Publications by authors named "Claas Ulrich"

36 Publications

New methods for assessing secondary performance attributes of sunscreens suitable for professional outdoor work.

J Occup Med Toxicol 2021 Jul 5;16(1):25. Epub 2021 Jul 5.

Institute for Health Research and Education, Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Am Finkenhügel 7a, 49076, Osnabrück, Germany.

Background: Outdoor workers (OW) are highly exposed to solar ultraviolet radiation (UVR) and thus at increased risk for developing skin cancer. An essential part of an overall strategy to reduce workplace UVR-exposure to OW's skin is the usage of sunscreens. However, compliance with regular sunscreen usage seems to be low, as products are usually designed for recreational sun exposure and thus do not meet the requirements of physically active OW. To date, no standardized test procedures assess the suitability of sunscreens for professional use. The aim of this pilot study was to develop standardized methods of testing secondary performance attributes (PA) to represent real-life working conditions of outdoor work.

Methods: Ten sunscreen products, carefully selected after a detailed market survey of all relevant producers available on the German market, were evaluated regarding their suitability for professional outdoor work on 24 healthy volunteers in a newly designed test procedure. In addition to three standardized efficacy characteristics, i.e., sun protection factor, water-resistance, and UVA protection, we evaluated each PA involving parameters typically associated with outdoor workplaces.

Results: We developed standardized methods for objectifying the suitability of sunscreen products for professional outdoor work. The test procedures used are well feasible and appropriate for testing the PA because they represent practical working conditions in detail - although the degree of discriminability of single test methods varied. The claimed sun protection factor (SPF) of the products was confirmed; bio-stability of the SPF after physical activity was achieved in most cases. While most products hardly irritate the eyes and are quickly absorbed, the evaluation of the subjective skin feeling and non-slip grip is inconsistent.

Conclusions: In this pilot study, for the first time secondary PA are defined and examined. Although further objectification of the PA assessment as well as the establishment of minimum standards should be sought, the new methods could already complement the so far mandatory labels and in this way provide a significant impetus for the current scientific and political focus on the improvement of occupational health in highly UVR-exposed OW.
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http://dx.doi.org/10.1186/s12995-021-00314-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256554PMC
July 2021

Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial.

Lancet Oncol 2021 06 14;22(6):848-857. Epub 2021 May 14.

Skin Cancer Center, Department of Dermatology, Harz Clinics, Quedlinburg, Germany.

Background: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy.

Methods: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants.

Findings: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths.

Interpretation: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy.

Funding: Regeneron Pharmaceuticals and Sanofi.
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http://dx.doi.org/10.1016/S1470-2045(21)00126-1DOI Listing
June 2021

High ROS Production by Celecoxib and Enhanced Sensitivity for Death Ligand-Induced Apoptosis in Cutaneous SCC Cell Lines.

Int J Mol Sci 2021 Mar 31;22(7). Epub 2021 Mar 31.

Department of Dermatology, Venerology and Allergology, Skin Cancer Center, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.

Incidence of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis has increased worldwide, and non-steroidal anti-inflammatory drugs as celecoxib are considered for treatment. We show here strong anti-proliferative effects of celecoxib in four cSCC cell lines, while apoptosis and cell viability largely remained unaffected. Impeded apoptosis was overcome in combinations with agonistic CD95 antibody or TNF-related apoptosis-inducing ligand (TRAIL), resulting in up to 60% apoptosis and almost complete loss of cell viability. Proapoptotic caspase cascades were activated, and apoptosis was suppressed by caspase inhibition. TRAIL receptor (DR5) and proapoptotic Bcl-2 proteins (Puma and Bad) were upregulated, while anti-apoptotic factors (survivin, XIAP, cFLIP, Mcl-1, and Bcl-w) were downregulated. Strongly elevated levels of reactive oxygen species (ROS) turned out as particularly characteristic for celecoxib, appearing already after 2 h. ROS production alone was not sufficient for apoptosis induction but may play a critical role in sensitizing cancer cells for apoptosis and therapy. Thus, the full therapeutic potential of celecoxib may be better used in combinations with death ligands. Furthermore, the immune response against cSCC/AK may be improved by celecoxib, and combinations with checkpoint inhibitors, recently approved for the treatment of cSCC, may be considered.
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http://dx.doi.org/10.3390/ijms22073622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036359PMC
March 2021

