Touquin, France

French Registry for Monitoring Pregnancies for Multiple Sclerosis

METHODOLOGY Prospective, observational, multicentric and national epidemiological study, within the scope of the OFSEP, including all groups of patients eligible to participate in the Observatoire Français de la Sclérose en Plaque (OFSEP) (definite MS, radiologically isolated syndromes, clinically isolated syndromes, neuromyelitis optica (NMO) and NMO spectrum disorders), with no age limit and an ongoing pregnancy. Women will be followed during pregnancy and in the year after and their children until 6 years of age. STATISTICAL ANALYSIS To be determined for each specific question. EXPECTED RESULTS Interactions between pregnancy and MS course have been well characterized before the therapeutic era. Neurologists and patients are lacking information to weigh benefits and risks of DMDs used immediately before or during pregnancy, including short and long-term risks to the mother and to the child, but also after delivery. This study should help provide better answers to those questions as well as to still controversial questions about locoregional analgesia and breastfeeding. By following these patients within the Observatoire Français de la Sclérose en Plaque (OFSEP) cohort, the investigator will also have access to a comprehensive description of MS before pregnancy but also in the long term.

Protocol of Diuretics Use in Congestive Therapy in Heart Failure

Diuretics are the main treatment for congestive decompensation of chronic heart failure. For symptomatic purposes, the goal is to decrease the volume overload. In these patients, loop diuretics are used in high doses, sometimes in combination with other classes of diuretics such as thiazides to achieve synergistic, faster and more effective action, and to combat diuretic's resistance. This use, well known to cardiologists and based on a rich pharmacology, more than 40 years old, lacks robust scientific data in real life. Current studies are mainly based on patients with renal insufficiency or limited to cardio-renal syndrome. The CARRESS-H study in 2012 is one of them. The protocol for the use of diuretics from this study was included in 2017 as a benchmark in a publication of the NEJM. It therefore seems necessary to consider the exercise of this protocol in the management of the decompensation of chronic cardiac heart failure. There is, to the investigator's knowledge, no similar study to test this protocol as a "real life" exercise.

