Clinical Features, Histological Characteristics, and Disease Outcomes of Mycosis Fungoides in Children and Adolescents: A Nationwide Multicentre Cohort of 46 Patients.

BACKGROUND: Our objective was to describe the clinical, histological characteristics, and disease outcome of a cohort of mycosis fungoides (MF) diagnosed during childhood including disease status at adulthood. METHODS: This is a retrospective multicentre survey of patients aged under 18 years at diagnosis with histologically confirmed MF. Patients' clinical and histological characteristics, treatments, and disease outcome (for patients followed for more than 12 months) were analysed. RESULTS: Forty-six patients were included (median age at diagnosis: 11 years; M:F sex ratio: 3:1) with 39 (85%) followed for at least 12 months. Thirty-nine patients (85%) had stage I MF. Hypopigmented patches were observed in 48% and folliculotropism in 43% patients. Immunophenotype of the skin infiltrate was predominantly CD8+ in 17% of patients. Initial management included a wait-and-see strategy in 6/39 (15%), skin-directed treatment in 27 (69%), and systemic treatment in 6 (15%) patients, respectively, with partial or complete clinical response (PR or CR) observed in 28 patients (72%). 14/39 patients (36%) relapsed after initial response. After a median follow-up period of 54 months, disease status at last news was PR or CR in 31/39 (79%), stable disease in 6 (15%), and progression in 2 (5%) patients. Histological transformation was observed in 3/39 (8%). Of the 15 patients followed until adulthood, 13 (87%) had persistent MF. DISCUSSION: This survey confirms the high frequency of hypopigmented and folliculotropic lesions and of CD8+ immunophenotype compared to adult MF patients. The long-term course is usually indolent but transformation may occur sometimes long after disease onset and the disease may persist during adulthood.

Early Phase of Primary Melanoma Growth from the Patient Point of view: A Prospective Cross Sectional Study on Melanoma over 1 mm in Thickness.

A Nodular Pink Lesion with an Uncommon Diagnosis: A QuizMost melanomas are diagnosed by the patients themselves or by their partners or relatives; they alone can describe its history. We designed a prospective cross-sectional study to describe patients' perception of morphology, growth pattern and kinetics of their primary melanoma over 1 mm in thickness before resection. Patients were interviewed with a questionnaire, a grid representing 9 possible scenarios of melanoma growth, and a set of 87 photographs of potential aspects of melanomas and precursors. Most patients were able to describe the growth of their melanoma and select pictures representative of its successive aspects before resection. Among 453 patients, 60% reported a preexisting lesion present for years. Growth pattern scenarios concurred with tumor kinetics but with no statistical difference between nodular and superficial spreading subtypes. These subjective patient-reported indicators about melanoma growth over time could dynamically complement its objective pathological analysis otherwise static at a single time point.

Detection of EGFR, KRAS and BRAF mutations in metastatic cells from cerebrospinal fluid.

BACKGROUND: In lung adenocarcinoma, molecular profiling of actionable genes has become essential to set up targeted therapies. However, the feasibility and the relevance of molecular profiling from the cerebrospinal fluid (CSF) in the context of meningeal metastasis have been poorly assessed. METHODS: We selected patients with stage IV lung adenocarcinoma harbouring metastatic cells in the CSF after cytological analysis. Seven samples from six patients were eligible for molecular testing of epidermal growth factor receptor (EGFR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS), v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) and human epidermal growth factor receptor 2 (HER2) mutations using quantitative polymerase chain reaction (PCR) high-resolution melting curve analysis and Sanger sequencing after DNA extraction from the cell pellets of the CSF. RESULTS: Five patients showed mutations in one or two actionable genes, two harboured an EGFR mutation (exons 19 and 21), one only a KRAS mutation, one both EGFR and KRAS mutations and one a BRAF mutation. In all cases, the results of mutation testing provided new major information for patient management, leading to therapeutic adaptation. CSF molecular analysis identified mutations not detected in other neoplastic sites for two patients. In one case, the EGFR p.Thr790Met was identified. CSF was also the only sample available for genetic testing for almost all patients at the time of disease progression. CONCLUSIONS: When cancer cells are present in the CSF, the molecular profiling from the cell pellets is relevant, as it can detect supplemental or different mutations compared to a previous analysis of the primitive tumour or plasma cell-free DNA and allows the adaptation of the treatment strategy.

