Publications by authors named "Carola Berking"

213 Publications

BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation.

Int J Mol Sci 2021 Nov 4;22(21). Epub 2021 Nov 4.

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstraße 14, 91052 Erlangen, Germany.

BRAF and MEK inhibitor (BRAFi/MEKi) combinations are currently the standard treatment for patients with BRAF mutant metastatic melanoma. Since the RAS/RAF/MEK/ERK-pathway is crucial for the function of different immune cells, we postulated an effect on their function and thus interference with anti-tumor immunity. Therefore, we examined the influence of BRAFi/MEKi, either as single agent or in combination, on the maturation of monocyte-derived dendritic cells (moDCs) and their interaction with T cells. DCs matured in the presence of vemurafenib or vemurafenib/cobimetinib altered their cytokine secretion and surface marker expression profile. Upon the antigen-specific stimulation of CD8 and CD4 T cells with these DCs or with T2.A1 cells in the presence of BRAFi/MEKi, we detected a lower expression of activation markers on and a lower cytokine secretion by these T cells. However, treatment with any of the inhibitors alone or in combination did not change the avidity of CD8 T cells in peptide titration assays with T2.A1 cells. T-helper cell/DC interaction is a bi-directional process that normally results in DC activation. Vemurafenib and vemurafenib/cobimetinib completely abolished the helper T-cell-mediated upregulation of CD70, CD80, and CD86 but not CD25 on the DCs. The combination of dabrafenib/trametinib affected DC maturation and activation as well as T-cell activation less than combined vemurafenib/cobimetinib did. Hence, for a potential combination with immunotherapy, our data indicate the superiority of dabrafenib/trametinib treatment.
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http://dx.doi.org/10.3390/ijms222111951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585071PMC
November 2021

Grade 4 Neutropenia Secondary to Immune Checkpoint Inhibition - A Descriptive Observational Retrospective Multicenter Analysis.

Front Oncol 2021 21;11:765608. Epub 2021 Oct 21.

Department of Dermatology, Venerology and Allergology, University Hospital Essen, Essen, Germany.

Introduction: Immune checkpoint inhibitors (ICI) are increasingly being used to treat numerous cancer types. Together with improved recognition of toxicities, this has led to more frequent identification of rare immune-related adverse events (irAE), for which specific treatment strategies are needed. Neutropenia is a rare hematological irAE that has a potential for a high mortality rate because of its associated risk of sepsis. Prompt recognition and timely treatment of this life-threatening irAE are therefore critical to the outcome of patients with immune-related neutropenia.

Methods: This multicenter international retrospective study was conducted at 17 melanoma centers to evaluate the clinical characteristics, diagnostics, treatment, and outcomes of melanoma patients with grade 4 neutropenia (<500 neutrophils/µl blood) treated with ICI between 2014 and 2020. Some of these patients received metamizole in addition to ICI (ICI+/met+). Bone marrow biopsies (BMB) of these patients were compared to BMB from non-ICI treated patients with metamizole-induced grade 4 neutropenia (ICI-/met+).

Results: In total, 10 patients (median age at neutropenia onset: 66 years; seven men) with neutropenia were identified, equating to an incidence of 0.14%. Median onset of neutropenia was 6.4 weeks after starting ICI (range 1.4-49.1 weeks). Six patients showed inflammatory symptoms, including fever (n=3), erysipelas (n=1), pharyngeal abscess (n=1), and mucositis (n=1). Neutropenia was diagnosed in all patients by a differential blood count and additionally performed procedures including BMB (n=5). Nine of 10 patients received granulocyte colony-stimulating factors (G-CSF) to treat their grade 4 neutropenia. Four patients received systemic steroids (including two in combination with G-CSF, and one in combination with G-CSF and additional ciclosporin A). Four patients were treated with one or more antibiotic treatment lines, two with antimycotic treatment, and one with additional antiviral therapy. Five patients received metamizole concomitantly with ICI. One fatal outcome was reported. BMB indicated a numerically lower CD4+ to CD8+ T cells ratio in patients with irNeutropenia than in those with metamizole-induced neutropenia.

Conclusion: Grade 4 neutropenia is a rare but potentially life-threatening side effect of ICI treatment. Most cases were sufficiently managed using G-CSF; however, adequate empiric antibiotic, antiviral, and antimycotic treatments should be administered if neutropenic infections are suspected. Immunosuppression using corticosteroids may be considered after other causes of neutropenia have been excluded.
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http://dx.doi.org/10.3389/fonc.2021.765608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567012PMC
October 2021

A disease network-based deep learning approach for characterizing melanoma.