Survival and Description of Care for Patients With Degenerate Vaterian Ampulloma

A Vater's ampulloma is a rare digestive tumour which accounts for under 1% of all digestive tumours. In terms of incidence, it is the 3rd most common biliary tract tumour after gallbladder cancer and common bile duct cancer. The incidence of ampullary adenocarcinoma is not well known although it is estimated to be around 0.49 per 100,000 people. The known risk factors are familial adenomatous polyposis (FAP) and Gardner's syndrome, HNPCC (Hereditary Non-Polyposis Colorectal Cancer) syndrome, Peutz-Jeghers syndrome, Crohn's disease and coeliac disease. Except in its highly localised forms, ampulla of Vater carcinoma carries a poor prognosis. It is a highly lymphophilic disease which commonly metastasises, particularly to the lymph nodes and liver. The prognosis is however considerably better than that of pancreatic adenocarcinoma. In one study which compared 71 ampullomas with 144 adenocarcinomas of pancreatic head, the 5-year survival was 60% for the ampullary carcinomas compared to 20% for pancreatic adenocarcinomas. More generally, the 5-year survival rate in the literature is between 40-60% and, depending on the study, 10-year survival is approximately 38% . The only curative treatment is complete excision (surgical or endoscopic) of the lesions which is possible in 80% of cases , with or without adjuvant treatment. The reference radical treatment is cephalic duodenopancreatectomy (CDP). The 5-year survival rate in cases of adenocarcinoma excised by CPD is in the region of 50%, rising to 60-70% if no lymph node invasion is present, compared to 30% when lymph nodes are invaded and median survival is approximately 4.5 years . The indication for adjuvant treatment is still debated: in view of the aggressive nature of the disease and the high recurrence rate, it would appear appropriate to offer adjuvant treatment, although several studies have failed to find any benefit on survival with post-operative radio-chemotherapy, the most widely studied treatment at present, compared to excision alone . There is only one single randomised study comparing these two forms of management, which shows no benefit in terms of 2 and 5-year survival, although only a small number of patients had an ampullary tumour in this study . The conclusions of several retrospective studies are more subtle, showing results in favour of adjuvant treatment in patients with lymph node disease or a large tumour (T3/T4) . Some groups have tested the merits of peroperative irradiation. It would appear that this technique does not improve survival, although data on this subject are extremely patchy . Administration of exclusive adjuvant chemotherapy has been examined in a single randomised study. In this phase III study (ESPAC 3), median overall survival of patients who received adjuvant chemotherapy with FUFOL Mayo for 6 months (n=101) or gemcitabine (n=98) was not significantly improved compared to survival in patients undergoing surgery and not receiving complementary treatment (57.1 versus 43 months, HR= 0.85, p=0.32). A subgroup analysis suggested that the benefit of chemotherapy could be greater in the subgroup of patients with RO resection (p= 0.057, 91% of cases). Mean survival in patients suffering inoperable tumours is between 9 and 20.4 months depending on the study . It should be noted however that most of these studies have included tumours other than ampullomas (particularly small bowel adenocarcinomas), making it more difficult to interpret these results, and also that many are old results dating from before the era of modern chemotherapies. At present there are no phase II studies specifically examining medical treatment of degenerated, inoperable Vater's ampullomas. Some groups propose chemotherapies with 5-FU or gemcitabine, analogous to the treatments used for intestinal, pancreatic or biliary tumours, although neither one has been shown to date to be superior to the other, nor have decision-making criteria been clearly established. One phase II study published in 2009 proposed CAPOX as the reference treatment in light of the promising results obtained. Patients suffering from ampullary cancer in this study however were combined with patients who were suffering from small bowel adenocarcinoma. In conclusion, a national cohort study is proposed to undertake a prospective analysis of the outcome of all patients treated for ampullary adenocarcinoma (particularly survival without recurrence and prognostic indicators for excised tumours and the duration of disease control for tumours treated with palliative chemotherapy). The treatment methods will be left to the free choice of the investigator and all patients may be included, regardless of stage of their disease. In this study, freezing of tumour fragments is encouraged, as this cohort will be supplemented by a later biological study. In order to recruit sufficient patient numbers, the study will be based on participation of the cooperative groups involved in the management of digestive cancers.

A New Breath for Malignant Hypertension: Implementation of the HAMA Cohort

Malignant hypertension is the most severe form of high blood pressure, fatal if left untreated. It has not disappeared, with an increasing incidence. Patients with the disease, mainly young (35 to 55 years of age), have an unfavorable cardiovascular prognosis (14% of cardiovascular and renal events at 4 years). Despite these facts, scientific research on the subject remains limited. The definitions and diagnostic criteria have not changed since 1929, and the therapeutic recommendations remain empirical. This first prospective and multicentric registry will increase and modernize the knowledge of the disease. From these data, diagnostic and therapeutic recommendations based on solid scientific evidence could be developed. The investigators want to first recruit 500 patients and define their prognosis at 5 years. The impact of the patient's phenotype, type and number of target organs affected will be studied. A modern definition, adapted to these results, could be proposed. The epidemiology of the disease, the care pathways, the target organ disorders and the management carried out in the centers will be described in detail.

Evaluation of the Benefit at 6 Months of a 3 Weeks Spa Treatment in the Type 2 Diabetic Patient.

