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).

Anaphylactic reaction to carboplatin diagnosed by skin testing-a reliable tool in platinum-based immediate-type hypersensitivity reactions.

Immediate-type hypersensitivity reactions (IHRs) to carboplatin (CA) are most commonly reported in ovarian cancer patients. A 54-year-old woman with stage IV melanoma suffering from metastasis in the entire right lower extremity was presented to our allergy outpatient clinic for diagnostic work-up due to an anaphylactic reaction with palmoplantar erythema, conjunctivitis along with facial erythema, and an incipient decrease in blood pressure during a chemotherapy regimen with dacarbazine and carboplatin upon re-administration. A subsequently carried out allergological work-up with skin testing (ST) revealed CA to be the culprit drug, whereas cisplatin (CI) was confirmed to be a safe alternative for the patient for following treatments. Here, we report a case of an IHR to carboplatin in a melanoma patient, with CI serving as a safe alternative diagnosed by skin testing.

Multi-objective Optimization of water resources in real time based on integration of NSGA-II and support vector machines.

One of the management strategies of water resources systems is the combination of simulation and optimization models to achieve the optimal policies of reservoir operation in the form of specific optimization. This study utilizes an integration of the NSGA-II multi-objective algorithm and WEAP simulator model so that the first objective is to maximize the reliability of providing the needs in front of the second goal, i.e., to minimize the drawdown the water table at the end of the operation time. The dam rule curve or the amount of released volume from the reservoir is optimized to supply downstream uses in these conditions. However, in certain optimizations, the optimal solutions cannot be generalized to other possible inputs to the reservoir, and if the inflow to the reservoirs changes, the obtained optimal solutions are no longer efficient and the system must be re-optimized in the form of an optimizer algorithm. Therefore, to solve this problem, a new method is extended on the basis of the combination of the support vector machine and NSGA-II algorithm for optimal real-time operation of the system. The results demonstrate that the average error rate of optimal rules derived from support vector machines is less than 2.5% compared to the output of the NSGA-II algorithm in the verification step, which indicates the efficiency of this method in predicting the optimal pattern of the dam rule curve in real time. In this structure, based on the inflow to the reservoir, the volume of water storage in the reservoir and changes in the reservoir storage (at the beginning of the month) and the downstream demands of the current month, the optimal release amount can be achieved in real time. Therefore, the developed support vector machine has the ability to provide optimal operation policies based on new data of the inflow to the dam in a way that allows us optimally manage the system in real time.

Short Term and Long-Term Efficacy of Calcipotriene/ Betamethasone Dipropionate Foam Combination.

Psoriasis is a well-known chronic disease characterized by the development of erythematous, indurated, scaly, pruritic plaques on the skin with cycles of remission and symptom flare-ups. The management of patients with chronic plaque psoriasis has been more challenging since the Covid-19 pandemic as health care professionals have had to adapt to remote consultations for some patients, and patients have had to adapt to the changing health landscape. The rapid resolution of psoriasis symptoms especially those with a substantial impact on quality of life can improve patient satisfaction and adherence, making it an important factor in successful treatment. Cal/BD foam contributes to improved patient adherence and treatment outcome through its rapid action and superior efficacy versus Cal or BD monotherapy, Cal/BD ointment and gel and clobetasol cream in the short-term flare treatment of psoriasis. Moreover, the benefits of proactive long-term management of psoriasis compared to reactive management and its favourable safety profile are higher efficacy and a better health-related quality of life. Cal/BD foam should be considered an effective topical treatment for short-term flare treatment and long-term control of adult psoriatic patients.

Long-term topical management of psoriasis: the road ahead.

Topical therapies have been available for the treatment of psoriasis for several decades. Despite this and the availability of several types of topicals, with varying potency, and numerous vehicles of administration, the majority of clinical data and guidance is on short-term use in the management of psoriasis. The aim of this manuscript is to review the unmet needs that exist in the long-term management of psoriasis and provide the dermatology community with an understanding that a treatment regimen with topical therapies could be the best treatment option at least for some phases of this chronic relapsing disease. We present a 'call to action' on the need for clinical alignment on terminology in the field and recommend the term 'long-term management' be adopted as the most appropriate in the context of this manuscript. This expert opinion report provides a detailed review of the limited evidence available regarding long-term use of topical therapies for the management of psoriasis, alongside our key considerations and recommendations to assist dermatologists with the implementation of topicals as part of long-term management strategies. Long-term management should be considered mandatory to ensure patients receive appropriate proactive treatment which may help optimize adherence and long-term outcomes.

The emerging role of mast cells in skin cancers: involved cellular and molecular mechanisms.

