Stefan Gattenlöhner

Universitätsklinikum Gießen und Marburg, Marburg, Hesse, Germany

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Publications (118)520.74 Total impact

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    ABSTRACT: Typical Burkitt lymphoma is characterized by an IG-MYC translocation and overall low genomic complexity. Clinically, Burkitt lymphoma has a favourable prognosis with very few relapses. However, the few patients experiencing disease progression and/or relapse have a dismal outcome. Here we report cytogenetic findings of seven cases of Burkitt lymphoma in which sequential karyotyping was performed at time of diagnosis and/or disease progression/relapse(s). After case selection, karyotype re-review and additional molecular analyses were performed in six paediatric cases, treated in Berlin-Frankfurt-Münster-Non-Hodgkin lymphoma study group trials, and one additional adult patient. Moreover, we analysed 18 cases of Burkitt lymphoma from the Mitelman database in which sequential karyotyping was performed. Our findings show secondary karyotypes to have a significant increase in load of cytogenetic aberrations with a mean number of 2, 5 and 8 aberrations for primary, secondary and third investigations. Importantly, this increase in karyotype complexity seemed to result from recurrent secondary chromosomal changes involving mainly trisomy 21, gains of 1q and 7q, losses of 6q, 11q, 13q, and 17p. In addition, our findings indicate a linear clonal evolution to be the predominant manner of cytogenetic evolution. Our data may provide a biological framework for the dismal outcome of progressive and relapsing Burkitt lymphoma. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 06/2015; DOI:10.1111/bjh.13501 · 4.96 Impact Factor
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    ABSTRACT: Phage display is an effective method for the generation of target-specific human antibodies. Standard phage display panning use purified proteins, antigen-transfected cells or tumor cell lines as target structure to generate specific antibodies. However, recombinant proteins can be difficult to express and purify in their native conformation and suitable cell lines are not always available. Additionally the antigen expression profile may change during cultivation and thus differ from the malignant cells in patient. Here we describe a method for the selection of specific antibodies from phage display libraries by panning against formalin-fixed paraffin-embedded (FFPE) tissue biopsies immobilized on glass slides, using small cell lung cancer (SCLC) as a case study. The human Tomlinson single-chain variable fragment (scFv) phage libraries I and J were panned against SCLC FFPE tissue slides for positive selection and healthy lung tissue for subtraction. The specificity of the selected scFv antibodies was confirmed in vitro by ELISA on immobilized SCLC cell membranes, by flow cytometry using the SCLC cell lines NCI-H69, NCI-H82 and DMS 273, and ex vivo against tissue microarrays containing 35 different SCLC samples and 20 types of normal organs. We monitored the internalization of three selected scFv antibodies and fused them with Pseudomonas exotoxin A (ETA') to produce immunotoxins whose cytotoxicity was confirmed by cell viability and apoptosis assays on different SCLC cell lines, achieving IC50 values of up to 23nM. The selection of SCLC-specific scFv antibodies by panning against FFPE tissue slides circumvents the challenges of using purified antigens or cell lines for antibody selection. Copyright © 2015. Published by Elsevier B.V.
    Immunology letters 06/2015; 166(2). DOI:10.1016/j.imlet.2015.05.013 · 2.37 Impact Factor
  • 06/2015; 5(2):485-504. DOI:10.3390/biom5020485
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    ABSTRACT: History and clinical findings: A 77 year old female patient was admitted for the evaluation of hyponatremia and a generalized papulous exanthema with severe pruritus. Investigations and diagnosis: The syndrome of inappropriate antidiuretic hormone secretion (SIADH) could be diagnosed as cause for hyponatremia. Biopsy of a soft tissue tumor revealed a T-cell lymphoma with widespread skelettal dissemination. Treatment and course: Chemotherapy caused a rapid response and improvement of general well-being. SIADH could be controlled by the specific vasopressin-2-receptor antagonist tolvaptan. Conclusions: In this patient, both the papulous exanthema and the SIADH are regarded as T-cell-lymphoma-associated paraneoplastic syndromes. © Georg Thieme Verlag KG Stuttgart · New York.