TWEAK-binding autoantibodies are generated during psoriatic arthritis and are not influenced by anti-TNF therapy.

BACKGROUND: TNF weakly inducer of apoptosis (TWEAK) is member of the TNF ligand superfamily. Various data support that TWEAK produced by synovial macrophages may contribute to synovitis observed in psoriatic arthritis (PsoA). In PsoA, anti-TNF therapy has been successful in agreement with the key role of TNF in the pathogenesis and the generation by PsoA patients of anti-TNF autoantibodies referred as "beneficial autoimmunity to pro-inflammatory mediators". However, the role of TNF-alpha in the regulation of TWEAK modulation of inflammation during PsoA remains unknown. METHODS: We have studied level course during anti-TNF therapy of serum soluble TWEAK. In the same cohort, we have investigated the generation of TWEAK-binding autoantibodies by PsoA patients before and after anti-TNF therapy. RESULTS: Patients with PsoA had significantly higher serum levels of TWEAK compared with controls [respective means (±SEM) were 645 pg/ml (64) and 467 pg/ml (23); (p = 0.006)] but serum soluble TWEAK levels were not correlated with BASDAI (Spearman's coefficients <0.003, p > 0.05). Our study showed that soluble TWEAK levels were not modulated by etanercept therapy [respective Means (±SEM) were 605 (95) (week 12) and 744 (97) (week 24) pg/ml; (p > 0.23)]. Anti-TWEAK autoantibodies were detected in 9/13 (69.2 %) PsoA patients at inclusion and only in 3/57 (5.3 %) healthy blood donors (p < 0.0001). These circulating antibodies were persistent in PsoA patients and detected at similar levels during etanercept therapy. Moreover we showed that they had a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. CONCLUSION: Our study revealed that during psoriatic arthritis (1) serum TWEAK was up regulated and (2) TWEAK-binding autoantibodies are generated. Both parameters were not influenced by anti-TNF therapy and persisted at high levels during anti-TNF therapy. For the first time we described here TWEAK-binding IgG autoantibodies with a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. Finally, our results suggest that TWEAK may be involved in PsoA pathogeny. Trial registration This clinical trial was approved by the local Ethics Committee "Comité de Protection des Personnes Sud-Méditerranée V" with the registration number: 2011-002954-29, and French health minister registration number AFSSAPS A110784-42 obtained the 08/22/2011. This clinical trial is registered in Clinical trial.gov under the number: NCT02164214.

Role of Inducible Co-Stimulator (ICOS) in cancer immunotherapy.

Introduction: The promotion of antitumor response by targeting co-stimulatory B7 superfamily members has become evident to create a new wave of cancer immunotherapy. Inducible Co-Stimulator (ICOS), which is expressed on activated T cells, gained interest in the translational medicine community.Areas covered: We performed an extensive literature review using the keywords 'ICOS' and 'cancer', and the Clinicaltrials.gov database for early phase clinical trials targeting ICOS. In this review, we highlight the dual role of ICOS in oncogenesis in different malignancies. We summarize the current state of knowledge about ICOS/ICOSL pathway targeting by immunotherapies.Expert opinion: Due to its multifaceted link with anti-tumor immunity, both antagonist and agonist antibodies might be of interest to target the ICOS/ICOSL pathway for tumor treatment. Indeed, ICOS activation might potentiate the effect of an inhibitory checkpoint blockade, while its neutralization could decrease the function of immunosuppressive Tregs and inhibit lymphoid tumor cells expressing Tfh markers.

Stereotactic radiosurgery combined with anti-PD1 for the management of melanoma brain metastases: A retrospective study of safety and efficacy.

