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Purpose To evaluate the protein expression characteristics of genes employed in a recently introduced prognostic gene expression assay for patients with cutaneous melanoma (CM). Methods We studied 37 patients with CM and 10 with benign (melanocytic) nevi (BN). Immunohistochemistry of primary tumor tissue was performed for eight proteins: COL6A6, DCD, GBP4, KLHL41, KRT9, PIP, SCGB1D2, SCGB2A2. Results The protein expression of most markers investigated was relatively low (e.g., DCD, KRT9, SCGB1D2) and predominantly cytoplasmatic in melanocytes and keratinocytes. COL6A6, GBP4, and KLHL41 expression was significantly enhanced in CM when compared to BN. DCD protein expression was significantly correlated with COL6A6, GBP4, and KLHL41. GBP4 was positively correlated with KLHL41 and inversely correlated with SCGB2B2. The latter was also inversely correlated with serum S100B levels at time of initial diagnosis. The presence of SCGB1D2 expression was significantly associated with ulceration of the primary tumor. KRT9 protein expression was significantly more likely found in acral lentiginous melanoma. The presence of DCD expression was less likely associated with superficial spreading melanoma subtype but significantly associated with non-progressive disease. The absence of SCGB2A2 expression was significantly more often observed in patients who did not progress to stage III or IV. Conclusions The expression levels observed were relatively low but differed in part with those found in BN. Even though we detected some significant correlations between the protein expression levels and clinical parameters (e.g., CM subtype, course of disease), there was no major concordance with the protective or risk-associated functions of the corresponding genes included in a recently introduced prognostic gene expression assay.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease manifesting in inverse body regions. In a systematic review, the role of hormones in HS will be presented to better understand the pathomechanisms of HS. The review is based on the PRISMA criteria. Systematic research was carried out using keywords. Subsequently, the data were analyzed based on the clinical response and other relevant information. The main focus of our systematic review was on HS manifestation, exacerbation, sex hormones, antiandrogen therapy, thyroid function, polycystic ovary syndrome, insulin resistance, and adipokines. In HS, there appears to be a dysregulated adipokine release that is shifted towards pro-inflammatory adipokines. Insulin resistance is significantly more common in HS than in healthy patients regardless of BMI, age, and gender. Insulin resistance in HS patients leads to further cardiovascular disease. The mechanism of insulin resistance and role of adipokines should be investigated in future studies to better provide the pathomechanisms of HS. The role of androgens seems to be important in a certain subgroup of female patients. Anti-androgenic therapy can be useful and helpful in some patients. However, further studies are needed to better understand the hormonal relationship in HS.

Aim: To find out whether treatment with immune checkpoint inhibitors (ICIs) results in volume increase of the spleen. Patient & methods: We studied 49 stage III and IV melanoma patients with an indication for ICIs. Computer tomographic-assisted volumetry of spleens was performed. Results: After 3 months, median spleen volume was significantly increased when compared with the baseline volume. At 3 months, the increase of spleen volume was significantly associated with the use of ipilimumab and ipilimumab plus nivolumab. There was no significant association between spleen volume increase and clinical parameters. Conclusion: The median spleen volume of patients with cutaneous melanoma increases during the first months of ICI treatment, which was particularly attributable to the use of anti-CTLA-4 and anti-CTLA-4/anti-PD-1 regimens.

Background Microcystic adnexal carcinoma (MAC) is a rare skin neoplasm that has not been characterized on a molecular basis. Objectives We aimed to assess expression profiles of hedgehog (HH) signaling molecules in MAC and control tumours. Methods Immunohistochemistry was performed for Sonic HH (SHH), Indian HH (IHH), Patched 1 (PTCH1), and Smoothened (SMO) on patients' MAC (n=26) tissue and control tumour tissue, including syringoma (SyG; n=11), trichoepithelioma (TE; n=11), and basal cell carcinoma (BCC; n=12). Results PTCH1 and SMO immunoreactivity was significantly higher in BCC than in SyG, TE, and MAC (P = 0.000002 and P = 0.029, respectively). The highest IHH expression was observed in BCC and TE when compared to SyG and MAC (P = 0.038). Notably, the highest SHH protein expression was observed in SyG as compared to MAC, TE, and even BCC (P = 0.00075). In MAC patients, SMO immunoreactivity significantly (r = 0.51; P = 0.0086) correlated with PTCH1 expression. Further correlation studies did not show significant associations between the HH expression markers assessed (P > 0.05). Conclusions Our results indicate that alterations of the HH signaling are unlikely to play a major role in the pathogenesis of MAC, which is in contrast to the morphologically similar BCC and TE. Our observation provides additional information to the limited molecular pathology knowledge on this rare tumour.

Purpose The purpose of this study was to validate the results of an 11-gene expression profiling (GEP) assay which aims to improve the precision of individual prognosis beyond conventional American Joint Committee on Cancer staging for patients with cutaneous melanoma. Methods The reverse transcriptase polymerase chain reaction test of 11 prospectively selected genes was performed on 291 formalin-fixed, paraffin-embedded primary tumours of patients with stage I–III cutaneous melanoma. The expression levels of eight prognostic and three reference genes were used in a predefined algorithm to calculate a numerical score (−0.84 to 3.53) and then assign each patient to a preselected risk group (low versus high score) for melanoma-specific survival (MSS). Results One hundred twenty-seven patients were allocated to the low-score group, with a corresponding five-year disease-free survival (DFS) and MSS of 95% and 99%, respectively. 164 patients were allocated to the high-score group, with a corresponding five-year DFS and MSS of 78% and 88%. Continuous regression analysis demonstrated decreasing MSS probabilities with increasing scores. In a multivariate cox regression, only the 11-GEP, tumour thickness and age were statistically associated with MSS (p = 0.0068, 0.002 and 0.0159). Conclusions The 11-GEP has been validated as an independent predictor of outcome for melanoma patients. More specifically, using an 11-GEP score cut-off of ≤0, the assay can identify patient cohorts with 10-year survival probabilities well above 90%. This information may be used in the decision-making for a potential adjuvant therapy.

The relevance of Hedgehog signaling in Merkel cell carcinoma has only been addressed by a few studies with conflicting results. Thus, we aimed to establish the expression of Hedgehog signaling molecules in Merkel cell carcinoma to characterize causes of aberrant expression and to correlate these findings with the clinical course of the patients. Immunohistochemistry was performed for Sonic, Indian, Patched 1 (PTCH1) and Smoothened on patients' tumor tissue. Respective mRNA expression was analyzed in 10 Merkel cell carcinoma cell lines using quantitative real-time polymerase chain reaction. PTCH1 sequencing and DNA methylation microarray analyses were carried out on tumor tissues as well as cell lines. PTCH1 immunoreactivity in Merkel cell carcinoma was similar to that of basal cell carcinomas, which both significantly differed from PTCH1 immunoreactivity in healthy skin. Most PTCH1 mutations found were synonymous or without known functional impact. However, on average, the promoter regions of both PTCH1 were hypomethylated independently from PTCH1 gene expression or Merkel cell polyomavirus status. PTCH1 and GLI1/2/3 genes were differently expressed in different cell lines; notably, there was a significant correlation between GLI2 and PTCH1 mRNA expression. Similar to PTCH1 protein expression in patient tissues, PTCH1 gene expression in Merkel cell carcinoma cell lines is highly variable, but due to the similar methylation pattern across Merkel cell carcinoma cell lines, effects other than methylation seem to be the reason for the differential expression and PTCH1 appears to be upregulated by GLI as a classical Hedgehog target gene.

