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Establishing a living biobank of pediatric high-grade glioma and ependymoma suitable for cancer pharmacology
No full textInternational audienceBackground: Brain tumors are the deadliest solid tumors in children and adolescents. Most of these tumors are glial in origin and exhibit strong heterogeneity, hampering the development of effective therapeutic strategies. In the past decades, patient-derived tumor organoids (PDT-O) have emerged as powerful tools for modeling tumoral cell diversity and dynamics, and they could then help define new therapeutic options for pediatric brain tumors.Methods: Through an integrative approach based on our expertise and a careful review of the literature about glioblastoma 3D primary cultures, we set up a standardized methodological pipeline for the establishment, characterization, and biobanking of PDT-O through direct 3D in vitro culture of the deadliest pediatric glial brain tumors. To assess PDT-O fidelity and validate their preclinical relevance, we performed comprehensive histological, molecular, and drug-response analyses.Results: Our methodological pipeline allowed the rapid and efficient generation of PDT-O recapitulating their parental tumor features, including intratumoral heterogeneity, even after several passages and cryopreservation/revival as 3D cultures. Moreover, we successfully performed preclinical test responses on these PDT-O to standard-of-care therapies and new therapeutic options. Finally, we identified ONC201 as a selective drug for pediatric glial tumor types not restricted to H3K27-altered glial tumors, as well as combination strategies to increase the therapeutic response to ONC201.Conclusions: Hence, we describe a fast and robust process to biobank PDT-O for pediatric glial brain tumors. These PDT-O models have the potential for patient-specific modeling even after long-term expansion in vitro, and we established the proof-of-concept of their usefulness to support powerful preclinical studies
Incisional Negative Pressure Wound Therapy devices applied after Total Ankle Arthroplasty: A Hospital-Based Health Technology Assessment
No full textInternational audienceIntroduction A portable, single-use incisional Negative Pressure Wound Therapy (iNPWT) device could be used directly on the wound incision following Total Ankle Arthroplasty (TAA). In order to support local decision-making in a French university hospital for the adoption of such device in this indication, a three-dimensional (clinical, economic and organizational) Hospital Based-Health Technology Assessment (HB-HTA) was conducted. Materials and methods The HB-HTA was based on: a literature review; results from the PICO-PTC single-site randomized controlled trial (ClinicalTrial.gov identifier NCT03886818); and semi-structured interviews with healthcare professionals. Results Two comparative retrospective cohort studies were retrieved from the literature review. They suggested a decreased incidence of wound healing complications with iNPWT compared to standard dressings, although no difference was found in the PICO-PTC study. There was no significant difference in the PICO-PTC study on Medicine-Surgery-Obstetrics hospital costs between the two strategies: €10,639.65 [CI 95% (7,997.45; 17,988.68)] in the iNPWT group versus €9,672.59 [CI 95% (7,966.29; 13,393.65)] in the standard dressings group. Adoption of this prophylactic strategy would result in an approval to pay a 1.5% supplement to the Medicine-Surgery-Obstetrics hospitalization costs. It could also improve professionals’ workflow, and facilitate wound healing monitoring for nurses in orthopedic departments compared to standard dressings. Conclusion The clinical effectiveness of the iNPWT single-use portable device could not be demonstrated compared to standard dressings for prophylactic use, in terms of the incidence of wound healing complications, in patients scheduled for TAA and not selected on the basis of risk factors. However, as this strategy may bring organizational benefits and has not been associated with significant economic costs, the adoption of iNPWT in orthopedic departments could be made according to the surgeon’s clinical expertise, based for instance on the patient’s risk factors for complications
Mechanical characterisation of femoral cancellous bone samples with metastases
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Prescribing and Dispensing of Oral Isotretinoin and Noncompliance with Recommendations in France before and during the COVID‐19 Pandemic