Int J Cancer 2021 Oct 29. Epub 2021 Oct 29.

College of Computer Science, Sichuan University, Chengdu, China.

Multiple types of genomic variations are present in cutaneous melanoma and some of the genomic features may have an impact on the prognosis of the disease. The access to genomics data via public repositories such as The Cancer Genome Atlas (TCGA) allows for a better understanding of melanoma at the molecular level, therefore making characterization of substantial heterogeneity in melanoma patients possible. Here, we proposed an approach that integrates genomics data, a disease network, and a deep learning model to classify melanoma patients for prognosis, assess the impact of genomic features on the classification and provide interpretation to the impactful features. We integrated genomics data into a melanoma network and applied an autoencoder model to identify subgroups in TCGA melanoma patients. The model utilizes communities identified in the network to effectively reduce the dimensionality of genomics data into a patient score profile. Based on the score profile, we identified three patient subtypes that show different survival times. Furthermore, we quantified and ranked the impact of genomic features on the patient score profile using a machine-learning technique. Follow-up analysis of the top-ranking features provided us with the biological interpretation of them at both pathway and molecular levels, such as their mutation and interactome profiles in melanoma and their involvement in pathways associated with signaling transduction, immune system and cell cycle. Taken together, we demonstrated the ability of the approach to identify disease subgroups using a deep learning model that captures the most relevant information of genomics data in the melanoma network.
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http://dx.doi.org/10.1002/ijc.33860DOI Listing
October 2021

Clinical determinants of long-term survival in metastatic uveal melanoma.

Cancer Immunol Immunother 2021 Oct 28. Epub 2021 Oct 28.

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.

This study aimed to identify prognostic factors in patients with metastatic uveal melanoma (UM) that were associated with long-term survival in a real-world setting. A total of 94 patients with metastatic UM were included from German skin cancer centers and the German national skin cancer registry (ADOReg). Data were analyzed for the response to treatment, progression-free survival, and overall survival (OS). Prognostic factors were explored with univariate Cox regression, log-rank, and χ2-tests. Identified factors were subsequently validated after the population was divided into two cohorts of short-term survival (< 2 years OS, cohort A, n = 50) and long-term survival (> 2 years OS, cohort B, n = 44). A poor ECOG performance status (hazard ratio [HR] 2.0, 95% confidence interval [CI] 1.0-3.9) and elevated serum LDH (HR 2.0, 95% CI 1.0-3.8) were associated with a poor OS, whereas a good response to immune checkpoint blockade (ICB, p < 0.001), radiation therapy (p < 0.001), or liver-directed treatments (p = 0.01) were associated with a prolonged OS. Long-term survivors (cohort B) showed a higher median number of organs affected by metastasis (p < 0.001), while patients with liver metastases only were more common in cohort A (40% vs. 9%; p = 0.002). A partial response to ICB was observed in 16% (12/73), being 21% (8/38) for combined ICB, 17% (1/6) for single CTLA4 inhibition, and 10% (3/29) for single PD1 inhibition. One complete response occurred in cohort B with combined ICB. We conclude that the response to ICB and the presence of extrahepatic disease were favorable prognostic factors for long-term survival.
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http://dx.doi.org/10.1007/s00262-021-03090-4DOI Listing
October 2021

How to Assess the Efficacy of Interventions for Actinic Keratosis? A Review with a Focus on Long-Term Results.

J Clin Med 2021 Oct 15;10(20). Epub 2021 Oct 15.

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.

Actinic keratoses (AK) are common lesions of the skin caused by cumulative sun exposure. Since AK may progress to invasive cutaneous squamous cell carcinoma (cSCC), guidelines uniformly recommend early and consequent treatment. A variety of interventions are available; however, most randomized controlled trials, meta-analyses, and guidelines focus on outcomes that are usually evaluated 8-12 weeks after the end of treatment. Importantly, these assessments can capture the short-term, transient outcomes, but do not allow any conclusions about long-term results to be drawn and do not reflect the probability of transition towards cSCC. Until now, few studies have assessed the long-term results of interventions for AK. Indeed, finding the most appropriate end-point and adjunct time point for determining the long-term results of interventions for AK remains a challenge. Here, we provide an overview of the different ways of measuring the efficacy of AK treatments, such as using recurrence rates or sustained clearance rates, and discuss methodological aspects. Furthermore, we highlight the importance of evidence from post-marketing surveillance trials for the detection of efficacy values and safety signals. Additionally, we emphasize that a follow-up period of 12 months might not be sufficient to reflect the long-term results and stress the urgent need for a longer follow-up period and regular risk-stratified surveillance.
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http://dx.doi.org/10.3390/jcm10204736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538594PMC
October 2021

Plasma-derived extracellular vesicles discriminate type-1 allergy subjects from non-allergic controls.

