Search

Fabien Grimaud,1 Guillaume Penaranda,2 Chloé Stavris,3 Frédérique Retornaz,3 Véronique Brunel,4 Sylvie Cailleres,4 Hervé Pegliasco,5 Jacques Le Treut,5 Vincent Grisoni,6 Emilie Coquet,1 Laurent Chiche,3 Amélie Rognon1 1Department of Pharmacy, Hôpital Européen, Marseille, France; 2Department of Biostatistics, Hôpital Européen, Marseille, France; 3Department of Internal Medicine, Hôpital Européen, Marseille, France; 4Department of Haemato-Oncology, Hôpital Européen, Marseille, France; 5Department of Pulmonology, Hôpital Européen, Marseille, France; 6Department of Urology, Hôpital Européen, Marseille, FranceCorrespondence: Amélie RognonDepartment of Pharmacy, Hôpital Européen, 6 Rue Désirée Clary, Marseille, 13003, FranceTel +33 4 13 42 73 00Fax +33 4 13 42 76 80Email a.rognon@hopital-europeen.frAim: To assess the efficacy and tolerance of programmed death-1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors and the impact of a standardised management-based protocol in a real-world setting.Patients and Methods: Data from patients who had received anti-PD-(L)1 were collected from our pharmacy database. Clinical response and toxicity were assessed using RECIST criteria and CTCAE version 5.0, respectively. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan–Meier method. Potential prognostic factors were identified using Cox’s model.Results: A total of 196 patients and 201 lines of treatment were included (median age: 66 (range: 38– 89) years). Types of cancer included non-small cell lung cancer (73%), transitional cell carcinoma (10%), renal cell carcinoma (6%), small cell lung cancer (5%), head and neck squamous cell carcinoma (4%) and classical Hodgkin’s lymphoma (1%). Twenty-five (12%) patients had pre-existing autoimmune conditions. Our standardised management-based protocol included 129 (64%) patients. Objective response rate was 29%, median OS was 10 months (IQR: 7– 15) and median PFS was 5 months (IQR: 1– 22). Patients with an abnormal baseline complete blood count had a worse OS (HR=2.48 [95% CI: 1.24– 4.96]; p=0.0103). Thirty-three (16%) patients experienced severe (grade 3 or 4) immune-related adverse event (irAE). There were three (1%) irAE-related deaths. AEs resolved faster when patients were assessed by an internist before anti-PD-(L)1 initiation (p=0.0205).Conclusion: PD-1 and PD-L1 inhibitors are effective and safe in a real-world setting. Implementation of a standardised management-based protocol with internal medicine specialists is an effective way to optimise irAE management.Keywords: immunotherapy, elderly, PD-1 inhibitor, PD-L1 inhibitor, PDL-1 inhibitor, safety, immune-related adverse events, solid tumours, prognostic biomarkers

The Lacq area in southwest France has been associated with continuous moderate induced seismic activity since 1969. However, the mechanisms driving this induced seismicity are not fully understood: reservoir depletion has been proposed as the main factor, and more recently wastewater injection has been suggested to play a more important role. The interpretation of these mechanisms relies heavily on the quality of earthquake locations, which we prove to be weak due to a lack of local instrumentation for several years. In order to provide the most complete and reliable induced event catalogue for the studies of the Lacq induced seismicity mechanisms and seismic hazard, we made an exhaustive compilation, analysis and improvement of all available catalogues. We also provided new earthquake detections and relocations in a 3-D velocity model from past and present temporary deployments never used for studying the Lacq area. Important remaining location uncertainties lead us to also carefully sort the events according to their location confidence, defining 3 classes of events (unconstrained location, location constrained within 2–3 km and 1–2 km, respectively). This new harmonized catalogue and the identification of well-constrained events, covering 50 yr of induced seismicity, allow us to propose that wastewater injection is almost certainly the main mechanism driving the seismicity, with (i) most of the constrained events located within the reservoir boundaries and (ii) the released seismic energy variations following variations in injection operations at different scales. In particular, we have also highlighted a change in the injection–seismicity relationship around 2010–2013. From 2013, despite lower injection volumes, seismicity remained persistent and some clusters of earthquakes were detected predominantly in spring, summer and early autumn, except in winter periods. From 2016, we observed a strong temporal relationship between days with higher rate/volume injections (approximately above 400 m3 d−1) and both clustered events and higher magnitude earthquakes (greater than 2.4). [ABSTRACT FROM AUTHOR]

