Publications by authors named "Jürgen C Becker"

266 Publications

New Insights into the Biological and Clinical Aspects of Merkel Cell Carcinoma.

Cancers (Basel) 2021 May 8;13(9). Epub 2021 May 8.

Translational Skin Cancer Research, German Cancer Consortium (DKTK), 45151 Essen, Germany.

The Special Issue in , "The Biological and Clinical Aspects of Merkel Cell Carcinoma", walks the avid reader through the interesting and sometimes even mysterious facets of Merkel cell carcinoma (MCC), starting at its carcinogenesis to also cover innovative treatment options [...].
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http://dx.doi.org/10.3390/cancers13092259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125810PMC
May 2021

Expression of Mismatch Repair Proteins in Merkel Cell Carcinoma.

Cancers (Basel) 2021 May 21;13(11). Epub 2021 May 21.

Institute for Prevention and Occupational Medicine of the German Social Accident Insurances (IPA), Ruhr-University Bochum, 44789 Bochum, Germany.

We aimed to assess for the first time the mismatch repair (MMR) protein expression in Merkel cell carcinoma (MCC). Immunohistochemistry was performed for MLH1, MSH2, MSH6, and PMS2 on patients' tumor tissue ( = 56), including neighbored healthy control tissue. In cases with low-level MMR expression (<10th percentile), we performed multiplex PCR in combination with high-resolution capillary electrophoresis in order to confirm microsatellite instability (MSI). Microscopic evaluation revealed a high median expression for all MMR proteins studied (91.6-96.3%). However, six patients (56/10.7%) had low-level MLH1 expression, six (55/10.9%) had low-level MSH2 expression, five (56/8.9%) had low-level MSH6 expression, and six (54/11.1%) had low-level PMS2 expression. Together, we observed nine (56/16.1%) patients who had low-level MMR expression of at least one protein. Of the patients with low-level MMR expression, MSI evaluation was possible in five cases, revealing one case with high-level MSI. In all MMR proteins assessed, low-level expression was significantly ( = 0.0004 to < 0.0001) associated with a negative Merkel cell polyomavirus (MCPyV) status. However, the expression profiles of the MMR proteins did not correlate with clinical outcome measures such as disease relapse or death ( > 0.05). MCC appears to be a malignancy characterized by low-level MMR rather than completely deficient MMR in a subset of cases, predominantly affecting MCPyV-negative tumors. Future studies will establish whether this subset of MCC patients respond better to immune checkpoint inhibitor therapy.
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http://dx.doi.org/10.3390/cancers13112524DOI Listing
May 2021

Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer.

Cancer Treat Rev 2021 Jun 2;97:102172. Epub 2021 Mar 2.

Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.

Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects. Here, we outline ongoing trials and review the rationale and evidence for the combination of avelumab, an anti-programmed death ligand 1 (PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody (mAb), with cetuximab, an anti-epidermal growth factor receptor (EGFR) IgG1 mAb. Avelumab is approved as a monotherapy for the treatment of Merkel cell carcinoma and urothelial carcinoma, and in combination with axitinib for renal cell carcinoma; cetuximab is approved in combination with chemotherapy for the treatment of squamous cell carcinoma of the head and neck (SCCHN) and RAS wild-type metastatic colorectal cancer, and in combination with radiation therapy for SCCHN. Avelumab binds to PD-L1 expressed on tumor cells and immune regulatory cells, thus blocking its interaction with programmed death 1 and reventing T-cell suppression; cetuximab inhibits the EGFR signaling pathway, inhibiting proliferation and inducing apoptosis. Both therapies have complementary mechanisms of action and may also activate the immune system to induce innate effector function through the binding of their Fc regions to natural killer (NK) cells. Furthermore, cetuximab combined with chemotherapy has been shown to induce immunogenic cell death and leads to an increase in tumor-infiltrating CD8+ T and NK cells, which should synergize with the immunostimulatory effects of avelumab. Prospective studies will investigate this combination and inform future treatment strategies.
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http://dx.doi.org/10.1016/j.ctrv.2021.102172DOI Listing
June 2021

Staphylococcus aureus Induces Signal Transducer and Activator of Transcription 5‒Dependent miR-155 Expression in Cutaneous T-Cell Lymphoma.

J Invest Dermatol 2021 Apr 20. Epub 2021 Apr 20.

LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Staphylococcal enterotoxins are believed to fuel disease activity in cutaneous T-cell lymphoma. Recent data support this by showing that antibiotics inhibit malignant T cells in skin lesions in mycosis fungoides and Sézary syndrome, the most common forms of cutaneous T-cell lymphoma. Yet, it remains incompletely characterized how staphylococcal enterotoxins fuel disease activity. In this study, we show that staphylococcal enterotoxins induce the expression of the oncogenic microRNA miR-155 in primary malignant T cells. Thus, staphylococcal enterotoxins and Staphyloccocus aureus isolates from lesional skin of patients induce miR-155 expression at least partly through the IL-2Rg‒Jak‒signal transducer and activator of transcription 5 pathway, and the effect is augmented by the presence of nonmalignant T cells. Importantly, mycosis fungoides lesions harbor S. aureus, express Y-phosphorylated signal transducer and activator of transcription 5, and display enhanced miR-155 expression, when compared with nonlesional and healthy skin. Preliminary data show that aggressive antibiotic therapy is associated with decreased Y-phosphorylated signal transducer and activator of transcription 5 and miR-155 expression in lesional skin in two patients with Sézary syndrome. In conclusion, we show that S. aureus and its enterotoxins induce enhanced expression of oncogenic miR-155, providing mechanistic insight into the role of S. aureus in cutaneous T-cell lymphoma. Our findings support that environmental stimuli such as bacteria can fuel disease progression in cutaneous T-cell lymphoma.
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http://dx.doi.org/10.1016/j.jid.2021.01.038DOI Listing
April 2021

Expression of Potential Targets for Cell-Based Therapies on Melanoma Cells.

