Annecy Cedex, France

French Observational Study of Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma in Real-World Settings

Chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in the Western World. The disease is characterized by the accumulation and proliferation of mature, monoclonal, CD5+ B-cells with specific immunophenotype in the peripheral blood (above 5x109/L), bone marrow and secondary lymphoid organs. Small lymphocytic leukemia (SLL) is characterized by similar tumor cells but without increased lymphocyte count. In Europe, CLL has been identified as the second most frequent hematological malignancies after multiple myeloma (Eurocare 5 study) and its standardized incidence in the world has been estimated to be 4/100000 person-years for men and 2.1/100000 person-years for women. In France, 4674 new cases have been observed in 2018 (FRANCIM). A proportion of patients can initially be monitored only while others with symptomatic disease at diagnosis or during follow-up require therapies. The management of these patients have considerably changed over the last decade. Indeed, beyond chemo-immunotherapy, multiple targeted therapies have been approved on the basis of phase 2 and randomized phase 3 clinical trials and have subsequently been used in daily practice. The management of patients with SLL is similar to that of those with CLL. In addition to therapeutic advances, the advent of new sequencing technologies has also identified CLL genetic features that are now being incorporated in patient routine evaluation. Conventional chemo-immunotherapy (CIT) has been the long-standing option for CLL patient without TP53 disruption and different regimens have emerged depending on patient comorbidities (fludarabine-cyclophosphamide-rituximab, FCR; bendamustin-rituximab, BR; GA101-chloraminophene, G-CLB). These regimens fail to be effective in patients with TP53 disruption and alternative strategies are proposed for them. The CLL therapeutic panel is now enriched by oral kinase inhibitors targeting the B-cell receptor signaling. The Bruton's tyrosine kinase inhibitors (BTKi) have been shown to provide prolonged response, even in cases where CIT usually failed, such as patients harboring TP53 disruption. In relapsed/refractory patients, median PFS with the BTKi ibrutinib is 44 months. In the frontline setting, ibrutinib has recently been shown to result in superior PFS and less infectious complications than standard CIT regimens. The advent of the BCL2 (B-cell lymphoma 2) inhibitor venetoclax has recently added another option for the treatment of CLL patients. BCL2 is an antiapoptotic molecule governing mitochondrial apoptosis and is strongly expressed in CLL cells. Inhibiting BCL2 with venetoclax as monotherapy led to 79% response rate in the relapse/refractory setting. Combining venetoclax to rituximab demonstrated better PFS than bendamustine-rituximab in relapsed/refractory patients. However, these treatment approaches also come with new challenges that are difficult to-address in phase 3 clinical trials and that deserve larger scale studies and longer follow-up. The emergence of drug resistance, the changes of safety profiles to deal with in routine practice and the observance of these orally administered drugs are emerging as new concerns. How these compounds change the incidence of typical CLL complication such as Richter transformation, immune cytopenias and infections remains to be determined. A growing body of concerns is also raising regarding the unlimited administration of some of this the compounds (costs, resistance, tolerance). Finally, the optimal order of use of these drugs is unknown. The advent of the BCL2 (B-cell lymphoma 2) inhibitor venetoclax has recently added another option for the treatment of CLL patients 11,12. BCL2 is an antiapoptotic molecule governing mitochondrial apoptosis and is strongly expressed in CLL cells. Inhibiting BCL2 with venetoclax as monotherapy led to 79% response rate in the relapse/refractory setting. Combining venetoclax to rituximab demonstrated better PFS than bendamustine-rituximab in relapsed/refractory patients12. However, these treatment approaches also come with new challenges that are difficult to-address in phase 3 clinical trials and that deserve larger scale studies and longer follow-up. The emergence of drug resistance, the changes of safety profiles to deal with in routine practice and the observance of these orally administered drugs are emerging as new concerns. How these compounds change the incidence of typical CLL complication such as Richter transformation, immune cytopenias and infections remains to be determined. A growing body of concerns is also raising regarding the unlimited administration of some of this the compounds (costs, resistance, tolerance). Finally, the optimal order of use of these drugs is unknown. Primary objective : Setting a prospective cohort of real-world CLL/SLL patients with symptomatic disease in order to evaluate medical practices and their change and representativity over time. Secondary objectives : Overall survival and long-term toxicity, Response and PFS at each line of therapy, Impact of therapeutic trajectories on patient outcome, Representativity of the studied population