Local seismic networks are usually designed so that earthquakes are located inside them (primary azimuthal gap <<180°) and close to the seismic stations (0-100 km). With these local or near-regional networks (0°-5°), many seismological observatories still routinely locate earthquakes using 1-D velocity models. Moving towards 3-D location algorithms requires robust 3-D velocity models. This work takes advantage of seismic monitoring spanning more than 30 yr in the Pyrenean region. We investigate the influence of a well-designed 3-D model with station corrections including basins structure and the geometry of the Mohorovicic discontinuity on earthquake locations. In the most favourable cases (GAP < 180° and distance to the first station lower than 15 km), results using 1-D velocity models are very similar to 3-D results. The horizontal accuracy in the 1-D case can be higher than in the 3-D case if lateral variations in the structure are not properly resolved. Depth is systematically better resolved in the 3-D model even on the boundaries of the seismic network (GAP > 180° and distance to the first station higher than 15 km). Errors on velocity models and accuracy of absolute earthquake locations are assessed based on a reference data set made of active seismic, quarry blasts and passive temporary experiments. Solutions and uncertainties are estimated using the probabilistic approach of the NonLinLoc (NLLoc) software based on Equal Differential Time. Some updates have been added to NLLoc to better focus on the final solution (outlier exclusion, multiscale grid search, S-phases weighting). Errors in the probabilistic approach are defined to take into account errors on velocity models and on arrival times. The seismicity in the final 3-D catalogue is located with a horizontal uncertainty of about 2.0 ± 1.9 km and a vertical uncertainty of about 3.0 ± 2.0 km. [ABSTRACT FROM AUTHOR]

No injection treatment has been proven to be effective in wrist osteoarthritis. When conservative measures fail, its management involves invasive surgery. Emergence of biotherapies based on adipose derived stem cells (ADSC) offers promising treatments for chondral degenerative diseases. Microfat (MF) and platelets-rich plasma (PRP) mixture, rich in growth factors and ADSC could be a minimally invasive injectable option in the treatment of wrist osteoarthritis. The aim of this uncontrolled prospective study was to evaluate the safety of a 4 mL autologous MF-PRP intra-articular injection, performed under local anesthesia. The secondary purpose was to describe the clinical and MRI results at 12 months of follow-up. Patients' data collected were: occurrence of adverse effects, Visual analog scale (VAS), Disabilities of the Arm, Shoulder and Hand score (DASH) and Patient-Rated Wrist Evaluation (PRWE) scores, wrist strength, wrist range of motion and 5-level satisfaction scale. No serious adverse event was recorded. A statistically significant decrease in pain, DASH, PRWE and force was observed at each follow-up. Our preliminary results suggest that intra-articular autologous MF and PRP injection may be a new therapeutic strategy for wrist osteoarthritis resistant to medical symptomatic treatment prior to surgical interventions., Competing Interests: J.M. received honorarium for educational support from FIDIA, HORIBA ARTHREX and MACOPHARMA. These manufacturers had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Other authors did not declare any conflict of interest.

Introduction: The treatment of fractures of the mandibular condylar process remains controversial, especially in children. The aim of this study was to assess the long-term clinical and radiographic outcomes of functional treatments for mandibular condylar fractures with an articular impact., Materials and Methods: Young patients (< 15 years of age) presenting with either a unilateral or a bilateral mandibular fracture of the condylar process were included in this retrospective study. The clinical analysis focused on investigation of joint amplitudes at 1, 2, 6, 12, and 24 months after the beginning of the treatment, and at the end of their physical growth for the long-term study. Other clinical parameters included temporomandibular joint (TMJ) disorders and facial asymmetry. Photographs of patients and panoramic X-rays were assessed to identify any growth disorders at the end of the follow-up., Results: One hundred and eight patients were included in this study, and 33 patients who were no longer undergoing mandibular growth at the time of the last follow-up were included in the long-term study. The mean age at the time of the trauma was 9.33 years, and the mean follow-up was 82.2 months. A significant improvement was observed in the maximal mouth opening (MMO), diduction, and propulsion in the first months after the trauma, reaching 44.31 mm (p < 0.0001), 10.50 mm (p = 0.0001), and 6.33 mm (p = 0.01), respectively, at 6 months. Three patients experienced a clinical posterior vertical insufficiency, one of which required a surgical procedure, while four patients exhibited a ramus asymmetry of up to 10 mm, albeit with no clinical consequences. One case of TMJ ankylosis was noted., Conclusion: Our study suggests that functional treatment is appropriate for fractures of the mandibular condyle with an articular impact in children, as it promotes mandibular growth and good functional recovery. Children have to be followed up, however, until completion of growth., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Perianal fistulas in Crohn's disease are frequent and disabling, with a major impact on patients' quality of life. Cell-based therapy using mesenchymal stem cells represents new hope for these patients, but long-term efficacy remains challenging. In a pilot study, including patients with refractory complex perianal fistulas, autologous adipose-derived stromal vascular fraction (ADSVF) combined with microfat achieved combined remission in 60% of cases, with a good safety profile at 1 year. The purpose of this study is to assess whether these results were maintained at longer term. The safety and efficacy data of the ten patients were evaluated retrospectively 3 years after injection on the basis of clinical and radiological data. MRI were analysed according to the MAGNIFI-CD score. No adverse event was attributed to the experimental stem-cell treatment. Combined remission was achieved in 7 patients (70%) and associated with a significant improvement in the MAGNIFI-CD MRI score. In conclusion, the safety and efficacy of ADSVF and microfat injection in Crohn's disease fistulas were maintained at 3 years, demonstrating that this innovative strategy is effective in producing a long-lasting healing effect. The ongoing multicentre randomized placebo-controlled trial (NCT04010526) will be helpful to define the place for this approach in the current therapeutic arsenal., (© 2022. The Author(s).)