    DMW - Deutsche Medizinische Wochenschrift 06/2015; 140(13):997-1000. DOI:10.1055/s-0041-102667 · 0.55 Impact Factor
  • A Brobeil · T Dreyer · R Schäffer · A Bräuninger · S Gattenlöhner
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    ABSTRACT: Neuroendokrine Tumoren des oberen Respirationstrakts sind insgesamt sehr selten. Zu unterscheiden sind das typische und das atypisches Karzinoid sowie das kleinzellige neuroendokrine Karzinom. Neuere Daten sprechen in Analogie zum bronchopulmonalen System für die Existenz eines großzelligen neuroendokrinen Karzinoms im Kopf-Hals-Bereich und für die Existenz eines kleinzelligen neuroendokrinen Karzinoms des Oropharynx mit Papillomavirusassoziation. Eine Reihe von Argumenten, die sich auf klinische und genetischen Daten stützt, spricht weiterhin dafür, dass Karzinoide und die schlecht differenzierten neuroendokrinen Karzinome sich nicht nur im Differenzierungsgrad unterscheiden, sondern dass es sich hierbei um grundverschiedene Tumorformen handelt. Abstract Epithelial neuroendocrine tumors of the upper respiratory tract are rare and are classified as typical and atypical carcinoid versus small cell neuroendocrine carcinoma. Furthermore, a giant cell variant of neuroendocrine carcinoma is suggested corresponding to the bronchopulmonary system as well as a recently described subtype of oropharyngeal small cell neuroendocrine carcinoma associated with human papillomavirus. Many arguments relying on clinical as well as on molecular findings indicate that the distinction between carcinoid and poorly differentiated neuroendocrine carcinoma does not only reflect different degrees of differentiation of otherwise related tumors but indicates the existence of substantially different types of neoplasms.
    Der Pathologe 05/2015; DOI:10.1007/s00292-015-0031-1 · 0.64 Impact Factor
  • Oral Oncology 05/2015; 51(5):e40. DOI:10.1016/j.oraloncology.2015.02.042 · 3.03 Impact Factor
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    ABSTRACT: Fetal human platelet antigen (HPA) genotyping is required to determine whether the fetus is at risk and whether prenatal interventions to prevent fetal bleeding are required in pregnant women with a history of fetal and neonatal alloimmune thrombocytopenia (FNAIT). Methods for noninvasive genotyping of HPA alleles with the use of maternal plasma cell-free DNA were published recently but do lack internal controls to exclude false-negative results. Cell-free DNA was isolated from plasma of four pregnant women with a history of FNAIT caused by anti-HPA-1a and controls. A primer panel was designed to target sequences flanking single-nucleotide polymorphisms (SNPs)/exonic regions of ITGB3 (HPA-1), ITGA2B (HPA-3), ITGA2 (HPA-5), CD109 (HPA-15), RHD, RHCE, KEL, DARC, SLC14A1, GYPA, GYPB, and SRY. These regions and eight anonymous SNPs were massively parallel sequenced by semiconductor technology. The mean (±SD) number of reads for targeted SNPs was 5255 (±2838). Fetal DNA was detected at a median of 4.5 (range, 2-8) polymorphic loci. The mean fractional fetal DNA concentration in cell-free maternal plasma was 8.36% (range, 4.79%-15.9%). For HPA-1, nonmaternal ITGB3 sequences (c.176T, HPA-1a) were detected in all HPA-1ab fetuses. One HPA-1bb fetus was unequivocally identified, showing the pregnancy was not at risk of FNAIT. We have successfully established massively parallel sequencing as a novel reliable method for noninvasive genotyping of fetal HPA-1a alleles. This technique may also allow the safe detection of other fetal blood group polymorphisms frequently involved in FNAIT and hemolytic disease of the newborn. © 2015 AABB.
