Introduction Kaposi sarcoma (KS) is a cancer of endothelial cells involving the skin and visceral organs. Electrochemotherapy (ECT) is an alternative treatment option for patients with cutaneous malignancies of skin and non-skin origin not suitable for conventional treatments. ECT exerts anti-tumour activity through enhanced drug delivery to tumour cells and cytotoxicity, inducing immunogenic tumour cell death and through a vascular-disrupting effect. Materials and methods In this multi-institutional prospective, observational study, we aimed to evaluate the outcomes of using ECT as a treatment modality for cutaneous Kaposi's Sarcoma within the InspECT (International Network for Sharing Practice on ECT) registry. Patients with superficial lesions of Kaposi Sarcoma from 19 European centres were included. They underwent at least one ECT session with bleomycin performed following the European Standard Operating Procedures, between March 2011 and June 2024. Results The analysis included 82 patients (mean age 71 years; median number of lesions/patient 2). Side effects were reported as mild and easily manageable. The response to treatment per patient was 80 % complete and 13 % partial. In the multivariate model, time since diagnosis to ECT and small tumour size showed a significant association with a complete response. One-year local progression-free survival (LPFS) in the whole population was 93 %, 2 years LPFS was 89 %. Conclusions In the present study, ECT showed antitumor activity and a favourable safety profile in patients with cutaneous Kaposi Sarcoma either not suitable for conventional treatments or that refused them. Better results were obtained in small tumours (<3 cm) using hexagonal electrodes.

Rationale: Tissue regeneration of skin and bone is an energy-intensive, ATP-consuming process that, if impaired, can lead to the development of chronic clinical pictures. ATP levels in the extracellular space including the exudate of wounds, especially chronic wounds, are low. This deficiency can be compensated by inorganic polyphosphate (polyP) supplied via the blood platelets to the regenerating site. Methods: The contribution of the different forms of energy derived from polyP (metabolic energy, mechanical energy and heat) to regeneration processes was dissected and studied both in vitro and in patients. ATP is generated metabolically during the enzymatic cleavage of the energy-rich anhydride bonds between the phosphate units of polyP, involving the two enzymes alkaline phosphatase (ALP) and adenylate kinase (ADK). Exogenous polyP was administered after incorporation into compressed collagen or hydrogel wound coverages to evaluate its regenerative activity for chronic wound healing. Results: In a proof-of-concept study, fast healing of chronic wounds was achieved with the embedded polyP, supporting the crucial regeneration-promoting activity of ATP. In the presence of Ca2+ in the wound exudate, polyP undergoes a coacervation process leading to a conversion of fibroblasts into myofibroblasts, a crucial step supporting cell migration during regenerative tissue repair. During coacervation, a switch from an endothermic to an exothermic, heat-generating process occurs, reflecting a shift from an entropically- to an enthalpically-driven thermodynamic reaction. In addition, mechanical forces cause the appearance of turbulent flows and vortices during liquid-liquid phase separation. These mechanical forces orient the cellular and mineralic (hydroxyapatite crystallite) components, as shown using mineralizing SaOS-2 cells as a model. Conclusion: Here we introduce the energetic triad: metabolic energy (ATP), thermal energy and mechanical energy as a novel theranostic biomarker, which contributes essentially to a successful application of polyP for regeneration processes.

To the Editor: Convolutional neural networks (CNNs) outperform dermatologists in classifying melanomas and nevi based on dermoscopic images.1,2 However, dermatologists consider more aspects than a dermoscopic image in clinical decision-making. Under less artificial conditions, dermatologists and CNNs show comparable performance.3 Recent findings emphasize the need for a collaborative utilization of CNNs alongside clinical expertise.4

