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Three supplementary tables showing: - Characteristics of the melanoma cell lines - Top 10 of significantly upregulated and downregulated genes upon PPARγ specific activation in A375 cells, as quantified by RNA-sequencing - Top 20 of deregulated pathways in RGZ vs Ctrl A375-Media, after an in-depth MS analysis, analyzed with Reactome

Supplementary Materials and methods

Four supplementary figures showing - PPARg activation regulates pro-inflammatory cytokine expression in A375 melanoma cells - Impact of RGZ exposure on the expression of PPARg-target genes and of pro-inflammatory cytokines in a variety of cancer cell lines - Impact of direct exposure to RGZ or T0070907 on interleukin receptor expression, proliferation, cell cycle, apoptosis and senescence of A375 cells, and on human fibroblasts, endothelial cells and monocytes - Impact of the exposure to RGZ or to RGZ-conditioned media collected from different human melanoma cells on human endothelial cells, human fibroblasts, murine fibroblasts and murine endothelial cells

In addition to improving insulin sensitivity in type 2 diabetes, the thiazolidinedione family of compounds and the pharmacologic activation of their best-characterized target PPARγ have been proposed as a therapeutic option for cancer treatment. In this study, we reveal a new mode of action for the thiazolidinedione rosiglitazone that can contribute to tumorigenesis. Rosiglitazone activated a tumorigenic paracrine communication program in a subset of human melanoma cells that involves the secretion of cytokines, chemokines, and angiogenic factors. This complex blend of paracrine signals activated nonmalignant fibroblasts, endothelial cells, and macrophages in a tumor-friendly way. In agreement with these data, rosiglitazone promoted human melanoma development in xenografts, and tumors exposed to rosiglitazone exhibited enhanced angiogenesis and inflammation. Together, these findings establish an important tumorigenic action of rosiglitazone in a subset of melanoma cells. Although studies conducted on cohorts of diabetic patients report overall benefits of thiazolidinediones in cancer prevention, our data suggest that exposure of established tumors to rosiglitazone may be deleterious.Significance: These findings uncover a novel mechanism by which the thiazolidinedione compound rosiglitazone contributes to tumorigenesis, thus highlighting a potential risk associated with its use in patients with established tumors. Cancer Res; 78(22); 6447–61. ©2018 AACR.

Chronic ulcers are a common but important dermatological problem and a major source of expense in the western countries. Skin graft is a surgical procedure in which skin or skin substitute is transplanted in order to close a wound. This article aims to review the different categories of grafts, their indications for the healing of chronic ulcers of the lower limbs, emphasizing the position of punch grafts in the treatment arsenal.Les ulcères chroniques représentent un problème dermatologique courant et donc une source majeure de dépenses dans les pays occidentaux. La greffe de peau est une intervention chirurgicale au cours de laquelle la peau ou un substitut de peau est transplanté afin de favoriser la cicatrisation d’une plaie. Cet article a pour but de faire le point sur les différentes catégories de greffe, leurs indications dans la prise en charge des ulcères chroniques des membres inférieurs en soulignant la place des greffes en pastilles dans l’arsenal thérapeutique à disposition.

Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFRi/MEKi) are beneficial for the treatment of solid cancers but are frequently associated with severe therapy-limiting acneiform skin toxicities. The underlying molecular mechanisms are poorly understood. Using gene expression profiling we identified IL-36γ and IL-8 as candidate drivers of EGFRi/MEKi skin toxicity. We provide molecular and translational evidence that EGFRi/MEKi in concert with the skin commensal bacterium Cutibacterium acnes act synergistically to induce IL-36γ in keratinocytes and subsequently IL-8, leading to cutaneous neutrophilia. IL-36γ expression was the combined result of C. acnes-induced NF-κB activation and EGFRi/MEKi-mediated expression of the transcription factor Kruppel-like factor 4 (KLF4), due to the presence of both NF-κB and KLF4 binding sites in the human IL-36γ gene promoter. EGFRi/MEKi increased KLF4 expression by blockade of the EGFR/MEK/ERK pathway. These results provide an insight into understanding the pathological mechanism of the acneiform skin toxicities induced by EGFRi/MEKi and identify IL-36γ and the transcription factor KLF4 as potential therapeutic targets.

