Pituitary surgery outcome in patients 75 years and older: a retrospective study.

BACKGROUND: As the population ages, the number of elderly patients with an indication for pituitary surgery is rising. Information on the outcome of patients aged over 75 is limited. This study reports a large series assessing the feasibility of surgical resection in this specific age range, focusing on surgical complications and postoperative results. METHODS: A retrospective cohort study of patients with pituitary adenomas and Rathke's cleft cysts was conducted. All patients were aged 75 years or over and treated by a single expert neurosurgical team. A control population included 2379 younger adult patients operated by the same surgeons during the same period. RESULTS: Between 2008 and 2022, 155 patients underwent surgery. Indication was based on vision impairment in most patients (79%). Median follow-up was 13 months (range: 3-96). The first surgery was performed with an endoscopic transsellar approach, an extended endonasal transtuberculum approach and a microscopic transcranial approach in 96%, 3%, and 1% of patients, respectively. Single surgery was sufficient to obtain volume control in 97% of patients. From Kaplan-Meier estimates, 2-year and 5-year disease control with a single surgery were 97.3% and 86.2%, respectively. Resection higher than 80% was achieved in 77% of patients. No vision worsening occurred. In acromegaly and Cushing's disease, endocrine remission was obtained in 90% of non-invasive adenomas. Surgical complications were noted in 5% of patients, with 30-day mortality, hematoma, cerebrospinal fluid leak, meningitis, and epistaxis occurring in 0.6%, 0.6%, 1.9%, 0.6%, and 1.3% respectively. New endocrine anterior deficits occurred in only 5%, while no persistent diabetes insipidus was noted. Compared with younger patients, the complication rate was not statistically different. CONCLUSIONS: Surgery beyond the age of 75, mainly relying on an endoscopic endonasal transsellar approach, is effective and safe, provided that patients are managed in tertiary centers.

CARMN-NOTCH2 fusion transcript drives high NOTCH2 expression in glomus tumors of the upper digestive tract.

Glomus tumors (GTs) are perivascular tumors mostly occurring in the distal extremities. Rare cases arise in the digestive tract and may be misdiagnosed with neuroendocrine or gastrointestinal stromal tumors. We aimed to specify the features of GT of the upper digestive tract. Clinical, histological, phenotypic, and molecular features of 16 digestive GTs were analyzed, of whom two underwent whole exome and RNA sequencing to search for gene alterations. RNA-sequencing disclosed a t(1:5)(p13;q32) translocation, which resulted in the fusion of CARMN and NOTCH2 in two GTs. The fusion gene encoded a protein sequence corresponding to the NOTCH2 intracellular domain that functions as transcription factor. These finding was supported by high expression of genes targeted by NOTCH. The CARMN-NOTCH2 translocation was detected in 14 out of 16 (88%) GTs of the upper digestive tract; but in only in two out of six cutaneous GTs (33%). Most digestive GT arose from the stomach (n = 13), and the others from duodenal (2) or oesophagous (1). Nuclear expression of NOTCH2 was detected in the 14 cases containing the fusion transcripts. The CARMN-NOTCH2 fusion transcript may contribute to activation of the NOTCH2 pathway in GT and drive tumor development. The high frequency of this translocation in GT of the upper digestive track suggest that detection of nuclear NOTCH2 expression may be useful diagnostic biomarker of these tumors.

Structural analysis of the impact of a novel androgen receptor gene mutation in two adult patients with mild androgen insensitivity syndrome.

