Left ventricular assist device-associated driveline infections as a specific form of complicated skin and soft tissue infection/acute bacterial skin and skin structure infection - issues and therapeutic options.

PURPOSE OF REVIEW: This review comments on the current guidelines for the treatment of wound infections under definition of acute bacterial skin and skin structure infections (ABSSSI). However, wound infections around a catheter, such as driveline infections of a left ventricular assist device (LVAD) are not specifically listed under this definition in any of the existing guidelines. RECENT FINDINGS: Definitions and classification of LVAD infections may vary across countries, and the existing guidelines and recommendations may not be equally interpreted among physicians, making it unclear if these infections can be considered as ABSSSI. Consequently, the use of certain antibiotics that are approved for ABSSSI may be considered as 'off-label' for LVAD infections, leading to rejection of reimbursement applications in some countries, affecting treatment strategies, and hence, patients' outcomes. However, we believe driveline exit site infections related to LVAD can be included within the ABSSSI definition. SUMMARY: We argue that driveline infections meet the criteria for ABSSSI which would enlarge the 'on-label' antibiotic armamentarium for treating these severe infections, thereby improving the patients' quality of life.

Extracellular vesicles from highly invasive melanoma subpopulations increase the invasive capacity of less invasive melanoma cells through mir-1246-mediated inhibition of CCNG2.

Invasive growth is a critical process in tumor progression, requiring the activation of various molecular processes in tumor cells at the invasive front. Intercellular communication between heterogeneous tumor cells enhances cellular activation and adaptation to specific microenvironments. One mechanism of intercellular communication is the delivery of miRNAs through tumor cell-derived extracellular vesicles (EVs). In this context we have observed that conditioned media from a highly invasive cell subpopulation (BLM-HI) enhances the invasive capacity of the parental cell line (BLM). Therefore, we hypothesized that this complex change of cellular behavior is influenced by EV-transported miRNAs. The treatment of BLM cells with EVs derived from BLM-HI cells resulted in a significantly enhanced invasive capacity, as observed in Matrigel-embedded spheroids and in 2D Boyden chamber assays, with a dose-dependent effect. Conversely, the invasive capacity of BLM cells was reduced when secretion of EVs was inhibited by a sphingomyelinase inhibitor. To investigate the molecular mechanisms behind this effect, we performed next-generation sequencing and identified an enrichment of miR-1246 in these EVs. In functional analyses we demonstrated that both the EV mediated delivery of miR-1246 as well as overexpression contributes to the enhanced invasiveness of BLM cells. We identified a binding site of miR-1246 in the 3'UTR of cyclin G2 (CCNG2) and demonstrated direct binding by a luciferase reporter assay.Increased expression of CCNG2 has been associated with cancer metastasis and poor patient outcomes in other malignancies. Our study demonstrates that intercellular communication contributes to the transfer of properties, such as increased invasive capacity, between heterogeneous melanoma cells via EV-transported miRNAs.

Systemic Activation of Neutrophils by Immune Complexes Is Critical to IgA Vasculitis.

In IgA vasculitis (IgAV) perivascular deposition of IgA1 immune complexes (IgA-ICs) is traditionally considered the fundamental trigger for polymorphonuclear neutrophil (PMN)-mediated damage. We propose that IgA-IC deposition, although mandatory, is not sufficient alone for IgAV. Serum IgA-IC levels and IgA-IC binding to PMNs were quantified in IgAV patients and controls. Activation of PMNs was evaluated by neutrophil extracellular trap (NET) release, adherence, and cytotoxicity assays and in a flow system to mirror conditions at postcapillary venules. In vitro results were related to findings in biopsies and a mouse vasculitis model. During acute IgAV flares we observed elevated serum levels of IgA-ICs and increased IgA-IC binding to circulating PMNs. This IgA-IC binding primed PMNs with consequent lowering of the threshold for NETosis, demonstrated by significantly higher release of NETs from PMNs activated in vitro and PMNs from IgAV patients with flares compared with surface IgA-negative PMNs after flares. Blocking of FcαRI abolished these effects, and complement was not essential. In the flow system, marked NETosis only occurred after PMNs had adhered to activated endothelial cells. IgA-IC binding enhanced this PMN tethering and consequent NET-mediated endothelial cell injury. Reflecting these in vitro findings, we visualized NETs in close proximity to endothelial cells and IgA-coated PMNs in tissue sections of IgAV patients. Inhibition of NET formation and knockout of myeloperoxidase in a murine model of IC vasculitis significantly reduced vessel damage in vivo. Binding of IgA-ICs during active IgAV primes PMNs and promotes vessel injury through increased adhesion of PMNs to the endothelium and enhanced NETosis.

