Can postoperative calcemia kinetics predict the risk of hypocalcemia for the management of parathyroid adenoma in ambulatory surgery?

INTRODUCTION: The goal of this study was to analyse the kinetics of corrected calcemia levels (Cac) after parathyroid excision and to determine the percentage of variation (ΔCa) in the initial hours after surgery, in order to entertain an early discharge. POPULATION AND METHODS: Were included in this study, patients undergoing operation for parathyroid adenoma responsible for primary hyperparathyroidism (PHP). The Cac was measure preoperatively and four hours after surgery, and then every day until patient discharge. Group A included patients for whom the Cac was inferior to 2.2mmol/L at least once postoperatively while group B included patients for whom the Cac was always equal or superior to 2.2mmol/L. The ΔCa represented the percentage of the fall in postoperative Cac with respect to preoperative Cac. RESULTS: Between 2010 and 2017, 156 patients fulfilled the inclusion criteria (women 80.8%, [sex ratio 1:4], median age 64 years old). Preoperative Cac was statistically significantly lower in group A compared to group B (2.67 vs. 2.82mmol/L; P<0.0001). In total, 9.6% of patients had calcium supplementation for hypocalcemia, symptomatic or not. Postoperative Cac reached its nadir value on postoperative day 2. At four hours postoperative, the risk of postoperative calcelmia falling below 2.2mmol/L appeared when the ΔCa was superior to 6% with a sensitivity of 92.9% and a negative predictive value of 97.4%. CONCLUSION: After excision of a parathyroid adenoma for PHP, the Cac falls rapidly and reaches its nadir value on day 2. If the fall in calcemia is less than 6% four hours after surgery (vs. preoperative level), early discharge within the framework of ambulatory surgery is possible.

TRα Mutations in Human.

Resistance to thyroid hormone alpha is an emerging syndrome, with up to now a limited number of published cases. Some features are common to most of the patients, but there is still some work to provide a comprehensive description of the full spectrum of the syndrome. A survey of the strategy to screen for and characterize the mutations in TR α gene is given.

Lesson to be remembered from a skull base tumor.

The natural history of giant prolactinomas is not known. While it is commonly accepted that the enlargement of microadenoma is rare and more limited than macroadenoma, it is so far uncommon that macroadenoma progress to giant adenoma. Thus, spontaneous enlargement of adenomas is poorly documented. We report the unusual history of undiagnosed microprolactinoma, revealed 12years later at the stage of a giant adenoma presenting as a skull base tumor. This unique observation provides information on the natural history of giant adenomas and arguments for particular attention to microadenomas with signs of invasion. Moreover, this clinical case highlights the need for a prolactin dosage for all midline skull base tumors.

Employment and professional outcomes in 803 patients undergoing bariatric surgery in a French reference center for obesity.

BACKGROUND: Very few studies have been performed on small populations about the links between employment and bariatric surgery. OBJECTIVE: To determine if rates of employment are increased among patients who have undergone bariatric surgery, to assess their post-operative health consequences (post-prandial weakness, diarrhea), and patients' ability to maintain post-operative advice (ie, 30 minutes of daily physical activity, 6 small meals daily) compared to non-employed post-surgical patients. METHODS: This cross-sectional study was performed in the Regional Reference Centre for Obesity, which is a partnership between the University Hospital and a clinic in Angers, France during 2012 using a self-administrated questionnaire completed by patients hospitalized for post-operative follow-ups after bariatric surgery. Issues investigated were their professional situation before and after the surgery, compliancy to post-operative advice, and any postoperative side effects. RESULTS: Employment rates were 64.4% before and 64.7% after the surgery (p=0.94). Of these, 30.6% maintained 30 minutes of daily physical activity vs. 41.0% of non-workers (p=0.02). 50.5% of employed patients and 57.3% of non-workers maintained 6 small meals a day after surgery (p=0.09). 8% of working patients reported post-prandial weaknesses and 8% reported diarrhea that caused problems at work. CONCLUSION: Employment rate remained stable after surgery. Having a job seemed to be an obstacle to managing 30 minutes of daily exercise, especially among women, but not maintaining 6 small meals a day. Therefore, working environment needs to be assessed to improve job quality and retention for patients who have undergone bariatric surgery.

Thyroidectomy in patients with a high BMI: a safe surgery?