Androgen receptor gene (AR) mutations are responsible for androgen insensitivity syndrome (AIS) presenting with a clinical phenotype that ranges from gynaecomastia and/ or infertility in mild AIS (MAIS) to complete testicular feminisation in complete AIS. We report a novel AR gene mutation in two unrelated adult patients with MAIS and we studied its functional impact using 3D modelling. Patient 1, referred for infertility, presented with gynaecomastia, mild hypospadias and bilateral testicular hypotrophy contrasting with high testosterone levels, an elevated FSH, an elevated androgen sensitivity index (ASI) and oligoasthenoteratospermia. In vitro fertilisation and intracytoplasmic sperm injection resulted in a successful twin pregnancy. Patient 2 referred for a decrease in athletic performance had surgically treated gynaecomastia, oligoasthenospermia, high testosterone levels and an elevated ASI. Despite his impaired spermogram, he fathered two children without assisted reproductive technology. AR gene sequencing in the two patients revealed a common novel missense mutation, Ala699Thr, in exon 4 within the ligand-binding domain. 3D modelling studies showed that this mutation may impact dimer stability upon ligand binding or may affect allosteric changes upon dimerisation. This study illustrates the value of structural analysis for the functional study of mutations and expands the database of AR gene mutations.

Foetal exposure to mitotane/Op'DDD: Post-natal study of four children.

OBJECTIVE: Mitotane/Op'DDD is used in the treatment of adrenocortical carcinoma and for other causes of hypercortisolism. Mitotane inhibits cortisol secretion and displays adrenolytic and antitumor actions. This compound is a metabolite of the pesticide and endocrine disruptor DDT (dichlorodiphenyltrichloroethane) and is classified among teratogenic compounds worldwide. However, little is known about its effects on human development. DESIGN: The outcome of four children exposed to mitotane during their intrauterine life was examined. PATIENTS: Patients having conceived while taking mitotane, or with detectable mitotane plasma levels, were retrospectively recruited via the French COMETE and FIRENDO networks. MEASUREMENTS: Mitotane in maternal plasma, adrenocortical hormones in children. RESULTS: Three women treated with mitotane gave birth to four children. During early pregnancy, all patients had detectable mitotane plasma levels (0.9, 2.4 and 6.7 mg/L, respectively). During pregnancy, no foetal malformations were detected. The four exposed newborns presented at birth with apparently normal adrenal function and genitalia. One twin female had a low birthweight. Evaluation at birth and after 3 months, 2 years and 7 years of follow-up showed no significant neurological abnormality. Evaluation of adrenocortical functions showed no cortisol deficiency. CONCLUSIONS: Unexpectedly, exposure of these four children to mitotane during foetal life seemed to have no clear teratogenic effect. However, considering the sub-therapeutic mitotane concentrations used here, the small number of cases, and because long-term follow-up is unknown, we strongly advise not to take mitotane during pregnancy and still recommend avoiding pregnancy, at least as long as mitotane plasma levels remain detectable.

Silent, but not unseen: multimicrocystic aspect on T2-weighted MRI in silent corticotroph adenomas.

OBJECTIVE: Silent corticotroph adenomas (SCAs) present as nonfunctional pituitary tumours in routine pre-operative evaluation. The objective of this study was to evaluate the diagnostic accuracy of MRI T2-weighted sequences for detecting the corticotroph subtype pre-operatively. DESIGN: The pre-operative T2-weighted MRI sequences were retrospectively evaluated in patients with SCA and two control groups: clinically manifest corticotroph macroadenomas (CSMs) and nonfunctional gonadotroph macroadenomas (NFGMs). All were selected from a registry of 1096 patients in whom transsphenoidal surgery was performed in the same tertiary reference centre. T2-weighted MRI sequences were independently classified by one senior endocrinologist and one senior radiologist who were blinded to the clinical and histological features. PATIENTS: Seventeen patients with SCA, 14 with CSM and 60 with NFGM were included in this study. MEASUREMENTS: Pituitary MRI with T2-weighted sequences. Two aspects were retained: multiple microcysts (MMs) and the absence of microcysts. Hormonal data included plasma prolactin, IGF-1, testosterone or oestradiol, LH, FT4, TSH, morning plasma cortisol and an ACTH-stimulation test, when available. RESULTS: Multiple microcysts were present in 76% (13/17) of SCAs, 21% (3/14) of CSMs and 5% (3/60) of NFGMs. The presence of MMs in clinically nonfunctioning macroadenomas had a sensitivity of 76% and a specificity of 95% for predicting SCA. CONCLUSION: The presence of MMs in T2-weighted MRI is a good diagnostic tool to suggest the corticotroph subtype in an apparently nonfunctional pituitary tumour.