Background In a small number of kindreds with familial hidradenitis suppurativa (HS) different mutations of NCSTN (nicastrin) have been identified. Blocking of NCSTN leads to impairment of the Notch and PI3K/AKT signalling pathway, which is assumed to play a pathogenic role in HS. However, very limited data are available concerning expression levels of these pathway components in HS skin. Objectives To analyse the mRNA and protein expression of NCSTN, Notch1-3, PIK3R3 and AKT3 in HS. Methods Skin samples from healthy controls, lesional and perilesional skin of HS patients with and without a positive family history were analysed by quantitative real-time RT-PCR and immunohistochemistry. Univariate statistical analyses were conducted regarding association between expression levels and patient's characteristics. Results Expression levels of all investigated genes showed significantly higher levels in lesional HS skin compared with healthy controls. Univariate analysis showed no association between a positive family history and mRNA expression levels. Perilesional HS skin of patients with mild disease severity (Hurley I) showed significant higher mRNA expression levels of the investigated pathway components compared to moderate (Hurley II) and severe disease (Hurley III). Conclusion We found no evidence for diminished expression levels of the Notch signalling. In contrast, the NCSTN, Notch and PI3K/AKT signalling components are overexpressed in HS. Future research is needed to investigate a possible pathogenetic role or to reveal a coactivation of these overexpressed components during inflammatory response in HS.

Background: Lefty and Nodal are transforming growth factor β‐related proteins, which, beside their role in determination of laterality during embryogenesis, have also been linked with cancer progression. Objectives: Prompted by the observed significant left‐sided laterality of Merkel cell carcinoma (MCC), we addressed whether Lefty and Nodal are expressed in MCC and correlated expression patterns with clinical parameters such as MCC laterality and patient outcome. Methods: Expression of Lefty and Nodal in primary MCC was assessed in 29 patients by immunohistochemistry. The histology (H‐)score was calculated and correlated with clinical parameters. Results: The median (range) H‐score of Lefty and Nodal was 17.6 (0–291) and 74.9 (0.7–272), respectively. There was a significant correlation between Lefty expression and Nodal expression (correlation coefficient of 0.60, P = 0.0006). There was no significant correlation between Lefty expression and Nodal expression with either tumour laterality, gender, age, Merkel cell polyomavirus status, disease stage, anatomical localization of primary tumours or disease relapse. On univariate analysis, low Lefty expression and Nodal expression were significantly associated with MCC‐specific death (P = 0.010 and P = 0.019, respectively). On univariate analysis, low Lefty expression was the only significant independent predictor for MCC‐specific death (P = 0.025) as indicated by an odds ratio of 14 (95% CI: 1.43–137.33). Conclusions: Lefty and Nodal are frequently expressed in MCC, but not correlated with tumour laterality. Importantly, our data suggest that a low level of Lefty expression in primary MCC is a strong predictor of MCC‐specific death.

Introduction: Actinic keratosis (AK) is a chronic disease which is mainly located across areas of sun-exposed skin. Clinical and subclinical lesions coexist across a large area resulting in a field cancerization. As these lesions have the potential to transform into invasive squamous cell carcinoma (iSCC), treatment is crucial. With global prevalence increasing, AK is expected to be the most common in situ carcinoma of the skin.Areas covered: In this article, we cover the established algorithm of treating AK and give an insight into the drugs under development. There are six compounds under development covering different treatment angles, from Sinecatechin a Polyphenon E which targets the link between HPV infection and development of AK, over Tirbanibulin which targets the SRC proto-oncogene and fast proliferating cells, to Tuvatexib a small-molecule dual VDAC/HK2 modulator that has shown that it can compete with the established therapies.Expert opinion: These new treatment options are moving us further toward a more individually tailored treatment for each patient considering his abilities, the size and location of his lesions but also the genetic bases as well as individual risk of transforming into a iSCC and possibly other factors contributing to each patients individual AK lesions.

Usually, SCC lesions are surrounded by a number of clinically visible and non-visible (subclinical) areas of actinically damaged skin containing cells with dysplasia, and thus may be designated actinic dysplasia syndrome. The epithelial damage is caused mainly by UV radiation, inducing mutations in keratinocytes that may confer growth advantages resulting in preneoplastic fields. The development of visible dysplastic lesions (actinic keratosis - AK) and subsequent progression to invasive SCC requires further mutations in cancer-associated genes, like tumour suppressor genes and cell cycle regulators. Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) represent a considerable advantage for the investigation of field cancerization. In addition, imaging allows the non-invasive monitoring of topical treatments for AKs. RCM provides in vivo horizontal skin sections with a high, 1-μm lateral resolution (similar to histopathology) but with a limited penetration (about 200 μm), which can hamper the visualization of important areas such as the dermal-epidermal junction. Conventional OCT has better penetration (1-2 mm) at the expense of a more limited resolution (much lower than histopathology). Line-field confocal OCT (LC-OCT) combines the high precision of RCM and the good penetration of OCT in a single device and therefore appears to be very useful in diagnosing/managing AKs.

Considering the rising incidence, cutaneous squamous-cell carcinoma (cSCC) has a high clinical relevance. In patients with localized cSCC, complete surgical resection is indicated. Radiotherapy should be performed in patients with non-resectable tumours or in patients who are not suitable for surgery. Systemic therapy is reserved for cSCC that are neither surgically nor radiotherapeutically curable due to their extensive local spread and/or local or distant metastasis. In the absence of prospective randomized phase 3 trials to evaluate and compare the efficacy and safety of chemotherapeutics, epidermal growth factor receptor (EGFR) inhibitors and anti-PD-1 antibodies, no final recommendation for systemic therapy can be given for patients with locally advanced or metastatic cSCC. Anti-PD-1 antibodies currently show promising results with response rates of up to 50% in both locally advanced and metastatic cSCC. Anti-PD-1 antibodies appear to achieve higher response rates compared with EGFR inhibitors, and the duration of response appears to be superior to both chemotherapy and EGFR inhibitors. Compared with chemotherapy, the side effect profile of anti-PD-1 antibodies appears to be favourable. Altogether, PD-1 inhibitors are expected to become the new standard of care for patients with locally advanced and metastatic cSCC. Currently, placebo-controlled clinical trials are investigating the adjuvant use of cemiplimab and pembrolizumab in patients undergoing resection and radiotherapy of high-risk cSCC. Patients not eligible for anti-PD-1 treatment, e.g. in organ transplant recipients, or in patients refractory to anti-PD-1 may be offered EGFR inhibitors and/or chemotherapies. Chemotherapies appear to be superior to EGFR inhibitors in terms of response rates, whereas EGFR inhibitors have a more favourable toxicity profile. EGFR inhibitors are therefore more suitable for multimorbid and/or frail elderly patients. By combining EGFR inhibitors with local therapy such as surgery or radiotherapy, response rates and duration of response may be improved.

