Publications by authors named "Stephan Grabbe"

195 Publications

Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy-Paradoxical ERK Activation and Beyond.

Int J Mol Sci 2021 Sep 13;22(18). Epub 2021 Sep 13.

Medical Center, Department of Dermatology, University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.

The advent of mitogen-activated protein kinase (MAPK) inhibitors that directly inhibit tumor growth and of immune checkpoint inhibitors (ICI) that boost effector T cell responses have strongly improved the treatment of metastatic melanoma. In about half of all melanoma patients, tumor growth is driven by gain-of-function mutations of BRAF (v-rat fibrosarcoma (Raf) murine sarcoma viral oncogene homolog B), which results in constitutive ERK activation. Patients with a BRAF mutation are regularly treated with a combination of BRAF and MEK (MAPK/ERK kinase) inhibitors. Next to the antiproliferative effects of BRAF/MEKi, accumulating preclinical evidence suggests that BRAF/MEKi exert immunomodulatory functions such as paradoxical ERK activation as well as additional effects in non-tumor cells. In this review, we present the current knowledge on the immunomodulatory functions of BRAF/MEKi as well as the non-intended effects of ICI and discuss the potential synergistic effects of ICI and MAPK inhibitors in melanoma treatment.
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http://dx.doi.org/10.3390/ijms22189890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469254PMC
September 2021

Dermatology Life Quality Index among Different Cultures: A Neglected Bias Needs to Be Addressed.

Dermatology 2021 Sep 24:1-2. Epub 2021 Sep 24.

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

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http://dx.doi.org/10.1159/000519321DOI Listing
September 2021

Light-Based Devices for the Treatment of Facial Erythema and Telangiectasia.

Dermatol Ther (Heidelb) 2021 Sep 25. Epub 2021 Sep 25.

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

Facial erythema is one of the most common outpatient complaints in dermatology. There are various causes of facial erythema and several devices are available for its treatment. Pulsed dye laser (PDL) and intense pulsed light (IPL) are the two common light devices used for these conditions. In this review, we evaluated the literature to assess efficacy of IPL versus PDL in facial erythema and telangiectasia. We searched published articles including clinical trials or reviews articles, case series, and case reports. Electronic databases (MEDLINE and PubMed) were searched to retrieve the articles. Reference lists of selected articles were also considered for the review. Articles published in English language until June 2021 were considered for this review.
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http://dx.doi.org/10.1007/s13555-021-00607-8DOI Listing
September 2021

The Status of Adjuvant and Neoadjuvant Melanoma Therapy, New Developments and Upcoming Challenges.

Target Oncol 2021 09 23;16(5):537-552. Epub 2021 Sep 23.

Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

The global incidence of malignant melanoma, the leading cause of skin cancer death, has steadily increased in recent years. Surgical excision is the treatment of choice for early-stage melanoma. However, 40-60% of patients with high-risk melanoma or with nodal involvement eventually experience loco-regional relapse or tumor progression. Adjuvant therapy aims to reduce the rate of recurrence in radically operated high-risk patients with melanoma and thus improves survival. Interferon-α has long been the only approved drug for adjuvant melanoma therapy, despite an unclear survival benefit. The landmark success of immune-checkpoint inhibitors and BRAF/MEK-directed targeted therapies in the treatment of patients with stage IV melanoma led to the initiation of clinical trials in the adjuvant setting. These trials demonstrated the efficacy of immune-checkpoint inhibitors and targeted therapies for the adjuvant treatment of high-risk patients with melanoma, as shown both by an increase in recurrence-free survival and the emergence of long-term survivors, finally resulting in the approval of the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab, PD1 inhibitors (nivolumab, pembrolizumab), and BRAF/MEK inhibitors for adjuvant melanoma therapy. This review aims to delineate the advances in adjuvant melanoma therapy, issuing particularly recent results from clinical trials. Moreover, we also discuss pending issues and future challenges, which comprise the adequate selection of adjuvant regimens for patient subgroups and the identification of markers likely to predict the individual response to adjuvant treatments. Last, we outline the role of emerging neoadjuvant approaches, which may complement adjuvant strategies and are currently investigated in clinical trials.
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http://dx.doi.org/10.1007/s11523-021-00840-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484171PMC
September 2021

LAight® Therapy Significantly Enhances Treatment Efficacy of 16 Weeks of Topical Clindamycin Solution in Hurley I and II Hidradenitis Suppurativa: Results from Period A of RELIEVE, a Multicenter Randomized, Controlled Trial.

Dermatology 2021 Sep 14:1-11. Epub 2021 Sep 14.

Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland.

Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory, burdensome skin disease where medical first-line treatment is still limited to long-term, topical and/or systemic antibiotics. The RELIEVE study aimed at evaluating the efficacy of LAight® therapy - a combination of intense pulsed light and radiofrequency - as an adjunct treatment to first-line therapies in Hurley stage I and II HS.

