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Body mass index affects imatinib exposure: Real-world evidence from TDM with adaptive dosing

FUNDAMENTAL & CLINICAL PHARMACOLOGY 2025年第1期39卷 e13049页

作者： Maroselli, Paul Fanciullino, Raphaelle Colle, Julien Farnault, Laure Roche, Pauline Venton, Geoffroy Costello, Regis Ciccolini, Joseph La Timone Univ Hosp Marseille AP HM PRISM Biogenopole Marseille France Inserm COMPO Ctr Rech Cancerol Marseille U1068 Marseille France La Concept Univ Hosp Marseille AP HM Pharm Unit Marseille France La Concept Univ Hosp Marseille AP HM Hematol Dept Marseille France

Background: Imatinib is the treatment of elderly or frail patients with chronic myeloid leukemia (CML). Trough levels of around 1000 ng/ml are considered as the target exposure. Objectives: We searched for baseline parameters associated with imatinib pharmacokinetics, and studied the clinical impact of subsequent adaptive dosing. Methods: We present data from 60 adult CML patients upon imatinib with therapeutic drug monitoring (TDM) and adaptive dosing. Results: Mean trough levels after treatment initiation were 994.2 +/- 560.6 ng/ml with 56% inter-patient variability). Only 29% of patients were in the therapeutic range. Body weight, height, body surface area, body mass index (BMI), and age were associated with imatinib plasma levels on univariate analysis. Age and BMI remained the only parameters associated with imatinib trough levels on multivariate analysis. As severe toxicities have been previously reported in patients with low BMI treated with standard imatinib, we evaluated the extent to which low BMI may lead to plasma overexposure. We found a statistically significant difference in trough imatinib levels in patients with BMI < 18.5 kg/m(2), with exposure +61.5% higher than in patients with 18.5 < BMI <= 24.9 and +76.3% higher than in patients with BMI >= 25. After TDM with adaptive dosing, a statistically significant difference in dosing between patients was observed, with doses ranging from 200 to 700 mg. No difference in toxicity or efficacy was observed regardless of BMI after adaptive dosing. Conclusion: Our data suggest that low BMI has a significant impact on imatinib exposure but that pharmacokinetically-guided dosing limits its clinical impact in patients.

关键词： adaptive dosing body mass index Imatinib pharmacokinetics therapeutic drug monitoring

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Adaptive dosing of high-dose busulfan in real-world adult patients undergoing haematopoietic cell transplant conditioning

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BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 2025年第4期91卷 1171-1181页

作者： Protzenko, Dorian Bouchacourt, Benjamin Carriat, Laure Maroselli, Paul Boeri, Clara Devillier, Raynier Ciccolini, Joseph Aix Marseille Univ Inserm Ctr Rech Cancerol Marseille U1068 COMPO Marseille France Paoli Calmettes Inst Hematol Dept Marseille France La Timone Univ Hosp Marseille AP HM PRISM Platform Biogenopole Marseille France Aix Marseille Univ Inserm Ctr Rech Cancerol Marseille U1068 OHIO Marseille France

AimTo evaluate the effectiveness of a Bayesian adaptive dosing strategy in achieving target busulfan exposure in adult patients undergoing haematopoietic cell transplantation (HCT). MethodsThis study included 71 adult patients scheduled to receive high-dose busulfan. Busulfan was administered to achieve a cumulative area under the curve (AUC) of 66.0 mg/L/h (16 000 mu M/min), 82.60 mg/L/h (20 000 mu M/min) or 87.6 mg/L/h (21 200 mu M/min) depending on the regimen. Individual pharmacokinetic (PK) parameters of busulfan were estimated from three blood samples using a one-compartment model and Bayesian estimation after the first standard dose. Individual PK parameters were used to adjust subsequent doses to achieve the target exposure. ResultsAll patients had their dose adjusted after the first dose administration. The final deviation from the target AUC was significantly improved compared to the initial deviation after standard mg/kg dosing (mean absolute deviation 19.5% vs 11.7%, P < .01). In addition, the proportion of patients with marked deviation from target exposure (ie, >25%) decreased significantly from 31% after standard dosing to 10% after PK-guided dosing (P < .01). Canonical busulfan-related toxicity, specifically veno-occlusive disease, was observed in 5% of patients who achieved successful PK-guided dosing. In contrast, one-third of patients with off-target exposure with poor dosing experienced toxicity. ConclusionThe Bayesian adaptive dosing strategy significantly improves the accuracy of achieving the target busulfan AUC in patients undergoing HCT. This approach not only reduces marked deviations from target exposure, but also reduces the incidence of busulfan-related toxicity, thereby maintaining a favourable toxicity/efficacy ratio.

