Articleshaematologica | 2013; 98 (7) 1089Corticosteroid can induce osteonecrosis in children with leukemia. Few studies have been designed to assess the influence of a wide range of cumulative steroid dose on this side effect. Prevalence, risk factors of symptomatic osteonecrosis and its impact on adults' Quality of Life were assessed in 943 patients enrolled in the French "Leucémies de l'Enfant et de l'Adolescent" (LEA) cohort of childhood leukemia survivors. During each medical visit, data on previous osteonecrosis diagnosis were retrospectively collected. Patients without a history but with suggestive symptoms were investigated with magnetic resonance imaging. The total steroid dose in equivalent of prednisone was calculated for each patient and its effect on osteonecrosis occurrence was studied in multivariate models. Cumulative incidence was 1.4% after chemotherapy alone versus 6.8% after transplantation (P<0.001). A higher cumulative steroid dose, age over ten years at diagnosis, and treatment with transplantation significantly increased the risk of osteonecrosis. A higher post-transplant steroid dose and age over ten years at time of transplantation were significant factors in the transplanted group. With patients grouped according to steroid dose quartile, cumulative incidence of osteonecrosis reached 3.8% in the chemotherapy group for a dose beyond 5835 mg/m 2 and 23.8% after transplantation for a post-transplant dose higher than 2055 mg/m 2 . Mean physical composite score of Quality of Life was 44.3 in patients with osteonecrosis versus 54.8% in patients without (P<0.001). We conclude that total and post-transplant cumulative steroid dose may predict the risk of osteonecrosis, a rare late effect with a strong negative impact on physical domains of Quality of Life. Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood

γδT cells hold a pivotal role in tumor immunosurveillance through their prompt activation and cytokine secretion, their ability to kill tumor cells in an Human Leukocyte Antigen (HLA)-unrestricted manner, and their combination of features of both innate and adaptive immunity. These unique properties and functional plasticity render them very attractive both as targets and vectors for cancer immunotherapy. Yet, these potent and fascinating antitumor effectors have not been extensively explored in melanoma. We provided here a detailed investigation of the phenotypic and functional properties of circulating and tumor-infiltrating γδT cells in melanoma patients, and their impact on clinical evolution. High proportions of circulating-and tumor-infiltrating γδT and δ2+ subset were associated with better clinical outcome. We reported however that circulating and tumor-infiltrating γδT cells from melanoma patients displayed an altered expression of NCR, KIR, and immune checkpoints, and identified NKp44, PD1, 41BB/ 41BBL, TIM3, and LAG3 as crucial checkpoints allowing immune escape and tumor progression. Notably, melanoma drastically impaired the ability of γδT cells to exhibit activation molecules, secrete cytokines, and display cytotoxicity toward melanoma in response to stimulation with phosphoantigens. It drove them toward regulatory and Th17 profiles associated with poor clinical outcomes. Our study highlights that melanoma hijacked γδT cells to escape from immune control, and revealed that circulating and tumor-infiltrating γδT cell features are promising potential biomarkers of clinical evolution. Such understanding of the physiopathology of γδT cells may help designing new therapeutic approaches exploiting the antitumor potential of γδT cells while counteracting their skewing by tumors to improve patient outcomes.

Patients with neurofibromatosis are prone to develop embryonal-type RMS that require the same treatment as sporadic cases.