OBJECTIVE: To study and compare the specific postoperative complications of thyroidectomy in a population with a BMI ≥25 with a population having a BMI below 25. DESIGN: A prospective study was carried out from September 2010 to January 2013. METHODS: Postoperative calcemia, laryngeal mobility, bleeding or infectious complications, postoperative hospital stay, and operation time were studied and compared statistically by a χ(2)-test or Student's t-test. RESULTS: A total of 240 patients underwent total thyroidectomy and 126 underwent a partial thyroidectomy. Of them, 168 patients had a BMI below 25 and 198 patients had a BMI ≥25. There was no statistically significant difference in the occurrence of early or permanent hypoparathyroidism, recurrent laryngeal nerve palsy, bleeding complications, or postoperative duration of hospital stay. There was, however, a significant operative time in patients with a BMI ≥25. CONCLUSION: Despite the longer operative time, thyroidectomy (total or partial) can be performed safely in patients with a BMI ≥25.

Pheochromocytoma revealed by acute heart failure. When should we operate? Presented at the ESES Congress, Gothenburg May 25-26, 2012.

PURPOSE: The aim of this study was to assess the safety and efficacy of adrenalectomy on patients with pheochromocytoma diagnosed at the time of an acute heart failure (AHF). METHODS: We reported cases of patients who presented an AHF secondary to a pheochromocytoma during a period of 10 years. The diagnosis of AHF was defined by a left ventricular ejection fraction of less than 30 % or the use of circulatory assistance. They had adrenalectomy as emergency surgery or later. Morbidity and mortality of surgery were studied. RESULTS: Thirteen patients required an adrenalectomy for AHF secondary to pheochromocytoma. Four patients (31 %) had an adrenalectomy in emergency. Nine patients (69 %) had a delayed surgery with a median delay of 25 days (7-180). Eight patients had circulatory assistance (61 %). Five of them had a circulatory assistance and a delayed surgery (38 %), two of them had a circulatory assistance followed by emergency surgery (at 1.5 and 3 days) and one had emergency surgery immediately followed by circulatory assistance. Emergency surgery was performed by laparotomy in all cases and delayed surgery by laparoscopy for seven patients (54 %). Perioperative complications consisted in: one circulatory arrest, two bleedings requiring transfusion, one intestinal ischaemia, one haemoperitoneum with re-operation (day 8). One patient died on day 5. Post-operative course of patients with delayed surgery was uneventful. CONCLUSIONS: AHF revealing a pheochromocytoma is a rare and serious event. Patients with emergency surgery have more complications than those with delayed surgery.

Evolution of class A G-protein-coupled receptors: implications for molecular modeling.

Class A or rhodopsin-like G-protein-coupled receptors (GPCRs) constitute the largest transmembrane receptor family of the human genome. Because of their biological and pharmaceutical importance, the evolutionary history of these receptors has been widely studied. Most studies agree on the classification of the 700 members of this family into a dozen of sub-families. However, the relationship between these sub-families remains controversial and the molecular processes that drove the evolution and diversification of such a large family have still to be determined. We review here the evolutionary analyses carried out on class A GPCRs either by phylogenetic methods or by multidimensional scaling (MDS). We detail the key molecular events driving the evolution of this receptor family. We analyze these events in view of the recently resolved crystal structures of GPCRs and we discuss the usefulness of evolutionary information to help molecular modeling.

Prognostic factors of disease-free survival after thyroidectomy in 170 young patients with a RET germline mutation: a multicenter study of the Groupe Francais d'Etude des Tumeurs Endocrines.

BACKGROUND: In hereditary medullary thyroid carcinoma (HMTC), prophylactic surgery is the only curative option, which should be properly defined both in time and extent. OBJECTIVES: To identify and characterize prognostic factors associated with disease-free survival (DFS) in children from HMTC families. DESIGN: We conducted a retrospective analysis of a multi-center cohort of 170 patients below age 21 at surgery. Demographic, clinical, genetic, biological data [basal and pentagastrine-stimulated calcitonin (CT and CT/Pg, respectively)], and tumor node metastasis (TNM) status were collected. DFS was assessed based on basal CT levels. Kaplan-Meier curves, Cox regression, and logistic regression models were used to determine factors associated with DFS and TNM staging. RESULTS: No patients with a preoperative basal CT <31 ng/ml had persistent or recurrent disease. Medullary thyroid carcinoma defined by a diameter ≥10 mm [hazard ratio (HR): 6.0; 95% confidence interval (95% CI): 1.8-19.8] and N1 status (HR: 20.8; 95% CI: 3.9-109.8) were independently associated with DFS. Class D genotype [odds ratio (OR): 48.5, 95% CI: 10.6-225.1], preoperative basal CT >30 ng/liter (OR: 43.4, 95% CI: 5.2-359.8), and age >10 (OR: 5.5, 95% CI: 1.4-21.8) were associated with medullary thyroid carcinoma ≥10 mm. No patient with a preoperative basal CT <31 ng/ml had a N1 status. Class D genotype (OR: 48.6, 95% CI: 8.6-274.1), and age >10 (OR: 4.6, 95% CI: 1.1-19.0) were associated with N1 status. CONCLUSION: In HMTC patients, DFS is best predicted by TNM staging and preoperative basal CT level below 30 pg/ml. Basal CT, class D genotype, and age constitute key determinants to decide preoperatively timely surgery.