Acoustic and Volumetric Measurements in Order to Objectify Bronchial Congestion in Patients With Obstructive Respiratory Pathologies Within the Framework of Their Management in Respiratory Physiotherapy for Decongestion

COPD is a chronic respiratory disease defined by permanent airway obstruction. Epidemiological data are scarce: the prevalence is difficult to estimate because of underdiagnosis and the difficultý to perform respiratory function tests (RFTs) in epidemiological studies. It is estimated at 7.5% in a population over 45 years of age, with the incidence appearing to stabilize in men and increase in women. Furthermore, in 2018, 25.4% of adult patients had daily tobacco use. In 2014, 81,600 individuals were on long-term disability (LTD) for chronic bronchitis without specifics. The 2017 report by the Directorate for Research, Studies, Evaluation and Statistics (DREES) on the health status of the population in France shows that: in 2013, approximately 19,000 deaths were related to COPD, 48% of which were due to the initial cause; the crude mortality rateś related to COPD were 96/100,000 adults aged 45 years or older in men and 41/100,000 in women ; in 2014, the annual number of hospitalizations for COPD exacerbation ranged from 100 000 to 160 000, depending on the indicator; crude hospitalization rates were 31/10 000 in men and 15.4/10 000 in women, with the highest rates (>20%) in the northern and eastern regions of France and in Reunion. Standardized hospitalization rates have increased́ since 2000, by 2% per year in men and 5% per year in women. The average direct costs of COPD increase with the level of severitý of the disease and rise on average from €7,628 per year for the least severe patients to €20,747 per year for patients on oxygen therapy. In this condition, a large part of the muscular work is taken up by breathing (fight against bronchial, parietal or fibrous resistances of the lung tissue, decrease of the exchange surface), requiring physiotherapeutic management. The physiotherapeutic treatment "respiratory rehabilitation", includes 4 items: respiratory physiotherapy for decongestion, muscular strengthening, improvement of endurance and therapeutic education. Within this framework, the techniques of de-cluttering are intended to decrease the hydrodynamic resistance of the bronchial tree. A systematic evaluation of the patient's condition is carried out by the practitioners to assess, at the time of the session, the bronchial congestion. In addition to their knowledge of the history of the patient they are following and the result of the oximetry measurement, practitioners rely on several indicators to assess the patient's bronchial congestion and define their therapeutic approach: cough, sputum, oximetry and peak expiratory flow, pulmonary auscultation which provides sound information, and a call maneuver which allows a subjective assessment of the volumes that can be mobilized thanks to haptic information. Sound expertise remains delicate: even the most educated human auditory system is not physiologically capable of detecting some of the relevant information. Multiple pathological breath sounds are referenced in the literature, for which different classifications exist, based on their frequency characteristics, their sound waveforms and their durations. As for the haptic evaluation of thoracic compliance, it also requires a strong experience of the practitioner. The current quantification criteria are therefore not very objective, depend on the practitioner's expertise and do not allow recommendations on the conduct of the session during the follow-up of the patients. Therefore, the objectification of bronchial congestion is clearly part of the improvement of the management of KR (Assess, Anticipate, Prevent, Treat). The design of specific tools dedicated to the quantified monitoring of relevant parameters of the lung condition is of definite interest to achieve these objectives. In this context, the MUKROBS project seeks to objectivize the bronchial congestion of COPD patients, during their management by respiratory physiotherapy techniques of de-congestion by means of modulation of the expiratory flow. The Sybille device, designed, developed and validated in the framework of a previous project funded by the ANR VirtualChest, allows continuous, non-invasive and simultaneous measurements of sound and displacement information at specific points of the thoracic cage. The investigators will conduct a measurement campaign in the context of follow-up in private practice. The measurements will be analyzed with numerical methods specifically developed in order to achieve an automatic identification of pathological respiratory sounds. The investigators will also try to localize bronchial obstructions and to correlate them with respiratory volume variations measured before, during and after the management session.