In recent years, many medical decision support software (diagnostic or therapeutic) have emerged to help doctors in their choices. For type 2 diabetes, apart from a decision-making aid tool posted on the HAS website, the Diascope tool can be cited. A group of 12 European experts came together to create this software to help doctors when diabetic patients do not reach their goal. They worked on more than 2000 clinical scenarios and thus established therapeutic recommendations. They prioritized the recommendations in 3 levels. For each patient profile, the most appropriate therapeutic proposals appear in green, inappropriate options appear in red, and acceptable but uncertain options appear in yellow. These two tools can help optimize patient management by finding the therapeutic strategy that is closest to the recommendations that are adapted to each patient. Therapeutic education, which has a key role in the care of these patients, has a demonstrated impact on quality improvement. In this prospective study, the authors also found a link between improved quality of life and lower HbA1c. This study uses the Diabetes Quality of Life (DQOL) score. A more appropriate score allowing a customization of the elements constituting the quality of life is the Audit of Diabetes-Dependent Quality of Life score (ADDQOL score). Physical activity is recommended for multiple reasons in Health. The summary of Inserm's collective expertise perfectly summarizes the benefits and the modalities of a physical activity for Health. There are clear international recommendations on the subject of moderate physical activity of at least 150 minutes per week, for example on the World Health Organization website or in the text of the recommendations of the American College of Sport Medicine and the American Heart Association. Adaptations of these recommendations for older people are also available. Walking and cycling are the two physical activities most cited in these documents because of their progressive and mild characteristics particularly suitable for patients with rheumatological indications and / or significant overweight. However, the practice of cycling can, depending on the natural terrain, involve efforts and pressures in joints and musculotendinous too important. This will often be the case in the natural environment of the most often hilly spas. In addition, there are many practical or psychological obstacles to cycling in a population of patients suffering from chronic pathologies: "it's too hard", "I do not know how to do it anymore", "it's for young people "," I am less strong than the others so I can not accompany them in their outings ".... The electric assistance bicycle (EVA) can then be useful. A very comprehensive report from the DGS (Direction Générale de la Santé : General Health Direction) of the Canton of Geneva takes stock of the positive impact of the dissemination of routine use of VAE (Available on http://www.impactsante.ch/pdf/EIS_VAE_2006.pdf). Still in Switzerland, J Welker, despite a provocative title, concludes that "The electric-assisted bicycle (EVA) is a physical activity in its own right and represents a means to fight sedentariness". These authors suggest from a study conducted in Lausanne that VAE even with a high attendance represents a real physical activity (> 6 MET) on hilly paths. It has been shown on small series with real-time measurements of the effort that the VAE with strong attendance was equivalent to a brisk walk and that the VAE with moderate assistance was intermediate in terms of physical effort between brisk walking and cycling without. It has also been shown that the use of VAE can achieve the objectives recommended for the practice of physical activity. The hydrotherapy has demonstrated its effectiveness especially for indications rheumatology and for the management of obesity (indication metabolic diseases). The benefit of the multifaceted actions implemented during a spa treatment concerns the symptoms, the reduction of pain and / or weight loss. As a result, randomized controlled trials have shown a benefit on quality of life. Metabolic disorders and especially diabetes and overweight are an indication of thermal cures. Two studies have shown positive results of a thermal cure on metabolic disorders. The first is a multicentre study in overweight or obese subjects (8% of whom are diabetic) who has demonstrated a significant benefit on weight and body mass index (BMI) of a spa treatment and the maintenance of this condition. improvement one year later compared to a control group. The second is a monocentric study in which a disappearance of a metabolic syndrome was observed one year after a spa treatment for 50% of patients included and 76% of patients followed at one year. Finally, an improvement in weight, BMI and fasting blood glucose at the end of a spa treatment was found in a preliminary study in 21 subjects with type 2 diabetes, with a decrease of 0.5% in glycated hemoglobin (HbA1c) 3 months after the beginning of the treatment. These positive data on parameters strongly correlated with diabetes (weight, BMI, metabolic syndrome), and on the glycemic parameters of a preliminary study with a small number of diabetic patients justify the completion of a multicenter study to evaluate the benefit to a patient. year of a 3 weeks spa treatment in the type 2 diabetic patient.

