Search Results
Search for other papers by Violeta Iotova in
Google Scholar
PubMed
Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
Search for other papers by Jerome Bertherat in
Google Scholar
PubMed
Search for other papers by George Mastorakos in
Google Scholar
PubMed
Search for other papers by Olaf Hiort in
Google Scholar
PubMed
Search for other papers by Alberto M Pereira in
Google Scholar
PubMed
Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Search for other papers by Anne Jouinot in
Google Scholar
PubMed
Search for other papers by Bernard Royer in
Google Scholar
PubMed
Search for other papers by Etienne Chatelut in
Google Scholar
PubMed
Search for other papers by Sotheara Moeung in
Google Scholar
PubMed
Department of Endocrinology, Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
Search for other papers by Guillaume Assié in
Google Scholar
PubMed
Pharmacokinetics and Pharmacochemistry Unit, Cochin Hospital, Paris Descartes University, AP-HP, Paris, France
Search for other papers by Audrey Thomas-Schoemann in
Google Scholar
PubMed
Department of Endocrinology, Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
Search for other papers by Jérôme Bertherat in
Google Scholar
PubMed
Search for other papers by François Goldwasser in
Google Scholar
PubMed
UMR8638 CNRS, Pharmacy UFR, University of Paris Descartes, PRES sorbonne Paris Cité, Paris, France
Search for other papers by Benoit Blanchet in
Google Scholar
PubMed
Background
The combination of mitotane and platinum-etoposide chemotherapy is a front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen shows limited efficacy. Pharmacokinetic drug–drug interaction between mitotane, a strong CYP3A4 inducer, and etoposide, which is a substrate of CYP3A4, may contribute to chemoresistance. The aim of this pilot study was to assess the pharmacokinetic interaction between mitotane and etoposide in ACC patients.
Methods
Five consecutive ACC patients treated with platinum etoposide (120–150 mg/m2 day 1–2–3 at cycle 1), with or without concomitant mitotane, were included. In the absence of limiting toxicity, a dose escalation of etoposide was proposed since cycle 2. Plasma etoposide concentrations were measured using liquid chromatography at 0, 4 and 24 h after each infusion. Clearance and area under the curve (AUC) of etoposide were determined at each cycle.
Results
Patients received two to six chemotherapy cycles, in association with mitotane (N = 4) or after mitotane discontinuation (N = 1). Etoposide clearance was two-fold higher with concomitant mitotane (4.95 L/h) than after mitotane discontinuation (2.53 L/h, P = 0.014), and 2.5-fold higher than that in reference population not treated with mitotane (1.81 L/h). Etoposide dose escalation was performed in four patients under mitotane, resulting in two minor tumor responses and one severe toxicity (febrile aplasia) at dose of 300 mg/m2/day. Tumor response was associated with higher etoposide AUC (267.3 vs 188.8 mg.h/L, P = 0.04).
Conclusion
A drug–drug interaction between mitotane and etoposide may contribute to the low efficacy of platinum-etoposide chemotherapy. This pilot study suggests further a potential benefit of increasing etoposide dose in ACC patients receiving mitotane.
Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Search for other papers by Anne Jouinot in
Google Scholar
PubMed
Search for other papers by Juliane Lippert in
Google Scholar
PubMed
Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
Search for other papers by Martin Fassnacht in
Google Scholar
PubMed
Search for other papers by Bruno de La Villeon in
Google Scholar
PubMed
Search for other papers by Amandine Septier in
Google Scholar
PubMed
Search for other papers by Mario Neou in
Google Scholar
PubMed
Search for other papers by Karine Perlemoine in
Google Scholar
PubMed
Search for other papers by Silke Appenzeller in
Google Scholar
PubMed
Department of Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Search for other papers by Mathilde Sibony in
Google Scholar
PubMed
Department of Digestive and Endocrine Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Search for other papers by Sébastien Gaujoux in
Google Scholar
PubMed
Department of Digestive and Endocrine Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Search for other papers by Bertrand Dousset in
Google Scholar
PubMed
Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Search for other papers by Rossella Libe in
Google Scholar
PubMed
Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Search for other papers by Lionel Groussin in
Google Scholar
PubMed
Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
Search for other papers by Cristina L Ronchi in
Google Scholar
PubMed
Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Search for other papers by Guillaume Assié in
Google Scholar
PubMed
Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Search for other papers by Jérôme Bertherat in
Google Scholar
PubMed
Background:
The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level.
Methods:
Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n = 26), chromosome alteration profiles were determined using SNP arrays (n = 14) and methylation profiles were determined using four-gene bisulfite pyrosequencing (n = 12).
Results:
Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients, respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were ‘Noisy’ (numerous and anarchic alterations) in 8/14 and ‘Chromosomal’ (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%).
Conclusions:
Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable and might be more robust for the prognostic assessment.
