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Sustained minimal residual disease (sMRD) negativity in transplant ineligible newly diagnosed multiple myeloma treated with isatuximab plus lenalidomide and dexamethasone with bortezomib (Isa-VRd) versus isa-rd: 12-24-month data from the phase 3 benefit trial (IFM 2020-05)
No full textInternational audienceIntroduction: Sustained minimal residual disease (sMRD) negativity has shown a stronger correlation with survival outcomes than MRD negativity at a single time point or at best response. We evaluated MRD negativity between 12 and 24 months in newly diagnosed multiple myeloma (NDMM) transplant-ineligible (TI) patients enrolled in the BENEFIT study.Methods: BENEFIT is a multicenter, phase 3 randomized trial comparing isatuximab-lenalidomide-dexamethasone with or without bortezomib (Isa-Rd ± V) in NDMM TI patients. In the Isa-VRd arm, bortezomib (V) was administered weekly for up to 18 months, dexamethasone was permanently discontinued after 12 months, and isatuximab-lenalidomide (Isa-R) was continued until progression. Data are presented in the intention-to-treat (ITT) population.Results: With a median follow-up of 33.4 months (95% CI, 33.0–34.0), 78 patients (29%) discontinued treatment, primarily due to progressive disease. At 24 months, the MRD negativity rate at 10⁻⁵ was significantly higher in the Isa-VRd arm (odds ratio [OR] 2.26; 95% CI, 1.35–3.79; p=0.002). Sustained MRD negativity at 10⁻⁵ was also more frequent in the Isa-VRd arm (OR 2.73; 95% CI, 1.50–4.80; p=0.0007). Similar results were observed for sMRD at the 10⁻⁶ threshold. Importantly, MRD negativity at both 10⁻⁵ and 10⁻⁶ was evaluated in the t(11;14) NDMM TI subgroup. In this subgroup, MRD negativity rates were consistently lower at all time points up to 24 months, consistent with recent observations from the MIDAS study. Due to the small number of patients per group, no subgroup-specific analysis was feasible. Larger cohorts are required to determine whether t(11;14) MM in TI patients achieves delayed or less frequent MRD negativity, potentially reflecting a MGUS-like phenotype. No new safety signals were observed in either treatment arm, including in high-risk multiple myeloma (HRMM) patients.Conclusion: The BENEFIT study continues to support the efficacy of the quadruplet Isa-VRd regimen in NDMM TI patients, notably through improved sustained MRD negativity rates. These data support Isa-VRd as a new standard of care (SOC) for NDMM TI patients aged 65–79 years, including those with HRMM.ClinicalTrials.gov Identifier: NCT0475187
Accounting for Misclassification of Binary Outcomes in External Control Arm Studies for Unanchored Indirect Comparisons: Simulations and Applied Example
No full textInternational audienceABSTRACT Single‐arm control trials are increasingly proposed as a potential approach for treatment evaluation. However, the limitations of this design restrict its methodological acceptability. Regulatory agencies have raised concerns about this approach, although it is sometimes required in applications based solely on such studies. Consequently, the need for accurate indirect treatment comparisons has become critical, especially when constructing external control arms using routinely collected data as outcome measurements may differ from those recorded in the single‐arm trial leading to potential misclassification of outcomes. This study aimed to quantify the bias from ignoring misclassification of a binary outcome within unanchored indirect comparisons, through simulations, and to propose a likelihood‐based method to correct this bias (i.e., the outcome‐corrected model). Simulations demonstrated that ignoring misclassification results in significant bias and poor coverage probabilities. In contrast, the outcome‐corrected model reduced bias, improved 95% confidence interval coverage probability and root mean square error in various scenarios. The methodology was applied to two hepatocellular carcinoma trials illustrating a practical application. The findings underscore the importance of addressing outcome misclassification in indirect comparisons. The proposed correction method may improve reliability in unanchored indirect treatment comparisons
Optimal Dual-VENC with 3D radial sampling for improved quantification in 4D Flow MRI: An in vitro validation study
No full textInternational audienceMotivation: Single-VENC encoding is not adapted for quantification of the complex flows occurring in the large anatomy covered by 4D Flow MRI with 3D radial sampling. Dual-VENC encoding improves quantification but comes at a cost of nearly doubled acquisition time. Goal: to investigate the performance of optimal combination dual-VENC for 4D Flow MRI with 3D radial sampling and its potential to reduce acquisition time Approach: velocity measurements with single-and dual-VENC were performed in a pulsatile flow phantom. To simulate acquisition time reduction, images were reconstructed with different undersampling factors. Results: Optimal dual-VENC consistently outperformed standard dual-VENC for all undersampling factors allowing significant reduction in acquisition time to the order of single-VENC durations. Impact Improved velocity quantification of fast arterial and slow venous flows in the same imaging volume with significantly shorter acquisition times may be achievable with 3D radial sampling and optimal combination dual-VENC 4D Flow MRI in patients
Head down tilt 15° increases cerebral perfusion before recanalization in acute ischemic stroke. A pre-clinical MRI study
