Ac, p=0.004; H3K18Ac, p=0.001; H4K12Ac, p=0.006; H4R3diMe, p=0.002) except for H3K4diMe (p=0.183). Correlation of the histone modification with the WHO-classification and clinical follow-up data, showed in the dichotomized groups ["low" (score 0-3), "moderate" (4-7) vs. "high" (≥8)] that patients with lower H3K18Ac levels ("low + moderate") had a significantly decreased relapse-free survival vs. patients with high H3K18Ac levels (p=0.038). The WHO classification and age were also of significant prognostic impact upon univariate analysis. A backwards Cox proportional hazards model revealed the independent prognostic effekt of H3K18Ac levels. Our data revealed low K18 acetylation levels of histone H3 as independent prognostic factor in organic hyperinsulinism. This result warrants validation with independent data sets of organic hyperinsulinism, but is in line with several previous studies in different cancer entities. The broad applicability of this potential biomarker might lead to standardized diagnostic tests in near future and may help to manage insulinoma patients more effectively.
    Hormone and Metabolic Research 11/2011; 43(12):858-64. DOI:10.1055/s-0031-1291271 · 2.04 Impact Factor
  • Zentralblatt für Chirurgie 10/2011; 136(05). DOI:10.1055/s-0031-1289055 · 1.19 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2011; 49(08). DOI:10.1055/s-0031-1285214 · 1.67 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 07/2011; 17(7). DOI:10.1007/s00761-011-2052-6 · 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 07/2011; 82(7):567-573. DOI:10.1007/s00104-011-2067-y · 0.52 Impact Factor
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    ABSTRACT: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are complex tumors whose incidence is rising and whose treatment requires precise classification and risk stratification. Selective review of the relevant literature, including recently published guidelines. GEP-NENs are initially classified by their degree of histological differentiation and their graded cell proliferation (Ki-67 index). In addition, there are GEP-NEN specific TNM staging protocols. The laboratory assessment includes the measurement of general tumor markers (synaptophysin, chromogranin A) as well as specific ones (hormones). The most important imaging technique for diagnosis is octreotide scintigraphy. The surgical treatment of GEP-NEN is based on oncological resection criteria whose aim is to achieve locally radical resection while preserving as much organ function as possible. Metastases, too, may be amenable to resection. The treatment options for unresectable metastases include radiofrequency ablation and chemoembolization, both of which are palliative methods of reducing tumor volume and hormone production. Other chemotherapeutic and nuclear-medical treatments can be applied depending on the extent of metastatic spread, the proliferation index, and the degree of hormone production by the tumor. The accurate diagnosis and appropriate treatment of GEP-NET currently gives most patients with this tumor a good prognosis, as long as it is discovered early. Early GEP-NETs have a favorable prognosis. Further advances in the diagnosis and treatment of this disease may result from structural changes in patient care, including the establishment of NET centers.
    Deutsches Ärzteblatt International 05/2011; 108(18):305-12. DOI:10.3238/arztebl.2011.0305 · 3.61 Impact Factor
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    ABSTRACT: 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.
    Der Chirurg 04/2011; 82(7):567-73. · 0.52 Impact Factor
  • W T Knoefel, A Raffel
    DMW - Deutsche Medizinische Wochenschrift 04/2011; 136(17):896. DOI:10.1055/s-0031-1275824 · 0.55 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. DOI:10.1016/j.mce.2010.05.021 · 4.24 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. DOI:10.1016/j.mce.2011.01.020 · 4.24 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. DOI:10.1677/ERC-10-0037 · 4.91 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. · 1.19 Impact Factor
  • Zentralblatt für Chirurgie 08/2010; 135(04):307-311. DOI:10.1055/s-0030-1247475 · 1.19 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2010; 48(08). DOI:10.1055/s-0030-1263401 · 1.67 Impact Factor
  • Zentralblatt für Chirurgie 08/2010; 48(08). DOI:10.1055/s-0030-1264027 · 1.19 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. DOI:10.1530/EJE-08-0916 · 3.69 Impact Factor
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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 / Visceral Medicine 01/2010; 26:283-288. DOI:10.1159/000322151 · 0.10 Impact Factor
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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. · 1.17 Impact Factor
  • Zentralblatt für Chirurgie 08/2009; 134(04). DOI:10.1055/s-0029-1238109 · 1.19 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. DOI:10.1186/1477-7819-7-56 · 1.20 Impact Factor

Publication Stats

735 Citations
187.38 Total Impact Points

Institutions

  • 2001–2013
    • Heinrich-Heine-Universität Düsseldorf
      • • Institute of Metabolic Physiology
      • • Department of Trauma and Hand Surgery
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2004–2012
    • Universitätsklinikum Düsseldorf
      • • Endocrine Cancer Centre
      • • Klinik für Allgemein-, Viszeral- und Kinderchirurgie
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2005–2008
    • Christian-Albrechts-Universität zu Kiel
      Kiel, Schleswig-Holstein, Germany
  • 2007
    • Philipps University of Marburg
      Marburg, Hesse, Germany