Frederic Castinetti

Context: Radiotherapy is used as second- or third-line treatment after transsphenoidal surgery for both functioning and nonfunctioning pituitary adenomas. Improved precision delivery may reduce side effects, but use overall has declined, partly due to improved surgical technique and advances in medical therapy, partly reflecting a shift from fractionated radiotherapy to stereotactic radiosurgery in appropriately selected patients, and also due to lack of clear, evidence-based guidelines. Questions remain regarding radiotherapy indications, optimal timing, choice of technique, and follow-up for efficacy and side effects. The aim of this Delphi panel was to establish expert consensus in these areas. Design: The Pituitary Society Steering Committee conducted a modified two-round Delphi panel with 29 international experts from five continents, including neuroendocrinologists, neurosurgeons and radiation oncologists. Results: Among the 26 initial statements, 22 (84.6%) reached agreement after Round 1. Four statements were reconsidered in Round 2, together with an additional question, after which 24 of 27 (88.9%) reached consensus. Panelists agreed that radiotherapy indication and timing should be assessed by expert multidisciplinary tumor boards, including a radiation oncologist, with the technique determined according to patient and adenoma characteristics. They emphasized controlling hormonal secretion while waiting for maximal radiotherapy efficacy in functioning adenomas. Long term follow-up > 10 years is required to assess for delayed efficacy, recurrence and side effects, although panelists agreed on the relatively low medium-term risk with modern techniques. Conclusion: Modified Delphi panel provides practical guidance regarding indications, timing, choice of technique and long-term follow-up of radiotherapy in pituitary adenomas. Modern techniques appear as effective and potentially safer vs. previous ones. Further long-term comparative data are needed.

Objective: The CHIRACIC trail supported the beneficial effect of adrenalectomy on hypertension in patients with unilateral adrenal incidentalomas associated with mild autonomous cortisol secretion (MACS). Additional assessments evaluated the impact of adrenalectomy on body weight excess, metabolic abnormalities and quality of life. Design: Multicenter superiority open-label randomized trial comparing adrenalectomy to conservative management. Methods: Following a run-in phase to control hypertension, receive lifestyle advice and treatment for comorbidities, patients underwent a workup including measurement of body mass index, visceral and total fat, fat mass, fasting blood glucose, HbA1c, oral glucose tolerance test, plasma lipids, and quality of life (QoL). Following randomization, assessment of comorbidities and adaptation of their treatment were performed every 3 months for 13 months. Workup was repeated at the end of the study. Results: Forty-eight patients were randomly assigned to adrenalectomy (n = 23) and conservative management (n = 25). 93%, 71% and 90% of patients were overweight/obese, prediabetics/diabetics and dyslipidemic, respectively. There was no statistically significant improvement in anthropometric and metabolic parameters after adrenalectomy as compared to conservative management: 21% and 4% of adrenalectomized and conservatively treated obese/overweight patients lost > 5% of body weight, respectively (difference 22%, 95% CI: −2% to 39%). Glycemic status improved in 44% and 33% of adrenalectomized and conservatively treated dysglycemic patients, respectively (difference 10%, 95% CI: −22% to 43%). Dyslipidemia improved in 20% of adrenalectomized and none of conservatively treated dyslipidemic patients. Changes in QoL were not different between groups. Conclusion: The beneficial effects of adrenalectomy on excess weight, metabolic disorders and QoL demonstrated in the CHIRACIC trial are more limited than those observed for hypertension. Additional randomized interventional studies involving a larger number of patients are needed to support the use of adrenalectomy in the treatment of these comorbidities.

