Concurrent optical and magnetic stimulation therapy in patients with lower extremity hard-to-heal wounds.

OBJECTIVE: The treatment of patients with hard-to-heal wounds represents a major multidisciplinary challenge. Therefore, the development and clinical validation of new technologies remains extremely important. The novel application of concurrent optical and magnetic stimulation (COMS) offers a promising noninvasive approach to support physiological wound healing processes, especially in hard-to-heal wounds. METHOD: In a multicentre, prospective, comparative, clinical trial, patients with hard-to-heal wounds on lower extremities of different aetiologies were treated with COMS as an adjunct to standard of care (SOC). The primary endpoint was safety; secondary endpoints were wound healing, pain and wound-specific quality of life (Wound-QoL). RESULTS: A total of 40 patients were enrolled in this study (intention to treat population (ITTP), n=40). Of these patients, 37 were included in the analysis of the primary endpoint (primary endpoint population, (PEP), n=37). A further subgroup of 30 patients was included in the analysis of the secondary endpoint (secondary endpoint population (SEP), n=30). Finally, the SEP was stratified regarding patients' responsiveness to SOC in an SOC non-responder subgroup (NRSG), n=21, and in an SOC responder subgroup (RSG), n=9. A total of 102 adverse events (AEs) were recorded, of which 96% were 'mild' or 'moderate', and 91% were either a singular or transient event. Only 11 AEs were serious and associated with inpatient treatments unrelated to the studied intervention. In the NRSG, reductions in wound size were found to be statistically significant within the different study periods. Additionally, an acceleration of the healing rate was detected between the baseline and the first four weeks of COMS treatment (p=0.041). The rate of near-complete and complete wound closure in the SEP after 12 weeks were 60% and 43%, respectively. Pain reduction across the treatment group was statistically significant (p≤0.002 for both the SEP and NRSG). The Wound-QoL score improved by 24% during the study (p=0.001). CONCLUSION: In this study, COMS treatment for patients with hard-to-heal wounds on lower extremities was a safe and effective novel treatment option, especially for patients who did not respond to SOC.

Impact of ovarian vein embolization in recurrent varicose veins of the lower extremity.

Background: The treatment success of catheter-based ovarian vein embolization due to peripheral varicose veins and ovarian vein reflux (OVR) should be investigated in this clinical investagtion. Patients and methods: For this study, 95 female patients were identified over a 5-year period (beginning of 2006 to end of 2011) after catheter-based coil (+/- chemical) embolization of the ovarian vein due to peripheral primary or recurrent varicose veins and proven reflux in the ovarian vein. Treatment success was retrospectively assessed in 2014 by means of a structured telephone interview (n=60), clinical examination (n=56), duplex ultrasound (n=56) and magnetic resonance imaging (n=51) in patients who were willing to participate in the study. Results: After an average of 51.9 months, 95.2% of the 60 included patients were diagnosed with recurrent varicose veins by duplex sonography and 88.1% by clinical examination. In 15.2%, a new intervention was required due to clinical symptoms. The median recurrence-free time was 47.0±5.5 months. A significant improvement by therapy was reported for all subjective symptoms in both pelvis and legs. No significant correlation between radiological findings and complaints or between radiological findings and clinical recurrence was found. Conclusions: The medical history of female patients with peripheral varicose veins should obligatorily include the question of symptoms in the pelvis. An appropriate diagnostic should follow in order to prevent a possible overlook of a pelvic leak point. Only then an individually adapted therapy for symptom relief is possible. Catheter-based ovarian vein embolization is one optional safe procedure that leads to significant improvement of subjective symptoms but does not necessarily prevent recurrent varicose veins.

Comorbidity and Therapeutic Approaches in Patients with Necrobiosis Lipoidica.

BACKGROUND: Necrobiosis lipoidica (NL) is a rare granulomatous disorder of unknown aetiology. Randomized controlled studies are not available due to it being an orphan disease. OBJECTIVES: We evaluated patients in 2 dermatological centres to cluster data about epidemiology, the therapeutic approaches for NL, and their efficacy. MATERIALS AND METHODS: Comorbidity and the efficacy of the applied treatment was assessed for 98 patients. RESULTS: We identified 54% of patients with concomitant diabetes and 19% with thyroidal disorders. Topical steroids (85.7%) were predominantly used followed by calcineurin inhibitors (31%) and phototherapy (41.8%). Systemically, fumaric acid esters were more frequently applied (26.8%) than steroids (24.4%) and dapsone (24.4%). Steroids, compression therapy, calcineurin inhibitors, phototherapy, fumaric acid esters, and dapsone showed remarkable efficacy. CONCLUSION: Therapeutic options were chosen individually in accordance with the severity of NL and presence of ulceration. Topical calcineurin inhibitors, systemic application of fumaric acid esters, and dapsone represent effective alternatives to the use of steroids.