Methods: The RELIEVE study was performed as a two-period multicenter randomized controlled trial with blinded assessment. For period A from week 0 to week 16, the 88 participating subjects were randomized into either an intervention group (IG) or a control group (CG). The IG received topical clindamycin 1% solution combined with 8 additional bi-weekly treatments with LAight® therapy. The CG was treated with topical clindamycin 1% solution only. After 16 weeks, patients entered open-label period B and both groups were treated exclusively with LAight® therapy for an additional 16 weeks (8 sessions). The primary efficacy endpoint was the change in International Hidradenitis Suppurativa Score System (∆IHS4) at week 16 to baseline. Secondary endpoints were DLQI, HiSCR, Pain-NRS, and HADS.

Results: In total, from the 88 patients enrolled in RELIEVE, 81 patients were included in the endpoint analysis after period A. After 16 weeks of treatment, the ∆IHS4 of the group treated with the combination of LAight® therapy and topical clindamycin 1% solution was -7.2 ± 6.7 (-60.0%), which was significantly higher in magnitude than the ∆IHS4 in the group treated with clindamycin 1% solution alone (-1.8 ± 5.6, -17.8%, p < 0.001). Secondary endpoints, including other clinical scores as well as patient-reported outcomes, confirmed that the efficacy of the combined treatment was superior to monotherapy.

Conclusion: The results of the primary endpoint analysis of period A of the RELIEVE study show that the combined therapy with LAight® and topical clindamycin 1% solution, resulted in a significantly higher decrease in disease severity and an improvement of quality of life in comparison to topical clindamycin 1% solution monotherapy. Treatment was well tolerated, and side effects were all mild and transitory. These data speak for the implementation of the combined treatment as a first-line therapy in Hurley stage I and II HS. LAight® therapy as long-term monotherapy (results from period B), will be analyzed in a consecutive paper.
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http://dx.doi.org/10.1159/000518540DOI Listing
September 2021

Chronic Kidney Disease-Associated Pruritus.

Toxins (Basel) 2021 07 28;13(8). Epub 2021 Jul 28.

Department of Dermatology, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.

Pruritus is a distressing condition associated with end-stage renal disease (ESRD), advanced chronic kidney disease (CKD), as well as maintenance dialysis and adversely affects the quality of life (QOL) of these patients. It has been reported to range from 20% to as high as 90%. The mechanism of CKD-associated pruritus (CKD-aP) has not been clearly identified, and many theories have been proposed to explain it. Many risk factors have been found to be associated with CKD-aP. The pruritus in CKD presents with diverse clinical features, and there are no set features to diagnose it.The patients with CKD-aP are mainly treated by nephrologists, primary care doctors, and dermatologists. Many treatments have been tried but nothing has been effective. The search of literature included peer-reviewed articles, including clinical trials and scientific reviews. Literature was identified through March 2021, and references of respective articles and only articles published in the English language were included.
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http://dx.doi.org/10.3390/toxins13080527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402524PMC
July 2021

Density of Conjugated Antibody Determines the Extent of Fc Receptor Dependent Capture of Nanoparticles by Liver Sinusoidal Endothelial Cells.

ACS Nano 2021 09 25;15(9):15191-15209. Epub 2021 Aug 25.

Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.

Despite considerable progress in the design of multifunctionalized nanoparticles (NPs) that selectively target specific cell types, their systemic application often results in unwanted liver accumulation. The exact mechanisms for this general observation are still unclear. Here we asked whether the number of cell-targeting antibodies per NP determines the extent of NP liver accumulation and also addressed the mechanisms by which antibody-coated NPs are retained in the liver. We used polysarcosine-based peptobrushes (PBs), which in an unmodified form remain in the circulation for >24 h due to the absence of a protein corona formation and low unspecific cell binding, and conjugated them with specific average numbers (2, 6, and 12) of antibodies specific for the dendritic cell (DC) surface receptor, DEC205. We assessed the time-dependent biodistribution of PB-antibody conjugates by imaging and flow cytometry. We observed that PB-antibody conjugates were trapped in the liver and that the extent of liver accumulation strongly increased with the number of attached antibodies. PB-antibody conjugates were selectively captured in the liver Fc receptors (FcR) on liver sinusoidal endothelial cells, since systemic administration of FcR-blocking agents or the use of F(ab') fragments prevented liver accumulation. Cumulatively, our study demonstrates that liver endothelial cells play a yet scarcely acknowledged role in liver entrapment of antibody-coated NPs and that low antibody numbers on NPs and the use of F(ab') antibody fragments are both sufficient for cell type-specific targeting of secondary lymphoid organs and necessary to minimize unwanted liver accumulation.
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http://dx.doi.org/10.1021/acsnano.1c05713DOI Listing
September 2021

Combination therapy of recalcitrant severe psoriasis with psoriatic arthritis, diabetes nephropathy, and liver cirrhosis.

J Cosmet Dermatol 2021 Aug 20. Epub 2021 Aug 20.

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

Objective: Treatment of recalcitrant moderate-to-severe psoriasis can be challenging. Combination therapy of biologics and immunosuppressive agents can be a new strategy for treating therapy-resistant cases with comorbidities, where many systemic medications are contraindicated.

Case Presentation: We report a case of a 62-year-old diabetic man with a 30-year history of severe plaque psoriasis and psoriatic arthritis with cirrhosis and diabetic nephropathy that was treated successfully in combination with apremilast and etanercept after multiple previous unsuccessful treatment attempts.