Inserm U1016-CNRS UMR8104, Paris, France
Hormonology Department, Cochin Hospital, Paris, France
Search for other papers by Fidéline Bonnet-Serrano in
Google Scholar
PubMed
Inserm U1016-CNRS UMR8104, Paris, France
Radiology Department, Cochin Hospital, Paris, France
Search for other papers by Maxime Barat in
Google Scholar
PubMed
Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France
Search for other papers by Anna Vaczlavik in
Google Scholar
PubMed
Search for other papers by Anne Jouinot in
Google Scholar
PubMed
Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France
Search for other papers by Lucas Bouys in
Google Scholar
PubMed
Hormonology Department, Cochin Hospital, Paris, France
INSERM, Physiopathologie et Pharmacotoxicologie Placentaire Humaine : Microbiote Pré & Post natal, Paris, France
Search for other papers by Christelle Laguillier-Morizot in
Google Scholar
PubMed
Search for other papers by Corinne Zientek in
Google Scholar
PubMed
Search for other papers by Catherine Simonneau in
Google Scholar
PubMed
Inserm U1016-CNRS UMR8104, Paris, France
Diabetology Department, Cochin Hospital, Paris, France
Search for other papers by Etienne Larger in
Google Scholar
PubMed
Search for other papers by Laurence Guignat in
Google Scholar
PubMed
Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France
Search for other papers by Lionel Groussin in
Google Scholar
PubMed
Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France
Search for other papers by Guillaume Assié in
Google Scholar
PubMed
Hormonology Department, Cochin Hospital, Paris, France
INSERM, Physiopathologie et Pharmacotoxicologie Placentaire Humaine : Microbiote Pré & Post natal, Paris, France
Search for other papers by Jean Guibourdenche in
Google Scholar
PubMed
UR 7537 BioSTM, Paris, France
Search for other papers by Ioannis Nicolis in
Google Scholar
PubMed
Search for other papers by Marie-Claude Menet in
Google Scholar
PubMed
Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France
Search for other papers by Jérôme Bertherat in
Google Scholar
PubMed
Objective
Large response of steroid precursors, including 17-hydroxyprogesterone, to adrenocorticotropic hormone (ACTH) has been described in adrenocortical tumors, suggesting the existence of intra-tumoral enzymatic deficiencies. This study aimed to compare steroidogenesis enzymes activity in unilateral and bilateral benign tumors using serum steroid profiling in liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in the basal state and after ACTH 1-24 stimulation.
Design and methods
A serum profile of seven consecutive adrenal steroids was determined in LC-MS/MS in the basal state (T0) and after ACTH 1-24 stimulation (T60) in 35 patients with bilateral adrenocortical tumors (BL), 38 patients with unilateral tumors (UL) and 37 control subjects (CT). Response amplitude of each individual steroid was evaluated by T60/T0 ratio, whereas enzymatic activity was assessed by the downstream/upstream steroid ratio. Adrenal volume was quantified by a semi-automatic segmentation method.
Results
For the seven steroids assayed, the amplitude of response to ACTH was higher in BL than in UL and in CT. The difference between BL and UL persisted even after matching patients on adrenal volume. On glucocorticoids pathway, enzymatic activity of CYP11B1 was significantly decreased in BL (78.3 (43.1-199.4)) in comparison to both UL (122.7 (13.8-228.4), P = 0.0002) and CT (186.8 (42.1-1236.3), P < 0.0001). On mineralocorticoids and androgens pathways, the enzymatic activity of CYP11B2 and CYP17A1-17,20 lyase was also lower in BL than UL and CT.
Conclusions
Decreased activity of distal steroidogenesis enzymes CYP11B1, CYP11B2 and CYP17A1-17,20 lyase, responsible for an explosive response to ACTH of upstream precursors in bilateral tumors, limits the synthesis of bioactive steroids, in particular cortisol, despite the increase in adrenal mass.
Significance statement
Activity of distal steroidogenesis enzymes (CYP11B1, CYP11B2 and CYP17A1 on glucocorticoids, mineralocorticoids and androgens pathways, respectively) is decreased in adrenocortical benign tumors. This decrease is more pronounced in bilateral lesions and seems to depend more on the nature of the lesion than on the increase in adrenal volume. It is responsible for the explosive response to ACTH of steroid precursors located upstream of these enzymes. It probably allows bioactive steroids, particularly cortisol, to stay in the normal range for a long time despite the increase in adrenal mass.