Inorganic materials are of increasing interest not only for bone repair but also for other applications in regenerative medicine. In this study, the combined effects of energy-providing, regeneratively active inorganic polyphosphate (polyP) and also morphogenetically active pearl powder on wound healing were investigated. Aragonite, the mineralic constituent of pearl nacre and thermodynamically unstable form of crystalline calcium carbonate, was found to be converted into a soluble state in the presence of a Ca2+-containing wound exudate, particularly upon addition of sodium polyP (Na-polyP), driven by the transfer of Ca2+ ions from aragonite to polyP, leading to liquid-liquid phase separation to form an aqueous Ca-polyP coacervate. This process is further enhanced in the presence of Ca-polyP nanoparticles (Ca-polyP-NP). Kinetic studies revealed that the coacervation of polyP and nacre aragonite in wound exudate is a very rapid process that results in the formation of a stronger gel with a porous structure compared to polyP alone. Coacervate formation, enabled by phase transition of crystalline aragonite in the presence of Na-polyP/Ca-polyP-NP and wound exudate, could also be demonstrated in a hydroxyethyl cellulose-based hydrogel used for wound treatment. Furthermore, it is shown that Na-polyP/Ca-polyP-NP together with nacre aragonite strongly enhances the proliferation of mesenchymal stem cells and promotes microtube formation in the in vitro angiogenesis assay with HUVEC endothelial cells. The latter effect was confirmed by gene expression studies, applying real-time polymerase chain reaction, using the biomarker genes VEGF (vascular endothelial growth factor) and hypoxia-inducible factor-1 alpha (HIF-1 alpha). Division of Escherichia coli is suppressed when suspended in a matrix containing Na-polyP/Ca-polyP-NP and aragonite. The potential medical relevance of these findings is supported by an animal study on genetically engineered diabetic mice (db/db), which demonstrated a marked increase in granulation tissue and microvessel formation in regenerating experimental wounds treated with Ca-polyP-NP compared to controls. Co-administration of aragonite significantly accelerated the wound healing-promoting effect of polyP in db/db mice. Based on these results, we propose that the ability of polyP to form a mixed coacervate with aragonite, in addition to its energy (ATP)-generating function, can decisively contribute to the regenerative activity of this polymer in wound repair. Polyphosphate (polyP) is a physiologically significant polymer with regenerative properties, crucial for supplying the metabolic fuel (ATP) essential for various regeneration processes in humans, including wound healing.

BACKGROUND:This study analysed treatment strategies with electrochemotherapy (ECT) in melanoma with limb in-transit metastases (ITM). METHODS:We audited AJCC v.8 stage IIIB-IIID patients treated across 22 centres (2006-2020) within the International Network for Sharing Practices of ECT (InspECT). RESULTS:452 patients were included, 58 % pre-treated (93 % had lower limb ITM, 44 % had ≤10 metastases [median size 1.5 cm]. Treatment strategies included first-line ECT (n = 145, 32 %), ECT with concurrent locoregional/systemic treatment (n = 163, 36 %), and salvage ECT (n = 144, 32 %). The objective response rate was 63 % (complete response [CR], 24 %), increasing to 74 % (CR, 39 %) following retreatment (median two ECT, range 1-8). CR rate in treatment-naïve and pre-treated patients was 50 % vs 32 % (p < 0.001). Bleomycin de-escalation was associated with lower CR (p = 0.004). Small tumour number and size, hexagonal electrode, retreatment, and post-ECT skin ulceration predicted response in multivariable analysis. At a median follow-up of 61 months, local and locoregional recurrence occurred in 55 % and 81 % of patients. Median local progression-free, new lesions-free, and regional recurrence-free survival were 32.9, 6.9, and 7.7 months. Grade-3 toxicity was 15 %. Concurrent treatment and CR correlated with improved regional control and survival. Concomitant checkpoint inhibition did not impact toxicity or survival outcomes. The median overall survival was 5.7 years. CONCLUSIONS:Among patients with low-burden limb-only ITM, standard-dose bleomycin ECT results in durable local response. Treatment naivety, low tumour volume, hexagonal electrode application, retreatment, and post-ECT ulceration predict response. CR and concurrent treatment correlate with improved regional control and survival outcomes. Combination with checkpoint inhibitors is safe but lacks conclusive support.

Anamnese und Befund: Die 71-jährige Patientin stellte sich mit "über Nacht" neu aufgetretenen Knoten an beiden Beinen und Schmerzen in den Sprunggelenken vor.Am Vortag habe sie auf einer Familienfeier üppig gegessen und Alkohol getrunken.Ein metabolisches Syndrom und ein chronischer Alkoholabusus konnten als Vorerkrankungen eruiert werden.Es zeigten sich an beiden Beinen, v.a. an den Oberschenkeln, unregelmäßig verteilt, multiple bis zu 3 cm große lividrote Knoten.Die Sprunggelenke beidseits waren diskret geschwollen, gerötet und leicht überwärmt.Diagnostik: Histologisch zeigte sich eine regelrechte Epidermis und obere Dermis.In der Subkutis war ein lobulär betontes entzündliches Infiltrat zu sehen.Randlich ließen sich nekrotische Anteile des Fettgewebes mit sog.Geisterzellen und fokaler Verseifung von Adipozyten nachweisen.Im Serum waren Lipase mit 4208 U/l (<60 U/l), Amylase 1693 U/l (<100 U