Conclusion: There are no data supporting the combination of apremilast and etanercept in the management of recalcitrant cases of moderate-to-severe psoriasis and multiple comorbidities including psoriatic arthritis, diabetic nephropathy, and cirrhosis. In patients who do not respond to multiple approaches for the treatment of psoriasis, combination therapy with biologic agents and new systemic medications may lead to dramatic disease control.
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http://dx.doi.org/10.1111/jocd.14367DOI Listing
August 2021

Treatment of Axillary hyperhidrosis.

J Cosmet Dermatol 2021 Aug 20. Epub 2021 Aug 20.

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

Background: Axillary hyperhidrosis characterized by excessive sweating in the axillary regions is a frustrating chronic autonomic disorder leading to social embarrassment, impaired quality of life and usually associated with palmoplantar hyperhidrosis. Identifying the condition and its cause is central to the management.

Aim: The aim of this article is to discuss treatment options for axillary hyperhidrosis.

Methods: Comprehensive literature search using PubMed and Google Scholar was performed to review relevant published articles related to diagnosis and treatment of axillary hyperhidrosis.

Results: Treatment modalities for axillary hyperhydrosis vary from topical and systemic agents to injectables, newer devices and surgical measures. None except for physical measures using devices or surgery, which destroys the sweat glands to remove them, is possibly permanent and most are associated with attendant side effects.

Conclusion: Several treatments including medical and surgical option are available for the treatment of axillary hyperhydrosis. Patient education is important component of its management. Individualized approach of management is necessary for optimal outcome of treatment.
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http://dx.doi.org/10.1111/jocd.14378DOI Listing
August 2021

Effect of estrogen in malignant melanoma.

J Cosmet Dermatol 2021 Aug 20. Epub 2021 Aug 20.

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

Background: Melanoma is associated with poor prognosis in its advanced stages. Potential influence of estrogen and its metabolites on melanoma growth has been suggested.

Aims: The objective of this review was to provide an overview on the evidence related to estrogen in malignant melanoma.

Materials And Methods: Literature search using PubMed, Google Scholar and relevant cross-references of the retrieved articles was performed to review relevant published articles related to estrogen and its effects in malignant melanoma.

Results: Effect of estrogen signaling on a tissue largely depends on the relative expression of estrogen receptors (ER) α and β. Gender differences in melanoma may be explained by the difference in expression of these receptors. ERβ is the principal ER in melanoma.

Discussion: Although there is uncertainty about role of estrogen in pathogenensis and progression of melanoma, evidence suggests that its growth and metastasis are influenced by estrogen stimulation. Role ER on the proliferation of melanoma cells is well described.

Conclusion: There is a need of safe and effective therapy for melanoma, especially for advanced cases. After the establishment of specific role of estrogen and its receptor, analysis of specific genetic mutation can be performed for proper utilization of targeted therapies.
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http://dx.doi.org/10.1111/jocd.14391DOI Listing
August 2021

Chronic venous insufficiency, cardiovascular disease, and mortality: a population study.

Eur Heart J 2021 Aug 13. Epub 2021 Aug 13.

Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz 55131, Germany.

Aims : Evidence regarding the health burden of chronic venous insufficiency (CVI), its clinical determinants, and impact on outcome is scarce.

Methods And Results : Systematic phenotyping of CVI according to established CEAP (Clinical-Etiologic-Anatomic-Pathophysiologic) classification was performed in 12 423 participants (age range: 40-80 years) of the Gutenberg Health Study from April 2012 to April 2017. Prevalence was calculated age- and sex-specifically. Multivariable Poisson regression models were calculated to evaluate the relation of CVI with cardiovascular comorbidities. Survival analyses were carried out to assess the CVI-associated risk of death. Replication of findings was done in an independent cohort study (MyoVasc, NCT04064450). The prevalence of telangiectasia/reticular, varicose veins, and CVI was 36.5% [95% confidence interval (CI), 35.6-37.4%], 13.3% [12.6-13.9%], and 40.8% [39.9-41.7%], respectively. Age, female sex, arterial hypertension, obesity, smoking, and clinically overt cardiovascular disease were identified as clinical determinants of CVI. Higher CEAP classes were associated with a higher predicted 10-year risk for incident cardiovascular disease in individuals free of cardiovascular disease (n = 9923). During a mean follow-up of 6.4 ± 1.6 years, CVI was a strong predictor of all-cause death independent of the concomitant clinical profile and medication [hazard ratio (HR) 1.46 (95% CI 1.19-1.79), P = 0. 0003]. The association of CVI with an increased risk of all-cause death was externally validated in the MyoVasc cohort [HR 1.51 (95% CI 1.11-2.05), P = 0.009].

Conclusion : Chronic venous insufficiency is highly prevalent in the population and is associated with the presence of cardiovascular risk factors and disease. Individuals with CVI experience an elevated risk of death, which is independent of age and sex, and present cardiovascular risk factors and comorbidities.
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http://dx.doi.org/10.1093/eurheartj/ehab495DOI Listing
August 2021

Synthesis of the Data on COVID-19 Skin Manifestations: Underlying Mechanisms and Potential Outcomes.

