Intestinal absorption of sphingosine: new insights on generated ceramide species using stable isotope tracing in vitro

International audienceDietary sphingomyelin (SM) has been reported to favorably modulate postprandial lipemia. Mechanisms underlying these beneficial effects on cardiovascular risk markers are not fully elucidated. Rodent studies showed that tritiated SM was hydrolyzed in the intestinal lumen into ceramides (Cer) and further to sphingosine (SPH) and fatty acids (FA) that were absorbed by the intestine. Our objective was to investigate the uptake and metabolism of SPH and/or tricosanoic acid (C23:0), the main FA of milk SM, as well as lipid secretion in Caco-2/TC7 cells cultured on semipermeable inserts. Mixed micelles (MM) consisting of different digested lipids and taurocholate were prepared without or with SPH, SPH and C23:0 (SPH+C23:0), or C23:0. Triglycerides (TG) were quantified in the basolateral medium, and sphingolipids were analyzed by tandem mass spectrometry. TG secretion increased 11-fold in all MM-incubated cells compared with lipid-free medium. Apical supply of SPH-enriched MM led to increased concentrations of total Cer in cells, and coaddition of C23:0 in SPH-enriched MM led to a preferential increase of C23:0 Cer and C23:0 SM. Complementary experiments using deuterated SPH demonstrated that SPH-d9 was partly converted to sphingosine-1-phosphate-d9, Cer-d9, and SM-d9 within cells incubated with SPH-enriched MM. A few Cer-d9 (2% of added SPH-d9) was recovered in the basolateral medium of (MM+SPH)-incubated cells, especially C23:0 Cer-d9 in (MM+SPH+C23:0)-enriched cells. In conclusion, present results indicate that MM enriched with (SPH+C23:0), such as found in postprandial micelles formed after milk SM ingestion, directly impacts sphingolipid endogenous metabolism in enterocytes, resulting in the secretion of TG-rich particles enriched with C23:0 Cer

Critères biologiques de l’insulinome chez les patients avec une néoplasie endocrinienne multiple de type 1 (NEM1)

International audienceUn insulinome est retrouvé chez 10 à 30 % des patients-NEM1. Le diagnostic de l’insulinome-NEM1 est, empiriquement, calqué sur celui de l’insulinome sporadique. L’objectif de cette étude rétrospective, multicentrique était de préciser les critères de diagnostic biologique de l’insulinome-NEM1. Trente-neuf patients (22 hommes), d’âge médian 26,5 ans, avec une NEM1 prouvée génétiquement et un insulinome, ont été inclus. L’insulinome était la première atteinte de la NEM1 chez 6 patients (15,4 %). Une cosécrétion d’hormones hyperglycémiantes était présente chez 8 patients (20,5 %). Trois patients (7,7 %) avaient bénéficié d’une chirurgie pancréatique antérieure à l’insulinome. L’hypoglycémie diagnostique a nécessité une épreuve de jeûne chez 28 patients (71,8 %). La durée médiane de l’épreuve de jeûne était de 24 heures. L’hypoglycémie est survenue au-delà de 48 heures de jeûne chez 6 patients (21,4 %). Lors de l’hypoglycémie diagnostique à 0,38 g/L (0,21 à 0,55 g/L), l’insulinémie était à 11,3 mU/L et le C peptide plasmatique à 2,21 ng/mL (médianes). Une insulinémie ≥ 3 mU/L et/ou un C-peptide plasmatique > 0,6 ng/mL étaient retrouvés chez 36 patients (92,3 %). Une insulinémie ≥ 3 mU/L ou un C-peptide plasmatique ≥ 0,6 ng/mL lors d’une hypoglycémie avait, respectivement, une sensibilité de 89 % et de 86 % pour affirmer l’insulinome. En conclusion, une glycémie veineuse inférieure à 0,55 g/L a une sensibilité de 100 % pour affirmer le diagnostic d’insulinome dans la NEM1. Les valeurs seuils d’insulinémie et de C-peptide à utiliser dans la NEM1 paraissent identiques à celles utilisées dans l’insulinome sporadique

Decoupling the trochlea from the condyles in total knee arthroplasty: The end of a curse?

