Publications by authors named "David Rafei-Shamsabadi"

19 Publications

  • Page 1 of 1

Clinical characteristics and therapy response in unresectable melanoma patients stage IIIB-IIID with in-transit and satellite metastases.

Eur J Cancer 2021 Jul 5;152:139-154. Epub 2021 Jun 5.

Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.

Introduction: Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients.

Methods: In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast (<6 months) distant progression) were analysed separately.

Results: Median follow-up time was 30.5 (range 0.8-154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40-0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45-1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%.

Conclusion: Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system.
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http://dx.doi.org/10.1016/j.ejca.2021.04.032DOI Listing
July 2021

Grade II-anaphylaxis after subcutaneous injection of mistletoe extract.

Contact Dermatitis 2021 May 7. Epub 2021 May 7.

Department of Dermatology and Allergology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1111/cod.13880DOI Listing
May 2021

Case Report: Blurred Vision and Eruptive Nevi - Bilateral Diffuse Uveal Melanocytic Proliferation With Mucocutaneous Involvement in a Lung Cancer Patient.

Front Oncol 2021 13;11:658407. Epub 2021 Apr 13.

Eye Center, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

We describe a case of a 65-year old patient presenting with unusual mucocutaneous melanocytic proliferations of a Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) imitating a multifocal melanoma in situ, which improved dramatically after plasmapheresis. The patient first presented at the dermatology department due to rapidly evolving brown and black macules on the glans penis. Further skin involvement of the perineal and perianal region, mamillae and oral mucosa was stated. Histology from a penile biopsy was compatible with a melanoma in situ. Due to the distribution pattern and elevated serum tumor marker S100B, metastatic melanoma was considered. Staging examinations using PET-CT scan however, revealed a lung tumor, later confirmed as a Non-small-cell lung cancer (NSCLC). Primary radio chemotherapy was initiated to treat NSCLC. Shortly after initiation of radio chemotherapy the patient developed massive vision impairment and a NSCLC-associated BDUMP was diagnosed which led to the correct classification of melanocytic skin lesions as mucocutaneous BDUMP manifestation. Plasmapheresis was started resulting in a rapid improvement of vision starting ten days after the first plasmapheresis. In contrast skin manifestations started to disappear with a marked delay 4 months after the last plasmapheresis cycle. This case highlights the importance of memorizing multiple rapidly progressing melanocytic skin and/or mucous membrane spots together with visual impairment as a possible paraneoplastic BDUMP that needs a fundamentally different therapeutic approach compared to multifocal melanoma in situ. What is already known about this topic? Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) is a paraneoplastic syndrome with melanocytic uveal proliferation leading to vision impairment. Extraocular manifestation is rare, mainly affect the subepidermal compartment and is hard to treat. Plasmapheresis has been shown to be an effective treatment mainly for vision improvement in some but not all cases. What does this study add? Our BDUMP case with widespread skin and mucosal involvement initially mimicked a multifocal melanoma and showed an excellent treatment response to plasmapheresis. Improvement of mucocutaneous lesions has not been documented well in the literature so far. We show a more than one year lasting follow up still underlining the beneficial effect of plasmapheresis in this case. In-vitro data supports the hypothesis that plasma exchange eliminates a "Cultured melanocyte elongation and proliferation (CMEP)" factor out of patient blood leading to decreased melanocyte proliferation shown numerically in-vitro and clinically in-vivo. Our case clearly indicates that before establishing a definite diagnosis and therapy in patients with rapidly evolving melanocytic skin and/or mucosal lesions BDUMP mimicking multifocal melanoma should be considered making a thorough diagnostic workup mandatory.
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http://dx.doi.org/10.3389/fonc.2021.658407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076566PMC
April 2021

Immune checkpoint inhibition therapy for advanced skin cancer in patients with concomitant hematological malignancy: a retrospective multicenter DeCOG study of 84 patients.