Clin Cosmet Investig Dermatol 2021 6;14:991-997. Epub 2021 Aug 6.

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

The incidence of coronavirus disease 2019 (COVID-19)-related skin manifestations has progressively grown, in parallel with the global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreading. The available evidence indicates that cutaneous signs are heterogeneous and can be divided as follows: a) erythematous rashes, b) lesions of vascular origin, c) vesicular rashes, d) urticarial rashes, and e) acute generalized exanthematous pustulosis (AGEP), erythema multiforme (EM) and other polymorphic/atypical reactions. Most cutaneous manifestations appear simultaneously or after respiratory and/or systemic symptoms such as fever, even if rarely urticaria has been reported as the first sign of the disease. It has been proposed that erythematous and vesicular rashes, as well as urticaria, are the result of immunological activation against Sars-CoV-2, similarly to other viral exanthems; alternatively, reactivation or co-infection of herpesviruses and drug hypersensitivity represent possible etiologic diagnosis that has to be considered. Regarding lesions of vascular origin, ischemic ones are the result of systemic hypercoagulability established in severe infections, whereas chilblains seem to be linked to the type I-interferon massively produced to halt virus replication. AGEP is triggered by drugs, whereas EM could represent a delayed immune response to the virus or a hypersensitivity reaction to drugs elicited by the inflammatory process built to fight the infection. A further pathogenic hypothesis is that the virus, or its particles detected in the skin (particularly in endothelium and eccrine glands), could be responsible for certain skin reactions, including chilblains and EM. From the available data, it appears that chilblains are correlated with younger age and less severe disease, while ischemic manifestations occur in the elderly with severe infection. In conclusion, larger studies are needed to confirm the suggested pathogenetic mechanisms of COVID-19-related skin reactions and to determine the potential prognostic significance of each one.
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http://dx.doi.org/10.2147/CCID.S325552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354337PMC
August 2021

Idiopathic guttate hypomelanosis: Presentation and Management.

J Cosmet Laser Ther 2021 Jul 25:1-8. Epub 2021 Jul 25.

Private Practitioner, Ahmedabad, India.

Idiopathic guttate hypomelanosis (IGH) is a benign, typically asymptomatic, acquired leukoderma characteristically affecting mature individuals. Although the etiopathogenesis is unclear, chronic sun exposure and senile degeneration are important triggers. Researchers have been engaged in a continuous effort to unveil the gray areas encompassing different aspects of IGH pathogenesis. IGH is a clinical diagnosis; however, histopathology and dermoscopy may aid in quetionable cases. Patients often seek cosmetic treatment. There has been no standard therapy for this condition. Newer treatment modalities range from topical agents to procedure-based therapies and have enhanced the therapeutic armamentarium. Here we discuss the pathogenesis, presentation, and management of IGH.
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http://dx.doi.org/10.1080/14764172.2021.1957116DOI Listing
July 2021

Psoriasis: Embarking a dynamic shift in the skin microbiota.

J Cosmet Dermatol 2021 Jun 5. Epub 2021 Jun 5.

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

Recent interest has arisen regarding the role of microbiome and its composition in the pathogenesis of psoriasis. Numerous studies have shown that there are alterations in skin flora arrangement between normal individuals and psoriatic patients. Psoriasis exacerbation could be interconnected with epidermal or mucosal colonization with streptococci, Malassezia, Staphylococcus aureus, or Candida albicans. The role of cutaneous and gut microbiome in psoriasis pathogenesis has recently been studied in both human and animal models. In this review, we try to evaluate various pathogenic mechanisms linking the microbiota and psoriasis. The literature research included peer-reviewed articles which included clinical trials, original reports, and scientific reviews. MEDLINE and PubMed databases were searched from January 1990 to March 2021, including the reference lists of articles meeting our criteria.
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http://dx.doi.org/10.1111/jocd.14273DOI Listing
June 2021

Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma-A Retrospective Multicenter ADOReg Study.

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

Department of Dermatology, University Medical Center Mainz, 55131 Mainz, Germany.

The advent of BRAF/MEK inhibitors (BRAFi/MEKi) has significantly improved progression-free (PFS) and overall survival (OS) for patients with advanced BRAF-V600-mutant melanoma. Long-term survivors have been identified particularly among patients with a complete response (CR) to BRAF/MEK-directed targeted therapy (TT). However, it remains unclear which patients who achieved a CR maintain a durable response and whether treatment cessation might be a safe option in these patients. Therefore, this study investigated the impact of treatment cessation on the clinical course of patients with a CR upon BRAF/MEK-directed-TT. We retrospectively selected patients with BRAF-V600-mutant advanced non-resectable melanoma who had been treated with BRAFi ± MEKi therapy and achieved a CR upon treatment out of the multicentric skin cancer registry ADOReg. Data on baseline patient characteristics, duration of TT, treatment cessation, tumor progression (TP) and response to second-line treatments were collected and analyzed. Of 461 patients who received BRAF/MEK-directed TT 37 achieved a CR. TP after initial CR was observed in 22 patients (60%) mainly affecting patients who discontinued TT (n = 22/26), whereas all patients with ongoing TT (n = 11) maintained their CR. Accordingly, patients who discontinued TT had a higher risk of TP compared to patients with ongoing treatment ( < 0.001). However, our data also show that patients who received TT for more than 16 months and who discontinued TT for other reasons than TP or toxicity did not have a shorter PFS compared to patients with ongoing treatment. Response rates to second-line treatment being initiated in 21 patients, varied between 27% for immune-checkpoint inhibitors (ICI) and 60% for BRAFi/MEKi rechallenge. In summary, we identified a considerable number of patients who achieved a CR upon BRAF/MEK-directed TT in this contemporary real-world cohort of patients with BRAF-V600-mutant melanoma. Sustained PFS was not restricted to ongoing TT but was also found in patients who discontinued TT.
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http://dx.doi.org/10.3390/cancers13102312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151093PMC
May 2021