BACKGROUND: Brain metastases can be effectively treated with stereotactic radiosurgery (SRS). Immune checkpoint inhibitors are now pivotal in metastatic melanoma care, but some concerns have emerged regarding the safety of their combination with radiation therapy. METHODS: We present a retrospective analysis of a cohort of patients treated by anti-PD1 and SRS as a sole modality of radiation therapy (no whole brain radiation therapy at any time) in a single institution. We included patients on anti-PD1 at the time of SRS or patients who started anti-PD1 within a maximum period of 3 months following SRS and were treated at least one year before the analysis. Clinical and serial imaging data were reviewed to determine the efficacy and the rate of adverse radiation effectss of the combination. RESULTS: A total of 50 patients were included. SRS targeted 1, 2 to 3 and >3 brain metastases in 17, 16 and 17 patients, respectively. Two patients died before the first evaluation. Nine patients presented with an increase in peritumoral oedema, three with intracranial haemorrhage and one patient with both oedema and haemorrhage. Median follow-up was 38.89 months (interquartile range 24.43; 45.28). Median overall survival from SRS was 16.62 months with 1-, 2- and 3-year rates of 60%, 40% and 35%, respectively. Median brain-Progression Free Survival was 13.2 months with 1, 2 and 3-year rates of 62.1%, 49.7% and 49.7%, respectively. CONCLUSIONS: This real-world cohort of patients treated with a homogeneous strategy combining upfront stereotactic radiosurgery and anti-PD1 shows remarkable survival rates and does not reveal unexpected toxicity.

ICOS is widely expressed in cutaneous T-cell lymphoma, and its targeting promotes potent killing of malignant cells.

The treatment of advanced-stage cutaneous T-cell lymphoma (CTCL) remains an unmet medical need. Mogamulizumab, anti-KIR3DL2, and brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate (ADC) coupled with monomethyl-auristatin-E (MMAE), provided encouraging results, but new targeted therapies are needed. Inducible T-cell costimulator (ICOS), a T-cell costimulatory receptor, is a promising therapeutic target, not only because it is expressed by malignant T cells in CTCL but also because of its connection with the suppressive activity of regulatory T (Treg) cells. Immunohistochemical analysis revealed that ICOS was widely expressed by malignant cells in skin biopsy specimens from 52 patients with mycosis fungoides and Sézary syndrome (SS), as well as in involved node biopsy specimens from patients with SS. Furthermore, flow cytometry demonstrated its strong expression by circulating tumor cells in all our patients with SS. Percentages of ICOS+ Treg cells were significantly higher in patients with SS than in healthy donors. We then investigated the preclinical efficacy of anti-ICOS ADCs generated by coupling murine anti-ICOS monoclonal antibodies with MMAE and pyrrolobenzodiazepine. In 3 CTCL cell lines (Myla, MJ, and HUT78), we observed a significant dose-dependent decrease in cell viability in the presence of anti-ICOS ADCs. In addition, anti-ICOS-MMAE ADCs had an in vitro and in vivo efficacy superior to BV in a mouse xenograft model (MyLa). Finally, we assessed the efficacy of anti-ICOS ADCs in ICOS+ patient-derived xenografts from patients with SS and angioimmunoblastic T-cell lymphoma. Collectively, our findings provide the preliminary basis for a therapeutic trial.

Inducible Co-Stimulator (ICOS) as a potential therapeutic target for anti-cancer therapy.

INTRODUCTION: The recent success of checkpoint-inhibitors in cancer treatment paved the way for the development of new strategies of agonist and antagonist agents against B7 superfamily members. Inducible Co-Stimulator (ICOS), a co-stimulatory receptor for T-cell enhancement, arouses interest. Areas covered: We performed an extensive literature search with PUBMED using the keywords 'ICOS' and 'cancer' to discuss its involvement in oncogenesis, its expression in different malignancies, and its targeting in relevant preclinical studies. We also searched the Clinicaltrials.gov database for recent updates on early phase clinical trials. Expert opinion: ICOS/ICOSL axis has a dual effect and might participate in anti-tumour T cell response as well as a pro-tumour response due to its connection with regulatory T-cells (Tregs) suppressive activity. Therefore, both antagonist and agonist antibodies might be of interest in the targeting ICOS/ICOSL pathway for cancer treatment. In preclinical studies, ICOS agonist monoclonal antibodies (mAbs) have shown to potentiate the effect of inhibitory checkpoint blockade. In contrast, antagonistic anti-ICOS mAbs could not only inhibit lymphoid tumour cells expressing ICOS, but also dampen immunosuppressive Tregs. Two agonist and one antagonist mAbs are evaluated in phase I/II trials. Efficacy, safety, and combination strategies with anti-ICOS agonist or antagonist have yet to be specified.