World Allergy Organ J 2021 Sep 28;14(9):100583. Epub 2021 Sep 28.

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Deutsches Zentrum Immuntherapie, Ulmenweg 18, 91054, Erlangen, Germany.

Background: Allergies are on the rise globally, with an enormous impact on affected individuals' quality of life as well as health care resources. They cause a wide range of symptoms, from slightly inconvenient to potentially fatal immune reactions. While allergies have been described and classified phenomenologically, there is an unmet need for easily accessible biomarkers to stratify the severity of clinical symptoms. Furthermore, biomarkers marking the success of specific immunotherapy are urgently needed.

Objectives: Plasma extracellular vesicles (pEV) play a role in coordinating the immune response and may be useful future biomarkers. A pilot study on differences in pEV content was carried out between patients with type I allergy, suffering from rhinoconjunctivitis with or without asthma, and voluntary non-allergic donors.

Methods: We examined pEV from 38 individuals (22 patients with allergies and 16 controls) for 38 chemokines, cytokines, and soluble factors using high-throughput data mining approaches.

Results: Patients with allergies had a distinct biomarker pattern, with 7 upregulated (TNF-alpha, IL-4, IL-5, IL-6, IL-17F, CCL2, and CCL17) and 3 downregulated immune mediators (IL-11, IL-27, and CCL20) in pEV compared to controls. This reduced set of 10 factors was able to discriminate controls and allergic patients better than the total array.

Conclusions: The content of pEV showed potential as a target for biomarker research in allergies. Plasma EV, which are readily measurable via blood test, may come to play an important role in allergy diagnosis. In this proof-of-principle study, it could be shown that pEV's discriminate patients with allergies from controls. Further studies investigating whether the content of pEVs may predict the severity of allergic symptoms or even the induction of tolerance to allergens are needed.
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http://dx.doi.org/10.1016/j.waojou.2021.100583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487953PMC
September 2021

A Chimeric IL-15/IL-15Rα Molecule Expressed on NFκB-Activated Dendritic Cells Supports Their Capability to Activate Natural Killer Cells.

Int J Mol Sci 2021 Sep 23;22(19). Epub 2021 Sep 23.

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.

Natural killer (NK) cells, members of the innate immune system, play an important role in the rejection of HLA class I negative tumor cells. Hence, a therapeutic vaccine, which can activate NK cells in addition to cells of the adaptive immune system might induce a more comprehensive cellular response, which could lead to increased tumor elimination. Dendritic cells (DCs) are capable of activating and expanding NK cells, especially when the NFκB pathway is activated in the DCs thereby leading to the secretion of the cytokine IL-12. Another prominent NK cell activator is IL-15, which can be bound by the IL-15 receptor alpha-chain (IL-15Rα) to be transpresented to the NK cells. However, monocyte-derived DCs do neither secrete IL-15, nor express the IL-15Rα. Hence, we designed a chimeric protein consisting of IL-15 and the IL-15Rα. Upon mRNA electroporation, the fusion protein was detectable on the surface of the DCs, and increased the potential of NFκB-activated, IL-12-producing DC to activate NK cells in an autologous cell culture system with ex vivo-generated cells from healthy donors. These data show that a chimeric IL-15/IL-15Rα molecule can be expressed by monocyte-derived DCs, is trafficked to the cell surface, and is functional regarding the activation of NK cells. These data represent an initial proof-of-concept for an additional possibility of further improving cellular DC-based immunotherapies of cancer.
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http://dx.doi.org/10.3390/ijms221910227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508776PMC
September 2021

c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma: a systematic review and one-arm meta-analysis.

Eur J Cancer 2021 11 22;157:348-357. Epub 2021 Sep 22.