Life (Basel) 2021 Mar 24;11(4). Epub 2021 Mar 24.

Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany.

Tumor antigen-specific redirection of cytotoxic T cells (CTLs) or natural killer (NK) cells including chimeric antigen receptor (CAR-) and T cell receptor (TCR-) cell therapy is currently being evaluated in different tumor entities including melanoma. Expression of melanoma-specific antigen recognized by the respective CAR or TCR directly or presented by HLA molecules is an indispensable prerequisite for this innovative therapy. In this study, we investigated in 168 FFPE tumor specimens of patients with stage I-IV melanoma the protein expression of HER2, TRP2, ABCB5, gp100, p53, and GD2 by immunohistochemistry (IHC). These results were correlated with clinical parameters. Membrane expression of HER2 and GD2 was also investigated in ten melanoma cell lines by flow cytometry for which corresponding tumors were analyzed by IHC. Our results demonstrated that gp100 was the most frequently overexpressed protein (61%), followed by TRP2 (50%), GD2 (38%), p53 (37%), ABCB5 (17%), and HER2 (3%). TRP2 expression was higher in primary tumors compared to metastases ( = 0.005). Accordingly, TRP2 and ABCB5 expression was significantly associated with lower tumor thickness of the primary ( = 0.013 and = 0.025). There was no association between protein expression levels and survival in advanced melanoma patients. Flow cytometric analysis revealed abundant surface expression of GD2 and HER2 in all melanoma cell lines. The discordant HER2 expression in situ and in vitro suggests a tissue culture associated induction. In summary, our data support the use of gp100 and GD2 as a potential target for developing engineered TCR- or CAR-cell therapies, respectively, against melanoma.
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http://dx.doi.org/10.3390/life11040269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064084PMC
March 2021

Classical and Variant Merkel Cell Carcinoma Cell Lines Display Different Degrees of Neuroendocrine Differentiation and Epithelial-Mesenchymal Transition.

J Invest Dermatol 2021 Feb 16. Epub 2021 Feb 16.

Group of Translational Skin Cancer Research (TSCR), University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, University Hospital Essen, Essen, Germany. Electronic address:

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer characterized by high invasiveness, early metastases, and high mortality. Because of the lack of suitable animal models, most functional studies are performed using cell lines, some of which lack classical neuroendocrine growth characteristics. Here, we scrutinized the molecular characteristics of classical MCC and variant MCC cell lines by differential gene expression and the respective epigenetic regulation by microRNAs and DNA methylation. Cutaneous squamous cell carcinoma cell lines were used for comparison. The most striking observation was a lower expression of epithelial-mesenchymal transition-related genes in classical MCCs, which was accompanied by higher expression of the epithelial-mesenchymal transition-regulating microRNA clusters miR-200c-141 and miR-183-96-182 and hypomethylation of the respective microRNA loci. Experimental expression of the MCC lineage factor ATOH1 in variant MCCs resulted in an increased expression of miR-200c-141 paralleled by a reduction of genes associated with epithelial-mesenchymal transition, thus demonstrating a connection between neuroendocrine characteristics and the lack of epithelial-mesenchymal transition. Together, our observations not only reinforce concerns about the use of variant MCCs as proper MCC representatives, but also suggest variant MCCs as cells locked in an intermediate state between neuroendocrine and epithelial differentiation.
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http://dx.doi.org/10.1016/j.jid.2021.01.012DOI Listing
February 2021

Mutational Landscape of Virus- and UV-Associated Merkel Cell Carcinoma Cell Lines Is Comparable to Tumor Tissue.

Cancers (Basel) 2021 Feb 5;13(4). Epub 2021 Feb 5.

Translational Skin Cancer Research, German Cancer Consortium (DKTK), 45141 Essen, Germany.

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous malignancy that is either associated with the integration of the Merkel cell polyomavirus or chronic UV exposure. These two types of carcinogenesis are reflected in characteristic mutational features present in MCC tumor lesions. However, the genomic characteristics of MCC cell lines used as preclinical models are not well established. Thus, we analyzed the exomes of three virus-negative and six virus-positive MCC cell lines, all showing a classical neuroendocrine growth pattern. Virus-negative cell lines are characterized by a high tumor mutational burden (TMB), UV-light-induced DNA damage, functionally relevant coding mutations, e.g., in and , and large amounts of copy number variations (CNVs). In contrast, virus-positive cell lines have a low TMB with few coding mutations and lack prominent mutational signatures, but harbor characteristic CNVs. One of the virus-negative cell lines has a local amplification associated with high mRNA expression. In conclusion, virus-positive and -negative MCC cell lines with a neuroendocrine growth pattern resemble mutational features observed in MCC tissue samples, which strengthens their utility for functional studies.
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http://dx.doi.org/10.3390/cancers13040649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914758PMC
February 2021

Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma.

Cancer Immunol Immunother 2021 Jul 13;70(7):2087-2093. Epub 2021 Jan 13.

Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany.

Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cutaneous malignancy with poor prognosis. In Europe, approved systemic therapies are limited to the PD-L1 inhibitor avelumab. For avelumab-refractory patients, efficient and safe treatment options are lacking.

Methods: At three different sites in Germany, clinical and molecular data of patients with metastatic MCC being refractory to the PD-L1 inhibitor avelumab and who were later on treated with combined IPI/NIVO were retrospectively collected and evaluated.

Results: Five patients treated at three different academic sites in Germany were enrolled. Three out of five patients investigated for this report responded to combined IPI/NIVO according to RECIST 1.1. Combined immunotherapy was well tolerated without any grade II or III immune-related adverse events. Two out of three responders to IPI/NIVO received platinum-based chemotherapy in between avelumab and combined immunotherapy.