No full textInternational audienceWe investigated the therapeutic effect of head down positioning at −15° (head down tilt; HDT15) on cerebral collateral flow and infarct growth in a rat model of large vessel occlusion (LVO) stroke, using multi-modal MRI. Twenty-eight Wistar rats were randomly assigned to HDT15 or flat position for 60 minutes, starting 30 minutes after occlusion of the middle cerebral artery, followed by reperfusion. The perfusion shift analysis, comparing post- versus pre-treatment voxel-level changes in time-to-peak perfusion maps, showed a significant increase in cerebral perfusion in the HDT15 group (common odds ratio 1.50; 95% CI 1.41-1.60; p < 0.0001), but not in the flat group (common odds ratio 0.97; 95% CI 0.92-1.03; p = 0.3503). Infarct growth at 24 hours was + 31.4% in the flat group (343 versus 250 mm 3 ; 95% CI 2.4 to 165.1; p = 0.0447) and + 15.4% in the HDT15 group (224 versus 192 mm 3 ; 95% CI -26.9 to 85.9; p = 0.2272). Our findings indicate that HDT15 acutely increases cerebral perfusion in LVO acute ischemic stroke and provides a tissue-saving effect before recanalization. Further research is needed to develop HDT15 as an emergency therapy to acutely increase collateral flow in ischemic stroke prior to recanalization therapy
Inhibiting the fructose transporter GLUT5 boosts testosterone production in a murine mLTC-1 leydig cell line
No full textInternational audienceOver the past few decades, a significant change globally in sugar intake has coincided with a rising incidence of male infertility, which is now a major public health concern. Diets rich in fructose have been implicated in both male infertility and increased susceptibility to metabolic disorders, such as obesity, diabetes, and related heart problems. While fructose is known to be present in seminal fluid and crucial for sperm motility, the precise role of fructose in testicular function remains largely unknown.GLUT5 is an exclusive fructose transporter essential for dietary fructose uptake in the intestine. It is also expressed mainly in germ and Leydig cells. We recently revealed that disrupting the Glut5 gene in male mice impairs spermatogenesis and steroidogenesis. However, its specific role within Leydig cells remains unexplored. Therefore, we investigated its role by inhibiting GLUT5 in a murine Leydig cell line (mLTC-1) using a specific inhibitor of GLUT5, MSNBA, combined with a multi-omics approach.Exposing mLTC-1 cells to MSNBA reduced the intracellular fructose content, limited cell proliferation, and enhanced progesterone and androgens production (Δ4-androstenedione and testosterone). The latter was associated with the upregulation of two genes and proteins involved in steroidogenesis, such as Hsd3b and steroidogenic acute regulatory protein (StAR). GLUT5 inhibition in mLTC-1 cells also modified lipid and carbohydrate metabolism. Lipidomic analysis showed decreased cholesterol esters and a shift in the ratio of polyunsaturated fatty acids (PUFAs) to monounsaturated fatty acids (MUFAs). These lipid changes correlated with alterations in the expression of mRNA-encoding enzymes involved in lipogenesis, such as ELOVL6. Metabolomics analysis showed a reduction in most glycolysis metabolites, except for pyruvate and lactate. However, pyruvate could conserve its level by a production through an amino acid pathway using the higher branched-chain amino acid content. Nevertheless, the activity of mitochondria measured by seahorse was not altered. The transcriptomic analysis performed by BRB-seq approach revealed an upregulation of several androgen-sensitive genes, such as Akap5, Slc39a9, an androgen receptor or lactate dehydrogenase A (Ldha), which produces lactate, and downregulation of several genes associated with the insulin pathway such as Tsc2 or the hexokinase Hkdc1.In conclusion, GLUT5 supported fructose intake in the murine Leydig cell line mLTC-1, leading to a reduction in cell proliferation. The consequences of inhibition of GLUT5 led to an increase in fatty acids cell content, a perturbation in glycolysis and amino-acid metabolism but an enhanced androgen production. Since androgens regulate spermatogenesis, hyperandrogenism induced by a lower fructose content in Leydig cells may be a primary cause leading to the disruption of sperm production and quality, as well as sexual behavior, as described in the GLUT5 KO mouse model
Psychometric properties of the Comprehensive Assessment of Acceptance and Commitment Therapy processes (CompACT) scale: Extending validity research to a French population
No full textInternational audienceContext: Prior research has identified that Acceptance and Commitment Therapy (ACT) may notably improve psychological flexibility. Despite its recognized effectiveness, French therapists and clinical researchers still lack the appropriate instruments to assess important parameters of ACT. For example, a previous standard in French, the AAQ-II, omits crucial variables that would fully represent ACT processes. In contrast, the CompACT scale, which encompasses the ensemble of ACT processes, through three dyadic processes (Openness to Experience, Behavioral Awareness, Valuation of Action), exhibits better suitability but lacks an empirically-validated adaptation in French. Therefore, this study aimed to translate, adapt, and validate the CompACT scale in French, focusing on both the general population and benzodiazepine users, the latter’s long-term use illustrates experiential avoidance, making them a highly relevant, alternative population for studying ACT processes. Statistical comparisons of these populations may be used to bring valuable insights and assess the scale’s construct validity.Method: The CompACT scale was translated and counter-translated by experts. An intermediate version was pre-tested by 34 participants, leading to the final version for psychometric validation with 423 French speakers (269 benzodiazepine users, 154 general population). The study evaluated structure, reliability, and various validities.Results: The French CompACT showed strong psychometric properties.Conclusion: Validating the French CompACT provides a reliable ACT process measure. This is crucial as psychological inflexibility contributes to numerous psychopathologies, making CompACT valuable for therapists
