Performance of [18F]fluorocholine PET/CT in MEN1-related primary hyperparathyroidism before initial surgery or for persistent/recurrent disease.

PURPOSE: The aims of the study were to evaluate the performance and robustness of [18F]fluorocholine PET/CT in detecting hyperfunctioning parathyroid glands in MEN1-related primary hyperparathyroidism (pHPT) at different stages of their disease. METHODS: Retrospective French multicenter study including patients with MEN1 pHPT who underwent [18F]fluorocholine PET/CT at initial diagnosis or for evaluation of persistent/recurrent disease. PET/CT were independently reviewed by two readers in a blinded manner. The assessment of PET/CT on a per-patient basis was assessed using a comprehensive set of criteria that considered pathological findings or agreement with alternative diagnostic methods in non-operated patients. The secondary objectives included the analysis of the performance of PET/CT at a per-lesion level, with reference to a pathological Gold Standard, and examining its interobserver reproducibility. RESULTS: A total of 71 MEN1 patients were included (73 PET/CT) in the study. At the per-patient level (entire cohort), [18F]fluorocholine PET/CT sensitivity ranged from 98.5 to 100% among the different readers. An average of 1.77 glands per PET was described, with 2.35 glands at the initial diagnosis (n = 23) and 1.5 in previously operated cases (n = 50). PET/CT detected more lesions than conventional imaging work-up (neck ultrasound and/or scintigraphy). At the per-lesion level (41 operated patients), sensitivity ranged across different readers from 84.4 to 87%, and specificity ranged from 94.7 to 98.8%. At initial diagnosis, all patients that exhibited 3 or more abnormal glands on PET underwent subtotal parathyroidectomy while 7 out of 13 patients with 1 or 2 gland abnormalities on PET underwent less than subtotal parathyroidectomy. Finally, the degree of inter-observer agreement was high. CONCLUSION: [18F]fluorocholine PET/CT is a reliable and robust imaging modality for the evaluation of MEN1-related pHPT and could guide surgeons in achieving the optimal benefit-risk ratio. This study gives a great impetus for its adoption as a primary diagnostic tool in this context.

Factors Associated with Survival in Anaplastic Thyroid Carcinoma: A Multicenter Study from the ENDOCAN-TUTHYREF Network.

Background: Anaplastic thyroid carcinoma (ATC) is a rare and frequently fatal type of thyroid cancer. The degree of heterogeneity in survival rates for ATC is incompletely studied. This study evaluated the factors associated with overall survival (OS) of patients with ATC using multicenter real-world data from a national tertiary care center network in France. Methods: In this multicenter, retrospective cohort study, all patients with ATC diagnosed between 2010 and 2020 were identified from the national database of the French ENDOCAN-TUTHYREF network. Factors associated with OS were examined in multivariable analyses using Cox proportional hazards models. Results: The study included 360 patients. Of these, 220 (61%) were female and the median age was 72 years (interquartile range: 62-80). The percentages of patients with pure and mixed (synchronously-transformed) ATC (p-ATC and st-ATC) were 62.5% and 26.7%, respectively. The median OS was 6.8 months [confidence interval, CI: 5.5-8.1]: not reached for stage IVa, 11.4 months [8.2-17.8] for IVb, and 4.6 months [3.5-5.7] for IVc. Surgery, radiation therapy to the neck, chemotherapy, and best supportive care were administered to 69 (19.2%), 214 (59.4%), 254 (70.6%), and 66 (18.3%) patients, respectively. In a multivariable analysis, including stage IVb-IVc patients, significantly higher OS was observed in patients with Eastern Cooperative Oncology Group performance-status of 0-1 (hazard ratio [HR], 0.6; [CI, 0.4-0.9], p < 0.02), stage IVb [HR, 0.5; CI, 0.4-0.8, p < 0.001], and multimodal treatment (surgery and chemoradiotherapy) [HR, 0.07; CI, 0.04-0.1, p < 0.001]. Variables associated with significantly worse OS included: p-ATC (vs. st-ATC) [HR, 1.83; CI, 1.33-2.51, p = 0.001] and a neutrophil-to-lymphocyte ratio (NLR) >5.05 [HR, 2.05, CI, 1.39-3.05, p < 0.001]. Conclusions: Factors independently associated with improved OS in ATC included: European Cooperative Oncology Group performance status, disease stage, multimodality treatment, synchronously transformed ATC, and lower NLR. Long-term OS was observed in selected patients with ATC who underwent multimodal treatment.