Tape stripping the stratum corneum for biomarkers of ultraviolet radiation exposure at sub-erythemal dosages: a study in human volunteers.

Biomarkers 2020 Sep 12;25(6):490-497. Epub 2020 Jul 12.

Coronel Institute of Occupational Health, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands.

Purpose: Prevalence of skin cancer is rapidly increasing. There is a need for non-invasive biomarkers to assess efficacy of prevention strategies aiming at reduction of exposure to ultraviolet radiation (UVR). Recently, stratum corneum (SC) biomarkers were applied in various inflammatory skin diseases. Here, we explore their suitability as candidate biomarkers for UVR.

Material And Methods: Twelve volunteers were exposed to a UVB-dose of 0.72 SED, three times a week, during three weeks. As candidate biomarkers, -isomers of urocanic acid (cUCA) and 25 immunological mediators were measured in the SC.

Results: Eight immunological markers significantly changed from baseline. Of them, IL-1RA/IL-1α and a placental growth factor (PIGF) showed gradual changes during UVR-exposure ( < 0.01 for linear trend). cUCA increased sharply already after the first exposure, however, reached a plateau in the second week.

Conclusions: SC represents a promising, non-invasive alternative to skin biopsy in detecting UVR-induced changes. cUCA is the marker of choice for assessment of single UVR-exposure; however, it is less suitable for cumulative UVR-dose. Immunological markers including IL-1RA/IL-1α and PIGF showed gradual changes, and therefore are convenient for monitoring chronic UVR-exposure. These candidate biomarkers might facilitate assessment of the efficacy of preventive measures in the workplace and general population.
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http://dx.doi.org/10.1080/1354750X.2020.1792551DOI Listing
September 2020

Phase 2 study of cemiplimab in patients with metastatic cutaneous squamous cell carcinoma: primary analysis of fixed-dosing, long-term outcome of weight-based dosing.

J Immunother Cancer 2020 06;8(1)

Department of Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.

Background: Cemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort (NCT02383212) and the pivotal Phase 2 study (NCT02760498). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study (NCT02760498).

Methods: The primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability.

Results: For Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan-Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%).

Conclusion: In patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses.

Trial Registration Number: Clinicaltrials.gov, NCT02760498. Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498.
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http://dx.doi.org/10.1136/jitc-2020-000775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304829PMC
June 2020

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

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

Department of Dermatology, Knappschaftskrankenhaus Recklinghausen, Recklinghausen, Germany.

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

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

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

Department of Dermatology, Knappschaftskrankenhaus Recklinghausen, Recklinghausen, Germany.

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

Prevalence and associated factors of skin cancer in aged nursing home residents: A multicenter prevalence study.

PLoS One 2019 22;14(4):e0215379. Epub 2019 Apr 22.

Department of Dermatology and Allergy, Clinical Research Center for Hair and Skin Science, Charité-Universitätsmedizin Berlin, Germany.

