Gut microbial dysbiosis in patients with Cushing’s disease in long-term remission: Relationship with cardiometabolic risk

Cushing's disease; Cardiovascular risk; Gut microbiotaEnfermedad de Cushing; Riesgo cardiovascular; Microbiota intestinalMalaltia de Cushing; Risc cardiovascular; Microbiota intestinalBackground: Patients with Cushing’s disease (CD) in remission maintain an increased cardiovascular risk. Impaired characteristics of gut microbiome (dysbiosis) have been associated with several cardiometabolic risk factors. Methods: Twenty-eight female non-diabetic patients with CD in remission with a mean ± SD) age of 51 ± 9 years, mean ( ± SD) BMI, 26 ± 4, median (IQR) duration of remission, 11(4) years and 24 gender-, age, BMI–matched controls were included. The V4 region of the bacterial 16S rDNA was PCR amplified and sequenced to analyse microbial alpha diversity (Chao 1 index, observed number of species, Shannon index) and beta diversity analysis through the Principal Coordinates Analysis (PCoA) of weighted and unweighted UniFrac distances. Inter-group difference in microbiome composition was analysed using MaAsLin2. Results: The Chao 1 index was lower in CD as compared with controls (Kruskal-Wallis test, q = 0.002), indicating lower microbial richness in the former. Beta diversity analysis showed that faecal samples from CS patients clustered together and separated from the controls (Adonis test, p<0.05). Collinsella, a genus form of the Actinobacteria phylum was present in CD patients only, whereas Sutterella, a genus from Proteobacteria phylum, was scarcely detectable/undetectable in CD patients as well as Lachnospira, a genus of the Lachnospiraceae family of the Firmicutes phylum. In CS, the Chao 1 index was associated with fibrinogen levels and inversely correlated with both triglyceride concentrations and the HOMA-IR index (p<0.05). Conclusions: Patients with CS in remission have gut microbial dysbiosis which may be one of the mechanisms whereby cardiometabolic dysfunctions persist after “cure”

Patient journey experiences may contribute to improve healthcare for patients with rare endocrine diseases

Patient journeys are instruments developed by EURORDIS, The Voice of Rare Disease Patients in Europe, to collect patients' experiences; they may identify gaps and areas deserving improvement, as well as elements positively considered by affected persons. As with other patient-reported experiences, they can complete the clinical evaluation and management of a specific disease, improving the often long diagnostic delay, therapy, patient education and access to knowledgeable multidisciplinary teams. This review discusses the utility of such patient-reported experience measures and summarises the experiences of patients with acromegaly, Addison's disease and congenital adrenal hyperplasia from different European countries. Despite rare endocrine diseases being varied and presenting differently, feelings of not having been taken seriously by health professionals, family and friends was a common patient complaint. Empathy and a positive patient-centred environment tend to improve clinical practice by creating a trustworthy and understanding atmosphere, where individual patient needs are considered. Offering access to adequate patient information on their disease, treatments and outcome helps to adapt to living with a chronic disease and what to expect in the future, contemplating the impact of a disease on patients' everyday life, not only clinical outcome but also social, financial, educational, family and leisure issues is desirable; this facilitates more realistic expectancies for patients and can even lead to a reduction in health costs. Patient empowerment with patient-centred approaches to these complex or chronic diseases should be contemplated more and more, not only for the benefit of those affected but also for the entire health system

Apport de l'imagerie dans la caractérisation des incidentalomes surrénaliens non sécrétants de plus de 4 cm

