Publications by authors named "Thierry Brue"

178 Publications

LACK OF DELAYED NEUROCOGNITIVE SIDE-EFFECTS OF GAMMA KNIFE RADIOSURGERY IN ACROMEGALY: THE LATER-AC STUDY.

Eur J Endocrinol 2021 Oct 1. Epub 2021 Oct 1.

T Brue, Endocrinology, Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Institut Marseille Maladies Rares (MarMaRa), Marseille, France and Assistance Publique-Hôpitaux de Marseille (AP-HM), Department of Endocrinology, Hôpital de la Conception, Centre de Référence des Maladies Rares de l'hypophyse HYPO, 13005, Marseille, France, Marseille, France.

Introduction: Persistent growth hormone hypersecretion can be observed in roughly 50% of patients operated for somatotroph adenomas, requiring additional treatments. Despite its proven antisecretory efficacy, the use of Gamma Knife radiosurgery (GK), is limited probably due to the lack of data on long term side effects, including potential cognitive consequences.

Methods: The Later-Ac study was a cross sectional exposed/unexposed non randomized study. The primary objective was to determine the long-term neurocognitive effects of GK focusing on memory, executive functions and calculation ability. Exposed patients had been treated by GK for acromegaly at least 5 years before inclusion. Unexposed patients (paired for age) had to be cured or controlled at last follow-up without any radiation technique. Patients of both groups were cured or controlled at last follow-up.

Results: 64 patients were evaluated (27 exposed and 37 unexposed). Mean follow-up after GK was 13±6 years (including 24 patients followed for at least 10 years). While up to 23.8% of the patients of the whole cohort presented at least one abnormal cognitive test, we did not observe any significant difference in neurocognitive function between both groups. During the follow-up, 11 patients presented at least one new pituitary deficiency (p=0.009 for TSH deficiency with a higher rate in exposed patients), 2 presented a stroke (1 in each group), and one, a meningioma (12 years after GK).

Conclusions: While GK exposes patients to a well-known risk of pituitary deficiency, it does not seem to induce long-term cognitive consequences in patients treated for acromegaly.
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http://dx.doi.org/10.1530/EJE-21-0826DOI Listing
October 2021

Cost-Utility of Acromegaly Pharmacological Treatments in a French Context.

Front Endocrinol (Lausanne) 2021 7;12:745843. Epub 2021 Oct 7.

Endocrinology Department, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France.

Objective: Efficacy of pharmacological treatments for acromegaly has been assessed in many clinical or real-world studies but no study was interested in economics evaluation of these treatments in France. Therefore, the objective of this study was to estimate the cost-utility of second-line pharmacological treatments in acromegaly patients.

Methods: A Markov model was developed to follow a cohort of 1,000 patients for a lifetime horizon. First-generation somatostatin analogues (FGSA), pegvisomant, pasireotide and pegvisomant combined with FGSA (off label) were compared. Efficacy was defined as the normalization of insulin-like growth factor-1 (IGF-1) concentration and was obtained from pivotal trials and adjusted by a network meta-analysis. Costs data were obtained from French databases and literature. Utilities from the literature were used to estimate quality-adjusted life year (QALY).

Results: The incremental cost-utility ratios (ICUR) of treatments compared to FGSA were estimated to be 562,463 € per QALY gained for pasireotide, 171,332 € per QALY gained for pegvisomant, and 186,242 € per QALY gained for pegvisomant + FGSA. Pasireotide seems to be the least cost-efficient treatment. Sensitivity analyses showed the robustness of the results.

Conclusion: FGSA, pegvisomant and pegvisomant + FGSA were on the cost-effective frontier, therefore, depending on the willingness-to-pay for an additional QALY, they are the most cost-effective treatments. This medico-economic analysis highlighted the consistency of the efficiency results with the efficacy results assessed in the pivotal trials. However, most recent treatment guidelines recommend an individualized treatment strategy based on the patient and disease profile.
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http://dx.doi.org/10.3389/fendo.2021.745843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531881PMC
October 2021

Fully endoscopic endonasal approach for the treatment of intrasellar arachnoid cysts.

Pituitary 2021 Oct 5. Epub 2021 Oct 5.

Department of Neurosurgery, Hôpital de La Timone, Marseille, France.

Purpose: To report our experience of endoscopic endonasal obliteration of symptomatic sellar arachnoid cyst (SAC).