关键词： adaptive dosing Bayesian busulfan haematopoietic cell transplant pharmacokinetics

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Vitamin D modulates the content of inflammatory microRNAs in extracellular vesicles from human adipocyte cells in inflammatory context

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BIOFACTORS 2025年第1期51卷 e70003页

作者： Payet, Thomas Astier, Julien Bournot, Lorrine Sicard, Flavie Robert, Stephane Lacroix, Romaric Wabitsch, Martin Landrier, Jean-Francois Mounien, Lourdes Aix Marseille Univ INSERM INRAE C2VN Marseille France Biomeostasis CRO Nutr Behav & Metab Disorders La Penne Sur Huveaune France PhenoMARS Aix Marseille Technol Platform CriBiom Marseille France Biogenopole Dept Haematol CHU Timone AP HM Marseille France Ulm Univ Med Ctr Dept Pediat & Adolescent Med Ulm Germany

Inflammation of adipose tissue is a contributing factor to many chronic diseases associated with obesity. We previously showed that micronutrients such as vitamin D (VD) limited this metabolic inflammation by decreasing inflammatory markers expression including miR-155 (microRNA-155) or miR-146a in different in vitro and in vivo models. These miRNAs could be incorporated into extracellular vesicles (EVs) in order to modulate the activity of target cells. Nevertheless, the role of VD on the miRNAs contained in EVs from adipose tissue in inflammatory conditions remains unclear. In this study, we used a human model of SGBS (Simpson-Golabi-Behmel syndrome) adipocytes preincubated with 1,25(OH)2D (the active form of VD) before an inflammatory stress with tumor necrosis factor alpha (TNF alpha). First, we confirmed by quantitative PCR that the expression of classical inflammatory factors (TNF alpha and chemokine ligand 2 [CCL2/MCP1]), miR-146a, and miR-155 was increased significantly under inflammatory conditions in SGBS cells and that VD prevented this up-regulation. Secondly, transmission electron microscope imaging of EVs preparations in supernatant allowed visualization of small and large vesicles under these conditions. Then, EVs were obtained with isolation kit and the expression of miR-155 and miR-146a were measured. The expression of miR-155 under TNF alpha effect was increased in EVs while miR-146a was not detected. Moreover, we also showed that the TNF alpha-mediated expression of miR-155 in EVs was significantly reduced by a VD pre-incubation of cells. Using miRNA PCR array, we also identified 33 miRNAs, organized in 5 clusters that were differentially regulated by TNF alpha and VD. Bioinformatic analysis of biological pathways revealed that the different miRNAs targeting genes that are involved in important cell process such as the regulation of transcription or protein phosphorylation. In conclusion, these results support for the first time that VD modulated

关键词： Vitamin D extracellular vesicles inflammation human adipocyte microRNAs

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Chapter 5: The roles of genetics in primary hyperparathyroidism

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ANNALES D ENDOCRINOLOGIE 2025年第1期86卷 101694-101694页

作者： Romanet, Pauline Coppin, Lucie Molin, Arnaud Santucci, Nicolas Le Bras, Maelle Odou, Marie-Francoise Aix Marseille Univ La Timone Univ Hosp AP HM InsermLab Mol Biol GEnOPeMMGBIOGENOPOLE Marseille France Univ Lille CHU Lille CNRS UMR9020InsermU1277CANTHER Canc Heterogene Plast Lille France Univ Normandy Caen Univ Hosp Reference Ctr Dev Disorders & Malformat Syndromes Dept GenetUNICAENRU7450BioTARGenAnddi Rares Net Caen France Dijon Univ Hosp Ctr Dept Digest Oncol & Endocrine Surg Dijon France Nantes Univ Hosp Dept Endocrinol Nantes France Univ Lille CHU Lille Inserm U1286 Infin F-59045 Lille France Lille Univ Hosp Dept Biochem & Mol Biol Lille France

