Increased Expression of Toll-Like Receptors by Monocytes and Natural Killer Cells in ANCA-Associated Vasculitis

INTRODUCTION: Toll-like receptors (TLRs) are a family of receptors that sense pathogen associated patterns such as bacterial cell wall proteins. Bacterial infections are associated with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Here, we assessed the expression of TLRs 2, 4, and 9 by peripheral blood leukocytes from patients with AAV, and investigated TLR mediated responses ex vivo. METHODS: Expression of TLRs was determined in 38 AAV patients (32 remission, 6 active disease), and 20 healthy controls (HC). Membrane expression of TLRs 2, 4, and 9, and intracellular expression of TLR9 by B lymphocytes, T lymphocytes, NK cells, monocytes and granulocytes was assessed using 9-color flowcytometry. Whole blood from 13 patients and 7 HC was stimulated ex vivo with TLR 2, 4 and 9 ligands and production of cytokines was analyzed. RESULTS: In patients, we observed increased proportions of TLR expressing NK cells. Furthermore, patient monocytes expressed higher levels of TLR2 compared to HC, and in a subset of patients an increased proportion of TLR4(+) monocytes was observed. Monocytes from nasal carriers of Staphylococcus aureus expressed increased levels of intracellular TLR9. Membrane expression of TLRs by B lymphocytes, T lymphocytes, and granulocytes was comparable between AAV patients and HC. Patients with active disease did not show differential TLR expression compared to patients in remission. Ex vivo responses to TLR ligands did not differ significantly between patients and HC. CONCLUSIONS: In AAV, monocytes and NK cells display increased TLR expression. Increased TLR expression by these leukocytes, probably resulting from increased activation, could play a role in disease (re)activation

Development of a Prediction Model for COVID-19 Acute Respiratory Distress Syndrome in Patients With Rheumatic Diseases: Results From the Global Rheumatology Alliance Registry

OBJECTIVE: Some patients with rheumatic diseases might be at higher risk for coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). We aimed to develop a prediction model for COVID-19 ARDS in this population and to create a simple risk score calculator for use in clinical settings. METHODS: Data were derived from the COVID-19 Global Rheumatology Alliance Registry from March 24, 2020, to May 12, 2021. Seven machine learning classifiers were trained on ARDS outcomes using 83 variables obtained at COVID-19 diagnosis. Predictive performance was assessed in a US test set and was validated in patients from four countries with independent registries using area under the curve (AUC), accuracy, sensitivity, and specificity. A simple risk score calculator was developed using a regression model incorporating the most influential predictors from the best performing classifier. RESULTS: The study included 8633 patients from 74 countries, of whom 523 (6%) had ARDS. Gradient boosting had the highest mean AUC (0.78; 95% confidence interval [CI]: 0.67-0.88) and was considered the top performing classifier. Ten predictors were identified as key risk factors and were included in a regression model. The regression model that predicted ARDS with 71% (95% CI: 61%-83%) sensitivity in the test set, and with sensitivities ranging from 61% to 80% in countries with independent registries, was used to develop the risk score calculator. CONCLUSION: We were able to predict ARDS with good sensitivity using information readily available at COVID-19 diagnosis. The proposed risk score calculator has the potential to guide risk stratification for treatments, such as monoclonal antibodies, that have potential to reduce COVID-19 disease progression

Immunological aspects in chronic lymphocytic leukemia (CLL) development

Chronic lymphocytic leukemia (CLL) is unique among B cell malignancies in that the malignant clones can be featured either somatically mutated or unmutated IGVH genes. CLL cells that express unmutated immunoglobulin variable domains likely underwent final development prior to their entry into the germinal center, whereas those that express mutated variable domains likely transited through the germinal center and then underwent final development. Regardless, the cellular origin of CLL remains unknown. The aim of this review is to summarize immunological aspects involved in this process and to provide insights about the complex biology and pathogenesis of this disease. We propose a mechanistic hypothesis to explain the origin of B-CLL clones into our current picture of normal B cell development. In particular, we suggest that unmutated CLL arises from normal B cells with self-reactivity for apoptotic bodies that have undergone receptor editing, CD5 expression, and anergic processes in the bone marrow. Similarly, mutated CLL would arise from cells that, while acquiring self-reactivity for autoantigens—including apoptotic bodies—in germinal centers, are also still subject to tolerization mechanisms, including receptor editing and anergy. We believe that CLL is a proliferation of B lymphocytes selected during clonal expansion through multiple encounters with (auto)antigens, despite the fact that they differ in their state of activation and maturation. Autoantigens and microbial pathogens activate BCR signaling and promote tolerogenic mechanisms such as receptor editing/revision, anergy, CD5+ expression, and somatic hypermutation in CLL B cells. The result of these tolerogenic mechanisms is the survival of CLL B cell clones with similar surface markers and homogeneous gene expression signatures. We suggest that both immunophenotypic surface markers and homogenous gene expression might represent the evidence of several attempts to re-educate self-reactive B cells

Impact of positron emission tomography with computed tomography for image-guided radiotherapy