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen - European Metropolitan Region of Nuremberg, Erlangen, Germany. Electronic address:

Background: Activating genomic alterations of the receptor tyrosine kinase KIT are found preferentially in certain melanoma subtypes such as acral and mucosal melanoma or melanoma arising in chronically sun-damaged skin. However, the therapeutic value of c-Kit inhibitors for these subtypes currently remains unclear.

Objectives: The objective of this study was to summarise the efficacy and safety of c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma.

Methods: We performed a systematic literature research in MEDLINE, Embase and CENTRAL and hand searched pertinent trial registers and conference abstracts for eligible trials until 23rd June 2020. Results were pooled using a random-effects model to calculate pooled proportions of objective response rates (ORRs) and severe adverse events (sAEs) from unselected KIT mutant or amplified cohorts.

Results: Nineteen single-arm studies with an overall sample size of 601 patients were included. The studies investigated imatinib (n = 8), nilotinib (n = 7), dasatinib (n = 3) and sunitinib (n = 1). The pooled ORR for all inhibitors was 15% (95% confidence interval [CI]: 12-18%). Subgroup analysis revealed the highest ORR (20%; 95% CI: 14-26%) for nilotinib. The ORR for mucosal melanoma was 14% (95% CI: 6-24%) and 22% for acral lentiginous melanoma (95% CI: 14-30%). At least one sAE was reported in 42% of patients (95% CI: 34-50%).

Conclusions: c-Kit inhibitors represent a valuable treatment option for patients with KIT-mutant melanoma, in particular for mutations of exons 11 and 13. Furthermore, high-quality trials are urgently needed to investigate putative combinations of specific targeted therapies with immunotherapy.
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http://dx.doi.org/10.1016/j.ejca.2021.08.015DOI Listing
November 2021

Onkologische Systemtherapie bis zum bitteren Ende?

Authors:
Carola Berking

J Dtsch Dermatol Ges 2021 Sep;19(9):1259-1260

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http://dx.doi.org/10.1111/ddg.14631_gDOI Listing
September 2021

Skin cancer classification via convolutional neural networks: systematic review of studies involving human experts.

Eur J Cancer 2021 10 8;156:202-216. Epub 2021 Sep 8.

First Department of Dermatology, School of Medicine, Faculty of Health Sciences, Aristotle University, Thessaloniki, Greece.

Background: Multiple studies have compared the performance of artificial intelligence (AI)-based models for automated skin cancer classification to human experts, thus setting the cornerstone for a successful translation of AI-based tools into clinicopathological practice.

Objective: The objective of the study was to systematically analyse the current state of research on reader studies involving melanoma and to assess their potential clinical relevance by evaluating three main aspects: test set characteristics (holdout/out-of-distribution data set, composition), test setting (experimental/clinical, inclusion of metadata) and representativeness of participating clinicians.

Methods: PubMed, Medline and ScienceDirect were screened for peer-reviewed studies published between 2017 and 2021 and dealing with AI-based skin cancer classification involving melanoma. The search terms skin cancer classification, deep learning, convolutional neural network (CNN), melanoma (detection), digital biomarkers, histopathology and whole slide imaging were combined. Based on the search results, only studies that considered direct comparison of AI results with clinicians and had a diagnostic classification as their main objective were included.

Results: A total of 19 reader studies fulfilled the inclusion criteria. Of these, 11 CNN-based approaches addressed the classification of dermoscopic images; 6 concentrated on the classification of clinical images, whereas 2 dermatopathological studies utilised digitised histopathological whole slide images.

Conclusions: All 19 included studies demonstrated superior or at least equivalent performance of CNN-based classifiers compared with clinicians. However, almost all studies were conducted in highly artificial settings based exclusively on single images of the suspicious lesions. Moreover, test sets mainly consisted of holdout images and did not represent the full range of patient populations and melanoma subtypes encountered in clinical practice.
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http://dx.doi.org/10.1016/j.ejca.2021.06.049DOI Listing
October 2021

A benchmark for neural network robustness in skin cancer classification.

Eur J Cancer 2021 09 11;155:191-199. Epub 2021 Aug 11.

Digital Biomarkers for Oncology Group, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Background: One prominent application for deep learning-based classifiers is skin cancer classification on dermoscopic images. However, classifier evaluation is often limited to holdout data which can mask common shortcomings such as susceptibility to confounding factors. To increase clinical applicability, it is necessary to thoroughly evaluate such classifiers on out-of-distribution (OOD) data.