Methods: From 2002 to 2019, we retrospectively reported the data of 17 cases of SAC operated in Timone University Hospital, Marseille, France. Preoperative clinical findings were collected including main symptoms, visual function and endocrinological assessment. Surgical procedure was homogeneous and consisted in endonasal fully endoscopic surgical obliteration of the cyst cavity with fat graft. Post-operative outcomes, complication and follow-up was reported.

Results: Visual disorders and/or headaches were the main symptoms. Our technique provided improvement for 83.3% of the patients suffering from visual disturbance and for 87.5% of those suffering from headaches. We reported 2 cases of cerebrospinal fluid (CSF) leakage (11.8%), but no meningitis. One case of definitive diabetes insipidus occurred and one case of postoperative syndrome of inappropriate antidiuretic hormone secretion was temporary. There was one case of recurrence reported. The mean follow-up was 39 months.

Conclusion: Patients with symptomatic SAC can be treated successfully by endoscopic endonasal obliteration of the cyst. This simple technique offers true benefits for the patients without craniotomy, but the complication rate remains high especially with the risk of CSF leakage. Special attention to skull base opening and closing could reduce this risk.
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http://dx.doi.org/10.1007/s11102-021-01187-8DOI Listing
October 2021

Novel mechanism of pituitary hormone deficiency: genetic variants shift splicing to produce a dominant negative transcription factor isoform.

Eur J Endocrinol 2021 Nov 26;185(6):C19-C25. Epub 2021 Nov 26.

Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

Recent studies have shown a novel mechanism of combined pituitary hormone deficiency associated with mutations in POU1F1, altering the balance of alternative-splicing, which results in over-expression of the beta isoform of POU1F1. These studies underscore the need for biologists, in the context of routine molecular diagnosis of this condition, to investigate alternative splicing in POU1F1 as well as in other genes.
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http://dx.doi.org/10.1530/EJE-21-0949DOI Listing
November 2021

Acromegaly in remission: a view from the partner.

Eur J Endocrinol 2021 Oct 21;185(6):K21-K25. Epub 2021 Oct 21.

Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Institut Marseille Maladies Rares (MarMaRa), Marseille, France.

Objective: A relative can be an asset in dealing with chronic illnesses, such as acromegaly, where quality of life (QoL) is altered even after remission. However, it has been shown that quality of life of caregivers can also be impacted. Our main objective was to compare the perception of acromegaly in remission in the patient-relative dyad.

Methods: In this observational study, 27 patients in remission and relatives were first asked to complete QoL, anxiety/depression and coping strategy questionnaires. Then, the patient's body image and self-esteem were evaluated from both the patient's and the relative's point of view using the same questionnaires with modified instructions.

Results: Relatives had overall an accurate estimation of patient body image using the Figure Rating Scale by Stunkard. However, there were wide variations between the patient's and the relative's responses regarding self-esteem and body perception. The QoL of relatives was not altered and was significantly higher in the social domain than for the patient.

Conclusions: Our results show that relatives require education concerning all the steps involved in the management of acromegaly, as they likely do not fully understand the sequelae of acromegaly.
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http://dx.doi.org/10.1530/EJE-21-0537DOI Listing
October 2021

Aggressive pituitary tumours and pituitary carcinomas.

Nat Rev Endocrinol 2021 11 7;17(11):671-684. Epub 2021 Sep 7.

Assistance Publique-Hôpitaux de Marseille (AP-HM), Endocrinology Department, Hôpital de la Conception, Reference Centre for Rare Pituitary Diseases HYPO, Marseille, France.

Although usually benign, anterior pituitary tumours occasionally exhibit aggressive behaviour, with invasion of surrounding tissues, rapid growth, resistance to conventional treatments and multiple recurrences. In very rare cases, they metastasize and are termed pituitary carcinomas. The time between a 'classical' pituitary tumour and a pituitary carcinoma can be years, which means that monitoring should be performed regularly in patients with clinical (invasion and/or tumour growth) or pathological (Ki67 index, mitotic count and/or p53 detection) markers suggesting aggressiveness. However, although both invasion and proliferation have prognostic value, such parameters cannot predict outcome or malignancy without metastasis. Future research should focus on the biology of both tumour cells and their microenvironment, hopefully with improved therapeutic outcomes. Currently, the initial therapeutic approach for aggressive pituitary tumours is generally to repeat surgery or radiotherapy in expert centres. Standard medical treatments usually have no effect on tumour progression but they can be maintained on a long-term basis to, at least partly, control hypersecretion. In cases where standard treatments prove ineffective, temozolomide, the sole formally recommended treatment, is effective in only one-third of patients. Personalized use of emerging therapies, including peptide receptor radionuclide therapy, angiogenesis-targeted therapy and immunotherapy, will hopefully improve the outcomes of patients with this severe condition.
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http://dx.doi.org/10.1038/s41574-021-00550-wDOI Listing
November 2021

Role of growth hormone in hepatic and intestinal triglyceride-rich lipoprotein metabolism.