    Transfusion 04/2015; 55(6pt2). DOI:10.1111/trf.13102 · 3.57 Impact Factor
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    ABSTRACT: Protein tyrosine phosphatase interacting protein 51 (PTPIP51) is upregulated in glioblastoma multiforme (GBM) and expression levels correlate with the grade of malignancy in gliomas. A similar correlation was reported for its interacting partner 14-3-3β, which has been shown to facilitate the interaction of PTPIP51 with cRAF (Raf1). Since the interaction of these signalling partners stimulates growth factor signalling downstream of the epidermal growth factor receptor (EGFR), a major drug target in GBM, we here investigated the impact of EGFR inhibition by small molecule inhibitors or monoclonal antibody on PTPIP51. The effect of EGFR inhibition on PTPIP51 mRNA, protein expression and its interaction profile in GBM was analyzed using the U87 cell line as model system. The transferability of the results to in vivo conditions was evaluated in cultured tumour cells from GBM patients. Cells were treated either to the small molecule tyrosine kinase inhibitor of EGFR Gefitinib or the monoclonal antibody Cetuximab in a time and dose dependent manner. Gefitinib treatment decreased the proliferation rate and induced apoptosis in U87 and primary tumour cells. The PTPIP51 interaction profile changed in correlation to the applied Gefitinib. Despite unchanged mRNA levels PTPIP51 protein was reduced. In contrast, treatment with Cetuximab had no effects on PTPIP51 expression. In conclusion, our results demonstrate the impact of EGFR inhibition by Gefitinib on PTPIP51 protein expression, a downstream regulator of MAPK signalling. These data will serve as a basis to unravel the precise role of PTPIP51-mediated signalling in GBM and its potential implications for Gefitinib-mediated therapy in future studies.
    Journal of Neuro-Oncology 04/2015; 123(1). DOI:10.1007/s11060-015-1763-8 · 2.79 Impact Factor
  • European Urology Supplements 04/2015; 14(2):e280. DOI:10.1016/S1569-9056(15)60277-9 · 3.37 Impact Factor
  • ECR 2015; 03/2015
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    ABSTRACT: The current standard treatment for acute myeloid leukemia (AML) is chemotherapy based on cytarabine and daunorubicine (7 + 3), but it discriminates poorly between malignant and benign cells. Dose-limiting off‑target effects and intrinsic drug resistance result in the inefficient eradication of leukemic blast cells and their survival beyond remission. This minimal residual disease is the major cause of relapse and is responsible for a 5-year survival rate of only 24%. More specific and efficient approaches are therefore required to eradicate malignant cells while leaving healthy cells unaffected. In this study, we generated scFv antibodies that bind specifically to the surface of AML blast cells and AML bone marrow biopsy specimens. We isolated the antibodies by phage display, using subtractive whole-cell panning with AML M2‑derived Kasumi‑1 cells. By selecting for internalizing scFv antibody fragments, we focused on potentially novel agents for intracellular drug delivery and tumor modulation. Two independent methods showed that 4 binders were internalized by Kasumi-1 cells. Furthermore, we observed the AML‑selective inhibition of cell proliferation and the induction of apoptosis by a recombinant immunotoxin comprising one scFv fused to a truncated form of Pseudomonas exotoxin A (ETA'). This method may therefore be useful for the selection of novel disease-specific internalizing antibody fragments, providing a novel immunotherapeutic strategy for the treatment of AML patients.
