Ralf Gutzmer

Hannover Medical School, Hanover, Lower Saxony, Germany

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Publications (173)614.8 Total impact

  • Journal der Deutschen Dermatologischen Gesellschaft 10/2014; 12(10). · 1.40 Impact Factor
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    ABSTRACT: Background: Aviscumine, a recombinant plant protein, is an immune modulator that induces ribotoxic stress at the 28S ribosomal RNA subunit. In this way cytokine release and T-cell responses are enhanced. This phase II trial was conducted to test the efficacy and safety of aviscumine in patients with systemically pre-treated metastatic melanoma stage IV. Methods: A total of 32 patients with progressive stage IV melanoma after failure of standard therapy were enrolled onto a single-arm, multi-centre, open-label, phase II trial. All patients had an ECOG performance status of 0 or 1. Patients received 350 ng aviscumine twice weekly by subcutaneous injection until progression. The primary end points were progression-free survival (PFS) and overall survival (OS). Safety was assessed as adverse events (AEs). Tumor response was assessed every eight weeks and survival of patients was followed up to one year after the end of therapy. Thirty one patients (intent-to-treat population (ITT)) were assessed for efficacy; safety was assessed in the whole population. Results: One patient achieved a partial response (PR) and 10 patients showed stable disease/no change (SD). The median progression-free survival (mPFS) was 63 days (95% CI 57–85) and median overall survival (mOS) was 335 days (95% CI 210–604). In total 210 treatment-emergent adverse events were recorded. Grade 1 or 2 AEs occurred in 72% of patients and were mostly application-site effects such as pruritus Grade 3–4 treatment-emergent drug-related adverse events occurred in 9% of patients. Conclusion: These results suggest that aviscumine may have a clinical impact in patients with previously treated metastatic melanoma and provide rationale for further clinical evaluation of this agent. In the light of effective new immune checkpoint blockers it might be a candidate for combinations with these agents. Trial registration: ClinicalTrials.gov: NCT00658437
    Journal for immunotherapy of cancer. 08/2014; 2.
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    ABSTRACT: Ipilimumab is an approved anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody introducing immune responses in melanoma patients. Treatment experiences from named-patient programs support the evaluation of the efficacy and tolerability of new medicines under usual circumstances of health care practice. Here, the largest ever reported cohort treated with ipilimumab 3 mg/kg alone is described.
    Journal of immunotherapy (Hagerstown, Md.: 1997) 07/2014; · 3.20 Impact Factor
  • Journal der Deutschen Dermatologischen Gesellschaft 07/2014; · 1.40 Impact Factor
  • C Ulrich, U Hillen, R Gutzmer
    07/2014; 65(7):580-1.
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    ABSTRACT: The incidence of non-melanoma skin cancer (NMSC) is increasing. Squamous cell carcinoma of the skin (SCC) is a tumor of the elderly. Due to the increasing life expectancy, SCC will become more and more frequent in the future. Generally SCC has a favorable prognosis. Standard therapy is microscopically- controlled excision. Therapy of advanced and metastatic SCC is still challenging. Patients with regional lymph node metastasis have ten-year survival rates less than 20 %; patients with distant metastases less than 10 %. Immunosuppression has been shown to be one of the key prognostic factors for metastasis. The article reviews SCC and focusses on patients being at risk for an unfavorable course.
    06/2014;
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    ABSTRACT: BRAF and MEK inhibitors are new targeted therapies which are used in the treatment of malignancies, in particular of malignant melanoma.