Purpose: To compare a single abdominal microfat (MF) injection mixed or not with platelet-rich plasma (PRP) Low Dose (LD) or High Dose (HD) in order to improve MRI parameters, alleviate pain and enhance functional capacity in knee osteoarthritis., Methods: Patients with symptomatic grade 2 to 4 knee osteoarthritis according to the International Cartilage Repair Society MRI classification were selected. They were prospectively assessed at baseline and at 3 and 6 months of follow-up. The primary endpoint was change in the maximum of value of cartilage relaxation time in T2 mapping sequences (T2max) at 3 months. Secondary endpoints were MRI grade severity and joint space assessment, Western Ontario and McMaster Universities Arthritis Index score, pain evaluation, knee range of motion, and patients' satisfaction. Adverse events were also collected. The complete cell counts and growth factors content of injected products were assessed to analyze their potential relationship with MRI and clinical outcomes., Results: Three groups of 10 patients received a single injection of 10 cc of a mix (1:1) containing MF-Saline, MF-PRP LD or MF-PRP HD. T2max did not change significantly over the time for any of the groups. All treatments significantly improved knee functional status and symptom relief at 3 and 6 months. All patients were responders in the MF/PRP HD at 3 months and significantly higher compared to MF/PRP LD. Half of the injected PRP in the MF/PRP LD group displayed red blood cell contamination of over 8%, which was correlated with an impairment of T2max., Conclusion: A single intra-articular injection of MF with or without PRP is safe and may offer a significant clinical improvement in patients with osteoarthritis., Level of Evidence: 2; randomized double-blind comparative parallel-group trial (RCT No.: NCT04352075)., (Copyright © 2021 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Background: Even though the manufacturing processes of the stromal vascular fraction for clinical use are performed in compliance with the good manufacturing practices applying to advanced therapy medicinal products, specifications related to stromal vascular fraction quality remain poorly defined. We analyzed stromal vascular fraction clinical batches from two independent good manufacturing practices-compliant manufacturing facilities, the Swiss Stem Cell Foundation (SSCF) and Marseille University Hospitals (AP-HM), with the goal of defining appropriate and harmonized release acceptance criteria., Methods: This retrospective analysis reviewed the biological characteristics of 364 batches of clinical-grade stromal vascular fraction. Collected data included cell viability, recovery yield, cell subset distribution of stromal vascular fraction, and microbiological quality., Results: Stromal vascular fraction from SSCF cohort demonstrated a higher viability (89.33% ± 4.30%) and recovery yield (2.54 × 10 5 ± 1.22 × 10 5 viable nucleated cells (VNCs) per mL of adipose tissue) than stromal vascular fraction from AP-HM (84.20% ± 5.96% and 2.25 × 10 5 ± 1.11 × 10 5 VNCs per mL). AP-HM batches were significantly less contaminated (95.71% of sterile batches versus 74.15% for SSCF batches). The cell subset distribution was significantly different (higher proportion of endothelial cells and lower proportion of leukocytes and pericytes in SSCF cohort)., Conclusions: Both centers agreed that a good manufacturing practices-compliant stromal vascular fraction batch should exert a viability equal or superior to 80%, a minimum recovery yield of 1.50 × 10 5 VNCs per mL of adipose tissue, a proportion of adipose-derived stromal cells at least equal to 20%, and a proportion of leukocytes under 50%. In addition, a multiparameter gating strategy for stromal vascular fraction analysis is proposed.

Rectangular V-amylose single crystals were prepared by adding racemic ibuprofen to hot dilute aqueous solutions of native and enzymatically-synthesized amylose. The lamellar thickness increased with increasing degree of polymerization of amylose and reached a plateau at about 7 nm, consistent with a chain-folding mechanism. The CP/MAS NMR spectrum as well as base-plane electron and powder X-ray diffraction patterns recorded from hydrated specimens were similar to those of V-amylose complexed with propan-2-ol. Amylose was crystallized in an orthorhombic unit cell with parameters a = 2.824 ± 0.001 nm, b = 2.966 ± 0.001 nm, and c = 0.800 ± 0.001 nm. A molecular model was proposed based on structural analogies with the V propan-2-ol complex and on assumptions on the stoichiometry of ibuprofen. The unit cell would contain four antiparallel 7-fold amylose single helices with ibuprofen molecules distributed inside and between the helices., (Copyright © 2021 Elsevier Ltd. All rights reserved.)