Rare duplication of the CDC73 gene and atypical hyperparathyroidism-jaw tumor syndrome: A case report and review of the literature.

BACKGROUND: Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is the rarest familial cause of primary hyperparathyroidism, with an incidence <1/1000000, caused by a pathogenic variant in the CDC73 (or HRPT2) gene that encodes parafibromin, a protein involved in many cellular mechanisms. Patients with HPT-JT have a 15-20% of risk of developing parathyroid carcinoma, whereas it accounts for only 1% of all cases of primary hyperparathyroidism. Patients also develop jaw tumors in 30% of cases, kidney abnormalities in 15% of cases, and uterine tumors in 50% of patients. CASE REPORT: Here are report two atypical cases of HPT-JT with variable expressivity in the same family. In front of an isolated primary hyperparathyroidism at 28 years of age of incidental discovery following a weight gain, the propositus benefited a first-line panel by Next-Generation Sequencing of the genes involved in familial hyperparathyroidism: CaSR, CDC73, MEN1, and RET. Genetic testing revealed the presence of a pathogenic germline variation CDC73: c.687_688dup; p.Val230Glufs*28, found only in nine families in the literature and allowing the diagnosis of HPT-JT. Given a history of primary hyperparathyroidism at 52 years and adenomyosis, the patient's mother also underwent a genetic analysis that found her daughter's variation and established her inherited trait. CONCLUSION: In view of the clinical and genotypic heterogeneity, we confirm the interest of using an extended gene panel for the diagnosis of familial primary hyperparathyroidism. CDC73 variations could be more frequent than described in the literature. The association of primary hyperparathyroidism with uterine involvement could be a new indication for analysis.

Value of Somatostatin Receptor PET/CT in Patients With MEN1 at Various Stages of Their Disease.

CONTEXT: Despite the growing evidence of the clinical value of somatostatin receptor (SSTR) positron emission tomography (PET) in the evaluation of neuroendocrine tumors (NETs), its role remains to be clarified at different time points in the journey of patients with multiple endocrine neoplasia type 1 (MEN1). The rarity of the disease is however a significant impediment to prospective clinical trials. OBJECTIVE: The goals of the study were to assess the indications and value of SSTR PET/computed tomography (CT) in patients with MEN1. METHODS: We retrospectively included patients from 7 French expert centers for whom data on SSTR PET/CT and morphological imaging performed at the same period were available. Detection rates of PET study were analyzed. RESULTS: One hundred and 8 patients were included. SSTR PET/CT was performed at screening (n = 33), staging (n = 34), restaging (n = 37), and for peptide receptor targeted radiotherapy selection (n = 4). PET detected positive pancreatic lesions in 91% of cases at screening, with results comparable with magnetic resonance imaging but superior to CT (P = .049). Metastases (mostly lymph node [LN]) were present at the screening phase in 28% of cases, possibly due to the suboptimal value of screening morphological imaging in the assessment of nodal metastases and/or a long delay between imaging studies. SSTR PET/CT was considered superior or complementary to the reference standard in the assessment of LN or distant metastases in the vast majority of cases and regardless of the clinical scenario. CONCLUSION: This study shows the potential added value of SSTR PET in the assessment of MEN1-associated NETs and provides great impetus toward its implementation in the evaluation of patients with MEN1.

Assessment of oro-dental manifestations in a series of acromegalic patients, the AcroDent study.