Conclusion: In this small retrospective study, we observed a high response rate and durable responses to subsequent combined immunotherapy with IPI/NIVO in avelumab-refractory metastatic MCC patients. In conclusion, our data suggest a promising activity of second- or third-line PD-1- plus CTLA-4-blockade in patients with anti-PD-L1-refractory MCC.
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http://dx.doi.org/10.1007/s00262-020-02832-0DOI Listing
July 2021

Merkel cell carcinoma-derived exosome-shuttle miR-375 induces fibroblast polarization by inhibition of RBPJ and p53.

Oncogene 2021 Feb 11;40(5):980-996. Epub 2020 Dec 11.

Department of Translational Skin Cancer Research, University Hospital Essen, Essen, Germany.

Merkel cell carcinoma (MCC) is a highly invasive and metastatic skin cancer. While high expression of miR-375 is a characteristic of MCC, it seems not to contribute to the malignant phenotype of MCC cells. miR-375 enrichment in MCC-derived extracellular vesicles suggests its intercellular signaling function. Here, we demonstrate that horizontally transferred miR-375 causes fibroblast polarization toward cancer-associated fibroblasts (CAFs). The polarization is evidenced by phenotypic changes and induction of α-SMA, CXCL2, and IL-1β. Fibroblast polarization is inhibited by specific antagomirs and mimicked by experimental miR-375 expression. Mechanistically, miR-375 downregulates RBPJ and p53, two key players regulating fibroblast polarization. In clinical MCC samples, in situ hybridization located miR-375 in CAFs, which correlated with high α-SMA protein and low RBPJ and TP53 expression; single-cell RNAseq revealed a disparate fibroblast polarization negatively correlating with p53 pathway-related gene expression. Thus, the functional role of miR-375 in MCC is to generate a pro-tumorigenic microenvironment by inducing fibroblast polarization.
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http://dx.doi.org/10.1038/s41388-020-01576-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862059PMC
February 2021

BRAF and MEK inhibition in melanoma patients enables reprogramming of tumor infiltrating lymphocytes.

Cancer Immunol Immunother 2021 Jun 4;70(6):1635-1647. Epub 2020 Dec 4.

Deutsches Konsortium Für Translationale Krebsforschung (DKTK), Partner Site Essen, Translational Skin Cancer Research, University of Duisburg-Essen, Universitätsstr. 1, 45141, Essen, Germany.

Background: Combined inhibition of BRAF/MEK is an established therapy for melanoma. In addition to its canonical mode of action, effects of BRAF/MEK inhibitors on antitumor immune responses are emerging. Thus, we investigated the effect of these on adaptive immune responses.

Patients, Methods And Results: Sequential tumor biopsies obtained before and during BRAF/MEK inhibitor treatment of four (n = 4) melanoma patients were analyzed. Multiplexed immunofluorescence staining of tumor tissue revealed an increased infiltration of CD4 and CD8 T cells upon therapy. Determination of the T-cell receptor repertoire usage demonstrated a therapy induced increase in T-cell clonotype richness and diversity. Application of the Grouping of Lymphocyte Interactions by Paratope Hotspots algorithm revealed a pre-existing immune response against melanoma differentiation and cancer testis antigens that expanded preferentially upon therapy. Indeed, most of the T-cell clonotypes found under BRAF/MEK inhibition were already present in lower numbers before therapy. This expansion appears to be facilitated by induction of T-bet and TCF7 in T cells, two transcription factors required for self-renewal and persistence of CD8 memory T cells.

Conclusions: Our results suggest that BRAF/MEK inhibition in melanoma patients allows an increased expansion of pre-existing melanoma-specific T cells by induction of T-bet and TCF7 in these.
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http://dx.doi.org/10.1007/s00262-020-02804-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139931PMC
June 2021

Cancer and Immune Checkpoint Inhibitor Treatment in the Era of SARS-CoV-2 Infection.

Cancers (Basel) 2020 Nov 16;12(11). Epub 2020 Nov 16.

Translational Skin Cancer Research, German Cancer Consortium (DKTK), Dermatology, University Duisburg-Essen, 45141 Essen, Germany.

Whether cancer patients receiving immune checkpoint inhibitors (ICI) are at an increased risk of severe infection and mortality during the corona pandemic is a hotly debated topic that will continue to evolve. Here, we summarize and discuss current studies regarding COVID-19 and anti-cancer treatment with an emphasis on ICI. Importantly, several lines of evidence suggest that patients currently treated with ICI do not display an increased vulnerability to infection with SARS-CoV-2. Data regarding morbidity and mortality associated with COVID-19 in cancer patients receiving ICI are less clear and often conflicting. Although mostly based on experimental data, it is possible that ICI can promote the exacerbated immune response associated with adverse outcome in COVID-19 patients. On the other hand, mounting evidence suggests that ICI might even be useful in the treatment of viral infections by preventing or ameliorating T cell exhaustion. In this context, the right timing of treatment might be essential. Nevertheless, some cancer patients treated with ICI experience autoimmune-related side effects that require the use of immunosuppressive therapies, which in turn may promote a severe course of infection with SARS-CoV-2. Although there is clear evidence that withholding ICI will have more serious consequences, further studies are urgently needed in to better evaluate the effects of ICI in patients with COVID-19 and the use of ICI during the corona pandemic in general.
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http://dx.doi.org/10.3390/cancers12113383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698088PMC
November 2020

Patched 1 expression in Merkel cell carcinoma.

J Dermatol 2021 Jan 12;48(1):64-74. Epub 2020 Nov 12.

Department of Dermatology, Translational Skin Cancer Research, German Cancer Consortium (DKTK) Partner Site Essen/Düsseldorf, University Duisburg-Essen, Essen, Germany.