J Clin Lipidol 2021 Aug 16. Epub 2021 Aug 16.

Aix Marseille Univ, APHM, INSERM, INRAE, C2VN, University Hospital La Conception, Department of Nutrition, Metabolic Diseases and Endocrinology, 147 boulevard Baille, Marseille 13005, France. Electronic address:

Background: Elevated plasma concentrations of hepatic- and intestinally-derived triglyceride-rich lipoproteins (TRL) are implicated in the pathogenesis of atherosclerotic cardiovascular disease and all-cause mortality. Excess of TRL is the driving cause of atherogenic dyslipidemia commonly occurring in insulin-resistant individuals such as patients with obesity, type 2 diabetes and metabolic syndrome. Interestingly, growth hormone (GH)-deficient individuals display similar atherogenic dyslipidemia, suggesting an important role of GH and GH deficiency in the regulation of TRL metabolism.

Objective: We aimed to examine the direct and/or indirect role of GH on TRL metabolism.

Methods: We investigated the effect on fasting and postprandial hepatic-TRL and intestinal-TRL metabolism of short-term (one month) withdrawal of GH in 10 GH-deficient adults.

Results: After GH withdrawal, we found a reduction in fasting plasma TRL concentration (significant decrease in TRL-TG, TRL-cholesterol, TRL-apoB-100, TRL-apoC-III and TRL-apoC-II) but not in postprandial TRL response. This reduction was due to fewer fasting TRL particles without a change in TG per particle and was not accompanied by a change in postprandial TRL-apoB-48 response. Individual reductions in TRL correlated strongly with increases in insulin sensitivity and decreases in TRL-apoC-III.

Conclusion: In this relatively short term 'loss of function' human experimental model, we have shown an unanticipated reduction of hepatic-TRL particles despite increase in total body fat mass and reduction in lean mass. These findings contrast with the atherogenic dyslipidemia previously described in chronic GH deficient states, providing a new perspective for the role of GH in lipoprotein metabolism.
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http://dx.doi.org/10.1016/j.jacl.2021.08.003DOI Listing
August 2021

More than a decade of real-world experience of pegvisomant for acromegaly: ACROSTUDY.

Eur J Endocrinol 2021 Aug 27;185(4):525-538. Epub 2021 Aug 27.

Division of Endocrinology and Pituitary Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Objective: To report the final long-term safety and efficacy analyses of patients with acromegaly treated with pegvisomant from the ACROSTUDY.

Design: Global (15 countries), multicentre, non-interventional study (2004-2017).

Methods: The complete ACROSTUDY cohort comprised patients with acromegaly, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. The main endpoints were long-term safety (comorbidities, adverse events (AEs), pituitary tumour volumes, liver tests) and efficacy (IGF1 changes).

Results: Patients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0-20.8 years) and followed up for a median of 7.4 years (range, 0-13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests occurred in 3.2% of patients. IGF1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7% at year 1, and reaching 75.4% at year 10 with the use of ≥30 mg PEGV/day in an increasing proportion of patients.

Conclusion: This comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and combination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control.
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http://dx.doi.org/10.1530/EJE-21-0239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428076PMC
August 2021

High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency.

Am J Hum Genet 2021 08 15;108(8):1526-1539. Epub 2021 Jul 15.

Instituto de Biociencias, Biotecnología y Biología Traslacional, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires, CABA CE1428EHA, Argentina.

Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387473PMC
August 2021

Pegvisomant treatment in acromegaly in clinical practice: Final results of the French ACROSTUDY (312 patients).

Ann Endocrinol (Paris) 2021 Jul 10. Epub 2021 Jul 10.

CRESTIC EA 3804, université de Reims Champagne Ardenne, UFR Sciences Exactes et Naturelles, Moulin de la Housse, BP 1039, 51687 Reims cedex 2, France; Service d'Endocrinologie-Diabète-Nutrition, CHU de Reims, hôpital Robert Debré, avenue du Général Koenig, 51092 Reims cedex, France. Electronic address:

Objective: We report the final analysis of the French ACROSTUDY, using data revised and enriched since the 2013 interim analysis. Our objective was to validate the use of pegvisomant (PEGV) in the treatment of acromegaly and to determine efficacy and safety.