OBJECTIVE: The dental and periodontal impact of GH/IGF-1 hypersecretion has been poorly investigated until now. Our aim is to precisely describe the oro-dental state of acromegalic patients and to study the impact of GH/IGF-1 hypersecretion on patients' reported oral health-related quality of life (OHRQoL). METHODS: After collecting characteristics of their disease, acromegalic patients answered the GOHAI questionnaire assessing their OHRQoL, the AcroQoL questionnaire and then benefited from a complete stomatological and radiological examination (orthopantomogram systematically, retro-alveolar radiography or Cone Beam CT if necessary). RESULTS: In total, 29 patients aged 59.1 ± 16.0 years were included. The average DMFT index (sum of Decayed, Missing and Filled Teeth per patient) was 19.0 ± 7.8. 16/29 patients had a gingivitis and 18/29 a mild to moderate chronic periodontitis, but no case of severe chronic periodontitis was found, probably because the frequency of a protective thick gingival biotype was increased (9/29). No case of generalized gingival hypertrophy or diffuse hypercementosis was observed. According to the Add-GOHAI score, only 8/26 patients had a satisfactory OHRQoL. This parameter was correlated to the acromegaly-specific quality of life according to the AcroQoL score. Interestingly, 11/29 patients had bulky oral bony outgrowths (OBO), such as large maxillary or mandibular tori and multiple vestibular exostosis. CONCLUSIONS: The unsatisfactory OHRQoL reported by acromegalic patients contrasts with a rather good objective oro-dental state and annual oral examination seems relevant in this population. Finally, we report that huge OBO could be helpful signposts for the diagnosis of acromegaly.

Re-treatment With Adjuvant Radioactive Iodine Does Not Improve Recurrence-Free Survival of Patients With Differentiated Thyroid Cancer.

Introduction: Loco regional persistence or recurrence of differentiated thyroid cancer (DTC) is frequent despite initial thyroidectomy and radioactive iodine therapy (RAI). The aim of this study was to analyze the impact of a complementary adjuvant RAI (Ad-RAI) on disease recurrence following re-operation on patients with locally persistent or recurrent DTC. Patients and Methods: A retrospective study of 85 patients with DTC was conducted. All patients were initially treated with total thyroidectomy and RAI, and re-operated for a locally persistent or recurrent disease. Propensity score was calculated to predict the impact of Ad-RAI on survival after reoperation, and to reduce the bias of the limited sample size and the prognostic tests. Results: 49 (58%) patients were re-treated with Ad-RAI after re-operation while 36 (42%) were only followed up. Disease recurrence after re-treatment (re-operation ± Ad-RAI) was detected in 31 patients (36.5%). In multivariate analysis, age >55 years (HR: 3.9 [1.6; 9.5]; p < 0.00001) was the main poor prognostic factor for recurrence-free survival. Three parameters independently influenced the decision to administer ad-RAI: low number of previous RAI administrations, Nx before re-operation, and pTg > 30 µg/l. These parameters were incorporated in the Propensity score calculation. If ad-RAI tended to improve recurrence-free survival (median survival 17.4 vs. 10.9 months), adjustment using the Propensity score removed any difference between the groups (p = 0.54), confirming the limited value of ad-RAI. Conclusion: In patients with locally persistent or recurrent DTC, age is the main independent prognostic factor. Adjuvant RAI does not improve recurrence-free survival of DTC patients.

EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness.

BACKGROUND: EZH2 is overexpressed and associated with poor prognosis in adrenocortical carcinoma (ACC) and its inhibition reduces growth and aggressiveness of ACC cells in culture. Although EZH2 was identified as the methyltransferase that deposits the repressive H3K27me3 histone mark, it can cooperate with transcription factors to stimulate gene transcription. METHODS: We used bioinformatics approaches on gene expression data from three cohorts of patients and a mouse model of EZH2 ablation, to identify targets and mode of action of EZH2 in ACC. This was followed by ChIP and functional assays to evaluate contribution of identified targets to ACC pathogenesis. RESULTS: We show that EZH2 mostly works as a transcriptional inducer in ACC, through cooperation with the transcription factor E2F1 and identify three positive targets involved in cell cycle regulation and mitosis i.e., RRM2, PTTG1 and ASE1/PRC1. Overexpression of these genes is associated with poor prognosis, suggesting a potential role in acquisition of aggressive ACC features. Pharmacological and siRNA-mediated inhibition of RRM2 blocks cell proliferation, induces apoptosis and inhibits cell migration, suggesting that it may be an interesting target in ACC. CONCLUSIONS: Altogether, these data show an unexpected role of EZH2 and E2F1 in stimulating expression of genes associated with ACC aggressiveness.

Age, thyroglobulin levels and ATA risk stratification predict 10-year survival rate of differentiated thyroid cancer patients.