European Multicentre Registry of Percutaneous Paravalvular Leak Closure

OBJECTIVES OF THE STUDY MAIN OBJECTIVE To evaluate the clinical results of the transcatheter closure of para-prosthetic leaks. SECONDARY OBJECTIVE Technical success of the procedure defined by successful placement of the prosthesis at the intended site with at least a 1 grade reduction in leakage and residual leakage grade 0-1 Change in quality of life after closure of para-prosthetic leakage at 3 months Evolution of clinical and biological markers of hemolysis and heart failure between at 3 months evolution of clinical markers of functional capacity 4. JUDGMENT CRITERIA 4.1 PRIMARY ENDPOINT -Clinical success of the procedure: Clinical success will be assessed on a composite endpoint at 2 years: - vital status, - hospitalization for heart failure, - blood transfusion for hemolysis, - surgical or percutaneous re-intervention on the treated valve. 4.2 SECONDARY ENDPOINTS The technical, echographic, biological and clinical data of the procedure and post procedure will be recorded as well as the complication rates. The EQ5D-5L quality of life score will be evaluated before the procedure, between 1 and 3 months, and post procedure. STUDY POPULATION INCLUSION CRITERIA To be included, each patient must meet all of the following conditions: - Patients aged 16 years and older, - Patients or the representative of the parental authority of the minor patient who does not object to participation in the observatory, - Patients referred for a para-prosthetic leak closure procedure NON-INCLUSION CRITERIA Patients presenting at least one of the following criteria cannot be included - Patients under 16 years of age, - Refusal of the patient or the representative of the parental authority of the minor patient to participate in the observatory.

Diagnostic Performance of Spot Urine Sample for the Monoclonal Components Detection in Patients With Multiple Myeloma

To evaluate the detection sensitivity of the urinary monoclonal component on a spot urine sample, compared to the reference measurement on 24-hour urine, in Multiple Myeloma patients. 300 evaluable patients are required. For each of them, both spot urine sample and 24h urine sample will be collected at Cycle1 Day1, Cycle 2 Day 1 and Cycle 4 Day 1. The detection of urine monoclonal component will be performed by urine protein electrophoresis (quantitative) and urine immunofixation (qualitative).

Objective and Perceived Health Status of Elderly People With Moderate or Severe Haemophilia in France: an Ancillary Study of the FranceCoag Registry

AVAJAK: Apixaban/Rivaroxaban Versus Aspirin for Primary Prevention of Thrombo-embolic Complications in JAK2V617F-positive Myeloproliferative Neoplasms

Task-sharing and Shifting Model for Acute Low Back Pain

Intraoperative Indocyanine Green Fluorescence Angiography in Colorectal Surgery to Prevent Anastomotic Leakage

