The "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) Project: An Expert Panel Opinion.

Actinic keratosis (AK) is an intraepithelial condition characterized by the development of scaly, erythematous lesions after repeated exposure to ultraviolet radiation. Significant immunosuppression is a risk factor for the development of AK and subsequent lesion progression to squamous cell carcinoma. Immunocompromised patients (ICPs), particularly organ transplant recipients, often have more advanced or complex AK presentations and an increased risk of skin carcinomas versus non-ICPs with AK, making lesions more difficult to treat and resulting in worse treatment outcomes. The recent "Personalising Actinic Keratosis Treatment" (PAKT) consensus reported that delivering patient-centric care may play a role in supporting better clinical outcomes and patient satisfaction with treatments for chronic dermatologic conditions such as AK, which require repeated cycles of treatment. Additionally, currently published guidance and recommendations were considered by the PAKT panel to be overly broad for managing ICPs with their unique and complex needs. Therefore, the "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) panel was established to build upon general recommendations from the PAKT consensus. The panel identified current gaps in guidance for AK care in ICPs, offered practical care approaches based on typical ICP scenarios, and highlighted the need to adapt AK management to optimize care and improve treatment outcomes in ICPs. In particular, dermatologists should establish collaborative and transparent relationships with patients' multidisciplinary teams to enhance overall care for patients' comorbidities: given their increased risk of progression to malignancy, earlier assessments/interventions and frequent follow-ups are vital.The panel also developed a novel "triage" tool outlining effective treatment follow-up and disease surveillance plans tailored to patients' risk profiles, guided by current clinical presentation and relevant medical history. Additionally, we present the panel's expert opinion on three fictional ICP scenarios to explain their decision-making process for assessing and managing typical ICPs that they may encounter in clinical practice.

Cumulative incidence and risk factors for cutaneous squamous cell carcinoma metastases in organ transplant recipients: The Skin Care in Organ Transplant Patients in Europe-International Transplant Skin Cancer Collaborative metastases study, a prospective multicenter study.

INTRODUCTION: Solid organ transplant recipients (SOTRs) are believed to have an increased risk of metastatic cutaneous squamous cell carcinoma (cSCC), but reliable data are lacking regarding the precise incidence and associated risk factors. METHODS: In a prospective cohort study, including 19 specialist dermatology outpatient clinics in 15 countries, patient and tumor characteristics were collected using standardized questionnaires when SOTRs presented with a new cSCC. After a minimum of 2 years of follow-up, relevant data for all SOTRs were collected. Cumulative incidence of metastases was calculated by the Aalen-Johansen estimator. Fine and Gray models were used to assess multiple risk factors for metastases. RESULTS: Of 514 SOTRs who presented with 623 primary cSCCs, metastases developed in 37 with a 2-year patient-based cumulative incidence of 6.2%. Risk factors for metastases included location in the head and neck area, local recurrence, size > 2 cm, clinical ulceration, poor differentiation grade, perineural invasion, and deep invasion. A high-stage tumor that is also ulcerated showed the highest risk of metastasis, with a 2-year cumulative incidence of 46.2% (31.9%-68.4%). CONCLUSIONS: SOTRs have a high risk of cSCC metastases and well-established clinical and histologic risk factors have been confirmed. High-stage, ulcerated cSCCs have the highest risk of metastasis.

HautTief Multidisciplinary Educational Program for Patients with Psoriasis or Atopic Dermatitis: A Randomized Controlled Study.

BACKGROUND: Improving health-related quality of life (HRQoL), disease severity, and treatment adherence through patient education is an increasingly important, yet relatively new area in dermatology. This randomized controlled trial aims to contribute to this growing area of research by exploring the effects of a 9-week educational program for patients with chronic skin diseases. OBJECTIVE: The aim of the study was to evaluate the effect of a multidisciplinary educational program on HRQoL and disease severity in patients with psoriasis or atopic dermatitis (AD). METHODS: Sixty-four patients with diagnosed psoriasis or AD were recruited from University Hospital Zurich and randomized (1:1) to the intervention or control group. To assess HRQoL, the following self-reported questionnaires were used: Dermatology Life Quality Index (DLQI), Skindex-29, EuroQol-5D (EQ-5D), RAND 36-Item Short Form Survey (SF-36), and Beck Depression Inventory (BDI) to measure depression symptoms. Psoriasis Area and Severity Index (PASI) and the Eczema Area and Severity Index (EASI) were used to capture disease extent. These scores were assessed at four study visits, which were performed at baseline and 3, 6, and 9 months after the start of the program. RESULTS: At month 6, an improvement of at least 25% in BDI was recorded in 15 (68.2%) of 22 patients in the intervention group and 6 (27.3%) of 22 patients in the control group (difference 40.9%, p = 0.016). 53.3% (16 of 30) of patients achieved an improvement in one subdomain of the SF-36 score (role limitations due to emotional problems) at 6-month follow-up, compared with 23.1% (6 of 26) of those not attending the educational program (difference 30.2%; p = 0.042). No significant differences in DLQI, Skindex-29, EQ-5D, PASI, and EASI between both groups at the three time points were found. CONCLUSION: An educational program may improve HRQoL and depression status of patients with psoriasis or AD.