    mAbs 03/2015; 7(2):390-402. DOI:10.1080/19420862.2015.1007818 · 4.73 Impact Factor
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    ABSTRACT: BACKGROUNDA risk of the prostate cancer patient is defined by both the objective and subjective criteria, that is, PSA concentration, Gleason score, and pTNM-stage. The subjectivity of tumor grading influences the risk assessment owing to a large inter- and intra-observer variability. Pathologists propose a central prostate pathology review as a remedy for this problem; yet, the review cannot eliminate the subjectivity from the diagnostic algorithm. The spatial distribution of cancer cell nuclei changes during tumor progression. It implies changes in complexity measured by the capacity dimension D0, the information dimension D1, and the correlation dimension D2.METHODS The cornerstone of the approach is a model of prostate carcinomas composed of the circular fractals CF(4), CF(6 + 0), and CF(6 + 1). This model is both geometrical and analytical, that is, its structure is well-defined, the capacity fractal dimension D0 can be calculated for the infinite circular fractals, and the dimensions D0, D1, D2 can be computed for their finite counterparts representing distribution of cell nuclei. The model enabled both the calibration of the software and the validation of the measurements in 124 prostate carcinomas. The ROC analysis defined the cut-off D0 values for seven classes of complexity.RESULTSThe Gleason classification matched in part with the classification based on the D0 values. The mean ROC sensitivity was 81.3% and the mean ROC specificity 75.2%. Prostate carcinomas were re-stratified into seven classes of complexity according to their D0 values. This increased both the mean ROC sensitivity and the mean ROC specificity to 100%. All homogeneous Gleason patterns were subordinated to the class C1, C4, or C7. D0 = 1.5820 was the cut-off D0 value between the complexity class C2 and C3 representing low-risk cancers and intermediate-risk cancers, respectively.CONCLUSIONS The global fractal dimensions eliminate the subjectivity in the diagnostic algorithm of prostate cancer. Those complexity measures enable the objective subordination of carcinomas to the well-defined complexity classes, and define subgroups of carcinomas with very low malignant potential (complexity class C1) or at a large risk of progression (complexity ass C7). Prostate © 2014 Wiley Periodicals, Inc.
    The Prostate 03/2015; 75(4). DOI:10.1002/pros.22926 · 3.57 Impact Factor
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    ABSTRACT: No prospective studies are available to date evaluating the combined analysis of chromosomal alterations via interphase FISH in different soft tissue sarcoma (STS) subtypes. We tested 64 consecutive sarcoma specimens with FISH probes to detect aberrations specific for a given STS subtype. We first determined the translocation frequency in the specific STS subtypes in 48 tumors, with the primary pathological diagnosis as the gold standard. Subsequently, to evaluate sensitivity and specificity, all FISH probes were hybridized to 16 STS of hitherto unknown diagnosis. DDIT3 translocations occurred in 8/10 (80%) of myxoid liposarcomas. FOXO1 translocations were noted in 4/4 (100%) of alveolar but in none of 7 embryonal rhabdomyosarcomas. All 15 (100%) Ewing sarcomas/PNET and 4 clear cell sarcomas (4/4) harbored EWSR1 translocations. SS18 rearrangements were demonstrated in 8/9 (89%) synovial sarcomas. MDM2 amplification was noted in 7/8 (88%) atypical lipomatous tumors/well-differentiated and 3/3 (100%) dedifferentiated liposarcomas, respectively, but not in four pleomorphic liposarcomas. Sensitivities and specificities ranged from 80% to 100% and from 93% to 100%, respectively, with the highest values observed for FOXO1 (100% each). We conclude, therefore, that is possible to accurately predict the STS subtype using a panel of different subtype-specific FISH probes, thereby greatly facilitating the differential diagnosis of these tumors.