Calciphylaxis and the arteriolosclerotic ulcer of Martorell (ASUM) represent two entities of cutaneous calcific arteriolopathies. Their differential diagnosis can be challenging, given similarities in their clinical and histological presentation. Calcification patterns have been proposed as a possible discriminative histological criterion, however, a systematic microstructural comparative analysis is lacking.The study aimed at a systematic comparative microstructural analysis of the calcification patterns in calciphylaxis versus ASUM.Skin biopsies of patients with leg ulcers due to calciphylaxis (20) and ASUM (69) diagnosed at three European wound care centres (Vienna, Bern, Zurich) were included. The extent of calcification, arteriolar calcification pattern and presence of extra-arteriolar calcification were assessed.All calciphylaxis and most ASUM patients (77%) presented with arteriolar calcification. Although the mean number of calcified vessels and the proportion of calcified area were significantly higher in calciphylaxis specimens (p = 0.003 and p = 0.0171), there was no significant difference in the pattern of arteriolar calcification (p = 0.177). Interestingly, extra-arteriolar calcification was detected in the majority of both calciphylaxis (93.3%) and ASUM samples (85.2%, p = 0.639). Notably, Alizarin Red S staining was superior to HE for the detection of calcifications of both entities (p = 0.014 and p 0.0001), and to von Kossa staining for ASUM samples (p = 0.0001). However, no differences could be observed between cases with uraemic and non-uraemic calciphylaxis or ulcerations located on the upper and lower leg.Our results indicate that extra-arteriolar calcification is not only present in calciphylaxis, but can also be detected in ASUM suggesting a lack of specificity for this finding. However, more specific calcification stains, such as Alizarin Red S, should be used in suspected cases, as calcifications may be overlooked using conventional HE staining.

Zusammenfassung. Vier Pathologien bilden zusammen die makrovaskulären Ursachen des Ulcus cruris: Venöse Ulzera (50 %), gemischte venös-arterielle Ulzera (20 %), arterielle Ulzera (5 %) und das Ulcus hypertonicum Martorell (5 %). Die übrigen 20 % verteilen sich auf sehr viele weitere Ursachen. Jedes Ulcus cruris erfordert eine vaskuläre (arterielle und venöse) Abklärung, gegebenenfalls ergänzt durch Biopsie, Mikrobiologie, und eine vertiefte internistische Diagnostik. Venöse Ulzera werden zunächst durch Kompression therapiert. Insuffiziente Stammvenen und deren Seitenäste werden saniert, sofern das tiefe Venensystem durchgängig ist. Okkludierte Beckenvenen werden nach Möglichkeit rekanalisiert und gestentet. Refraktäre venöse Ulzera werden je nach Fläche mit Spalthaut oder Punch Grafts gedeckt. Je nach Ausdehnung der Dermatolipofasziosklerose kann zuvor die Fibrose mit der «Shave-Therapie» oder Fasziektomie abgetragen werden. Mit der Unterdruck-Wundtherapie können tiefere oder kritisch kolonisierte Wunden konditioniert werden. Hautersatzverfahren sind eine Alternative zur Behandlung oberflächlicher venöser Ulzera ohne Epithelisierungstendenz. Für alle weiteren Indikationen muss ihr Stellenwert noch näher untersucht werden. In der chirurgischen Behandlung komplexer chronischer Wunden führt der Aufbau einer Neo-Dermis vor einer Hautverpflanzung zu einer stabileren Narbe. Gemischte venös-arterielle Ulzera (Ulcus cruris mixtum) heilen langsamer und rezidivieren häufiger. Die Kompressionstherapie muss reduziert werden. Bei ausbleibendem Therapieerfolg wird eine arterielle Revaskularisation angestrebt, womit das gemischte in ein venöses Ulcus cruris umgewandelt wird. Arterielle Ulzera (Ulcus cruris arteriosum) benötigen in aller Regel eine arterielle Revaskularisation und danach eine Spalthautverpflanzung. Das Ulcus hypertonicum Martorell ist noch vielerorts unbekannt und wird oft mit dem Pyoderma gangraenosum verwechselt, was die Therapie in eine falsche Richtung lenkt. Wundchirurgie in kleinerer oder grösserer Form, Antibiotika-Therapie bei klinisch relevanter Superinfektion, und Hautverpflanzungen, oft mehrfach wiederholt, führen in aller Regel zur Abheilung dieser äusserst schmerzhaften und bei falscher Behandlung potenziell lebensgefährlichen Wunden.