Seborrheic keratosis (SK) is the most common benign epidermal tumor in clinical dermatological practice. This review summarizes current knowledge about the clinical and histological appearance, epidemiology, pathogenesis, and treatment of SK. There are different subtypes of SK based on clinical presentation and histologic findings. Several factors, including age, genetic predisposition, and possibly also exposure to ultraviolet radiation, are thought to contribute to the development of SK. The lesions can occur on all areas of the body except for the palms and soles, but the most common sites are the face and upper trunk. The diagnosis is usually made clinically, and in some cases by dermatoscopy or histology. Many patients prefer to have the lesions removed for cosmetic reasons although there is no medical indication. Treatment options include surgical therapy, laser therapy, electrocautery, cryotherapy, and topical drug therapy, which is currently in development. Treatment should be individualized depending on the clinical picture and patient preference.

Amorphous calcium carbonate (ACC), precipitated in the presence of inorganic polyphosphate (polyP), has shown promise as a material for bone regeneration due to its morphogenetic and metabolic energy (ATP)-delivering properties. The latter activity of the polyP-stabilized ACC ("ACC∙PP") particles is associated with the enzymatic degradation of polyP, resulting in the transformation of ACC into crystalline polymorphs. In a novel approach, stimulated by these results, it was examined whether "ACC∙PP" also promotes the healing of skin injuries, especially chronic wounds. In in vitro experiments, "ACC∙PP" significantly stimulated the migration of endothelial cells, both in tube formation and scratch assays (by 2- to 3-fold). Support came from ex vivo experiments showing increased cell outgrowth in human skin explants. The transformation of ACC into insoluble calcite was suppressed by protein/serum being present in wound fluid. The results were confirmed in vivo in studies on normal (C57BL/6) and diabetic (db/db) mice. Topical administration of "ACC∙PP" significantly accelerated the rate of re-epithelialization, particularly in delayed healing wounds in diabetic mice (day 7: 1.5-fold; and day 13: 1.9-fold), in parallel with increased formation/maturation of granulation tissue. The results suggest that administration of "ACC∙PP" opens a new strategy to improve ATP-dependent wound healing, particularly in chronic wounds.

Insufficient metabolic energy,in the form of adenosine triphosphate(ATP),and bacterial infections are among the main causes for the development of chronic wounds.Previously we showed that the physi-ological inorganic polymer polyphosphate(polyP)massively accelerates wound healing both in animals(diabetic mice)and,when incorporated into mats,in patients with chronic wounds.Here,we focused on a hydrogel-based gel formulation,supplemented with both soluble sodium polyP(Na-polyP)and amor-phous calcium polyP nanoparticles(Ca-polyP-NP).Exposure of human epidermal keratinocytes to the gel caused a significant increase in extracellular ATP level,an effect that was even enhanced when Na-polyP was combined with Ca-polyP-NP.Furthermore,it is shown that the added polyP in the gel is converted into a coacervate,leading to encapsulation and killing of bacteria.The data on human chronic wounds showed that the administration of hydrogel leads to the complete closure of these wounds.Histological analysis of biopsies showed an increased granulation of the wounds and an enhanced microvessel forma-tion.The results indicate that the polyP hydrogel,due to its properties to entrap bacteria and generate metabolic energy,is a very promising formulation for a new therapy for chronic wounds.

ZusammenfassungDie seborrhoische Keratose (SK) ist der häufigste gutartige epidermale Tumor in der klinisch‐dermatologischen Praxis. Diese Übersicht fasst den Kenntnisstand zu Klinik, Histologie, Epidemiologie, Pathogenese und Therapie von SK zusammen. Anhand des klinischen und histologischen Bildes unterscheidet man verschiedene Typen der SK. Es wird vermutet, dass mehrere Faktoren, darunter das Alter, eine genetische Prädisposition und möglicherweise auch die Exposition gegenüber ultravioletter Strahlung mit der Entstehung der Tumoren in Verbindung stehen. Die Läsionen können an allen Körperregionen auftreten, mit Ausnahme der Handflächen und Fußsohlen, die häufigsten Stellen sind jedoch das Gesicht und der obere Rumpf. Die Diagnose erfolgt meistens klinisch, in manchen Fällen unter Zuhilfenahme eines Dermatoskops oder durch Biopsie. Viele Patienten bevorzugen es, SK aus kosmetischen Gründen zu entfernen, obwohl keine medizinische Indikation hierzu vorliegt. Bei den Behandlungsmöglichkeiten wird zwischen chirurgischen, chirurgisch‐destruierenden (Laser, Elektrodesikkation/‐kaustik, Kryotherapie) und topisch‐medikamentösen Verfahren unterschieden. Letztere sind aktuell in klinischer Entwicklung. Die Behandlung wird abhängig vom klinischen Bild und der Präferenz des Patienten individuell angepasst.

