Untersuchung der Langzeitergebnisse von Interventionen für die aktinische Keratose

Actinic keratosis (AK) is an extremely common skin lesion that develops due to high cumulative exposure to ultraviolet radiation. Accordingly, AK primarily affects the sun-exposed areas of Caucasian individuals such as the balding scalp, face, neck, and also the upper trunk or dorsal sides of the extremities. AK has the potential to develop into invasive squamous cell carcinoma of the skin, although the rate of progression of a single lesion is probably low. Due to the lack of biomarkers that can predict the likelihood of progression, national and international guidelines recommend early and consequent therapy, although the immediate morbidity and mortality arising from AK as a precancerous lesion are low. Due to an increasingly aging population with a high prevalence of AK, the health economic importance of AK is high. A variety of field- or lesion-directed procedures are available for the treatment of AK. They range from ablative interventions to topical drug-mediated therapies. Most interventions are compared to placebo, although direct head-to-head comparisons of distinct active interventions are rare. Furthermore, most guideline recommendations and meta-analyses published to date tend to focus on short-term efficacy outcomes assessed three to six months after the end of treatment and on AK lesions located on the head or face. Therefore, the aim of this thesis is to investigate the long-term efficacy as well as the efficacy of interventions for AK in extracranial and extrafacial locations. For this purpose, several systematic reviews and meta-analyses or network meta-analyses were performed according to the principles of evidence-based medicine. This thesis includes four publications that address these research questions. Publication I examined sustained clearance rates reported at least 12 months or later after the end of treatment. Data were extracted from 15 randomized controlled trials involving 4252 patients and examined with several network meta-analyses. The interventions photodynamic therapy (PDT), imiquimod, and cryosurgery showed the highest patient-specific clearance rates compared with placebo. The quality of evidence here was heterogeneous and was rated highest for PDT. In publication II, recurrence rates from nine randomized controlled trials involving 1948 patients were analyzed after follow-up of at least 12 months. Patient-specific recurrence rates were lowest for PDT and cryosurgery. Lesion-specific recurrence rates were lowest for placebo, followed by PDT. Overall, recurrence rates were surprisingly high for all interventions studied, ranging from 39% to 85%. These results highlight that AK is a chronic skin disease in which most patients will suffer a relapse regardless of the therapy chosen. Close follow-up and retreatment during the course of the disease are therefore indicated in most cases. Publication III focused on phase IV trials, which are an important source of long-term outcomes of interventions for AK because of the oftentimes large number of included patients, long follow-up times, and real-world context. A total of 11 studies with 4109 patients were identified. The patient-specific clearance rate was highest for ingenol mebutate at 88.9 %, followed by PDT at 75 %. Publication IV specifically investigated the efficacy of interventions at extracranial and extrafacial sites, as lesions in these localizations often respond more poorly and thus show a less favorable long-term disease outcome. A total of 13 randomized controlled trials involving 1380 patients were identified in which these localizations were separately investigated and reported. In a network meta-analysis, cryosurgery showed the highest patient-specific and lesion-specific clearance rates compared with placebo, albeit rated as low-quality evidence. Overall, the results from these four publications have immediate practical relevance and provide valuable and evidence-based decision support in clinical practice. Furthermore, these publications provide an evidence-based framework for guideline recommendations and also for relevant health care payers and involved stakeholders. Due to the high prevalence of AK in an increasingly aging population and the resulting high costs of therapy for society as a whole, it is imperative that therapeutic interventions are prioritized that have proven long-term efficacy and clear AK lesions located in difficult-to-treat areas.Die aktinische Keratose (AK) ist eine außerordentlich häufige Hautveränderung, die aufgrund einer hohen kumulativen Exposition gegenüber Ultraviolettstrahlung entsteht. Dementsprechend betriff sie vor allem die