    06/2014;
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    ABSTRACT: ZusammenfassungHintergrundOrgantransplantierte Patienten entwickeln vermehrt nicht-melanozytäre Hauttumoren. Aufgrund des multiplen Auftretens und aggressiven Wachstumsverhaltens stellt die chirurgische Therapie oftmals eine Herausforderung dar. Die Umstellung der immunsuppressiven Therapie auf einen mTOR-Inhibitor kann eine antitumorale Wirkung haben.Patienten und MethodikIn einer monozentrischen retrospektiven Erhebung wurden im Zeitraum von 2008 bis 2010 organtransplantierte Patienten erfasst, die sich aufgrund von nicht-melanozytären Hauttumoren vorgestellt hatten. Erfahrungen mit Patienten, die aufgrund von nicht-melanozytären Hauttumoren auf eine Therapie mit einem mTOR-Inhibitor umgestellt wurden, werden detailliert dargestellt und aktuelle Studiendaten dazu zusammengefasst.ErgebnisseInsgesamt wurden 60 organtransplantierte Patienten mit nicht-melanozytären Hauttumoren erfasst. Aufgrund der Entwicklung von vielen nicht-melanozytären Hauttumoren innerhalb weniger Jahre wurde die systemische immunsuppressive Therapie bei 7 Patienten auf Everolimus und bei 5 Patienten auf Sirolimus umgestellt. Acht Patienten konnten hinsichtlich der Anzahl neu entstehender nicht-melanozytärer Hauttumoren nach Umstellung ausgewertet werden, 4 Patienten mussten die neue immunsuppressive Therapie aufgrund verschiedener Nebenwirkungen wieder absetzen. In den 12 Monaten vor Umstellung der Immunsuppression entwickelten die 8 Patienten histologisch gesichert 16 Plattenepithelkarzinome, 3 Basalzellkarzinome und 22 Morbus Bowen. In den 12 Monaten nach Umstellung auf einen mTOR-Inhibitor war die Zahl der Plattenepithelkarzinome (n = 2) und der Morbus Bowen (n = 3), nicht jedoch die der Basalzellkarzinome (n = 2) signifikant reduziert. Auch 5 kürzlich publizierte prospektiv-randomisierte Studien konnten ein vermindertes Auftreten nicht-melanozytärer Hauttumoren nach Umstellung der immunsuppressiven Therapie auf einen mTOR-Inhibitor bei organtransplantierten Patienten zeigen.SchlussfolgerungEine Umstellung der immunsuppressiven Therapie auf einen mTOR-Inhibitor sollte bei organtransplantierten Patienten mit nicht-melanozytären Hauttumoren diskutiert werden.
    Journal der Deutschen Dermatologischen Gesellschaft 06/2014; 12(6). · 1.40 Impact Factor
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    ABSTRACT: With an incidence of 70 to over 800 new cases per 100 000 persons per year, basal cell carcinoma (BCC) is a very common disease, accounting for about 80% of all cases of non-melanoma skin cancer. It very rarely metastasizes. A variety of treatments are available for the different subtypes and stages of BCC.
    Deutsches Ärzteblatt international. 05/2014; 111(22):389-95.
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    ABSTRACT: In the case of a positive sentinel lymph node (SLN), melanoma patients are recommended to proceed to complete lymph node dissection (CLND). However, CLND for SLN-positive patients - especially with minimal tumor burden in SLN - is becoming more controversial. We analyzed the clinical course of 305 SLN-positive patients with a mean follow-up of 51.1 months by Kaplan-Meier analyses. Overall, 58/305 (17%) patients did not undergo CLND. These were compared with a matched selection of 58 comparable patients who underwent CLND. Moreover, 106/305 patients with minimal tumor burden in SLN (<0.1 mm diameter of the largest tumor deposit) were analyzed separately. Of these 106 patients, 34 did not undergo CLND, whereas 72/106 patients were treated by CLND. In the matched groups, the CLND group and the non-CLND group did not differ significantly with respect to clinical characteristics, characteristics of the primary melanoma, and histopathological parameters of SLN. There were no differences in recurrence-free survival (P=0.765) and overall survival (P=0.844). The total number of regional lymph node metastases and time to regional lymph node metastases were not significantly higher for non-CLND patients. The subgroup of patients with minimal tumor burden in SLN also did not benefit significantly from CLND. In our analyses from a single German center, we could not find any evidence for a therapeutic survival benefit for CLND after positive SLN. However, future prospective randomized trials should confirm these data.