J Immunother Cancer 2020 10;8(2)

Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Background: Skin cancers are known for their strong immunogenicity, which may contribute to a high treatment efficacy of immune checkpoint inhibition (ICI). However, a considerable proportion of patients with skin cancer is immuno-compromised by concomitant diseases. Due to their previous exclusion from clinical trials, the ICI treatment efficacy is poorly investigated in these patients. The present study analyzed the ICI treatment outcome in advanced patients with skin cancer with a concomitant hematological malignancy.

Methods: This retrospective multicenter study included patients who were treated with ICI for locally advanced or metastatic melanoma (MM), cutaneous squamous cell carcinoma (cSCC), or Merkel cell carcinoma (MCC), and had a previous diagnosis of a hematological malignancy irrespective of disease activity or need of therapy at ICI treatment start. Comparator patient cohorts without concomitant hematological malignancy were extracted from the prospective multicenter skin cancer registry ADOREG. Treatment outcome was measured as best overall response, progression-free (PFS), and overall survival (OS).

Results: 84 patients (MM, n=52; cSCC, n=15; MCC, n=17) with concomitant hematological malignancy were identified at 20 skin cancer centers. The most frequent concomitant hematological malignancies were non-Hodgkin's lymphoma (n=70), with chronic lymphocytic leukemia (n=32) being the largest entity. While 9 patients received ICI in an adjuvant setting, 75 patients were treated for advanced non-resectable disease (55 anti-PD-1; 8 anti-PD-L1; 5 anti-CTLA-4; 7 combinations). In the latter 75 patients, best objective response (complete response+partial response) was 28.0%, disease stabilization was 25.3%, and 38.6% showed progressive disease (PD). Subdivided by skin cancer entity, best objective response was 31.1% (MM), 26.7% (cSCC), and 18.8% (MCC). Median PFS was 8.4 months (MM), 4.0 months (cSCC), and 5.7 months (MCC). 1-year OS rates were 78.4% (MM), 65.8% (cSCC), and 47.4% (MCC). Comparison with respective ADOREG patient cohorts without hematological malignancy (n=392) revealed no relevant differences in ICI therapy outcome for MM and MCC, but a significantly reduced PFS for cSCC (p=0.002).

Conclusions: ICI therapy showed efficacy in advanced patients with skin cancer with a concomitant hematological malignancy. Compared with patients without hematological malignancy, the observed ICI therapy outcome was impaired in cSCC, but not in MM or MCC patients.
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http://dx.doi.org/10.1136/jitc-2020-000897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583786PMC
October 2020

Proteomic Profiling of Fibroblasts Isolated from Chronic Wounds Identifies Disease-Relevant Signaling Pathways.

J Invest Dermatol 2020 11 17;140(11):2280-2290.e4. Epub 2020 Apr 17.

Department of Dermatology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Department of Biology, University of Fribourg, Fribourg, Switzerland. Electronic address:

Chronic skin wounds accompany many prevalent age-related diseases and are a major cause of morbidity and mortality. Both keratinocytes and fibroblasts contribute to the pathomechanisms in chronic skin wounds. Dysregulated pathways in the epidermis have been extensively studied, but little is known of the influence of dermal fibroblasts on chronic wounding. We isolated fibroblasts from chronic wounds, propagated them in vitro, and analyzed them using proteomic profiling in combination with functional characterization of the proteomic changes. Chronic wound-associated fibroblasts exhibit a unique proteome profile characteristic of lysosomal dysfunction and dysregulated TGFβ signaling. They display a decreased propensity for cell proliferation and migration, combined with an enhanced ability to contract the extracellular matrix. With these properties, chronic wound-associated fibroblasts actively contribute to pathological inabilities to close wounds and represent potential targets for pharmacological interference for changing cellular phenotypes.
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http://dx.doi.org/10.1016/j.jid.2020.02.040DOI Listing
November 2020

Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients.

J Immunother Cancer 2020 03;8(1)

Center for Dermatooncology, Department of Dermatology, Eberhard Karls University of Tuebingen, Eberhard Karls University of Tuebingen, Tubingen, Germany.

Background: Nivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior local brain radiotherapy were excluded. We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM.

Methods: Patients with MBM treated with nivolumab plus ipilimumab in 23 German Skin Cancer Centers between April 2015 and October 2018 were investigated. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS.