    Pathology - Research and Practice 12/2014; 210(12). DOI:10.1016/j.prp.2014.09.009 · 1.56 Impact Factor
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    ABSTRACT: Rhabdomyosarcoma (RMS) is a rare and aggressive soft tissue sarcoma with limited treatment options and a high failure rate during standard therapy. New therapeutic strategies based on targeted immunotherapy are therefore much in demand. The epidermal growth factor receptor (EGFR) has all the characteristics of an ideal target. It is overexpressed in up to 80 % of embryonal RMS and up to 50 % of alveolar RMS tumors. We therefore tested the activity of the EGFR-specific recombinant immunotoxin (IT) 425(scFv)-ETA' against EGFR(+) RMS cells in vitro and ex vivo. We tested the specific binding and internalization behavior of 425(scFv)-ETA' in RMS cell lines in vitro by flow cytometry, compared to the corresponding imaging probe 425(scFv)-SNAP monitored by live cell imaging. The cytotoxic activity of 425(scFv)-ETA' was tested using cell viability and apoptosis assays. Specific binding of the IT was confirmed on formalin-fixed paraffin-embedded tissue samples from two RMS patients. We confirmed the specific binding of 425(scFv)-ETA' to RMS cells in vitro and ex vivo. Both the IT and the corresponding imaging probe were rapidly internalized. The IT killed EGFR(+) RMS cells in a dose-dependent manner, while showing no effect against control cells. It showed specific apoptotic activity against one selected RMS cell line. This is the first study showing the promising therapeutic potential of a recombinant, EGFR-targeting, ETA'-based IT on RMS cells. We confirmed the selective killing with IC50 values of up to 50 pM, and immunohistochemical staining confirmed the specific ex vivo binding to primary RMS material.
    Journal of Cancer Research and Clinical Oncology 11/2014; 141(6). DOI:10.1007/s00432-014-1884-z · 3.01 Impact Factor
  • Archiv für Klinische und Experimentelle Ohren- Nasen- und Kehlkopfheilkunde 10/2014; 272(2). DOI:10.1007/s00405-014-3318-6 · 1.61 Impact Factor
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    ABSTRACT: Context Bisphosphonates are common drugs used in the management of bone metabolic diseases. Because of their recently increased use, their adverse effects, especially bisphosphonate-related osteonecrosis of the jaw (BRONJ), are monitored more frequently. BRONJ is a critical challenge in craniofacial surgery and is difficult to treat. Its occurrence is either spontaneous or follows dentoalveolar surgery. Typical complications of BRONJ are painful exposed bone, pathological fractures, extra-oral fistula, and local infections. Objective The aim of this paper is to report a rare case of bacterial embolism in the internal jugular vein after a BRONJ-induced submandibular abscess resulting in bacterial sepsis, multi-organ failure syndrome, and death. Case Illustration A 59-year-old female patient developed severe BRONJ (stage II) with recurrent abscesses after oral osteoporosis therapy with alendronic acid. A subsequent submandibular abscess led to bacterial embolism of the left internal jugular vein, causing sepsis and death. Discussion Prevention, early detection and management of BRONJ remain a crucial challenge in craniofacial clinical practice. Despite several therapeutic approaches described in the current literature, none have undergone bedside application. Conclusion Considering this report of death after recurrent abscesses following BRONJ, the use of bisphosphonates should be carefully monitored in order to prevent such severe complications.
    Journal of Cranio-Maxillofacial Surgery 10/2014; 42(7). DOI:10.1016/j.jcms.2014.02.009 · 2.60 Impact Factor
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    ABSTRACT: The prevalence of systemic atherosclerosis and overactive bladder (OAB)/detrusor overactivity (DO) increases almost simultaneously with age, but an association between these diseases is not yet proven. We aimed to evaluate changes in bladder function and morphology, including vascularization, in apoE(-/-)LDLR(-/-) double knockout mice suffering from systemic atherosclerosis, but without involvement of the central nervous system.