Consensus statement on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxoedema and scleroedema.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present consensus provides an update to the 2017 European Dermatology Forum Guidelines, focusing on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, updated strategies for the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this consensus provides clinicians with an overview of the diagnosis and treatment of scleromyxoedema and scleroedema (of Buschke).

[Interdisciplinary centers for autoimmune diseases in Germany]. / Interdisziplinäre Zentren für Autoimmunerkrankungen in Deutschland.

BACKGROUND: Interdisciplinary medical treatment is required to care for patients with complex autoimmune diseases. Although there are an increasing number of interdisciplinary centers for autoimmune diseases in Germany, they are not yet available throughout the country and the focuses and interdisciplinary structures are not organized according to a generally agreed standard. Furthermore, they are not regularly reflected in the general care structure. THE AIM OF THE WORK: To analyze the care structure using as an example an established center and a clinical case to demonstrate the usefulness of in-house standardized procedures. MATERIAL AND METHODS: In order to determine the status quo regarding interdisciplinary centers for autoimmune diseases in Germany, a university hospital is exemplarily presented for a structural analysis and a case presentation from another center to demonstrate the importance of an interdisciplinary patient care. RESULTS: At the selected center for autoimmune diseases of the university hospital, patients with autoimmune diseases receive interdisciplinary care from experts from various disciplines. The structures are anchored in an organizational chart. The case report demonstrates a standardized diagnostic and therapeutic pathway (standardized operating procedures, SOP) in a patient with systemic sclerosis and lung involvement. DISCUSSION: The article discusses which measures are necessary across disciplines for comprehensive diagnostics and treatment of certain autoimmune diseases, which challenges arise during implementation and which advantages can arise compared to guidelines because, among other things, they can be immediately adapted. The establishment of a national consensus for the structure, necessary settings and implementation into patient care within an interdisciplinary center for autoimmune diseases is desirable.

Intravenous treatment of calcinosis cutis with sodium thiosulfate - A case series.

Calcinosis cutis is defined as the deposition of calcium salts in the skin. The dystrophic form is the most common and usually occurs in chronic inflammatory processes associated with collagenoses. Therapeutic options include surgical excision as well as a few pharmacological treatments. Overall, the evidence for the known therapeutic interventions is very limited and there is a lack of valid recommendations. Intravenous sodium thiosulfate has been used successfully in the treatment of calciphylaxis. In our case series, five patients with dystrophic calcinosis cutis received intravenous sodium thiosulfate for at least six cycles on five consecutive days per month, with single doses of 12.5 g and 25.0 g, respectively. A reduction in the calcified lesions could not be proven with certainty, but stable disease conditions were achieved. Intravenous sodium thiosulfate may counteract the progression of calcinosis cutis. The successful use of epicutaneously applied sodium thiosulfate, as described in the literature, suggests that a higher cutaneous bioavailability can be achieved to exert a lytic effect on calcinosis cutis. This is further supported by the reported efficacy of high-dose sodium thiosulfate in the treatment of calciphylaxis.

Combination therapy for Sneddon syndrome to reduce the incidence of cerebrovascular complications.

