Synergistic Bcl-2 inhibition by ABT-737 and cyclosporine A

Survival of lymphocytes and melanocyte stem cells critically depends on B cell lymphoma 2 (Bcl-2). In T lymphocytes, a basal calcineurin activity maintains Bcl-2 expression in naïve cells, and the activation of the calcineurin pathway orchestrates the regulation of the intrinsic apoptosis pathway after antigen recognition. Therefore, calcineurin inhibitors might potentiate the pro-apoptotic effect of pharmacological Bcl-2 inhibitors on lymphatic cells. In vitro, a reduced Bcl-2 expression in lymphocytes exposed to calcineurin inhibitors increased their sensitivity to the small molecule Bcl-2 inhibitor ABT-737. This correlated with an augmented pro-apoptotic activity of ABT-737 on lymphocytes in combination with cyclosporine A in naïve mice in vivo. Interestingly, similar processes were observed in melanocytes. ABT-737 induced a fur depigmentation at the site of injection, and this effect was expanded to a generalized depigmentation in combination with cyclosporine A. Thus, inhibiting calcineurin increases the pro-apoptotic potency of ABT-737 in cells depending on Bcl-2 for survival. The increased efficacy of Bcl-2 inhibitors in combination with cyclosporine A might be relevant to exploit their anti-neoplastic and immuno-modulatory propertie

An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition

Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug tolerance. Antagonizing these adaptive responses could improve drug effects, thereby thwarting the emergence of acquired resistance. In this study, we reveal that inflammatory niches consisting of tumor-associated macrophages and fibroblasts contribute to treatment tolerance through a cytokine-signaling network that involves macrophage-derived IL-1β and fibroblast-derived CXCR2 ligands. Fibroblasts require IL-1β to produce CXCR2 ligands, and loss of host IL-1R signaling in vivo reduces melanoma growth. In tumors from patients on treatment, signaling from inflammatory niches is amplified in the presence of MAPK inhibitors. Signaling from inflammatory niches counteracts combined BRAF/MEK (MAPK/extracellular signal–regulated kinase kinase) inhibitor treatment, and consequently, inhibiting IL-1R or CXCR2 signaling in vivo enhanced the efficacy of MAPK inhibitors. We conclude that melanoma inflammatory niches adapt to and confer drug tolerance toward BRAF and MEK inhibitors early during treatmen

Cervicofacial Botryomycosis: Is Atopic Dermatitis a Predisposing Factor?

Background: Botryomycosis is a rare infectious disease which usually affects the skin. The low virulence of the bacteria tending to form grains and the immune status of the host are important factors in the development of the disease. Methods: We report a case of cervicofacial botryomycosis and review the current literature. Results: A 47-year-old male with a long history of moderate-to-severe atopic dermatitis presented with painful and suppurative nodules of the head and neck. A skin biopsy revealed granules consisting of Gram-positive bacterial colonies in a blossom-like assembly in the center and an eosinophilic rim in the periphery, which are pathognomonic features of botryomycosis. The lesions responded well to systemic antibiotics; however, they rapidly relapsed upon cessation of the treatment. Conclusions: We highlight the well-defined histologic features and recall an almost forgotten disease. We review common predisposing conditions and present evidence that atopic dermatitis might be an additional predisposing factor. © 2014 S. Karger AG, Base

Clinical observation of panniculitis in two patients with BRAF-mutated metastatic melanoma treated with a combination of a BRAF inhibitor and a MEK inhibitor