The relevance of Hedgehog signaling in Merkel cell carcinoma has only been addressed by a few studies with conflicting results. Thus, we aimed to establish the expression of Hedgehog signaling molecules in Merkel cell carcinoma to characterize causes of aberrant expression and to correlate these findings with the clinical course of the patients. Immunohistochemistry was performed for Sonic, Indian, Patched 1 (PTCH1) and Smoothened on patients' tumor tissue. Respective mRNA expression was analyzed in 10 Merkel cell carcinoma cell lines using quantitative real-time polymerase chain reaction. PTCH1 sequencing and DNA methylation microarray analyses were carried out on tumor tissues as well as cell lines. PTCH1 immunoreactivity in Merkel cell carcinoma was similar to that of basal cell carcinomas, which both significantly differed from PTCH1 immunoreactivity in healthy skin. Most PTCH1 mutations found were synonymous or without known functional impact. However, on average, the promoter regions of both PTCH1 were hypomethylated independently from PTCH1 gene expression or Merkel cell polyomavirus status. PTCH1 and GLI1/2/3 genes were differently expressed in different cell lines; notably, there was a significant correlation between GLI2 and PTCH1 mRNA expression. Similar to PTCH1 protein expression in patient tissues, PTCH1 gene expression in Merkel cell carcinoma cell lines is highly variable, but due to the similar methylation pattern across Merkel cell carcinoma cell lines, effects other than methylation seem to be the reason for the differential expression and PTCH1 appears to be upregulated by GLI as a classical Hedgehog target gene.
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http://dx.doi.org/10.1111/1346-8138.15611DOI Listing
January 2021

The HDAC Inhibitor Domatinostat Promotes Cell-Cycle Arrest, Induces Apoptosis, and Increases Immunogenicity of Merkel Cell Carcinoma Cells.

J Invest Dermatol 2021 Apr 28;141(4):903-912.e4. Epub 2020 Sep 28.

Department of Translational Skin Cancer Research (TSCR), German Cancer Consortium (DKTK), Partner Site Essen, German Cancer Research Center, Heidelberg, Germany; Department of Dermatology, University Hospital Essen, Essen, Germany. Electronic address:

Merkel cell carcinoma (MCC) is a rare, highly aggressive skin cancer for which immune modulation by immune checkpoint inhibitors shows remarkable response rates. However, primary or secondary resistance to immunotherapy prevents benefits in a significant proportion of patients. For MCC, one immune escape mechanism is insufficient for recognition by T cells owing to the downregulation of major histocompatibility complex I surface expression. Histone deacetylase inhibitors have been demonstrated to epigenetically reverse the low major histocompatibility complex I expression caused by the downregulation of the antigen-processing machinery. Domatinostat, an orally available small-molecule inhibitor targeting histone deacetylase class I, is currently in clinical evaluation to overcome resistance to immunotherapy. In this study, we present preclinical data on domatinostat's efficacy and mode of action in MCC. Single-cell RNA sequencing revealed a distinct gene expression signature of antigen processing and presentation, cell-cycle arrest, and execution phase of apoptosis on treatment. Accordingly, functional assays showed that domatinostat induced G2M arrest and apoptosis. In the surviving cells, antigen-processing machinery component gene transcription and translation were upregulated, consequently resulting in increased major histocompatibility complex I surface expression. Altogether, domatinostat not only exerts direct antitumoral effects but also restores HLA class I surface expression on MCC cells, therefore, restoring surviving MCC cells' susceptibility to recognition and elimination by cognate cytotoxic T cells.
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http://dx.doi.org/10.1016/j.jid.2020.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987731PMC
April 2021

UV-type specific alteration of miRNA expression and its association with tumor progression and metastasis in SCC cell lines.

J Cancer Res Clin Oncol 2020 Dec 31;146(12):3215-3231. Epub 2020 Aug 31.

Division of Molecular Cell Biology, Skin Cancer Center, Elbe Kliniken Stade-Buxtehude, 21614, Buxtehude, Germany.

Purpose: UV exposure is the main risk factor for development of cutaneous squamous cell carcinoma (cSCC). While early detection greatly improves cSCC prognosis, locally advanced or metastatic cSCC has a severely impaired prognosis. Notably, the mechanisms of progression to metastatic cSCC are not well understood. We hypothesized that UV exposure of already transformed epithelial cSCC cells further induces changes which might be involved in the progression to metastatic cSCCs and that UV-inducible microRNAs (miRNAs) might play an important role.

Methods: Thus, we analyzed the impact of UV radiation of different quality (UVA, UVB, UVA + UVB) on the miRNA expression pattern in established cell lines generated from primary and metastatic cSCCs (Met-1, Met-4) using the NanoString nCounter platform.

Results: This analysis revealed that the expression pattern of miRNAs depends on both the cell line used per se and on the quality of UV radiation. Comparison of UV-induced miRNAs in cSCC cell lines established from a primary tumor (Met-1) and the respective (un-irradiated) metastasis (Met-4) suggest that miR-7-5p, miR-29a-3p and miR-183-5p are involved in a UV-driven pathway of progression to metastasis. This notion is supported by the fact that these three miRNAs build up a network of 81 potential target genes involved e.g. in UVA/UVB-induced MAPK signaling and regulation of the epithelial-mesenchymal transition. As an example, PTEN, a target of UV-upregulated miRNAs (miR-29a-3p, miR-183-5p), could be shown to be down-regulated in response to UV radiation. We further identified CNOT8, the transcription complex subunit 8 of the CCR4-NOT complex, a deadenylase removing the poly(A) tail from miRNA-destabilized mRNAs, in the center of this network, targeted by all three miRNAs.

Conclusion: In summary, our results demonstrate that UV radiation induces an miRNA expression pattern in primary SCC cell line partly resembling those of metastatic cell line, thus suggesting that UV radiation impacts SCC progression beyond initiation.
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http://dx.doi.org/10.1007/s00432-020-03358-9DOI Listing
December 2020

High-resolution analysis of Merkel Cell Polyomavirus in Merkel Cell Carcinoma reveals distinct integration patterns and suggests NHEJ and MMBIR as underlying mechanisms.

PLoS Pathog 2020 08 24;16(8):e1008562. Epub 2020 Aug 24.

Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Merkel Cell Polyomavirus (MCPyV) is the etiological agent of the majority of Merkel Cell Carcinomas (MCC). MCPyV positive MCCs harbor integrated, defective viral genomes that constitutively express viral oncogenes. Which molecular mechanisms promote viral integration, if distinct integration patterns exist, and if integration occurs preferentially at loci with specific chromatin states is unknown. We here combined short and long-read (nanopore) next-generation sequencing and present the first high-resolution analysis of integration site structure in MCC cell lines as well as primary tumor material. We find two main types of integration site structure: Linear patterns with chromosomal breakpoints that map closely together, and complex integration loci that exhibit local amplification of genomic sequences flanking the viral DNA. Sequence analysis suggests that linear patterns are produced during viral replication by integration of defective/linear genomes into host DNA double strand breaks via non-homologous end joining, NHEJ. In contrast, our data strongly suggest that complex integration patterns are mediated by microhomology-mediated break-induced replication, MMBIR. Furthermore, we show by ChIP-Seq and RNA-Seq analysis that MCPyV preferably integrates in open chromatin and provide evidence that viral oncogene expression is driven by the viral promoter region, rather than transcription from juxtaposed host promoters. Taken together, our data explain the characteristics of MCPyV integration and may also provide a model for integration of other oncogenic DNA viruses such as papillomaviruses.
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http://dx.doi.org/10.1371/journal.ppat.1008562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470373PMC
August 2020

Differences in site-specific incidence and relative survival of cutaneous and mucocutaneous genital squamous cell carcinoma in Germany, 2007-2015.

Int J Cancer 2020 11 18;147(10):2772-2779. Epub 2020 Jun 18.

Cancer Registry of North Rhine-Westphalia, Bochum, Germany.

Direct comparisons of the incidence and survival of cutaneous vs mucocutaneous genital squamous cell carcinomas (SCCs) are lacking even though they may bring important insights. We aimed to compare incidence rates and survival of cutaneous and mucocutaneous genital SCCs head-to-head, using the same source population, cancer registry methodology and statistical methods in a population of predominantly white Caucasian descent. Using data (2007-2015) from the population-based cancer registry of North Rhine-Westphalia, (population of 18 million people), we estimated age-specific and age-standardized (old European standard) incidence rates and age-standardized relative 5-year survival of SCC with the period approach for the period 2012 to 2015. Overall, 83 650 SCC cases were registered. The age-standardized incidence rates (per 100 000 person-years) of cutaneous SCCs were 36.5 (SE 0.17) and 17.0 (SE 0.11) among men and women, respectively, with corresponding rates for mucocutaneous genital skin, 1.3 (SE 0.03) and 4.5 (SE 0.06) for men and women, respectively. In all age groups, incidence rates of mucocutaneous genital SCCs were higher in women than men. Men had higher cutaneous SCC incidence at all nongenital subsites than women, with the exception of the lower extremities. Five-year relative survival was considerably lower for mucocutaneous genital SCCs (men: 71%, women: 75%), especially of the scrotal skin (67%) and labia majora (62%) than for SCC of nongenital skin (men: 93%, women: 97%). Given their relatively high incidence together with a lower survival probability, future studies are warranted to establish therapies for advanced mucocutaneous genital SCC, such as immune checkpoint inhibition.
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http://dx.doi.org/10.1002/ijc.33109DOI Listing
November 2020

A digital mRNA expression signature to classify challenging Spitzoid melanocytic neoplasms.

FEBS Open Bio 2020 07 5;10(7):1326-1341. Epub 2020 Jun 5.

Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+), Maastricht, the Netherlands.

Spitzoid neoplasms are a challenging group of cutaneous melanocytic proliferations. They are characterized by epithelioid and/or spindle-shaped melanocytes and classified as benign Spitz nevi (SN), atypical Spitz tumors (AST), or malignant Spitz tumors (MST). The intermediate AST category represents a diagnostically challenging group since on purely histopathological grounds, their benign or malignant character remains unpredictable. This results in uncertainties in patient treatment and prognosis. The molecular properties of Spitzoid lesions, especially their transcriptomic landscape, remain poorly understood, and genomic alterations in melanoma-associated oncogenes are typically absent. The aim of this study was to characterize their transcriptome with digital mRNA expression profiling. Formalin-fixed paraffin-embedded samples (including 27 SN, 10 AST, and 14 MST) were analyzed using the NanoString nCounter PanCancer Pathways Panel. The number of significantly differentially expressed genes in SN vs. MST, SN vs. AST, and AST vs. MST was 68, 167, and 18, respectively. Gene set enrichment analysis revealed upregulation of pathways related to epithelial-mesenchymal transition and immunomodulatory-, angiogenesis-, hormonal-, and myogenesis-associated processes in AST and MST. A molecular signature of SN vs. MST was discovered based on the top-ranked most informative genes: NRAS, NF1, BMP2, EIF2B4, IFNA17, and FZD9. The AST samples showed intermediate levels of the identified signature. This implies that the gene signature can potentially be used to distinguish high-grade from low-grade AST with a larger study cohort in the future. This combined histopathological and transcriptomic methodology is promising for prospective diagnostics of Spitzoid neoplasms and patient management in dermatological oncology.
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http://dx.doi.org/10.1002/2211-5463.12897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327909PMC
July 2020

Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy.

J Clin Invest 2020 08;130(8):4266-4281

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

Understanding tumor resistance to T cell immunotherapies is critical to improve patient outcomes. Our study revealed a role for transcriptional suppression of the tumor-intrinsic HLA class I (HLA-I) antigen processing and presentation machinery (APM) in therapy resistance. Low HLA-I APM mRNA levels in melanoma metastases before immune checkpoint blockade (ICB) correlated with nonresponsiveness to therapy and poor clinical outcome. Patient-derived melanoma cells with silenced HLA-I APM escaped recognition by autologous CD8+ T cells. However, targeted activation of the innate immunoreceptor RIG-I initiated de novo HLA-I APM transcription, thereby overcoming T cell resistance. Antigen presentation was restored in interferon-sensitive (IFN-sensitive) but also immunoedited IFN-resistant melanoma models through RIG-I-dependent stimulation of an IFN-independent salvage pathway involving IRF1 and IRF3. Likewise, enhanced HLA-I APM expression was detected in RIG-Ihi (DDX58hi) melanoma biopsies, correlating with improved patient survival. Induction of HLA-I APM by RIG-I synergized with antibodies blocking PD-1 and TIGIT inhibitory checkpoints in boosting the antitumor T cell activity of ICB nonresponders. Overall, the herein-identified IFN-independent effect of RIG-I on tumor antigen presentation and T cell recognition proposes innate immunoreceptor targeting as a strategy to overcome intrinsic T cell resistance of IFN-sensitive and IFN-resistant melanomas and improve clinical outcomes in immunotherapy.
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http://dx.doi.org/10.1172/JCI131572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410049PMC
August 2020

Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial.