Ovarian hyperstimulation syndrome (OHSS) due to mutations in the follicle-stimulating hormone receptor.

Ovarian hyperstimulation syndrome (OHSS) is usually a complication of assisted reproductive techniques, more rarely an affection complicating a spontaneous gestation. The cause of hyper responsiveness of ovaries to the gonadotropins used in the controlled stimulation is still largely unknown. In contrast, a few cases of spontaneous hyperstimulation syndrome have been elucidated by the identification of mutations of the follicle-stimulating hormone (FSH) receptor, broadening its specificity and making it hypersensitive to human chorionic gonadotropin (hCG). Surprisingly, the mutations were located in the transmembrane domain of the receptor rather than in the extracellular hormone-binding site. No such mutation has been found in iatrogenic cases. However, allelic variants of the FSH receptors have been associated with the response to FSH in stimulation procedures, as well as with the severity of OHSS when present.

Hypochloremia and hyponatremia as the initial presentation of cystic fibrosis in three adults.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Most diagnoses of CF are made during infancy or childhood, and are based on respiratory or digestive involvement. Initial extracellular dehydration leading to the diagnosis of CF is usual in infants but has only exceptionally been reported in adults. We describe three new adult cases of CF initially presenting with depletive hyponatremia and hypochloremia following exposure to heat. At first consultation, these patients had no symptoms suggestive of CF. One patient presented with a seizure induced by hyponatremia. The two other patients were siblings carrying a novel c.4434insA mutation in exon 24 of CFTR. Acute dehydration is a very rare initial manifestation of CF but may be life-threatening. The possibility of CF should not be ignored in cases of depletive hyponatremia, hypochloremia or hypokalemic metabolic alkalosis, even in otherwise healthy patients.

Molecular pathology of the FSH receptor: new insights into FSH physiology.

Manipulations of mouse genome have helped to elucidate gonadotrophin function but important differences subsist between rodent and human reproduction. Studies of patients with mutations of gonadotrophins or gonadotrophin receptors genes allow understanding their physiological effects in humans. The correlation of the clinical phenotypes of patients with in vitro studies of the mutated receptor residual function and histological and immunohistological studies of the ovarian biopsies permits to understand which stages of follicular development are under FSH control. Total FSH receptor (FSHR) inactivation causes infertility with an early block of follicular maturation remarkably associated with abundant small follicles as in prepubertal ovaries and demonstrates the absolute requirement of FSH for follicular development starting from the primary stage. Partial FSHR inactivation, characterized by normal-sized ovaries, can sustain follicular development up to the early antral stages but incremental levels of FSH stimulation seem to be required for antral follicular growth before selection. These findings contrast with the traditional view of an initial gonadotrophin-independent follicular growth prior to the preantral-early antral stages. The presence of numerous reserve follicles in the ovaries of these patients may permit a future treatment of their infertility. The study of reduced FSHbeta or FSHR activity in genetically modified male mice models and in men suggests a minor impact of the FSHR on masculine fertility. Further studies on patients with a demonstrated total FSHbeta or FSHR inactivation are required to elucidate reported differences in spermatogenesis impairment. Finally, the studies of mutations of gonadotrophins and their receptors demonstrate differences in gonadotrophin function between genetically modified rodents and humans which suggest prudence in extrapolating observations in rodents to human reproduction. Ovarian hyperstimulation syndrome (OHSS) can infrequently arise spontaneously during pregnancy, but most often it is an iatrogenic complication of ovarian stimulation treatments with ovulation drugs for in vitro fertilization. The first genetic cause of familial recurrent spontaneous OHSS was identified as a broadening specificity of the FSHR for hCG due to naturally occurring heterozygous mutations located unexpectedly in the transmembrane domain of the FSHR. Broadening specificity of a G protein-coupled receptor is extremely rare. These observations led to the identification of the etiology of this previously unexplained syndrome and permitted to conceive novel models of FSHR activation. Susceptibility to iatrogenic OHSS or its clinical severity may be associated with FSHR polymorphisms with slightly different activities in vivo as suggested by several studies. The study of larger cohorts is needed to evaluate the clinical impact of these observations in the management of patients undergoing IVF protocols.