Sunlight comprises radiation of different wavelengths, of which UVA and UVB are most important with respect to human skin diseases. Next to erythema, edema, and sunburns, UV radiation causes skin cancer. UV radiation of any wavelength is now considered as a class I carcinogen to humans. The mutagenic effects of UV radiation depend on DNA damage following direct absorption by nuclear DNA, resulting in cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts that, if not repaired by nucleotide excision repair pathway, result in characteristic UV signature mutations (C→T or CC→TT transition). In addition, increased formation of reactive oxygen species by UV exposure may cause formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine leading to T→G transversion. In addition, UV radiation has been shown to induce a number of immune modulations that largely result in local and potentially also in systemic immunosuppression, which may not only impair control of dysplastic and neoplastic skin lesions but also affect immuno-pathological and infectious skin diseases. Recent find-ings have shown that ambient doses of high-energy visible light, beyond the UV range, may also cause damage to human skin.

BACKGROUND Mutations in kinetochore gene KNSTRN accelerate the development of cutaneous squamous cell carcinoma (SCC) and may correlate with different histological classifications of actinic keratosis (AKs). OBJECTIVE To determine KNSTRN gene mutation frequency in healthy skin (HS), actinically damaged skin (ADS), in AKs with different histomorphological gradings and invasive SCCs. METHODS All samples were histologically evaluated. AK lesions were additionally classified according to their upwards (AK I-III) and downwards (PRO I-III) directed growth pattern. Mutation analyses of all samples were performed using the Sanger method. RESULTS With one exception, all detected mutations in KNSTRN gene showed an alanine-to-glutamate substitution at codon 40 (p.Ala40Glu). p.Ala40Glu mutation was found in 6.9% (2/29) of HS, in 16.1% (5/31) of ADS, in 18.3% (20/109) of AKs and in 30.0% (9/30) of invasive SCCs. Further stratification of AKs using the common AK classification of Rowert-Huber revealed the p.Ala40Glu mutation in 14.7% (5/43), 13.3% (4/30) and 24.4% (11/45) (AK I, II and III). In contrast, the new PRO classification showed a distribution of 3.6% (1/28) in PRO I, 21.7% (13/60) in PRO II and 28.6% (6/21) in PRO III. Mutation frequency in HS showed significant differences compared to AKs classified as PRO III and invasive SCCs (P

Background Dysregulation of microRNAs (miRNAs) key regulators may contribute to the pathogenesis of malignancies. miRNA machinery genes such Dicer and Drosha have been reported to be biomarkers in different cancer types. Objectives We aimed to evaluate Drosha and Dicer protein expression in cutaneous T-cell lymphoma (CTCL). Methods We performed Drosha and Dicer immunohistochemistry in 45 patients with mycosis fungoides and subtypes. Drosha and Dicer expression scores were correlated with clinical parameters including disease-specific death (DSD), stage of disease and different laboratory data. Uni- and multivariate statistics were performed. Results On univariate analysis, elevated serum LDH and low Drosha expression were significantly associated with advanced stage (P = 0.032 and 0.0062, respectively) and lymphoma-specific death (LSD; P = 0.017 and P = 0.005, respectively). Moreover, elevated circulating CD4+/CD26- lymphocytes were significantly associated with advanced stage (P = 0.032) and DSD (P = 0.0098). On multivariate analysis, low Drosha expression remained in the logistic regression model as significant independent predictor for advanced disease stages [P = 0.013; odds ratio: 5 (confidence interval) CI 1.3-19.3]. Moreover, low Drosha expression (P = 0.026) and elevated LDH (P = 0.025) remained as significant independent predictors for DSD with odds ratios of 13.5 (CI 1.3-134.4 and 8.7 CI 1.3-57.2, respectively). Conclusions Low Drosha expression is an independent predictor for advanced stage as well as LSD in CTCL patients indicating a tumour suppressor gene function of Drosha in this disorder.

BACKGROUND Actinic keratoses (AKs) can histologically be classified by the extent of atypical keratinocytes throughout the epidermis or their pattern of basal proliferation. Currently, no data on the inter-rater reliability of both scores is available. OBJECTIVE To evaluate the inter-rater reliability of the two classification schemes; histological grade (AK I-III) and basal proliferation (PRO I-III). METHODS Histological images of 54 AKs were classified by 21 independent dermatopathologists with regard to basal proliferation (PRO I-III), histological grade (AK I-III) and assumed risk of progression into invasive carcinoma. RESULTS Overall, of the 54 AKs 16.7% (9/54) were classified as AK I, 66.7% (36/54) as AK II, and 16.7% (9/54) as AK III. With regards to basal growth pattern, 25.9% (14/54) were classified as PRO I, 42.6% (23/54) as PRO II, and 31.5% (17/54) as PRO III. We observed a highly significant inter-rater reliability for PRO-grading (P < 0.001) which was higher than for AK-grading (Kendall's W coefficient: AK = 0.488 vs. PRO = 0.793). We found substantial agreement for assumed progression risk for AKs with worsening basal proliferation (k = 0.759) compared to moderate agreement (k = 0.563) for different AK-gradings. CONCLUSIONS Histological classification of basal growth pattern (PRO) showed higher inter-rater reliability compared to the established classification of atypical keratinocytes throughout epidermal layers. Moreover, experienced dermatopathologists considered basal proliferation to be more important in terms of progression risk than upwards directed growth patterns. It should be considered to classify AKs according to their basal proliferation pattern (PRO I-III).

Purpose Nodular melanoma (NM) is associated with worse disease outcome when compared to superficial spreading melanoma (SSM). We aimed to perform a single-center analysis of prognostic factors in patients with NM and compare the data with SSM patients. Methods We studied 228 patients with NN and 396 patients with SSM. Patients with in situ melanomas or stage IV at diagnosis were not included in the study. Data were analyzed using the Mann–Whitney test, Chi-square test, Kaplan–Meier curves including the log-rank test, and logistic regression model. Results When compared to patients with SSM, patients with NM had less likely lower Clark level, higher tumor thickness, less likely tumor regression, more often ulcerated tumors, and less likely a history of precursor lesions such as a nevus. Within a 5-year follow-up we observed significantly more disease relapses and deaths in NM patients than in SSM patients. On multivariate analysis, disease relapse in NM patients was independently predicted by tumor thickness and positive SLNB, whereas melanoma-specific death of NM patients was independently predicted by male sex and tumor thickness. Histologic regression also remained in the logistic regression model as a significant independent negative predictor of NM death. Conclusions We did not observe that NM subtype was per se a significant independent predictor for disease relapse or melanoma-specific death. Among the well-known prognostic factors such as tumor thickness and male sex, NM is also associated with other unfavorable factors such as absence of regression.

Side effects of foam sclerotherapy for varicose veins can include both deep (DVT) and superficial leg vein thrombosis (SVT). The risk factors that favor the development of SVT or DVT after foam sclerotherapy are still largely unclear. The aim of our retrospective analysis was to use a larger group of patients with thromboembolic complications to identify both patient-related and procedure-related risk factors for thromboembolic complications from foam sclerotherapy.A total of 170 patients who received foam sclerotherapy were examined. With reference to a cut-off date, March 17th, 2020, the 85 most recent patients with thromboembolic complications (study group A) were included and compared to the most recent 85 patients without thromboembolic complications (control group B), after sclerotherapy with foamed sclerosant.Patients with a thromboembolic complication were more likely to have thrombophilia (11/85 vs. 3/85). The mean BMI values in group A (25.9 ± 5.1) were significantly lower than in group B (28.0 ± 7.2) (P = 0.034). Thromboembolic complications were more likely to appear after foam sclerotherapy on the lower leg (61/105) than on the thigh (1/13) (P 0.001), particularly after dorsal than after ventral foam sclerotherapy (39 of 47 vs. 5 of 40, P 0.001). Of the 39 thromboembolic complications on the dorsal lower leg, 23 were muscle vein thromboses.The risk of muscle vein thrombosis after foam sclerotherapy is especially increased in slender patients with sclerosed, dorsal lower legs.