Background/Aim: Pyoderma gangrenosum (PG) is a rare, neutrophilic dermatosis often associated with an underlying disease, and clinical data or larger studies are rare. Methods: In this retrospective study, disease characteristics, clinical manifestations, and treatment response were evaluated in a Swiss cohort of PG patients. Results: In participating centers, 34 cases (21 females) of PG were analyzed based on clinical and histological presentation between 2002 and 2012. The mean age at diagnosis was 61.2 years; 50% of the patients experienced only 1 episode of PG. In 13 cases (out of 20), recurrences occurred during PG therapy; 64.1% showed only 1 lesion simultaneously. The predominant localization was the lower limb (67%). The lesions were disseminated in 26.6%. At the time of diagnosis or recurrence, the mean diameter was 37.6 mm and the mean ulcer size was 10.3 cm2. C-reactive protein (CRP) was elevated in 73.2%; leukocytosis was present in 58.9% and neutrophilia in 50.9%. At least 1 associated comorbidity was present in 85% (the most prominent being cardiovascular disease). The most often used systemic treatments were steroids (68.3%), cyclosporine A (31.7%), dapsone (31.7%), and infliximab (13.3%), and the most often used topicals were tacrolimus 0.1% (48.3%) and corticosteroids (35%). PG healed completely at discharge in 50.8%. The average time to diagnosis was 8 months, and the mean duration to healing was 7.1 months. Conclusion: PG is a difficult-to-diagnose skin disease. Here, markers for inflammation such as CRP, leukocytosis, and neutrophilia were elevated in 50-73% of the PG patients.

Introduction: Colchicine is an ancient, but rarely used drug. Little data exist on its efficacy and safety in patients suffering from skin diseases. The objective of our study was to determine whether colchicine showed favorable efficacy and safety in our patients during the last 20 years.Methods: The hospital database was searched for patients treated with colchicine in the last 20 years (January 1, 1998 to December 31, 2017). Overall, total of 41 patients were included in our study.Results: In 63.4% of all patients, either a complete response or an improvement of disease was observed. Adverse events occurred rarely.Discussion: Colchicine is an effective and safe treatment.

Leg ulcers (ulcus cruris): The frequent macrovascular causes

IMPORTANCE Squamous cell carcinoma (SCC) is the most frequent malignant neoplasm found in solid organ transplant recipients and is associated with a more aggressive disease course and higher risk of metastasis and death than in the general population. OBJECTIVES To report the clinicopathologic features of and identify factors associated with aggressive SCC in solid organ transplant recipients. METHODS This retrospective multicentric case series included 51 patients who underwent solid organ transplantation and were found to have aggressive SCC, defined by nodal or distant metastasis or death by local progression of primary SCC. Standard questionnaires were completed by the researchers between July 18, 2005, and January 1, 2015. Data were analyzed between February 22, 2016, and July 12, 2016. RESULTS Of the 51 participants, 43 were men and 8 were women, with a median age of 51 years (range, 19-71 years) at time of transplantation and 62 years (range, 36-77 years) at time of diagnosis of aggressive SCC. The distribution of aggressive SCC was preferentially on the face (34 [67%]) and scalp (6 [12%]), followed by the upper extremities (6 [12%]). A total of 21 tumors (41%) were poorly differentiated, with a median tumor diameter of 18.0 mm (range, 4.0-64.0 mm) and median tumor depth of 6.2 mm (range, 1.0-20.0 mm). Perineural invasion was present in 20 patients (39%), while 23 (45%) showed a local recurrence. The 5-year overall survival rate was 23%, while 5-year disease-specific survival was 30.5%. CONCLUSIONS AND RELEVANCE Results of this case series suggest that anatomical site, differentiation, tumor diameter, tumor depth, and perineural invasion are important risk factors in aggressive SCC in solid organ transplant recipients.