The healing of chronic wounds is impaired by a lack of metabolic energy. In previous studies, we showed that physiological inorganic polyphosphate (polyP) is a generator of metabolic energy by forming ATP as a result of the enzymatic cleavage of the high-energy phosphoanhydride bonds of this polymer. Therefore, in the present study, we investigated whether the administration of polyP can substitute for the energy deficiency in chronic wound healing. Methods: PolyP was incorporated into collagen mats and applied in vitro and to patients in vivo. Results: (i) In vitro studies: Keratinocytes grown in vitro onto the polyP/collagen mats formed long microvilli to guide them to a favorable environment. HUVEC cells responded to polyP/collagen mats with an increased adhesion and migration propensity as well as penetration into the mats. (ii) In vivo - human clinical studies: In a "bench to bedside" process these promising in vitro results were translated from the laboratory into the clinic. In the proof-of-concept application, the engineered polyP/collagen mats were applied to chronic wounds in patients. Those mats impressively accelerated the re-epithelialization rate, with a reduction of the wound area to 65% after 3 weeks and to 36.6% and 22.5% after 6 and 9 weeks, respectively. Complete healing was achieved and no further treatment was necessary. Biopsy samples from the regenerating wound area showed predominantly myofibroblasts. The wound healing process was supported by the use of a polyP containing moisturizing solution. Conclusion: The results strongly recommend polyP as a beneficial component in mats for a substantial healing of chronic wounds.

IntroductionCutaneous squamous cell carcinoma (cSCC) is a frequent skin cancer with a high risk of recurrence characterized by tumor infiltration and, in advanced cases, a poor prognosis. ECT (electrochemotherapy) is an alternative treatment option for locally advanced or recurrent cSCC that is unsuitable for surgical resection. In this study, we aimed to evaluate the data in the InspECT (International Network for Sharing Practice on ECT) registry of the referral centers and to clarify the indications for the use of ECT as a treatment modality for cSCC.Materials and methodsPatients with primary, recurrent or locally advanced cSCC from 18 European centers were included. They underwent at least one ECT session with bleomycin between February 2008 and November 2020, which was performed following the European Standard Operating Procedures.ResultsThe analysis included 162 patients (mean age of 80 years; median, 1 lesion/patient). Side effects were mainly local and mild (hyperpigmentation, 11%; ulceration, 11%; suppuration, 4%). The response to treatment per patient was 62% complete and 21% partial. In the multivariate model, intravenous drug administration and small tumor size showed a significant association with a positive outcome (objective response). One-year local progression-free survival was significantly better (p<0.001) in patients with primary tumors (80% (95% C.I. 70%-90%) than in patients with locally advanced disease (49% (95% C.I. 30%-68%).ConclusionIn the present study, ECT showed antitumor activity and a favorable safety profile in patients with complex cSCC for whom there was no widely accepted standard of care. Better results were obtained in primary and small tumors (<3 cm) using intravenous bleomycin administration.

Hidradenitis suppurativa (HS) is a chronic, progressive inflammatory disorder of follicular occlusion with pubertal onset that presents as painful inflammatory nodules, sinus tracts, and tunnelling in apocrine-gland-rich areas, such as the axilla, groin, lower back, and buttocks. The disease course is complicated by contractures, keloids, and immobility and is often associated with a low quality of life. It is considered a disorder of follicular occlusion with secondary inflammation, though the exact cause is not known. Management can often be unsatisfactory and challenging due to the chronic nature of the disease and its adverse impact on the quality of life. A multidisciplinary approach is key to prompt optimal disease control. The early stages can be managed with medical treatment, but the advanced stages most likely require surgical intervention. Various surgical options are available, depending upon disease severity and patient preference. In this review an evidence-based outline of surgical options for the treatment of HS are discussed. Case reports, case series, cohort studies, case-control studies, and Randomized Clinical Trials (RCT)s available in medical databases regarding surgical options used in the treatment of HS were considered for the review presented in a narrative manner in this article.