INTRODUCTION: Differentiated thyroid cancer (DTC) is the most common of endocrine cancers. Many studies have focused on recurrence-free survival of DTC patients, however, few studies have addressed overall survival rates. Given its very good prognosis, estimating overall or long-term survival in patients with DTC seems rational. So far, neither the impact of pre- and post-ablation thyroglobulin, nor that of initial American Thyroid Association (ATA) risk stratification on long-term disease-specific survival, have been sufficiently studied. OBJECTIVE: The aim of this study was to determine the factors that influence long-term disease-specific survival and thyroglobulin levels in patients with DTC who have been previously treated with thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND METHODS: This observational retrospective study included 1093 patients who were treated for DTC between 1995 and 2010 and are still monitored in our tertiary center. Only patients who needed RAI ablation after thyroidectomy were included in this study. Patients who were treated with RAI following rhTSH stimulation, patients who presented positive anti-thyroglobulin antibodies, and patients who had micro-cancers were excluded. Pre-ablation stimulated thyroglobulin (Pre-ablation sTg) was measured after thyroid hormone withdrawal (THW), just before RAI. RESULTS: According to ATA standards, 29 patients (2.7%) were classified as high-risk patients. Initial ATA high-recurrence risk rating (HR 21.9; 95% CI: 8.5-56.3), age>55 years (HR 23.8; 95%-CI: 7.5-75.3) and pre-ablation sTg≥30 µg/l (HR 8.4; 95% CI: 4.6-15.3) significantly impacted ten-year survival. Moreover, age over 45 years, ATA moderate-risk and follicular DTC were also significant. Ten-year survival was lower in ATA high-risk patients (51% vs 95% and 93% for the low and intermediate risk; p<10-7), patients older than 55 years (82% vs 98%; p<10-7), and in patients with pre-ablation sTg≥30 (78% vs 95%; p<10-7). Three rates of long-term survival were distinguished: excellent (survival rate of 99% in patients<55 years with pre-ablation sTg <30µg/l) representing 59% of the cohort, moderate (survival rate of 94.5% in patients <55 years with pre-ablation sTg ≥30µg/l or ≥55 years with pre-ablation sTg <30 µg/l) representing 38% of the cohort, and low (survival rate of 49% in patients ≥55 years with pre-ablation sTg ≥30µg/l) representing 3% of the cohort. CONCLUSION: Initial ATA high-risk classification, age over 55 years old and pre-ablation sTg ≥30 µg/l are the main negative factors that influence the ten-year survival in DTC. We suggest three categories of overall survival rates. Patients older than 55 years with pre-ablation sTg ≥30 µg/l have the worst survival rate.

Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex.

SUMOylation is a highly conserved and dynamic post-translational mechanism primarily affecting nuclear programs for adapting organisms to stressful challenges. Alteration of SUMOylation cycles leads to severe developmental and homeostatic defects and malignancy, but signals coordinating SUMOylation are still unidentified. The adrenal cortex is a zonated endocrine gland that controls body homeostasis and stress response. Here, we show that in human and in mouse adrenals, SUMOylation follows a decreasing centripetal gradient that mirrors cortical differentiation flow and delimits highly and weakly SUMOylated steroidogenic compartments, overlapping glomerulosa, and fasciculata zones. Activation of PKA signaling by acute hormonal treatment, mouse genetic engineering, or in Carney complex results in repression of small ubiquitin-like modifier (SUMO) conjugation in the inner cortex by coordinating expression of SUMO pathway inducers and repressors. Conversely, genetic activation of canonical wingless-related integration site signaling maintains high SUMOylation potential in the outer neoplastic cortex. Thus, SUMOylation is tightly regulated by signaling pathways that orchestrate adrenal zonation and diseases.-Dumontet, T., Sahut-Barnola, I., Dufour, D., Lefrançois-Martinez, A.-M., Berthon, A., Montanier, N., Ragazzon, B., Djari, C., Pointud, J.-C., Roucher-Boulez, F., Batisse-Lignier, M., Tauveron, I., Bertherat, J., Val, P., Martinez, A. Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex.

Stimulated Thyroglobulin and Thyroglobulin Reduction Index Predict Excellent Response in Differentiated Thyroid Cancers.