Microarray analysis refines classification of non-medullary thyroid tumours of uncertain malignancy.

Conventional histology failed to classify part of non-medullary thyroid lesions as either benign or malignant. The group of tumours of uncertain malignancy (T-UM) concerns either atypical follicular adenomas or the recently called 'tumours of uncertain malignant potential'. To refine this classification we analysed microarray data from 93 follicular thyroid tumours: 10 T-UM, 3 follicular carcinomas, 13 papillary thyroid carcinomas and 67 follicular adenomas, compared to 73 control thyroid tissue samples. The diagnosis potential of 16 selected genes was validated by real-time quantitative RT-PCR on 6 additional T-UM. The gene expression profiles in several groups were examined with reference to the mutational status of the RET/PTC, BRAF and RAS genes. A pathological score (histological and immunohistochemical) was estimate for each of the T-UM involved in the study. The correlation between the T-UM gene profiles and the pathological score allowed a separation of the samples in two groups of benign or malignant tumours. Our analysis confirms the heterogeneity of T-UM and highlighted the molecular similarities between some cases and true carcinomas. We demonstrated the ability of few marker genes to serve as diagnosis tools and the need of a T-UM pathological scoring.

Relevance of Ki-67 and prognostic factors for recurrence/progression of gonadotropic adenomas after first surgery.

OBJECTIVE: Gonadotropin-secreting pituitary adenomas carry a high risk of local recurrence or progression (R/P) of remnant tumor after first surgery. The clinical characteristics and the long-term outcome of these silent adenomas, which show no signs of endocrine hyperfunction, differ from those of other types of pituitary adenomas. However, to date, no study has focused specifically on gonadotropic adenomas. MATERIALS AND METHODS: To identify prognostic factors of R/P of remnants, we studied the postoperative outcome of 32 gonadotropic pituitary adenomas, defined on immunohistochemical staining, according to their clinical and radiological characteristics as well as the Ki-67 labeling index (LI). RESULTS: The Ki-67 LI failed to provide independent information for the identification of patients at risk of progression of remnants or recurrence. Multivariate survival analysis (Cox regression) showed that neither invasiveness nor remnant tumors nor hyposomatotropism influenced tumor recurrence. The strongest predicting factors of R/P were the antero-posterior (AP) diameter in the sagittal plane (P = 0.014), and the age of the patient at surgery (P = 0.047), with younger patients being at greater risk. Hazard ratios were 2.11 for each 5 mm increase in AP diameter and 0.57 for every 10 years of age. CONCLUSION: The two simple clinical criteria revealed by our study, the AP diameter of the tumor and the age of the patient, should be helpful in planning clinical management and radiological monitoring after first surgery of gonadotropic adenomas, while awaiting the identification of other pathological parameters.

[Malignant nodular hidradenoma and multiple nodular hidradenomas in a hypogonadic patient]. / Hidradénome nodulaire malin et hidradénomes nodulaires multiples chez un malade hypogonadique.

BACKGROUND: We report a case of multiple benign nodular hidradenomas associated with malignant nodular hidradenoma in a hypogonadic patient. CASE-REPORT: A 49 year-old man presented 11 benign nodular hidradenomas in the pectoral region. A malignant nodular hidradenoma had recently appeared in this region some distance from the pre-existing benign modular hidradenomas. This patient had peripheral hypogonadism associated with congenital bilateral cryptorchidia responsible for gynecomastia due to "relative hyperestrogenism". Large numbers of estrogen receptors were demonstrated in each of the benign nodular hidradenomas. The malignant nodular hidradenoma mass was unavailable and screening for these receptors was not possible. DISCUSSION: Cases of multiple nodular hidradenoma are extremely rare: we have seen only two. To the best of our knowledge, there have been no reports to date of combined malignant nodular hidradenoma and multiple benign nodular hidradenoma. However, there is histological evidence of transition forms. The coexistence of endocrine anomalies associated with this type of tumour has never been reported. However, the presence of estrogen receptors has occasionally been demonstrated in benign nodular hidradenomas. Our patient's endocrine disease may have played a role in the presentation of multiple hidradenomas, but this cannot be demonstrated.

[Use of cabergoline in persisting Cushing's disease]. / Utilisation de la cabergoline dans la maladie de Cushing non contrôlée.