Patients And Methods: Patients with acromegaly treated with PEGV and followed up for at least 5 years were included. Eighty-eight investigators from 62 clinical centers in France included patients from April 2007 to April 2014. PEGV dose and administration frequency were determined by the physicians, based on their clinical evaluation and local habits. No additional examinations beyond those performed in normal follow-up were required. Minimum recommended follow-up included check-ups at treatment initiation, 6 months, 12 months and then annually.

Results: In total, 312 patients were enrolled. Mean age was 46.1±14.3 years at introduction of PEGV. Median PEGV treatment duration was 6.3 years and median follow-up was 5.6 years. Median dose at initiation was 10mg/day. The percentages of patients with IGF-1 ≤ ULN (upper limit of normal) were 10% (n=300) at baseline, 54% at 6 months (n=278), and 61.7% (n=253) at 2 years, then stabilizing at 64.4% (n=180) at 5 years. Mean PEGV dose was 17.4±11.7mg in patients with controlled disease versus 21.1±17.3mg in those without control at 5 years. At 5 years, 21.8% of patients (54/248) were receiving >30mg PEGV per day. In patients with at least one pituitary imaging procedure during the 5-year follow-up (n=292), the most recent image showed stable tumor volume in 212 subjects (72.6%), increased volume in 13 (4.5%), and decreased volume in 30 (10.3%). No PEGV treatments were permanently discontinued due to transaminase elevation. There were no cases of liver failure.

Conclusion: The French ACROSTUDY showed normalization of IGF-1 levels in 64.4% of a real-life cohort of patients, mostly with uncontrolled disease despite multiple prior therapies. Long-term follow-up showed a sustained effectiveness and good long-term safety.
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http://dx.doi.org/10.1016/j.ando.2021.05.004DOI Listing
July 2021

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

Clin Endocrinol (Oxf) 2021 Jul 5. Epub 2021 Jul 5.

Department of Endocrinology, Aix Marseille Univ, APHM, INSERM, MMG, Marmara Institute, La Conception Hospital, Marseille, France.

Antisecretory data shows a highly effective and prolonged blockade of cortisol secretion with osilodrostat. The drawback is the occurrence of adrenal insufficiency (AI) in roughly a quarter of treated patients. In this short manuscript, we report three cases of atypical adrenal insufficiency with osilodrostat.
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http://dx.doi.org/10.1111/cen.14551DOI Listing
July 2021

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

J Endocr Soc 2021 Mar 9;5(3):bvaa205. Epub 2021 Feb 9.

Royal Veterinary College, University of London, London, UK.

The designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.
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http://dx.doi.org/10.1210/jendso/bvaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874572PMC
March 2021

Pre-term birth in women exposed to Cushing's disease: the baby-cush study.

Eur J Endocrinol 2021 Mar;184(3):469-476

Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Institut Marseille Maladies Rares (MarMaRa), Marseille, France.

Design: Hypercortisolism during pregnancy is a risk factor for prematurity. Long-term exposure to hypercortisolism may lead to permanent comorbidities, such as hypertension or diabetes, even after remission. Our aim was to determine whether women with a history of Cushing's disease (and being eu-, hypo- or hypercortisolic at the time of pregnancy) had the same risks of comorbidities, and especially prematurity, during pregnancy.

Methods: It was a retrospective multicentric study focusing on mothers with a history of Cushing's disease or diagnosed during pregnancy, followed in French tertiary referral centers. We compared the outcomes of pregnancies depending on the cortisolic status at the time of pregnancy.

Results: A total of 60 patients (78 pregnancies including 21 with hypercortisolism, 32 with hypocortisolism and 25 in eucortisolism in 25) were evaluated. The overall rate of preterm birth was 24.3%, with a peak in women diagnosed during pregnancy (62.5%), a high risk in hypercortisolic (33%) and hypocortisolic (19.3%), and a low risk (8%) in eucortisolic women Gestational diabetes and hypertension were observed in 21% and 10.4% of the whole cohort, with a higher risk in hypercortisolic women. Cesarean delivery was performed in 33.7% of the cohort.

Conclusions: Being non-eucortisolic at the time of pregnancy increases the risk of prematurity and comorbidities compared to the general population. Women with a history of Cushing's disease should thus be carefully monitored during pregnancy. The high rate of cesarean delivery emphasizes the fact that these pregnancies should always be considered at risk.
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http://dx.doi.org/10.1530/EJE-20-1224DOI Listing
March 2021

Adrenal Crisis May Occur Even In Patients With Asymptomatic Covid-19.