sonnenexponierten Areale kaukasischer Individuen wie die unbehaarte Kopfhaut, das Gesicht, den Hals, aber auch den oberen Stamm oder die Streckseiten der Extremtäten. Die AK hat das Potential, sich in ein invasives Plattenepithelkarzinom der Haut zu entwickeln, obwohl die Progressionsrate einer einzelnen Läsion vermutlich gering ist. Aufgrund fehlender Biomarker, welche die Progressionswahrscheinlichkeit vorhersagen können, empfehlen nationale und internationale Leitlinien eine frühzeitige und konsequente Therapie, obwohl die unmittelbare Morbidität und Mortalität der AK als präkanzeröse Läsion gering sind. Aufgrund einer zunehmend alternden Bevölkerung mit einer hohen AK-Prävalenz ist die gesundheitsökonomische Bedeutung der AK hoch. Zur Behandlung der AK steht eine Vielzahl an feld- oder läsionsgerichteten Verfahren zu Verfügung. Sie reichen von ablativen Maßnahmen bis hin zu topischen arzneimittelgestützten Therapien. Die meisten Interventionen werden dabei gegenüber Placebo verglichen, wobei direkte Vergleichsstudien selten sind. Weiterhin fokussieren die meisten bisher veröffentlichten Leitlinienempfehlungen und Metaanalysen eher auf die kurzfristige Wirksamkeit drei bis sechs Monate nach Therapieende und auf AK-Läsionen am Kopf bzw. Gesicht. Das Ziel dieser Arbeit ist es daher, die Langzeitwirksamkeit sowie die Wirksamkeit von Interventionen für die AK in extrakraniellen und extrafazialen Lokalisationen zu untersuchen. Dafür wurden mehrere systematische Übersichtsarbeiten und Metaanalysen bzw. Netzwerk-Metaanalysen nach den Grundsätzen der evidenzbasierten Medizin durchgeführt. Diese Dissertation umfasst vier Veröffentlichungen, welche diese Fragestellungen bearbeiten. In Veröffentlichung I wurden die nachhaltigen Abheilungsraten mindestens 12 Monate nach Therapieende oder länger untersucht. Dabei wurden Daten aus 15 randomisierten kontrollierten Studien mit 4252 Patienten extrahiert und mit mehreren Netzwerk-Metaanalysen untersucht. Die Interventionen photodynamische Therapie (PDT), Imiquimod und Kryochirurgie zeigten die höchsten patientenbezogenen Abheilungsraten gegenüber Placebo. Die Qualität der Evidenz wurde hierbei heterogen bewertet und war am höchsten für die PDT. In Veröffentlichung II wurden die Rezidivraten aus neun randomisierten kontrollierten Studien mit 1948 Patienten ebenfalls nach einer Nachbeobachtung von mindestens 12 Monaten analysiert. Patientenbezogen waren die Rezidivraten für die PDT und die Kryochirurgie am geringsten. Läsionsbezogen waren die Rezidivraten am geringsten für Placebo, gefolgt von der PDT. Insgesamt waren die Rezidivraten für alle untersuchten Therapien überraschend hoch mit einer Spannweite von 39 % bis 85 %. Diese Ergebnisse unterstreichen, dass die AK eine chronische Hauterkrankung darstellt, bei der die meisten Patienten ein Rezidiv unabhängig von der gewählten Therapie erleiden. Eine engmaschige Nachbeobachtung und erneute Behandlungen im Krankheitsverlauf sind daher in vielen Fällen angezeigt. In Veröffentlichung III wurde der Fokus auf Studien der Phase IV gesetzt, die aufgrund der oftmals hohen Fallzahl, der langen Nachbeobachtungszeit und des Echtweltkontexts eine wichtige Quelle für die Langzeitergebnisse von Interventionen für die AK darstellen. Insgesamt wurden hierbei 11 Studien mit 4109 Patienten identifiziert. Die patientenbezogene Abheilungsrate war hier für den Wirkstoff Ingenolmebutat mit 88,9 % am höchsten, gefolgt von der PDT mit 75 %. In Veröffentlichung IV wurde die Wirksamkeit der Therapie für die AK speziell an extrakranialen und extrafazialen Lokalisationen untersucht, da Läsionen in diesen Bereichen häufig schlechter ansprechen und damit auch einen ungünstigeren längerfristigen Krankheitsverlauf zeigen. Insgesamt wurden 13 randomisierte kontrollierte Studien mit 1380 Patienten identifiziert, in denen diese Lokalisationen gesondert untersucht und berichtet wurden. In einer Netzwerk-Metaanalyse zeigte die Kryochirurgie die höchste komplette patientenbezogene und läsionsbezogene Ansprechrate gegenüber Placebo, was allerdings mit einer niedrigen Qualität der Evidenz bewertet wurde. Insgesamt haben die Ergebnisse aus diesen vier Veröffentlichungen eine unmittelbare Praxisrelevanz und liefern eine wertvolle und evidenzbasierte Entscheidungshilfe im klinischen Alltag. Weiterhin bieten diese Arbeiten eine evidenzbasierte Grundlage für Leitlinienempfehlungen und auch für die relevanten Kostenträger im Gesundheitswesen. Aufgrund der hohen Prävalenz der AK in einer zunehmend alternden Bevölkerung und der damit gesamtgesellschaftlich hohen Therapiekosten ist es unumgänglich, dass Therapien priorisiert werden, die auch im längerfristigen Behandlungsverlauf und an Problemlokalisationen wirksam sind