Gonadotropic status in adult women with pituitary stalk interruption syndrome.

OBJECTIVE: Pituitary stalk interruption syndrome (PSIS) is a rare cause of congenital hypopituitarism. Limited data exist on the gonadotropic status and fertility of adult women with PSIS. Our study aims to describe pubertal development and the evolution of gonadotropic function and fertility in adult women with PSIS. DESIGN: A retrospective multicentric French study. METHODS: We described gonadotropic function in 56 adult women with PSIS from puberty onward. We compared live birth rates per woman with PSIS with age-matched controls from the large French epidemiological cohort (CONSTANCES). Additionally, we assessed height, body mass index (BMI), blood pressure, other metabolic parameters, and socioeconomic status. RESULTS AND CONCLUSIONS: Among 56 women with PSIS, 36 did not experience spontaneous puberty. Of these, 13 underwent ovarian stimulation, resulting in 7 women having a total of 11 children. In the subgroup with spontaneous puberty (n = 20), 4 had a total of 8 pregnancies, while 6 developed secondary gonadotropic deficiency. Women with PSIS had fewer children than controls (0.33 vs 0.63, P = .04). Median height was also lower (160.5 vs 165.0 cm, P < .0001). Although mean blood pressure was lower in women with PSIS compared with controls (111.3/65.9 ± 11.2/8.1 vs 118.7/72.1 ± 10.1/7.7 mmHg, P < .001), there were no significant differences in other metabolic parameters, notably BMI and lipid profile. Employment/academic status was not different in the 2 groups, but fewer women with PSIS were in relationships (42% vs 57.6% in controls, P = .02). The fertility prognosis in patients with PSIS needs optimization. Patients should be informed about the likelihood of declining gonadotropic function over time.

Prognostic Impact of Hypothalamic Perforation in Adult Patients With Craniopharyngioma: A Cohort Study.

CONTEXT: Outcome of craniopharyngioma is related to its locoregional extension, which impacts resectability and the risk of surgical complications. To maximize resection and minimize complications, optic tract localization, temporal lobe extension, and hypothalamic involvement are essential factors for surgical management. OBJECTIVE: To assess the outcome of craniopharyngiomas depending on their relation to the hypothalamus location. METHODS: We conducted a retrospective analysis of 79 patients with a craniopharyngioma who underwent surgery from 2007 to 2022. Craniopharyngiomas were classified in 3 groups, depending on the type of hypothalamus involvement assessed by preoperative magnetic resonance imaging: infra-hypothalamic (type A, n = 33); perforating the hypothalamus (type B, n = 40); and supra-hypothalamic (type C, n = 6). Surgical strategy was guided by the type of hypothalamic involvement, favoring endonasal approaches for type A and type B, and transcranial approaches for type C. RESULTS: Long-term disease control was achieved in 33/33 (100%), 37/40 (92%), and 5/6 (83%) patients in type A, B, and C, respectively. In type B, vision was improved in 32/36 (89%) patients, while hypothalamic function was improved, stable, or worsened in 6/40 (15%), 32/40 (80%), and 2/40 (5%) patients, respectively. Papillary craniopharyngiomas were found in 5/33 (15%), 9/40 (22%), and 3/6 (50%) patients in types A, B, and C, respectively. In 4 patients, BRAF/MEK inhibitors were used, with significant tumor shrinkage in all cases. CONCLUSION: Craniopharyngiomas located below the hypothalamus or perforating it can be safely treated by transsphenoidal surgery. For supra-hypothalamic craniopharyngiomas, postoperative results are less favorable, and documenting a BRAF mutation may improve outcome, if targeted therapy was efficient enough to replace surgical debulking.

Nutritional Status of Vegetarian Patients Before and After Bariatric Surgery: a Monocentric Retrospective Observational Case-Control Study.