Treatment Update of Port-Wine Stain: A Narrative Review.

J Drugs Dermatol 2021 May;20(5):515-518

Background: Port-wine stain (PWS) is a congenital vascular malformation affecting 0.3–0.5% of normal population. These characteristic lesions arise due to the interplay of vascular, neural, and genetic factors. Treatment options include lasers, cosmetic tattooing, electrotherapy, cryosurgery, derma-abrasion, and skin grafting; however, none of these treatment alternatives appears to be satisfactory and is unable to provide consistent, satisfactory responses or even complete cures. Currently, laser is the treatment of choice, as it is comparatively safe and more effective than other procedures. The most commonly used modality is pulsed dye laser (PDL). The literature research includes peer-reviewed articles (clinical trials or scientific reviews). Studies were identified by searching electronic databases (MEDLINE and PubMed) to January 2020 and reference lists of respective articles. Only articles published in English language were included. J Drugs Dermatol. 20(5): doi:10.36849/JDD.5005.
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http://dx.doi.org/10.36849/JDD.5005DOI Listing
May 2021

Complement-Opsonized Nano-Carriers Are Bound by Dendritic Cells (DC) via Complement Receptor (CR)3, and by B Cell Subpopulations via CR-1/2, and Affect the Activation of DC and B-1 Cells.

Int J Mol Sci 2021 Mar 11;22(6). Epub 2021 Mar 11.

Department of Dermatology, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.

The development of nanocarriers (NC) for biomedical applications has gained large interest due to their potential to co-deliver drugs in a cell-type-targeting manner. However, depending on their surface characteristics, NC accumulate serum factors, termed protein corona, which may affect their cellular binding. We have previously shown that NC coated with carbohydrates to enable biocompatibility triggered the lectin-dependent complement pathway, resulting in enhanced binding to B cells via complement receptor (CR)1/2. Here we show that such NC also engaged all types of splenic leukocytes known to express CR3 at a high rate when NC were pre-incubated with native mouse serum resulting in complement opsonization. By focusing on dendritic cells (DC) as an important antigen-presenting cell type, we show that CR3 was essential for binding/uptake of complement-opsonized NC, whereas CR4, which in mouse is specifically expressed by DC, played no role. Further, a minor B cell subpopulation (B-1), which is important for first-line pathogen responses, and co-expressed CR1/2 and CR3, in general, engaged NC to a much higher extent than normal B cells. Here, we identified CR-1/2 as necessary for binding of complement-opsonized NC, whereas CR3 was dispensable. Interestingly, the binding of complement-opsonized NC to both DC and B-1 cells affected the expression of activation markers. Our findings may have important implications for the design of nano-vaccines against infectious diseases, which codeliver pathogen-specific protein antigen and adjuvant, aimed to induce a broad adaptive cellular and humoral immune response by inducing cytotoxic T lymphocytes that kill infected cells and pathogen-neutralizing antibodies, respectively. Decoration of nano-vaccines either with carbohydrates to trigger complement activation in vivo or with active complement may result in concomitant targeting of DC and B cells and thereby may strongly enhance the extent of dual cellular/humoral immune responses.
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http://dx.doi.org/10.3390/ijms22062869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001596PMC
March 2021

Regulatory T Cells Prevent Neutrophilic Infiltration of Skin during Contact Hypersensitivity Reactions by Strengthening the Endothelial Barrier.

J Invest Dermatol 2021 Aug 4;141(8):2006-2017. Epub 2021 Mar 4.

Department of Dermatology, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany. Electronic address:

The healing phase of contact hypersensitivity reactions is critically dependent on regulatory T cells (Tregs), but even the early inflammatory phase, that is, 6-24 hours after induction of a contact hypersensitivity reaction, is susceptible to Treg-mediated suppression. To investigate the underlying mechanisms, we injected Tregs before the challenge and analyzed the skin-infiltrating cells as early as 6 hours later. Early on, we found mainly neutrophils in the challenged skin, but only a few T cells. This influx of neutrophils was blocked by the injection of Tregs, indicating that they were able to prevent the first wave of leukocytes, which are responsible for starting an immune reaction. As an underlying mechanism, we identified that Tregs can tighten endothelial junctions by inducing intracellular cAMP, leading to protein kinase A-RhoA‒dependent signaling. This eventually reorganizes endothelial junction proteins, such as Notch3, Nectin 2, Filamin B, and VE-cadherin, all of which contribute to the tightening of the endothelial barrier. In summary, Tregs prevent the leakage of proinflammatory cells from and into the tissue, which establishes a mechanism to downregulate immune reactions.
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http://dx.doi.org/10.1016/j.jid.2021.01.027DOI Listing
August 2021

Factors accelerating recurrences and secondary tumors in cutaneous squamous cell carcinoma.