CONTEXT: Despite its good prognosis, differentiated thyroid cancer (DTC) is characterized by high rates of disease persistence and recurrence. Estimation of long-term remission (excellent response) thanks to specific parameters could help to individualize the active surveillance schedule. OBJECTIVE: Evaluation of the ability of stimulated thyroglobulin (Tg) and Tg reduction index (TRI) to predict long-term remission in patients with DTC managed by thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND INTERVENTIONS: Observational retrospective study of 1093 patients treated for DTC between 1995 and 2010. Preablation stimulated thyroglobulin (presTg) was measured under thyroid hormone withdrawal just before RAI. Recombinant human TSH-stimulated thyroglobulin (sTg) was measured at first evaluation of the initial management 6 to 12 months after RAI. TRI was calculated based on pre-Tg and sTg. RESULTS: After univariate and multivariate analyses, lymph node invasion (N1, OR = 2.08; 95% CI, 1.19 to 3.64), presTg (OR = 4.04; 95% CI, 2.56 to 6.38), sTg (OR = 2.62; 95% CI, 2.05 to 3.34), and TRI (OR = 0.43; 95% CI, 0.21 to 0.88) were identified as independent prognostic factors influencing the rate of disease persistence or recurrence after the initial management. Receiver operating characteristic analysis identified presTg cutoff (<10 µg/L) to predict excellent response, with a negative predictive value of 94%, and validated for higher stages (T3/T4, N1). Furthermore, sTg <1 µg/L predicts excellent response. TRI >60% for the entire cohort and 62.5% for locally advanced disease (T3/T4, N1) was sensitive predictor for excellent response. CONCLUSION: This study identifies presTg, sTg, and TRI as highly sensitive predictors of excellent response in patients with DTC and subsequently disease-free status. The cutoff of such parameters is also adapted for patients with higher tumor stages (T3/T4, N1).

Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas.

OBJECTIVES: Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival. DESIGN: Multicenter retrospective study by members of the French Society of Endocrinology. METHODS: Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (n = 23) or lactotroph (n = 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment. RESULTS: The median treatment duration was 6.5 cycles (range 2-24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0-72). Overall survival was significantly higher among responders (P = 0.002); however, ten patients relapsed 5 months (0-57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success. DISCUSSION: Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.

Time course of Graves' orbitopathy after total thyroidectomy and radioiodine therapy for thyroid cancer.

The risk of cancer is relatively higher in Graves' patients presenting simultaneously with thyroid nodules. Radioiodine (RAI) therapy recommended in high-risk differentiated thyroid carcinoma may be associated with worsening of a pre-existing Graves' orbitopathy (GO) or developing a new onset. The impact of RAI therapy in patients with differentiated thyroid cancer on the course of a pre-exisiting GO has not been specifically investigated.The aim of this study is to assess the influence of RAI treatment administered for differentiated thyroid cancer on the course of a pre-existing GO.This is a retrospective multicenter study including 35 patients from the University Hospital of Clermont-Ferrand (7 patients) and Lyon-Est (6 patients) in France and from a literature review published as case reports or studies (22 patients).Seven patients exhibited a worsened pre-existing GO after total thyroidectomy followed by RAI treatment for thyroid cancer. Older men, those who initially presented with a lower clinical score of GO before RAI therapy, received higher doses of I especially when prepared with recombinant thyroid-stimulating hormone, and/or not prepared with glucocorticoids during RAI are at a higher risk to worsen their GO.This study is the first and complete study collection. We describe worsening of GO in 20% of patients after RAI treatment for thyroid cancer and determine a pool of predictive factors.

PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development.

Adrenal cortex physiology relies on functional zonation, essential for production of aldosterone by outer zona glomerulosa (ZG) and glucocorticoids by inner zona fasciculata (ZF). The cortex undergoes constant cell renewal, involving recruitment of subcapsular progenitors to ZG fate and subsequent lineage conversion to ZF identity. Here we show that WNT4 is an important driver of WNT pathway activation and subsequent ZG differentiation and demonstrate that PKA activation prevents ZG differentiation through WNT4 repression and WNT pathway inhibition. This suggests that PKA activation in ZF is a key driver of WNT inhibition and lineage conversion. Furthermore, we provide evidence that constitutive PKA activation inhibits, whereas partial inactivation of PKA catalytic activity stimulates ß-catenin-induced tumorigenesis. Together, both lower PKA activity and higher WNT pathway activity lead to poorer prognosis in adrenocortical carcinoma (ACC) patients. These observations suggest that PKA acts as a tumour suppressor in the adrenal cortex, through repression of WNT signalling.

Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

Adrenal cortex tumors are divided into benign forms, such as primary hyperplasias and adrenocortical adenomas (ACAs), and malignant forms or adrenocortical carcinomas (ACCs). Primary hyperplasias are rare causes of adrenocorticotropin hormone-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely "functional," i.e., producing steroids. When functional, adenomas result in endocrine disorders, such as Cushing's syndrome (hypercortisolism) or Conn's syndrome (hyperaldosteronism). By contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors (ACTs) led to the identification of potentially causative genes, most of them being involved in protein kinase A (PKA), Wnt/ß-catenin, and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders, and in fine to provide in vivo tools for therapeutic screens. In this article, we will provide an overview on the existing mouse models (xenografted and genetically engineered) of ACTs by focusing on the role of PKA and Wnt/ß-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases.

EZH2 is overexpressed in adrenocortical carcinoma and is associated with disease progression.

Adrenal Cortex Carcinoma (ACC) is an aggressive tumour with poor prognosis. Common alterations in patients include constitutive WNT/ß-catenin signalling and overexpression of the growth factor IGF2. However, the combination of both alterations in transgenic mice is not sufficient to trigger malignant tumour progression, suggesting that other alterations are required to allow development of carcinomas. Here, we have conducted a study of publicly available gene expression data from three cohorts of ACC patients to identify relevant alterations. Our data show that the histone methyltransferase EZH2 is overexpressed in ACC in the three cohorts. This overexpression is the result of deregulated P53/RB/E2F pathway activity and is associated with increased proliferation and poorer prognosis in patients. Inhibition of EZH2 by RNA interference or pharmacological treatment with DZNep inhibits cellular growth, wound healing and clonogenic growth and induces apoptosis of H295R cells in culture. Further growth inhibition is obtained when DZNep is combined with mitotane, the gold-standard treatment for ACC. Altogether, these observations suggest that overexpression of EZH2 is associated with aggressive progression and may constitute an interesting therapeutic target in the context of ACC.

Amiodarone-Induced Thyrotoxicosis Recurrence After Amiodarone Reintroduction.

Reintroduction of amiodarone in patients with a history of amiodarone-induced thyrotoxicosis (AIT) is rarely used. To date, the risk of AIT recurrence after amiodarone reintroduction is unpredicted. The aim of the study was to evaluate the risk of AIT recurrence. Retrospectively, from 2000 to 2011, all euthyroid patients with a history of AIT with amiodarone reintroduction were included. Type and severity of the first AIT, amiodarone chronology, and thyroid function evolution after reintroduction of amiodarone were investigated: 46 of 172 patients with AIT history needed amiodarone reintroduction. At first AIT episode, the mean age was 62.2 ± 16 years with male gender predominance; 65% of patients were classified as type 1 AIT. AIT recurred in 14 patients (30%), 12 patients developed hypothyroidism (26%), and 20 patients remained euthyroid (44%). Characteristics of type 1 AIT during the first episode, namely briefer exposure period to amiodarone and longer duration of treatment to normalize thyroid hormones, were predictive of AIT recurrence; 73% of patients (8 of 11) with previous episode of type 1 AIT, who did not receive a preventive thioamide treatment, developed a second episode of AIT. Thioamide preventive treatment could be useful to prevent type 1 AIT recurrence. In conclusion, AIT recurrence after amiodarone reintroduction is 4 times more frequent in patients with type 1 AIT history. Thyroid ablation before amiodarone reintroduction in patients with a history of type 1 AIT is preferred. Preventive thioamide treatment could be suggested in patients with type 1 AIT history pending for surgery.

Acute and Chronic Pheochromocytoma-Induced Cardiomyopathies: Different Prognoses?: A Systematic Analytical Review.