Consensus-Based Recommendations on the Prevention of Squamous Cell Carcinoma in Solid Organ Transplant Recipients: A Delphi Consensus Statement.

IMPORTANCE: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs). OBJECTIVE: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs. EVIDENCE REVIEW: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses. FINDINGS: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC. CONCLUSIONS AND RELEVANCE: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

Skin Cancer Development in Solid Organ Transplant Recipients in Switzerland (Swiss Transplant Cohort Study).

IMPORTANCE: Skin cancer, in particular squamous cell carcinoma, is the most frequent malignancy among solid organ transplant recipients with a higher incidence compared to the general population. OBJECTIVE: To determine the skin cancer incidence in organ transplant recipients in Switzerland and to assess the impact of immunosuppressants and other risk factors. DESIGN: Prospective cohort study of solid organ transplant recipients in Switzerland enrolled in the Swiss Transplant Cohort Study from 2008 to 2013. PARTICIPANTS: 2,192 solid organ transplant recipients. MATERIALS AND METHODS: Occurrence of first and subsequent squamous cell carcinoma, basal cell carcinoma, melanoma and other skin cancers after transplantation extracted from the Swiss Transplant Cohort Study database and validated by medical record review. Incidence rates were calculated for skin cancer overall and subgroups. The effect of risk factors on the occurrence of first skin cancer and recurrent skin cancer was calculated by the Cox proportional hazard model. RESULTS: In 2,192 organ transplant recipients, 136 (6.2%) developed 335 cases of skin cancer during a median follow-up of 32.4 months, with squamous cell carcinoma as the most frequent one. 79.4% of skin cancer patients were male. Risk factors for first and recurrent skin cancer were age at transplantation, male sex, skin cancer before transplantation and previous transplantation. For a first skin cancer, the number of immunosuppressive drugs was a risk factor as well. CONCLUSIONS AND RELEVANCE: Skin cancer following solid organ transplantation in Switzerland is greatly increased with risk factors: age at transplantation, male sex, skin cancer before transplantation, previous transplantation and number of immunosuppressive drugs.

Comparison of Personality Traits among Patients with Psoriasis, Atopic Dermatitis, and Stress: A Pilot Study.

BACKGROUND: Psoriasis and atopic dermatitis are chronic skin diseases that greatly affect the quality of life. Both diseases can be triggered or exacerbated by stress. OBJECTIVE: We aimed to differentiate personality traits between patients with chronic skin conditions and people treated for stress in a pilot study. METHODS: Patients participating voluntarily in educational programs in Belgium and Switzerland were recruited to complete personality trait questionnaires, including the Temperament and Character Inventory (TCI) and the Tridimensional Personality Questionnaire (TPQ). A comparison was made with patients treated for work-related stress. RESULTS: A total of 48 and 91 patients suffering from skin diseases and work-related stress, respectively, were included in the study. Based on the questionnaires, we found that dermatology patients were less persistent and impulsive than those with work-related stress. Dermatology patients also exhibited more rigidness and less focus on performance. Finally, patients with work-related stress seem more likely to change in response to health-promoting programs than patients with chronic dermatoses. CONCLUSION: Patients with chronic skin diseases may perceive and cope with stress differently in comparison to patients with work-related stress due to inherent personality traits. Therefore, stress coping mechanisms may differ among different diseases. More research is needed into the design of educational interventions and the impact of personality traits in disease-specific groups.