Lancet 2020 05;395(10236):1558-1568

Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), University of Duisburg-Essen, Essen, Germany. Electronic address:

Background: Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced-ie, unresectable or metastatic-melanoma. This criterion, however, excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population.

Methods: We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1-12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing.

Findings: Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n=56), nivolumab (n=59), or placebo (n=52). As of July 2, 2019, at a median follow-up of 28·4 months (IQR 17·7-36·8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12·4 months (95% CI 5·3-33·3) in the nivolumab group and 6·4 months (3·3-9·6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0·23 (97·5% CI 0·12-0·45; p<0·0001), and for the nivolumab group versus placebo group was 0·56 (0·33-0·94; p=0·011). In the nivolumab plus ipilimumab group, recurrence-free survival at 1 year was 75% (95% CI 61·0-84·9) and at 2 years was 70% (55·1-81·0); in the nivolumab group, 1-year recurrence-free survival was 52% (38·1-63·9) and at 2 years was 42% (28·6-54·5); and in the placebo group, this rate was 32% (19·8-45·3) at 1 year and 14% (5·9-25·7) at 2 years. Treatment-related grade 3-4 adverse events were reported in 71% (95% CI 57-82) of patients in the nivolumab plus ipilimumab group and in 27% (16-40) of those in the nivolumab group. Treatment-related adverse events of any grade led to treatment discontinuation in 34 (62%) of 55 patients in the nivolumab plus ipilimumab group and seven (13%) of 56 in the nivolumab group. Three deaths from adverse events were reported but were considered unrelated to the study treatment.

Interpretation: Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3-4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease.

Funding: Bristol-Myers Squibb.
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http://dx.doi.org/10.1016/S0140-6736(20)30417-7DOI Listing
May 2020

MicroRNAs in the Pathogenesis, Diagnosis, Prognosis and Targeted Treatment of Cutaneous T-Cell Lymphomas.

Cancers (Basel) 2020 May 13;12(5). Epub 2020 May 13.

LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark.

Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of potentially devastating primary skin malignancies. Despite decades of intense research efforts, the pathogenesis is still not fully understood. In the early stages, both clinical and histopathological diagnosis is often difficult due to the ability of CTCL to masquerade as benign skin inflammatory dermatoses. Due to a lack of reliable biomarkers, it is also difficult to predict which patients will respond to therapy or progress towards severe recalcitrant disease. In this review, we discuss recent discoveries concerning dysregulated microRNA (miR) expression and putative pathological roles of oncogenic and tumor suppressive miRs in CTCL. We also focus on the interplay between miRs, histone deacetylase inhibitors, and oncogenic signaling pathways in malignant T cells as well as the impact of miRs in shaping the inflammatory tumor microenvironment. We highlight the potential use of miRs as diagnostic and prognostic markers, as well as their potential as therapeutic targets. Finally, we propose that the combined use of miR-modulating compounds with epigenetic drugs may provide a novel avenue for boosting the clinical efficacy of existing anti-cancer therapies in CTCL.
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http://dx.doi.org/10.3390/cancers12051229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281391PMC
May 2020

Staphylococcus aureus enterotoxins induce FOXP3 in neoplastic T cells in Sézary syndrome.

Blood Cancer J 2020 05 14;10(5):57. Epub 2020 May 14.

Department of Immunology and Microbiology; LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark.

Sézary syndrome (SS) is a heterogeneous leukemic subtype of cutaneous T-cell lymphoma (CTCL) with generalized erythroderma, lymphadenopathy, and a poor prognosis. Advanced disease is invariably associated with severe immune dysregulation and the majority of patients die from infectious complications caused by microorganisms such as, Staphylococcus aureus, rather than from the lymphoma per se. Here, we examined if staphylococcal enterotoxins (SE) may shape the phenotype of malignant SS cells, including expression of the regulatory T-cell-associated marker FOXP3. Our studies with primary and cultured malignant cells show that SE induce expression of FOXP3 in malignant cells when exposed to nonmalignant cells. Mutations in the MHC class II binding domain of SE-A (SEA) largely block the effect indicating that the response relies at least in part on the MHC class II-mediated antigen presentation. Transwell experiments show that the effect is induced by soluble factors, partly blocked by anti-IL-2 antibody, and depends on STAT5 activation in malignant cells. Collectively, these findings show that SE stimulate nonmalignant cells to induce FOXP3 expression in malignant cells. Thus, differences in exposure to environmental factors, such as bacterial toxins may explain the heterogeneous FOXP3 expression in malignant cells in SS.
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http://dx.doi.org/10.1038/s41408-020-0324-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225173PMC
May 2020

Impact of a preceding radiotherapy on the outcome of immune checkpoint inhibition in metastatic melanoma: a multicenter retrospective cohort study of the DeCOG.

J Immunother Cancer 2020 05;8(1)

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

Background: Immune checkpoint inhibition (ICI) is an essential treatment option in melanoma. Its outcome may be improved by a preceding radiation of metastases. This study aimed to investigate the impact of a preceding radiotherapy on the clinical outcome of ICI treatment.