Effects of Patients' Expectation in Dermatology: Evidence from Experimental and Clinical Placebo Studies and Implications for Dermatologic Practice and Research.

Patients' expectations towards the benefit of a treatment are key determinants of placebo responses and can affect the development and course of medical conditions and the efficacy and tolerability of active medical treatment. The mechanisms mediating these placebo and nocebo effects have been best described in the field of experimental pain and placebo analgesia. However, also in dermatology experimental and clinical studies demonstrate that various skin diseases such as inflammatory dermatoses and allergic reactions can be modulated by patients' expectations. Dermatologists should consider the important modulatory role of patients' expectations on the efficacy and tolerability of specific treatments and the key role of verbal information, patients' prior treatment experiences (associative learning), and the quality and quantity of doctor-patient communication in shaping treatment expectation. As a consequence, techniques aiming at maximizing patients' expectation effects should be implemented into daily clinical routine. By contrast, in clinical studies expectation effects should be maximally controlled and harmonized to improve the "assay sensitivity" to detect new compounds. Further translational studies, also in dermatoses that have not been investigated yet, are needed to better characterize the mechanisms underlying patients' expectation and to gain further insights into potential clinical implications of these effects in dermatologic conditions. Therefore, in this review, we provide a brief overview on the concept of expectation effects on treatment outcome in general, summarize what is already known about this topic for dermatologic diseases, and finally present the relevance of this topic in clinical dermatology.

Association of wound genesis on varying aspects of health-related quality of life in patients with different types of chronic wounds: Results of a cross-sectional multicentre study.

Patients with chronic wounds are significantly impaired in their health-related quality of life (HRQoL). The validated Wound-QoL questionnaire allows assessing the impact of chronic wounds on different aspects of HRQoL including physical, psychological, and everyday life-related impairments. The aim of our study was to investigate associations of these HRQoL dimensions with age, sex, and particularly wound genesis. In this retrospective, cross-sectional, multicentre study, Wound-QoL questionnaires from clinical routine of patients with venous leg ulcers, arterial leg ulcers, mixed leg ulcers, and diabetic foot ulcers (DFU) were evaluated. Effects of wound genesis, sex, and age were assessed with analysis of variance as well as correlation and multiple linear regression analyses. The completed questionnaires of 381 patients (f = 152/m = 229; mean age 68.9) were included. The wound genesis groups showed significantly different distributions of age and sex. We also found significant differences between those groups in everyday life-related QoL, with the greatest impairments in patients with DFU. Physical QoL scores showed significant differences between men and women depending on diagnosis group: in patients with venous leg ulcers, women had greater impairment of physical QoL than men. Independent of the underlying diagnosis, women had significantly higher scores in the psychological subscale as well as in the Wound-QoL sum scale. Within the subgroup of arterial leg ulcer patients, overall HRQoL sum score was significantly worse in older patients. Regression analyses supported negative effects of DFU diagnosis and female sex on HRQoL. Our data offer evidence that HRQoL shows clinically relevant differences between patients with chronic wounds of different genesis. Moreover, our data revealed that HRQoL is associated with age and sex, which should be considered when treating the patient groups. In order to be able to capture these important aspects and to offer individualised and patient-oriented treatments, the Wound-QoL should be implemented as a quick and uncomplicated standard instrument in daily routine. Patients with chronic wounds are significantly impaired in their health-related quality of life. Validated Wound-QoL questionnaire is a quick and easy-to-use instrument for daily practice. Wound-related quality of life shows clinically relevant differences between patients with chronic wounds of different genesis. Wound-related quality of life is associated with age and sex, which should be considered when treating these patient groups. Health-related quality of life should be regularly objectified in all patients with chronic wounds with a validated measuring instrument.

Pilot study on the influence of cold atmospheric plasma on bacterial contamination and healing tendency of chronic wounds.