Cabergoline is a dopaminergic agonist with demonstrated efficiency of for the treatment of prolactin-secreting pituitary tumors. It has also been reported effective for patients with hypercortisolism uncontrolled by conventional therapies. We describe the use of cabergoline in three patients with Cushing's disease, one of them presenting a silent ACTH-secreting pituitary tumor. Those patients underwent surgery and only one has been treated with radiation therapy. However persisting hypercortisolism motivated the use of cabergoline. We describe a decrease or a normalization in hypercortisolism; for one of the subjects, tumor growth seemed to be stopped. While cabergoline can induce a suppression of cortisol secretion or a corticotroph tumor shrinkage, the sites of action remain unclear.

Aberrant adrenal sensitivity to multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol hypersecretion: a prospective clinical study.

BACKGROUND: Incidentally discovered adrenal tumours are frequently associated with subclinical autonomous cortisol hypersecretion of unknown origin. Aberrant hormone receptors have been observed in case reports of overt Cushing's syndrome. The question arises as to whether such receptors may be present in the functioning adrenal incidentaloma, which is common and might be a subclinical stage of Cushing's syndrome. PATIENTS AND METHODS: Twenty-one consecutive patients with a unilateral incidentaloma, the biochemical features of subclinical cortisol hypersecretion and/or the scintigraphic features of an autonomously functioning adrenal adenoma were investigated for plasma cortisol responses to various stimuli: upright posture, meal, combined hypothalamic-hormones, the vasopressin analogue terlipressin, glucagon, angiotensin II, the serotonin 5-HT4 agonist cisapride, and ACTH. Six normal controls were similarly investigated. All subjects were studied during 8 mg per day dexamethasone in order to avoid any ACTH-dependent variation of plasma cortisol. RESULTS: The most constant responses in adrenal incidentalomas were observed after stimulation by terlipressin (18/20 patients, 28-415% cortisol increase) and cisapride (17/21 patients, 25-364% cortisol increase). Eighteen out of 21 patients responded to several stimuli (cortisol increase >or= 25%), and all responded to at least one stimulus other than ACTH, while such responses were absent in the controls. Plasma ACTH remained suppressed in all subjects throughout the study. CONCLUSIONS: Aberrant membrane receptors detected by in vivo stimulation tests appear to be common in autonomously functioning unilateral adrenocortical adenomas. These receptors may be involved in the modulation of cortisol secretion in adrenal incidentaloma, with potential therapeutic consequences for the control of subclinical cortisol hypersecretion.

Activating mutations of TSH receptor.

Mechanisms of activation of G protein-coupled receptor by the agonist, are supposed to rely on release from structural constraints, then allowing the "relaxed" receptor to activate the G protein. By analogy with experimental works on alpha1b adrenergic receptor, showing that mutations could result in constitutive activation of the receptor, it was hypothezised, that similar but spontaneous somatic mutations of the Thyrotropin-receptor could be the cause of thyroid toxic adenomas. This hypothesis has been confirmed. Furthermore, the rare cases of familial non autoimmune hyperthyroidism have been shown to be caused by germline mutations of Thyrotropin receptor, as well as the cases of non autoimmune neonatal hyperthyroidism. Beside the constitutive activation of the Thyrotropin-receptor a case of sensitization of the Thyrotropin-receptor to hCG by a mutation in the extracellular domain has been identified as the cause of familial gestational hyperthyroidism. All those mutation studies have been helpful in understanding the mechanisms of activation of glycoproteic hormones. A first model had been proposed, according to datas obtained from these mutations. In this model, the extracellular domain of the receptor exerts an inhibitory action on the transmembrane domain, and this interaction has to be disrupted to allow for activation of the receptor. However, recent experimental datas suggest that interaction between extracellular domain and transmembrane domain are more complex than just inhibitory, and that upon activation, the extracellular domain may convert from an inhibitory structure to an activating one.

[New medical treatments for polycystic ovary syndrome]. / Les nouveaux traitements médicaux du syndrome des ovaries polykystiques.

Polycystic ovary syndrome (PCO) is a polygenic disease worsened by obesity and environmental factors. PCO is characterized by chronic menstrual irregularity and hypofertility and metabolic disorders. Routine care includes appropriate diet, exercise and annual check-up to search for high blood pressure. Laboratory tests should include a lipid profile and fasting serum glucose. Insulin sensitizing drugs improve the metabolic pattern, induce ovulation and increase pregnancy rate. Here, we review the different therapeutic options for these patients.