    The Journal of Urology 08/2014; 193(1). DOI:10.1016/j.juro.2014.08.098 · 3.75 Impact Factor
  • P Waliszewski · F Wagenlehner · S Gattenlöhner · W Weidner
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    ABSTRACT: Hintergrund Ein möglicher Ansatz komplexe Muster im Tumorgewebe objektiv klassifizieren zu können, ist die mathematische Erfassung der Verteilung von Tumorzellkernen, die als geometrische Repräsentation der Krebszellen dienen, durch fraktale Dimensionen. Die Existenz, sowie die Veränderungen der fraktalen Struktur der Verteilung der Zellkerne haben wichtige Konsequenzen für eine objektive Klassifizierung der Tumoren. Weiterhin kann auch die Komplexität des Tumorwachstums in verschiedenen Karzinomen sowie die interzellulären Interaktionen im Gewebesystem dadurch verglichen werden. Ergebnisse In dieser Arbeit stellen wir eine theoretische Einführung in die fraktale Geometrie sowie in die Algorithmen, die auf der Rényi-Familie der fraktalen Dimensionen basieren, dar. Wir führen ein geometrisches Modell für die Bewertung von Prostatakarzinomgeweben ein und erklären den Zusammenhang zwischen dem geometrischen Tumormuster und den fraktalen Dimensionen der Rényi-Familie.
    Der Urologe 07/2014; 53(8). DOI:10.1007/s00120-014-3472-x · 0.44 Impact Factor
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    ABSTRACT: Significant intra- and interobserver variability ranging between 40 and 80% is observed in tumor grading of prostate carcinoma. By combining geometric and statistical methods, an objective system of grading can be designed. The distributions of cell nuclei in two-dimensional patterns of prostate cancer classified subjectively as Gleason score 3+3, 3+4, 4+3, 4+4, 4+5, 5+4, and 5+5 were analyzed with algorithms measuring the global fractal dimensions of the R,nyi family and with the algorithm for the local connected fractal dimension (LCFD). The dimensions for global fractal capacity, information, and correlation (standard deviation) were 1.470 (045), 1.528 (046), and 1.582 (099) for homogenous Gleason grade 3 (n = 16), 1.642 (034), 1.678 (041), and 1.673 (084) for homogenous Gleason grade 4 (n=18), and 1.797 (042), 1.791 (026), and 1.854 (031) for homogenous Gleason grade 5 (n=12), respectively. The LCFD algorithm can be used to distinguish both qualitatively and quantitatively between mixed and heterogeneous patterns, such as Gleason score 3+4=7a (intermediate risk cancer) and Gleason score 4+3=7b (high-risk cancer). Sensitivity of the method is 89.3%, and specificity 84.3%. The method of fractal geometry enables both an objective and quantitative grading of prostate cancer.
    Der Urologe 07/2014; 53(10). DOI:10.1007/s00120-014-3470-z · 0.44 Impact Factor
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    ABSTRACT: The treatment of rhabdomyosarcoma (RMS) remains challenging, with metastatic and alveolar RMS offering a particularly poor prognosis. Therefore, the identification and evaluation of novel antigens, which are suitable targets for immunotherapy, is one attractive possibility to improve the treatment of this disease. Here we show that chondroitin sulfate proteoglycan 4 (CSPG4) is expressed on RMS cell lines and RMS patient material. We evaluated the immunotoxin (IT) αMCSP-ETA', which specifically recognizes CSPG4 on the RMS cell lines RD, FL-OH1, TE-671 and Rh30. It is internalized rapidly, induces apoptosis and thus kills RMS cells selectively. We also demonstrate the specific binding of this IT to RMS primary tumor material from three different patients.
    Cancer Letters 07/2014; 352(2). DOI:10.1016/j.canlet.2014.07.006 · 5.62 Impact Factor

Publication Stats

1k Citations
520.74 Total Impact Points

Institutions

  • 2011–2015
    • Universitätsklinikum Gießen und Marburg
      Marburg, Hesse, Germany
    • Justus-Liebig-Universität Gießen
      • Institut für Parasitologie
      Gieben, Hesse, Germany
  • 2013–2014
    • Vitos Gießen-Marburg
      Gieben, Hesse, Germany
    • Philipps University of Marburg
      Marburg, Hesse, Germany
  • 2010–2011
    • Medical University of Graz
      • Institute of Pathology
      Gratz, Styria, Austria
  • 1994–2011
    • University of Wuerzburg
      • • Department of Pathology
      • • Institute for Pathology
      Würzburg, Bavaria, Germany