Results: Three hundred and eighty patients were included in this study and 31% had symptomatic MBM (60/193 with data available) at the time of start nivolumab plus ipilimumab. The median follow-up was 18 months and the 2 years and 3 years OS rates were 41% and 30%, respectively. We identified the following independently significant prognostic factors for OS: elevated serum lactate dehydrogenase and protein S100B levels, number of MBM and Eastern Cooperative Oncology Group performance status. In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (p=0.085). In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (p=0.996). Local therapy with stereotactic radiosurgery or surgery led to an improvement in OS compared with not receiving local therapy (p=0.009), regardless of the timepoint of the local therapy. Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (p=0.119).

Conclusion: Immunotherapy with nivolumab plus ipilimumab, particularly in combination with stereotactic radiosurgery or surgery improves OS in asymptomatic and symptomatic MBM.
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http://dx.doi.org/10.1136/jitc-2019-000333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206917PMC
March 2020

MicroRNA-146a regulates immune-related adverse events caused by immune checkpoint inhibitors.

JCI Insight 2020 03 26;5(6). Epub 2020 Mar 26.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany.

Immune checkpoint inhibitor (ICI) therapy has shown a significant benefit in the treatment of a variety of cancer entities. However, immune-related adverse events (irAEs) occur frequently and can lead to ICI treatment termination. MicroRNA-146a (miR-146a) has regulatory functions in immune cells. We observed that mice lacking miR-146a developed markedly more severe irAEs compared with WT mice in several irAE target organs in 2 different murine models. miR-146a-/- mice exhibited increased T cell activation and effector function upon ICI treatment. Moreover, neutrophil numbers in the spleen and the inflamed intestine were highly increased in ICI-treated miR-146a-/- mice. Therapeutic administration of a miR-146a mimic reduced irAE severity. To validate our preclinical findings in patients, we analyzed the effect of a SNP in the MIR146A gene on irAE severity in 167 patients treated with ICIs. We found that the SNP rs2910164 leading to reduced miR-146a expression was associated with an increased risk of developing severe irAEs, reduced progression-free survival, and increased neutrophil counts both at baseline and during ICI therapy. In conclusion, we characterized miR-146a as a molecular target for preventing ICI-mediated autoimmune dysregulation. Furthermore, we identified the MIR146A SNP rs2910164 as a biomarker to predict severe irAE development in ICI-treated patients.
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http://dx.doi.org/10.1172/jci.insight.132334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213806PMC
March 2020

Context Dependent Role of Type 2 Innate Lymphoid Cells in Allergic Skin Inflammation.

Front Immunol 2019 6;10:2591. Epub 2019 Nov 6.

Experimental Dermatology and Allergy Research Group, Department of Dermatology and Allergology, University Medical Center Giessen, Justus Liebig University Giessen, Giessen, Germany.

The discovery of innate lymphoid cells (ILC) has profoundly influenced the understanding of innate and adaptive immune crosstalk in health and disease. ILC and T cells share developmental and functional characteristics such as the lineage-specifying transcription factors and effector cytokines, but importantly ILC do not display rearranged antigen-specific receptors. Similar to T cells ILC are subdivided into 3 different helper-like subtypes, namely ILC1-3, and a killer-like subtype comprising natural killer (NK) cells. Increasing evidence supports the physiological relevance of ILC, e.g., in wound healing and defense against parasites, as well as their pathogenic role in allergy, inflammatory bowel diseases or psoriasis. Group 2 ILC have been attributed to the pathogenesis of allergic diseases like asthma and atopic dermatitis. Other inflammatory skin diseases such as allergic contact dermatitis are profoundly shaped by inflammatory NK cells. This article reviews the role of ILC in allergic skin diseases with a major focus on ILC2. While group 2 ILC are suggested to contribute to the pathogenesis of type 2 dominated inflammation as seen in atopic dermatitis, we have shown that lack of ILC2 in type 1 dominated contact hypersensitivity results in enhanced inflammation, suggesting a regulatory role of ILC2 in this context. We provide a concept of how ILC2 may influence context dependent the mutual counterbalance between type I and type II immune responses in allergic skin diseases.
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http://dx.doi.org/10.3389/fimmu.2019.02591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851052PMC
November 2020

Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone.