The findings of most studies suggest that depression and anxiety disorders are the most common psychiatric comorbidities in patients with hidradenitis suppurativa/acne inversa (HS/AI).In a prospective study, 51 patients with HS/AI were further examined for psychiatric comorbidity using a standardized interview and questionnaires.In psychiatric examination, 29.4% of HS/AI patients had additional mental symptoms, mainly manifested as depressive disorder. The HS/AI patients were rather young and female, and they showed a high incidence of nicotine and alcohol use, and a positive family history of paternal alcohol dependence. In addition, HS/AI patients experienced more severe psychosocial impairments in the form of lack of partnership and lower school attainment.Acne inversa is a severe chronic inflammatory skin disease that, like other inflammatory dermatoses, is associated with mental comorbidity and psychosocial impairments. Since especially young patients are affected, a psychiatric-psychotherapeutic cotreatment should be considered already at an early stage.HINTERGRUND: Die Befunde der vereinzelten durchgeführten Studien legen nahe, dass v. a. Depressionen und Angststörungen als häufigste psychiatrische Komorbiditäten bei Patienten mit einer Hidradenitis suppurativa/Acne inversa (HS/AI) vorkommen.Im Rahmen einer prospektiven Studie wurden 51 Patienten mit einer HS/AI hinsichtlich einer psychiatrischen Komorbidität mittels eines standardisierten Interviews und Fragebögen näher untersucht.Bei der fachpsychiatrischen Untersuchung fand sich bei 29,4 % der HS/AI-Patienten eine zusätzliche psychische Symptomatik, die sich v. a. in Form einer depressiven Störung manifestierte. Die HS/AI-Patienten waren eher jung, eher Frauen und wiesen ein häufiges Vorkommen von Nikotin- und Alkoholkonsum und eine positive Familienanamnese für eine paternale Alkoholabhängigkeit auf. Darüber hinaus bestanden bei den HS/AI-Patienten deutlicher psychosoziale Einschränkungen in Form von fehlender Partnerschaft und eine durch die vorhandenen Symptome deutliche psychische Belastung.Die Acne inversa ist eine schwere chronische entzündliche Hauterkrankung, die ähnlich wie andere inflammatorische Dermatosen mit psychischer Komorbidität und psychosozialen Beeinträchtigungen einhergeht. Da v. a. junge Patienten betroffenen sind, sollte frühzeitig eine psychiatrisch-psychotherapeutische Mitbehandlung erwogen werden.

Aim: To estimate the comparative efficacy of cemiplimab, a programmed cell death protein 1 inhibitor, versus EGFR inhibitors, pembrolizumab and platinum-based chemotherapy in terms of overall survival (OS) and progression-free survival. Patients & methods: We performed an indirect treatment comparison of cemiplimab and other available systemic therapies for patients with advanced cutaneous squamous cell carcinoma. Results: Cemiplimab was associated with benefits in OS (hazard ratios range: 0.07–0.52) and progression-free survival (hazard ratios range: 0.30–0.67) versus EGFR inhibitors and pembrolizumab (data from KEYNOTE-629). Cemiplimab was more efficacious versus platinum-based chemotherapy in terms of OS. Conclusion: Cemiplimab may offer improvements in survival for advanced cutaneous squamous cell carcinoma patients compared with existing systemic therapies.

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.

Not only for cutaneous angiosarcoma (CAS) patients but also for advanced and therapy-refractory patients with classic Kaposi sarcoma (CKS) and human immunodeficiency virus (HIV)-associated Kaposi sarcoma (HIV-KS) there is a high need for more effective treatment modalities. The aim of this work was to study programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) protein expression and related immune parameters in CKS, HIV-KS, and CAS and correlate it with other immunologic parameters and clinical data. Immunohistochemistry was performed on formalin-fixed paraffin-embedded tumor tissue of 19 CKS, 7 HIV-KS, and 12 CAS patients using antibodies against the following (and they are): PD-1, PD-L1, CD4, CD8, CD56, and FOXP3. PD-1 expression significantly correlated with PD-L1 expression Moreover, PD-1 and PD-L1 expression significantly correlated with CD56 and FOXP3 expression. High intratumoral FOXP3 expression was significantly associated with disease relapse (P=0.029). CD4 and FOXP3 expression was significantly higher in CKS and CAS, as compared with HIV-KS. All in all, PD-1 and PD-L1 expression was relatively weak and did not significantly differ between CKS, HIV-KS, and CAS patients. Nevertheless, PD-1 was positive in 31.6% of CKS, 28.6% of HIV-KS, and 33.3% of CAS patients. PD-L1 was expressed in 36.6% of CKS, 28.6% of HIV-KS, and 41.7% of CAS patients. We have provided evidence that PD-1/PD-L1 signalling is of importance in angiosarcomas such as CKS, HIV-KS, and CAS. Our results support the notion that the use of PD-1/PD-L1 inhibitors may represent an effective strategy against these tumors.

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.

Background Topical immune response modifiers are established for actinic keratosis (AK) treatment and efforts are underway to make further improvements to their efficacy and safety. Objectives To investigate the optimal dosing regimens of the Toll-like receptor 7/8 agonist resiquimod in terms of efficacy, safety and tolerability. Methods In a multicentre, partly placebo-controlled, double-blind clinical trial, we randomized 217 patients with AK lesions to 0·03% resiquimod gel once-daily application three times per week for 4 weeks or seven times within 2 weeks or five times for 1 week (arms 1/2/3) followed by a treatment-free interval of 8 weeks and one repetition of the cycle. In two additional arms (arms 4/5), patients applied either resiquimod gel 0·01% or 0·03% three times per week up to a biological end point defined by skin erosion or for a maximum duration of 8 weeks. Clearance was assessed clinically and histologically. Results Complete clinical clearance ranged from 56% to 85% with the highest rate observed in arm 2. Resiquimod 0·03% gel was more effective than 0·01% gel. Clearance rates in arms 1/2/3 were comparable and higher than with placebo and were reached with 24, 14 and 10 gel applications, respectively. Overall, 128 patients (59%) experienced treatment-related adverse reactions. Conclusions Resiquimod 0·03% gel is more effective than 0·01% gel. From the perspectives of safety and tolerability, the lower concentration and shorter duration are preferable. The clinical response in arms 2/3 was reached with fewer gel applications. The dosing regimens that used the biological end point (arms 4/5) proved equally efficacious as predefined treatment durations and may therefore be suitable for personalized AK treatment.