Around 10% of cases of primary hyperparathyroidism are thought to be genetic in origin, some of which are part of a syndromic form such as multiple endocrine neoplasia types 1, 2A or 4 or hyperparathyroidismjaw tumor syndrome, while the remainder are cases of isolated familial primary hyperparathyroidism. Recognition of these genetic forms is important to ensure appropriate management according to the gene and type of variant involved, but screening for a genetic cause is not justified in all patients presenting primary hyperparathyroidism. The indications for genetic analysis have made it possible to propose a decision tree that takes into account whether the presentation is familial or sporadic, syndromic or isolated, patient age, and histopathological type of parathyroid lesion. Thus, the first consensus recommendation is to propose genetic screening to any patient with a familial form of primary hyperparathyroidism (>= 2 1st or 2nd degree relatives) or in syndromic presentation or a sporadic isolated presentation if the patient is under 50 years of age, or over 50 with a recurrent or multi-glandular form, carcinoma, atypical parathyroid tumor and/or loss of parafibromin expression. The panel of genes currently recommended for first-line treatment comprises MEN1, CDKN1B, CDC73, CASR, GNA11, AP2S1 and GCM2. Other genes may also be involved in familial primary hyperparathyroidism, but in a much more rarely and less consistently. The second recommendation is to propose genetic screening, up to and including whole-genome sequencing in the event of inconclusive panel analysis, to patients with proven familial primary hyperparathyroidism and/or pediatric onset. The role of the genetic practitioner is to interpret the sequencing data by categorizing the variants into 5 classes of pathogenicity. The aim of genetic analysis is to identify the genetic variant involved in the patient's phenotype, in order to make or refute a diagnosis of hereditary primary hyperparathyroidi

关键词： Primary hyperparathyroidism Genetic analysis Syndromic form Familial form Genetic counseling

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Deconvoluted Methylation Profiles Discriminate between Closely Related Melanocytic Nevi

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JOURNAL OF INVESTIGATIVE DERMATOLOGY 2025年第5期145卷 1222-1226.e4页

作者： Aldea, Daniel Macagno, Nicolas Marechal, Elise Moreno, Mathias Romanet, Pauline Pertuit, Morgane Garcia, Jeremy Degardin, Nathalie Mallet, Stephanie James, Isabelle Captier, Guillaume Barlier, Anne Etchevers, Heather C. Aix Marseille Univ MarMaRa Inst Marseille Med Genet INSERMU1251 Marseille France La Timone Hosp Assistance Publ Hop Marseille Dept Pathol BioGenoPole Marseille France La Timone Hosp Assistance Publ Hop Marseille Dept Mol Biol BioGenoPole Marseille France La Timone Hosp Assistance Publ Hop Marseille Dept Pediat Plast Surg Marseille France La Timone Hosp Assistance Publ Hop Marseille Dept Dermatol Venereol & Oncodermatol Marseille France Clin Val Ouest Ecully France Univ Montpellier Montpellier Univ Hosp Dept Pediat Surg Lab Anat Montpellier France

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Tatton-Brown-Rahman syndrome: A new multiple endocrine neoplasia syndrome with intellectual disability?

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ANNALES D ENDOCRINOLOGIE 2025年第2期86卷 101680-101680页

作者： Le Collen, Lauriane Charnay, Theo Ly, Sang Delemer, Brigitte Lagarde, Arnaud Ascone, Giuliana Daly, Adrian F. Barlier, Anne Romanet, Pauline Lille Univ Hosp Inserm CNRS UMR 1283 8199 Inst Pasteur Lille EGID Lille France Univ Lille Lille France Nancy Univ Hosp Dept Mol Med Div Biochem Mol BiolNutr Nancy France Univ Reims Dept Endocrinol Diabetol Reims France Univ Reims Dept Clin Genet Reims France Aix Marseille Univ La Timone Univ Hosp APHM InsermMMGLab Mol Biol GEnOPeBIOGENOPOLE Marseille France Aix Marseille Univ INSERM MMG Marseille France Univ Liege Ctr Hosp Univ CHU Liege Dept Endocrinol Domaine Univ Sart Tilman B-4000 Liege Belgium GCS Auragen F-69003 Lyon France

