TIE-2 Signaling Activation by Angiopoietin 2 On Myeloid-Derived Suppressor Cells Promotes Melanoma-Specific T-cell Inhibition

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune suppressive cells detected in several human cancers. In this study, we investigated the features and immune suppressive function of a novel subset of monocytic MDSC overexpressing TIE-2 (TIE-2+ M-MDSC), the receptor for the pro-angiogenic factor angiopoietin 2 (ANGPT2). We showed that patients with melanoma exhibited a higher circulating rate of TIE-2+ M-MDSCs, especially in advanced stages, as compared to healthy donors. The distribution of the TIE-2+ M-MDSC rate toward the melanoma stage correlated with the serum level of ANGPT2. TIE-2+ M-MDSC from melanoma patients overexpressed immune suppressive molecules such as PD-L1, CD73, TGF-β, and IL-10, suggesting a highly immunosuppressive phenotype. The exposition of these cells to ANGPT2 increased the expression of most of these molecules, mainly Arginase 1. Hence, we observed a profound impairment of melanoma-specific T-cell responses in patients harboring high levels of TIE-2+ M-MDSC along with ANGPT2. This was confirmed by in vitro experiments indicating that the addition of ANGPT2 increased the ability of TIE-2+ M-MDSC to suppress antitumor T-cell function. Furthermore, by using TIE-2 kinase-specific inhibitors such as regorafenib or rebastinib, we demonstrated that an active TIE-2 signaling was required for optimal suppressive activity of these cells after ANGPT2 exposition. Collectively, these results support that TIE-2+ M-MDSC/ANGPT2 axis represents a potential immune escape mechanism in melanoma

PD‐L1 in circulating exosomes of Merkel cell carcinoma

International audienceExosomes, as potential circulated biomarkers, have recently become a topic of interest in the field of oncology. Immune checkpoint molecule PD-L1 has recently been detected in circulating exosomes from cancer patients. The purpose of this work was to evaluate PD-L1 levels in circulating exosomes (Exo-PD-L1) isolated from patients' plasma suffering from Merkel cell carcinoma (MCC). We conducted a prospective bicentric cohort study. PD-L1 was analysed in circulating exosomes from plasma samples of patients suffering from MCC stage I to IV (according to the AJCC 8). Exosomes from 34 patients corresponding to 66 samples were analysed. PD-L1 was identified in circulating exosomes of MCC patients. Exo-PD-L1 levels of MCC patients were similar to healthy donors and lower than other cancers such as melanoma. Exo-PD-L1 levels tended to be higher in MCC patients with distant metastases. Furthermore, Exo-PD-L1 levels did not significantly vary over the course of the disease whatever the disease course or the response to treatment. This study assessed the presence of PD-L1 in circulating exosomes of MCC patients. The low levels of Exo-PD-L1 and small changes over the course of the disease may be due to the metastatic dissemination of MCC, which is mainly through the skin and lymph nodes rather than blood. PD-L1 was identified in circulating exosomes of MCC patients and tends to be higher in advanced disease. This preliminary study is a proof of concept of PD-L1 detection in circulating exosomes of MCC patients

BRAF mutation screening in melanoma

International audienceAs the detection of the BRAF V600E mutation has a direct impact on treatment decision, an accurate screening for BRAF mutations in patients with advanced or metastatic melanoma is mandatory. Nevertheless, BRAF oncogene mutation status between different samples from the same patient has been studied with conflicting results. This study investigated the intrapatient homogeneity of BRAF mutation status using pyrosequencing in primary tumors and different metastatic sites of melanoma patients. Paired samples of lymphatic, visceral, and subcutaneous metastases and primary melanoma from 45 metastatic melanoma patients were tested for BRAF mutations using a pyrosequencing assay and by Sanger sequencing. Overall, sequencing for BRAF mutation status was performed in 114 paired samples from 45 patients. Eighteen patients (40%) carried a BRAF mutation, including BRAF V600E (12/18), BRAF V600K (5/18), and BRAF V600R (1/18) mutations. Multiple BRAF mutations (V600E and V600K) were found in one patient. Among the patients with BRAF mutations, a good agreement in BRAF mutation status was found between the first and second tumor samples genotyped (91%; Cohen's κ coefficient: 0.81). Discordance in BRAF mutation status was found only in four patients, involving all three patients in whom sentinel lymph node (SLN) metastases were sampled. These SLNs exhibited a wild-type genotype and were discordant with the other BRAF-mutated samples found in the same patient. The intrapatient BRAF status was predominantly homogeneous. However, SLN genotyping using pyrosequencing might be inaccurate in determining the actual mutation status of melanoma. Further studies are required to confirm the lack of reliability of SLN