Impact of aging on gut-lung-adipose tissue interactions and lipid metabolism during influenza infection in mice
No full textInternational audienceInfluenza remains a major threat to human health, especially for the elderly. Aging leads to substantial changes to lung function, gut microbiota, and white adipose tissue (WAT)-a key endocrine organ regulating energy balance and lipid metabolism. In the current study, we performed a multi-omics analysis to investigate how influenza impacts the gut-lung-adipose tissue axis differently with age at days 2, 4, 7, 14, and 28 post-infection (dpi). Compared to young-adult mice, aged mice experienced worse disease outcomes following infection, along with distinct WAT alterations, including impaired browning, heightened inflammation, and reduced innate immune cell recruitment. Age-related differences were also evidenced in infection-driven shifts in gut microbiota. Akkermansia levels rose only in young mice from 4 dpi, while Faecalibaculum and Muribaculum expanded exclusively in aged mice at 7 dpi, the only timepoint at which their abundance correlated with lung pathology. Serum metabolomics at 7 dpi also revealed age-dependent metabolic responses to infection. Compared to their non-infected counterparts, young mice had lower levels of p-Cresol-sulfate and Indoxyl-sulfate alongside higher triglycerides, whereas aged mice showed disrupted glycerophospholipid metabolism. By pinpointing specific gut bacteria as potential probiotics and identifying lipid pathways associated with disease progression, these findings could lead to the development of targeted, age-specific strategies to mitigate influenza severity in the elderly.Influenza A virus (IAV) infections remain a major global public health challenge, driving recurrent seasonal outbreaks and occasional pandemics, and significantly contributing to severe respiratory diseases 1 . Worldwide, IAV infections are estimated to cause 3 to 5 million cases of severe illness and approximately 290,000 to 650,000 respiratory deaths each year 2 . Influenza-related morbidity and mortality disproportionately affect several at-risk populations, including individuals with obesity and those aged 65 and over 3,4 . Notably, more than 90% of annual influenza-related deaths occur among the elderly 5 .Chronological aging is associated with a marked decline in both innate and adaptive immunity, a process known as immunosenescence 6 . This age-related immune dysfunction weakens the host's ability to defend against respiratory intruders and to generate an effective response following vaccination 4 . Additionally, inflammaging, a state of chronic low-grade inflammation, is a hallmark of the aging immune system 7 . Advanced age also leads to progressive impairment of pulmonary functions, including reduced lung elasticity, weakened respiratory muscles, diminished lung capacity, and impaired mucociliary clearance of inhaled pathogens 8,9 . Other factors, such as comorbidities and nutritional deficiencies, further compromise the ability of older adults to respond to</div
Multicentric Validation of Early Quantitative 177Lu-PSMA SPECT/CT for mCRPC Response Assessment
No full textInternational audienc
Causes of Death and Comorbidities in Adult Patients With Late-Onset Pompe Disease: A French Pompe Registry Retrospective Study.
No full textInternational audienceBackground and ObjectivesMortality in Late-Onset Pompe Disease (LOPD) has been associated with the rapid progression of respiratory and motor impairment. However, an in-depth approach to the exact causes of death in these patients is still lacking.MethodsIn this retrospective cohort study, we analyzed the cause of death and the comorbidities of all deceased patients from the French Late-Onset Pompe Disease registry.ResultsBy the time of the last extraction, 60 patients diagnosed with LOPD and monitored were registered as deceased in the French national registry, out of a total of 260 patients included. The median age of death was 70.5 years, while the median age of diagnosis was 58 years. The causes of death were divided into disease-related, accounting for 46.6% of deaths, and non-disease-related, comprising 28.3% of total deaths. Fifteen patients (25%) died of an unknown cause. The most frequent etiology of disease-related death was respiratory failure (n = 14), while for the non-disease-related group, malignant neoplasm was the most common (n = 8). Patients in the non-disease-related death group had significantly higher forced vital capacity (FVC) values compared to those in the disease-related death group (54.7% vs. 38%). Treatment-wise, the median period elapsed from diagnosis to ERT introduction was higher in the disease-related group.DiscussionThis is the first study to focus on the specific causes of death of LOPD patients. The majority of the LOPD deaths in the French registry were attributed to respiratory failure and malignant neoplasms