Objective: The objective of the study was to establish a dermoscopic skin cancer benchmark in which classifier robustness to OOD data can be measured.

Methods: Using a proprietary dermoscopic image database and a set of image transformations, we create an OOD robustness benchmark and evaluate the robustness of four different convolutional neural network (CNN) architectures on it.

Results: The benchmark contains three data sets-Skin Archive Munich (SAM), SAM-corrupted (SAM-C) and SAM-perturbed (SAM-P)-and is publicly available for download. To maintain the benchmark's OOD status, ground truth labels are not provided and test results should be sent to us for assessment. The SAM data set contains 319 unmodified and biopsy-verified dermoscopic melanoma (n = 194) and nevus (n = 125) images. SAM-C and SAM-P contain images from SAM which were artificially modified to test a classifier against low-quality inputs and to measure its prediction stability over small image changes, respectively. All four CNNs showed susceptibility to corruptions and perturbations.

Conclusions: This benchmark provides three data sets which allow for OOD testing of binary skin cancer classifiers. Our classifier performance confirms the shortcomings of CNNs and provides a frame of reference. Altogether, this benchmark should facilitate a more thorough evaluation process and thereby enable the development of more robust skin cancer classifiers.
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http://dx.doi.org/10.1016/j.ejca.2021.06.047DOI Listing
September 2021

Evaluation of Long-term Clearance Rates of Interventions for Actinic Keratosis: A Systematic Review and Network Meta-analysis.

JAMA Dermatol 2021 Sep;157(9):1066-1077

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg (FAU), Erlangen, Germany.

Importance: Multiple interventions are available for the treatment of actinic keratosis (AK). However, most randomized clinical trials and meta-analyses focus on short-term efficacy outcomes.

Objective: To investigate and synthesize the long-term efficacy (≥12 months) of interventions for AK from parallel-arm randomized clinical trials.

Data Sources: Searches in MEDLINE, Embase, and Central were conducted from inception until April 6, 2020. The reference lists of the included studies and pertinent trial registers were hand searched. The study was completed February 27, 2021.

Study Selection: Two reviewers screened the titles and abstracts of 2741 records. Finally, 17 published reports (original studies and follow-up reports) referring to 15 independent randomized clinical trials with an overall sample size of 4252 patients were included.

Data Extraction And Synthesis: Two reviewers independently extracted data on study, patient, and intervention characteristics. Network meta-analysis (NMA) of each outcome was conducted with a frequentist approach. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidance for NMA was used to assess the certainty of evidence. The revised Cochrane risk-of-bias tool for randomized clinical trials was used to evaluate the methodologic quality.

Main Outcomes And Measures: Participant complete clearance, participant partial clearance, and lesion-specific clearance were the outcomes, with each assessed at least 12 months after the end of treatment.

Results: Data from 15 independent randomized clinical trials including 4252 patients were extracted and synthesized. Ten studies were included in an NMA for the outcome of participant complete clearance, with photodynamic therapy with aminolevulinate (ALA-PDT) showing the most favorable risk ratio (RR) compared with placebo (RR, 8.06; 95% CI, 2.07-31.37; GRADE, moderate), followed by imiquimod, 5% (RR, 5.98; 95% CI, 2.26-15.84; GRADE, very low), photodynamic therapy with methyl aminolevulinate (MAL-PDT) (RR, 5.95; 95% CI, 1.21-29.41; GRADE, low), and cryosurgery (RR, 4.67; 95% CI, 1.36-16.66; GRADE, very low). Similarly, ALA-PDT had the highest RR in the NMA for lesion-specific clearance (RR, 5.08; 95% CI, 2.49-10.33; GRADE, moderate). No NMA was possible for participant partial clearance owing to poor reporting of this outcome.

Conclusions And Relevance: This systematic review and network meta-analysis found that therapy including ALA-PDT, imiquimod, 5%, MAL-PDT, and cryosurgery was associated with significant long-term efficacy in the NMA. This study provides data for a possible use in an evidence-based framework for selecting interventions with sustained lesion clearance.
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http://dx.doi.org/10.1001/jamadermatol.2021.2779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340012PMC
September 2021

Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis.

Cancers (Basel) 2021 Jul 4;13(13). Epub 2021 Jul 4.

Department of Dermatology, DRK Krankenhaus Rabenstein, 09117 Chemnitz, Germany.

Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB.

Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, = 55) versus those with both liver and extra-hepatic metastasis (cohort B, = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan-Meier method. Log-rank tests, χ tests, and t-tests were performed to detect significant differences between both cohorts.

Results: The median OS of the overall population was 16 months (95% CI 13.4-23.7) and the median PFS, 2.8 months (95% CI 2.5-3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts.

Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.
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http://dx.doi.org/10.3390/cancers13133359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268645PMC
July 2021

NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism.

Cell 2021 Aug 6;184(16):4268-4283.e20. Epub 2021 Jul 6.

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.
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http://dx.doi.org/10.1016/j.cell.2021.06.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349839PMC
August 2021

How Neural Crest Transcription Factors Contribute to Melanoma Heterogeneity, Cellular Plasticity, and Treatment Resistance.

Int J Mol Sci 2021 May 28;22(11). Epub 2021 May 28.

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.

Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.
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http://dx.doi.org/10.3390/ijms22115761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198848PMC
May 2021

Malignant Tumours Presenting as Chronic Leg or Foot Ulcers.

J Clin Med 2021 May 22;10(11). Epub 2021 May 22.

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Ulmenweg 18, 91054 Erlangen, Germany.

Our purpose was to collect data on the incidence of malignant skin tumours presenting as chronic leg or foot ulcers in a tertiary centre, and to analyse the frequency and type of initial clinical misdiagnoses in these cases. A retrospective chart review of cases with melanoma or other malignant neoplasms of the skin of the lower extremity treated in a tertiary centre during January 2010 until February 2020 was conducted to identify cases that presented as chronic ulcers. Out of 673 cases, 26 (3.9%) were identified with a total of 27 malignant tumours presenting as chronic ulcers of the lower leg or foot. Therefrom, seven were diagnosed as melanoma, eight as squamous cell carcinoma, and twelve as basal cell carcinoma. The mean interval until diagnosis for all tumour types was 44.4 months (median 24 months). A delay in correct treatment occurred in 12 out of 26 cases (46%) as a result of misdiagnosis with subsequent treatment as chronic leg or foot ulcers of a different etiology. Misdiagnoses were venous ulcer, traumatic wound, mixed arterial and venous ulcer, arterial ulcer, and ulcer of an unknown origin. Malignant ulcers presenting as chronic ulcers are rare, but often lead to misdiagnosis.
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http://dx.doi.org/10.3390/jcm10112251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196993PMC
May 2021

Factors Influencing the Adjuvant Therapy Decision: Results of a Real-World Multicenter Data Analysis of 904 Melanoma Patients.

Cancers (Basel) 2021 May 12;13(10). Epub 2021 May 12.

Department of Dermatology, Venereology and Allergology, University Hospital Essen, 45147 Essen, Germany.

Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in mutant patients). Of these patients, 76.9% (95% CI 74-80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68-80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24-38), and fear of adverse events (21.1%, 95% CI 16-28) and impaired quality of life (11.9%, 95% CI 7-16). Of all -mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47-59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.
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http://dx.doi.org/10.3390/cancers13102319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151445PMC
May 2021

Risk Factors for Relapse after Intentional Discontinuation of Immune Checkpoint Inhibitors in Melanoma Patients.

J Immunother 2021 Jul-Aug 01;44(6):239-241

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Deutsches Zentrum Immuntherapie (DZI).

Immune checkpoint inhibitors (ICIs) have tremendously changed the therapeutic landscape of melanoma since they are associated with a durable response, allowing for intentional discontinuation of therapy after complete or partial remission. However, a subset of patients develops a relapse after cessation of ICI treatment and may not respond to reinduction of ICIs. The aim of the present study was to identify risk factors for relapse after intentional discontinuation of ICI therapy. Patients with intentional discontinuation of ICI therapy for metastatic or unresectable melanoma from 5 German university hospitals were analyzed retrospectively. Clinicopathologic and follow-up data of 87 patients were collected and analyzed by univariate and multivariate Cox proportional-hazards models. The following parameters were associated with relapse after cessation of ICI treatment in the univariate Cox regression analysis: concurrent radiotherapy and ICI, best overall response, and presence of brain metastases. Duration of treatment, type of primary tumor, body mass index, programmed-death ligand 1 expression, and lactate dehydrogenase levels did not significantly influence the risk for relapse. In the multivariate analysis, partial remission [hazard ratio 4.217 (95% confidence interval: 1.424-12.49), P=0.009] and stable disease [3.327 (1.204-9.19), P=0.02] were associated with a significant decrease in progression-free survival compared with complete remission. Concurrent radiotherapy and ICI [3.619 (1.288-10.168), P=0.015] are additional independent risk factors for decreased progression-free survival upon ICI discontinuation, whereas the presence of brain metastasis did not reach statistical significance on multivariate analysis.
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http://dx.doi.org/10.1097/CJI.0000000000000375DOI Listing
October 2020