Pheochromocytoma and paraganglioma (PPG) are rare and late-diagnosed catecholamine secreting tumors, which may be associated with unrecognized and/or severe cardiomyopathies. We performed a computer-assisted systematic search of the electronic Medline databases using the MESH terms "myocarditis," "myocardial infarction," "Takotsubo," "stress cardiomyopathy," "cardiogenic shock", or "dilated cardiomyopathy," and "pheochromocytoma" or "paraganglioma" from 1961 to August 2012. All detailed case reports of cardiomyopathy due to a PPG, without coronary stenosis, and revealed by acute symptoms were included and analyzed. A total of 145 cases reports were collected (49 Takotsubo Cardiomyopathies [TTC] and 96 other Catecholamine Cardiomyopathies [CC]). At initial presentation, prevalence of high blood pressure (87.7%), chest pain (49.0%), headaches (47.6%), palpitations (46.9%), sweating (39.3%), and shock (51.0%) were comparable between CC and TTC. Acute pulmonary edema (58.3% vs 38.8%, P = 0.03) was more frequent in CC. There was no difference in proportion of patients with severe left ventricular systolic dysfunction (LV Ejection Fraction [LVEF] < 30%) at initial presentation between both groups (P = 0.15). LVEF recovery before (64.9% vs 40.8%, P = 0.005) and after surgical resection (97.7% vs 73.3%, P = 0.001) was higher in the TTC group. Death occurred in 11 cases (7.6%). In multivariate analysis, only TTC was associated with a better LV recovery (0.15 [0.03-0.67], P = 0.03). Pheochromocytoma and paraganglioma can lead to different cardiomyopathies with the same brutal and life-threatening initial clinical presentation but with a different recovery rate. Diagnosis of unexplained dilated cardiomyopathy or TTC should lead clinicians to a specific search for PPG.

Leydig cell tumor in a patient with 49,XXXXY karyotype: a review of literature.

49,XXXXY pentasomy or Fraccaro's syndrome is the most severe variant of Klinefelter's syndrome (KS) affecting about 1/85000 male births. The classical presentation is the triad: mental retardation, hypergonadotropic hypogonadism and radio ulnar synostosis. Indeed, the reproductive function of Fraccaro's syndrome is distinguished from KS. Besides, Leydig cell tumors are described in cases of KS, but never documented in the Klinefelter variants.We describe a young adult of 22 years old who presented with hyper gonadotropic hypogonadism, delayed puberty and bilateral micro-cryptorchidism. Chromosomal pentasomy was confirmed since infancy. Bilateral orchidectomy revealed a unilateral well-circumscribed Leydig cell tumor associated with bilateral Leydig cell hyperplasia.Inspired from reporting the first case of Leydig cell tumor in a 49,XXXXY patient, we summarize the particularities of testicular function in 49,XXXXY from one side, and the risk and mechanisms of Leydig cell tumorigenesis in Klinefelter variants on the other side. The histological destructions in 49,XXXXY testes and hypogonadism are more profound than in Klinefelter patients, with early Sertoli, Leydig and germ cell destruction. Furthermore, the risk of Leydigioma development in KS and its variants remains a dilemma. We believe that the risk of Leydigioma is much higher in KS than the general population. By contrast, the risk could be lower in the Klinefelter variants with more than 3 supplementary X chromosomes, owing to an earlier and more profound destruction of Leydig cells rendering them irresponsive to chronic Luteinizing hormone (LH) stimulation.

mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD).

Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating mutations of the PRKAR1A tumor suppressor gene that encodes the regulatory subunit R1α of the cAMP-dependent protein kinase (PKA). In human and mouse adrenocortical cells, these mutations lead to increased PKA activity, which results in increased resistance to apoptosis that contributes to the tumorigenic process. We used in vitro and in vivo models to investigate the possibility of a crosstalk between PKA and mammalian target of rapamycin (mTOR) pathways in adrenocortical cells and its possible involvement in apoptosis resistance. Impact of PKA signaling on activation of the mTOR pathway and apoptosis was measured in a mouse model of PPNAD (AdKO mice), in human and mouse adrenocortical cell lines in response to pharmacological inhibitors and in PPNAD tissues by immunohistochemistry. AdKO mice showed increased mTOR complex 1 (mTORC1) pathway activity. Inhibition of mTORC1 by rapamycin restored sensitivity of adrenocortical cells to apoptosis in AdKO but not in wild-type mice. In both cell lines and mouse adrenals, rapid phosphorylation of mTORC1 targets including BAD proapoptotic protein was observed in response to PKA activation. Accordingly, BAD hyperphosphorylation, which inhibits its proapoptotic activity, was increased in both AdKO mouse adrenals and human PPNAD tissues. In conclusion, mTORC1 pathway is activated by PKA signaling in human and mouse adrenocortical cells, leading to increased cell survival, which is correlated with BAD hyperphosphorylation. These alterations could be causative of tumor formation.