    Melanoma research 05/2014; · 2.06 Impact Factor
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    ABSTRACT: Background Organ transplant recipients are prone to the development of non-melanoma skin cancer. Organ transplant recipients often develop multiple non-melanoma skin cancers and the tumors show an aggressive growth pattern, therefore surgical therapy can be difficult. Switch of the immunosuppressive regimen to mTOR-inhibitors such as everolimus or sirolimus can have an antitumor effect.Patients and Methods In a monocentric retrospective study we evaluated organ transplant recipients who presented with non-melanoma skin cancer in the years 2008–2010. Experience with patients who were switched to an mTOR-inhibitor due to non-melanoma skin cancer are reported in detail, and recent clinical studies are reviewed.Results60 organ transplant recipients with non-melanoma skin cancer were evaluated. Due to the development of multiple non-melanoma skin cancer within a few years, the immunosuppressive regimen was switched to everolimus in 7 patients and to sirolimus in 5 patients. Eight patients were evaluable for the effect of mTOR-inhibitors on the development of non-melanoma skin cancer; 4 patients had to discontinue the medication with mTOR-inhibitors early due to various side effects. In the year before the switch to mTOR-inhibitors, 8 patients developed 16 squamous cell carcinomas, 3 Basal cell carcinomas and 22 cases of Bowen's disease. All tumors were histologically confirmed. In the year after switch of immunosuppression, the rate of squamous cell carcinomas (n = 2) and Bowen's disease (n = 3), but not of basal cell carcinomas (n = 2) was significantly reduced. Moreover, 5 prospective randomized trials recently have demonstrated a reduced number of non-melanoma skin cancers in organ transplant recipients after switch of the immunosuppressive regimen to mTOR-inhibitors.Conclusion Switch of the immunosuppressive regimen to mTOR-inhibitors should be considered for organ transplant recipients suffering from multiple non-melanoma skin cancers.
    Journal der Deutschen Dermatologischen Gesellschaft 05/2014; · 1.40 Impact Factor
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    ABSTRACT: L19-IL2 is a recombinant protein comprising the cytokine IL2 fused to the single-chain monoclonal antibody L19. In previous studies, intralesional injection with IL2 has shown efficacy for the locoregional treatment of cutaneous/subcutaneous metastases in patients with advanced melanoma. The objectives of this study were to investigate whether (i) intralesional delivery of a targeted form of IL2 would yield similar results, with reduction of injection frequency and treatment duration; and (ii) systemic immune responses were induced by the local treatment. Patients with stage IIIB/IIIC melanoma and cutaneous/subcutaneous injectable metastases received weekly intratumoral injections of L19-IL2 at a maximum dose of 10 MIU/week for 4 consecutive weeks. Tumor response was evaluated 12 weeks after the first treatment. Twenty-four of 25 patients were evaluable for therapy-induced responses. A complete response (CR) by modified immune-related response criteria (irRC) of all treated metastases was achieved in 6 patients (25%), with long-lasting responses in most cases (5 patients for ≥24 months). Objective responses were documented in 53.9% of all index lesions [44.4% CR and 9.5% partial responses (by irRC)], and 36.5% of these remained stable, while 9.5% progressed. Toxicity was comparable with that of free IL2, and no serious adverse events were recorded. A significant temporary increase of peripheral regulatory T cells and natural killer cells, sustained increase of absolute CD4(+) lymphocytes, and decrease of myeloid-derived suppressor cells were observed upon treatment. Finally, we recorded encouraging data about the progression time to distant metastases and overall survival. Cancer Immunol Res; 2(7); 1-11. ©2014 AACR.