BACKGROUND: Cold atmospheric plasma (CAP) has been used successfully for wound treatment, with thrice weekly treatment intervals. In this study, we wished to investigate whether comparably beneficial results can be achieved even with once weekly CAP treatment. PATIENTS AND METHODS: In this randomized clinical pilot study (RCT) patients with therapy-refractory chronic wounds were examined over a maximum of twelve weeks. Groups 1 and 2 were treated with CAP once and twice a week, respectively. Patients in Group 3 received placebo therapy once a week. RESULTS: Wound area decreased significantly by 63.0 % in Group 1 (n = 14, P = 0.005) and by 46.8 % in Group 2 (n = 13, P = 0.007). In Group 3 (n = 10) the wounds grew on average 17.5 % larger. A significant reduction in pain was measured in both CAP-treated groups (Group 1: P = 0.042; Group 2: P = 0.027). Only in Group 2 was there a significant improvement in wound-specific quality of life (P = 0.005). After the 12-week CAP treatment, the reduction in bacterial load compared to the day of study inclusion averaged 50.4 % for Group 1 and 35.0 % for Group 2. CONCLUSIONS: Our RCT shows that treatment with CAP improves various aspects of wound healing in patients with therapy-refractory chronic wounds. The results obtained for once weekly treatment with CAP were not inferior to those obtained when CAP treatment was three times a week. Treatment once a week is also easier and more economical to implement in clinical routine.

Prospective clinical study on the efficacy of bacterial removal with mechanical debridement in and around chronic leg ulcers assessed with fluorescence imaging.

Bacterial colonisation in wounds delays healing, mandating regular bacterial removal through cleaning and debridement. Real-time monitoring of the efficacy of mechanical debridement has recently become possible through fluorescence imaging. Red fluorescence, endogenously produced during bacterial metabolism, indicates regions contaminated with live bacteria (>104 CFU/g). In this prospective study, conventional and fluorescence photos were taken of 25 venous leg ulcers before and after mechanical debridement, without use of antiseptics. Images were digitally segmented into wound bed and the periwound regions (up to 1.5 cm outside bed) and pixel intensity of red fluorescence evaluated to compute bacterial area. Pre-debridement, bacterial fluorescence comprised 10.4% of wound beds and larger percentages of the periwound area (~25%). Average bacterial reduction observed in the wound bed after a single mechanical debridement was 99.4% (p<0.001), yet periwound bacterial reduction was only 64.3%. On average, across bed and periwound, a single mechanical debridement left behind 29% of bacterial fluorescence positive tissue regions. Our results show the substantial effect that safe, inexpensive, mechanical debridement can have on bacterial load of venous ulcers without antiseptic use. Fluorescence imaging can localise bacterial colonised areas and showed persistent periwound bacteria post-debridement. Fluorescence-targeted debridement can be used quickly and easily in daily practice.

Influence of placebo effects on quality of life and wound healing in patients with chronic venous leg ulcers.

INTRODUCTION: Placebo effects are used in the treatment of various medical conditions. To date, there is little scientific data in this regard as it relates to skin diseases in general and hardly any data with respect to wound healing in particular. MATERIAL AND METHODS: In a prospective randomized controlled trial, patients with chronic venous leg ulcers were observed for a period of 14 weeks. The objective was to investigate whether raising patients' expectations with regard to a novel wound treatment might have an effect on wound healing processes as well as wound-related quality of life, anxiety, depression and pain. RESULTS: Overall, 20 patients were included in the trial. They were stratified based on gender and randomized to either the intervention (IG) or the control group (CG). In both groups, the wound area decreased significantly over the course of the observation period. Unlike patients in the CG, those in the IG experienced significant improvement in wound-related quality of life (wound-QoL) in terms of both the overall score and the various subscales. Neither group showed significant changes with respect to pain, anxiety and depression. CONCLUSIONS: Our study is the first to show that - merely by raising patients' expectations for a novel treatment - placebo effects can significantly improve quality of life in patients with chronic venous leg ulcers. In the future, our findings should be integrated into the development of treatment concepts for patients with chronic wounds and should be investigated in larger cohorts.

Pruritus in patients with chronic leg ulcers: A frequent and often neglected problem.