Aggressive and metastatic pituitary neuroendocrine tumors constitute a rare, yet biologically distinct group of lesions, marked by rapid growth, therapeutic resistance, and unpredictable clinical behavior. Despite their rarity, they contribute disproportionately to morbidity due to the absence of reliable prognostic and therapeutic frameworks. Recent evidence has reframed aggressiveness as a multidimensional process shaped by somatic variants, chromosomal instability, and epigenetic remodeling. Recurrent alterations in ATRX, TP53, and SF3B1; widespread copy number losses; and lineage-specific methylation and transcriptomic profiles help delineate tumors with early malignant potential. Single-cell and immune profiling studies reveal proliferative, migratory, and immunoevasive subpopulations that may underpin variable clinical trajectories and treatment responses. Clinically, temozolomide remains the only systemic therapy with consistent benefit, while immune checkpoint inhibitors, anti-VEGF agents, and peptide receptor radionuclide therapy show emerging efficacy in selected settings. Progress will rely on harmonizing diagnostic criteria, integrating molecular and imaging biomarkers, and embedding translational endpoints into clinical trials. Together, these advances define a path toward more precise recognition and management of aggressive pituitary tumors.

Treatment of acromegaly includes surgery followed by chronic medical therapy for persistent growth hormone (GH) excess, and, in some patients, radiation. Treatment is aimed at biochemical normalization, which improves survival and comorbidities. However, many patients experience lifelong burden related to persistent acromegaly manifestations and adverse treatment effects. Long-acting somatostatin receptor ligand (SRL) therapy with octreotide or lanreotide has been the cornerstone of management. Pasireotide long-acting release, a somatostatin receptor multiligand, achieves more favorable biochemical control rates but is associated with an increased risk of hyperglycemia. Pegvisomant, a GH receptor antagonist, can be used as monotherapy or in combination with SRLs. The spectrum of medical therapy has expanded with the advent of oral octreotide capsules; the oral selective somatostatin receptor subtype 2 agonist, paltusotine; and monthly self-administered subcutaneous octreotide. This review outlines the updates to current acromegaly treatment options and their impact on patient outcomes.

L’hypopituitarisme se définit par le déficit d’une ou plusieurs hormones hypophysaires.L’hypopituitarisme congénital est lié à des mutations de facteurs de transcriptionimpliqués dans le développement hypophysaire. Identifier les mécanismes et étiologiesd’hypopituitarisme congénital doit permettre d’améliorer les traitements des patients.Dans cette optique, ce travail a porté sur 3 aspects :Clarifier les mécanismes permettant la différenciation des lignées hypophysaires. Aucours du développement hypophysaire chez la souris, il existe un phénomène complexed’interaction entre 2 facteurs de transcription à homéodomaine paired (Prop1 et Hesx1),la voie Wnt-ßcaténine et les co-répresseurs de la famille Groucho/TLE. Ces interactionssont nécessaires à l’expression d’un autre facteur de transcription hypophysaire, Pit-1(Pou1f1), impliqué dans la différentiation des lignées hypophysaires somato-lactotropeset thyréotropes. Nous avons démontré in vitro, que les co-répresseurs de la famille TLEjouaient un rôle inhibiteur direct sur l’activation de l’early enhancer de POU1F1 à e12-e13, indépendamment de l’action de HESX1. Nos modèles de souris transgéniquesavec expression permanente de HESX1 et TLE3 permettent de mettre en évidence lerôle inhibiteur majeur de HESX1, et le rôle accessoire de TLE3. Les mutations dePROP1 étant à l’origine d’une expression persistante de HESX1 et TLE3, il est probablequ’ils jouent un rôle dans le déficit en sous-unité alpha observé chez les patientsdéficitaires en PROP1.Identifier et analyser la signification fonctionnelle de nouveaux variants alléliques dugène d’un facteur de transcription à homéodomaine LIM, LHX4. La mutation T99fs deLHX4 est à l’origine d’un phénotype hypophysaire très variable au sein d’une mêmefamille, en termes de déficits et de morphologie hypophysaires, et d’anomalies extrahypophysairesassociées. Les études fonctionnelles ont montré que cette mutation étaitresponsable d’un phénomène d’haplo-insuffisance. Cette nouvelle mutation permetd’enrichir le spectre phénotypique des patients chez lesquels doit être effectué unséquençage du gène LHX4 à la recherche d’étiologie de déficit hypophysaire combinémultiple.Identifier des mécanismes nécessaires au développement de l’axe thyréotrope. Dessouris exprimant une nouvelle recombinase Cre sous contrôle du promoteur de la Tshßont été croisées avec des souris transgéniques pour lesquelles les gènes de Pitx2 oud’Isl1 (2 facteurs de transcription impliqués dans le développement hypophysaire)étaient encadrés de séquences flox. Les modèles permettaient ainsi l’inactivation dePitx2 et Isl1 au sein des cellules thyréotropes au cours de l’embryogenèse. L’étudephénotypique retrouve un déficit de croissance compatible avec un déficit thyréotropepartiel en cas d’inactivation de Pitx2 : ce phénotype est probablement lié à unmécanisme compensateur assuré par PITX1, un facteur de transcription àhoméodomaine bicoïde possédant le même homéodomaine et domaine C terminal quePITX2. A l’inverse, l’inactivation de Isl& se traduit par un déficit thyréotrope complet. Lefait que les transcrits de l’ensemble des facteurs de transcription nécessaires audéveloppement de l’axe thyréotrope soient diminués dans ce modèle souligne le rôlemajeur de ISL1 dans la fonction et la maintenance de l’axe thyréotrope.Nos résultats permettent de mieux appréhender certains des nombreux mécanismes etfacteurs impliqués dans le développement hypophysaire chez la souris, et dans lapathologie hypophysaire chez l’homme.