A Study Evaluating Platinum-Pemetrexed-Atezolizumab (+/-Bevacizumab) for Patients With Stage IIIB/IV Non-squamous Non-small Cell Lung Cancer With EGFR Mutations, ALK Rearrangement or ROS1 Fusion Progressing After Targeted Therapies

In patients with an EGFR mutation, several phase III studies comparing EGFR tyrosine kinase inhibitors (TKIs) with chemotherapy have shown a benefit of TKI over chemotherapy, with no demonstrated benefit on overall survival. After a first line of treatment with a TKI, most patients progress and are eligible according to the mechanism of progression to a TKI of 3rd generation in case of T790M resistance or chemotherapy. In patients with ALK translocation, crizotinib has been shown to be beneficial in first line compared to a platinum doublet.Despite these major advances, most patients are progressing after targeted treatments and chemotherapy and are facing the problem of anti-PD1 / PDL1 treatment.

EPIgenetics and in Vivo Resistance of Chronic Myeloid Leukemia Stem Cells to Tyrosine Kinase Inhibitors

Chronic myeloid leukemia (CML) is a model of leukemogenesis because the malignant transformation of a hematopoietic stem cell is considered as the consequence of a unique major event: the translocation t(9;22) which is able to produce the BCR-ABL chimeric protein. The treatment of CML has made considerable progress with the development of tyrosine kinase inhibitors (TKI) targeting the BCR-ABL protein activity. Despite the efficacy of these drugs, several studies showed the existence of intra-clonal heterogeneity and the in vivo survival of a leukemic stem cell (LSC) subset by: - A detectable residual disease in the majority of cases, and after treatment for several years. - The relapse of about half of patients after stopping TKI; these relapses are the proof of the in vivo persistence of LSC, even when CML clone is particularly sensitive to TKI. - Cases of unexplained TKI resistance (no BCR-ABL mutation etc…) The mechanisms involved in in vivo survival of LSC remain largely unknown. Mechanisms independent of BCR-ABL TK activity could be responsible of LSC survival. However, the fact that CML is the consequence of t(9; 22) if it appears in a HSC, suggests that a stem cell specific biological status should play a role in the emergence of the disease and probably the special feature of this cell subset. Several studies showed the essential role of epigenetic factors in stem cell behavior (quiescence, self-renewal, or differentiation process). Epigenetic dysregulation of some gene expression was observed in CML cells and changes in DNA methylation are involved in CML progression towards accelerated or blast phase, more resistant to TKIs. These observations led to clinical trial combining TKI with epigenetic drugs which results confirmed the in vivo involvement of epigenetic mechanisms during CML progression. However, the role of epigenetics in the early resistance of a chronic phase CML cell subset remains unknown. The hypothesis is that epigenetic features could participate in TKI resistance of CML LSC and their survival in bone marrow. In order to identify new mechanisms and/or new targets involved in LSC resistance, investigator choose a global approach of DNA methylation profile with an HM450K microarray. Investigator analyzed the sorted CML CD34+ CD15- cell subset (n=6) in comparison with: 1) CD34+ CD15- cells from healthy donors (hematopoietic grafts), in order to eliminate specificities of normal hematopoietic hierarchy, 2) the CD34-CD15+ sub-clone from the CML clone before any treatment in order to eliminate characteristic of CML mature compartment. The CD34+CD15- cells showed a specific DNA methylation profile, from diagnosis and from this level of cell hierarchy ((Bourgne et al., oral communication, SFH meeting 2017, manuscript submitted). In order to identify biomarkers specific to CML cells, investigator removed abnormally methylated regions that are differently methylated during hematopoietic differentiation. After this step, 825, 2210 and 1461 probes identified regions specifically dysmethylated in CD34-CD15+, CD34+ CD15- CML cells and both respectively. Investigator also observed changes in expression of epigenetic actors. These results validate our hypothesis. With the recent data published in literature, they strongly argue in favor of the involvement of epigenetic dysregulation in native intra-clonal heterogeneity, and justify this original translational research project.