Actinic keratoses (AKs) are defined as intraepithelial proliferation of atypical keratinocytes. Given their potential for progression to invasive squamous cell carcinoma, they may eventually evolve into a life-threatening disease. In recent decades, there has been a significant increase in the incidence of AKs, primarily due to changes in recreational activities and demographic trends in industrialized countries. As it is currently impossible to predict if and when a given AK might progress to invasive carcinoma, rigorous treatment of field cancerization is a key component in preventing potential progression. In addition to a broad armamentarium of procedures as well as pharmaceutical treatment options, primary prevention through diligent UV protection likewise plays a crucial role. New clinical, histomorphological, or molecular classifications are needed to be able to reliably stratify patients based on their individual risk. Especially in light of socio-economic aspects, such a step might prevent over- and undertreatment of an ever-growing patient population and help develop treatment concepts based on individual patient needs.

BACKGROUND Koebnerized non-melanoma skin cancer following skin trauma represents a rare and obscure event. OBJECTIVES To study molecular pathological parameters in koebnerized squamous cell carcinomas (K-SCCs) occurring after complete tumour removal. METHODS We assessed two patients with multiple sclerosis who were on treatment with dimethylfumarate (DMF) preceded by long-term azathioprine therapy. Both patients rapidly developed several K-SCCs following histopathologically proven complete excision of cutaneous SCCs. We performed immunohistochemistry for p53, p16, Ki-67, TET-2, IDH-2, 5-hmc and 5-mc. PCR was carried out for the detection of human papilloma viruses. Mutation analysis was performed for BRAF, K-RAS and EGFR. RESULTS All lesions investigated were negative for HPV DNA. Mutations were not detected. Healthy appearing skin of both patients showed relatively high Ki-67, p16 and p53 expression which was comparable to the expression observed in primary SCCs as well as K-SCCs. Protein expression of Ki-67, p16 and mutant p53 was barely detected in the specimens of the healthy controls. A decreased protein expression of TET-2 enzyme was seen in all tumours and healthy appearing skin when compared to the skin of healthy controls. CONCLUSIONS We observed two patients with K-SCCs developing under DMF treatment. In healthy appearing skin of patients with K-SCCs, wound healing processes, including induction of proliferation and growth factor release, might promote the growth of preneoplastic keratinocytes and cancer formation on the basis of pre-existing altered epigenetic pathways and cell cycle dysregulation. Although fumarates can reduce TET-2 expression, the role of DMF intake in the development of K-SCCs remains unclear.

Argon plasma coagulation (APC) is an electrosurgical technique which can be used to ablate skin lesions with limited invasion depth into dermal tissue. Hence, APC might be well suited for the removal of epithelial tumours. However, there are no data on the effects of APC on human skin tissue. Thus, the aim of this study was to determine the extent of epidermal and dermal damage after APC of human skin. We performed APC ex-vivo on 91 freshly resected human skin samples, which were obtained after reconstructive surgical closures in actinically damaged areas. Tissue effects were evaluated histologically and compared across different power settings. Using 15, 30, and 45 W, median (interquartile range; IQR) coagulation depths were 110.0 µm (91.7-130.0), 113.3 µm (85.8-135.0), and 130.0 µm (100.0-153.3.0), respectively. Median (IQR) thickness of necrosis zone was 30.0 µm (23.3-40.0) at 15 W, 26.7 µm (20.0-41.6) at 30 W, and 43.3 µm (30.8-57.5) at 45 W. The Kruskal-Wallis test showed significant differences between 15 and 30 W versus 45 W for coagulation depth (P = 0.0414), necrosis zone (P = 0.0017), and necrosis according to overlaying epidermal thickness (P = 0.0467). In summary, APC is a simple and controllable electrosurgical technique to remove epidermal tissue with limited penetration to the dermis. Thus, APC is particularly suited for the ablation of epithelial skin lesions and, therefore, may serve as possible treatment approach for intraepithelial neoplasms such as actinic keratosis.

Background/Aims: Actinic keratosis area and severity index (AKASI) is a new assessment tool to quantify the severity of actinic damage on the head. Thus far, it has not been evaluated in monitoring the efficacy of field-directed topical treatments in actinic keratosis (AK) in routine clinical practice. Thus, the aim of this study was to determine treatment outcomes by using AKASI 3 months after the initiation of topical application of diclofenac sodium 3% in hyaluronic acid 2.5% gel (DFS) in patients with AKs on the head. Methods: We performed a retrospective analysis of patients with AKs who had AKASI scores prior to and after treatment with DFS. Results: Of the 24 patients included, 20 (83.3%) showed an improvement in AKASI, 2 (8.3%) a stable AKASI, and 2 (8.3%) a worsening of AKASI after a median (interquartile range) follow-up period of 91.5 days (89.8–104.3). The median AKASI reduction was 31.4% (16.7–59.1). The Wilcoxon test showed significant differences (p = 0.0008) between baseline and posttreatment AKASI values. Conclusions: AKASI is an easy-to-use quantitative tool for assessing the treatment outcome of field-directed therapies. Field-directed therapies of AK should no longer be monitored by assessments based on lesion counts alone.

Background Common histological classification schemes of actinic keratoses (AK) do not evaluate growth patterns at basal epidermal aspects of AK. Until now, the importance of basal epidermal growth patterns of AK has not been studied. Objective To investigate the extent of atypical keratinocytes throughout the epidermis and variation in basal growth patterns of AK. Methods AK lesions occurring on the head/face from patients seen in routine practice were assessed histologically. We determined histological grade (AK I-III), basal growth patterns of atypical keratinocytes (crowding, budding and papillary sprouting) and accompanying parameters. Results Of the 246 lesions included, 28.0% were histologically classified as AK I, 46.7% as AK II and 25.2% as AK III. Approximately 26.4% of the basal growth patterns were classified as crowding (pro I), 49.6% as budding (pro II), 17.9% as papillary sprouting (pro III) and 6.1% without basal directed growth. No significant correlation of the histological AK I-III grading and underlying growth patterns was observed (P = 0.4666). However, adnexal structure involvement (OR = 2.37; 95% CI 1.21-4.65), infiltration (OR = 2.53; 95% CI 1.31-4.90) and increased number of vessels (OR = 2.56; 95% CI 1.42-4.65) were independent positive predictive markers for pro II and pro III basal growth patterns. Conclusions Basal growth patterns (pro I-III) in AK do not correlate with the established AK I-III histological grading system. Besides the degree of upward extension, varying degrees of downward extension exist. Histological classification should consider both, upwards and downward growth patterns when assessing AK.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine tumor of the skin with an increasing incidence. The clinical course is variable and reliable prognostic factors are scarce. Tumor angiogenesis has been shown to have prognostic impact in different types of cancer. The aim of our study was to determine potential prognostic factors, including tumor vascularization, for clinical outcome of MCC.The medical records of 46 patients with MCC diagnosed between 1997 and 2010 were analyzed retrospectively. Tissue samples were immune-stained for the lymphatic endothelial vessel marker podoplanin/D2-40 and the panvascular marker CD31. These immunostained sections were analyzed using computer-assisted morphometric image analyses. Aside from the parameters of tumor vascularization, clinicopathologic features were investigated, and progression-free survival (PFS) and tumor-specific survival (TSS) were assessed. Univariate and multivariate analyses were performed to determine prognostic factors.Male sex of the MCC patients and a high cross-sectional whole vessel area (WVA) in relation to the entire tumor area as determined on CD31-stained tumor sections were found to be negative prognostic factors for PFS in a univariate and multivariate regression analysis. Ulceration of the primary tumor was significantly associated with both impaired PFS and TSS.Our results indicate a high prognostic impact of tumor vascularization on the clinical outcome of MCC patients. Male sex and ulceration of the primary MCC were identified as independent unfavorable prognostic markers for the clinical outcome. As an outlook, MCC patients with increased angiogenesis might be identified and subjected to a targeted anti-angiogenic treatment.