Skin cancers are the most common cancers worldwide. They can be divided into nonmelanoma skin cancers (NMSC) including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and less common lymphomas and merkel cell carcinoma, and melanomas. Melanomas comprise less than 5% of skin cancer rate but are responsible for more than 90% of skin cancer death. Mast cells (MCs) are multifunctional cells that play an important role in inflammatory and allergic reactions. They attract other key players of the immune system by releasing cytokines. Healthy human skin comprises MCs under physiological status, and the number can increase under certain conditions including skin malignancies postulating their possible role in pathogenesis of and immunity against skin cancers. MCs respond to cytokines released by tumor stromal cells, release mediators (including histamine and tryptase), and induce the neovascularization, degradation of extracellular matrix (ECM), and induce mitogenesis. However, MCs may use molecular mechanisms to exert immunosuppressive activity including releasing complement C3, lower expression of CD40L, and overexpression of enzymes with vitamin D3 metabolizing activity including CYP27A1 and CYP27B1. This review summarizes the current knowledge on the role of MCs in pathogenesis and immunity against skin cancers.

Topical Treatment of Psoriasis Vulgaris: The Swiss Treatment Pathway.

Topical treatment is crucial for the successful management of plaque psoriasis. Topicals are used either as a stand-alone therapy for mild psoriasis or else in combination with UV or systemic treatment for moderate-to-severe disease. For the choice of a suitable topical treatment, the formulation matters and not just the active substances. This expert opinion paper was developed via a non-structured consensus process by Swiss dermatologists in hospitals and private practices to illustrate the current treatment options to general practitioners and dermatologists in Switzerland. Defining treatment goals together with the patient is crucial and increases treatment adherence. Patients' personal preferences and pre-existing experiences should be considered and their satisfaction with treatment and outcome regularly assessed. During the induction phase of "classical" mild-to-moderate psoriasis, the fixed combination of topical calcipotriol (Cal) 50 µg/g and betamethasone dipropionate (BD) 0.5 mg/g once daily is frequently used for 4-8 weeks. During the maintenance phase, a twice weekly (proactive) management has proved to reduce the risk of relapse. Of the fixed combinations, Cal/BD aerosol foam is the most effective formulation. However, the individual choice of formulation should be based on a patient's preference and the location of the psoriatic plaques. Tailored recommendations are given for the topical management of specific areas (scalp, facial, intertriginous/genital, or palmoplantar lesions), certain symptoms (hyperkeratotic or hyperinflammatory forms) as well as during pregnancy or a period of breastfeeding. As concomitant basic therapy, several emollients are recommended. If topical treatment alone does not appear to be sufficient, the regimen should be escalated according to the Swiss S1-guideline for the systemic treatment of psoriasis.

The attentive focus on T cell-mediated autoimmune pathogenesis of psoriasis, lichen planus and vitiligo.

T cell-mediated autoimmune skin diseases develop as a result of the aberrant immune response to the skin cells with T cells playing a central role. These chronic inflammatory skin diseases encompass various types including psoriasis, lichen planus and vitiligo. These diseases show similarities in their immune-pathophysiology. In the last decade, immunomodulating agents have been very successful in the management of these diseases thanks to a better understanding of the pathophysiology. In this review, we will discuss the immunopathogenic mechanisms and highlight the role of T lymphocytes in psoriasis, lichen planus and vitiligo. This study could provide new insights into a better understanding of targeted therapeutic pathways and biological therapies.

General practice recommendations for the topical treatment of psoriasis: a modified-Delphi approach.

BACKGROUND: Although GPs are usually the first port of call for patients with psoriasis, there is a lack of consistent and up-to-date clinical recommendations for interventions for patients with mild-to-moderate disease. AIM: To provide practical recommendations for GPs to optimise psoriasis treatment with topical therapies in four key areas: patient identification; treatment decision making with topical theory; topical treatment outcomes; and optimising patient adherence. DESIGN & SETTING: A consensus-seeking programme (modified-Delphi approach) was undertaken to assess the literature and develop recommendations for GPs, based on evidence and expert opinion. METHOD: Three dermatologists compiled 47 questions that were subsequently ranked and refined according to clinical relevance or importance using an online survey. Thereafter, 19 dermatologists from different European countries developed statements and clinical recommendations for the top seven ranked topical treatment and GP-relevant questions based on literature research and clinical experience. The final recommendations were based on 100% agreement among a final panel of seven experts. RESULTS: The clinical effectiveness, fast onset of action, tolerability, cosmetic acceptability, and practicability of topical therapy, in addition to good physician-patient communication, are important for optimising patient adherence and maximising efficacy. Topical treatments combining corticosteroids and vitamin D analogues (administered as fixed combination) are well-established first-line treatments in mild-to-moderate psoriasis. CONCLUSION: Simple but detailed practical guidance is provided, which is formed from evidence and expert clinical recommendations, to assist GPs with the optimal use of topical agents based on efficacy, tolerability, disease severity, site of psoriasis, patient lifestyle and preferences, and intended duration of treatment.