BACKGROUND: Sneddon syndrome is an occlusive vasculopathy that presents clinically with generalized livedo racemosa on the skin and transient ischemic attacks, strokes, and cognitive or motor deficits in the central nervous system. Antiplatelet or anticoagulant therapy is recommended. Due to the limited therapeutic efficacy and the resulting serious complications, we propose combination therapy with additional infusion cycles of alprostadil and captopril and report initial long-term results. PATIENTS AND METHODS: We performed a systematic retrospective analysis of all patients with primary Sneddon syndrome who received combination therapy in our clinic between 1995 and 2020. Therapeutic outcomes were evaluated using descriptive statistics compared to historical controls receiving monotherapy. We also analyzed the event rate of complications when combination therapy was discontinued. RESULTS: During the 99.7 patient-years of follow-up, there were no transient ischemic attacks and the stroke rate dropped to 0.02 per patient-year. In comparison, the rates of transient ischemic attacks and strokes in the historical controls ranged from 0.08 to 0.035 per patient-year. After discontinuation of alprostadil therapy, eight events occurred in three patients. CONCLUSIONS: Combination therapy reduces the long-term incidence of ischemic events in patients with primary Sneddon syndrome.

Anti-acid therapy in SSc-associated interstitial lung disease: long-term outcomes from the German Network for Systemic Sclerosis.

OBJECTIVES: Gastroesophageal reflux disease (GERD) occurs frequently in patients with SSc. We investigated whether the presence of GERD and/or the use of anti-acid therapy, specifically proton-pump inhibitors (PPIs), are associated with long-term outcomes, especially in SSc-associated interstitial lung disease (SSc-ILD). METHODS: We retrospectively analysed patients with SSc and SSc-ILD from the German Network for Systemic Sclerosis (DNSS) database (2003 onwards). Kaplan-Meier analysis compared overall survival (OS) and progression-free survival (PFS) in patients with GERD vs without GERD (SSc and SSc-ILD), and PPI vs no PPI use (SSc-ILD only). Progression was defined as a decrease in either percentage predicted forced vital capacity of ≥10% or single-breath diffusing capacity for carbon monoxide of ≥15%, or death. RESULTS: It was found that 2693/4306 (63%) registered patients with SSc and 1204/1931 (62%) with SSc-ILD had GERD. GERD was not associated with decreased OS or decreased PFS in patients in either cohort. In SSc-ILD, PPI use was associated with improved OS vs no PPI use after 1 year [98.4% (95% CI: 97.6, 99.3); n = 760 vs 90.8% (87.9-93.8); n = 290] and after 5 years [91.4% (89.2-93.8); n = 357 vs 70.9% (65.2-77.1); n = 106; P < 0.0001]. PPI use was also associated with improved PFS vs no PPI use after 1 year [95.9% (94.6-97.3); n = 745 vs 86.4% (82.9-90.1); n = 278] and after 5 years [66.8% (63.0-70.8); n = 286 vs 45.9% (39.6-53.2); n = 69; P < 0.0001]. CONCLUSION: GERD had no effect on survival in SSc or SSc-ILD. PPIs improved survival in patients with SSc-ILD. Controlled, prospective trials are needed to confirm this finding.

Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in Melanoma.

Activating BRAF mutations occurs in 50-60% of malignant melanomas. Although initially treatable, the development of resistance to BRAF-targeted therapies (BRAFi) is a major challenge and limits their efficacy. We have previously shown that the BRAFV600E signaling pathway mediates the expression of EZH2, an epigenetic regulator related to melanoma progression and worse overall survival. Therefore, we wondered whether inhibition of EZH2 would be a way to overcome resistance to vemurafenib. We found that the addition of an EZH2 inhibitor to vemurafenib improved the response of melanoma cells resistant to BRAFi with regard to decreased viability, cell-cycle arrest and increased apoptosis. By next-generation sequencing, we revealed that the combined inhibition of BRAF and EZH2 dramatically suppresses pathways of mitosis and cell cycle. This effect was linked to the downregulation of Polo-kinase 1 (PLK1), a key regulator of cell cycle and proliferation. Subsequently, when we inhibited PLK1, we found decreased cell viability of melanoma cells resistant to BRAFi. When we inhibited both BRAF and PLK1, we achieved an improved response of BRAFi-resistant melanoma cells, which was comparable to the combined inhibition of BRAF and EZH2. These results thus reveal that targeting EZH2 or its downstream targets, such as PLK1, in combination with BRAF inhibitors are potential novel therapeutic options in melanomas with BRAF mutations.