Non-melanoma-skin cancer is an emerging clinical problem in the elderly, fair skinned population which predominantly affects patients aged older than 70 years. Its steady increase in incidence rates and morbidity is paralleled by related medical costs. Despite the fact that many elderly patients are in need of care and are living in nursing homes, specific data on the prevalence of skin cancer in home care and the institutional long-term care setting is currently lacking. A representative multicenter prevalence study was conducted in a random sample of ten institutional long-term care facilities in the federal state of Berlin, Germany. In total, n = 223 residents were included. Actinic keratoses, the precursor lesions of invasive cutaneous squamous cell carcinoma were the most common epithelial skin lesions (21.1%, 95% CI 16.2 to 26.9). Non-melanoma skin cancer was diagnosed in 16 residents (7.2%, 95% CI 4.5 to 11.3). None of the residents had a malignant melanoma. Only few bivariate associations were detected between non-melanoma skin cancer and demographic, biographic and functional characteristics. Male sex was significantly associated with actinic keratosis whereas female sex was associated with non-melanoma skin cancer. Smoking was associated with an increased occurrence of non-melanoma skin cancer. Regular dermatology check-ups in nursing homes would be needed but already now due to financial limitations, lack of time in daily clinical practice and limited number of practising dermatologists, it is not the current standard. With respect to the worldwide growing aging population new programs and decisions are required. Overall, primary health care professionals should play a more active role in early diagnosis of skin cancer in nursing home residents. Dermoscopy courses, web-based or smartphone-based applications and teledermatology may support health care professionals to provide elderly nursing home residents an early diagnosis of skin cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215379PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476496PMC
January 2020

Structured Expert Consensus on Actinic Keratosis: Treatment Algorithm Focusing on Daylight PDT.

J Cutan Med Surg 2017 May/Jun;21(1_suppl):3S-16S. Epub 2017 Apr 13.

Department of Dermatology and Allergology, Vest Hospital, Academic Teaching Hospital University of Bochum, Recklinghausen, Germany.

Background: A practical and up-to-date consensus among experts is paramount to further improve patient care in actinic keratosis (AK).

Objectives: To develop a structured consensus statement on the diagnosis, classification, and practical management of AK based on up-to-date information.

Methods: A systematic review of AK clinical guidelines was conducted. This informed the preparation of a 3-round Delphi procedure followed by a consensus meeting, which combined the opinions of 16 clinical experts from 13 countries, to construct a structured consensus statement and a treatment algorithm positioning daylight photodynamic therapy (dl-PDT) among other AK treatment options.

Results: The systematic review found deficiencies in current guidelines with respect to new AK treatments such as ingenol mebutate and dl-PDT. The Delphi panel established consensus statements across definition, diagnosis, classification, and management of AK. While the diagnosis of AK essentially rests on the nature of lesions, treatment decisions are based on several clinical and nonclinical patient factors and diverse environmental attributes. Participants agreed on ranked treatment preferences for the management of AK and on classifying AK in 3 clinical situations: isolated AK lesions requiring lesion-directed treatment, multiple lesions within a small field, and multiple lesions within a large field, both requiring specific treatment approaches. Different AK treatment options were discussed for each clinical situation.

Conclusions: The results provide practical recommendations for the treatment of AK, which are readily transferable to clinical practice, and incorporate the physician's clinical judgement. The structured consensus statement positioned dl-PDT as a valuable option for patients with multiple AKs in small or large fields.
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http://dx.doi.org/10.1177/1203475417702994DOI Listing
April 2017

The barrier function of organotypic non-melanoma skin cancer models.

J Control Release 2016 07 27;233:10-8. Epub 2016 Apr 27.

Institute for Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany. Electronic address:

Non-melanoma skin cancer (NMSC) is the most frequent human cancer with continuously rising incidences worldwide. Herein, we investigated the molecular basis for the impaired skin barrier function of organotypic NMSC models. We unraveled disturbed epidermal differentiation by reflectance confocal microscopy and histopathological evaluation. While the presence of claudin-4 and occludin were distinctly reduced, zonula occludens protein-1 was more wide-spread, and claudin-1 was heterogeneously distributed within the NMSC models compared with normal reconstructed human skin. Moreover, the cancer altered stratum corneum lipid packing and profile with decreased cholesterol content, increased phospholipid amount, and altered ceramide subclasses. These alterations contributed to increased surface pH and to 1.5 to 2.6-fold enhanced caffeine permeability of the NMSC models. Three topical applications of ingenol mebutate gel (0.015%) caused abundant epidermal cell necrosis, decreased Ki-67 indices, and increased lactate dehydrogenase activity. Taken together, our study provides new biological insights into the microenvironment of organotypic NMSC models, improves the understanding of the disease model by revealing causes for impaired skin barrier function in NMSC models at the molecular level, and fosters human cell-based approaches in preclinical drug evaluation.
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http://dx.doi.org/10.1016/j.jconrel.2016.04.037DOI Listing
July 2016