International audienc

Pharmacokinetic Consideration of Venetoclax in Acute Myeloid Leukemia Patients: A Potential Candidate for TDM? A Short Communication

International audienceBackground: Venetoclax (VNX)-based regimens have demonstrated significantly favorable outcomes in patients with acute myeloid leukemia (AML) and are now becoming the standard treatment. Tyrosine kinase inhibitors are administered at a fixed dose, irrespective of body surface area or weight. For such orally targeted therapies, real-world data have highlighted a larger pharmacokinetic (PK) interindividual variability (IIV) than expected. Even if VNX PKs have been well characterized and described in the literature, only 1 clinical trial–based PK study has been conducted in patients with AML. This study aimed to evaluate the PK of VNX in AML patients. Material and methods: We retrospectively analyzed all patients treated with a combination of VNX–azacitidine between January and July 2022 at our center, using at least 1 available VNX blood sample. Based on a previously published population PK model, individual PK parameters were estimated to evaluate the exposure and IIV. Results: and Discussion. Twenty patients received VNX in combination with azacitidine, according to the PK data. A total of 93 plasma concentrations were collected. The dose of VNX was 400 mg, except in 7 patients who received concomitant posaconazole (VNX 70 mg). The patients' weight ranged from 49 kg to 108 kg (mean = 78 kg). Mean individual clearance was 13.5 ± 9.4 L/h with mean individual daily area under the concentration–time curves of 35.8 mg.h/L with significant IIV (coefficient of variation = 41.1%). Ten patients were still alive (8 in complete response), but all experienced at least 1 hematological toxicity of grade ≥ 3. Conclusions: Based on the observed large PK variability in the data from our real-world AML patients, the risk of drug interactions and the recommended fixed-dosage regimen of VNX therapeutic drug monitoring may be useful

Sex estimation from coxal bones using deep learning in a population balanced by sex and age

International audienceIn the field of forensic anthropology, researchers aim to identify anonymous human remains and determine the cause and circumstances of death from skeletonized human remains. Sex determination is a fundamental step of this procedure because it influences the estimation of other traits, such as age and stature. Pelvic bones are especially dimorphic, and are thus the most useful bones for sex identification. Sex estimation methods are usually based on morphologic traits, measurements, or landmarks on the bones. However, these methods are time-consuming and can be subject to inter- or intra-observer bias. Sex determination can be done using dry bones or CT scans. Recently, artificial neural networks (ANN) have attracted attention in forensic anthropology. Here we tested a fully automated and data-driven machine learning method for sex estimation using CT-scan reconstructions of coxal bones. We studied 580 CT scans of living individuals. Sex was predicted by two networks trained on an independent sample: a disentangled variational auto-encoder (DVAE) alone, and the same DVAE associated with another classifier (C$_{recon}$). The DVAE alone exhibited an accuracy of 97.9%, and the DVAE + C$_{recon}$ showed an accuracy of 99.8%. Sensibility and precision were also high for both sexes. These results are better than those reported from previous studies. These data-driven algorithms are easy to implement, since the pre-processing step is also entirely automatic. Fully automated methods save time, as it only takes a few minutes to pre-process the images and predict sex, and does not require strong experience in forensic anthropology

Outcome of large B-cell lymphoma patients treated with tafasitamab plus lenalidomide either before or after CAR-T-cells.

International audienceTafasitamab plus lenalidomide (TAFA-LEN) treatment relevance pre- or post-anti-CD19 CAR T-cell is currently debated. We analyzed large B-cell lymphoma patients in the DESCAR-T registry treated with axi-cel or tisa-cel in ≥3rd line (L3+) and TAFA-LEN before (n=15, 'TL-pre-CAR-T' set) or directly after (n=52, 'TL-post-CAR-T' set) CAR T-cell. We compared TAFA-LEN v. other treatments using inverse probability weighting in the TL-post-CAR-T set. In the TL-post-CAR-T' set, the median follow-up duration (mFUD) was 7 months, and the median progression-free survival, overall survival and duration of response since the 1st treatment for progression (mPFS2/mOS2/mDOR2) were 3, 4.7 and 8.1 months, respectively. The best overall response rate (bORR) and best complete response rate (bCRR) after TAFA-LEN were 13.5% and 7.7%, respectively. Outcomes were better for patients who relapsed >6 months after CAR T-cell (mPFS2: 5.6 vs. 2 months, p=0.0138; mOS2: not reached vs. 3.8 months, p=0.0034). bORR and bCRR between TAFA-LEN and other treatments were 20.6% vs. 24.9% and 11.6% vs. 15.6%, respectively. Outcomes were similar between TAFA-LEN and other treatments (mPFS2: 2.9 [2-2.6] vs. 2.4 [1.5-4.2] months, p=0.91; mOS2: 3.3 [1.8-6.4] vs. 5.5 [4.4-6.3] months, p=0.06). In an exploratory analysis of the TL-pre-CAR-T set (mFUD since CAR T-cell: 2.8 months), the median TAFA-LEN treatment duration prior to CAR-T was 3.7 months and no patients were reported to become CD19 negative. The bORR, bCRR, 6-month PFS and OS rates after CAR T-cell infusion were 45.5%, 36.4%, 20.1% and 58.2%, respectively. Neither TAFA-LEN nor comparative salvage treatments improved outcomes of patients who relapsed after CAR T-cell

Quantification of Circulating HBV RNA Expressed from Intrahepatic cccDNA in Untreated and NUC Treated Patients with Chronic Hepatitis B