The obesity pandemic is associated with an increasing number of bariatric surgeries which allow improvement in obesity-related comorbidities and life expectancy but potentially induce nutritional deficiencies. Vegetarianism becomes more and more popular and exposes as well to vitamin and micronutrient deficiencies. Only one study has explored the impact of vegetarianism on the preoperative nutritional status of eligible patients for bariatric surgery, but none in postoperative care. MATERIALS AND METHODS: We conducted a retrospective case-control study in our cohort of bariatric patients, matching 5 omnivores for each vegetarian. We compared their biological profile regarding vitamin and micronutrient blood levels before and 3, 6, 12, and 30 months after surgery. RESULTS: We included 7 vegetarians including 4 lacto-ovo-vegetarians (57%), 2 lacto-vegetarians (29%), and one lacto-ovo-pesco-vegetarian (14%). Three years after surgery with equivalent daily standard vitamin supplementation, the two groups showed a similar biological profile including blood levels of ferritin (p = 0.6), vitamin B1 (p = 0.1), and B12 (p = 0.7), while the total median weight loss at 3 years was comparable (39.1% [27.0-46.6] in vegetarians vs 35.7% [10.5-46.5] in omnivores, p = 0.8). We observed no significant difference between vegetarians and omnivores before surgery regarding comorbidities and nutritional status. CONCLUSION: It seems that, after bariatric surgery, vegetarian patients taking a standard vitamin supplementation do not show an increased risk of nutritional deficiencies compared to omnivores. However, a larger study with a longer follow-up is needed to confirm these data, including an evaluation of different types of vegetarianism such as veganism.

Estrogen and Progesterone Therapy and Meningiomas.

Meningiomas are common intracranial tumors with a female predominance. Their etiology is still poorly documented. The role of sexual hormones has long been evoked, and data have been conflicting across studies. However, a dose-dependent relationship between the incidence and growth of meningiomas and hormonal treatment with the progestin cyproterone acetate (CPA) has recently been established. CPA-associated meningiomas seem to be mainly located in the anterior and middle skull base, are more likely to be multiple, may harbor P1K3CA mutations in up to one-third of cases, and are more common with a longer duration of treatment. A similar but lower risk of meningiomas has been recently reported with the use of chlormadinone acetate and nomegestrol acetate as progestin treatments. Concerning hormonal replacement therapy (HRT) in menopausal patients, evidence from epidemiological studies seem to favor an increased risk of meningiomas in treated patients although a recent study failed to show an increased growth of meningiomas in HRT treated vs nontreated patients. Until larger studies are available, it seems wise to recommend avoiding HRT in patients with meningiomas. Evidence from published data does not seem to support an increased risk of meningiomas with oral contraceptive oral contraceptive (OR) use. Data are too scarce to conclude on fertility treatments. Based on studies demonstrating the expression of hormonal receptors in meningiomas, therapies targeting these receptors have been tried but have failed to show an overall favorable clinical outcome in meningioma treatment.

Outcome of giant pituitary tumors requiring surgery.

Objective: The management of giant pituitary tumors is complex, with few publications and recommendations. Consequently, patient's care mainly relies on clinical experience. We report here a first large series of patients with giant pituitary tumors managed by a multidisciplinary expert team, focusing on treatments and outcome. Methods: A retrospective cohort study was conducted. Giant pituitary tumors were defined by a main diameter > 40mm. Macroprolactinomas sensitive to dopamine agonists were excluded. All patients were operated by a single neurosurgical team. After surgery, multimodal management was proposed, including hormone replacement, radiotherapy and anti-tumor medical therapies. Outcome was modeled using Kaplan-Meyer representation. A logistic regression model was built to identify the risk factors associated with surgical complications. Results: 63 consecutive patients presented a giant adenoma, most often with visual defects. Patients were operated once, twice or three times in 59%, 40% and 1% of cases respectively, mainly through endoscopic endonasal approach. Giant adenomas included gonadotroph, corticotroph, somatotroph, lactotroph and mixed GH-PRL subtypes in 67%, 14%, 11%, 6% and 2% of patients respectively. Vision improved in 89% of patients with prior visual defects. Severe surgical complications occurred in 11% of patients, mainly for tumors > 50 mm requiring microscopic transcranial approach. Additional radiotherapy was needed for 29% of patients, 3 to 56 months after first surgery. For 6% of patients, Temozolomide treatment was required, 19 to 66 months after first surgery. Conclusions: Giant pituitary tumors require multimodal management, with a central role of surgery. Most often, tumor control can be achieved by expert multidisciplinary teams.

Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients.

Objective: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a heterogeneous disease characterized by adrenal macronodules and variable levels of cortisol excess, with not clearly established clinical diagnostic criteria. It can be caused by ARMC5 germline pathogenic variants. In this study, we aimed to identify predictive criteria for ARMC5 variants. Methods: We included 352 consecutive index patients from 12 European centers, sequenced for germline ARMC5 alteration. Clinical, biological and imaging data were collected retrospectively. Results: 52 patients (14.8%) carried ARMC5 germline pathogenic variants and showed a more distinct phenotype than non-mutated patients for cortisol excess (24-h urinary free cortisol 2.32 vs 1.11-fold ULN, respectively, P < 0.001) and adrenal morphology (maximal adrenal diameter 104 vs 83 mm, respectively, P < 0.001) and were more often surgically or medically treated (67.9 vs 36.8%, respectively, P < 0.001). ARMC5-mutated patients showed a constant, bilateral adrenal involvement and at least a possible autonomous cortisol secretion (defined by a plasma cortisol after 1 mg dexamethasone suppression above 50 nmol/L), while these criteria were not systematic in WT patients (78.3%). The association of these two criteria holds a 100% sensitivity and a 100% negative predictive value for ARMC5 pathogenic variant. Conclusion: We report the largest series of index patients investigated for ARMC5 and confirm that ARMC5 pathogenic variants are associated with a more severe phenotype in most cases. To minimize negative ARMC5 screening, genotyping should be limited to clear bilateral adrenal involvement and autonomous cortisol secretion, with an optimum sensitivity for routine clinical practice. These findings will also help to better define PBMAH diagnostic criteria.

Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine.

BACKGROUND: Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yielding infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology. METHODS: 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. FINDINGS: A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromosomal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link. INTERPRETATION: We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogenesis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility. FUNDING: Université Paris Saclay, Agence Nationale de Biomédecine.

Complications Requiring Intensive Nutritional Care After Bariatric Surgery Result in More Long-Term Weight Loss but Has No Impact on Nutritional Deficiencies and Depression-Anxiety Scores.

PURPOSE: Bariatric surgery is associated with significant weight loss and improvement in comorbid conditions but in rare cases can expose to complications requiring intensive nutritional care (INC). INC in this context is poorly described and no data are available concerning long-term impact. MATERIALS AND METHODS: We retrospectively reviewed charts of bariatric patients who were hospitalized in our institution between 2013 and 2018. We identified patients with a postoperative complication requiring INC and we described their nutritional management (INC group). These patients were compared with controls matched to age, gender, preoperative BMI, and type of surgery selected from our database (control group). The primary endpoint was the percentage of total weight loss (%TWL) at 2.5 years. Secondary endpoints were improvement of co-morbidities, vitamin deficiencies, and depression/anxiety scores. RESULTS: The INC group consisted of 18 patients among which 77.8% had sleeve gastrectomy (SG). Half of these patients underwent revisional surgery. The most common complication was fistula formation (66.7%). Patients in the INC group, compared to the control group, showed a significantly higher %TWL at 2.5 years (33.6% vs 26.1%, P = 0.03). There was no significant difference in either reduction of preoperative comorbidities or depression/anxiety scores between the two groups. The number of patients with more than three nutritional deficiencies was similar in both groups. Thiamine deficiency was only observed in the INC group. CONCLUSION: Complications requiring INC after bariatric surgery occur mainly after revisional surgery and may increase long-term %TWL but have no impact on nutritional deficiencies or symptoms of anxiety/depression.

Pituitary surgery as alternative to dopamine agonists treatment for microprolactinomas: a cohort study.