Endocr Pract 2020 Aug;26(8):929-930

Department of Endocrinology, La Conception Hospital, 147 Boulevard Baille, 13005 Marseille, France.. Electronic address:

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http://dx.doi.org/10.4158/1934-2403-26.8.929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836718PMC
August 2020

Corticotroph tumor progression after bilateral adrenalectomy (Nelson's syndrome): systematic review and expert consensus recommendations.

Eur J Endocrinol 2021 Mar;184(3):P1-P16

Section on Genetics & Endocrinology Eunice Kennedy Shriver National Insitute of Child Health & Human Development (NICHD) National Institute of Health (NIH), NIH Clinical Research Center, Bethesda, Maryland, USA.

Background: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing.

Methods: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018.

Results: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients).

Conclusions: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.
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http://dx.doi.org/10.1530/EJE-20-1088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060870PMC
March 2021

Risk factors and management of pasireotide-associated hyperglycemia in acromegaly.

Endocr Connect 2020 Dec;9(12):1178-1190

Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.

Pasireotide, a multireceptor-targeted somatostatin analog with highest affinity for somatostatin receptor subtype (SST) 5, has demonstrated superior efficacy over the SST2-preferential somatostatin analogs octreotide and lanreotide. The safety profile is similar to those of octreotide and lanreotide, except for a higher frequency and degree of hyperglycemia. This analysis investigated baseline characteristics and occurrence and management of hyperglycemia during pasireotide treatment in patients with acromegaly treated in two prospective clinical studies, SOM230C2305 (C2305) and SOM230C2402 (C2402; PAOLA). One hundred and seventy-eight patients naïve to medical therapy at baseline (C2305) and 125 uncontrolled on first-generation somatostatin analogs at baseline (C2402) received long-acting pasireotide in these studies. Of patients treated with pasireotide in studies C2305 and C2402, respectively, 75.3 (134/178) and 65.6% (82/125) developed hyperglycemia or experienced worsening of existing hyperglycemia. Occurrence of hyperglycemia during pasireotide treatment was less frequent in patients with lower age (<40 years, C2402; <30 years, C2305), normal glucose tolerance, and no history of hypertension or dyslipidemia at baseline. Thirteen (4%) patients discontinued pasireotide because of hyperglycemia-related adverse events. Metformin alone or in combination with other oral antidiabetic medications controlled elevations in glucose levels in most pasireotide-treated patients; 78% of C2305 patients and 73 (pasireotide 40 mg) and 60% (pasireotide 60 mg) of C2402 patients achieved the ADA/EASD goal of HbA1c <7% (<53 mmol/mol) at the end of the core phase. Not all patients develop hyperglycemia, and it is reversible upon pasireotide withdrawal. Close monitoring, patient education and prompt action remain key elements in addressing hyperglycemia during pasireotide treatment.
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http://dx.doi.org/10.1530/EC-20-0361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774766PMC
December 2020

Characterization of the ability of a, second-generation SST-DA chimeric molecule, TBR-065, to suppress GH secretion from human GH-secreting adenoma cells.

Pituitary 2021 Jun 12;24(3):351-358. Epub 2021 Jan 12.

Laboratoire de Biologie Moléculaire et Biochimie, Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Hôpital de la Conception, Marseille, France.

Context: Somatostatin (SST) and dopamine (DA) inhibit growth hormone (GH) secretion and proliferation of GH-secreting pituitary adenomas (GHomas) through binding to SSTR2 and D2R receptors. Chimeric SST-DA compounds (Dopastatins) display increased potency in inhibiting GH secretion, as compared with individual SST or DA analogs (alone or combined).

Objective: To assess the efficacy of a second-generation dopastatin, TBR-065, in suppressing GH secretion from human GH- and GH/prolactin(PRL)-omas.

Design: We compared the ability of TBR-065 to inhibit GH secretion from primary cultures of human GH- or GH/PRLoma cells to that of the first generation dopastatin, TBR-760 (formerly BIM-23A760), octreotide (OCT) and cabergoline (CAB), the later either alone or combined. We investigated whether there was any impact of BIM-133, the metabolite of TBR-065, on the ability of TBR-065 to inhibit GH in these cultures.

Methods: 17 GH- and GH/PRLomas were included in this study. Inhibition of GH secretion by TBR-065, TBR-760, OCT and CAB (0.1 pM to 0.1 µM) was assessed over a period of 8 h.