Many pathological conditions are characterized by a deficiency of metabolic energy. A prominent example is nonhealing or difficult-to-heal chronic wounds. Because of their unique ability to serve as a source of metabolic energy, inorganic polyphosphates (polyP) offer the opportunity to develop novel strategies to treat such wounds. The basis is the generation of ATP from the polymer through the joint action of two extracellular or plasma membrane-bound enzymes alkaline phosphatase and adenylate kinase, which enable the transfer of energy-rich phosphate from polyP to AMP with the formation of ADP and finally ATP. Building on these findings, it was possible to develop novel regeneratively active materials for wound therapy, which have already been successfully evaluated in first studies on patients.

Background: Masseter muscle hypertrophy (MMH) usually presents with cosmetic concerns as it may lead to widening of the lower face. Apart from the traditional surgical approaches, botulinum toxin type A (BTA) injection is a non-invasive treatment option available. There are no standard guidelines for this procedure. Objectives: To study the efficacy of botulinumtoxin A in MMH for lower face contouring. Methodology: The Cochrane Library, PubMed/MEDLINE, Google-scholar, Science-Direct database, and ResearchGate from inception until September 2021 were searched using the keywords "botulinumtoxin type A," "masseter muscle hypertrophy," "lower face contouring," and "masseter botox." All available retrospective and prospective studies, case-series, case-reports, and expert reviews were included with an emphasis on efficacy of BTA in MMH and units injected into the muscle, points of placement, adverse events, and the duration of its effect. Reference lists of the resultant articles, as well as relevant reviews, were also searched. Result: 40 articles were shortlisted for the review, of which 14 studies with sample-size >= 10 in accordance with the study requirements were summarized in a tabular form for analysis and easy comparison and reference. Conclusion: BTA injection is a non-invasive, safe, and effective treatment for MMH. The optimum number of BTA units could not be ascertained due to wide variability in the studies as well as ethnicity of patients and extent or some measurement of MMH. The points of placement of injection should be well within the boundaries of the masseter muscle. The maximum effect of BTA after a single injection session is usually seen in similar to 3 months, and the duration may last for 6-12 months. Multiple injection sessions may be required to maintain a long-term effect. Injection technique and total number of injection units of neuromodulator must be individualized for each patient.

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 20, Issue 1 p. 95-101 Clinical LetterFree to Read Die Bedeutung des gepulsten Farbstofflasers bei der Behandlung akraler infantiler Hämangiome Ulrike Nikfarjam, Corresponding Author Ulrike Nikfarjam ulrike.nikfarjam@unimedizin-mainz.de Hautklinik der Universitätsmedizin Mainz Korrespondenzanschrift Dr. med. Ulrike Nikfarjam Hautklinik der Universitätsmedizin Mainz Langenbeckstraße 1 55131 Mainz E-Mail: ulrike.nikfarjam@unimedizin-mainz.deSearch for more papers by this authorJoanna Wegner, Joanna Wegner Hautklinik der Universitätsmedizin MainzSearch for more papers by this authorStephan Grabbe, Stephan Grabbe Hautklinik der Universitätsmedizin MainzSearch for more papers by this authorHadrian Schepler, Hadrian Schepler orcid.org/0000-0001-8217-5645 Hautklinik der Universitätsmedizin MainzSearch for more papers by this authorEva Juchems, Eva Juchems Hautklinik der Universitätsmedizin MainzSearch for more papers by this author Ulrike Nikfarjam, Corresponding Author Ulrike Nikfarjam ulrike.nikfarjam@unimedizin-mainz.de Hautklinik der Universitätsmedizin Mainz Korrespondenzanschrift Dr. med. Ulrike Nikfarjam Hautklinik der Universitätsmedizin Mainz Langenbeckstraße 1 55131 Mainz E-Mail: ulrike.nikfarjam@unimedizin-mainz.deSearch for more papers by this authorJoanna Wegner, Joanna Wegner Hautklinik der Universitätsmedizin MainzSearch for more papers by this authorStephan Grabbe, Stephan Grabbe Hautklinik der Universitätsmedizin MainzSearch for more papers by this authorHadrian Schepler, Hadrian Schepler orcid.org/0000-0001-8217-5645 Hautklinik der Universitätsmedizin MainzSearch for more papers by this authorEva Juchems, Eva Juchems Hautklinik der Universitätsmedizin MainzSearch for more papers by this author First published: 18 January 2022 https://doi.org/10.1111/ddg.14635_gAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume20, Issue1January 2022Pages 95-101 RelatedInformation