S1 guideline: Differential diagnosis of acute and chronic redness of the lower legs.

Acute or chronic redness of the lower leg is a frequent reason for visits to clinics and practices. The differential diagnosis is often challenging. The aim of this guideline is to define criteria and procedures for the differential diagnosis of acute or chronic, unilateral or bilateral redness of the lower leg. Finding the correct diagnosis is essential for selecting an appropriate treatment and can help to reduce the inappropriate use of antibiotics. The guideline committee identified the most relevant differential diagnoses: 1. erysipelas, 2. stasis dermatitis, 3. hyperergic ictus reaction, 4. superficial and deep vein thrombosis, 5. gout, 6. chronic allergic contact dermatitis, and 7. acute toxic or allergic contact dermatitis. Algorithms/diagnostic pathways, each of which can be broken down into anamnesis, clinical examination, and diagnostics, have been developed for these seven diagnoses. In addition, the guideline group identified over 40 other relevant diagnoses and summarized their characteristics in a table to facilitate further differential diagnoses.

Low-dose total skin electron beam therapy plus oral bexarotene maintenance therapy for cutaneous T-cell lymphoma.

BACKGROUND: Total skin electron beam therapy (TSEBT) combined with systemic therapy or maintenance treatment is a reasonable approach to enhance the remission rate and duration in mycosis fungoides (MF) and Sézary syndrome (SS). This study assesses the efficacy of oral bexarotene therapy after low-dose TSEBT for patients with MF and SS. METHODS: In this prospective observational study, we recruited MF/SS patients for treatment with low-dose total skin electron beam therapy (TSEBT) with or without bexarotene therapy to describe outcomes and toxicities. RESULTS: Forty-six subjects with MF or SS underwent TSEBT between 2016 and 2021 at our institute. Following TSEBT, 27 patients (59 %) received oral bexarotene treatment. The median follow-up was 13 months. The overall response rate (ORR) for the cohort was 85 %. The response rate was significantly higher with combined modality (CM) than TSEBT alone (96 % vs. 68 %, p = 0.03). Median progression-free survival (PFS) for the CM was 17 months versus five months following TSEBT alone (p = 0.001). One patient (4 %) in the retinoid group discontinued the bexarotene therapy because of adverse events. The administration of bexarotene therapy did not increase radiation-related toxicities. CONCLUSIONS: Response rate and progression-free survival might be improved with TSEBT in combination with oral bexarotene compared to TSEBT alone.

Ocular syphilis - a case series of four patients.

Ocular manifestations of syphilis with visual impairment symptoms may occur already at the stage of secondary syphilis. They may also be the only manifestation of syphilis and mimic other diseases of the eye. Therefore, in all patients with uveitis, optic neuritis, optic atrophy, acute ocular muscle paresis, or loss of visual acuity, syphilis infection should be ruled out, even if the medical history does not initially raise suspicion. Ocular involvement should be treated as neurosyphilis. Delayed diagnosis and inadequate therapy are often associated with irreversible consequences for the affected patient. As with any syphilis infection, HIV infection should be considered and excluded, especially in the case of ocular manifestations.

Diagnostic Value of Laboratory Parameters for Distinguishing Between Herpes Zoster and Bacterial Superficial Skin and Soft Tissue Infections.

Clinical differentiation between herpes zoster and bacterial superficial skin and soft tissue infections of the face can be difficult. In addition, diagnosis can be complicated by bacterial superinfection of lesional herpes zoster. The aim of this study was to determine whether inflammatory parameters, such as C-reactive protein (CRP) and blood counts, might be reliable biomarkers to distinguish between skin and soft tissue infections and herpes zoster when the face is infected. The study data (multivariate analysis and area under the curve) identified CRP (0.880) and leukocytes (0.730) together as the parameters that best discriminate between skin and soft tissue infections and herpes zoster. A CRP threshold ≥ 2.05 mg/dl indicated a diagnosis of skin and soft tissue infection with a sensitivity of 80% and specificity of 83.8%. For leukocytes ≥ 7.3×109/l, diagnosis of skin and soft tissue infection had a sensitivity of 75% and specificity of 67.6%. Thus, when differential diagnosis is difficult, CRP and leukocytes should be determined, while parameters such as neutrophils or immature granulocytes do not add diagnostic value.