Results: All tumors expressed SSTR2 and D2R mRNAs. GH suppression was higher with TBR-065 as compared with TBR-760 (E = 57 ± 5.6% vs. 41.1 ± 12.5%, respectively, p < 0.001) or with OCT + CAB (E = 56.8 ± 7.2% vs. 44.4 ± 9.4%, p < 0.001). BIM-133 did not have any impact on the activity of TBR-065.

Conclusion: TBR-065 has significantly improved efficacy in suppressing GH secretion as compared to current available therapies and may represent a new promising option for the treatment of acromegaly.
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http://dx.doi.org/10.1007/s11102-020-01113-4DOI Listing
June 2021

The risks of medical treatment of prolactinoma.

Ann Endocrinol (Paris) 2021 Feb 26;82(1):15-19. Epub 2020 Dec 26.

Service d'endocrinologie, hôpital de la Conception, 147, boulevard Baille, 13005 Marseille, France; Aix Marseille université, centre de références maladies rares HYPO, Assistance Publique-Hôpitaux de Marseille, Marseille, France.

First-line treatment of prolactinoma is usually medical, based on dopamine agonists receptors, mainly cabergoline. The classical side-effects of cabergoline (low blood pressure and nausea) have been well known since it was first introduced. Other side-effects, however, are more controversial or simply less frequent, but need to be considered during monitoring. This review will focus on these side-effects: cardiac valvular fibrosis, pleural, pericardial and retroperitoneal fibrosis, addictive/compulsive behaviors, and risks secondary to significantly decreased tumor volume. We will also describe how such side-effects should be monitored and managed. In our opinion, the low prevalence of these side-effects should not cast doubt on the role of cabergoline in the therapeutic algorithm of prolactinoma.
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http://dx.doi.org/10.1016/j.ando.2020.12.008DOI Listing
February 2021

ESE audit on management of Adult Growth Hormone Deficiency in clinical practice.

Eur J Endocrinol 2020 Dec 1. Epub 2020 Dec 1.

T Kocjan, Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, Ljubljana, Slovenia.

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform.

Aims: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD.

Design: On-line survey in endocrine centres throughout Europe.

Patients And Methods: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018.

Results: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved.

Conclusion: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.
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http://dx.doi.org/10.1530/EJE-20-1180DOI Listing
December 2020

Women's perceptions of femininity after craniopharyngioma: a qualitative study.

Clin Endocrinol (Oxf) 2021 05 9;94(5):880-887. Epub 2020 Dec 9.

Department of Gynecology-Obstetric and Reproductive Medicine, AP-HM, Hôpital La Conception-Hôpital Nord, Marseille, France.

Background: Previous quantitative studies have shown a reduced quality of life in patients treated for craniopharyngioma (CP). However, few have assessed their sexual quality of life and other issues related to patient intimacy have not yet been addressed. Standardized questionnaires limit the approach to sexuality and the exploration of patient experiences. A qualitative study, which allows in-depth analysis, may represent an interesting approach to explore intimacy in women with a history of CP.

Objective: To assess the impact of a CP history on femininity and relationships in women.

Design And Patients: A qualitative study with semi-structured interviews was conducted with 15 adult women treated for CP during childhood, adolescence or at childbearing age up to 40 years of age. Interviews were audio recorded, anonymized and transcribed literally. Data analysis was carried out with an inductive approach according to the grounded theory method.

Results: Three main themes were identified: (a) apparent changes leading to altered self-perception that may impact on femininity and generate lower self-esteem; (b) managing the hidden disabilities of the disease inducing a need for permanent control; and (c) building parenthood and couple relationships: coping with sexual dysfunction and infertility.

Conclusions: Our study highlighted alterations in self-perception and femininity due to body change and disability resulting from CP treatment, impacting both couple and social relationships. Interviewing women who underwent CP surgery at different ages highlighted specific needs and different expectations of medical professionals which emphasize the importance of offering both global and personalized care.
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http://dx.doi.org/10.1111/cen.14378DOI Listing
May 2021

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

Ann Endocrinol (Paris) 2021 Feb 3;82(1):52-58. Epub 2020 Dec 3.

Aix-Marseille University, Marseille Medical Genetics, INSERM, Department of endocrinology, La Conception Hospital, Marseille, France. Electronic address:

Adrenocortical 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 2years, 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.
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http://dx.doi.org/10.1016/j.ando.2020.12.003DOI Listing
February 2021

Somatostatin receptor ligands induce TSH deficiency in thyrotropin-secreting pituitary adenoma.