BACKGROUND Treatment with selective BRAF or MEK inhibitors is frequently associated with cutaneous toxicities, including squamous cell carcinoma (SCC), papillomas and rash. These cutaneous adverse effects are typically observed at a lower incidence during combined BRAF and MEK inhibitor therapy. PATIENTS AND METHODS Two male patients with stage IV metastatic BRAF-mutated melanoma were treated with a combination of a selective BRAF inhibitor and a selective MEK inhibitor (dabrafenib and trametinib, or encorafenib (LGX818) and binimetinib (MEK162)) within two different clinical trials. Ten and 150 days after treatment start respectively, the patients developed painful nodules on the legs. In addition, one patient developed symmetrical articulation pain and intermittent fever episodes. RESULTS Based on the clinical and histological presentation, erythema nodosum-like panniculitis was diagnosed in both cases. No other aetiology could be found. After receiving topical or oral steroid treatment and anti-inflammatory analgesics, the painful nodular lesions disappeared several weeks later. In one case, a rebound of the painful nodules was observed when the combination treatment (dabrafenib and trametinib) was resumed after a 1-week unscheduled treatment interruption. CONCLUSIONS Panniculitis has previously been described in association with BRAF inhibitor treatment, but not MEK inhibitor treatment. Combination treatment is usually associated with a lower incidence of cutaneous adverse events (AEs), as compared to monotherapy. Panniculitis was observed in two patients during combined BRAF and MEK inhibitor treatment. These cases illustrate the need for further research in a larger patient population to identify a possible link between combined BRAF and MEK inhibitor treatment and the incidence of panniculitis

Treatment of vulvar Paget disease with topical imiquimod: a case report and review of the literature

BACKGROUND: Extramammary Paget's disease is a cutaneous neoplasm that presents as erythematous crusted patches and plaques reminiscent of contact dermatitis or inverse psoriasis that can be a challenge to treat in a tissue-sparing manner. The most commonly involved site for this rare disorder is the anogenital region. Surgery is considered as the gold standard therapy. In the last years, the topical use of imiquimod cream in the treatment of this condition has been reported. MAIN OBSERVATIONS: We present a case of a 59-year-old woman with primary extramammary Paget's disease of the vulva, in which a conservative approach to therapy was desired, and who underwent complete and stable remission with imiquimod cream. We also review the previous reports of patients with extramammary Paget's disease treated with imiquimod cream. CONCLUSIONS: Imiquimod therapy may be an alternative for primary as well as recurring extramammary Paget's disease. Treatment-associated morbidity is minimal compared with other therapies, such as surgery which may be debilitating

Heterogeneous Tumor Subpopulations Cooperate to Drive Invasion

SummaryClonal selection and transcriptional reprogramming (e.g., epithelial-mesenchymal transition or phenotype switching) are the predominant theories thought to underlie tumor progression. However, a “division of labor” leading to cooperation among tumor-cell subpopulations could be an additional catalyst of progression. Using a zebrafish-melanoma xenograft model, we found that in a heterogeneous setting, inherently invasive cells, which possess protease activity and deposit extracellular matrix (ECM), co-invade with subpopulations of poorly invasive cells, a phenomenon we term “cooperative invasion”. Whereas the poorly invasive cells benefit from heterogeneity, the invasive cells switch from protease-independent to an MT1-MMP-dependent mode of invasion. We did not observe changes in expression of the melanoma phenotype determinant MITF during cooperative invasion, thus ruling out the necessity for phenotype switching for invasion. Altogether, our data suggest that cooperation can drive melanoma progression without the need for clonal selection or phenotype switching and can account for the preservation of heterogeneity seen throughout tumor progression

Primary cutaneous CD8+ small- to medium-sized Lymphoproliferative disorder in extrafacial sites: Clinicopathologic features and concept on their classification

ABSTRACT: Three cases with CD8+ small- to medium-sized lymphoproliferations in the skin at extrafacial sites are described. Clinically, the patients presented with papulonodular or plaque-like lesions without preceding patches. Histopathologically, nonepidermotropic nodular or diffuse infiltrates were composed of small- to medium-sized pleomorphic lymphocytes, which expressed CD8 (more than 80% of the cells) and granzyme B (60%-70% of the cells), but were negative for CD4, CD30, and CD56. There was no association with Epstein-Barr virus. A clonal T-cell population was detected in 2 patients. Staging examinations did not reveal extracutaneous involvement. The 2 patients with solitary lesions underwent complete remission after radiation therapy, whereas 1 patient developed multifocal lesions and several recurrences. These CD8+ small- to medium-sized lymphoproliferations of the skin at extrafacial sites may belong to a spectrum of phenotypically and prognostically heterogeneous cutaneous small- to medium-sized lymphoid proliferations, which are characterized by an indolent course in most patients