Importance of microRNAs in Skin Oncogenesis and Their Suitability as Agents and Targets for Topical Therapy.

Skin cancer is the most common cancer worldwide, with rapidly increasing incidence and consistent mortality. Skin cancer encompasses melanoma and non-melanoma skin cancer, which in turn is mainly divided into cutaneous squamous cell carcinoma and basal cell carcinoma. Small noncoding micro-RNAs (miRNAs) regulate protein expression after transcription and play a role in the development and progression of skin cancer. Deregulated expression of miRNAs in skin cancer is associated with cell proliferation, angiogenesis, metastasis, apoptosis, immune response, and drug resistance. Specific patterns of miRNAs in specific skin cancer types can be used as diagnostic markers. For therapeutic purposes, both miRNA and chemically modified variants thereof as well as miRNA antagonists (antagomiRs) or RNA inhibitors may be applied topically. Due to their specific physicochemical properties, physical or chemical diffusion promoters are used with varying degrees of success. There is no question by now that such preparations have a high potential for the treatment of epithelial skin tumors in particular.

Update on dermatomyositis in adults.

Dermatomyositis (DM) in adults has a prevalence of 6-7 per 100,000 population per year. This dedicated compact overview was prepared due to an increasing incidence as well as an often underestimated systemic involvement and new developments in myositis-specific antibodies (MSA). The spectrum of clinical dermatological and systemic symptoms is described. Related diagnostic procedures are depicted, and therapeutic regimens based on the German S2k guidelines and the current literature are presented. The urgency of an early diagnosis is emphasized as about 30 % of patients with DM manifest a tumor. Etiopathology is often associated with pulmonary fibrosis, and inflammation of myositis can cause irreversible muscle damage. Clinical signs and correct interpretation of serological markers can deliver valuable information on the extent of DM, and provide an indication for further diagnostic procedures, prognosis and choice of therapy.

S2k guidelines for the diagnosis and treatment of herpes zoster and postherpetic neuralgia.

The present guidelines are aimed at residents and board-certified specialists in the fields of dermatology, ophthalmology, ENT, pediatrics, neurology, virology, infectious diseases, anesthesiology, general medicine and any other medical specialties involved in the management of patients with herpes zoster. They are also intended as a guide for policymakers and health insurance funds. The guidelines were developed by dermatologists, virologists, ophthalmologists, ENT physicians, neurologists, pediatricians and anesthesiologists/pain specialists using a formal consensus process (S2k). Readers are provided with an overview of the clinical and molecular diagnostic workup, including antigen detection, antibody tests and viral culture. Special diagnostic situations and complicated disease courses are discussed. The authors address general and special aspects of antiviral therapy for herpes zoster and postherpetic neuralgia. Furthermore, the guidelines provide detailed information on pain management including a schematic overview, and they conclude with a discussion of topical treatment options.

COVID-19 and implications for dermatological and allergological diseases.

COVID-19, caused by the coronavirus SARS-CoV-2, has become pandemic. A further level of complexity opens up as soon as we look at diseases whose pathogenesis and therapy involve different immunological signaling pathways, which are potentially affected by COVID-19. Medical treatments must often be reassessed and questioned in connection with this infection. This article summarizes the current knowledge of COVID-19 in the light of major dermatological and allergological diseases. It identifies medical areas lacking sufficient data and draws conclusions for the management of our patients during the pandemic. We focus on common chronic inflammatory skin diseases with complex immunological pathogenesis: psoriasis, eczema including atopic dermatitis, type I allergies, autoimmune blistering and inflammatory connective tissue diseases, vasculitis, and skin cancers. Since several other inflammatory skin diseases display related or comparable immunological reactions, clustering of the various inflammatory dermatoses into different disease patterns may help with therapeutic decisions. Thus, following these patterns of skin inflammation, our review may supply treatment recommendations and thoughtful considerations for disease management even beyond the most frequent diseases discussed here.