No full textInternational audienceIntroduction: The coronavirus disease 2019 (COVID-19) pandemic disrupted care organization in France, likely changing the use of oral isotretinoin and worsening noncompliance with recommendations. We described the number of dispensations of isotretinoin, use of teleconsultation, and noncompliance with recommendations, before and during the COVID period.Methods: This nationwide cohort included all subjects with isotretinoin dispensation between 2019 and 2022, using data from the French Health Data System (SNDS). The pre-COVID period corresponded to 2019, and the COVID period to 2020, 2021, and 2022. The first lockdown took place between March and May 2020. We calculated the relative change in the number of total and first dispensations and the difference in the percentage of teleconsultation and noncompliance with recommendations, including treatment initiation by dermatology specialists, prescription renewal, and pregnancy testing (PT), for each month, using 2019 as the reference. PT compliance was assessed in women aged 11-50 years.Results: A total of 2,020,624 dispensations were identified between 2019 and 2022, including 18.1% of first dispensations. Compared with the pre-COVID period, the number of total dispensations decreased (April 2020: -12.6%; May 2020: -9.7%), as did the number of first dispensations (March 2020: -18.3%; April 2020: -37.6%). Nevertheless, the number of total and first dispensations increased over the other months. The teleconsultation rate was close to 0 in the pre-COVID period and increased by 21.8% in April 2020. Noncompliance with treatment initiations by dermatologists increased throughout the COVID period compared with the pre-COVID period (mean: 2.2%; range: -0.5% to 5.5%). Noncompliance with prescription renewal and PT increased during the first lockdown (April 2020: 8.9% and 9.5%, respectively), and tended to stabilize thereafter.Conclusions: The effect of the COVID-19 pandemic on isotretinoin use was mainly observed during the first lockdown. This study also highlights persistent noncompliance and the need to assess the new French communication actions
Implementing a nurse-led safety planning intervention in emergency departments to prevent suicide reattempts: a stepped-wedge randomized controlled trial protocol (French multicentre randomized controlled trial with a stepped-wedge design)
No full textInternational audienceSuicide prevention is a worldwide challenge, and an emergency department (ED) visit is a key moment to prevent subsequent suicide risk. Previous studies reported the effectiveness of safety plan interventions (SPI), which are recommended by the suicide prevention resource centre and various health ministries. The safety plan encompasses a range of strategies to prevent and manage suicidal thoughts and actions. Our study (PROTECT) aims to evaluate the effectiveness of the SPI before patient discharged after suicide attempt by nurses and other health care professionals in the ED. Secondly, we will examine the implementation of the intervention among healthcare professionals and patients. The primary outcome is the reduction of suicidal behavior at six months, including suicide reattempts and death by suicide, after the index suicide attempt in patients who received the SPI compared to those who received the practices as usual. The effectiveness of the SPI will be evaluated through a multicenter stepped-wedge cluster randomized controlled trial. 2,387 people who have attempted suicide will be identified in 20 EDs and will first be observed during a control phase. The control group (observation phase) is defined by the administration of usual practices, which include the suicidal recontact program (Vigilans) combined with specialized follow-up tailored to each patient. Initially, the research teams will train emergency professionals in the use of the SPI (transition phase). Finally, an intervention phase will be activated during which the SPI will be implemented in addition to practices as usual. PROTECT is the first study to largely evaluate the effectiveness of the SPI and is the first ongoing study with a large number of included participants and participating centres. Significant findings may aid in the adoption of novel nursing care approaches to prevent suicide reattempts in the ED. The present trial has been registered on the ClinicalTrials.gov database (NCT05609487) since 8 November 2022
Anticoagulant management in emergency settings: 2024 guidelines from the French Society of Emergency Medicine (SFMU), the French Society of Anaesthesia and Intensive Care Medicine (SFAR), the French Society of Thrombosis and Haemostasis (SFTH) and the French Working Group on Perioperative Haemostasis (GIHP)*
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Definition of clinical immunology around the globe
No full textInternational audienceImmunology has gradually become a core part of many medical specialties. Immune cells and immune mediators are now known to participate in the pathogenesis of a wide variety of diseases and therapies based on the modulation of immune function are increasingly used. Traditionally, clinical immunologists have studied patients with inborn errors of immunity (IEI), previously known as primary immunodeficiencies, and with allergic conditions. More recently, clinical immunology has become involved with a broader array of disorders. The Clinical Immunology Committee of the International Union of Immunological Societies set out to understand how clinical immunologists perceive their specialty to identify similarities and differences in training and practice around the globe. For this purpose, a specific questionnaire was designed and distributed amongst our member societies. More than 500 participants answered the questionnaire, 80% of whom had completed their training. Roughly two thirds of respondents were physicians directly involved in patient care. We found that though the number of diseases and processes in which immune mechanisms are involved has considerably grown, 90% of participants agree with the 1993 World Health Organization definition of Clinical Immunology. We propose that the increased complexity of the field opens a need for multidisciplinary teams of clinicians and basic researchers and for a broader training of specialists