Plasmacytoid DCs (pDCs) and γδT cells are both critical players in immunosurveillance against pathogens and cancer due to their ability to sense microbes and cell stress through recognition of pathogen-associated molecular patterns or altered metabolism [phosphoantigens (PAgs)]. Their unique features, high functional plasticity and ability to interact with many immune cell types allow them to bridge innate and adaptive immunity, initiating and orientating widely immune responses, hence contributing to protective and pathogenic immune responses. Yet, despite strategic and closed missions, potential interactions between pDCs and γδT cells are still unknown. Here we investigated whether there is interplay between pDCs and γδT cells and the underlying molecular mechanisms. Purified human pDCs and γδT cells were cocultured in presence of TLR-L, PAg, and zoledronate (Zol) to mimic both infectious and tumor settings. We demonstrated that TLR7/9L-or Zol-stimulated pDCs drive potent γδT-cell activation, Th1 cytokine secretion and cytotoxic activity. Conversely PAg-activated γδT cells trigger pDC phenotypic changes and functional activities. We provided evidence that pDCs and γδT cells cross-regulate each other through soluble factors and cell-cell contacts, especially type I/II IFNs and BTN3A. Such interplay could be modulated by blocking selective immune checkpoints. Our study highlighted crucial bidirectional interactions between these key potent immune players. The exploitation of pDC-γδT cells interplay represents a promising opportunity to design novel immunotherapeutic strategies and restore appropriate immune responses in cancers, infections and autoimmune diseases.

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ObjectivespDCs and γδ T cells emerge as potent immune players participating in the pathophysiology of cancers, yet still remaining enigmatic while harbouring a promising potential for clinical translations. Despite strategic and closed missions, crosstalk between pDCs and γδ T cells has not been deciphered yet in cancers, especially in melanoma where the long‐term control of the tumor still remains a challenge.MethodsThis prompted us to explore the interplay between pDCs and γδ T cells in the context of melanoma, investigating the reciprocal features of pDCs or γδ T cells, the underlying molecular mechanisms and its impact on clinical outcomes.ResultsTLRL‐activated pDCs from the blood and tumor infiltrate of melanoma patients displayed an impaired ability to activate, to modulate immune checkpoints and trigger the functionality of γδ T cells. Conversely, γδ T cells from the blood or tumor infiltrate of melanoma patients activated by PAg were defective in triggering pDCs’ activation and modulation of immune checkpoints, and failed to elicit the functionality of pDCs. Reversion of the dysfunctional cross‐talks could be achieved by specific cytokine administration and immune checkpoint targeting. Strikingly, we revealed an increased expression of BTN3A on circulating and tumor‐infiltrating pDCs and γδ T cells from melanoma patients, but stressed out the potential impairment of this molecule.ConclusionOur study uncovered that melanoma hijacked the bidirectional interplay between pDCs and γδ T cells to escape from immune control, and revealed BTN3A dysfunction. Such understanding will help harness and synergise the power of these potent immune cells to design new therapeutic approaches exploiting their antitumor potential while counteracting their skewing by tumors to improve patient outcomes.

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ObjectivesThe rising prevalence of musculoskeletal disorders increases pressure on primary care services. In France, patients with musculoskeletal disorders are referred to physiotherapist (PT) by family physician (FP). To improve access to musculoskeletal care, a new model of task sharing and shifting is implemented between FPs and PTs for patients with acute low back pain. This new model enables French PTs to expand their usual scope of practice by receiving patients as first-contact practitioner, diagnosing low back pain, prescribing sick leave and analgesic medication. The aim of this study is to investigate the acceptability of FPs and PTs regarding this new model.DesignA cross-sectional survey design was used. Acceptability was measured using a questionnaire on the perception of the model and the perception of PTs’ skills to manage low back pain. Descriptive analyses were performed to compare results among participants.SettingFrench FPs and PTs working in multidisciplinary primary healthcare centres were invited to complete an online survey.ParticipantsA total of 174 respondents completed the survey (81 FPs and 85 PTs).ResultsA majority of participants had a positive perception of the task sharing and shifting model. A majority of the participants were mostly or totally favourable towards the implementation of the model (FPs: n=46, 82% and PTs: n=40, 82%). The perceived level of competencies of PTs to manage acute low back pain was high. The confidence level of FPs was higher than that of PTs regarding PTs’ ability to adequately diagnose low back pain, refer patient to physiotherapy and prescribe sick leave or analgesic medication.ConclusionBased on this limited sample of participants, there appears to be good acceptability of the task sharing and shifting model for acute low back pain. Additional studies are needed to better determine the factors affecting the acceptability of such a model.