Comparison of guidelines for the management of patients with high‐risk and advanced cutaneous squamous cell carcinoma – a systematic review

The management of high‐risk cutaneous squamous cell carcinoma (cSCC) can be a challenge as evidence from high quality clinical trials is rare. Guideline developers are challenged to provide practical and useful guidance for clinicians even in the absence of good evidence. In order to compare treatment recommendations for high‐risk and advanced cSCC among national and international guidelines and to extract the most precise guidance provided, a systematic search was carried out in guideline databases Medline and Embase with a cutoff of 4 March 2019. Treatment recommendations for predefined clinical scenarios were extracted from selected guidelines and compared qualitatively. Five guidelines published from 2015 to 2018 were included. Excision of high‐risk tumours with margin assessment was recommended in all guidelines. A safety margin of at least 6 mm was suggested in four guidelines. There was no clear recommendation to perform a sentinel lymph node biopsy in any guideline. Lymph node dissection was uniformly recommended in the presence of nodal disease. Treatment for metastatic cSCC was poorly characterized and restricted to the use of chemotherapy and epidermal growth factor receptor inhibitors. Recommendations for the management of high‐risk and advanced cSCC were limited. We propose that guidelines should be updated to reflect recent advances in checkpoint blockade for metastatic cSCC

The more the better? An appraisal of combination therapies for actinic keratosis

Actinic keratoses (AK) are common precancerous lesions of the skin. Numerous interventions exist for the treatment of AK, including lesion‐ and field‐directed approaches. In daily practice, different treatment modalities are often combined to maximize clearance rates. However, whether a combination therapy is preferable to monotherapy in terms of efficacy and safety has been subject of intense debate. In this review, we summarize the current knowledge on the efficacy and safety of local combination therapies for the treatment of patients with AK. Combination approaches of cryosurgery followed by photodynamic therapy (PDT), laser‐assisted PDT, PDT in combination with topical interventions and microneedling‐assisted PDT have shown slightly better efficacy results with similar tolerability compared to the respective monotherapy. However, the individual usage of combination therapies should be checked on a case‐by‐case basis and take into account individual patient‐ and lesion‐specific aspects as more resources are needed and because the individual monotherapies are already highly effective

The Systemic Management of Advanced Melanoma in 2016

Melanoma is a common type of skin cancer with a high propensity to metastasize. Tyrosine kinase inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway and immune checkpoint blockade have recently revolutionized the management of unresectable and metastatic disease. However, acquired resistance and primary non-response to therapy require novel treatment strategies and combinations. The purpose of this review is to provide a brief and up-to-date overview on the clinical management and current trial landscape in melanoma. We summarize the most pertinent studies on BRAF/MEK inhibitors and blockade of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Although most agents show robust antitumor efficacy as single agents, further improvements have been achieved by the combination of both approved and developing drugs. We discuss ongoing trials and evaluate future approaches that may provide additional efficacy with less toxicity. (C) 2016 S. Karger GmbH, Freibur

