Combined inhibition of MEK and Plk1 has synergistic anti-tumor activity in NRAS mutant melanoma

About one third of cancers harbor activating mutations in rat sarcoma viral oncogene homolog (RAS) oncogenes. In melanoma, aberrant neuroblastoma-RAS (NRAS) signaling fuels tumor progression in about 20% of patients. Current therapeutics for NRAS driven malignancies barely impact overall survival. To date, pathway interference downstream of mutant NRAS seems to be the most promising approach. In this study, data revealed that mutant NRAS induced Plk1 expression, and pharmacologic inhibition of Plk1 stabilized the size of NRAS mutant melanoma xenografts. The combination of MEK and Plk1 inhibitors resulted in a significant growth reduction of NRAS mutant melanoma cells in vitro, and regression of xenografted NRAS mutant melanoma in vivo. Independent cell cycle arrest and increased induction of apoptosis underlies the synergistic effect of this combination. Data further suggest that the p53 signaling pathway is of key importance to the observed therapeutic efficacy. This study provides in vitro, in vivo and first mechanistic data, that a MEK/Plk1 inhibitor combination might be a promising treatment approach for patients with NRAS driven melanoma. Since mutant NRAS signaling is similar across different malignancies, this inhibitor combination could also offer a previously unreported treatment modality for NRAS mutant tumors of other cell origins

Updated S2 K guidelines for the management of bullous pemphigoid initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or, most frequently, generalized bullous lesions. A subset of patients only develops excoriations, prurigo-like lesions, and eczematous and/or urticarial erythematous lesions. The disease, which is significantly associated with neurological disorders, has high morbidity and severely impacts the quality of life. OBJECTIVES AND METHODOLOGY The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology sought to update the guidelines for the management of BP based on new clinical information, and new evidence on diagnostic tools and interventions. The recommendations are either evidence-based or rely on expert opinion. The degree of consent among all task force members was included. RESULTS Treatment depends on the severity of BP and patients' comorbidities. High-potency topical corticosteroids are recommended as the mainstay of treatment whenever possible. Oral prednisone at a dose of 0.5 mg/kg/day is a recommended alternative. In case of contraindications or resistance to corticosteroids, immunosuppressive therapies, such as methotrexate, azathioprine, mycophenolate mofetil or mycophenolate acid, may be recommended. The use of doxycycline and dapsone is controversial. They may be recommended, in particular, in patients with contraindications to oral corticosteroids. B-cell-depleting therapy and intravenous immunoglobulins may be considered in treatment-resistant cases. Omalizumab and dupilumab have recently shown promising results. The final version of the guideline was consented to by several patient organizations. CONCLUSIONS The guidelines for the management of BP were updated. They summarize evidence- and expert-based recommendations useful in clinical practice

Clinical Challenges in the Management of Leishmania/HIV Coinfection in a Nonendemic Area: A Case Report

We report on a 37-year-old male HIV-positive patient with generalized cutaneous leishmaniasis undiagnosed for several years. Upon presentation, visceral leishmaniasis was diagnosed in addition to cutaneous manifestation of the disease. Over a period of three years, several different treatment regimens including liposomal amphotericin B, liposomal amphotericin B with miltefosine, liposomal amphotericin B with interferon, and pentamidine combined fluconazole and allopurinol were applied until Leishmania PCR from blood turned negative. This case supports the necessity of multidrug combinational and sequential therapy over a very prolonged period of time in severely immunosuppressed patients infected with Leishmania and highlights the tremendous individual but also economic burden of this disease

Evidence for altered mast cell proliferation and apoptosis in cutaneous mastocytosis

Mastocytosis presents as a focal or generalized increase of mast cells, particularly in the skin, but also in other organs. Activating mutations of KIT (formerly c-kit), the receptor of the mast cell growth factor stem cell factor (SCF), appear to play a key role in the pathogenesis of sporadic adult onset mastocytosis. However, these mutations are not present in childhood-onset and familial mastocytosis and also fail to explain the heterogeneity of adult-onset disease. Other factors such as prolonged survival of mast cells may therefore participate in causing and modulating the pathological increase of mast cells in mastocytosis.; To examine the expression of proliferation and apoptosis markers in the mast cells of cutaneous mastocytosis lesions in order to gain further insight into the pathogenesis of mastocytosis.; Lesional cutaneous biopsies from eight infants with solitary mastocytomas, five children with multiple mastocytomas, 11 children with generalized urticaria pigmentosa, 12 adults with urticaria pigmentosa, and skin from seven normal controls were used in this study. Serial sections were stained with toluidine blue to quantify mast cell numbers and with antibodies against the proliferation marker Ki67 protein, the tumour suppressor protein p53, and the inhibitor of cyclins and cyclin-dependent kinases p21WAF1/CIP1, using the alkaline phosphatase antialkaline phosphatase technique. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling (TUNEL) method was used to assess apoptosis.; Cutaneous mast cell counts were significantly increased in all patient sections, particularly in childhood lesions, and similarly, a small but significant increase of proliferation was found in the lesional mast cells of all patients. Enhanced mast cell numbers and proliferation was associated with a significant decrease of TUNEL staining, particularly in mastocytomas. p53 expression was highly variable, with an overall significant increase in all patient skin mast cells, whereas p21 expression was barely observed at all.; These findings further support the concept that an imbalance of mast cell proliferation and apoptosis is prevalent in mastocytosis lesions that may account in part for the increased focal mast cell accumulation in this condition

Systemic lupus erythematosus. Unusual cutaneous manifestations

Various different mucocutaneous symptoms may affect up to 80 % of systemic lupus erythematosus (SLE) patients. To investigate, various unspecific, but otherwise typical clinical symptoms of skin and mucous membranes that arise in SLE patients other than those defined as SLE criteria such as butterfly rash, chronic cutaneous lupus erythematosus, oral ulcers, and increased photosensitivity. Extensive search of peer-reviewed scientific articles was performed, medical histories of several SLE patients seen in our department were analyzed, and the rare disease courses in three SLE patients are presented. Here we present a variety of unspecific but typical mucocutaneous manifestations in SLE patients: periungual erythema, periungual telangiectasia and periungual splinter hemorrhage, papules on the dorsum of the hands, scaling erythema, sometimes associated with necrosis, especially of the ears, along with complement deficiency, and the bizarre necroses of antiphospholipid syndrome. Furthermore, we show the typical clinico-histological features of neutrophilic urticarial dermatosis, as well as those of bullous SLE and finally a severe course of bacterial sepsis with Neisseria flavescens/macacae. Here we show several unspecific but rather typical mucocutaneous symptoms in lupus patients that are indicative of SLE and thus may lead to an early diagnosis. Also, life-threatening bacterial sepsis may occur with microorganisms that are commonly considered "apathogenic", such as Neisseria flavescens/macacae, which exclusively affect immunosuppressed patients