We describe for the first time the case of a woman presenting with Tatton-Brown-Rahman syndrome (TBRS) and multiple endocrine neoplasia (MEN). She developed primary hyperparathyroidism at age 13, a pituitary cyst at age 14, adrenal tumor at age 21, and metastatic insulinoma at age 34. In addition, she showed intellectual disability, obesity, multiple lipomas, facial dysmorphia, hemihypertrophy and kyphoscoliosis. At age 35, genome analysis revealed a pathogenic de-novo heterozygous germline DNMT3A variant, while classic MEN syndromes were ruled out by targeted somatic and germline genetic testing. This case highlights not only the importance of genomic analysis in patients with multiple and atypical conditions, but also the need for a multidisciplinary approach for TBRS patients, including in adulthood, involving endocrinologists to enhance understanding and optimize monitoring of this syndrome. (c) 2025 Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： Multiple endocrine neoplasia Overgrowth Kyphoscoliosis Tatton-Brown-Rahman syndrome Whole genome sequencing MEN1

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Pharmacology and pharmacokinetics of antibody-drug conjugates, where do we stand?

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CANCER TREATMENT REVIEWS 2025年 135卷 102922-102922页

作者： Geraud, Arthur Gougis, Paul de Nonneville, Alexandre Beaufils, Mathilde Billon, Emilien Brisou, Gabriel Gravis, Gwenaelle Greillier, Laurent Guerin, Mathilde Mezni, Essia Mitry, Emmanuel Noel, Robin Pignon, Josephine Sabatier, Renaud Seguin, Lorene Spano, Jean-Philippe Vicier, Cecile Viret, Frederic Goncalves, Anthony Ciccolini, Joseph Aix Marseille Univ Inst Paoli Calmettes CRCM Dept Med OncolINSERM Marseille France Aix Marseille Univ Ctr Rech Cancerol Marseille CRCM COMPO Team Inserm U1068 F-13009 Marseille France Pitie Salpetriere AP HP Dept Med Oncol F-75013 Paris France Sorbonne Univ Pitie Salpetriere Hosp AP HP INSERMClin Invest Ctr CIC 1901Dept Pharmacol Paris France Inst Curie Residual Tumor & Response Treatment Lab INSERM U932 Immun & CancRT2Lab Paris France Aix Marseille Univ Inst Paoli Calmettes CRCM Dept Hematol F-13009 Marseille France Aix Marseille Univ AMU AP HM Dept Multidisciplinary Oncol & Therapeut Innovat F-13015 Marseille France La Timone Univ Hosp Marseille AP HM Biogenopole F-13005 Marseille France

Antibody-drug conjugates (ADCs) are a rising therapeutic class in oncology and hematology, with eleven drugs approved by the US Food and Drug Administration as of January 2025. These "magic bullets" have a complex structure, including a monoclonal antibody, a linker, attachment sites, and a payload usually disrupting microtubules, targeting DNA, or inhibiting topoisomerase 1. By targeting specific tumor antigens, they are expected to be exquisitely effective in releasing "supertoxic" payloads inside tumor cells after intracellular trafficking. Additionally, they may exert a bystander effect, wherein the released payloads act on neighboring cells, amplifying their therapeutic impact regardless of target expression. ADCs have been game-changing drugs to treat tumors with once dismal prognoses or with previously considered unactionable targets, such as HER2-low or triple-negative breast cancer. To what extent there is room for personalized medicine to improve the toxicity/ efficacy ratio remains unknown. However, there are inherent issues related to the complexity of the pharmacokinetics of ADCs and their assessments: efficacy or toxicity may be influenced by the clearance of the intact ADC, the circulating payload, or the payload-linker complex. Deciphering these multifaceted exposure-outcomes relationships for both efficacy and safety endpoints, is critical for advancing precision medicine and enabling personalized dosing strategies. To improve future developments and broaden their therapeutic scope, several strategies can be developed, including developing adequate combinations with other treatment classes (cytotoxic agents, immune-checkpoint inhibitors, oral molecular-targeted therapies). In this review, we will discuss the PK/ PD aspects of ADCs and their dosing to improve their use in current and future indications.