A step-wise approach for establishing a multidisciplinary team for the management of tuberous sclerosis complex: a Delphi consensus report.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder associated with mutations in TSC1 and TSC2 genes, upregulation of mammalian target of rapamycin signaling, and subsequent tumor formation in various organs. Due to the many manifestations of TSC and their potential complications, management requires the expertise of multiple medical disciplines. A multidisciplinary care approach is recommended by consensus guidelines. Use of multidisciplinary teams (MDTs) has been shown to be beneficial in treating other complex diseases, such as cancer. In a lifelong disease such as TSC, an MDT may facilitate the transition from pediatric to adult care. However, little guidance exists in the literature regarding how to organize an MDT in TSC. METHODS: To discuss the best approach to assembling an MDT, this project was initiated in October 2017 with a meeting of 12 physicians from various specialties and various countries. Following this first meeting, the experts generated statements on the most important aspects to implement in establishing an MDT for TSC by 3 rounds of selection using a Delphi process via electronic correspondence. Finally, TSC patient advocates reviewed the findings and provided additional insights from a patient perspective. RESULTS: A 3-step roadmap was recommended, starting with identifying a single individual to begin organizing care (Step 1), then establishing a small core team (Step 2), and finally, establishing a larger multi-disciplinary team (Step 3). Because of the multisystemic nature of TSC, the MDT should include specialists such as a neurologist, a neurosurgeon, a nephrologist, a urologist, a pulmonologist, an ophthalmologist, a cardiologist, a dermatologist, a geneticist, and a psychiatrist/psychologist. The MDT should recommend a care plan for each patient based on the individual's needs and in consultation with him/her or his/her family. Some of the most important aspects of an MDT that were agreed upon included identifying a case manager to help coordinate care, providing access to health care professionals of varying specialties, and including a lead physician who takes medical responsibility for patients' overall care. CONCLUSIONS: The results of our consensus provide guidance to support the initiation of an MDT in TSC.

Prevalence of Actinic Keratosis in Patients Attending General Practitioners in Switzerland.

BACKGROUND: Most of the data concerning the prevalence of actinic keratosis (AK) originate from the USA and Australia, and recently from Austria and Spain, but are based on populations in dermatology practices. Switzerland is the leading country with skin cancer incidence in Europe. AK prevalence among the Swiss population is therefore an important public health issue. OBJECTIVE: To assess the prevalence of AK in the outpatient Swiss population in general practice. METHODS: General practitioners captured AK diagnosis stage and localization in consecutive patients, who attended the physician for any reason. RESULTS: A total of 2,844 consecutive patients (55.7% female) were enrolled in 59 general practitioners' offices. AK prevalence was 25.3% and increased steadily with age; 33% of men and 19% of women were diagnosed with AK. Every second AK patient declared leisure-related UV exposure, while only 23% were exposed to UV occupationally; 16% of the patients were UV exposed both occupationally and during leisure. AK distribution among sun-exposed body sites and extent of disease varied by sex. CONCLUSION: In Switzerland AK is a common diagnosis in dermatology practices. Since up to 5% of AK may progress to invasive squamous cell carcinoma (SCC), prevention of AK, as well as education of patients and general practitioners, may play a critical role for subsequent SCC development. This is the first study on AK prevalence in Switzerland identifying patients most affected by AK. These results will help to define future approaches to target general practitioners for education, screening, and specific intervention in patients with AK.

Sirolimus for Secondary Prevention of Skin Cancer in Kidney Transplant Recipients: 5-Year Results.

Purpose Transplant recipients who develop cutaneous squamous cell carcinomas are at high risk for multiple subsequent skin cancers. Sirolimus has been shown to reduce the occurrence of secondary skin cancers, but no study included a follow-up exceeding 2 years. We extended at 5 years the TUMORAPA randomized trial of sirolimus-based immunosuppressive regimen versus calcineurin inhibitor-based immunosuppression. Methods Kidney transplant recipients receiving calcineurin inhibitors who had at least one cutaneous squamous cell carcinoma were randomly assigned to receive sirolimus as a substitute for calcineurin inhibitors (n = 64) or to maintain their initial treatment (n = 56). The primary end point was survival free of squamous cell carcinoma at 5 years. Secondary end points included the occurrence of other skin cancers, renal function, patient and graft survival, and treatment tolerance. Results Survival free of cutaneous squamous cell carcinoma was significantly longer in the sirolimus group than in the calcineurin inhibitor group ( P = .007). In the sirolimus group, the number of patients with new skin cancers was significantly lower compared with the calcineurin inhibitor group: 22% versus 59% for squamous cell carcinomas ( P < .001), 34% versus 66% for other skin cancers ( P < .001), and 20% versus 37.5% for basal cell carcinomas ( P < .05). Kidney graft function, patients, and graft survival were similar in both groups. In the sirolimus group, the mean number of serious adverse effects per patient decreased from 1.16 during the first 2 years, to 0.83 between years 2 and 5. Conclusion In kidney transplant recipients with previous cutaneous squamous cell carcinomas, the antitumoral effect of conversion from calcineurin inhibitors to sirolimus was maintained at 5 years, and sirolimus tolerance was satisfactory.