Characterization and Treatment Outcomes of Malignant Histiocytoses in a Retrospective Series of 141 Cases in France
No full textInternational audienceMalignant histiocytoses (MH) are rare and poorly understood cancers, with no established therapeutic guidelines. We conducted a national retrospective study of MH diagnosed in France between 2000 and 2023. All cases underwent centralized histological review, and several malignant tumors with a stroma highly enriched in histiocytes were excluded. In total, 141 patients were included, with a median age of 62 years (range, 1-87). The cases comprised either primary MH (64%) or MH associated with other hematologic malignancies (36%). Phenotypes corresponded to histiocytic (43%), interdigitating dendritic cell (37%) or Langerhans cell (12%) sarcomas, or high-grade indeterminate dendritic cell tumors (10%), as per the World Health Organization classification. Tumor cells were almost universally positive for CSF1R and PU.1, and 85% showed phosphorylated extracellular signal-regulated kinase positivity. Next-generation sequencing was performed in 75 cases. Mutations in the MAPK pathway were more frequent in secondary compared with primary MH (90% vs 55%; P = .0012). PTPN11 mutations were exclusively observed in primary MH (P = .0035). Mutations in genes related to DNA methylation mechanisms (TET2, ASXL1, DNMT3A) and TP53 were present in 20% and 14% of cases, respectively. Although therapeutic regimens varied considerably, our results demonstrate that surgical resection in localized cases, and the use of BRAF or MEK inhibitors achieved the highest complete response rates, at 63% and 21%, respectively. The prognosis remains poor, with a 5-year overall survival rate of 31%, which is comparable to that of T/natural killer cell lymphomas. Prospective follow-up and a standardized treatment approach in specialized reference centers are crucial to improving patient survival. This trial was registered at www.clinicaltrials.gov as #NCT04437381
Take Caution of Normal Visual Acuity in Posterior Cortical Atrophy!
No full textInternational audienceHigher-order visual symptoms of patients with posterior cortical atrophy (PCA) are not well recognized in routine ophthalmological examination. More specifically, vision as assessed by the Snellen or Monoyer chart may not be sensitive enough. We hypothesized increased visual difficulties related to 1) visual crowding and to 2) short distances/larger stimuli. We therefore aimed at comparing 1) far visual acuity measures using the Monoyer (each line is presented separately) and the ETDRS charts (all lines are presented at the same time), as well as 2) far and closer visual acuity using the ETDRS chart (at 4 and at 2 meters). These tests were performed in a group of patients with PCA (PCA-AD) and a group of typical amnesic form (T-AD as a control group) of Alzheimer disease (AD) without any ophthalmologic pathology. While the Monoyer chart did not allow to distinguish between the two groups, the PCA-AD group specifically displayed a decrease of visual acuity when the ETDRS chart, rather than the Monoyer chart, was tested at 4 meters (effect of visual crowding), and another decrease when the ETDRS chart was tested at 2 meters, rather than at 4 meters (effect of stimulus size/distance). This uncommon decrease of visual acuity with closer distance correlated with a score of higher-order visual symptoms (Q-ACP). The present study incites ophthalmologists to pay attention to the possible discrepancy between different conditions of visual acuity assessment and preconizes to combine these conditions for a better evaluation
The mutational landscape of ARMC5 in Primary Bilateral Macronodular Adrenal Hyperplasia: an update
No full textInternational audienceBackground Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a rare cause of Cushing’s syndrome due to bilateral adrenocortical macronodules. Germline inactivating variants of the tumor suppressor gene ARMC5 are responsible for 20–25% of apparently sporadic PBMAH cases and 80% of familial presentations. ARMC5 screening is now routinely performed for PBMAH patients and families. Based on literature review and own observation, this study aims to give an overview of both published and unpublished ARMC5 genetic alterations and to compile the available evidence to discriminate pathogenic from benign variants. Results 146 different germline variants (110 previously published and 36 novel) are identified, including 46% missense substitutions, 45% truncating variants, 3% affecting splice sites, 4% in-frame variants and 2% large deletions. In addition to the germline events, somatic 16p loss-of-heterozygosity and 104 different somatic events are described. The pathogenicity of ARMC5 variants is established on the basis of their frequency in the general population, in silico predictions, familial segregation and tumor DNA sequencing. Conclusions This is the first extensive review of ARMC5 pathogenic variants. It shows that they are spread on the whole coding sequence. This is a valuable resource for genetic investigations of PBMAH and will help the interpretation of new missense substitutions that are continuously identified