    Cancer immunology research. 04/2014;
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    ABSTRACT: BACKGROUND: Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system. PATIENTS AND METHODS: Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. RESULTS: Progression-free survival (PFS) as well as overall survival (OS) were similar in patients treated with either BRAFi. High pretreatment LDH was associated with shorter PFS and OS in both groups. During therapy, peripheral lymphocytes decreased by 24.3% (median, P < 0.0001) in vemurafenib-treated patients but remained unchanged in dabrafenib-treated patients (+1.2%, P = 0.717). Differentiation of peripheral lymphocytes of vemurafenib-treated patients showed a significant decrease in CD4+ T cells (P < 0.05). Within CD4+ T cells obtained during treatment, an increase in CCR7+CD45RA+ (naïve) and a decrease in CCR7+CD45RA- (central memory) populations were found (P < 0.01 for both). Furthermore, secretion of interferon-γ and interleukin-9 by CD4+ T cells was significantly lower in samples obtained during vemurafenib treatment compared with baseline samples. CONCLUSION: While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4+ T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents.
    Annals of Oncology 02/2014; · 7.38 Impact Factor
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    ABSTRACT: Head or neck location of primary cutaneous melanomas has been described as an adverse prognostic factor, but this has to be reassessed after the introduction of sentinel lymph node (SLN) excision (SLNE). Descriptive statistics, Kaplan-Meier estimates and Cox proportional hazard models were used to study retrospectively a population of 2302 consecutive melanoma patients from three German melanoma centres undergoing SLNE. Approximately 10% of the patients (N=237) had a primary melanoma located at the head or neck (HNM). In both the SLN-positive and SLN-negative subpopulation, patients with HNM were significantly older, more frequently men and had thicker primaries compared with patients with tumours in other locations. The proportion of positive SLNs was lower in HNM compared with other locations of the primary (20 vs. 26%, P=0.048). The false-negative rate was higher in HNM (17.5 vs. 8.4%, P=0.05). In patients with HNM, the SLN status was a significant factor for recurrence-free survival but not for overall survival. SLN-negative HNM patients had a significantly worse overall survival than the SLN negatives with primaries at other sites, whereas the prognosis of the SLN-positive patients was similar in both groups. The prevalence of lymph node metastases after SLNE is lower in patients with HNM compared with other melanoma locations. As a result, the prognostic information provided by the SLN for HNM seems less important. Decision making for SLNE in HNM should be carefully balanced considering the potential morbidity of the procedure.
    Melanoma research 12/2013; · 2.06 Impact Factor
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    ABSTRACT: Most patients with BRAFV600-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAFV600-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a “long tail” of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAFV600-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies. SIGNIFICANCE: The use of RAF inhibitors for BRAFV600-mutant metastatic melanoma improves patient outcomes, but most patients demonstrate early or acquired resistance to this targeted therapy. We reveal the genetic landscape of clinical resistance mechanisms to RAF inhibitors from patients using whole-exome sequencing, and experimentally assess new observed mechanisms to define potential subsequent treatment strategies. Cancer Discov; 4(1); 1–16. ©2013 AACR.
    Cancer Discovery 11/2013; · 15.93 Impact Factor
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    ABSTRACT: Background: Histamine is an important mediator of allergic diseases. It modulates the cytokine expression of various subtypes of antigen-presenting cells by four known receptors, H1R-H4R. The effects of histamine on myeloid dendritic cells (mDC) are unclear. Methods: Monocytes and mDC were isolated from human PBMC. Histamine receptor expression was evaluated by real-time PCR. Cells were stimulated with histamine and histamine receptor ligands, and restimulated with polyinosinic-polycytidylic acid (poly I:C), and supernatants were analyzed by protein array and ELISA. Results: Monocytes and mDC express H1R and H2R without significant differences between the two cell types, whereas H4R mRNA was significantly higher in mDC compared with monocytes and H3R mRNA was not detected in any cell type. Prestimulation with histamine caused a significant decrease in poly I:C-induced expression of interferon-γ-induced protein (IP-10) in mDC and monocytes. Stimulation with specific H1R, H2R and H4R agonists and antagonists showed that the observed effect was mediated via H2R and H4R in monocytes and mDC. Conclusion: Monocytes and mDC have similar histamine receptor repertoires with regard to H1R, H2R and H3R, but H4R expression is higher on mDC. Histamine stimulation shows similar functional effects on both cell types, i.e., downregulation of TLR3-induced IP-10 production. This might be a new mechanism how histamine fosters a Th2 milieu. © 2013 S. Karger AG, Basel.