The ARE-binding protein Tristetraprolin (TTP) is a novel target and mediator of calcineurin tumor suppressing function in the skin.

An increased incidence of skin inflammatory diseases is frequently observed in organtransplanted patients being treated with calcineurin inhibitor-based immunosuppressive agents. The mechanism of increased skin inflammation in this context has however not yet been clarified. Here we report an increased inflammation following inhibition of calcineurin signaling seen in both chemically induced mouse skin tumors and in tumors grafted from H-rasV12 expressing primary human keratinocytes (HKCs). Following UVB or TPA treatment, we specifically found that deletion of the calcineurin gene in mouse keratinocytes (MKCs) resulted in increased inflammation, and this was accompanied by the enhanced production of pro-inflammatory cytokines, such as TNFα, IL-8 and CXCL1. Furthermore, expression of the RNA-binding protein, tristetraprolin (TTP) was down-regulated in response to calcineurin inhibition, wherein TTP was shown to negatively regulate the production of pro-inflammatory cytokines in keratinocytes. The induction of TTP following TPA or UVB treatment was attenuated by calcineurin inhibition in keratinocytes, and correspondingly, disruption of calcineurin signaling down-regulated the amounts of TTP in both clinical and H-rasV12-transformed keratinocyte tumor models. Our results further demonstrated that calcineurin positively controls the stabilization of TTP in keratinocytes through a proteasome-dependent mechanism. Reducing the expression of TTP functionally promoted tumor growth of H-rasV12 expressing HKCs, while stabilizing TTP expression counteracted the tumor-promoting effects of calcineurin inhibition. Collectively these results suggest that calcineurin signaling, acting through TTP protein level stabilization, suppresses keratinocyte tumors by downregulating skin inflammation.

Swiss (German) Version of the Actinic Keratosis Quality of Life questionnaire.

BACKGROUND: Actinic keratosis (AK) is a sun-induced skin lesion that may progress to invasive squamous cell carcinoma of the skin. Recently, the Actinic Keratosis Quality of Life questionnaire (AKQoL) was designed for patients with AK in Denmark as a specific quality of life instrument for AK patients. OBJECTIVE: The objective of this study was to adapt the AKQoL for the German language region of Switzerland and to evaluate its psychometric properties (validity, reliability). METHODS: Translation and cultural adaptation of the questionnaire were assessed by using the technique of cognitive interviewing. During the translation process, 34 patients with AK from the Department of Dermatology, University Hospital Zurich, were interviewed in 3 sessions of cognitive interviewing. The translated questionnaire was then distributed together with the Dermatology Life Quality Index (DLQI) to a second group of 113 patients for validation and reliability testing. Within this group, we measured the internal consistency by the Cronbach coefficient α and Spearman correlation coefficient between the AKQoL and the DLQI. RESULTS: The problems encountered during the translation process led to changes in 5 categories as described by Epstein: stylistic changes, change in breadth, change in actual meaning, change in frequency and time frame, change in intensity. We found a Cronbach α of 0.82, an acceptable internal consistency. The Spearman correlation coefficient between total scores of AKQoL and DLQI was 0.57. CONCLUSION: We culturally adapted and validated a Swiss (German) version of the AKQoL questionnaire applicable for the population of a university center in Switzerland to measure and monitor the quality of life in patients with AK.

TLR4 as a negative regulator of keratinocyte proliferation.

TLR4 is an innate immune receptor with expression in human skin, keratinocytes as well as squamous cell carcinoma (SCC) of the skin. In the present study we investigate the role of TLR4 as a negative regulator of keratinocyte proliferation. We present here that the expression of TLR4 increased with the differentiation of cultured keratinocytes in a passage-dependent manner or under calcium-rich conditions. Moreover, the down-regulation of TLR4 by specific knockdown increased the proliferation of HaCaT keratinocytes in vitro. In addition, subcutaneously injected HaCaT keratinocytes with shTLR4 formed growing tumors in nude mice. In contrast, we observed lower proliferation and increased migration in vitro of the SCC13 cell line stably overexpressing TLR4 in comparison to SCC13 TLR4 negative cells. In vivo, SCC13 TLR4-overexpressing tumors showed delayed growth in comparison to TLR4 negative tumors. The overexpression of TLR4 in SCC13 tumor cells was followed by phosphorylation of ERK1/2 and JNK and increased expression of ATF3. In gene expression arrays, the overexpression of TLR4 in tumor cells correlated with gene expression of ATF-3, IL-6, CDH13, CXCL-1 and TFPI. In summary, TLR4 negatively regulates the proliferation of keratinocytes and its overexpression reduces tumor growth of SCC cells.