Cancer Immunol Immunother 2019 Sep 17;68(9):1417-1428. Epub 2019 Aug 17.

Department of Dermatology and Venereology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Hauptstrasse 7, 79104, Freiburg, Germany.

Systemic immunotherapy with PD-1 inhibitors is established in the treatment of metastatic melanoma. However, up to 60% of patients do not show long-term benefit from a PD-1 inhibitor monotherapy. Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases. Combination therapy of systemic and local immunotherapies is a promising treatment option in melanoma patients. We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4 and CD8 T cells and a higher PD-1 expression in the inflammatory infiltrate of the tumor microenvironment in metastases from patients with subsequent treatment response. All responding patients further showed a profound increase of the absolute eosinophil count (AEC) in the blood. Our case series supports the concept that patients with initial resistance to PD-1 inhibitor therapy and injectable lesions can profit from an additional intralesional IL-2 therapy which was well tolerated. Response to this therapy is accompanied by increase in AEC and a strong T cell-based inflammatory infiltrate.
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http://dx.doi.org/10.1007/s00262-019-02377-xDOI Listing
September 2019

Impact of radiation, systemic therapy and treatment sequencing on survival of patients with melanoma brain metastases.

Eur J Cancer 2019 03 7;110:11-20. Epub 2019 Feb 7.

Skin Cancer Center at the University Cancer Centre, Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; National Center for Tumor Diseases (NCT), Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Background: Combining stereotactic radiosurgery (SRS) and active systemic therapies (STs) achieved favourable survival outcomes in patients with melanoma brain metastases (MBMs) in retrospective analyses. However, several aspects of this treatment strategy remain poorly understood. We report on the overall survival (OS) of patients with MBM treated with a combination of radiotherapy (RT) and ST as well as the impact of the v-Raf murine sarcoma viral oncogene homolog B (BRAF)-V600 mutation (BRAFmut) status, types of RT and ST and their sequence.

Patients And Methods: Data of 208 patients treated with SRS or whole brain radiation therapy (WBRT) and either immunotherapy (IT) or targeted therapy (TT) within a 6-week interval to RT were analysed retrospectively. OS was calculated from RT to death or last follow-up. Univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic features associated with OS.

Results: The median follow-up was 7.3 months. 139 patients received IT, 67 received TT and 2 received IT and TT within 6 weeks to RT (WBRT 45%; SRS 55%). One-year Kaplan-Meier OS rates were 69%, 65%, 33% and 18% (P < .001) for SRS with IT, SRS with TT, WBRT with IT and WBRT with TT, respectively. Patients with a BRAFmut receiving IT combined with RT experienced higher OS rates (88%, 65%, 50% and 18%). TT following RT or started before and continued thereafter was associated with improved median OS compared with TT solely before RT (12.2 [95% confidence interval {CI} 9.3-15.1]; 9.8 [95% CI 6.9-12.6] versus 5.1 [95% CI 2.7-7.5]; P = .03).

Conclusion: SRS and IT achieved the highest OS rates. A BRAFmut appears to be a favourable prognostic factor for OS. For the combination of RT and TT, the sequence appears to be crucial. Combinations of WBRT and ST achieved unprecedentedly high OS rates and warrant further studies.
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http://dx.doi.org/10.1016/j.ejca.2018.12.023DOI Listing
March 2019

The efficacy of re-challenge with BRAF inhibitors after previous progression to BRAF inhibitors in melanoma: A retrospective multicenter study.

Oncotarget 2018 Sep 28;9(76):34336-34346. Epub 2018 Sep 28.

Department of Dermatology and Allergy, University Hospital Munich (LMU), 80337 Munich, Germany.