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer in the world and the third in France. Its incidence is steadily rising in developing nations. Anastomotic leak (AL) is a major problem in colorectal surgery affecting at least 7% of patients operated on for left colonic cancer. It is the most feared complication after colorectal anastomosis, associated with mortality, prolonged hospitalization, impaired health related quality of life (HRQoL) and increased health care costs. Intraoperative fluorescence angiography (IOFA) with indocyanine green (ICG) may help preventing AL. Available studies on the effects of IOFA with ICG are heterogeneous and randomized controlled trial are scarce. Our aim is to demonstrate that IOFA with ICG could lead to a reduction of AL rate after left-sided or low anterior resection with anastomosis for CRC. The FLUOCOL-1 study is the first national, multicenter, single blind, randomized, 2-arm, phase III superiority clinical trial. The primary endpoint is the occurrence of an AL 90 days post-operation. AL is defined as any anastomotic dehiscence with leakage into the pelvic cavity diagnosed upon imaging or at surgical exploration or any isolated pelvic organ-space infection with no evidence of fistula as defined by the International Study Group of Rectal Cancer. The study population will be made of adult patients with left-sided or high rectal cancer scheduled to undergo elective left colectomy or high rectal resection (by open, laparoscopy or robotic surgery) and with expected stapled or handsewn intraperitoneal anastomosis. The exclusion criteria are mainly an emergent surgery; rectal cancer requiring total mesorectal excision and anastomosis expected below the peritoneal reflection; CRC requiring total or subtotal colectomy; CRC requiring transverse colectomy; recurrent CRC and locally advanced colorectal cancer requiring multi-visceral excision. The 26 participating centres are equipped with a scope with near-infrared (NIR) light source allowing real-time ICG perfusion assessment. The co-investigators are experienced digestive surgeons trained to work with and without IOFA. They have considerable experience in working together on research projects and have a proven track-record of efficacy. Moreover, this study will receive valuable support from the Surgery Research Network (FRENCH) and the Surgical Research on Rectal Cancer Group (GRECCAR), which have proved their ability to recruit patients into various multicentric studies and with which the FLUOCOL-1 project has been discussed. The duration of participation for each patient is 90 days. The 3 study visits are superimposed to the schedule of standard of care (V1: pre-operation visit of selection and inclusion; Surgery; V2: 30-day post-operation visit and V3: 90-day post-operation visit). The surgeon will do the 1:1 randomization between V1 and the day before surgery (D-30 to D-1). To reduce the risk of bias, patients will be blinded to the study group and the randomization will be stratified on participating centres, Body Mass Index (BMI), physical status classification score (=ASA score), preoperative treatment and tumor location. Patient will be assigned in the intervention (IOFA) or the control group (no IOFA). At the exception of the information given on the study to the patient, the gathering of the written consent, the randomization and the HRQoL questionnaires, the patient will be treated following standard of care. Study data are the data systematically collected in the patient medical file except for the HRQoL questionnaires that will be collected under the supervision of a research technician financed by the study. The technician will capture the study data and the de-identified pdf version of the medical reports (consultations and hospitalizations) in the electronic Case Report Form (eCRF) after every visit. A total of 1010 patients will be necessary (39 patients in each centre during 36 months). An interim analysis for efficacy and futility is scheduled when half of the participants will have been recruited. The ICG will be graciously provided by the manufacturer (SERB). An investigator meeting will be organized twice a year during the annual GRECCAR and FRENCH meetings. Newsletters will be sent every 3 months. In case of positive results favoring IOFA, this study would define the use of IOFA as a standard of care in colorectal surgery. At the patient level, a significantly lower rate of AL will reduce hospital stay and stoma rate, and will ensure improved postoperative recovery, faster return to normal activity and better long-term oncologic outcomes.

Auvergne-Rhône-Alpes-Limousin Research Database for Still's Diseases in Children and Adults

Analysis of Biological Characteristics of Advanced ALK-rearranged NSCLC

BioEXALK is a prospective study evaluating the biological characteristics of advanced ALK-rearranged NSCLC treated with new generation TKIs in first line, included in the national EXPLORE ALK cohort (GFPC 03-2019). Explore ALK GFPC 03-2019 is a non-interventional, national, multi-center cohort of ALK-rearranged NSCLC patients, whose RCB reference is 2020-A00771-38 and which obtained an approval from the IDF II Ethic Committee on 25/05/2020. Biological analysis will be performed on tissue at diagnosis and at the time of disease progression when available and on circulating tumor DNA (ctDNA) on three timepoints (diagnosis, at first tumor evaluation and at the time of disease progression). - Tissue : RNAseq will be performed on tumor biopsy (10 slides of 5 microns) to identify the ALK fusion partner and its variant and associated co-mutations.. - ctDNA : NGS panel on DNA including a large panel of fusions and mutations will be performed on blood samples (30mL on EDTA or STRECKs tubes) at diagnosis, at the time of the first evaluation and at the time of progression). For plasma testing, after obtained patient consent, blood samples (35mL on EDTA or STRECKs tubes) at diagnosis, at the first evaluation and at disease progression will be taken. The ALKis include alectinib and brigatinib as first-line therapy or other drugs with marketing authorizations (lorlatinib, entrectinib) or in early access programs (EAPs). Liquid biopsies will be analyzed with a NGS panel allowing the identification of ALK fusion partners and resistance mechanisms (mutations, fusions, copy number variations). Samples will be sent for centralized analysis to the Léon Bérard Center (Lyon). For biological analysis on tissue obtained at diagnosis, the ALK fusion partner and its variant will be identified by RNAseq. Whenever a tissue re-biopsy is performed at the time of disease progression as part of the standard of care management of the patient, the remaining tissue sample will be collected as part of the BioExALK study, so that RNAseq analysis will be performed to look for resistance mechanisms. Tissue samples (10 slides of 5 microns) will be sent for centralized analysis to the Rouen University Hospital.