An update on Peginterferon beta-1a Management in Multiple Sclerosis: results from an interdisciplinary Board of German and Austrian Neurologists and dermatologists.

BACKGROUND: Interferon (IFN) beta drugs have been approved for the treatment of relapsing forms of multiple sclerosis (RMS) for more than 20 years and are considered to offer a favourable benefit-risk profile. In July 2014, subcutaneous (SC) peginterferon beta-1a 125 µg dosed every 2 weeks, a pegylated form of interferon beta-1a, was approved by the EMA for the treatment of adult patients with RRMS and in August 2014 by the FDA for RMS. Peginterferon beta-1a shows a prolonged half-life and increased systemic drug exposure resulting in a reduced dosing frequency compared to other available interferon-based products in MS. In the Phase 3 ADVANCE trial peginterferon beta-1a demonstrated significant positive effects on clinical and MRI outcome measures versus placebo after one year. Furthermore, in the ATTAIN extension study, sustained efficacy with long-term treatment for nearly 6 years was shown. MAIN TEXT: In July 2016, an interdisciplinary panel of German and Austrian experts convened to discuss the management of side effects associated with peginterferon beta-1a and other interferon beta-based treatments in MS in daily practice. The panel was composed of experts from university hospitals and private clinics comprised of neurologists, dermatologists, and an MS nurse. In this paper we report recommendations regarding best practices for adverse event management, focussing on peginterferon beta-1a. Injection site reactions (ISRs) and influenza-like illness are the most common adverse effects of interferon beta therapies and can present a burden for MS patients leading to non-adherence and discontinuation of therapy. Peginterferon beta-1a shows improved pharmacological properties. In clinical trials, the adverse event (AE) profile of peginterferon beta-1a was similar to other interferon beta formulations. The most common AEs were mild to moderate ISRs, influenza-like illness, pyrexia, and headache. Current information on the underlying cause of skin reactions associated with SC interferon treatment, and the management strategies for these AEs are limited. In pivotal trials, ISRs were mainly characterized and classified by neurologists, while dermatologists were only rarely consulted. CONCLUSIONS: This report addresses expert recommendations on the management of most relevant adverse effects related to peginterferon beta-1a and other interferon betas, based on literature and interdisciplinary experience.

Galactose-deficient IgA1 in skin and serum from patients with skin-limited and systemic IgA vasculitis.

BACKGROUND: IgA vasculitis (IgAV) encompasses a systemic form involving kidneys, gut, skin, or joints, and a skin-limited form. One characteristic feature of systemic IgAV is deposition of galactose-deficient IgA1 (GD-IgA1) in kidneys (as in IgA nephropathy). The relevance of GD-IgA1 for cutaneous vasculitis is unknown. OBJECTIVE: We investigated whether GD-IgA1 is deposited perivascularly in systemic and also skin-limited IgAV and whether its serum levels differ between both forms. METHODS: In a case-control study, deposition of GD-IgA1 was analyzed immunohistochemically by KM55 antibody in skin biopsy specimens from 12 patients with skin-limited IgAV and 4 with systemic IgAV. GD-IgA1 levels were compared by enzyme-linked immunosorbent assay in sera from 15 patients each with skin-limited and systemic IgAV and from 11 healthy individuals. RESULTS: All biopsy samples from systemic IgAV, and also from skin-limited IgAV, revealed perivascular GD-IgA1 deposition. The average GD-IgA1 concentration in serum was significantly higher in systemic IgAV than in skin-limited IgAV, despite overlap between the groups. LIMITATIONS: Although high GD-IgA1 levels may be predictive of systemic IgAV, patient numbers were too low to determine cutoff values for systemic versus skin-limited IgAV. CONCLUSION: Perivascular GD-IgA1 deposition is a prerequisite for systemic and skin-limited IgAV; however, high GD-IgA1 levels in some patients with systemic IgAV suggest a dose-dependent effect of GD-IgA1 in IgAV.