    International Archives of Allergy and Immunology 11/2013; 163(1):11-19. · 2.25 Impact Factor
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    ABSTRACT: In advanced cutaneous squamous cell carcinoma (cSCC), efficient medical treatment options are limited in case surgery and radiotherapy failed, particularly since most patients are of higher age and suffer from comorbidities. In many tumor entities, the epidermal growth factor receptor (EGFR) has been established as an important therapeutic target, and blockade of EGFR signaling by monoclonal antibodies or small molecules achieves a therapeutic benefit. EGFR expression is also often dysregulated in cSCC. We report here two patients with advanced cSCC treated with the EGFR inhibitor cetuximab and summarize the current published experience with the use of EGFR inhibitors in cSCC. © 2013 S. Karger AG, Basel.
    Dermatology 11/2013; · 2.02 Impact Factor
  • N. Thiessen, M. Alter, A. Kapp, R. Gutzmer
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    ABSTRACT: Beim oralen Lichen ruber mucosae handelt es sich um eine entzündliche Erkrankung der Mundschleimhaut unklarer Pathogenese. Aufgrund der chronischen Entzündung ist bei 1–2 % der Patienten mit einer malignen Entartung im Sinne eines Plattenepithelkarzinoms zu rechnen, was wir hier an einem exemplarischen Fall darstellen.
    Der Hautarzt 11/2013; 64(11). · 0.50 Impact Factor
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    Journal der Deutschen Dermatologischen Gesellschaft 11/2013; 11(11):1041-1047. · 1.40 Impact Factor
  • N Thiessen, M Alter, A Kapp, R Gutzmer
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    ABSTRACT: Oral lichen planus is a mucosal inflammatory disease whose pathogenesis is unclear. The chronic inflammation leads to development of a squamous cell carcinoma in 1-2% of the patients; we present an exemplary case.
    Der Hautarzt 10/2013; · 0.50 Impact Factor

Publication Stats

2k Citations
614.80 Total Impact Points

Institutions

  • 1997–2014
    • Hannover Medical School
      • • Department for Dermatology and Allergy
      • • Clinic for Dermatology, Allergology and Venerology
      • • Division for Immunodermatology and Allergy Research
      Hanover, Lower Saxony, Germany
  • 2013
    • University Medical Center Schleswig-Holstein
      Kiel, Schleswig-Holstein, Germany
    • Klinikum Ludwigshafen
      Ludwigshafen, Rheinland-Pfalz, Germany
    • Universitätsklinikum Schleswig - Holstein
      Kiel, Schleswig-Holstein, Germany
    • Medical University of Vienna
      • Research Division of Biology and Pathobiology of the Skin
      Vienna, Vienna, Austria
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany
  • 2012
    • Universitätsklinikum Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2010
    • Universitätsmedizin Göttingen
      • Department of Dermatology, Venereology and Allergology
      Göttingen, Lower Saxony, Germany
  • 2008
    • University of Tuebingen
      • Department of Dermatology
      Tübingen, Baden-Wuerttemberg, Germany
  • 2007
    • Behörde für Stadtentwicklung und Umwelt
      Hamburg, Hamburg, Germany
  • 2004
    • Hochschule Hannover
      Hanover, Lower Saxony, Germany
    • Georg-August-Universität Göttingen
      Göttingen, Lower Saxony, Germany