Sebastian Haferkamp

University Hospital Regensburg

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Jochen Utikal

German Cancer Research Center

Dirk Schadendorf

Essen University Hospital

Bastian Schilling

Universitätsklinikum Würzburg

Friedegund Meier

University Hospital Carl Gustav Carus

Konstantin Drexler

University Hospital Regensburg

Ralf Gutzmer

Ruhr University Bochum

Carola Berking

Friedrich-Alexander-Universität Erlangen-Nürnberg

Markus V. Heppt

Friedrich-Alexander-Universität Erlangen-Nürnberg

Michael Weichenthal

University Hospital Schleswig-Holstein

Mark Berneburg

University Hospital Regensburg

Cooperative Institutions

Heidelberg University

231

University Hospital Regensburg

199

University of Regensburg

192

German Cancer Research Center

163

Ludwig-Maximilians-Universität München

156

University Hospital Heidelberg

128

LMU Klinikum

108

Deutschen Konsortium für Translationale Krebsforschung

Charité - Universitätsmedizin Berlin

National Center for Tumor Diseases

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Real-World Therapy with Pembrolizumab: Outcomes and Surrogate Endpoints for Predicting Survival in Advanced Melanoma Patients in Germany

Cancers (2022)

Peter Mohr Emilie Scherrer Chalid Assaf Marc Bender Carola Berking

Knowledge on the real-world characteristics and outcomes of pembrolizumab-treated advanced melanoma patients in Germany and on the value of different real-world endpoints as surrogates for overall survival (OS) is limited. A sample of 664 pembrolizumab-treated patients with advanced melanoma from the German registry ADOReg was used. We examined OS, real-world progression-free survival (rwPFS), real-world time to next treatment (rwTtNT), and real-world time on treatment (rwToT). Spearman's rank and iterative multiple imputation (IMI)-based correlation coefficients were computed between the OS and the rwPFS, rwTtNT, and rwToT and reported for the first line of therapy and the overall sample. The median OS was 30.5 (95%CI 25.0-35.4) months, the rwPFS was 3.9 months (95%CI 3.5-4.9), the rwTtNT was 10.7 months (95%CI 9.0-12.9), and the rwToT was 6.2 months (95%CI 5.1-6.8). The rwTtNT showed the highest correlation with the OS based on the IMI (rIMI = 0.83), Spearman rank correlations (rs = 0.74), followed by the rwToT (rIMI = 0.74 and rs = 0.65) and rwPFS (rIMI = 0.69 and rs = 0.56). The estimates for the outcomes and correlations were similar for the overall sample and those in first-line therapy. The median OS was higher compared to recent real-world studies, supporting the effectiveness of pembrolizumab in regular clinical practice. The rwTtNT may be a valuable OS surrogate, considering the highest correlation was observed with the OS among the investigated real-world endpoints.

Real world data

Surrogate endpoint

Rank correlation

Log-rank test

10.3390/cancers14071804

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Citations (7)

Facharztprüfung Dermatologie und Venerologie

Esther von Stebut Marcus Maurer Mark Berneburg Kerstin Steinbrink Jürgen Bauer

10.1055/b000000044

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Citations (1)

RB1 is the crucial target of the Merkel cell polyomavirus Large T antigen in Merkel cell carcinoma cells

Oncotarget (2016)

Sonja Hesbacher Lisa Pfitzer Katharina Wiedorfer Sabrina Angermeyer Andreas Borst

The pocket protein (PP) family consists of the three members RB1, p107 and p130 all possessing tumor suppressive properties. Indeed, the PPs jointly control the G1/S transition mainly by inhibiting E2F transcription factors. Notably, several viral oncoproteins are capable of binding and inhibiting PPs. Merkel cell polyomavirus (MCPyV) is considered as etiological factor for Merkel cell carcinoma (MCC) with expression of the viral Large T antigen (LT) harboring an intact PP binding domain being required for proliferation of most MCC cells. Therefore, we analyzed the interaction of MCPyV-LT with the PPs. Co-IP experiments indicate that MCPyV-LT binds potently only to RB1. Moreover, MCPyV-LT knockdown-induced growth arrest in MCC cells can be rescued by knockdown of RB1, but not by p107 or p130 knockdown. Accordingly, cell cycle arrest and E2F target gene repression mediated by the single PPs can only in the case of RB1 be significantly reverted by MCPyV-LT expression. Moreover, data from an MCC patient indicate that loss of RB1 rendered the MCPyV-positive MCC cells LT independent. Thus, our results suggest that RB1 is the dominant tumor suppressor PP in MCC, and that inactivation of RB1 by MCPyV-LT is largely sufficient for its growth supporting function in established MCPyV-positive MCC cells.