International audienceTherapeutic effectiveness in radiotherapy is partly related to correct staging of the disease and then precise therapeutic targeting. Positron emission tomography (PET) allows the stage of many cancers to be determined and therefore is essential before deciding on radiation treatment. The definition of the therapeutic target is essential to obtain correct tumour control and limit side effects. The part of adaptive radiotherapy remains to be defined, but PET by its functional nature makes it possible to define the prognosis of many cancers and to consider radiotherapy adapted to the initial response allowing an increase over the entire metabolic volume, or targeted at a subvolume at risk per dose painting, or with a decrease in the dose in case of good response at interim assessment

Mid-p strategy versus ITV strategy in locally advanced lung cancer. A randomized phase II study

International audiencePurpose/Objective The overall survival (OS) of patients (pts) with non-resectable locally advanced non-small cell lung carcinoma (LA-NSCLC) is poor, in part due to insufficient local control (LC) using conformal irradiation techniques (RT). The personalization of the RT margins may impact the LC and the outcome. Internal Target Volume strategy (ITV) versus "Mid-position" strategy (Mid-p), was compared in a prospective non-comparative randomized monocentric phase II trial in NSCLC patients treated by definitive radiotherapy. Planning Target volumes and mean lung dose were previously reported as significantly reduced using the Mid-p strategy (DOI: 10.1259/bjr.20190692). We report here the clinical results. Material and Methods Eligible patients were randomized (2:1) to be treated with Mid-p or ITV strategies. Patients with proven LA-NSCLC, non-resected, non-metastatic treated by definitive RT could be included. The main objective was to evaluate the 1-year progression-free-survival (PFS) rate in the two arms. 36 pts were planned in the Mid-p arm, Fleming single-stage design (1-sided =0.1, 80% power, P0=30%, P1=50%). Secondary objectives were to evaluate 1-y and 2-y LC, OS and acute/middle term toxicity (NCI-CTCAE v4).Results 54 pts were randomized from 09/12 to 05/18. 3 patients finally did not receive radiotherapy and were excluded from the analysis. Median age was 65.2 y, 2/3 of the patients were male and had IIIA NSCLC stages, 31% received concomitant chemotherapy. 34 pts and 17 pts were included in the analysis in the Mid-p arm and ITV arm respectively. Median RT dose was 66 Gy in the Mid-p arm and 62 Gy in the ITV arm. Median PFS were 9.3 months and 10.3 months in the Mid-p arm and ITV arms respectively. 1-year PFS rate were 38% (1-sided CI95% = 25-) and 47% (CI95% = [27;[) in the Mid-p/ITV arm respectively. Efficacy in Mid-p arm is below that expected (starting hypothesis p0=30%, p1=50%). 2-year PFS rates were 15% (Mid-p) and 12% (ITV). 2-years LC rates were 65% (CI95% [48;81]) and 76% (CI95% [53;94]) in the Mid-p/ITV arms respectively. The analysis of the type of local failures (in field versus border of fields) is under analysis and will be available for the congress.No grade 4 or toxic deaths related to RT were reported. Grade 3 acute lung toxicity were reported in 12% and 23% in Mid-p and in ITV arms respectively. Grade 2 and Grade 3 late radiation fibrosis were reported in 29% and 15% respectively in the Mid-p arm, versus 23% and 29% using ITV strategy. Conclusion Two-year LC and PFS in LA-NSCLC seems similar in this non comparative Phase II randomized study using Mid-p or ITV strategies. The details of local relapses regarding RT fields and margins are under analysis and will be presented during the congress.Conflict of interest: this study was granted by Elekta

Staging of newly diagnosed Ewing sarcoma: Results of bone marrow aspiration and biopsy versus (18)FDG-PET/CT imaging for bone marrow involvement

BACKGROUND Ewing sarcoma (ES) is an aggressive bone or extraosseous tumour with an unfavourable prognosis when bone marrow metastases are present at diagnosis. The gold standard diagnosis for bone marrow (BM) involvement is cytological and pathological analysis through bone marrow aspiration and biopsy (BMAB). Several recent studies suggest that these invasive and painful procedures could be replaced by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography ((18)FDG-PET/CT), as this nuclear imaging technique is highly sensitive at detecting bone and extraosseous metastases of ES. METHODS In order to study the precision of (18)FDG-PET/CT in the evaluation of bone marrow metastases at diagnosis, we compared the imaging results with cytological/histological analyses performed on BM samples. We retrospectively studied 180 patients with ES recorded at the Léon Bérard Centre over the past 10 years, who were evaluated by (18)FDG-PET/CT and BMAB at diagnosis. RESULTS Of the 180 patients, 13 displayed marrow metastases by cytological/histological examination, and only one of these did not have (18)FDG-PET/CT signs of bone marrow involvement, whereas the 167 remaining patients without marrow metastasis all had a negative (18)FDG-PET/CT, except for one. Hence, the sensitivity and specificity of (18)FDG-PET/CT in these patients was 92.3% and 99.4%, respectively. The overall survival at five years of all patients was 67.4% but decrease to 38.5% in the group with bone marrow metastases. CONCLUSION Given the results presented herein the bone sarcoma group of the French Sarcoma Group suggests that invasive BMAB no longer be systematically performed for the staging at the diagnosis of ES