Daylight PDT with MAL - current data and practical recommendations of an expert panel.

J Dtsch Dermatol Ges 2015 Dec;13(12):1240-9

Department of Dermatology and Allergology, Vest Hospital, Teaching Hospital, Recklinghausen, Germany.

Photodynamic Therapy (PDT) is one of the standard treatment modalities for actinic keratoses (AKs). Daylight PDT (DL-PDT) with MAL cream is a rather recent development, which, instead of an artificial light source, uses daylight for the activation of the photosensitizer. The present review summarizes available data based on a selective literature search, highlights practical aspects, and reflects the authors' expert knowledge in using DL-PDT. With respect to efficacy, study data shows that DL-PDT is noninferior to conventional PDT (cPDT). However, given that DL-PDT is markedly less painful, it is significantly better tolerated than cPDT. In Europe, DL-PDT can be performed from March to October, on sunny as well as on cloudy days. UV protection of untreated areas of the body should be observed. Outside temperature should not fall below 10°C. On hot days, patients should be advised to stay in the shade if necessary. Representing a useful addition to current therapeutic options, DL-PDT with MAL cream is, among others, suitable for patients with field cancerization and/or those who have experienced severe pain associated with cPDT.
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http://dx.doi.org/10.1111/ddg.12807DOI Listing
December 2015

European Dermatology Forum Guidelines on topical photodynamic therapy.

Eur J Dermatol 2015 Jul-Aug;25(4):296-311

Topical photodynamic therapy (PDT) is a widely approved therapy for actinic keratoses, squamous cell carcinoma in-situ, superficial and certain thin basal cell carcinomas. Recurrence rates are typically equivalent to existing therapies, although inferior to surgery for nodular basal cell carcinoma. PDT can be used both as a lesional or as a field therapy and has the potential to delay/reduce the development of new lesions. PDT has also been studied for its place in the treatment of, as well as its potential to prevent, superficial skin cancers in immune-suppressed patients, although sustained clearance rates are lower than for immunocompetent individuals. Many additional indications have been evaluated, including photo-rejuvenation and inflammatory and infective dermatoses. This S2 guideline considers all current and emerging indications for the use of topical photodynamic therapy in Dermatology, prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence. An unabridged version of this guideline is available online at: http://www.euroderm.org/edf/index.php/edf-guidelines.
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http://dx.doi.org/10.1684/ejd.2015.2570DOI Listing
June 2016

In reply.

Authors:
Claas Ulrich

Dtsch Arztebl Int 2014 Aug;111(33-34):565

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http://dx.doi.org/10.3238/arztebl.2014.0565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165186PMC
August 2014

Update of the European guidelines for basal cell carcinoma management.

Eur J Dermatol 2014 May-Jun;24(3):312-29

Département de Dermatologie, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75017 Paris, France.

Background: European guidelines for the management of basal cell carcinoma (BCC) prepared by the former BCC subcommittee of the Guidelines Committee of the European Dermatology Forum (EDF) were published in 2006.

Objectives: To present updated guidelines that include consensual expert definitions on various BCC types, prognosis and risk factors for BCC as well as review recommendations for diagnosis and treatment reflecting current published evidence.