Merkel cell polyomavirus

Merkel cell

Polyomavirus Infections

Cell of origin

10.18632/oncotarget.8793

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Citations (89)

Hyperkeratose der Brustwarze und des Warzenhofs: eine histopathologische Falle!

JDDG Journal der Deutschen Dermatologischen Gesellschaft (2018)

D. Sander Wolfgang Dietmaier Marion Wobser Sebastian Haferkamp

Sander

10.1111/ddg.13677_g

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Citations (1)

Fistulising skin metastases in Crohn’s disease: a case report and review of the literature

Journal of Medical Case Reports (2024)

Tanja Elger Johanna Loibl Christa Buechler Sebastian Haferkamp Jens Werner

Abstract Background Metastatic Crohn’s disease is a rare disorder characterized by various granulomatous skin lesions that occur independently of gastrointestinal tract involvement. However, currently there is no standardized care or specific treatment. Therapeutic approaches include immunosuppressive agents, such as corticosteroids, azathioprine, and monoclonal antibodies targeting inflammatory cytokines like tumor necrosis factor (TNF). Case presentation We present a case of a 29-year-old western European woman with significant blind ending abdominal subcutaneous fistulas and abscesses, who sought evaluation in the dermatology department. Histological examination revealed multiple epithelioid cell granulomas. There was no evidence of infectious or rheumatologic diseases such as sarcoidosis. The tentative diagnosis was metastatic Crohn’s disease, which was not related to an intestinal manifestation of the disease. The patient responded to infliximab but had to discontinue it due to an allergic reaction. Subsequent adalimumab treatment failed to induce clinical remission; thus, therapy was switched to ustekinumab, resulting in a positive response. Written informed consent for publication of their clinical details and clinical images was obtained from the patient. For our study more than 1600 publications were screened for cases of metastatic Crohn’s disease on PubMed database. 59 case reports with 171 patients were included in the analysis and evaluated for localization, diagnostic and therapeutic approaches, and complications and were summarized in this review. Conclusion The successful ustekinumab treatment of a patient with metastatic Crohn's disease underscores the potential of this minimally investigated therapeutic option, highlighting the need for future treatment guidelines given the increasing prevalence of such cases.

Ustekinumab

Surgical oncology

10.1186/s13256-024-04569-1

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Citations (2)

Real-world use of talimogene laherparepvec in Germany: a retrospective observational study using a prescription database

Future Oncology (2020)

Karly S. Louie Victoria Banks Florian Scholz Hartmut Richter Katarina Öhrling

Aim: There is a growing body of data on real-world use of talimogene laherparepvec (T-VEC). We aimed to characterize real-world T-VEC use using a nationally representative German prescription database covering 60% of prescriptions reimbursed. Patients & methods: A retrospective analysis was conducted using the German IMS® LRx prescription database, analyzing patients aged ≥18 years with an initial T-VEC prescription at 106 plaque-forming units (PFU)/ml and ≥1 subsequent prescription at 108 PFU/ml. Median time on T-VEC treatment, patient characteristics and patterns of T-VEC use were described. Results: Of 127 patients prescribed T-VEC, 72 patients (57%) met study criteria. About two-thirds of these patients initiated T-VEC in 2017. Median age at T-VEC initiation was 74 years (range: 44 to 91). Most prescriptions (88%) were dispensed from hospitals. At study end, 26 (36%) patients remained on T-VEC; 46 (64%) had ended treatment. Median duration of T-VEC treatment for all patients was 18.7 weeks (95% CI: 15.3-26.9) and was longer among those who initiated treatment in 2017 versus 2016 (26.7 vs 15.6 weeks, respectively). Median volume administered for the first 106 PFU/ml and second 108 PFU/ml was 4 ml; the volume decreased for subsequent administrations (2 ml by the eighth administration and 1 ml by the 16th administration). Conclusion: This real-world prescription database study showed that patients who initiated treatment in 2017 had a treatment duration in clinical practice that corresponded with the European Summary of Product Characteristics guideline of continuing T-VEC for ≥6 months. Additional long-term data linking drug use with clinical outcomes are needed.