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

A Trial of Early Detection of Molecular Relapse With Circulating Tumour DNA Tracking and Treatment With Palbociclib Plus Fulvestrant Versus Standard Endocrine Therapy in Patients With ER Positive HER2 Negative Breast Cancer

The TRAK-ER trial is a multi-centre, randomised, open-label trial in patients with early stage oestrogen reception positive (ER+) human epidermal growth receptor-2 negative (HER2-) breast cancer, whom have detectable circulating DNA (ctDNA) but no overt macroscopic disease on imaging. TRAK-ER aims to demonstrate that fulvestrant plus palbociclib improves relapse free survival compared to standard endocrine therapy in this patient group. Despite current treatment, patients with ER+HER2- breast cancer are considered high-risk of distant recurrence for more than the first two decades after initial diagnosis. ctDNA analysis provides a non-invasive, serial source of tumour material which can monitor tumour dynamics and detect molecular relapse. TRAK-ER will be split into two phases, the first surveillance phase aims to investigate the use of ctDNA to identify and predict the risk of molecular relapse in early ER+/HER2- breast cancer patients whom are receiving adjuvant endocrine therapy with no overt macroscopic disease on imaging. Using ctDNA assays, patients enrolled on TRAK-ER will receive ctDNA testing on a three-monthly basis for up to three years. In the instance where ctDNA is detected, imaging will determine whether overt disease is present. If a patient had a positive ctDNA detection and no macroscopic disease on the staging scan, the patient will be randomised to one of the treatment groups in the second phase of TRAK-ER, the treatment phase. The treatment phase of TRAK-ER will be a randomised, open-label study which aims to determine whether fulvestrant plus palbociclib (intervention arm) improves relapse free survival compared to standard endocrine therapy (control arm) in patients carried through from the surveillance phase. Patients on each arm will receive treatment (fulvestrant plus palbociclib or standard endocrine therapy) for up to 24 months. Six monthly imaging will determine the presence of macroscopic disease. If macroscopic disease is observed, the patient will discontinue TRAK-ER treatment and commence standard therapy outside of the TRAK-ER trial.

Safety and Efficacy of Itacitinib in Adults with Systemic Sclerosis

Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue-disease characterized by fibrosis, inflammation, and vasculopathy. SSc is responsible for skin fibrosis that can either be limited or diffuse. The latter phenotype of the disease is commonly associated with visceral involvement and therefore similar to graft versus host disease (GvHD) reaction. It can be life threatening in case of pulmonary or cardiovascular involvement. Nonetheless SSc remains a severe disease responsible for important disability and a poor quality of life. There is a growing body of evidence that supports the implication of the JAK-STAT tyrosine kinases pathway in the activation of fibroblasts of patients with SSc. A genetic polymorphism of STAT4 was found to be associated with the diffuse form of the disease and inhibition of STAT4 gene is associated with a decrease in TGF-ß and IL-6 cytokines activation, which are two major cytokines implicated in SSc pathogenesis. Recently, Pedroza et al. confirmed the implication of STAT3 in skin fibrosis mechanisms. Indeed, the authors showed an enhanced activation of STAT3 and demonstrated in vivo that the inhibition of STAT3 phosphorylation prevented skin fibrosis in a murine model of SSc. These data were confirmed by a work of Zhang et al. who showed that the inhibition of JAK1 was also needed to prevent skin and lung fibrosis. Altogether these works confirmed the implication of the JAK pathway in fibrosis mechanism. Itacitinib is a Janus kinase inhibitor that specifically targets JAK1 and decreases STAT3 phosphorylation. Itacitinib was shown to efficiently treat patients with myelofibrosis, rheumatoid arthritis, and chronic plaque psoriasis. Very interestingly, itacitinib efficacy has also been reported in patients with acute GvHD. Altogether these data and studies reinforced the investigator's working hypothesis. The efficacy and safety of this proposal must be tested.