Search for other papers by Estelle Bonnet in
Google Scholar
PubMed
Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service de psychopathologie du développement, Bron, France
Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre de biologie et pathologie Est, Service d’hormonologie, d’endocrinologie moléculaire et des maladies rares, Bron, France
Search for other papers by Mathias Winter in
Google Scholar
PubMed
Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre de biologie et pathologie Est, Service d’hormonologie, d’endocrinologie moléculaire et des maladies rares, Bron, France
Search for other papers by Delphine Mallet in
Google Scholar
PubMed
Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service Endocrinologie Moléculaire et Maladies Rares, Bron, France
Search for other papers by Ingrid Plotton in
Google Scholar
PubMed
Search for other papers by Claire Bouvattier in
Google Scholar
PubMed
Search for other papers by Maryse Cartigny in
Google Scholar
PubMed
Search for other papers by Laetiti Martinerie in
Google Scholar
PubMed
Search for other papers by Michel Polak in
Google Scholar
PubMed
Search for other papers by Anne Bachelot in
Google Scholar
PubMed
Search for other papers by Frédéric Huet in
Google Scholar
PubMed
Search for other papers by Sabine Baron in
Google Scholar
PubMed
Search for other papers by Muriel Houang in
Google Scholar
PubMed
Search for other papers by Sylvie Soskin in
Google Scholar
PubMed
Search for other papers by Anne Lienhardt in
Google Scholar
PubMed
Search for other papers by Jérôme Bertherat in
Google Scholar
PubMed
Search for other papers by Cyril Amouroux in
Google Scholar
PubMed
Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service de chirurgie Uro-viscérale et de Transplantation de l’Enfant, Bron, France
Search for other papers by Aurore Bouty in
Google Scholar
PubMed
Search for other papers by Lise Duranteau in
Google Scholar
PubMed
Search for other papers by Rémi Besson in
Google Scholar
PubMed
Search for other papers by Alaa El Ghoneimi in
Google Scholar
PubMed
Search for other papers by Dinane Samara-Boustani in
Google Scholar
PubMed
Search for other papers by François Becmeur in
Google Scholar
PubMed
Search for other papers by Nicolas Kalfa in
Google Scholar
PubMed
Search for other papers by Françoise Paris in
Google Scholar
PubMed
Search for other papers by François Medjkane in
Google Scholar
PubMed
Hospices Civils de Lyon, Groupement Hospitalier Est, Service d’endocrinologie, Bron, France
Search for other papers by Aude Brac de la Perrière in
Google Scholar
PubMed
Centre National de Référence Maladies Rares du développement génital du fœtus à l’adulte DEV-GEN, Hospices Civils de Lyon, Bron, France
Search for other papers by Patricia Bretones in
Google Scholar
PubMed
Université Claude Bernard, Lyon, France
Search for other papers by Hervé Lejeune in
Google Scholar
PubMed
Centre National de Référence Maladies Rares du développement génital du fœtus à l’adulte DEV-GEN, Hospices Civils de Lyon, Bron, France
Université Claude Bernard, Lyon, France
Search for other papers by Marc Nicolino in
Google Scholar
PubMed
Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service de chirurgie Uro-viscérale et de Transplantation de l’Enfant, Bron, France
Université Claude Bernard, Lyon, France
Search for other papers by Pierre Mouriquand in
Google Scholar
PubMed
Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service de chirurgie Uro-viscérale et de Transplantation de l’Enfant, Bron, France
Search for other papers by Daniela-Brindusa Gorduza in
Google Scholar
PubMed
Centre National de Référence Maladies Rares du développement génital du fœtus à l’adulte DEV-GEN, Hospices Civils de Lyon, Bron, France
Search for other papers by Claire-Lise Gay in
Google Scholar
PubMed
Objectives
To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency since molecular diagnoses became available.
Methods
Clinical, laboratory, and therapeutic data were retrieved from the medical records of 52 patients with a molecular diagnosis of SRD5A2 (n = 31) or HSD17B3 (n = 21) deficiency. Temporal trends regarding age at assessment and initial sex assignment over 1994–2020 were qualitatively analyzed. Age at molecular diagnosis was compared between two subgroups of patients according to their year of birth.
Results
Fifty-eight percent (n = 30) patients were diagnosed during the perinatal period, 33% (n = 17) during infancy, and 9% (n = 5) during adolescence or adulthood. Over the studied period, the patients’ age at initial assessment and diagnosis frankly decreased. The median (range) age at diagnostic confirmation was 10.5 (0–53.2) years for patients born before 2007 and 0.4 (0–9.3) years for those born in 2007 or later (P = 0.029). Genetic testing identified 27 different variants for the SRD5A2 gene (30% novel, n = 8) and 18 for the HSD17B3 gene (44% novel, n = 8). Before 2002, most patients were initially assigned as females (95%, n = 19), but this proportion dropped for those born later (44%, n = 14; P < 0.001). The influence of initial genital appearance on these decisions seemingly decreased in the most recent years. Therapeutic interventions differed according to the sex of rearing. Ten percent (n = 2) patients requested female-to-male reassignment during adulthood.
Conclusion
This study showed, over the past two decades, a clear trend toward earlier diagnosis and assignment of affected newborns as males.