J Craniomaxillofac Surg 2021 Apr 12;49(4):317-322. Epub 2021 Feb 12.

Department of Oral and Maxillofacial Surgery of the University Medical Center of the Johannes Gutenberg-University, Augustusplatz 2, 55131, Mainz, Germany.

To investigate factors that affect and also decrease the duration for recurrences and secondary tumors in cSCC. A retrospective study was conducted for all patients who were treated for a cSCC of the head and neck between 2009 and 2016. Anamnestic as well as epidemiological and histological data were noted and correlated with the occurrence of recurrences and secondary cancers. The duration between surgery and these events was used to determine if histological factors accelerate their occurrence. The highest risk for recurrences was seen in patients with previous skin cancers (RR 3.23). Histological ulceration (p = 0.003) and grading (p = 0.031) of the tumor were found as significant factors accelerating the time to relapse. Surrounding chronic precancerotic lesions (p < 0.001) and poor tumor grading (p = 0.035) were found as significant factors accelerating the time until a secondary cSCC was observed. Known risk factors increase not only the risk for a cSCC but also for recurrences. Specific histologic findings can help to adjust follow-up intervals to identify recurrences and secondary tumors at an early stage as these were shown to decrease the duration for a further event.
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http://dx.doi.org/10.1016/j.jcms.2021.02.009DOI Listing
April 2021

Simvastatin in vitiligo: an update with recent review of the literature.

Int J Dermatol 2021 Oct 7;60(10):e390-e396. Epub 2021 Feb 7.

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

Patients with vitiligo often seek medical attention, as it diminishes their quality of life resulting in significant morbidity. Several topical and systemic therapies are in vogue targeting the immunological aspect of this disease, but results are often unsatisfactory, and complete cure remains elusive. Recently, simvastatin, a 3-hydroxy-3-methylyglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, is being evaluated for vitiligo management because of its multimodal action, easy availability, and low cost. The proposed multimodal actions range from anti-inflammatory, antioxidant, to immunomodulatory properties which may be of therapeutic benefit in vitiligo patients. The authors intend to evaluate the role of simvastatin as a novel therapeutic agent for vitiligo along with relevant review of literature.
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http://dx.doi.org/10.1111/ijd.15330DOI Listing
October 2021

Grüntee-Extrakt als erfolgreiche topische Behandlungsoption bei Kindern mit Condylomata acuminata im Perianalbereich.

J Dtsch Dermatol Ges 2021 Jan;19(1):113-115

Hautklinik, Universitätsmedizin der Johannes Gutenberg--Universität Mainz.

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http://dx.doi.org/10.1111/ddg.14173_gDOI Listing
January 2021

Immune signature as predictive marker for response to checkpoint inhibitor immunotherapy and overall survival in melanoma.

Cancer Med 2021 03 15;10(5):1562-1575. Epub 2021 Jan 15.

Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

Background: Malignant melanoma is an immunogenic skin cancer with an increasing global incidence. Advanced stages of melanoma have poor prognoses. Currently, there are no reliable parameters to predict a patient's response to immune checkpoint inhibitor (ICI) therapy.

Methods: This study highlights the relevance of a distinct immune signature in the blood for response to ICI therapy and overall survival (OS). Therefore, the immune cell composition in the peripheral blood of 45 melanoma patients prior to ICI therapy was analyzed by flow cytometry and complete blood count.

Results: Responders to ICI therapy displayed an abundance of proliferating CD4 T cells, an increased lymphocyte-to-monocyte ratio, a low platelet-to-lymphocyte ratio, low levels of CTLA-4 Treg, and (arginase 1 ) polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC). Nevertheless, non-responders with similar immune cell compositions also benefited from therapy displaying increased long-term OS.

Conclusions: Our study demonstrated that the observed immune signature in the peripheral blood of melanoma patients prior to treatment could identify responders as well as non-responders that benefit from ICI immunotherapies.
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http://dx.doi.org/10.1002/cam4.3710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940230PMC
March 2021

The Functional Crosstalk between Myeloid-Derived Suppressor Cells and Regulatory T Cells within the Immunosuppressive Tumor Microenvironment.

Cancers (Basel) 2021 Jan 8;13(2). Epub 2021 Jan 8.

Department of Dermatology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany.