Methods: These guidelines (S1 type) were prepared by the new BCC subgroup of the European Dermatology Forum (EDF)'s Guidelines Committee through extensive literature review (up to 2012) and expert experience; they were extensively discussed within the EDF subcommittee and approved by peer reviewers of the EDF. Results BCC is a common tumour with an incidence rising worldwide. Three major clinical types of BCC are recognized: nodular, superficial and morpheaform. Four histological subtypes are defined: superficial, nodular, infiltrative and morpheaform. On the basis of the risk of relapse, three prognosis groups have been identified: high, intermediate and low risk. According to these classifications and evidence-based evaluation of the therapeutic strategies available, a decision tree is proposed for the management of BCCs.

Conclusions: The guidelines offer a useful tool that will help dermatologists to select the most appropriate treatment for individual patients.
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http://dx.doi.org/10.1684/ejd.2014.2271DOI Listing
May 2015

Skin changes following organ transplantation: an interdisciplinary challenge.

Dtsch Arztebl Int 2014 Mar;111(11):188-94

Outpatient Clinic for the Follow-up Care of Immunosuppressed Patients, Skin Tumor Center, Charité - Universitätsmedizin Berlin, Department of Hematology, Oncology, and Tumor Immunology Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Medical Director, Charité - Universitätsmedizin Berlin, Department of Cardiac, Cardiothoracic and Vascular Surgery, German Heart Institute Berlin, Department of General, Visceral, and Transplant Surgery, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin.

Background: The immunosuppressants used in transplantation medicine significantly elevate the incidence of neoplasia, particularly in the skin. The cumulative incidence of non-melanocytic skin cancer (NMSC) in renal transplant recipients was 20.5% in a study carried out in German centers. Data on more than 35 000 renal transplant recipients in the USA document a cumulative NMSC incidence of over 7% after 3 years of immunosuppression.

Method: The authors selectively review publications obtained by a PubMed search to discuss the incidence of, and major risk factors for, skin tumors and infectious diseases of the skin in immunosuppressed patients.

Results: The main risk factors for skin tumors are age at the time of transplantation, light skin color, previous and present exposure to sunlight, and the type and duration of immunosuppressive treatment. Squamous-cell carcinoma (SCC) is the most common kind of skin tumor in immunosuppressed patients. Human herpesvirus 8 and Merkel-cell polyoma virus also cause neoplasia more often in immunosuppressed patients than in the general population. Surgical excision is the treatment of choice. Actinic keratosis markedly elevates the risk that SCC will arise in the same skin area (odds ratio 18.36, 95% confidence interval 3.03-111). Patients with multiple actinic keratoses can be treated with photodynamic therapy or with acitretin. To lower the skin cancer risk, organ transplant recipients should apply medical screening agents with a sun protection factor of at least 50 to exposed skin areas every day. 55% to 97% of organ transplant recipients have skin infections; these are treated according to their respective types.

Conclusion: Squamous-cell carcinoma of the skin adds to the morbidity and mortality of transplant recipients and is therefore among the major oncological challenges in this patient group. Structured concepts for interdisciplinary care enable risk-adapted treatment.
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http://dx.doi.org/10.3238/arztebl.2014.0188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977442PMC
March 2014

[Association Dermatologic Oncology (ADO). Treatment of advanced squamous cell carcinoma].

J Dtsch Dermatol Ges 2013 Jul;11(7):699

Universitätsklinikum Essen (AöR), Klinik für Dermatologie, Hufelandstraße 55 45147 Essen.

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http://dx.doi.org/10.1111/ddg.12151DOI Listing
July 2013

Management of cutaneous side effects of EGFR inhibitors: recommendations from a German expert panel for the primary treating physician.

J Dtsch Dermatol Ges 2011 Mar 8;9(3):195-203. Epub 2010 Nov 8.

Department of Dermatology, Allergy and Venereology, Skin Cancer Center, Hannover Medical School, Germany.

