Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors: A Nonrandomized Controlled Trial

Antitumor activity; Monotherapy; Solid tumorsActividad antitumoral; Monoterapia; Tumores sólidosActivitat antitumoral; Monoteràpia; Tumors sòlidsImportance Mismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti–programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor. Objective To assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors. Design, Setting, And Participants The GARNET trial was a phase 1, open-label, single-group, multicenter study that began enrolling May 8, 2017. Participants had advanced or recurrent dMMR and microsatellite instability–high (MSI-H) or polymerase epsilon (POLE)–altered solid tumors. The data cut for this interim analysis was from November 1, 2021, with median follow-up of 27.7 months. Interventions Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal. Main Outcomes and Measures The primary objective was to evaluate objective response rate and duration of response in patients with dMMR solid tumors by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Results The efficacy population included 327 patients (median [range] age, 63 [24-85] years; 235 [71.9%] female; 7 [2.1%] Asian, 6 [1.8%] Black, and 206 [63.0%] White patients), with 141 patients (43.1%) with dMMR endometrial cancer, 105 patients (32.1%) with dMMR colorectal cancer, and 81 patients (24.8%) with other dMMR tumor types. All patients had at least 1 previous line of therapy. Objective response rate assessed per blinded independent central review for dMMR solid tumors was 44.0% (95% CI, 38.6% to 49.6%). Median duration of response was not reached (range, ≥1.18 to ≥47.21 months); 72.2% of responders (104 of 144) had a response lasting 12 or more months. Median progression-free survival was 6.9 months (95% CI, 4.2 to 13.6 months); probability of progression-free survival at 24 months was 40.6% (95% CI, 35.0% to 46.1%). Median overall survival was not reached (95% CI, 31.6 months to not reached). The most frequent immune-related adverse events were hypothyroidism (25 [6.9%]), alanine aminotransferase increase (21 [5.8%]), and arthralgia (17 [4.7%]). No new safety concerns were identified. Conclusions And Relevance In this nonrandomized controlled trial, dostarlimab was a well-tolerated treatment option with rapid, robust, and durable antitumor activity in patients with diverse dMMR solid tumors. These findings suggest that dostarlimab provides meaningful long-term benefit in a population with high unmet need. Trial Registration ClinicalTrials.gov Identifier: NCT02715284This study was funded by GSK

370 Time course of treatment-related adverse events (TRAEs) during dostarlimab therapy in the GARNET trial

BackgroundDostarlimab is a humanized programmed death 1 (PD-1) receptor monoclonal antibody that blocks interaction with the ligands PD-L1 and PD-L2. Dostarlimab is approved as a monotherapy in adult patients (pts) with mismatch repair deficient (dMMR; US) or dMMR/microsatellite-instability high (EU) recurrent or advanced endometrial cancer that has progressed progressing on or following prior treatment with a platinum-containing regimen. GARNET is a phase 1 study assessing antitumor activity and safety of dostarlimab monotherapy in pts with solid tumors.MethodsPts with dMMR solid tumors, mismatch repair proficient endometrial cancer, and non-small cell lung cancer that progressed on or after prior therapy received 500 mg of dostarlimab IV every 3 weeks (Q3W) for 4 cycles, then 1000 mg IV every 6 weeks (Q6W) for up to 2 years or until disease progression or discontinuation. Here, we report TRAEs by cycle.ResultsA total of 515 pts were included. Of these pts, 60 (11.7%) experienced TRAEs leading to treatment interruption, and 25 (4.9%) experienced TRAEs leading to discontinuation. TRAEs of any grade with overall incidence of ≥10% of pts are shown (table 1). The majority of TRAEs occurred during cycles 1–3, with highest incidence during cycle 1. Grade 3 or 4 TRAEs were rare; those seen in ≥1% of pts are shown. Immune-related (ir) TRAEs of any grade with overall incidence of ≥2% of pts are shown. Most cases (96.9%) of irTRAEs occurred during cycles 1–8. The peak incidence of hypothyroidism occurred during cycle 4; in addition, frequency was increased during cycles 5–8, compared with cycles 1–4. No deaths were attributed to dostarlimab.Abstract 370 Table 1Time course of adverse events in the GARNET trialConclusionsNo new safety signals were detected with dostarlimab compared to other anti–PD-1 inhibitors. Most TRAEs were low grade. The majority of TRAEs and grade ≥3 TRAEs occurred in the first 3 cycles (first 12 weeks), but some cases occurred later, suggesting a need for ongoing monitoring. Few increases in the incidence of TRAEs were seen during cycle 5 following the transition to the 1000-mg Q6W dosing schedule; the TRAEs with increased incidence after the transition were fatigue and lipase increased. An increase in the frequency of the irTRAE hypothyroidism was seen after transitioning to the 1000-mg Q6W schedule

ERS statement on standardisation of cardiopulmonary exercise testing in chronic lung diseases