The primary treatment for active Cushing’s Syndrome (CS) is the surgical removal of the causative tumor. Alternative therapeutic strategies, particularly pharmaceutical approaches, are required when surgery is not feasible, unsuccessful, or in cases of recurrence. Osilodrostat, an adrenal steroidogenesis inhibitor, is approved in Europe and USA for adult patients with CS. The recommended strategy involves gradual titration to achieve eucortisolism, but this approach has limitations. Delayed disease control can be harmful in severe cases, and frequent clinical and laboratory monitoring may be challenging for some patients or during global health crises. To address these challenges, experts have introduced the block-and-replace (B&R) strategy which they consider suitable for selected patients. Due to limited guidance on patient selection and safe implementation, a group of French experts (the authors) who had the opportunity to use osilodrostat outside of clinical trials developed a position statement on B&R. They highlight that osilodrostat B&R strategy is effective and safe, especially when other treatment options are less beneficial. This position paper, while offering a valuable clinical framework, is expert-driven rather than evidence-based, emphasizing the need for further studies, particularly randomized controlled trials, comparing B&R and titration strategies across diverse populations.

While most individuals with familial medullary thyroid carcinoma (fMTC) carry RET mutations, in some instances the causative mutations remain unknown. We studied two related families with RET -negative fMTC in 21 affected individuals through linkage analysis, exome/genome sequencing, and high-density array comparative genomic hybridization. We identified a novel heterozygous 40kb intragenic SLC30A9 deletion which segregated with the disease in all affected individuals. The mutant transcript escaped nonsense-mediated decay and resulted in the production of N-terminally truncated proteins via translation reinitiation from in-frame AUG codons located downstream of the deletion. These proteins localized to the endoplasmic reticulum suggesting protein misfolding. Introducing the deletion in an MTC cell line resulted in significant upregulation of genes involved in the unfolded protein response, ER-associated degradation, and the PI3K-Akt pathway. Furthermore, the deletion was associated with increased cell proliferation, migration, and clonogenic capacity, supporting an oncogenic role. These findings expand the genetic background of fMTC beyond RET mutations and implicate translation reinitiation in the etiology of cancer susceptibility syndromes secondary to structural genomic variants.

Although radiation therapy is used less frequently in the treatment of functioning and nonfunctioning pituitary adenomas, it still plays a role to control volume and secretion. Radiation therapy remains to be considered in the therapeutic algorithm for these diseases, as mentioned in all recent national and international guidelines. Recent studies have focused on the use of stereotactic approaches, either given as a single dose or as a fractionated one. However, some patients may still benefit from conformal fractionated radiotherapy. The choice among these procedures is currently based mainly on adenoma’s profile in terms of size, quality of the radiological definition, invasiveness, and aggressiveness, as well as local availability. Endocrine efficacy in functioning pituitary adenomas and tumor control in nonfunctioning pituitary adenomas seem equivalent regardless of the technique. This review will try to determine whether gender should also be considered as a predictive factor of efficacy and toxicity.