BRAF and MEK inhibition is efficient in patients with BRAF V600-mutated metastatic melanoma, but due to acquired resistance the duration of response (DoR) is often only short-lived. In this retrospective multicenter study with 60 patients suffering from inoperable or metastatic melanoma we evaluated the efficacy of re-challenge with a BRAF inhibitor (BRAF2) with or without MEK-inhibition after progressive disease upon previous treatment with a BRAF inhibitor (BRAF1) with or without MEK inhibition. Treatment with BRAF1 led to a disease control rate (DCR) of 90% with 12% complete responses (CR), 58% partial responses (PR) and 20% stable diseases (SD), the median progression-free survival (PFS) was 9.9 and DoR 10.7 months. BRAF2 with (68%) or without (32%) additional MEK inhibition was initiated after a median interval of 3.4 months. DCR after re-challenge with BRAF2 was 57%, 8% CR, 20% PR and 28% SD, median PFS was 5.0 and DoR 14.0 months. The duration of the treatment interval or the treatment in the interval did not influence the DCR or PFS to BRAF2. The only predictive factor for response to BRAF2 was previous response to BRAF1; all patients with CR to BRAF1 achieved disease control with BRAF2, but only 60% of the patients with PR to BRAF1 (p=0.002). Addition of MEK inhibition to BRAF2 after treatment with BRAF1 as monotherapy did not significantly increase the DCR or PFS compared to patients treated solely with mono- or combination therapy. In conclusion re-challenge with a BRAF inhibitor is a meaningful therapeutic option for patients with BRAF V600-mutated metastatic melanoma.
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http://dx.doi.org/10.18632/oncotarget.26149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188134PMC
September 2018

Lack of Type 2 Innate Lymphoid Cells Promotes a Type I-Driven Enhanced Immune Response in Contact Hypersensitivity.

J Invest Dermatol 2018 09 9;138(9):1962-1972. Epub 2018 Mar 9.

Allergy Research Group, Department of Dermatology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Experimental Dermatology and Allergy Research Group, Department of Dermatology and Allergology, University Medical Center Giessen and Marburg, Campus Giessen, Justus Liebig University, Giessen, Germany. Electronic address:

Allergic contact dermatitis and its animal model, contact hypersensitivity, are T-cell-mediated inflammatory skin diseases that require activation of the innate immune system. Here we investigate the role of innate lymphoid cells (ILCs) during the elicitation phase of 2,4,6-trinitrochlorobenzene-induced contact hypersensitivity using Eomes x Rorc(γt)-Cre x Rosa26R reporter mice. Ear swelling responses, cutaneous ILC numbers, and cytokine production were determined at different time points. Functional analyses were performed in a CD90.1/.2 congenic adoptive transfer model that allowed selective antibody-mediated depletion of ILCs before hapten challenge, and in RoraIl7r mice, which lack ILC2. Hapten challenge induced early increases of natural killer cells in skin and ear draining lymph nodes corresponding to the peak ear swelling response. In contrast, ILC1, 2, and 3 showed a delayed increase in numbers corresponding to the contact hypersensitivity resolution phase. Hapten challenge induced increased marker cytokines in all ILC subtypes and an activated phenotype in ILC2. Depletion of all ILC resulted in a significantly enhanced ear swelling response. Similarly, ILC2-deficient mice (RoraIl7r) displayed increased ear swelling responses on hapten challenge, suggesting that ILC2 act as negative regulators in the type 1-dominated immune response of contact hypersensitivity.
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http://dx.doi.org/10.1016/j.jid.2018.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117454PMC
September 2018

Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition.

Eur J Cancer 2017 09 22;82:56-65. Epub 2017 Jun 22.

Department of Dermatology and Allergy, University Hospital Munich (LMU), Frauenlobstr. 9-11, 80337 Munich, Germany. Electronic address:

Background: Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date.

Patients And Methods: Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression.

Results: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p = 0.002) as independent risk factors for poor survival. Patients with elevated CRP and LDH and a REC <1.5% were at highest risk for disease progression and death (p = 0.001).

Conclusions: Blood markers predict survival in metastatic UM treated with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high REC may help identify patients with better prognosis.
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http://dx.doi.org/10.1016/j.ejca.2017.05.038DOI Listing
September 2017

Diagnostics in Hymenoptera venom allergy: current concepts and developments with special focus on molecular allergy diagnostics.