OBJECTIVE: Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment. DESIGN: Follow-up of a cohort of consecutive patients treated by surgery. METHODS: Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients presented with a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan-Meier representation. A cox regression model was used to predict remission. RESULTS: Median follow-up was 18.2 months (range: 2.8-155). In this cohort, 14/114 (12%) patients were not cured by surgery, including ten early surgical failures and four late relapses occurring 37.4 months (33-41.8) after surgery. From Kaplan-Meier estimates, 1-year and 5-year disease free survival was 90.9% (95% CI: 85.6-96.4%) and 81% (95% CI: 71.2-92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P < 0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty. CONCLUSIONS: In well-selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.

Diabetes Increases Severe COVID-19 Outcomes Primarily in Younger Adults.

CONTEXT: Diabetes is reported as a risk factor for severe coronavirus disease 2019 (COVID-19), but whether this risk is similar in all categories of age remains unclear. OBJECTIVE: To investigate the risk of severe COVID-19 outcomes in hospitalized patients with and without diabetes according to age categories. DESIGN SETTING AND PARTICIPANTS: We conducted a retrospective observational cohort study of 6314 consecutive patients hospitalized for COVID-19 between February and 30 June 2020 in the Paris metropolitan area, France; follow-up was recorded until 30 September 2020. MAIN OUTCOME MEASURE(S): The main outcome was a composite outcome of mortality and orotracheal intubation in subjects with diabetes compared with subjects without diabetes, after adjustment for confounding variables and according to age categories. RESULTS: Diabetes was recorded in 39% of subjects. Main outcome was higher in patients with diabetes, independently of confounding variables (hazard ratio [HR] 1.13 [1.03-1.24]) and increased with age in individuals without diabetes, from 23% for those <50 to 35% for those >80 years but reached a plateau after 70 years in those with diabetes. In direct comparison between patients with and without diabetes, diabetes-associated risk was inversely proportional to age, highest in <50 years and similar after 70 years. Similarly, mortality was higher in patients with diabetes (26%) than in those without diabetes (22%, P < 0.001), but adjusted HR for diabetes was significant only in patients younger than age 50 years (HR 1.81 [1.14-2.87]). CONCLUSIONS: Diabetes should be considered as an independent risk factor for the severity of COVID-19 in young adults more so than in older adults, especially for individuals younger than 70 years.

Adrenal ganglioneuromas: a retrospective multicentric study of 104 cases from the COMETE network.

OBJECTIVE: Adrenal ganglioneuromas are rare, differentiated, neuroblastic tumors that originate from the peripheral sympathetic nervous system. Because of their rarity, information is limited, derived from small cases series. Our objective was to characterize this tumor and provide help for its management. METHODS: A retrospective multicenter analysis of adrenal ganglioneuromas from 20 French centers belonging to the COMETE network and one Belgian center. RESULTS: Among the 104 cases identified, 59.6% were women (n = 62/104), median age at diagnosis was 29 years, with 24 pediatric cases. 60.6% (n = 63/104) were incidentalomas. Ganglioneuromas were non-secreting tumors in 90.8% of cases (n = 89/98), whereas the preoperative hormonal evaluation was indeterminate for 9.2% of patients (n = 9/98). CT imaging, performed on 96 patients, revealed large tumors (median diameter of 50 mm) with a non-contrast density > 10 Hounsfield units in 98.1% (n = 52/53) and calcifications in 64.6% of cases (n = 31/48). Increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 26.7% (n = 8/30) and 42.2% (n = 19/45) of the tumors, respectively. All 104 patients underwent surgery. No recurrence was observed among the 42 patients who had an imaging follow-up (mean 29.6 months, median 18 months (4-156)). CONCLUSION: Adrenal ganglioneuromas are large tumors, mostly nonfunctioning, without benign imaging features. Although the duration of follow-up was limited in our series, no recurrence was identified. A review of the literature confirms the absence of postoperative recurrence. Based on all available data, in the absence of special circumstances (genetic form, uncertain histological diagnosis), long-term follow-up is not necessary after complete surgery for patients with an adrenal ganglioneuroma.

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

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.

Recurrence-Free Survival Analysis in Locally Advanced Pheochromocytoma: First Appraisal.