Inhibitors of the epidermal growth factor receptor (EGFR) are increasingly used in the treatment of various entities of malignant tumors. Patients treated with EGFR inhibitors very likely develop cutaneous side effects. The development of a papulopustular, follicular exanthema during the first weeks of therapy correlates with therapeutic benefit. However, this exanthema and other cutaneous side effects can impair the quality of life of the patient and might limit the therapy with the EGFR inhibitor. For an optimal therapeutic benefit and quality of life an adequate management of cutaneous side effects is necessary. A panel of German dermatologists developed on the basis of personal experience and current literature consensus recommendations for the management of cutaneous side effects of EGFR inhibitors.
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http://dx.doi.org/10.1111/j.1610-0387.2010.07561.xDOI Listing
March 2011

Results of a randomized, placebo-controlled safety and efficacy study of topical diclofenac 3% gel in organ transplant patients with multiple actinic keratoses.

Eur J Dermatol 2010 Jul-Aug;20(4):482-8. Epub 2010 May 27.

Skin Cancer Centre Charité, Department of Dermatology, Charité Universitätsmedizin, Charité-Platz 1, 10117 Berlin, Germany.

Increasing incidence rates of cutaneous malignancies, paralleling rising survival times of grafts and patients in organ transplant recipients, represents an escalating challenge for dermatologists worldwide. Especially, invasive squamous cell carcinomas (SCC) in immuno-compromised patients are characterized by significantly increased morbidity and mortality and characteristically outnumber basal cell carcinoma in this population. Effective management of actinic keratoses (AK) could help to prevent the further development of invasive SCC. Diclofenac in hyaluronic acid has previously shown to be an effective and well tolerated option for the treatment of AK in immuno-competent patients. However, its safety and efficacy in organ-transplant patients has not been evaluated in a controlled study so far. 32 organ transplant patients (kidney (+/- pancreas), liver, heart) screened at our specialized transplant dermatology outpatient clinic were found eligible and were randomized to either active treatment (24) or vehicle (8). Patients who had stable status of the transplanted graft in the 12 months prior to entering the study and >/= 3 AK lesions in a contiguous 50 cm2 area on the face, forehead, hands or balding scalp were eligible for inclusion in the study. Treatment of AK with 3% diclofenac in 2.5% hyaluronic acid or placebo twice daily was conducted over a total of 16 weeks, followed by a final evaluation 4 weeks after last application of the study drug. Biopsies were taken from the treated areas at the final visit to verify clinical clearance. Patients were assessed for safety variables that included adverse events, local skin reactions, laboratory results, dosage of immunosuppressive medication and indication of graft rejection. A 24 months follow up was conducted after the end of treatment. 87% (n = 28/32) of the patients completed the 16 week treatment phase and presented for final evaluation 4 weeks after end of treatment. In the diclofenac 3% gel treatment group, a complete clearance of AK lesions was achieved in 41% (9/22) compared to 0% (0/6) in the vehicle group. Side effects in most of the patients included a mild erythema and a mild to moderate swelling of the areas treated. No graft rejections or trends for a deterioration of graft function were detected. No meaningful trends were observed in laboratory results. In 55% of the previously cleared patients, new AK developed in the study area after an average of 9.3 months. None of these patients developed invasive SCC in the study area within 24 months of follow-up. This study demonstrated a greater lesion clearance rate of AKs in OTRs treated with diclofenac 3% gel than with vehicle. Despite recurrent AK in 55% of the previously cleared patients, the 24 month results showed no invasive SCC in this group. This study suggests that diclofenac 3% gel is not only an efficient and well tolerated treatment for multiple AKs in OTRs but also may prevent invasive SCC in these high-risk patients.
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http://dx.doi.org/10.1684/ejd.2010.1010DOI Listing
September 2010

Treatment of multiple, multiform actinic keratoses on the head with imiquimod 5% cream.

Eur J Dermatol 2009 Jul-Aug;19(4):355-9. Epub 2009 May 25.

Skin Cancer Centre Charité, Clinic of Dermatology, Venereology and Allergology, Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.