Allergo J Int 2017 11;26(3):93-105. Epub 2017 Apr 11.

Department of Dermatology and Venerology, Medical Center - University of Freiburg, Hauptstraße 7, 79104 Freiburg, Germany.

Background: The high rate of asymptomatic sensitization to Hymenoptera venom, difficulty in correctly identifying Hymenoptera and loss of sensitization over time make an accurate diagnosis of Hymenoptera venom allergy challenging. Although routine diagnostic tests encompassing skin tests and the detection of venom-specific IgE antibodies with whole venom preparations are reliable, they offer insufficient precision in the case of double sensitized patients or in those with a history of sting anaphylaxis, in whom sensitization cannot be proven or only to the presumably wrong venom.

Methods: Systematic literature research and review of current concepts of diagnostic testing in Hymenoptera venom allergy.

Results and Discussion: Improvements in diagnostic accuracy over recent years have mainly been due to the increasing use of molecular allergy diagnostics. Detection of specific IgE antibodies to marker and cross-reactive venom allergens improves the discrimination between genuine sensitization and cross-reactivity, and this provides a better rationale for prescribing venom immunotherapy. The basophil activation test has also increased diagnostic accuracy by reducing the number of Hymenoptera venom sensitizations overlooked with routine tests. This paper reviews current concepts of diagnostic testing in Hymenoptera venom allergy and suggests fields for further development.
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http://dx.doi.org/10.1007/s40629-017-0014-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406443PMC
April 2017

Bullous Delayed Pressure Urticaria Responding to Omalizumab.

Acta Derm Venereol 2016 Mar;96(3):416-7

Allergy Research Group, Department of Dermatology, Medical Center - University of Freiburg, Hauptstrasse 7, DE-79104, Freiburg, Germany.

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http://dx.doi.org/10.2340/00015555-2224DOI Listing
March 2016

IgE recognition of chimeric isoforms of the honeybee (Apis mellifera) venom allergen Api m 10 evaluated by protein array technology.

Mol Immunol 2015 Feb 17;63(2):449-55. Epub 2014 Oct 17.

Laboratory of Molecular Entomology and Bee Pathology, Ghent University, Krijgslaan 281 S2, B-9000 Ghent, Belgium. Electronic address:

Api m 10 has recently been established as novel major allergen that is recognized by more than 60% of honeybee venom (HBV) allergic patients. Previous studies suggest Api m 10 protein heterogeneity which may have implications for diagnosis and immunotherapy of HBV allergy. In the present study, RT-PCR revealed the expression of at least nine additional Api m 10 transcript isoforms by the venom glands. Two distinct mechanisms are responsible for the generation of these isoforms: while the previously known variant 2 is produced by an alternative splicing event, novel identified isoforms are intragenic chimeric transcripts. To the best of our knowledge, this is the first report of the identification of chimeric transcripts generated by the honeybee. By a retrospective proteomic analysis we found evidence for the presence of several of these isoforms in the venom proteome. Additionally, we analyzed IgE reactivity to different isoforms by protein array technology using sera from HBV allergic patients, which revealed that IgE recognition of Api m 10 is both isoform- and patient-specific. While it was previously demonstrated that the majority of HBV allergic patients display IgE reactivity to variant 2, our study also shows that some patients lacking IgE antibodies for variant 2 display IgE reactivity to two of the novel identified Api m 10 variants, i.e. variants 3 and 4.
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http://dx.doi.org/10.1016/j.molimm.2014.09.018DOI Listing
February 2015

Pruritic intertriginous vesiculopustular eruption.

J Dtsch Dermatol Ges 2014 Sep 1;12(9):827-30. Epub 2014 Aug 1.

Department of Dermatology, Medical Center - University of Freiburg.

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http://dx.doi.org/10.1111/ddg.12329DOI Listing
September 2014

Recombinant allergens rarely allow identification of Hymenoptera venom-allergic patients with negative specific IgE to whole venom preparations.

J Allergy Clin Immunol 2014 Aug;134(2):493-4

Department of Dermatology, Allergy Research Group, Medical Center - University of Freiburg, Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2014.05.035DOI Listing
August 2014
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