Thèse présentée sous la forme d'une "Thèse Article"Introduction : la prise en charge des tumeurs surrénaliennes non sécrétantes de plus de 4 cm représente toujours une problématique complexe. En effet, il n’existe pas d’arguments bibliographiques en faveur de l’usage de l’imagerie pour la caractérisation de leur potentielle malignité. L’objectif de notre étude était de déterminer la précision de la tomodensitométrie et de la TEP/TDM au 18F-FDG dans les tumeurs surrénaliennes de grade taille.Matériel et méthodes : les patients suivis dans notre centre pour des incidentalomes surrénaliens non sécrétants de plus de 4 cm, ayant bénéficié au diagnostic d’une tomodensitométrie standard et d’une TEP/TDM au 18F-FDG, ont été inclus rétrospectivement. Les patients n’ayant pas bénéficié d’une chirurgie d’emblée ont été suivis dans notre centre et ont bénéficié d’évaluations cliniques, biologiques et d’imagerie pendant au moins 3 ans ou jusqu’à ce qu’une indication de chirurgie soit posée.Résultats : 81 patients ont été inclus dans cette étude : 44 patients (54.3) ont été opérés d’emblée alors que les 37 autres ont été suivis, parmi eux, 21 patients (25.9%) ont été opérés après un délai moyen de 19 mois. Parmi les 65 patients opérés, 13 (20%) étaient porteurs de lésions malignes (3 métastases et 10 corticosurrénalomes malins) : Une densité spontanée 1.5. Parmi les 24 patients suivis au moins 3 ans, 5 (20.8%) ont développé un hypercorticisme (infra clinique pour 4 d’entre eux).Conclusions : les tumeurs surrénaliennes de grandes tailles sont à haut risque de malignité. L’association d’une densité spontanée < 10 et d’un ratio SUV < 1.5 comme argument de bénignité a fait sa preuve dans cette étude et pourrait permettre un suivi rapproché des patients plutôt qu’une chirurgie d’emblée. Le suivi hormonal devrait se focaliser sur le risque de développer un hypercorticisme

Synergistic cortisol suppression by ketoconazole–osilodrostat combination therapy

International audienceSummary Here, we describe a case of a patient presenting with adrenocorticotrophic hormone-independent Cushing’s syndrome in a context of primary bilateral macronodular adrenocortical hyperplasia. While initial levels of cortisol were not very high, we could not manage to control hypercortisolism with ketoconazole monotherapy, and could not increase the dose due to side effects. The same result was observed with another steroidogenesis inhibitor, osilodrostat. The patient was finally successfully treated with a well-tolerated synergitic combination of ketoconazole and osilodrostat. We believe this case provides timely and original insights to physicians, who should be aware that this strategy could be considered for any patients with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic. Learning points Ketoconazole–osilodrostat combination therapy appears to be a safe, efficient and well-tolerated strategy to supress cortisol levels in Cushing syndrome. Ketoconazole and osilodrostat appear to act in a synergistic manner. This strategy could be considered for any patient with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic. Considering the current cost of newly-released drugs, such a strategy could lower the financial costs for patients and/or society

Osilodrostat in Cushing's disease: The risk of delayed adrenal insufficiency should be carefully monitored

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Management of Cushing's syndrome during pregnancy: solved and unsolved questions

International audienceWith fewer than 200 reported cases, Cushing's syndrome (CS) in pregnancy remains a diagnostic and therapeutic challenge. In normal pregnancies, misleading signs may be observed such as striae or hypokalemia, while plasma cortisol and urinary free cortisol may rise up to 2- to 3-fold. While the dexamethasone suppression test is difficult to use, reference values for salivary cortisol appear valid. Apart from gestational hypertension, differential diagnosis includes pheochromocytoma and primary aldosteronism. The predominant cause is adrenal adenoma ( sometimes without decreased ACTH), rather than Cushing's disease. There are considerable imaging pitfalls in Cushing's disease. Aberrant receptors may, in rare cases, lead to increased cortisol production during pregnancy in response to HCG, LHRH, glucagon, vasopressin or after a meal. Adrenocortical carcinoma (ACC) is rare and has poor prognosis. Active CS during pregnancy is associated with a high rate of maternal complications: hypertension or preeclampsia, diabetes, fractures; more rarely, cardiac failure, psychiatric disorders, infection and maternal death. Increased fetal morbidity includes prematurity, intrauterine growth retardation and less prevalently stillbirth, spontaneous abortion, intrauterine death and hypoadrenalism. Therapy is also challenging. Milder cases can be managed conservatively by controlling comorbidities. Pituitary or adrenal surgery should ideally be performed during the second trimester and patients should then be treated for adrenal insufficiency. Experience with anticortisolic drugs is limited. Metyrapone was found to allow control of hypercortisolism, with a risk of worsening hypertension. Cabergoline may be an alternative option. The use of other drugs is not advised because of potential teratogenicity and/or lack of information. Non-hormonal (mechanical) contraception is recommended until sustained biological remission is obtained

