Effective Melanoma Immunotherapy in Mice by the Skin-Depigmenting Agent Monobenzone and the Adjuvants Imiquimod and CpG

Background: Presently melanoma still lacks adequate treatment options for metastatic disease. While melanoma is exceptionally challenging to standard regimens, it is suited for treatment with immunotherapy based on its immunogenicity. Since treatment-related skin depigmentation is considered a favourable prognostic sign during melanoma intervention, we here aimed at the reverse approach of directly inducing vitiligo as a shortcut to effective anti-melanoma immunity. Methodology and Principal Findings: We developed an effective and simple to use form of immunotherapy by combining the topical skin-bleaching agent monobenzone with immune-stimulatory imiquimod cream and cytosine-guanine oligodeoxynucleotides (CpG) injections (MIC therapy). This powerful new approach promptly induced a melanoma antigen-specific immune response, which abolished subcutaneous B16. F10 melanoma growth in up to 85% of C57BL/6 mice. Importantly, this regimen induced over 100 days of tumor-free survival in up to 60% of the mice, and forcefully suppressed tumor growth upon re-challenge either 65- or 165 days after MIC treatment cessation. Conclusions: MIC therapy is effective in eradicating melanoma, by vigilantly incorporating NK-, B-and T cells in its therapeutic effect. Based on these results, the MIC regimen presents a high-yield, low-cost and simple therapy, readily applicable in the clini

Tumor-infiltrating T-cells: important players in clinical outcome of advanced melanoma patients

Immune escape mechanisms are prevalent in tumors, while their influence on the potency of antitumor immunotherapy has yet to be distinguished. We recently showed that increased numbers of intratumoral T cells rather than immune-escape-mechanisms significantly correlated with clinical outcome of advanced melanoma patients to subsequent autologous tumor cell vaccination. Our data emphasize the therapeutic relevance of tumor-infiltrating T cells for the clinical outcom

The HGF/MET pathway as target for the treatment of multiple myeloma and B-cell lymphomas

Hepatocyte growth factor (HGF) and its receptor MET are essential during embryonic development and throughout postnatal life. However, aberrant MET activation, due to overexpression, mutations, or autocrine ligand production, contributes to the development and progression of a variety of human cancers, often being associated with poor clinical outcome and drug resistance. B cell malignancies arise from B cells that are clonally expanded at different stages of differentiation. Despite major therapeutic advances, most mature B cell malignancies remain incurable and biologically-oriented therapeutic strategies are urgently needed. This review addresses the role of the HGF/MET pathway during B cell development and discusses how its aberrant activation contributes to the development of B cell lymphoproliferative disorders, with particular emphasis on multiple myeloma and diffuse large B cell lymphoma. These insights, combined with the recent development of clinical-grade agents targeting the MET pathway, provide the rationale to envision the HGF/MET pathway as a new promising target for the treatment of B cell malignancies

The impact of scars on health-related quality of life after breast surgery: a qualitative exploration

Purpose The purpose of this research was to explore women’s experiences after breast surgery with scar characteristics and symptoms, and its impact on their health-related quality of life (HRQOL). Material andmethods A qualitative study using semi-structured face-to-face interviewswas conducted among women following prophylactic, oncologic, or reconstructive breast surgery in the Netherlands. A directed content analysis was performed using guiding themes. Themes were “physical and sensory symptoms,” “impact of scar symptoms,” “personal factors,” “impact of scar interventions,” and “change over time.” Results The study population consisted of 26 women after breast surgery. Women experienced a wide range of symptoms like adherence, stiffness, pain, and uncomfortable sensations. Scar characteristics as visibility, location, texture, and size, influenced satisfaction with their appearance. The impact of scar symptoms is reflected in physical, social, emotional, and cognitive functioning, thereby affecting HRQOL. The experienced impact on HRQOL depended on several factors, like personal factors as the degree of acceptance and environmental factors like social support. Conclusion Women can experience a diversity of scar characteristics and symptoms, which play a central role in the perceived impact on HRQOL. Since scarring can have a considerable impact on HRQOL, scarring after prophylactic, oncologic and reconstructive breast surgery should be given more attention in clinical practice and research. Implications for Cancer Survivors Considering scarring as a common late effect after breast surgery and understanding the variety of experiences, which could impact HRQOL of women, can be beneficial in sufficient information provision, expectation management, and informed decision making

c-Cbl is involved in met signaling in B cells and mediates hepatocyte growth factor-induced receptor ubiquitination

Hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase Met are key regulators of epithelial motility and morphogenesis. Recent studies indicate that the HGF/Met pathway also plays a role in B cell differentiation, whereas uncontrolled Met signaling may lead to B cell neoplasia. These observations prompted us to explore HGF/Met signaling in B cells. In this study, we demonstrate that HGF induces strong tyrosine phosphorylation of the proto-oncogene product c-Cbl in B cells and increases Cbl association with the Src family tyrosine kinases Fyn and Lyn, as well as with phosphatidylinositol-3 kinase and CrkL. In addition, we demonstrate that c-Cbl mediates HGF-induced ubiquitination of Met. This requires the juxtamembrane tyrosine Y1001 (Y2) of Met, but not the multifunctional docking site (Y14/15) or any additional C-terminal tyrosine residues (Y13-16). In contrast to wild-type c-Cbl, the transforming mutants v-Cbl and Z0Z/3 Chl, which lack the ubiquitin ligase RING finger domain, suppress Met ubiquitination. Our findings identify c-Cbl as a negative regulator of HGF/Met signaling in B cells, mediating ubiquitination and, consequently, proteosomal degradation of Met, and suggest a role for CbI in Met-mediated tumorigenesi

The efficacy and safety of non-pharmacological therapies for the treatment of acne vulgaris: A systematic review and best-evidence synthesis

Background: Acne vulgaris is a multifaceted skin disorder, affecting more than 85% of young individuals worldwide. Pharmacological therapy is not always desirable because of the development of antibiotic resistance or the potential risk of adverse effects. Non‐pharmacological therapies can be viable alternatives for conventional therapies. However, sufficient evidence‐based support in the efficacy and safety of non‐pharmacological therapies is lacking. Objective: To assess the efficacy and safety of several non‐pharmacological therapies in the treatment of acne vulgaris. Methods: A systematic literature review, including a best‐evidence synthesis, was performed to identify literature. Three electronic databases were accessed and searched for studies published between January 2000 and May 2017. Results: Thirty‐three eligible studies were included in our systematic review. Three main types of non‐pharmacological therapies were identified laser‐ and light‐based therapies, chemical peels and fractional microneedling radiofrequency. The majority of the included studies demonstrated a significant reduction in acne lesions. However, only seven studies had a high methodologic quality. Based on these seven trials, a best‐evidence synthesis was conducted. Strong evidence was found for glycolic acid (10–40%). Moderate evidence was found for amino fruit acid (20–60%), intense pulsed light (400–700 and 870–1200 nm) and the diode laser (1450 nm). Initially, conflicting evidence was found for pulsed dye laser (585–595 nm). The most frequently reported side‐effects for non‐pharmacological therapies included erythema, tolerable pain, purpura, oedema and a few cases of hyperpigmentation, which were in most cases mild and transient. Conclusion: Circumstantial evidence was found for non‐pharmacological therapies in the treatment of acne vulgaris. However, the lack of high methodological quality among included studies prevented us to draw clear conclusions, regarding a stepwise approach. Nevertheless, our systematic review including a best‐evidence synthesis did create order and structure in resulting outcomes in which a first step towards future research is generated

Melanocyte-specific immune response in a patient with multiple regressing nevi and a history of melanoma

Background/Aim: Regressing nevi are considered an example of an efficient early antitumoral response preventing the development of neoplasia. The underlying mechanism has not been elucidated, although an immune-based destruction of melanocytes is supposed. The aim of this study was to provide evidence of an effective immunosurveillance of pigment lesions in a patient at high risk of melanoma. Case Report: A patient with the dysplastic nevus syndrome and a history of melanoma was included in this study. Since 2003, a marked regression of almost all nevi was observed. Immunohistochemistry was performed and the antigen specificity of T-cells was analyzed on T-cells isolated from a regressing nevus by flow cytometry using HLA-A2-peptide tetramers containing Mart-1(26-35), gp100(280-288), gp100(209-217) and tyrosinase(369-377). Immunohistochemistry of the regressing nevi showed a strong infiltrate of CD4 + and CD8 + T-cells. Flow cytometric analyses demonstrated the presence of a CD8 + T-cell response against gp100(280-288) and Mart-1(26-35) both in peripheral blood and in a regressing nevus. Conclusion: These findings indicate that an immune reaction against melanocyte differentiation antigens can target specifically nevi without signs of vitiligo and suggests that boosting the anti-melanocyte immune response in patients at high risk for melanoma may prevent tumor development at an early stage