Programmed cell death 1 (PD-1) and its ligands (PD-L1) play a major role in the immune responses of a variety of cancers. To investigate the expression of PD-L1 in different progression forms of cutaneous squamous cell carcinoma (cSCC) and keratoacanthoma (KA). We performed immunohistochemical staining of 21 KA, 26 actinic keratoses (AK), 20 Bowen´s diseases (BD), and 26 high-risk cSCC. The staining patterns were assessed using the tumour proportion score and staining intensity evaluation. Immunohistology scores were statistically analysed. PD-L1 expression of tumour cells as well as tumour-infiltrating cells (TILs) was significantly higher in KA and cSCC when compared to AK and BD (P = 0.00028 and P = 0.00033, respectively). We observed a very strong positive correlation between the PD-L1 protein expression of tumour cells of KA and the PD-L1 protein expression of TILs (r = 0.97; P

Actinic keratoses (AKs) are intraepithelial atypical proliferations of keratinocytes that develop in skin that has undergone long-term exposure to ultraviolet radiation. Given the ageing population and an increasing prevalence of AK, the socio-economic burden of AK is likely to rise over the coming years. Areas of subclinical (non-visible) sun damage in the periphery of visible AK lesions contain the same genetic changes as those found in the lesions themselves, and are known as areas of field cancerization. AK lesions and the field are associated with an increased risk of skin cancer, including invasive squamous cell carcinoma. Although effective in clearing visible AK, lesion-directed therapies do not address field cancerization and can lead to high recurrence rates. In contrast, field-directed therapies, such as ingenol mebutate, imiquimod and diclofenac, can clear both visible and subclinical AK lesions and reduce the development of new lesions in the treated field. Additionally, preclinical studies suggest that field therapy may prevent or delay the recurrence of non-melanoma skin cancer. AK treatment guidelines now recognize the importance of treating the field in patients with AK, and adaptation of treatment guidelines into clinical practice is warranted. Physician and patient education around the consequences of leaving the field of cancerization untreated is necessary in order to reduce the increasing burden associated with AK.

Background: It is unclear if there are any distinct AK patient populations that might respond best to a given treatment. Objective: To identify if a distinct subgroup of patients with AK might respond better to treatment with ingenol mebutate (IngMeb) versus diclofenac sodium (DS). Methods: Complete clearance of AK and mean lesion reduction at end of first treatment course and week 17 were evaluated within subgroups. Results: 502 patients (255 IngMeb; 247 DS) were included in the analysis. At week 17, complete clearance was achieved by more patients treated with IngMeb versus DS within the majority of patient subgroups, including patients with

Background Decreased number of T-regulatory cells (Tregs) and/or their loss of function potentially lead to uncontrolled immune-mediated inflammatory responses. There are only few data available on Tregs in hidradenitis suppurativa (HS) - a disease in which it has been suggested that host immune factors and an overactive immune system of the follicular epithelium play a pathogenetic role. Objectives To analyse frequencies of Tregs subpopulations in blood of HS patients in comparison with a healthy control group. Materials & methods Blood samples obtained from HS patients and healthy controls were evaluated by flow cytometry and enzyme-linked immunosorbent assay. Results The frequency of natural Tregs among CD4+ T lymphocytes were significantly reduced in the HS group compared to the healthy controls. The proportion of activated Tregs, non-suppressive Tregs and proliferating Tregs showed no significant difference when compared to controls. Regarding Tregs frequencies, there was no significant difference between the three Hurley stages. Serum concentrations of IL-10, TGF-s1 and IL-17A did not show significant differences between the HS and control group. Conclusion The reduction of natural Tregs observed in blood of HS patients could be the result of Tregs homing to sites of inflammatory hot spots in HS skin. Further studies are justified evaluating the role of circulating Tregs during the evolution of HS lesions and as a biomarker for treatment response.

Background The role of T regulatory lymphocytes (Tregs) and their immunosuppressive mechanisms in the context of programmed death (PD)-1 blockade is not completely understood. Objectives To assess the impact of PD-1-blocking antibody treatment on Treg subpopulations in the blood. Methods We studied circulating Treg subpopulations in patients with melanoma under nivolumab or pembrolizumab treatment using flow cytometry and correlated these findings with clinical outcomes. Results These analyses revealed that the frequency of CD4+ CD25++ CD127- PD-1+ lymphocytes (PD-1+ Tregs) significantly decreased after the first cycle of immunotherapy (23% vs. 8·6%, P = 0·043). Compared with patients who did not show a significant decline of PD-1+ Tregs after the first treatment, those who did had better clinical outcomes with respect to progression-free survival (PFS, P = 0·022) and melanoma-specific death (MSD, P = 0·0038). Multivariate analysis confirmed that a significant decline of PD-1+ Tregs in peripheral blood after the first treatment cycle is a significant predictor of more favourable PFS and MSD (P = 0·04 and 0·017, respectively). Interestingly, the occurrence of immune-related adverse events was also an independent predictor for decreased risk of MSD (P = 0·047; odds ratio 0·064, 95% confidence interval 0·0042-0·97). Conclusions We provide preliminary evidence that circulating PD-1+ Tregs rapidly decline after the initiation of treatment with PD-1-blocking antibodies, which is associated with reduced risk of melanoma progression and MSD. Patients showing no decrease of these PD-1+ Tregs in peripheral blood are characterized by an impaired response to immune checkpoint blockade and worse outcome. What's already known about this topic? Programmed death (PD)-1-blocking antibodies are highly effective in melanoma treatment. However, more than half of patients do not benefit from this therapy and to date it is difficult to predict which patients will respond to it. What does this study add? PD-1-blocking antibody therapy rapidly results in a decline of circulating PD-1+ T regulatory cells (Tregs). What is the translational message? Patients showing a decrease of PD-1+ Tregs appear to have better clinical outcome under PD-1 treatment.

Background/Aims: Perturbations in the expression of microRNAs (miRNAs) and their maturing machinery components such as Dicer have been previously described for basal cell carcinoma (BCC). However, the mutational status of Dicer in BCC is unclear. Further, the sclerodermiform subtype of BCC (sBCC) has not been previously investigated regarding its methylation profile or its smallRNA expression profile via RNA sequencing. We conducted this study to investigate the mutational status of Dicer in BCC. Methods: Dicer sequencing was performed on the Illumina MiSeq System in a total of 16 BCC samples (8 nodular BCCs, 8 sBCCs) and mapped against the human reference genome (i.e., hg19). Dicer sequencing was performed in all 16 BCC samples. We performed whole genome methylation profiling with Infinium MethylationEPIC BeadChips as well as mRNA and smallRNA sequencing in 5 sBCCs with the Illumina NextSeq500 next-generation sequencing system. Results: Compared to the wildtype Dicer sequence, we found 5 to 7 variants per sBCC sample including insertion, deletion, and multiple nucleotide variants. Global methylation profiles were highly similar between groups. mRNA sequencing revealed S100A9, KRT14, KRT10, S100A8, S100A7, COX1, KRT1, COX3, and smallRNA sequencing analysis miR-21, miR-99a, miR26-a-2, let-7f, let-7g, let-7i, miR-100, and miR-205 were the most strongly expressed in sBCCs. Conclusion: We identified a variety of Dicer mutations that could play a role in aberrant miRNA expression in BCC. The noted RNA sequences should be further evaluated in functional studies to explore their potential pathogenetic role in sBCC. CA extern