Eur J Endocrinol 2021 Jan;184(1):1-8

Centre de Référence des Maladies Rares de la Thyroïde et des Récepteurs Hormonaux TRH Centre de Référence des Maladies Rares de l'Hypophyse HYPO Service d'Endocrinologie, Diabétologie et Nutrition, CHU d'Angers, Institut MITOVASC, Université d'Angers, Angers, France.

Objective: Somatostatin receptor ligands (SRL) are useful to control central hyperthyroidism in patients with thyrotropin-secreting pituitary adenoma (TSH pituitary adenoma). The aim of this study was to describe the frequency of thyrotropin deficiency (TSH deficiency) in patients with TSH pituitary adenoma treated by SRL.

Design: Retrospective study.

Methods: Patients with central hyperthyroidism due to TSH pituitary adenoma treated by short or long-acting SRL were retrospectively included. TSH deficiency was defined by a low FT4 associated with non-elevated TSH concentrations during SRL therapy. We analysed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency.

Results: Forty-six patients were included. SRL were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%) after a median time of 4 weeks (4-7) and for a median duration of 3 months (2.5-3). The TSH deficiency occurred after one to three injections of long-acting SRL used as first-line therapy in 6/7 cases. There were no differences in terms of clinical and hormonal features, size of adenomas or doses of SRL between patients with or without TSH deficiency.

Conclusions: SRL can induce TSH deficiency in patients with central hyperthyroidism due to TSH pituitary adenoma. Thyrotropic function should be assessed before the first three injections of SRL in order to track TSH deficiency and reduce the frequency of injections when control of thyrotoxicosis rather than tumour reduction is the aim of the treatment.
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http://dx.doi.org/10.1530/EJE-20-0484DOI Listing
January 2021

Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort.

Clin Endocrinol (Oxf) 2021 02 21;94(2):277-289. Epub 2020 Dec 21.

Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Faculté des Sciences médicales et paramédicales, Institut Marseille Maladies Rares (MarMaRa), Marseille, France.

Context: The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non-acquired hypopituitarism.

Aims: To describe main phenotype patterns and their evolution through life.

Design: Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2.

Results: Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations.

Conclusion: This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long-term follow-up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.
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http://dx.doi.org/10.1111/cen.14355DOI Listing
February 2021

Pegvisomant in combination or pegvisomant alone after failure of somatostatin analogs in acromegaly patients: an observational French ACROSTUDY cohort study.

Endocrine 2021 01 28;71(1):158-167. Epub 2020 Sep 28.

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, 94275, Le Kremlin-Bicêtre, France.

Objective: After surgery, when somatostatin analogs (SAs) do not normalise IGF-I, pegvisomant (PEG) is indicated. Our aim was to define the medical reasons for the treatment of patients with PEG as monotherapy (M) or combined with SA, either as primary bitherapy, PB (PEG is secondarily introduced after SA) or as secondary bitherapy, SB (SAs secondarily introduced after PEG).

Methods: We retrospectively analysed French data from ACROSTUDY.

Results: 167, 88 and 57 patients were treated with M, PB or SB, respectively, during a median time of 80, 42 and 70 months. The median PEG dose was respectively 15, 10 and 20 mg. Before PEG, the mean IGF-I level did not differ between M and PB but the proportion of patients with suprasellar tumour extension was higher in PB group (67.5% vs. 44.4%, P = 0.022). SB regimen was used preferentially in patients with tumour increase and IGF-I level difficult to normalise under PEG. In both secondary regimens, the decrease of the frequency of PEG's injections, compared to monotherapy was confirmed. However, the mean weekly dose of PEG between M and PB remained the same.

Conclusions: The medical rationale for continuing SAs rather than switching to PEG alone in patients who do not normalise IGF-I under SAs was a tumour concern with suprasellar extension and tumour shrinkage under SA. A potential explanation for introducing SA in association with PEG appears to be a tumour enlargement and difficulties to normalise IGF-I levels under PEG given alone. In both regimens, the prospect of lowering PEG injection frequency favoured the choice.
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http://dx.doi.org/10.1007/s12020-020-02501-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835180PMC
January 2021

Correction to: MEN2-related pheochromocytoma: current state of knowledge, specific characteristics in MEN2B, and perspectives.

Endocrine 2020 Jul 14. Epub 2020 Jul 14.

Department of Endocrinology, Aix-Marseille University, INSERM U1251, Endo-ERN Reference Center for Rare Genetic Tumor Syndromes, Assistance Publique-Hopitaux de Marseille, Marseille, France.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1007/s12020-020-02408-zDOI Listing
July 2020

Germinal defects of SDHx genes in patients with isolated pituitary adenoma.