Immune checkpoint inhibitors (ICI) have led to profound and durable tumor regression in some patients with metastatic cancer diseases. However, many patients still do not derive benefit from immunotherapy. Here, the accumulation of immunosuppressive cell populations within the tumor microenvironment (TME), such as myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and regulatory T cells (Treg), contributes to the development of immune resistance. MDSC and Treg expand systematically in tumor patients and inhibit T cell activation and T effector cell function. Numerous studies have shown that the immunosuppressive mechanisms exerted by those inhibitory cell populations comprise soluble immunomodulatory mediators and receptor interactions. The latter are also required for the crosstalk of MDSC and Treg, raising questions about the relevance of cell-cell contacts for the establishment of their inhibitory properties. This review aims to outline the current knowledge on the crosstalk between these two cell populations, issuing particularly the potential role of cell adhesion molecules. In this regard, we further discuss the relevance of β2 integrins, which are essential for the differentiation and function of leukocytes as well as for MDSC-Treg interaction. Lastly, we aim to describe the impact of such bidirectional crosstalk for basic and applied cancer research and discuss how the targeting of these pathways might pave the way for future approaches in immunotherapy.
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http://dx.doi.org/10.3390/cancers13020210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827203PMC
January 2021

Role of Hypoxia and the Adenosine System in Immune Evasion and Prognosis of Patients with Brain Metastases of Melanoma: A Multiplex Whole Slide Immunofluorescence Study.

Cancers (Basel) 2020 Dec 13;12(12). Epub 2020 Dec 13.

Department of Radiation Oncology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany.

Following the introduction of immune checkpoint inhibitors, a substantial prolongation of the overall survival has been achieved for many patients with multiple brain metastases from melanoma. However, heterogeneity between individual tumor responses is incompletely understood. In order to determine the impact of the individual tumor phenotype on the prognosis of melanoma patients, we examined surgical sections from 33 patients who were treated with radiotherapy (whole-brain radiotherapy, WBRT, stereotactic radiotherapy, STX, or both) and Ipilimumab. We analyzed multiplex staining of the hypoxia marker GLUT-1, the adenosine (ADO)-associated enzymes CD73 and CD39, and CD8, a marker of cytotoxic T lymphocytes (CTL) on a single-cell basis using QuPath. Additionally, the MOSAIC interaction analysis algorithm was used to explore the hypothesis that CTL systematically avoid GLUT-1 tumor areas. Our results revealed, that a strong GLUT-1 expression, low numbers of CTL, or exclusion of CTL from the tumor were correlated with significant prognostic detriment. Hypoxic tumors overall have smaller amounts of CTL, and spatial analysis revealed a repellent effect of hypoxia on CTL. In contrast to in vitro studies, specific upregulation of ADO-related enzymes CD73 and CD39 in GLUT-1 tumor regions was never observed. In this study, we could show direct in vivo evidence for hypoxia-mediated immunosuppression in melanoma. Moreover, this study suggests a significant prognostic relevance of the tumor immune phenotype, the strength of CD8 infiltration in the tumor, and the expression of hypoxia marker GLUT-1 on melanoma cells. Last, our results suggest a temporal stability of the microenvironment-mediated immunosuppressive phenotype in melanoma.
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http://dx.doi.org/10.3390/cancers12123753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763902PMC
December 2020

Platelet-Derived GARP Induces Peripheral Regulatory T Cells-Potential Impact on T Cell Suppression in Patients with Melanoma-Associated Thrombocytosis.

Cancers (Basel) 2020 Dec 5;12(12). Epub 2020 Dec 5.

Department of Dermatology, University Medical Center Mainz, 55131 Mainz, Germany.

Platelets have been recently described as an important component of the innate and adaptive immunity through their interaction with immune cells. However, information on the platelet-T cell interaction in immune-mediated diseases remains limited. Glycoprotein A repetitions predominant (GARP) expressed on platelets and on activated regulatory T cells (Treg) is involved in the regulation of peripheral immune responses by modulating the bioavailability of transforming growth factor β (TGF-β). Soluble GARP (sGARP) exhibits strong regulatory and anti-inflammatory capacities both in vitro and in vivo, leading to the induction of peripheral Treg. Herein, we investigated the effect of platelet-derived GARP on the differentiation, phenotype, and function of T effector cells. CD4CD25 T cells cocultured with platelets upregulated FoxP3, the master transcription factor for Treg, were anergic, and were strongly suppressive. These effects were reversed by using a blocking anti-GARP antibody, indicating a dependency on GARP. Importantly, melanoma patients in different stages of disease showed a significant upregulation of GARP on the platelet surface, correlating to a reduced responsiveness to immunotherapy. In conclusion, our data indicate that platelets induce peripheral Treg via GARP. These findings might contribute to diseases such as cancer-associated thrombocytosis, wherein poor prognosis and metastasis are associated with high counts of circulating platelets.
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http://dx.doi.org/10.3390/cancers12123653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762193PMC
December 2020

Hemophagocytic lymphohistiocytosis of a melanoma patient under BRAF/MEK-inhibitor therapy following anti-PD1 inhibitor treatment: a case report and review to the literature.