International audienceObjective: A convenient, reproducible biomarker of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) transcriptional activity is lacking. We measured circulating HBV RNA (cirB-RNA) in untreated and nucleos(t)ide analogues (NUC) treated chronic hepatitis B (CHB) patients to define its correlation with intrahepatic viral markers and HBV core-related antigen (HBcrAg). Design: Paired liver biopsy and serum samples were collected from 122 untreated and 30 NUC-treated CHB patients. We measured cirB-RNA, HBV DNA, hepatitis B surface antigen (HBsAg), HBcrAg and alanine aminotransferase levels. cirB-RNA was quantified using an investigational HBV RNA assay for use on the cobas 6800 system. The test detects a region spanning the HBV canonical polyadenylation site. cccDNA and 3.5 kb RNA in liver tissue were assessed by quantitative PCR and droplet digital PCR. Results: cirB-RNA was detectable in 100% of HBeAg(+) chronic hepatitis (CH), 57% and 14% of HBeAg(-) CH and chronic infection untreated patients and 47% of NUC-treated patients. cirB-RNA undetectability was associated with lower intrahepatic cccDNA transcriptional activity, as well as serum HBcrAg, but no significant differences in HBsAg, in both untreated and treated patients. In untreated HBeAg(-) patients, cirB-RNA correlated with intrahepatic 3.5 kb RNA and cccDNA transcriptional activity, serum HBV DNA and HBcrAg, but not with HBsAg or total cccDNA levels. Combined undetectability of both cirB-RNA and HBcrAg detection in untreated HBeAg(-) patients identified a subgroup with the lowest levels of intrahepatic transcriptionally active cccDNA. Conclusion: Our results support the usefulness of quantification of circulating HBV RNA expressed from cccDNA as an indicator of intrahepatic active viral reservoir in both untreated and NUC-treated CHB patients

Speech markers of Cancer-Related Cognitive Impairment: A pilot study

International audienceSpeech is sensitive to mild cognitive changes due to age-related diseases, and prosodic features can identify patients with early-stage dementia from controls. Few studies have investigated speech markers of subtle cognitive impairment in non-neurodegenerative pathologies in younger populations, such as Cancer-Related Cognitive Impairment (CRCI). Little is known about the cognitive mechanisms underlying CRCI, but it is frequently encountered by cancer patients who mainly report memory-related concerns (i.e., forgetting words). Despite its substantial impact on patient quality of life, CRCI is difficult to detect with neuropsychological tools and often remains underdiagnosed. Our aim is to test whether previously documented speech markers are likely to detect CRCI in patients with breast cancer. We compared speech rate, F0 variability and pause duration in 11 breast cancer survivors with a cognitive complaint, 11 breast cancer survivors without any cognitive complaint and 10 controls in two narrative tasks (memory-based; picture-based). A Bayesian analysis showed no significant effects of group or task, but a qualitative analysis of pauses allowed us to generate hypotheses about the cognitive mechanisms underlying the patients’ reported memory concerns. Even though speech markers specific to CRCI have yet to be defined, prosodic analysis is a promising approach for detecting subtle cognitive impairment

Predictors and Risk Score for Immune Checkpoint-Inhibitor-Associated Myocarditis Severity

International audienceBackground: Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this 'cardiomyotoxicity' are lacking. Methods: A multicenter registry collected data retrospectively from 17 countries between 2014-2023. A multivariable cox regression model (hazard-ratio(HR), [95%confidence-interval]) was used to determine risk factors for the primary composite outcome: severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardio-muscular symptoms, diagnostics, and treatments. Time-dependent covariates were used and missing data were imputed. A point-based prognostic risk score was derived and externally validated. Results: In 748 patients (67% male, age 23-94), 30-days incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17% respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (HR=3.60[1.93-6.72]), presence of cardio-muscular symptoms (HR=2.60 [1.58-4.28]), low QRS-voltage on presenting electrocardiogram (HR for ≤0.5mV versus >1mV=2.08[1.31-3.30]), left ventricular ejection fraction (LVEF) <50% (HR=1.78[1.22-2.60]), and incremental troponin elevation (HR=1.86 [1.44-2.39], 2.99[1.91-4.65], 4.80[2.54-9.08], for 20, 200 and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-days primary outcome incidence increased gradually from 3.9%(risk-score=0) to 81.3%(risk-score=4). This risk-score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low risk patients who were managed with no immunosuppression resulting in no cardio-myotoxic events. Conclusions: ICI-myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low-QRS voltage, depressed LVEF, and cardio-muscular symptoms. A risk-score incorporating these features performed well

Daratumumab (DARA) + Bortezomib/Thalidomide/Dexamethasone (D-VTd) Followed by DARA Maintenance in Transplant-Eligible (TE) Newly Diagnosed Multiple Myeloma (NDMM): >6-Year Update of the Phase 3 CASSIOPEIA Study

International audienc