The aim of this study was to test whether an investigational two layer stocking exerting 27-29 mmHg pressure at the medial supramalleolar level, but without compression in the foot and heel, is easier to put on and take off than a standard stocking of the same compression class (23-32 mmHg), and also to assess the prevention of diurnal oedema with both types of stocking.This was an open label randomised controlled trial, which included 47 patients. All participants were at least 65 years of age and suffered from chronic venous disease class C3 - C6 in one leg. The primary end point was donning success; secondary endpoints were doffing success, prevention of diurnal oedema over one day, and the comfort of wearing the stocking. Patients were randomly allocated to one of two groups. Both types of compression stocking were compared in each group for ease of donning and doffing in the manner of a crossover study. Subsequently, patients wore the stocking type assigned to their group for a whole day to evaluate comfort and the effect on diurnal leg volume.All participants were able to don the investigational stocking unaided, compared with 75% for the standard stocking (p .001). Unaided removal success was 100% with the investigational stocking vs. 66% for the standard stocking (p .001). There was no significant difference in leg volume reduction between the study groups after a day of wear. The investigational stocking was also rated as being more comfortable than the standard stocking (p .001).The investigational stocking, which has no compression in the foot or heel area, is significantly easier to don and doff, with no inferiority in oedema prevention, compared with a standard stocking of the same compression class.

Clinical differential diagnosis of arteriolosclerotic ulcers of Martorell is challenging due to the lack of clearly affirmative instrument-based diagnostic criteria. The aim of this study was to develop vascular histomorphological diagnostic criteria differentiating Martorell ulcers from other types of leg ulcers. The histomorphology of patients diagnosed with arteriolosclerotic ulcers of Martorell (n���=���67) was compared with that of patients with venous leg ulcers, necrotizing leukocytoclastic vasculitis, pyoderma gangrenosum, and non-ulcerative controls (n���=���15 each). In a multivariable logistic regression model, the rates of arteriolar calcification (odds ratio (OR) 42.71, 95% confidence interval (CI) 7.43-443.96, p���

Chronic insufficiency of lower extremity venous valves represents a frequent structural disorder of the vascular system being responsible for a substantial global disease load. While in the field of superficial valve insufficiency surgical as well as endoluminal interventions represent good therapeutic options with high rates of complete remission of symptoms, only limited options exist in the field of deep venous reflux today. Bioengineered, autologous cell-based, endothelialized valve constructs may open up new therapeutic options in these patients, potentially offering novel treatment options in cases with severe insufficiency of deep venous segments in the future. Areas covered: This review summarizes previous reports focusing on venous valve replacement and bioengineering, also including first preclinical in vivo studies and first clinical trials in patients. In particular, the aspects of current technical and medical limitations of venous valve bioengineering approaches preventing clinical translation and potential solutions by upcoming technologies will be discussed as part of this review. Expert commentary: Bioengineered replacement valves may open up novel options in the treatment of venous valve disease in defined patient groups in the future. However, preventing thromboembolic complications will remain the bottle-neck for clinical translation of the technologies involved.

Background Forty percent of patients with chronic venous insufficiency (CVI) do not wear their indicated and prescribed compression stockings. Difficulties in donning and a feeling of constraint are the most common reasons for non-adherence. Objective The aim was to develop a compression stocking system that is easy to don and dose adjustable. Methods A modular compression stocking kit composed of an understocking and three superimposable leggings (SLLLs) was developed. Substocking pressures ( P ) at the thinnest part above the ankle (cB level) were 17 mm (understocking) + 15 + 10 + 10 mmHg (3 superimposed leggings; Hatra method). Twenty healthy subjects and 20 patients over 65 years with CVI donned the SLLL compression kit. P was measured in vivo (Picopress method) at the transition of the Achilles tendon to the calf muscle (level cB1) during rest and ankle movements (DSI; dynamic stiffness index) and compared with a strong compression stocking of 40 mmHg (S40). Results Twenty (20/20) patients aged over 65 with CVI (C4–6) successfully donned the SLLL compression kit without aid, compared with 12 (12/20) who were able to don the S40 without aid ( p = .02). In vivo resting P at level cB1 was 34.3 mmHg (SLLL) compared with 37.3 mmHg (S40) ( p = .1). The DSI was 16.1 (SLLL) compared with 17.9 ( p = .79; S40; CVI group). Conclusion The physical properties of the SLLL compression stocking kit correspond to the characteristics of a strong stocking at rest and exercise (DSI). The donning success rate is excellent (100%). A further potential advantage is that the SLLL leg compression kit is dose adjustable, according to indication or patient tolerance. Wearing comfort over periods of several days and clinical effectiveness need to be investigated in future trials.