The objective of this non-controlled interventional clinical study was to evaluate the efficacy of imiquimod in the treatment of fields with multiple, multiform AK. 180 office-based dermatological practices in Germany participated. Patients with clinically typical, visible AK lesions on the head were treated with 5% imiquimod cream 3 times per week for 4 weeks followed by a 4 week treatment pause. If lesions were still present, a second treatment course of treatment (COT) was given. Complete clearance rate, i.e. no clinically visible AK lesions in the treatment area, was the main outcome measure. 829 patients were enrolled. The complete clearance rate was 40.5% after the first COT and 68.9% overall. Altogether, 85.4% of the 7,427 baseline lesions were cleared. Patients with hyperkeratotic/hypertrophic lesions showed comparable responses. Local skin reactions were the most commonly reported adverse effects, causing discontinuation in only 4 patients. Severity of the local skin reactions was a strong predictor of the outcome. Patients with multiple multiform AK on the head can be successfully and safely treated with topical imiquimod in daily practice. Assurance of patient understanding that treatment success is closely correlated to proper drug administration is important.
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http://dx.doi.org/10.1684/ejd.2009.0692DOI Listing
September 2009

Topical treatment of field cancerization.

Authors:
Claas Ulrich

Cancer Treat Res 2009 ;146:439-46

Department of Dermatology, Transplant-Aftercare Unit, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.

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http://dx.doi.org/10.1007/978-0-387-78574-5_36DOI Listing
September 2010

Sunscreens in organ transplant patients.

Nephrol Dial Transplant 2008 Jun;23(6):1805-8

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http://dx.doi.org/10.1093/ndt/gfn292DOI Listing
June 2008

Skin infections in organ transplant recipients.

J Dtsch Dermatol Ges 2008 Feb 9;6(2):98-105. Epub 2007 Nov 9.

Department of Dermatology, Allergy, Venereology, Charité University Hospital, Berlin, Germany.

In contrast to the well-described high risk of skin cancer in organ transplant recipients, skin infections in these patients are not as well explored. Skin infections caused by viruses, bacteria or fungi represent a growing diagnostic and therapeutic challenge in the dermatological aftercare of organ transplant recipients. Differing immunosuppressive drugs and their variable dosage in chronologic sequence after transplantation probably influence the type and appearance of skin infections. The typical chronology of skin infections are wound infections, pyoderma or the reactivation of herpes viruses in the first month post-transplant; the main problems in months 2-5 are opportunistic infections and reactivation of varicella-zoster virus. After 6 months as immunosuppression is reduced, the spectrum of causative organisms approaches that of the general population; mycoses and human papilloma virus (HPV) infections dominate. A causal connection exists between infection with oncogenic viruses such as HPV, Epstein-Barr virus and human herpesvirus 8 and specific skin cancers (squamous cell carcinoma, Kaposi sarcoma and post-transplant lymphoproliferative disorders). Dermatological care of organ transplant recipients using appropriate diagnostic methods adapted to the modified clinical pattern may lead to early adequate treatment.
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http://dx.doi.org/10.1111/j.1610-0387.2007.06431.xDOI Listing
February 2008

Azathioprine, UV light, and skin cancer in organ transplant patients--do we have an answer?

Nephrol Dial Transplant 2007 Apr 18;22(4):1027-9. Epub 2007 Jan 18.

Department of Dermatology, Skin Cancer Center Charité, Universitätsmedizin Berlin, Schumannstrasse 20-21, 10117 Berlin, Germany.

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http://dx.doi.org/10.1093/ndt/gfl762DOI Listing
April 2007

Successful treatment of nephrogenic fibrosing dermopathy in a kidney transplant recipient with photodynamic therapy.

Nephrol Dial Transplant 2005 Jan;20(1):220-2

Department of Dermatology (Skin Cancer Centre Charité), Charité University Hospital Berlin, Germany.