Eur J Endocrinol 2020 Oct;183(4):369-379

Aix Marseille Univ, APHM, INSERM, MMG, Hospital La Conception, Laboratory of Molecular Biology, Marseille, France.

Background: The '3PAs' syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In '3PAs' syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases.

Objective: To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations.

Design: Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of '3PAs' syndrome.

Results: A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology.

Conclusions: We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.
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http://dx.doi.org/10.1530/EJE-20-0054DOI Listing
October 2020

Multivariable Prediction Model for Biochemical Response to First-Generation Somatostatin Receptor Ligands in Acromegaly.

J Clin Endocrinol Metab 2020 09;105(9)

Department of Medicine, Endocrinology section, Pituitary Center Rotterdam, Erasmus University Medical Center, Rotterdam, the Netherlands.

Context: First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs.

Objective: To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1 ≤ 1.3 × ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction.

Design: Retrospective multicenter study.

Setting: Eight participating European centers.

Methods: We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy.

Results: Lower IGF-1 concentration at baseline (odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.72-0.95 IGF-1 ULN, P = .0073) and lower bodyweight (OR = 0.99, 95% CI 0.98-0.99 kg, P = .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (OR = 1.40, (1.19-1.65) IGF-1 ULN, P ≤ .0001), the presence of type 2 diabetes (oral medication OR = 2.48, (1.43-4.29), P = .0013; insulin therapy OR = 2.65, (1.02-6.70), P = .045), and higher bodyweight (OR = 1.02, (1.01-1.04) kg, P = .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (OR = 0.96, (0.94-0.99) year, P = .0070). Baseline IGF-1 and growth hormone concentration at diagnosis were associated with absolute IGF-1 reduction (β = 0.90, standard error (SE) = 0.02, P ≤ .0001 and β  = 0.002, SE = 0.001, P = .014, respectively).

Conclusion: Baseline IGF-1 concentration was the best predictor of biochemical response to fg-SRL, followed by bodyweight, while younger patients were more likely to achieve nonresponse.
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http://dx.doi.org/10.1210/clinem/dgaa387DOI Listing
September 2020

Parasellar Meningiomas.

Neuroendocrinology 2020 3;110(9-10):780-796. Epub 2020 Jun 3.

Department of Neurosurgery, University Hospital of Erlangen, Erlangen, Germany.

Parasellar spaces remain particularly singular, comprising the most important neurovascular structures such as the internal carotid artery and optic, oculomotor, and trigeminal nerves. Meningiomas are one of the most frequent tumors arising from parasellar spaces. In this location, meningiomas remain mostly benign tumors with WHO grade I and a meningothelial subtype. Progestin intake should be investigated and leads mostly to conservative strategies. In the case of benign nonsymptomatic tumors, observation should be proposed. Tumor growth will lead to the proposition of surgery or radiosurgery. In the case of an uncertain diagnosis and an aggressive pattern, a precise diagnosis is required. For cavernous sinus and Meckel's cave lesions, complete removal is rarely considered, leading to the proposition of an endoscopic endonasal or transcranial biopsy. Optic nerve decompression could also be proposed via these approaches. A case-by-case discussion about the best approach is recommended. A transcranial approach remains necessary for tumor removal in most cases. Vascular injury could lead to severe complications. Cerebrospinal fluid leakage, meningitis, venous sacrifice, visual impairment, and cranial nerve palsies are more frequent complications. Pituitary dysfunctions are rare in preoperative assessment and in postoperative follow-up but should be assessed in the case of meningiomas located close to the pituitary axis. Long-term follow-up is required given the frequent incomplete tumor removal and the risk of delayed recurrence. Radiosurgery is relevant for small and well-limited meningiomas or intra-cavernous sinus postoperative residue, whereas radiation therapy and proton beam therapy are indicated for large, extended, nonoperable meningiomas. The place of the peptide receptor radionuclide therapyneeds to be defined. Targeted therapy should be considered in rare, recurrent, and aggressive parasellar meningiomas.
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http://dx.doi.org/10.1159/000509090DOI Listing
July 2021

Correction to: MEN2-related pheochromocytoma: current state of knowledge, specific characteristics in MEN2B, and perspectives.

Endocrine 2020 Sep;69(3):695

Department of Endocrinology, Aix-Marseille University, INSERM U1251, Endo-ERN Reference Center for Rare Genetic Tumor Syndromes, Assistance Publique-Hopitaux de Marseille, Marseille, France.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1007/s12020-020-02365-7DOI Listing
September 2020
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