There is a paucity of studies regarding pruritus in patients with chronic leg ulcers. Data were collected using newly developed questionnaires for patients and physicians to evaluate pruritus in individuals with chronic leg ulcers. The results show that a total of 50 patients with chronic leg ulcers were included in this prospective study. Frequent pruritus was observed in 32.0% of the participants, while 36.0% reported occasional pruritus. The average pruritus intensity was 3.5 points (0-10 numeric rating scale [NRS]) and was found to increase with age. Patients experiencing pruritus achieved a higher Wound-quality of life (QoL) score (32.1) as that of patients without pruritus (25.8). Additional dermatological findings around the wounds included xerosis (26.0%), eczema (4.0%), and excoriations (2.0%). Pruritus was reported by all subjects with eczema and 84.6% of those with xerosis. The pruritus lasted significantly longer in women (average 98.4 months) vs men (average 37.5 months). Interestingly, men reported more intense pruritus than women (4.4 vs 2.8). Females reported more frequent use of skin care products than males. In conclusion, the current data show that two-thirds of patients with chronic leg ulcers suffer from moderate intense pruritus. Therefore, pruritus is a frequent and often neglected problem that should be regularly evaluated in all patients with chronic leg ulcers and considered in future therapy concepts.

Metastatic Merkel cell carcinoma and myasthenia gravis: contraindication for therapy with immune checkpoint inhibitors?

BACKGROUND: PD-1/PD-L1 inhibitors are promising approaches for advanced Merkel cell carcinoma (MCC). Nevertheless, these inhibitors bear a high risk for induction of immune-related adverse events (irAEs), particularly flares of preexisting autoimmune diseases. Neurological irAEs of PD-1/PD-L1 inhibitors are possibly underestimated and potentially fatal toxicities. Additionally, exacerbations of preexisting myasthenia gravis (MG) with a high MG-specific-related mortality have been reported. CASE PRESENTATION: A 61-year-old woman with a history of MG since 2005 was treated with azathioprine and pyridostigmine after thymectomy. In March 2016, she was diagnosed with MCC. Six months later the tumor had progressed to stage IV and metastases were detected in lymph nodes and the pancreas. The immunosuppressive therapy was therefore changed to mycophenolatmofetil (MMF) and an immune checkpoint blockade with the PD-1 inhibitor pembrolizumab was initiated in November 2016. Due to MMF-induced liver toxicity, MMF was switched to cyclosporine A (CsA) with normalized liver transaminases six weeks later. After six cycles of pembrolizumab the patient achieved a partial response. Follow up analysis sixty-five weeks later revealed a long-lasting tumor response with a partial remission of pancreatic and inguinal metastases and no flare of MG. CONCLUSIONS: Patients with a preexisting MG can be considered for treatment with immune checkpoint inhibitors if they have a life-threatening cancer and if other effective, long-lasting treatment options are not available. The risks and benefits of therapy should be weighed in a multidisciplinary setting and should be discussed thoroughly with the patient. Exacerbation of underlying MG can be potentially life-threatening and requires close monitoring in collaboration with neuromuscular specialists.

S1 Guidelines - Dermatoses associated with dermal lymphostasis.

The objective of the present S1 guidelines is to present current knowledge about dermatologically relevant diseases associated with localized dermal lymphostasis, thus facilitating their early detection, diagnostic workup, and targeted treatment. Whenever possible, treatment should be based on stage-appropriate and clearly defined algorithms. The numerous issues regarding differential diagnosis and treatment clinicians are confronted with in everyday clinical practice seem to warrant the publication of up-to-date guidelines. These guidelines focus on patients of all age groups and genders exhibiting skin lesions caused by dermal lymphostasis. Specific recommendations are provided with respect to the diagnosis and differential diagnosis of the various clinical manifestations. In this context, comorbid skin diseases such as atopic dermatitis, psoriasis, hidradenitis suppurativa, urticaria, and contact dermatitis will be highlighted, including their treatment and associated specific risks. Several other relevant current guidelines are referenced as regards the distinction from and treatment of common cofactors and comorbid conditions.

S1-Leitlinie - Dermatosen bei dermaler Lymphostase.