BACKGROUND AND OBJECTIVES Cutaneous squamous cell carcinoma (SCC) is known for its capacity to metastasize via lymphatic vessels. In recent studies, the level of lymphangiogenesis has been reported as a potential prognostic factor for several skin tumors. The aim of this study was to quantify lymphangiogenesis in SCC using either computer-assisted image analysis or the Chalkley count technique. Vascular parameters were evaluated and compared with respect to their predictive power for tumor metastasis. PATIENT AND METHODS In this case-control study, clinical and histological data of 15 metastatic and 15 nonmetastatic SCC patients were retrospectively analyzed. SCC samples were immunostained for the lymphatic endothelial marker D2-40 and the panvascular marker CD31, and analyzed using computer-assisted morphometric image analyses within hot spots as well as the digitalized Chalkley counting method. RESULTS Lymphatic vessel density, relative lymphatic vessel area, and lymphatic Chalkley count were significantly elevated in metastatic SCC. Tumor thickness was significantly higher in metastatic SCC, and had the highest predictive power for metastatic disease. Tumor thickness was a significant predictor of lymphangiogenic parameters. CONCLUSIONS Lymphangiogenesis is elevated in metastatic SCC but its extent is influenced by tumor thickness. Tumor thickness remains the most reliable predictive factor for metastatic disease.

Background The long-term outcome of patients with melanoma who had recurrence after negative sentinel lymph node (SLN) biopsy has rarely been evaluated systematically. Methods We searched our databases for melanoma patients with SLN biopsy from the end of 1999 and the beginning of 2011. Data was analyzed using uni- and multivariate statistics as well as Kaplan–Meier curves. Results Data of 651 patients with melanoma was available for statistics. We observed 451 (69.3%) patients with negative SLN who had no evidence of disease recurrence during follow-up. Recurrence in SLN negative patients was found in 50 (7.7%) cases. Tumor subtypes such as invasive lentigo maligna melanoma and acral melanoma (odds ratio 15.2, P = 0.015) and tumor thickness > 2 mm (odds ratio 3.1, P = 0.0017) were independent predictors for recurrence in patients with negative SLN. Patients with negative SLN and subsequent recurrence had a significantly (P = 0.036) reduced 5-year melanoma-specific survival (MSS) when compared with positive SLN patients. Recurrence of disease in positive SLN patients was observed after a median of 39 months when compared to patients with negative SLN and recurrence (28 months, P = 0.0079). Negative SLN with recurrence was an independent predictor for worse recurrence free and melanoma-related survival. Conclusions Patients with negative SLN and recurrence experience earlier disease relapses and poorer MSS when compared to patients with positive SLN status implicating that more stringent follow-up procedures are warranted in patients with higher tumor thickness and invasive lentigo maligna and acral melanoma, despite a negative SLN.

CircularRNAs (circRNAs) are a reinvented class of abundant, stable, and evolutionary conserved non-coding RNAs with pivotal impacts on the cellular regulatory network and epigenetics by sequestering microRNAs (miRNAs) like a sponge.Purpose of the present study was to investigate circRNA expression in cutaneous squamous cell carcinoma (cSCC).A total of six cSCC and six non-lesional skin (control) biopsies were harvested. Microarray based circRNA expression was determined in the cSCC (n=3) and compared with the non-lesional skin (n=3) from a group of 13,617 distinct human circRNAs found in the Arraystar circRNA Array V2.0 (Arraystar, Rockville, USA). Microarray data were validated by quantitative real-time reverse transcription polymerase chain reaction in a separate group (cSCC, n=3 and non-lesional skin, n=3). miRNA binding to miRNA response elements (MREs) sequence data were acquired bioinformatically. Further data mining was performed to identify circRNAs containing MRE sequences that interacted with previously described miRNAs playing a role in cSCC formation.A total of 322 circRNAs (143 up- and 179 down-regulated; fold change ≥2 and p0.05) were identified as differentially expressed in cSCC. Furthermore, we identified a total of 1603 MREs that were part of the differentially expressed circRNAs. Among those circRNAs, a complementary MRE sequence was identified in 23 miRNAs previously known to be cSCC relevant.This study showed that circRNAs are differentially expressed in cSCC and play an important role in tumor formation by interfering with cSCC relevant miRNAs through miRNA sequence complementary MREs participating in epigenetic control.

Background: Despite there being over 35,000 different long noncoding RNA (lncRNA) sequences described little is known regarding their molecular–pathological role in cutaneous squamous cell carcinoma (cSCC). Materials & methods: In this pilot study, lncRNA and mRNA expression profiles were determined in cSCC and control (n = 6) by an Arraystar human lncRNA Microarray. Kyoto Encyclopedia of Genes and Genomes pathway enrichment and gene ontology analysis of mRNAs was performed. Results: Analysis of differential expression revealed 1516 upregulated lncRNAs and 2586 downregulated lncRNAs in cSCC compared with controls. Data analysis identified known oncogenic lncRNAs, such as the HOX transcript antisense RNA HOTAIR, among the differentially expressed lncRNA sequences. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that focal adhesion, extracellular matrix and the oncogenic phosphatidylinositol 3′-kinase-Akt signaling pathway had the highest enrichment scores. Conclusion: This study provides the first evidence for differential expression of lncRNA in cSCC and serves as a template for further, larger functional in-depth analyses regarding cSCC molecular lncRNAs.

Background There are several clinical and histological classification systems for grading actinic keratosis (AK) lesions. The Olsen clinical classification scheme grades AK lesions according to their thickness and degree of hyperkeratosis (grades 1–3). The Roewert-Huber histological classification system grades AK lesions based on the extent of epidermal atypical keratinocytes (AK I–III). Objective The aim of this study was to determine whether there is a correlation between these clinical and histological AK classification schemes. Methods One AK lesion from patients in three pivotal clinical studies and routine practice was assessed clinically and histologically. A match in grading was defined as Olsen grade 1 being classified histologically as AK I, Olsen grade 2 as AK II and Olsen grade 3 as AK III. Results Of the 892 lesions included, 29.0% were classified as Olsen grade 1, 59.6% as Olsen grade 2 and 11.3% as Olsen grade 3; 19.2% were histologically classified as AK I, 69.6% as AK II and 11.2% as AK III. Only 480 lesions (53.8%) had a matching clinical and histological classification. Of these matches, most were ‘Olsen grade 2 = AK II’ (83.1%). The Spearman's rank correlation coefficient for clinical and histological classification was r = 0.0499 (P = 0.137). Conclusions Clinical classification of AK lesions using the system of Olsen does not accurately match histological classification of the same lesions using the system of Roewert-Huber. Consequently, it is not possible to draw conclusions about the histology of AK lesions from their clinical appearance. This finding reinforces the need to treat all AK lesions as well as field cancerization.