Calcipotriol/betamethasone dipropionate aerosol foam in the treatment of psoriasis: new perspectives for the use of an innovative topical treatment from real-life experience.

The fixed-dose combination of calcipotriol/betamethasone dipropionate (Cal/BD foam) in aerosol foam formulation is approved for the treatment of plaque psoriasis, and showed prompt onset of action, persistent efficacy and safety both in clinical trials and in real-life studies. The use of Cal/BD foam and its future perspectives of use were discussed during the symposium "Go beyond with topical treatment in psoriasis", held at the 2019 World Congress of Dermatology. We herein present the key topics of the symposium, namely the importance of Cal/BD foam in overcoming poor adherence, the possibility of a proactive (long-term) management of psoriasis and its potential role beyond mild psoriasis. Furthermore, proper adherence to treatment is crucial to achieve optimal clinical outcomes. In clinical trials and real-life experiences, Cal/BD foam has proven to have a fast onset of action and a good benefit/risk ratio due to increased efficacy and similar safety profile compared with other Cal/BD formulations. Given its chronic nature, psoriasis requires a long-term management, also due to the presence of underlying 'silent' inflammation that persists beyond resolution of flares. Cal/BD foam appears a favorable treatment for long-term management, and a specific trial is ongoing to investigate this new proactive approach. Lastly, evidence both from clinical studies and real-life experiences supports the use of Cal/BD foam in patients with moderate-to-severe disease, and this approach also showed greater effectiveness over some non-biologic systemic treatments. Therefore, Cal/BD foam may be considered as the new gold standard in topical therapy for patients with plaque psoriasis.

Calcipotriol/betamethasone dipropionate aerosol foam for the treatment of psoriasis vulgaris: case series and review of the literature.

An aerosol foam formulation of a once-daily, fixed-dose combination of a synthetic vitamin D3 analog/synthetic corticosteroid (calcipotriol [Cal] 50 µg/g and betamethasone dipropionate [BD] 0.5 mg/g) has recently been introduced for the topical treatment of plaque psoriasis in adults. Data from several sources - randomized controlled trials, case reports (as highlighted in this review), and real-world evidence (RWE) - underscore the considerable and rapid clinical response, effectiveness, and favorable safety and tolerability of Cal/BD aerosol foam in mild-to-moderate psoriatic patients previously treated with class 3 or 4 topical corticosteroids, in patients unsatisfied with ongoing phototherapy in combination with topical therapy and in patients with moderate-to-severe psoriasis. In addition, our case series, considered together with other RWE, highlights that Cal/BD aerosol foam is more effective and with greater levels of patient preference and acceptability than comparator preparations. Thus, Cal/BD aerosol foam offers several treatment advantages, including relief of itch, and is an appropriate first-line topical therapy for consideration in patients with psoriasis of any severity.

Implementation and evaluation of a rehabilitation concept in a patient suffering from Scleredema Adultorum Buschke: a case report.

PURPOSE: Scleredema Adultorum Buschke is a disorder manifesting indurations of the skin mostly followed by musculoskeletal impairment. Data regarding this fact are seldom found and documentation of functional outcome of physical therapies and modalities related to Scleredema Adultorum Buschke is fragmentary. The aim of this case report is to demonstrate and to document an effective concept of rehabilitation in a patient suffering from Scleredema Adultorum Buschke. METHODS: A treatment plan was developed containing therapeutic ultrasound, manual lymphatic drainage, and physiotherapy. Assessments were performed at baseline and after therapy. RESULTS: Treatment by physical therapies of presented patient resulted in an improved functionality. Five out of eight Short Form-36 questionaire sections increased in terms of enhanced general health and level of activity. CONCLUSIONS: Musculoskeletal impairment in a patient suffering from Scleredema Adultorum Buschke can be reduced by a multimodal concept of rehabilitation. Implications for Rehabilitation Rehabilitation professional should suspect scleredema in patients with diffuse skin thickening where hands and feet are spared Essential reactivating physical activity should be supported by skin softening physical modalities irrespective of etiology or primary therapy. There is a need for functional outcome measures and documentation in the rehabilitation of Scleredema Adultorum Buschke.