10.2217/fon-2019-0838

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Citations (6)

Depigmentierung der Wimpern bei einer Patientin mit metastasiertem Melanom

JDDG Journal der Deutschen Dermatologischen Gesellschaft (2022)

Veronika Zenderowski Konstantin Drexler Mark Berneburg Sebastian Haferkamp

10.1111/ddg.14806_g

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Citations (0)

Intracellular localization of Crimean-Congo Hemorrhagic Fever (CCHF) virus glycoproteins

Virology Journal (2005)

Sebastian Haferkamp Lisa Fernando Tino F. Schwarz Heinz Feldmann Ramon Flick

Abstract Background Crimean-Congo Hemorrhagic Fever virus (CCHFV), a member of the genus Nairovirus , family Bunyaviridae , is a tick-borne pathogen causing severe disease in humans. To better understand the CCHFV life cycle and explore potential intervention strategies, we studied the biosynthesis and intracellular targeting of the glycoproteins, which are encoded by the M genome segment. Results Following determination of the complete genome sequence of the CCHFV reference strain IbAr10200, we generated expression plasmids for the individual expression of the glycoproteins G N and G C , using CMV- and chicken β-actin-driven promoters. The cellular localization of recombinantly expressed CCHFV glycoproteins was compared to authentic glycoproteins expressed during virus infection using indirect immunofluorescence assays, subcellular fractionation/western blot assays and confocal microscopy. To further elucidate potential intracellular targeting/retention signals of the two glycoproteins, GFP-fusion proteins containing different parts of the CCHFV glycoprotein were analyzed for their intracellular targeting. The N-terminal glycoprotein G N localized to the Golgi complex, a process mediated by retention/targeting signal(s) in the cytoplasmic domain and ectodomain of this protein. In contrast, the C-terminal glycoprotein G C remained in the endoplasmic reticulum but could be rescued into the Golgi complex by co-expression of G N . Conclusion The data are consistent with the intracellular targeting of most bunyavirus glycoproteins and support the general model for assembly and budding of bunyavirus particles in the Golgi compartment.

Crimean–Congo hemorrhagic fever

10.1186/1743-422x-2-42

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Citations (60)

Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial

The Lancet (2023)

Jürgen C. Becker Selma Ugurel Ulrike Leiter Friedegund Meier Ralf Gutzmer

Clinical endpoint

Interim analysis

10.1016/s0140-6736(23)00769-9

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Citations (33)

The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence

Aging (2009)

Sebastian Haferkamp Sieu L. Tran Therese M. Becker Lyndee L. Scurr Richard Kefford

Oncogene-induced senescence acts as a barrier against tumour formation and has been implicated as the mechanism preventing the transformation of benign melanocytic lesions that frequently harbour oncogenic B-RAF or N-RAS mutations. In the present study we systematically assessed the relative importance of the tumour suppressor proteins p53, p21(Waf1), pRb and p16(INK4a) in mediating oncogene-induced senescence in human melanocytes. We now show that oncogenic N-RAS induced senescence in melanocytes is associated with DNA damage, a potent DNA damage response and the activation of both the p16(INK4a)/pRb and p53/p21(Waf1) tumour suppressor pathways. Surprisingly neither the pharmacological inhibition of the DNA damage response pathway nor silencing of p53 expression had any detectable impact on oncogene-induced senescence in human melanocytes. Our data indicate that the pRb pathway is the dominant effector of senescence in these cells, as its specific inactivation delays the onset of senescence and weakens oncogene-induced proliferative arrest. Furthermore, we show that although both p16(INK4a) and p21(Waf1) are upregulated in response to N-RAS(Q61K), the activities of these CDK inhibitors are clearly distinct and only the loss of p16(INK4a) weakens senescence. We propose that the ability of p16(INK4a) to inhibit the cyclin D-dependent kinases and DNA replication, functions not shared by p21(Waf1), contribute to its role in senescence. Thus, in melanocytes with oncogenic signalling only p16(INK4a) can fully engage the pRb pathway to alter chromatin structure and silence the genes that are required for proliferation.

Senescence

Retinoblastoma protein

10.18632/aging.100051

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Citations (70)