Methods: This multicenter retrospective cohort study included patients who received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or anti-programmed cell death protein 1 (PD-1) ICI with or without preceding radiotherapy for unresectable metastatic melanoma. ICI therapy outcome was measured as best overall response (BOR), progression-free (PFS) and overall survival (OS). Response and survival analyses were adjusted for confounders identified by directed acyclic graphs. Adjusted survival curves were calculated using inverse probability treatment weighting.

Results: 835 patients who received ICI (anti-CTLA-4, n=596; anti-PD-1, n=239) at 16 centers were analyzed, whereof 235 received a preceding radiotherapy of metastatic lesions in stage IV disease. The most frequent organ sites irradiated prior to ICI therapy were brain (51.1%), lymph nodes (17.9%) and bone (17.9%). After multivariable adjustment for confounders, no relevant differences in ICI therapy outcome were observed between cohorts with and without preceding radiotherapy. BOR was 8.7% vs 13.0% for anti-CTLA-4 (adjusted relative risk (RR)=1.47; 95% CI=0.81 to 2.65; p=0.20), and 16.5% vs 25.3% for anti-PD-1 (RR=0.93; 95% CI=0.49 to 1.77; p=0.82). Survival probabilities were similar for cohorts with and without preceding radiotherapy, for anti-CTLA-4 (PFS, adjusted HR=1.02, 95% CI=0.86 to 1.25, p=0.74; OS, HR=1.08, 95% CI=0.81 to 1.44, p=0.61) and for anti-PD-1 (PFS, HR=0.84, 95% CI=0.57 to 1.26, p=0.41; OS, HR=0.73, 95% CI=0.43 to 1.25, p=0.26). Patients who received radiation last before ICI (n=137) revealed no better survival than those who had one or more treatment lines between radiation and start of ICI (n=86). In 223 patients with brain metastases, we found no relevant survival differences on ICI with and without preceding radiotherapy.

Conclusions: This study detected no evidence for a relevant favorable impact of a preceding radiotherapy on anti-CTLA-4 or anti-PD-1 ICI treatment outcome in metastatic melanoma.
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http://dx.doi.org/10.1136/jitc-2019-000395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228559PMC
May 2020

alpha-toxin inhibits CD8 T cell-mediated killing of cancer cells in cutaneous T-cell lymphoma.

Oncoimmunology 2020 17;9(1):1751561. Epub 2020 Apr 17.

LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.

and its toxins have been linked to disease progression and mortality in advanced stages of cutaneous T-cell lymphoma (CTCL). CD8 T cells play a crucial role in anti-cancer responses and high CD8 T cell numbers in tumor lesions are associated with a favorable prognosis in CTCL. Here, we show that CD8 T cells from both healthy donors and Sézary syndrome patients are highly susceptible to cell death induced by Staphylococcal alpha-toxin, whereas malignant T cells are not. Importantly, alpha-toxin almost completely blocks cytotoxic killing of CTCL tumor cells by peptide-specific CD8 T cells, leading to their escape from induced cell death and continued proliferation. These findings suggest that alpha-toxin may favor the persistence of malignant CTCL cells by inhibiting CD8 T cell cytotoxicity. Thus, we propose a novel mechanism by which colonization with may contribute to cancer immune evasion and disease progression in CTCL.
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http://dx.doi.org/10.1080/2162402X.2020.1751561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185203PMC
April 2020

T-Cell Repertoire in Combination with T-Cell Density Predicts Clinical Outcomes in Patients with Merkel Cell Carcinoma.

J Invest Dermatol 2020 11 15;140(11):2146-2156.e4. Epub 2020 Apr 15.

Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address:

The integrity of the immune system represents a pivotal risk factor and prognostic biomarker for Merkel cell carcinoma. A higher density of tumor-associated T cells correlates with improved Merkel cell carcinoma-specific survival, but the prognostic importance of the T-cell infiltrate reactivity is unknown. We evaluated the T-cell receptor repertoire associated with 72 primary Merkel cell carcinomas and correlated metrics of the T-cell receptor repertoire with clinicopathologic characteristics and patient outcomes. We showed that a high Simpson's Dominance index (SDom) was significantly associated with fewer metastases (P = 0.01), lower stage at presentation (P = 0.02), lower final stage at last follow-up (P = 0.05), and longer time to first lymph node metastasis (P = 0.04). These correlations were mostly preserved in the Merkel cell polyomavirus-negative subgroup. Combining SDom with CD3 or CD8 T-cell density revealed three distinct prognostic groups with respect to disease-specific survival. Patients with both high SDom and high CD3 or CD8 T-cell density had markedly improved disease-specific survival compared with patients with low SDom and low CD3 or CD8 T-cell density (P = 0.002 and P = 0.03, respectively). Patients with either high SDom or high CD3 or CD8 had intermediate disease-specific survival. Our findings demonstrate that the quality of the tumor-associated T-cell infiltrate informs patient prognosis in primary Merkel cell carcinoma beyond the T-cell density.
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http://dx.doi.org/10.1016/j.jid.2020.02.031DOI Listing
November 2020

Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma.

Cancers (Basel) 2020 Apr 9;12(4). Epub 2020 Apr 9.

Department of Dermatology, University Hospital Würzburg, 97082 Würzburg, Germany.

Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer with frequent viral etiology. Indeed, in about 80% of cases, there is an association with Merkel cell polyomavirus (MCPyV); the expression of viral T antigens is crucial for growth of virus-positive tumor cells. Since artesunate-a drug used to treat malaria-has been reported to possess additional anti-tumor as well as anti-viral activity, we sought to evaluate pre-clinically the effect of artesunate on MCC. We found that artesunate repressed growth and survival of MCPyV-positive MCC cells in vitro. This effect was accompanied by reduced large T antigen (LT) expression. Notably, however, it was even more efficient than shRNA-mediated downregulation of LT expression. Interestingly, in one MCC cell line (WaGa), T antigen knockdown rendered cells less sensitive to artesunate, while for two other MCC cell lines, we could not substantiate such a relation. Mechanistically, artesunate predominantly induces ferroptosis in MCPyV-positive MCC cells since known ferroptosis-inhibitors like DFO, BAF-A1, Fer-1 and β-mercaptoethanol reduced artesunate-induced death. Finally, application of artesunate in xenotransplanted mice demonstrated that growth of established MCC tumors can be significantly suppressed in vivo. In conclusion, our results revealed a highly anti-proliferative effect of the approved and generally well-tolerated anti-malaria compound artesunate on MCPyV-positive MCC cells, suggesting its potential usage for MCC therapy.
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http://dx.doi.org/10.3390/cancers12040919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225937PMC
April 2020

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma (cSCC) - short version, part 2: epidemiology, surgical and systemic treatment of cSCC, follow-up, prevention and occupational disease.