Das Ziel dieser S1-Leitlinie ist es, aktuelles Wissen über dermatologisch relevante Krankheitsbilder bei lokal begrenzter dermaler Lymphostase an allen Lokalisationen des Hautorgans zu vermitteln, um diese frühzeitig zu erkennen, diagnostisch zu sichern und gezielt zu behandeln. Wann immer möglich, sollte diese Therapie anhand klar definierter Algorithmen stadiengerecht erfolgen. Die im klinischen Alltag häufig auftauchenden differenzialdiagnostischen und therapeutischen Fragen lassen eine aktuelle Leitlinie notwendig erscheinen. Diese Leitlinie fokussiert auf Patienten jeglichen Alters und Geschlechts mit Hautveränderungen, die im kausalen Zusammenhang mit dermaler Lymphostase stehen. In konkreten Handlungsempfehlungen werden die Diagnostik und Differenzialdiagnostik der verschiedenen Manifestationsformen bei gleichzeitig auftretender dermatologischer Komorbidität wie beispielsweise atopische Dermatitis, Psoriasis vulgaris, Acne inversa, Urtikaria, Kontaktekzeme sowie ihre Therapien unter Berücksichtigung besonderer Risiken veranschaulicht. Für die Abgrenzung und Behandlung häufiger therapierelevanter Kofaktoren und Komorbidität wird auf mehrere andere hierfür relevante aktuelle Leitlinien verwiesen.

Postsurgical Treatment of Split Skin Graft Donor Sites in Dermatological Departments.

The surgical removal of split skin grafts (SSGs) leads to superficial wounds that can be covered with different wound dressings. Currently, international guidelines that recommend a standard treatment of the donor sites are not yet established. We developed a questionnaire to evaluate the treatment of SSG donor sites and sent it to all dermatological departments in Germany. Altogether 78 of the 115 contacted departments in Germany participated in our cross-sectional trial. Our analysis reveals that multiple wound dressings with different frequencies of replacement are used. On an average, complete reepithelialization of the donor site takes 14-21 days. Foams and coated gauzes are used in 73% of all surgical procedures for postsurgical treatment of SSG donor sites. Still, neither a significant faster reepithelialization nor a lower rate of wound healing disorders can be assigned to any of the wound dressings. The results of our study indicate that a large number of wound care products and treatment strategies are currently applied on SSG donor sites in dermatological departments in Germany. The selection of the wound dressing is not based on scientific data but rather on the experience of individual experts.

Sebaceous tumours: more than skin deep.

CLINICAL PRESENTATION: A 77-year-old man presented to our skin cancer centre with various cutaneous tumours occurring in 2006-2017. Histopathology showed a 'hidradenocarcinoma' on the left upper back (2006) and a sebaceous adenoma (figure 1) on the left shoulder (2011). In 2017, he developed a sebaceous carcinoma on the middle upper back, which manifested as a slowly enlarging, asymptomatic nodule. Medical history was significant for curative resection of colorectal cancer in 1988.gutjnl;67/11/1957/F1F1F1Figure 1Clinical appearance of the sebaceous adenoma on the patient's left shoulder in 2011.The most recent lesion was subjected to extensive immunohistochemical assessment. The neoplastic cells were positive for cytokeratin 5/6, cytokeratin 7, cluster of differentiation antigen 10, adipophilin, androgen receptor, epithelial membrane antigen, KI67 antigen, MLH1 and PMS2, but stained negative for gross cystic disease fluid protein 15, prostate-specific antigen, carbohydrate antigen 19/9, CDX2 protein, hepatocyte-specific antigen, carcinoembryonic antigen, cluster of differentiation antigen 117 and cytokeratin 19. Given the variety of histological manifestations of the patient's skin neoplasms, further studies were performed. They revealed positive nuclear expression signals for MLH1, MSH6 and PMS2, whereas MSH2 expression was absent in almost all tumour cells (figure 2). Positron emission tomography (PET)/CT and colonoscopy did not detect any pathological findings. However, molecular genetic analysis of peripheral blood showed a heterozygous deletion of exon 7 of the MSH2 gene. Subsequently, several family members tested positive for MSH2 mutations and underwent genetic counselling.gutjnl;67/11/1957/F2F2F2Figure 2(A-D) Histopathological images of the patient's most recent lesion (diaminobenzidine, original magnification, ×100). The tumour cells demonstrated strong nuclear positivity for MLH1 (A) and PMS2 (B), but were essentially negative for MSH6 (C) and MSH2 (D). QUESTION: What is your diagnosis? DIAGNOSIS: Muir-Torre syndrome (MTS).