Pregnancy after Tubal Sterilization in a Woman Treated with Biologics for Severe Psoriasis

<p></p><p><b>Article full text</b></p> <p><br></p> <p>The full text of this article can be found here<b>.</b> <a href="https://link.springer.com/article/10.1007/s13555-018-0232-7">https://link.springer.com/article/10.1007/s13555-018-0232-7</a></p><p></p><p></p><p> </p><p><br></p> <p><b>Provide enhanced content for this article</b></p> <p><br></p> <p>If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <a href="http://www.medengine.com/Redeem/”mailto:[email protected]”"><b>[email protected]</b></a>.</p> <p><br></p> <p>The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.</p> <p><br></p> <p>Other enhanced features include, but are not limited to:</p> <p><br></p> <p>• Slide decks</p> <p>• Videos and animations</p> <p>• Audio abstracts</p> <p>• Audio slides</p><br><p></p

Efficacy and survival of biologic agents in psoriasis: a practical real-life 12-year experience in a French dermatology department

International audienceBackground: Drug survival in a real-life setting is critical to long-term use of biologics for psoriasis. Objective: We describe our 12-year experience with biologics in psoriasis patients. Patients and Methods: All patients treated with biologics including infliximab, adalimumab (ADA), etanercept (ETA), and ustekinumab (UST) for psoriasis vulgaris between January 2005 and December 2016 were retrospectively analyzed. Results: In total, 545 treatment series were administered to 269 patients, including 211 treatment series with ADA, 135 with ETA, 77 with infliximab, and 122 with UST. ADA and ETA were initiated most often as first-line therapy; 65.3% of treatment sequences were discontinued. UST had the highest drug survival. The major reason for treatment termination was a loss of efficacy (44.9%). Definitive discontinuation increased with the number of biologic therapy sequences. Limitations: Subjects were not randomized to the different treatments. Conclusions: In a long-term real-life setting, drug survival of UST is better than that of TNF-a inhibitors for both biologic-naive and biologic-experienced patients with psoriasis

Vitiligo under anti–programmed cell death-1 therapy is associated with increased survival in melanoma patients

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Personalized follow-up of circulating DNA in resected stage III/IV melanoma: PERCIMEL multicentric prospective study protocol

International audienceBackground: With more than 15,000 new cases /year in France and 2,000 deaths, cutaneous melanoma represents approximately 4% of incidental cancers and 1.2% of cancer related deaths. In locally advanced (stage III) or resectable metastatic (stage IV) melanomas, medical adjuvant treatment is proposed and recent advances had shown the benefit of anti-PD1/PDL1 and anti-CTLA4 immunotherapy as well as anti-BRAF and anti-MEK targeted therapy in BRAF V600 mutated tumors. However, the recurence rate at one year is approximately 30% and justify extensive research of predictive biomarkers. If in metastatic disease, the follow-up of circulating tumor DNA (ctDNA) has been demonstrated, its interest in adjuvant setting remains to be precised, especially because of a lower detection rate. Further, the definition of a molecular response could prove useful to personalized treatment. Methods: PERCIMEL is an open prospective multicentric study executed through collaboration of the Institut de Cancérologie de Lorraine (non-profit comprehensive cancer center) and 6 French university and community hospitals. A total of 165 patients with resected stage III and IV melanoma, eligible to adjuvant imunotherapy or anti-BRAF/MEK kinase inhibitors will be included. The primary endpoint is the presence of ctDNA, 2 to 3 weeks after surgery, defined as mutated ctDNA copy number calculated as the allelic fraction of a clonal mutation relative to total ctDNA. Secondary endpoints are recurrence-free survival, distant metastasis-free survival and specific survival. We will follow ctDNA along treatment, quantitatively through ctDNA mutated copy number variation, qualitatively through the presence of cfDNA and its clonal evolution. Relative and absolute variations of ctDNA during follow-up will be also analyzed. PERCIMEL study aims at provide scientific evidence that ctDNA quantitative and qualitative variations can be used to predict the recurrence of patients with melanoma treated with adjuvant immunotherapy or kinase inhibitors, thus defining the notion of molecular recurrence

Impact of adjuvant radiation therapy on survival and recurrence in patients with stage I-III Merkel cell carcinoma: A retrospective study of 312 patients

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