Long noncoding RNAs (lncRNAs) are fundamental regulators of pre- and post-transcriptional gene regulation. Over 35,000 different lncRNAs have been described with some of them being involved in cancer formation. The present study was initiated to describe differentially expressed lncRNAs in basal cell carcinoma (BCC). Patients with BCC (n = 6) were included in this study. Punch biopsies were harvested from the tumor center and nonlesional epidermal skin (NLES, control, n = 6). Microarray-based lncRNA and mRNA expression profiles were identified through screening for 30,586 lncRNAs and 26,109 protein-coding transcripts (mRNAs). The microarray data were validated by RT-PCR in a second set of BCC versus control samples. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of mRNAs were performed to assess biologically relevant pathways. A total of 1851 lncRNAs were identified as being significantly up-regulated, whereas 2165 lncRNAs were identified as being significantly down-regulated compared to nonlesional skin (p

For many decades and until recently, medical approach to dermatologic diseases has been based on the physician’s ability to recognize and treat symptoms. Nowadays, advances in the understanding of the biology of diseases and in technologies for intervening against them have allowed physicians to diagnose and treat underlying disease pro- cesses rather than simply addressing the symptoms. This means that rather than addressing ‘the disease in humans’, physicians can now address the particular pathologic (biologic, molecular) disturbance as it presents in the individual patient, i.e., physicians now can practice something much closer to ‘personalized medicine’, leading to greater benefits for the patients and the health of society in general. The deeper understanding of ultraviolet radiation, the importance of photo- protection and increased knowledge about signalling pathways of melanoma and carcinoma have led to more complete care for the dermatologic patient. The current popularity for excessive exposure to the sun, without adequate application of the appropriate photoprotection remedies, is the origin of melanoma, but also for the weakening of the structure and func- tions of the skin. Indeed, fragility of the skin can affect humans around the world. In the senior population, this skin fragility is accompanied by pruritus, whereas atopic dermatitis is an inflammatory disease with highest prevalence in children and adolescents. Acne, the number one reason for dermatologic consultations worldwide, increases its prevalence in adoles- cents and in females. Senescent alopecia affects humans after menopause and andropause. The articles in this publication present an overview of the current advanced understanding of the diagnosis and therapeutic approaches in 6 fields of der- matology – dermatopaediatry and gerontodermatology, oncodermatology, hair loss, atopic dermatitis, photoprotection and acne – and thereby serve as a useful compendium of updated information and references for all healthcare professionals who see patients with presentations of the symptoms of these diseases.

Background Paraneoplastic hyperleucocytosis (PH) is sporadically seen in patients with advanced solid tumors. Case presentation We report a female patient with disseminated melanoma metastases. Two days after the first dosage of combined immunotherapy using the cytotoxic T lymphocyte antigen-4 (CTLA-4) blocker ipilimumab and the programmed death receptor-1 (PD-1) blocker nivolumab the patient developed asymptomatic hyperleucocytosis (over 120.000 leucocytes per μl) associated with elevated granulocyte colony-stimulating factor blood levels. Hematological and infectious disorders could be ruled out. Although paraneoplastic hyperleucocytosis spontaneously resolved she died from progressive disease about 60 days after start of treatment. Conclusions PH is extremely rare in malignant melanoma, however, most patients who developed this complication had preceding immunotherapies such as interleukin-2. The latter observation and the fact that our patient developed PH rapidly after initiation of ipilimumab and nivolumab immunotherapy indicate an immune-mediated mechanism which may trigger PH under unknown circumstances. The development of paraneoplastic hyperleucocytosis indicates a very poor prognosis.

Actinic keratosis (AK) is a common skin condition that results from exposure to chronic ultraviolet (UV) radiation. AK is characterized by visible, scaly lesions; sub-clinical lesions may also be present within a field of UV-exposed skin. These lesions exist on a disease continuum with squamous cell carcinoma. Field therapies, such as ingenol mebutate, aim to treat the visible and sub-clinical lesions within an area of sun-damaged skin. Areas covered: According to the SmPC, ingenol mebutate has a proposed dual mechanism of action that induces cell death necrosis with the production of a local pro-inflammatory response and stimulation of apoptosis. In clinical trials, efficacy of ingenol mebutate has been shown through clearance of AK lesions. Adverse events and local skin responses generally resolved within 2-4 weeks from the end of treatment, depending on body location. Expert opinion: AK can be treated using lesion-directed or topical therapies. Topical treatment with ingenol mebutate has been shown to have superior efficacy compared with diclofenac/sodium hyaluronate. The short and simple treatment regimen may improve patient adherence to ingenol mebutate and satisfaction with treatment. It might be worth evaluating further indications for ingenol mebutate including treatment of basal cell carcinoma.

Actinic keratoses (AKs) can progress into invasive squamous cell carcinoma and thus may become a life threatening disease. Argon plasma coagulation (APC) might complement the therapeutic armamentarium in particular for AK lesions. However, there is no data on APC-induced micromorphological changes following the treatment of AKs. We aimed to determine in vivo APC-induced effects on the epidermis and dermoepidermal junction (DEJ) zone in AK lesions. We performed APC in 108 AKs using the spray mode with a power setting of 15 W and a flow rate of 2.0 L/min. Before and after the intervention, optical coherence tomography (OCT) was performed. After APC, 74.2% (46/62) lesions presented with clearly demarcated DEJ and without any epidermal tissue left, 25.8% (16/62) of treated lesions showed residual epidermal tissue left. In 19.4% (12/62), parts of the DEJ and in 6.5% (4/62), the entire DEJ could not be discriminated. The χ2 test showed a significant (P = 0.0025) association between the presence of hyperkeratosis prior to APC and intact DEJ after APC. In conclusion, APC as shown by OCT is a well controllable treatment modality for AKs causing only limited damage to dermal tissue. Further studies are needed to evaluate clinical outcome as well as recurrence rates.

BACKGROUND In addition to the extent of atypical keratinocytes throughout the epidermis, actinic keratoses (AKs) are histologically characterized by downward-directed basal-layer expansion. It is not known whether this growth pattern correlates with the risk of developing invasive squamous cell carcinoma (iSCC). OBJECTIVES To characterize the prevalence of downward-directed basal-layer expansion of AKs adjacent to iSCC. METHODS The epidermis overlying and adjacent to iSCCs was assessed histologically. We determined the histological grade (AK I-III), basal growth pattern (PRO I-III) and accompanying parameters such as adnexal involvement. RESULTS Among 307 lesions, 52·4% of AKs were histologically classified as AK grade I, 38·1% as AK II and 6·8% as AK III (χ2 -test, P < 0·001). Only 2·6% of adjacent epidermal samples did not show any atypical keratinocytes. The epidermis adjacent to iSCCs was classified as having a PRO I basal growth pattern in 25·7%, PRO II in 31·9% and PROIII in 39·4% of cases. Only 2·9% of AKs showed no basal growth (χ2 -test, P < 0·001). In total 118 AKs (48·8%) showed extension into adnexal structures. These AKs were graded as PRO I in 18·6% of cases, PRO II in 30·5% and PRO III in 50·8%. The epidermis above iSCCs could be assessed only for upwards-directed growth and showed no significant differences in the three AK grades (P = 0·42). CONCLUSIONS Basal proliferative AKs, as well as atypical keratinocytes restricted to the lower third of the epidermis, are most commonly seen adjacent to iSCC, with less evidence for full-thickness epidermal dysplasia. Our study supports the important role of dysplastic keratinocytes in the epidermal basal layer and their potential association with iSCC.