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

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

Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants

Background Small molecules tackling mutated BRAF (BRAFi) are an important mainstay of targeted therapy in a variety of cancers including melanoma. Albeit commonly reported as side effect, the phototoxic potential of many BRAFi is poorly characterized. In this study, we evaluated the phototoxicity of 17 distinct agents and investigated whether BRAFi‐induced phototoxicity can be alleviated by antioxidants. Methods The ultraviolet (UV) light absorbance of 17 BRAFi was determined. Their phototoxic potential was investigated independently with a reactive oxygen species (ROS) and the 3T3 neutral red uptake (NRU) assay in vitro. To test for a possible phototoxicity alleviation by antioxidants, vitamin C, vitamin E phosphate, trolox, and glutathione (GSH) were added to the 3T3 assay of selected inhibitors. Results The highest cumulative absorbance for both UVA and UVB was detected for vemurafenib. The formation of ROS was more pronounced for all compounds after irradiation with UVA than with UVB. In the 3T3 NRU assay, 8 agents were classified as phototoxic, including vemurafenib, dabrafenib, and encorafenib. There was a significant correlation between the formation of singlet oxygen (P = .026) and superoxide anion (P < .001) and the phototoxicity observed in the 3T3 NRU assay. The phototoxicity of vemurafenib was fully rescued in the 3T3 NRU assay after GSH was added at different concentrations. Conclusion Our study confirms that most of the BRAF inhibitors exhibited a considerable phototoxic potential, predominantly after exposure to UVA. GSH may help treat and prevent the phototoxicity induced by vemurafenib

The Role of Immune Checkpoint Blockade in Uveal Melanoma

Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies

Clonality of CD4+ Blood T Cells Predicts Longer Survival With CTLA4 or PD-1 Checkpoint Inhibition in Advanced Melanoma

Recognition of cancer antigens drives the clonal expansion of cancer-reactive T cells, which is thought to contribute to restricted T-cell receptor (TCR) repertoires in tumor-infiltrating lymphocytes (TILs). To understand how tumors escape anti-tumor immunity, we investigated tumor-associated T-cell repertoires of patients with advanced melanoma and after blockade of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD-1). TCR Vβ-gene spectratyping allowed us to quantify restrictions of T-cell repertoires and, further, diversities of T-cell clones. In this study, we show that the blood TCR repertoires were variably restricted in CD4+ and extensively restricted in CD8+ T cells of patients with advanced melanoma, and contained clones in both T-cell fractions prior to the start of immunotherapy. A greater diversification especially of CD4+ blood T-cell clones before immunotherapy showed statistically significant correlations with long-term survival upon CTLA4 or PD-1 inhibition. Analysis of TILs and corresponding blood available in one patient indicated that blood clonality may at least partially be related to the clonal expansion in the tumor microenvironment. In patients who developed severe immune-related adverse events (IrAEs), CD4+ and CD8+ TCR spectratypes became more restricted during anti-CTLA4 treatment, suggesting that newly expanded oligoclonal T-cell responses may contribute to IrAEs. This study reveals diverse T-cell clones in the blood of melanoma patients prior to immunotherapy, which may reflect the extent to which T cells are able to react against melanoma and potentially control melanoma progression. Therefore, the T-cell clonality in the circulation may have predictive value for antitumor responses from checkpoint inhibition

Dermal fillers do not induce upregulation of NLRP3 inflammasomes or expression of inflammatory cytokines in granulomas

Background: Filling materials have increasingly been used in aesthetics over the last decades. Understanding the pathophysiology of granuloma formation as a very relevant unwanted side effect of filler application may be essential to help avoid these adverse events. Aims: Our aim was to investigate the role of the inflammasome in the formation of filler granuloma, as a central column of the innate immune response. Methods RPMI 1640 medium was used for growth of THP-1 cells and the induction of THP-1 macrophages. Sonication was applied in order to crush the acrylic particles of the filler. ELISA was the method of analysis for the specific cytokines. Biopsy specimens of filler granuloma were analyzed by various immunohistochemical methods. GraphPad Prism 5 software was used for the statistical data analysis. Results: Neither was the sensor NALP3 overexpressed, nor could an elevated expression of cleaved IL-1 beta, IL-18, or IFN-gamma be detected. Furthermore, no increased expression of IL-8 or IL-1 beta was detectable in vitro. Conclusion No increased inflammasome activation could be observed;however, filler granulomas were infiltrated with granulocytes and macrophages. Therefore, we speculate that an unspecific immune response might be the key player in the formation of filler granuloma