"I Feel I'm in Best Hands with You!": A Survey of Patient Satisfac-tion in a German University Skin Cancer Centre.

Acta Derm Venereol 2021 Jun 28;101(6):adv00482. Epub 2021 Jun 28.

Department of Dermatology, University Hospital Erlangen, DE-91054 Erlangen, Germany.

An important measure of hospital quality is the satisfaction of patients. The aim of this cross-sectional study, performed in the dermato-oncology unit of the university hospital in Erlangen, Germany, was to assess skin cancer patients' degree of satisfaction with healthcare services. Self-administered questionnaires on patient satisfaction regarding contact with staff, need for information, and recommendation of the skin cancer centre were distributed in the day-care unit and the outpatient department to patients between April and June 2017. Results were reported descriptively and subgroup differences were explored using the Mann-Whitney U test, binary logistic regression, or χ2 test. Overall, 496 of 571 questionnaires were returned (86.9%). The median of all satisfaction items ranged between 1 (very good) and 2 (good). The majority of patients wanted more detailed information about skin cancer (46.7%, 142/304). Long waiting times were often criticized (22.8%; 80/351). Particular attention in addressing specific needs and fears may further increase patient satisfaction.
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http://dx.doi.org/10.2340/00015555-3837DOI Listing
June 2021

Pretreatment metastatic growth rate determines clinical outcome of advanced melanoma patients treated with anti-PD-1 antibodies: a multicenter cohort study.

J Immunother Cancer 2021 05;9(5)

Department of Dermatology, University Medical Center Mainz, Mainz, Germany.

Background: Checkpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies.

Methods: MGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB-IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR.

Results: Pretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, p<0.0001), in the confirmation cohort (HR 3.62, 95% CI 2.19 to 5.98, p<0.0001) and in the independent validation cohort (HR 2.57, 95% CI 1.56 to 4.25, p=0.00023). Prior lines of systemic treatment did not influence the significance of MGR. Importantly, the prognostic impact of MGR was independent of total tumor burden, diameter of the largest metastasis, number of prior lines of systemic treatment, LDH, as well as liver and brain metastasis (discovery and confirmation cohorts: both p<0.0001). Superiority of MGR compared with these variables was confirmed in the independent multicenter validation cohort (HR 2.92, 95% CI 1.62 to 5.26, p=0.00036).

Conclusions: High pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens.
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http://dx.doi.org/10.1136/jitc-2021-002350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126291PMC
May 2021

SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases.

Ann Rheum Dis 2021 10 6;80(10):1312-1316. Epub 2021 May 6.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany

Objectives: To better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs).

Methods: Patients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded.

Results: Vaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p<0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12-8.85) for controls and 6.90 (6.45-7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID.

Conclusions: Immune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.
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http://dx.doi.org/10.1136/annrheumdis-2021-220461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103562PMC
October 2021

Long-term recurrence rates of actinic keratosis: A systematic review and pooled analysis of randomized controlled trials.

J Am Acad Dermatol 2021 Apr 16. Epub 2021 Apr 16.

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen, Erlangen, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.04.017DOI Listing
April 2021

Inflammatory markers in autoimmunity induced by checkpoint inhibitors.

J Cancer Res Clin Oncol 2021 Jun 10;147(6):1623-1630. Epub 2021 Apr 10.

Department of Dermatology, Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany.

Purpose: Immune checkpoint inhibitors (ICI) are highly effective in several cancer entities, but also invoke a variety of immune-related adverse events (irAE). These are mostly reversible, but can be life-threatening or even fatal. Currently, the pathogenesis is not fully understood, but crucial for effective treatment. Prediction and early detection of irAE could be facilitated and treatment optimized if relevant biomarkers and effector mechanisms were better characterized.