Background: Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin-Goltz syndrome) presents various symptoms and can disfigure patients. The estimated prevalence is around 1:100,000. Objective: To systematically investigate the clinical manifestations of NBCCS patients of the Zurich register and compare them with those described in 4 epidemiological studies performed in other countries. Methods: We analyzed patient characteristics and clinical manifestations in a register of 30 NBCCS patients in Zurich, Switzerland. We compared our findings to the results of 4 epidemiological studies performed in America, Australia, Japan and the UK. Results: We obtained information concerning basal cell carcinomas (BCCs) and jaw cysts from 28 patients out of our population of 30 NBCCS patients. The mean age at onset of the first BCC was 24 years, and the mean age at diagnosis of the first jaw cyst was 15.6 years. The average number of jaw cysts was 8.4; the average number of BCCs was 207. 72.5% of the examined BCCs showed a nodular histology, but we also found scirrhous and superficial types. Conclusion: The disease burden associated with NBCCS diagnosed in Swiss patients is significant and comparable to that of other countries. Regular skin examination and oromaxillary examinations should be performed early in diagnosis, and patients should undergo early UV protection. Nodular BCC is the most common BCC subtype in this patient population.

In addition to improving insulin sensitivity in type 2 diabetes, the thiazolidinedione family of compounds and the pharmacologic activation of their best-characterized target PPARγ have been proposed as a therapeutic option for cancer treatment. In this study, we reveal a new mode of action for the thiazolidinedione rosiglitazone that can contribute to tumorigenesis. Rosiglitazone activated a tumorigenic paracrine communication program in a subset of human melanoma cells that involves the secretion of cytokines, chemokines, and angiogenic factors. This complex blend of paracrine signals activated nonmalignant fibroblasts, endothelial cells, and macrophages in a tumor-friendly way. In agreement with these data, rosiglitazone promoted human melanoma development in xenografts, and tumors exposed to rosiglitazone exhibited enhanced angiogenesis and inflammation. Together, these findings establish an important tumorigenic action of rosiglitazone in a subset of melanoma cells. Although studies conducted on cohorts of diabetic patients report overall benefits of thiazolidinediones in cancer prevention, our data suggest that exposure of established tumors to rosiglitazone may be deleterious. Significance: These findings uncover a novel mechanism by which the thiazolidinedione compound rosiglitazone contributes to tumorigenesis, thus highlighting a potential risk associated with its use in patients with established tumors. Cancer Res; 78(22); 6447–61. ©2018 AACR.

Zusammenfassung: Hintergrund: Das Ulcus cruris ist ein häufiges Symptom einer heterogenen Krankheitsgruppe, das stark belastend ist und aufgrund der langen Abheilungsdauer und aufwendigen Wundversorgung erhebliche Kosten verursacht. Es gibt wenig Information zur Abheilungsdauer und der Notwendigkeit einer Spitalbehandlung bei Ulzera verschiedener Ätiologien. Material und Methoden: In einer retrospektiven Studie wurden die Abheilungsdauer und die Häufigkeit der Hospitalisation von 355Patienten mit Ulcus cruris in der Wundsprechstunde einer universitären Klinik untersucht. Ergebnisse: Bei einer durchschnittlichen Behandlungsdauer von 6,1Monaten für alle Ulzera waren nach 3Monaten 32,0 % und nach 6Monaten 54,2 % abgeheilt. Für die venösen Ulzera waren die Abheilungsraten mit 45,5 und 63,0 % nach 3 respektive 6Monaten höher, während nach 6Monaten lediglich 30,0 % der Patienten mit gemischt arteriell-venösen Ulzera und 35,0 % mit Ulcus hypertonicum Martorell eine Abheilung zeigten. Zudem wurden 71 % der Patienten der letzteren Gruppen mindestens 1-mal hospitalisiert im Vergleich zu 47 % der Patienten mit venösem Ulkus, und die durchschnittliche Hospitalisationsdauer war mit 30 vs. 23Tagen länger. Schlussfolgerungen: Diese Daten zeigen, dass sich die Abheilungsdauer von Ulzera je nach Ätiologie erheblich unterscheidet und insbesondere Ulzera, die durch eine Arteriosklerose mitverursacht sind, eine längere Behandlungsdauer benötigen. Da Letztere auch häufiger und länger hospitalisiert werden, ergeben sich erhebliche soziale und ökonomische Konsequenzen

Human papillomavirus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/beta-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT secretion may thus represent a promising approach for therapeutic intervention. Funding Agencies|Swiss National Science Foundation (SNF); Swiss Cancer League; Promedica Foundation Zurich; University of Zurich Research Priority Program "Translational Cancer Research"; Kanton of Zurich