Medical management of adrenocortical carcinoma: Current recommendations, new therapeutic options and future perspectives

International audienceAdrenocortical carcinoma is a rare malignant tumor of poor prognosis, frequently requiring additional treatments after initial surgery. Due to its adrenolytic action, mitotane has become the first-line medical treatment in patients with aggressive adrenocortical carcinoma. Over the last 2 years, apart from the classical chemotherapy based on etoposide and platinum salts, several studies reported the use of drugs such as temozolomide, tyrosine kinase inhibitors or immunotherapy, with more or less convincing results. The aim of this review is to give further insights in the use of these drugs, and to describe potential therapeutic perspectives based on recent pangenomic studies, for the future management of these still difficult to treat tumors.Le corticosurrénalome malin est une tumeur rare, de mauvais pronostic, nécessitant fréquemment le recours à des traitements médicamenteux après la chirurgie initiale. Depuis de nombreuses années, le mitotane est le traitement de 1re ligne des corticosurrénalomes agressifs, du fait de ses propriétés adrénolytiques. Cependant, ce traitement est souvent insuffisant et associé à une chimiothérapie de type Etoposide/Platine. Au cours des 2 dernières années, plusieurs études ont rapporté l’efficacité plus ou moins probante de nouvelles molécules telles que le temozolomide, les inhibiteurs tyrosine kinase ou l’immunothérapie. L’objectif de cette revue est de préciser les résultats de ces différentes études, et d’apporter quelques données de perspectives basées sur les études pangénomiques, dans l’objectif de mieux appréhender ce que pourrait être la prise en charge de ces tumeurs dans les années à venir

Gut microbial dysbiosis in patients with Cushing's disease in long-term remission. Relationship with cardiometabolic risk

Patients with Cushing's disease (CD) in remission maintain an increased cardiovascular risk. Impaired characteristics of gut microbiome (dysbiosis) have been associated with several cardiometabolic risk factors. Twenty-eight female non-diabetic patients with CD in remission with a mean ± SD) age of 51 ± 9 years, mean (± SD) BMI, 26 ± 4, median (IQR) duration of remission, 11(4) years and 24 gender-, age, BMI-matched controls were included. The V4 region of the bacterial 16S rDNA was PCR amplified and sequenced to analyse microbial alpha diversity (Chao 1 index, observed number of species, Shannon index) and beta diversity analysis through the Principal Coordinates Analysis (PCoA) of weighted and unweighted UniFrac distances. Inter-group difference in microbiome composition was analysed using MaAsLin2. The Chao 1 index was lower in CD as compared with controls (Kruskal-Wallis test, q = 0.002), indicating lower microbial richness in the former. Beta diversity analysis showed that faecal samples from CS patients clustered together and separated from the controls (Adonis test, p<0.05). Collinsella, a genus form of the Actinobacteria phylum was present in CD patients only, whereas Sutterella, a genus from Proteobacteria phylum, was scarcely detectable/undetectable in CD patients as well as Lachnospira, a genus of the Lachnospiraceae family of the Firmicutes phylum. In CS, the Chao 1 index was associated with fibrinogen levels and inversely correlated with both triglyceride concentrations and the HOMA-IR index (p<0.05). Patients with CS in remission have gut microbial dysbiosis which may be one of the mechanisms whereby cardiometabolic dysfunctions persist after "cure"

Aggressive pituitary tumours and pituitary carcinomas

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