25-Hydroxyvitamin-D3 serum modulation after use of sunbeds compliant with European Union standards: A randomized open observational controlled trial.

BACKGROUND: Regular use of sunbed exposure has been reported to increase 25-hydroxyvitamin-D3 [25(OH)D] serum levels. However, the influence of sunbeds compliant with the recent European Union standard EN-60335-2-27 on 25(OH)D serum levels is unknown. OBJECTIVE: We investigated the impact of standard sunbed use compliant with the European Union standard on 25(OH)D serum modulation and well-being. METHODS: In a randomized controlled study, 25(OH)D serum levels were measured at enrollment, after 1 week, and after completion of the 12-week period of sunbed use with twice weekly exposure and compared with the control group without any sunbed exposure. RESULTS: In the sunbed intervention group (N = 31), a 27% increase of mean 25(OH)D levels was noted 1 week after starting sunbed use (P < .01). However, after 12 weeks, mean 25(OH)D levels had declined and were no longer different from baseline (P = .06). After 12 weeks, 25(OH)D levels did not differ between the intervention and control group (P = .36). Also the 5-item World Health Organization Well-Being Index score did not differ between the sunbed and control groups (P = .19). LIMITATIONS: For ethical reasons recruitment was limited to persons actively seeking sunbed exposure. CONCLUSIONS: Standard use of sunbeds compliant with the European Union standard induced a transient increase of 25(OH)D levels, whereas no change in well-being was observed.

IL-12 protects from psoriasiform skin inflammation.

Neutralization of the common p40-subunit of IL-12/23 in psoriasis patients has led to a breakthrough in the management of moderate to severe disease. Aside from neutralizing IL-23, which is thought to be responsible for the curative effect, anti-p40 therapy also interferes with IL-12 signalling and type 1 immunity. Here we dissect the individual contribution of these two cytokines to the formation of psoriatic lesions and understand the effect of therapeutic co-targeting of IL-12 and IL-23 in psoriasis. Using a preclinical model for psoriatic plaque formation we show that IL-12, in contrast to IL-23, has a regulatory function by restraining the invasion of an IL-17-committed γδT (γδT17) cell subset. We discover that IL-12 receptor signalling in keratinocytes initiates a protective transcriptional programme that limits skin inflammation, suggesting that collateral targeting of IL-12 by anti-p40 monoclonal antibodies is counterproductive in the therapy of psoriasis.

Considerations on long-term immuno-intervention in the treatment of multiple sclerosis: an expert opinion.

INTRODUCTION: As management of multiple sclerosis (MS) requires life-long treatment with disease-modifying agents, any risks associated with long-term use should be considered when evaluating therapeutic options. AREAS COVERED: Immune cells of the innate and adaptive immune systems play various roles in the pathogenesis of MS. MS therapies affect the immune system, each with a unique mode of action, and consequently possess different long-term safety profiles. Rare, but serious safety concerns, including an increased risk of infection and cancer, have been associated with immunosuppressant use. The risks associated with newer immunosuppressive agents, which target specific elements of MS disease pathophysiology, are not yet fully established as the duration of clinical trials is relatively short and post-marketing experience is limited. Non-immunosuppressants used to treat MS have well-defined safety profiles established over a large number of patient-years demonstrating them to be well-tolerated long-term treatment options. When considering the long-term use of disease-modifying agents for treating MS, classification as immunosuppressants or non-immunosuppressants can be useful when evaluating potential risks associated with chronic use. EXPERT OPINION: A successful therapeutic strategy for any serious, chronic disease such as MS should weigh effectiveness versus long-term safety of available treatments.

Bowenoid Actinic Keratosis and Bowen's Disease Treated Successfully with Ingenol Mebutate.

Ingenol mebutate (IM) is a topical pharmacotherapy approved in Switzerland since 2012 for treating non-hypertrophic, non-hyperkeratotic actinic keratosis (AK). We report 2 cases with off-label use of IM. The first case of bowenoid AK was treated with 150 µg IM for 3 consecutive days with an almost complete clinical remission of the lesion. The second case of Bowen's disease was treated with 500 µg IM for 2 consecutive days leading to complete clinical remission.

Ingenol Mebutate 150 mg as Physician-Directed Treatment of Bowen's Disease Under Occlusion.

Ingenol mebutate (IM) is a topical pharmacotherapy approved in Switzerland since 2012 for treating non-hypertrophic, non-hyperkeratotic actinic keratosis. We report a case with off-label use of IM where Bowen's disease has been successfully treated with physician-directed IM 0.015% gel under occlusion over the chest area.