Melanoma Res 2021 02;31(1):81-84

Departments of Dermatology.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening condition. HLH in infants and young children is usually inherited, which is then classified as primary HLH. Secondary HLH, in contrast, is caused by many different conditions such as infections, cancer or medication and affects mostly adults. HLH is a hyperinflammatory condition, which may mimic an acute septic shock. We report on a 68-year-old patient with malignant melanoma with lymph node metastases. Due to the lymphogenic progression, treatment was switched from nivolumab to dabrafenib and trametinib. Twenty-one days after initiation of BRAF/MEK inhibitor therapy, the patient presented to our emergency department with clinical signs of infection such as fever and fatigue. Laboratory tests showed excessive inflammation levels without identifying an underlying pathogen. Two days later, the patient developed an increasing pancytopenia. After extending the diagnosis, we found very high ferritin levels, hypertriglyceridemia, hypofibrinogenemia and a soluble CD25 receptor. Based on the laboratory results, prolonged fever and splenomegaly, we were able to diagnose HLH as the underlying condition. We immediately initiated treatment with intravenous prednisone, which remarkably improved the clinical symptoms. After full recovery, we reinitiated anti-tumor treatment with vemurafenib and cobimetinib, which was tolerated without side effects. Due to the relatively nonspecific nature of the clinical signs and symptoms and the significant overlap with other diseases such as sepsis, the diagnosis of HLH is often delayed. This explains, in part, the high morbidity and mortality rate. Our case shows that early treatment with steroids is effective. However, much work remains in order to raise awareness and improve the understanding of the pathophysiology of this condition.
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http://dx.doi.org/10.1097/CMR.0000000000000703DOI Listing
February 2021

Complication of Soft Tissue Fillers: Prevention and Management Review.

J Drugs Dermatol 2020 Sep;19(9):829-832

The use of dermal fillers has increased manifold over the past decade, which has been attributed to the ever-increasing need of the population for being young. Fillers have become quite popular both among patients and treating physicians due to their quick and quite predictable results. Filler injection is a safe procedure in the hands of an experienced provider using appropriate technique. Nevertheless, various adverse effects to fillers have been reported that range from mild injection site complications, such as pain and bruising, to severe complications, like tissue necrosis, retinal artery occlusion, and infections. The esthetic provider should be aware of and be able to quickly recognize such complications, and be confident in managing them. In this article we highlight the various adverse effects noted with the use of fillers and discuss prevention and management. J Drugs Dermatol. 2020;19(9):829-832. doi:10.36849/JDD.2020.5084.
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http://dx.doi.org/10.36849/JDD.2020.10.36849/JDD.2020.5084DOI Listing
September 2020

Transient Multivalent Nanobody Targeting to CD206-Expressing Cells via PH-Degradable Nanogels.

Cells 2020 10 1;9(10). Epub 2020 Oct 1.

Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.

To target nanomedicines to specific cells, especially of the immune system, nanobodies can be considered as an attractive tool, as they lack the Fc part as compared to traditional antibodies and, thus, prevent unfavorable Fc-receptor mediated mistargeting. For that purpose, we have site-specifically conjugated CD206/MMR-targeting nanobodies to three types of dye-labeled nanogel derivatives: non-degradable nanogels, acid-degradable nanogels (with ketal crosslinks), and single polymer chains (also obtained after nanogel degradation). All of them can be obtained from the same reactive ester precursor block copolymer. After incubation with naïve or MMR-expressing Chinese hamster ovary (CHO) cells, a nanobody mediated targeting and uptake could be confirmed for the nanobody-modified nanocarriers. Thereby, the intact nanogels that display nanobodies on their surface in a multivalent way showed a much stronger binding and uptake compared to the soluble polymers. Based on their acidic pH-responsive degradation potential, ketal crosslinked nanogels are capable of mediating a transient targeting that gets diminished upon unfolding into single polymer chains after endosomal acidification. Such control over particle integrity and targeting performance can be considered as highly attractive for safe and controllable immunodrug delivery purposes.
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http://dx.doi.org/10.3390/cells9102222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600184PMC
October 2020

Systemische Immunsuppression in Zeiten von COVID‐19: Müssen wir umdenken?

J Dtsch Dermatol Ges 2020 Aug;18(8):810-814

Hautklinik, Universitätsklinikum der Ruprecht-Karls-Universität, Heidelberg.

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http://dx.doi.org/10.1111/ddg.14194_gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460968PMC
August 2020

Systemic immunosuppression in times of COVID-19: Do we need to rethink our standards?

J Dtsch Dermatol Ges 2020 08 2;18(8):810-813. Epub 2020 Aug 2.

Department of Dermatology, University Hospital of the Ruprecht-Karls-University, Heidelberg, Germany.

The current SARS-CoV-2 pandemic particularly endangers older people with pre-existing cardiopulmonary and metabolic conditions. However, it is also currently under discussion whether patients under immunosuppressive therapy also have a higher risk of suffering a severe course of the COVID-19 disease. In principle though, there is currently no data available for a general reduction or pause of immunosuppression in patients with autoimmune diseases because of the SARS-CoV-2 pandemic. However, since there is currently neither an effective therapy nor corresponding vaccination protection, the indication for a prolonged immunosuppressive therapy should be made with special care. In particular, immunotherapeutic agents that produce long-term effects (e.g., rituximab) should be used with special caution. In contrast, immunomodulating substances that do not suppress antiviral immunity (e.g. systemic immunoglobulins, doxycycline), or that have intrinsic effects on SARS-CoV-2 (calcineurin inhibitors, chloroquine, hydroxychloroquine) may be useful alternatives.
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http://dx.doi.org/10.1111/ddg.14194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436367PMC
August 2020
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