J Dtsch Dermatol Ges 2020 Apr 4;18(4):400-413. Epub 2020 Apr 4.

Department of Dermatology, Knappschaftskrankenhaus Recklinghausen, Recklinghausen, Germany.

Actinic keratoses (AKs) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guidelines for actinic keratosis and cutaneous squamous cell carcinoma were developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guidelines are aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AKs and cSCC. The guidelines are also aimed at affected patients, their relatives, policy makers and insurance funds. In the second part, we will address aspects relating to epidemiology, etiology, surgical and systemic treatment of cSCC, follow-up and disease prevention, and discuss AKs and cSCC in the context of occupational disease regulations.
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http://dx.doi.org/10.1111/ddg.14072DOI Listing
April 2020

Expression of Programmed Cell Death Proteins in Kaposi Sarcoma and Cutaneous Angiosarcoma.

J Immunother 2020 06;43(5):169-174

Institute for Prevention and Occupational Medicine of the German Social Accident Insurances, Ruhr-University Bochum (IPA), Bochum.

Not only for cutaneous angiosarcoma (CAS) patients but also for advanced and therapy-refractory patients with classic Kaposi sarcoma (CKS) and human immunodeficiency virus (HIV)-associated Kaposi sarcoma (HIV-KS) there is a high need for more effective treatment modalities. The aim of this work was to study programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) protein expression and related immune parameters in CKS, HIV-KS, and CAS and correlate it with other immunologic parameters and clinical data. Immunohistochemistry was performed on formalin-fixed paraffin-embedded tumor tissue of 19 CKS, 7 HIV-KS, and 12 CAS patients using antibodies against the following (and they are): PD-1, PD-L1, CD4, CD8, CD56, and FOXP3. PD-1 expression significantly correlated with PD-L1 expression Moreover, PD-1 and PD-L1 expression significantly correlated with CD56 and FOXP3 expression. High intratumoral FOXP3 expression was significantly associated with disease relapse (P=0.029). CD4 and FOXP3 expression was significantly higher in CKS and CAS, as compared with HIV-KS. All in all, PD-1 and PD-L1 expression was relatively weak and did not significantly differ between CKS, HIV-KS, and CAS patients. Nevertheless, PD-1 was positive in 31.6% of CKS, 28.6% of HIV-KS, and 33.3% of CAS patients. PD-L1 was expressed in 36.6% of CKS, 28.6% of HIV-KS, and 41.7% of CAS patients. We have provided evidence that PD-1/PD-L1 signalling is of importance in angiosarcomas such as CKS, HIV-KS, and CAS. Our results support the notion that the use of PD-1/PD-L1 inhibitors may represent an effective strategy against these tumors.
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http://dx.doi.org/10.1097/CJI.0000000000000317DOI Listing
June 2020

Survival of patients with advanced metastatic melanoma: The impact of MAP kinase pathway inhibition and immune checkpoint inhibition - Update 2019.

Eur J Cancer 2020 05 13;130:126-138. Epub 2020 Mar 13.

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

Background: Recent therapeutic strategies, particularly MAP kinase pathway inhibitors (BRAF, MEK) and immune checkpoint blockers (CTLA-4, PD-1), have been put on the test for their differential impact on long-term survival of metastatic melanoma patients. Various agents, dose regimens and combinations have been tested against each other vigorously within these two therapy groups. However, results from prospective head-to-head comparative trials comparing both strategies against each other are still lacking.

Methods: We performed an exploratory analysis of survival data from selected clinical trials representative for these two treatment strategies in advanced metastatic melanoma. 84 Kaplan-Meier survival curves from 26 trials were digitised and grouped by therapy strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging.

Results: Survival curves grouped together by therapy strategy revealed a high concordance, with a larger extent in the first-line setting compared to higher treatment lines. In first-line therapy, the averaged 3-year OS proportions were 41.3% for BRAF plus MEK inhibition, 49.9% for PD-1 inhibition, and 58.4% for CTLA-4 plus PD-1 inhibition. Comparison of the mean PFS and OS curves of kinase inhibition and checkpoint blockade revealed a superiority of combined BRAF plus MEK inhibition within the first 12 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockade. In second-line or higher, BRAF plus MEK inhibition was superior to anti-PD-1 monotherapy throughout the first three years; averaged 3-year OS proportions were 42.4% for BRAF plus MEK inhibition, and 40.1% for PD-1 inhibition.

Conclusions: and relevance: These results need confirmation by head-to-head comparative randomised clinical trials.
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http://dx.doi.org/10.1016/j.ejca.2020.02.021DOI Listing
May 2020

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma - short version, part 1: diagnosis, interventions for actinic keratoses, care structures and quality-of-care indicators.

J Dtsch Dermatol Ges 2020 Mar;18(3):275-294

Department of Dermatology, Knappschaftskrankenhaus Recklinghausen, Recklinghausen, Germany.

Actinic keratoses (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guideline is aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AK and cSCC. The guideline is also aimed at affected patients, their relatives, policy makers and insurance funds. In the first part, we will address aspects relating to diagnosis, interventions for AK, care structures and quality-of-care indicators.
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http://dx.doi.org/10.1111/ddg.14048DOI Listing
March 2020