The objective of this document was to standardise published cardiopulmonary exercise testing (CPET) protocols for improved interpretation in clinical settings and multicentre research projects. This document: 1) summarises the protocols and procedures used in published studies focusing on incremental CPET in chronic lung conditions; 2) presents standard incremental protocols for CPET on a stationary cycle ergometer and a treadmill; and 3) provides patients’ perspectives on CPET obtained through an online survey supported by the European Lung Foundation. We systematically reviewed published studies obtained from EMBASE, Medline, Scopus, Web of Science and the Cochrane Library from inception to January 2017. Of 7914 identified studies, 595 studies with 26 523 subjects were included. The literature supports a test protocol with a resting phase lasting at least 3 min, a 3-min unloaded phase, and an 8- to 12-min incremental phase with work rate increased linearly at least every minute, followed by a recovery phase of at least 2–3 min. Patients responding to the survey (n=295) perceived CPET as highly beneficial for their diagnostic assessment and informed the Task Force consensus. Future research should focus on the individualised estimation of optimal work rate increments across different lung diseases, and the collection of robust normative data.The document facilitates standardisation of conducting, reporting and interpreting cardiopulmonary exercise tests in chronic lung diseases for comparison of reference data, multi-centre studies and assessment of interventional efficacy. http://bit.ly/31SXeB

Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Multi-messenger Observations of a Binary Neutron Star Merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ∼ 1.7 {{s}} with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of {40}-8+8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 {M}ȯ . An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ∼ 40 {{Mpc}}) less than 11 hours after the merger by the One-Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ∼10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ∼ 9 and ∼ 16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC 4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta.</p

La végétation alluviale de la Loire entre le Charolais et l'Anjou (essai de modélisation de l'hydrosystème)

La Loire, souvent qualifiée de "dernier fleuve sauvage d'Europe", a été aménagée dès l'Antiquité. A la différence de nombreux grands fleuves, elle n'a que peu bénéficiée de recherches en écologie. La végétation alluviale constitue un excellent intégrateur des conditions physiques, biologiques et anthropiques de l'hydrosystème. La caractérisation des communautés végétales a été réalisée grâce aux méthodes phytosociologiques, complétées par une quantification des paramètres abiotiques structurant le fonctionnement de l'hydrosystème(hydrologie, flux énergétiques, caractères édaphiques). L'étude des successions dans les forêts alluviales a fait l'objet d'une approche structurale. Ces investigations ont été menées sur sept sites répartis sur 500km du cours moyen de la Loire. Les analyses statistiques ont permis de confirmer les corrélations qui existaient entre les conditions stationnelles et la flore associée ; elles ont également permis de mettre en évidence et de hiérarchiser les facteurs abiotiques qui structuraient le mieux la distribution spatiale des communautés végétales. Ainsi, l'inondabilité, la texture du substrat et le positionnement par rapport au flux énergétiques sont d'excellents paramètres intégrateurs. Les connaissances acquises permettent d'établir une typologie écologique et phytosociologiques complète de la végétation, ainsi que l'élaboration de schémas d'organisation et d'évolution des communautés végétales dans le temps. Pour les forêts alluviales, la méthode architecturale a démontré son efficience sur la Loire dans la compréhension des processus sylvigéniques. Enfin, la confrontation de ces résultats autorise la mise en place d'un modèle prédictif d'évolution de la végétation. Ce modèle permettra de tester différents scénarios de gestion ou d'aménagement de l'hydrosystème dans un souci de conservation dynamique de la biodiversité.TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

Evaluation de l'exposition du fœtus picard et de sa mère aux pesticides, et identification des principales voies d'exposition

Les pesticides sont des contaminants chimiques utilisés dans l agriculture dans l industrie ou comme produits ménagers. Ils sont désormais présents dans l ensemble des compartiments environnementaux et contaminent donc l ensemble de la chaîne alimentaire jusqu à l homme. Plusieurs études menées sur la santé animale ou humaine ont mis en cause ces composés dans l apparition de cancers, de troubles neurologiques ou de troubles sur la reproduction ou le développement. L impact de ces composés sur le fœtus qui est dans une phase de développement et est donc très vulnérable, est désormais un sujet d inquiétude majeur. Il est donc indispensable de disposer de données d exposition et d imprégnation du fœtus aux pesticides, ainsi que de mieux comprendre les mécanismes et les principales voies d exposition de la population à ces composés. C est dans ce contexte que ce projet MecoExpo s est proposé de développer une méthode analytique permettant de caractériser l imprégnation du fœtus aux pesticides, et de fournir ainsi les premières données d occurrences françaises dans ce domaine. Cette stratégie s est appuyée sur la chromatographie liquide couplée à la spectrométrie de masse en tandem, afin de mesurer simultanément 18 composés, pesticides parents et métabolites, dans des échantillons de cheveux maternels et de méconium (premières selles du nouveau-né), qui est un biomarqueur d exposition relativement nouveau et encore peu utilisé à l heure actuelle. Les deux matrices sélectionnées sont représentatives d une grande fenêtre temporelle d exposition puisqu elles permettent de caractériser l exposition du fœtus pendant les 6 derniers mois de la grossesse. La stratégie ainsi développée a été appliquée à la cohorte MecoExpo recrutée pendant l année 2011 en Picardie (462 méconiums et 268 cheveux maternels). Les analyses ont permis d identifier 4 principaux contaminants auxquels l homme et le fœtus sont exposés en Picardie : deux métabolites issus de la famille des organophosphates (DMTP et DEP), ainsi que deux métabolites de la famille des carbamates (EU et ETU). Les concentrations moyennes mesurées peuvent être de plusieurs dizaines de ng.g-1 pour le DEP, jusqu à plusieurs centaines de ng.g-1. Lors de ce projet, différentes informations comportementales ont également été recueillies sur le mode de vie des familles incluses dans cette étude, afin de rechercher les principales voies d exposition du fœtus et de l homme en général, à ce type de composés. Les concentrations mesurées dans les échantillons biologiques ont pu être corrélées avec des facteurs comportementaux comme l alimentation ou l exposition aux pesticides au domicile ou sur le lieu de travail. Les données générées lors de ce projet constituent aujourd hui la première source d information concernant l imprégnation du fœtus aux pesticides en France.AMIENS-BU Santé (800212102) / SudocSudocFranceF