关键词： Antibody-dug conjugate (ADC) Pharmacokinetics Pharmacodynamics Exposure-efficacy relationship (EER) Exposure-safety relationship (ESR) Therapeutic drug monitoring (TDM)

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Update on Tissue Factor Detection in Blood in 2024: A Narrative Review

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HAMOSTASEOLOGIE 2024年第5期44卷 368-376页

作者： Bonifay, Amandine Cointe, Sylvie Plantureux, Lea Lacroix, Romaric Dignat-George, Francoise Aix Marseille Univ INSERM 1263 INRAE 1260 C2VN Marseille France CHU Timone APHM Dept Hematol Biogenopole Marseille France

Tissue factor (TF) is a transmembrane protein essential for hemostasis. Different forms of active TF circulate in the blood, either as a component of blood cells and extracellular vesicles (EVs) or as a soluble plasma protein. Accumulating experimental and clinical evidence suggests that TF plays an important role in thrombosis. Many in-house and commercially available assays have been developed to measure TF-dependent procoagulant activity or antigen in blood and have shown promising results for the prediction of disease outcomes or the occurrence of thrombosis events in diseases such as cancer or infectious coagulopathies. This review addresses the different assays that have been published for measuring circulating TF antigen and/or activity in whole blood, cell-free plasma, and EVs and discusses the main preanalytical and analytical parameters that impact results and their interpretation, highlighting their strengths and limitations. In the recent decade, EVTF assays have been significantly developed. Among them, functional assays that use a blocking anti-TF antibody or immunocapture to measure EVTF activity have higher specificity and sensitivity than antigen assays. However, there is still a high variability between assays. Standardization and automatization are prerequisites for the measurement of EVTF in clinical laboratories.

关键词： tissue factor extracellular vesicles functional assays antigenic assays flow cytometry

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THERAPEUTIC POTENTIAL OF CD146 EXTRACELLULAR VESICLES FOR THE TREATMENT OF ATHEROSCLEROSIS

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ATHEROSCLEROSIS 2023年 379卷 S2-S2页

作者： Dubrou, C. Blin, M. Fallague, K. Bachelier, R. Chareyre, C. Robert, S. Bertaud, A. Lacroix, R. Dignat-George, F. Bardin, N. Blot-Chabaud, M. Leroyer, A. Aix Marseille Univ Ctr Rech Cardiovasc & Nutr Marseille France Biogenopole Assistance Publ Hop Marseille Hematol Dept Marseille France Biogenopole Assistance Pub Hop Marseille Immunol Dept Marseille France

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Updates on the genetics of multiple endocrine neoplasia

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ANNALES D ENDOCRINOLOGIE 2024年第2期85卷 127-135页

作者： Sahakian, Nicolas Castinetti, Frederic Romanet, Pauline Reznik, Yves Brue, Thierry Aix Marseille Univ AP HM Inserm MMGMarMaRa Marseille France La Conception Univ Hosp AP HM Dept Endocrinol CRMR HYPO Marseille France Timone Univ Hosp AP HM Lab Mol Biol Biogenopole Marseille France Univ Hosp Caen Dept Endocrinol Diabet Metab Disorders Caen France

Multiple endocrine neoplasia (MEN) is a group of syndromes with a genetic predisposition to the appearance of endocrine tumors, and shows autosomal dominant transmission. The advent of molecular genetics has led to improvements in the management of MEN in terms of diagnosis, prognosis and therapy. The genetics of MEN is the subject of regular updates, which will be presented throughout this paper. MEN1, the first to be described, is associated with the MEN1 gene. MEN1 is well known in terms of the observed phenotype, with genetic analysis being conclusive in 90% of patients with a typical phenotype, but is negative in around 10% of families with MEN1. Improvement in analysis techniques and the identification of other genes responsable for phenocopies allows the resolution of some, but not all, cases, notably non-familial forms suspected to be fortuitous assocations with tumors. MEN4 is a rare phenocopy of MEN1 linked to constitutional mutations in the CDKN1B gene. Though it closely resembles the phenotype of MEN1, published data suggests the appearance of tumors is later and less frequent in MEN4. MEN2, which results from mutations in the RET oncogene, shows a strong genotype-phenotype correlation. This correlation is particularly evident in the major manifestation of MEN2, medullary thyroid carcinoma (MTC), in which disease aggressiveness is dependent on the pathogenic variant of RET . However, recent studies cast doubt on this correlation between MTC and pathogenic variant. Lastly, the recent description of families carrying a mutation in MAX, which is known to predispose to the development of pheochromocytoma and paraganglioma, and presents a phenotypic spectrum that evokes MEN, suggests the existence of another syndrome, MEN5. (c) 2024 Elsevier Masson SAS. All rights reserved.

关键词： MEN1 Mosaic Phenocopies MEN2 RET Genotype-phenotype correlation CDKN1B MEN4 MAX MEN5

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