Tumor-associated B-cells induce tumor heterogeneity and therapy resistance.

In melanoma, therapies with inhibitors to oncogenic BRAFV600E are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3. Consistently, resistance of melanomas to BRAF and/or MEK inhibitors is associated with increased CD20 and IGF-1 transcript levels in tumors and IGF-1 expression in tumor-associated B cells. Furthermore, first clinical data from a pilot trial in therapy-resistant metastatic melanoma patients show anti-tumor activity through B-cell depletion by anti-CD20 antibody. Our findings establish a mechanism of acquired therapy resistance through tumor-associated B cells with important clinical implications.Resistance to BRAFV600E inhibitors often occurs in melanoma patients. Here, the authors describe a potential mechanism of acquired drug resistance mediated by tumor-associated B cells-derived IGF-1.

Identification of proteins derived from Listeria monocytogenes inducing human dendritic cell maturation.

Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that can promote antitumor immunity when pulsed with tumor antigens and then matured by stimulatory agents. Despite apparent progress in DC-based cancer immunotherapy, some discrepancies were reported in generating potent DCs. Listeria monocytogenes as an intracellular microorganism is able to effectively activate DCs through engaging pattern-recognition receptors (PRRs). This study aimed to find the most potent components derived from L. monocytogenes inducing DC maturation. The preliminary results demonstrated that the ability of protein components is higher than DNA components to promote DC maturation and activation. Protein lysate fractionation demonstrated that fraction 2 HIC (obtained by hydrophobic interaction chromatography) was able to efficiently mature DCs. F2HIC-matured DCs are able to induce allogeneic CD8(+) T cells proliferation better than LPS-matured DCs and induce IFN-γ producing CD8(+) T cells. Mass spectrometry results showed that F2HIC contains 109 proteins. Based on the bioinformatics analysis for these 109 proteins, elongation factor Tu (EF-Tu) could be considered as a PRR ligand for stimulating DC maturation.

RanBP3 Regulates Melanoma Cell Proliferation via Selective Control of Nuclear Export.

Chromosome region maintenance 1-mediated nucleocytoplasmic transport has been shown as a potential anticancer target in various malignancies. However, the role of the most characterized chromosome region maintenance 1 cofactor ran binding protein 3 (RanBP3) in cancer cell biology has never been investigated. Utilizing a loss-of-function experimental setting in a vast collection of genetically varied melanoma cell lines, we observed the requirement of RanBP3 in melanoma cell proliferation and survival. Mechanistically, we suggest the reinstatement of transforming growth factor-ß (TGF-ß)-Smad2/3-p21(Cip1) tumor-suppressor axis as part of the RanBP3 silencing-associated antiproliferative program. Employing extensive nuclear export sequence analyses and immunofluorescence-based protein localization studies, we further present evidence suggesting the requirement of RanBP3 function for the nuclear exit of the weak nuclear export sequence-harboring extracellular signal-regulated kinase protein, although it is dispensable for general CRM1-mediated nuclear export of strong nuclear export sequence-harboring cargoes. Rendering mechanistic support to RanBP3 silencing-mediated apoptosis, consequent to extracellular signal-regulated kinase nuclear entrapment, we observed increased levels of cytoplasmically restricted nonphosphorylated/active proapoptotic Bcl-2-antagonist of cell death (BAD) protein. Last, we present evidence suggesting the frequently activated mitogen-activated protein kinase signaling in melanoma as a potential founding basis for a deregulated post-translational control of RanBP3 activity. Collectively, the presented data suggest RanBP3 as a potential target for therapeutic intervention in human melanoma.

Case report: spontaneous rupture of spleen in patient with Plasmodium ovale malaria.

Malaria may lead to spontaneous splenic rupture as a rare but potentially lethal complication. Most frequently, this has been reported in patients infected with Plasmodium falciparum and Plasmodium vivax, while other parasitic agents are less likely to be the cause.We report a 29-year-old British Caucasian, who after returning from a business trip in Democratic Republic Congo was diagnosed with tertian malaria caused by Plasmodium ovale.During his in-patient stay, the patient suffered a splenic rupture requiring immediate surgical intervention and splenectomy. Following this surgical intervention, there was an uneventful recovery, and the patient was discharged in a good general condition.

Malignant syphilis in a HIV infected patient.

We present a 47 year old female white HIV-1 infected patient with multiple painless rupioid skin lesions, a CD4 count of 155 cells/mm3, positive syphilis serology and a histopathology conspicuous for malignant syphilis. She could be successfully treated with Benzathine-Benzylpenicillin (Retarpen®) 2,4 Mega I.E., 3x intramuscularly in weekly intervals.