Methods: This study included a total of 45 irAE in patients with metastatic melanoma who were treated with ICI. All patients underwent a complete work-up with exclusion of other causes. Longitudinal blood samples were analyzed for a panel of soluble markers and compared to baseline and to patients who did not experience any irAE. Measurements included LDH, interleukin (IL)-6, IL-1β, IL-17, C-reactive protein (CRP) and tumor necrosis factor (TNF)-alpha as well as tumor markers S100 and melanoma inhibitory activity (MIA).

Results: During the early onset of irAE increases in serum IL-6 (from mean 24.4 pg/ml at baseline to 51.0 pg/ml; p = 0.003) and CRP (from mean 7.0 mg/l at baseline to 17.7 mg/l; p = 0.001) and a decrease in MIA (from mean 5.4 pg/ml at baseline to 4.8 pg/ml; p = 0.035) were detected. No changes in IL-17 were noted. These effects were observed for irAE of different organ systems.

Conclusion: Increases of a combination of IL-6 and CRP serum levels can be used for the early detection of irAE and tailored management. Interestingly, changes in MIA serum levels also correlate with irAE onset.
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http://dx.doi.org/10.1007/s00432-021-03550-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076116PMC
June 2021

Sister-Mary-Joseph-Knoten der Brust - Beschreibung einer neuen Entität?

J Dtsch Dermatol Ges 2021 Jul;19 Suppl 1:14-16

Hautklinik, Universitätsklinikum Erlangen, Erlangen, Deutschland.

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http://dx.doi.org/10.1111/ddg.14473DOI Listing
July 2021

Safety of topical interventions for the treatment of actinic keratosis.

Expert Opin Drug Saf 2021 Jul 27;20(7):801-814. Epub 2021 Apr 27.

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Actinic keratosis (AK) are proliferations of atypical keratinocytes that may eventually progress to cutaneous squamous cell carcinoma. Therefore, AK requires consequent and early treatment. A variety of effective approaches is currently available for the clearance of AK. These interventions may be applied either in a lesion-directed or field-directed mode as AK can occur as single or multiple lesions. Field-directed approaches typically comprise topical drug-mediated interventions which aim at eliminating all visible lesions and also at clearing subclinical changes of the actinically damaged field. However, most treatment options are associated with local adverse events such as erythema, scaling, pain, and rarely with systemic symptoms. This expert review provides a comprehensive and up-to-date overview of the safety considerations of the commonly prescribed topical treatment agents cyclooxygenase inhibitors, 5-fluorouracil, imiquimod, ingenol mebutate, and photodynamic therapy. All these therapies have been proven efficient, yet they differ considerably regarding their safety profile. In the future, safety concerns will relate to long-term and irreversible adverse drug events instead of application site reactions. In particular, the rate of treatment-associated non-melanoma skin cancers will increasingly come into focus and warrant investigation in postmarketing surveillance trials with a long-term follow-up.
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http://dx.doi.org/10.1080/14740338.2021.1915280DOI Listing
July 2021

Lipase elevation and type 1 diabetes mellitus related to immune checkpoint inhibitor therapy - A multicentre study of 90 patients from the German Dermatooncology Group.

Eur J Cancer 2021 05 31;149:1-10. Epub 2021 Mar 31.

Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Carl Neuberg Str. 1, 30625, Hannover, Germany. Electronic address:

Aim: Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear.

Patients And Methods: Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres.

Results: We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1-181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of ICI resulted in decrease of lipase after reinduction of ICI lipase levels increased again in 12 of 24 patients. In 18 patients (27%), ICI was continued unchanged, and in 12 (67%) of them, lipase levels normalised. Twenty-two patients were identified with newly diagnosed type I diabetes mellitus related to ICI, and 12 (55%) thereof had also lipase elevation mainly shortly before or after the diagnosis of diabetes. Fourteen (64%) patients had other irAE, mainly thyroiditis. Irrespective of lipase elevation, patients frequently showed a rapid onset with ketoacidosis, decreased c-peptide, and strongly increased blood glucose levels.

Conclusion: Increased serum lipase during ICI is often not associated with pancreatitis but with other irAE as possible cause. Therefore, it might be sufficient to regularly monitor blood glucose levels and perform further workup only in case of signs or symptoms of pancreatitis and/or exocrine pancreas insufficiency.
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http://dx.doi.org/10.1016/j.ejca.2021.02.017DOI Listing
May 2021
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