CONTEXT: The behavior of locally advanced pheochromocytoma (LAP) remains unknown. OBJECTIVE: We characterized the population with LAP and recurrence-free survival (RFS). METHODS: This retrospective multicentric study was run within the ENDOCAN-COMETE network and French Group of Endocrine Tumors (GTE) from 2003 to 2018, including patients from 11 French referral centers with LAP as defined by capsular invasion, vascular invasion, adipose tissue invasion, and/or positive locoregional lymph nodes at diagnosis without evidence of distant metastasis. The main outcome measure was recurrence, defined as tumor reappearance, including local site and/or distant metastasis. The primary endpoint was RFS analysis; secondary endpoints were characterization, overall survival (OS), and prognostic factors of recurrence. RESULTS: Among 950 patients, 90 (9%) exhibited LAP criteria and 55 met inclusion criteria (median age, 53 years; 61% males; 14% with germline mutation; 84% with catecholamine excess). LAP was defined by 31 (56%) capsular invasions, 27 (49%) fat invasions, 6 (11%) positive lymph nodes, and 22 (40%) vascular invasions. After median follow-up of 54 months (range, 6-180), 12 patients (22%) had recurrences and 3 (5%) died of metastatic disease. Median RFS was 115 months (range, 6-168). Recurrences were local in 2 patients, distant in 2, and both local and distant in 8 patients. Median OS of patients was not reached. Size above 6.5 cm (P = 0.019) and Ki-67 > 2% (P = 0.028) were identified as independent significant prognostic factors in multivariate analysis. CONCLUSION: LAP represents 9% of pheochromocytoma's population and has a metastatic behavior. This study paves the way for future pathological TNM classification.

Coexistence of Autoimmune Hyper- and Hypothyroidism in a Kindred with Reduced Sensitivity to Thyroid Hormone.

INTRODUCTION: Resistance to thyroid hormone beta (RTHß) is a rare disease with an autosomal dominant transmission. Diagnosis may be challenging especially in patients with hyper- or hypothyroidism. CASE PRESENTATION: A 31-year-old male patient with suppressed thyroid-stimulating hormone (TSH), elevated free thyroxine and free triiodothyronine, along with high thyroid receptor antibodies was diagnosed with Graves' disease. Benzylthiouracil was started. One month later, reduced sensitivity to thyroid hormones was suspected because of persistently high thyroid hormone levels contrasting with high TSH level. Molecular analysis highlighted a 10c.1357C>T p.P453S mutation in the thyroid hormone receptor beta gene (THRB). RTHß was diagnosed. Several relatives also had RTHß (the mother, the young son, and 2 out of 3 siblings). Autoimmune hypothyroidism was present in the mother, whereas 2 out of 3 siblings had asymptomatic autoimmunity. DISCUSSION/CONCLUSION: Both Graves' disease and autoimmune hypothyroidism were described in patients with RTHß. We show here for the first time that autoimmune hypo- and hyperthyroidism may coexist in kindred with RTHß. Seven previously published cases of Graves' disease and RTHß were retrieved and analyzed. Treatments and thyroid hormone level targets are discussed as well as the possible link between RTHß and autoimmune thyroid diseases.

Laparoscopic Revision of Bariatric Surgeries in Two Patients with Severe Resistant Hypocalcemia After Endocrine Cervical Surgery.

Severe hypocalcemia complicating cervical endocrine surgery in patients with gastric bypass can constitute a major concern. When usual therapies fail to maintain calcemia within the normal range without secondary adverse events, reversal of the bariatric surgery should be considered. We herein report the outcomes of laparoscopic revision of bariatric surgeries in two patients suffering from severe resistant hypocalcemia following cervical surgery, requiring in one case recombinant PTH administration and, in the other, daily intravenous calcium injections. The Roux-en-Y gastric bypass was switched to sleeve gastrectomy in the first patient, and in the second patient, the biliopancreatic diversion with duodenal switch was revised, to restore the upper and distal parts of the alimentary tract. Rapid improvement of hypocalcemia was observed in both cases.