Characterisation and cartography of foetal exposure to pesticides and theirs metabolites in meconium and maternal hair by UPLC-MS/MS

Pesticides use has increased since 1940s and one million tonnes are presently dispersed every year in the world. Human exposure to pesticides through the environment and the food is therefore inevitable and the detection of foetal exposure to pesticides is important because some effects on human health have been reported, particularly in the case of an exposure during the early stages of development like the prenatal period. The aim of this study is to characterize the foetal exposure to pesticides and metabolites through meconium (baby's first faeces) and maternal hair analysis. These matrices are representative of the foetal exposure during a wide window of pregnancy since meconium is an accumulative matrix starting its formation from the third month of gestation and all xenobiotics will be accumulating in meconium over the last two trimesters of pregnancy. For this sample collection, a collaboration with 11 nurseries in Picardie was established in order to include 700 couples mother/child, and an analytical strategy for the quantification of pesticides and metabolites based on liquid chromatography-tandem mass spectrometry system was developed. This method targets the main pesticide families used in Picardie (carbamates, organophosphates, pyrethroids, phenylureas and phenoxy herbicides) and 21 compounds were selected. This selection is based on the quantity used in Picardie, their toxicity and their physico-chemical properties. These target compounds have been measured with limits of quantification between 0.2 ng.g-1 and 200 ng.g-1 according to the molecule. These results have demonstrated a significant exposure of the foetus to organophosphate pesticides, dithiocarbamates and pyrethroids that are also used as domestic pesticides. Indeed, the highest detection rate was observed for the metabolites of organophosphates and dithiocarbamates (probably mancozeb which is the main pesticide used in Picardie) with respective percentage of detection of 57.9% and 22.8%. The parent pesticides were rarely detected and only in very low concentration unless for cyfluthrin and cypermethrin which have been quantified in high concentrations between 43.8-479.8 ng.g-1 in 7.6% of the meconium samples. A correlation between concentration measured in meconium and maternal hair was investigated for each couple mother/child, and these first exposure data for the foetus in France have been mapped with geo-localization software

Development of an analytical strategy based on LC–MS/MS for the measurement of different classes of pesticides and theirs metabolites in meconium : Application and characterisation of foetal exposure in France

It is important to evaluate the impact of pesticides on human health because exposure to these compounds has been linked to harmful effects in many research studies. This exposure may be particularly harmful during the early stages of development (e.g. the prenatal period). The aim of the present study was to develop an analytical strategy for quantifying a number of pesticides and their metabolites in meconium (the neonate׳s first faeces), in order to characterize the extent of foetal exposure. The meconium sample was dried and grinded in order to homogenize the sample, prior to solid–liquid extraction and a purification by solid-phase extraction using a weak anion mixed-mode polymeric sorbent. Analyte separation and quantification was performed by liquid chromatography coupled to electrospray-triple quadrupole mass spectrometry. Five pesticide families (carbamates, organophosphates, pyrethroids, phenylureas and phenoxy herbicides) and their metabolites could be quantified in meconium with limits of quantification ranging between 0.2 ng/g and 200 ng/g. This method was applied to a set of 171 meconium samples collected in the Picardie region of northern France. The highest prevalence was observed for metabolites of organophosphates and carbamates (57.9% and 22.8%, respectively). The parent pesticides were rarely present and were only found at very low concentrations, except for the pyrethroids cyfluthrin and cypermethrin, which were found in 7.6% of meconium samples at concentrations of between 43.8 and 480 ng/g. The most frequently detected contaminant was the organophosphate metabolite dimethyl thiophosphate detected in 49.1% of the samples and quantified with a median concentration of 344 ng/g. These data evidence significant foetal exposure to organophosphate pesticides, pyrethroids and carbamates