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http://dx.doi.org/10.1093/ndt/gfh473DOI Listing
January 2005

Immunosuppressants and skin cancer in transplant patients: focus on rapamycin.

Dermatol Surg 2004 Apr;30(4 Pt 2):628-33

Department of Dermatology, Edouard Herriott Hospital, Lyon, France.

Background: The responsibility of immunosuppressants for the increased risk of skin cancers in organ transplant recipients is widely recognized. Discerning the role of each drug is complicated owing to the fact that most patients generally have combinations of several medications.

Objective: This article will discuss the role of the main immunosuppressants in the pathogenesis of skin cancers.

Methods: This work consists of a review of the most significant publications.

Results: Experimental and clinical studies suggest that corticosteroids, azathioprine, cyclosporine (CsA), and tacrolimus increase the incidence of skin cancer. Each drug may act through two different mechanisms including the impairment of the systemic immunosurveillance and a direct oncogenic effect. CsA was shown to be oncogenic independently of its immunosuppressive effect. By contrast, several works on mice have found that rapamycin inhibits tumor growth while being immunosuppressive. Furthermore, rapamycin was shown to inhibit several UV-induced mechanisms involved in skin carcinogenesis. Preliminary clinical studies have reported a lower incidence of skin malignancy in patients treated with rapamycin compared to CsA from the time of transplantation.

Conclusion: New immunosuppressive strategies for transplant patients with skin cancer are not only based on minimizing immunosuppression. Data suggest that rapamycin could have a protective effect against skin cancer. Further studies are required to assess accurately the efficacy and tolerance of rapamycin in these patients.
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http://dx.doi.org/10.1111/j.1524-4725.2004.30148.xDOI Listing
April 2004

Comparative epidemiology and pathogenic factors for nonmelanoma skin cancer in organ transplant patients.

Dermatol Surg 2004 Apr;30(4 Pt 2):622-7

Department of Dermatology, Charité Hospital, Berlin, Germany.

Background: Organ transplantation has been performed for almost 40 years with steadily increasing success regarding long-time survival of the graft as well as quality of life for the patient. An increase of skin cancers as a consequence of the lowered cellular immune response seems to parallel the overall increased survival rate of organ transplant recipients. Against the background of chronic immunosuppression, known risk factors like the amount of sun exposure before and after transplantation and oncogenic viruses as well as the genetic background and place of residence (latitude) are strongly related with the increased skin cancer incidence. The goal of this review is to compare the epidemiologic prevalence of nonmelanoma skin cancer between various geographic locations and to highlight pathogenesis factors.

Methods: This study was based on a review of the current literature.

Results: The increasing incidence of nonmelanoma skin cancer paralleling a prolonged survival of patients after organ transplantation represents a significant reason for morbidity and long-term mortality in organ transplant recipients worldwide. The incidence of nonmelanoma skin cancer in liver, kidney, and heart transplant recipients varies from 1.5% to 22%, 2% to 24%, and 6% to 34%, respectively, within 5 years of transplantation depending on geographic location and other pathogenesis factors. Ultraviolet radiation (UVR) as well as immunosuppressant therapy are crucial risk factors regarding the induction and progression of skin cancer. UVR is related to the induction of DNA damage as well as interference with Langerhans cell antigen presentation and a TH1-TH2 shift induced via release of IL-10. Whereas the overall duration of immunosuppression and the accumulative dosage applied are relevant measures in the pathogenesis of an increased tumor risk, individual differences between specific immunosuppressive agents are more difficult to assess.

Conclusions: Multiple international studies assess risk factors and pathophysiology of skin cancer in organ transplant patients, with variable results in the literature. Large multicenter studies with thorough multivariant analysis may provide useful information for center-independent analysis of pathogenesis factors for transplant-related skin cancer.
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http://dx.doi.org/10.1111/j.1524-4725.2004.30147.xDOI Listing
April 2004
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