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Luc Pijnenburg, Joe-Elie Salem, Benedicte Lebrun-Vignes, Jean Sibilia, Rose-Marie Javier, and Laurent Arnaud

Objective: Atrial Fibrillation (AF) may be triggered by intravenous bisphosphonates (IVBPs) such as zoledronic acid or pamidronic acid. Our objective was to confirm the association between AF and IVBPs in a real-life large pharmacovigilance database.

Design: A systematic analysis of VigiBase the World Health Organization pharmacovigilance database.

Methods: Analysis of adverse events reported as “Atrial Fibrillation” (according to the Medical Dictionary for Drug Regulatory Activities) associated with the use of zoledronic acid or pamidronic acid, in VigiBase, the World Health Organization global Individual Case Safety Report (ICSR) database. All ICSRs reporting AF associated with zoledronic acid or pamidronic acid were analysed in a disproportionality analysis determining the lower end of the 95% credibility interval for the Information Component (IC025), showing a statistical association when >0.

Results: 530 ICSRs reporting on the association between AF and IVBPs were extracted. Bayesian disproportionality analysis detected a significant association between AF and use of zoledronic acid (IC025=1.83) and pamidronic acid (IC025=2.16). Further analysis of these ICSRs determined that AF was severe in 85.0% of cases and with a mortality of 17.7%. The risk of severe AF was increased (OR: 2.98 [95%CI: 1.17-7.57], p=0.02) following zoledronic acid versus pamidronic acid, after adjustment for age and gender.

Conclusions: This is the first VigiBase pharmacoepidemiological study confirming the association between IVBPs and AF. Most AF were severe, with a high frequency of lethal outcome. The risk of severe AF was increased following zoledronic acid use compared to pamidronic acid, advocating for a cautious use of IVBPs.

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Srdjan Pandurevic, Luca Bergamaschi, Carmine Pizzi, Laura Patton, Paola Rucci, Francesca Corzani, Carolina Cecchetti, Carla Pelusi, Paola Altieri, Valentina Vicennati, Guido Di Dalmazi, Flaminia Fanelli, Djuro Macut, Uberto Pagotto, and Alessandra Gambineri

Objective

Research into cardiovascular disease (CV) prevention has demonstrated a variety of ultrasound (US) markers predicting risk in the general population but which have been scarcely used for polycystic ovary syndrome (PCOS). Obesity is a major factor contributing to CV disease in the general population, and it is highly prevalent in PCOS. However, it is still unclear how much risk is attributable to hyperandrogenism. This study evaluates the most promising US CV risk markers in PCOS and compares them between different PCOS phenotypes and BMI values.

Design

Women fulfilling the Rotterdam criteria for PCOS were recruited from our outpatient clinic for this cross-sectional study.

Methods

Participants (n = 102) aged 38.9 ± 7.4 years were stratified into the four PCOS phenotypes and the three BMI classes (normal-weight, overweight, obese). They were assessed for clinical and biochemical parameters together with the following US markers: coronary intima-media thickness (cIMT), flow-mediated vascular dilation (FMD), nitroglycerine-induced dilation (NTG), and epicardial fat thickness (EFT).

Results

There was no statistical difference among the four phenotypes in terms of cIMT, FMD, NTG or EFT, however all the US parameters except NTG showed significant differences among the three BMI classes. Adjusting for confounding factors in multiple regression analyses, EFT retained the greatest direct correlation with BMI and cIMT remained directly correlated but to a lesser degree.

Conclusions

This study showed that obesity rather than the hyperandrogenic phenotype negatively impacts precocious US CV risk markers in PCOS. In addition, EFT showed the strongest association with BMI, highlighting its potential for estimating CV risk in PCOS.

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Mette Hansen Viuff, Kirstine Stochholm, Angela Lin, Agnethe Berglund, Svend Juul, and Claus Højbjerg Gravholt

Objective

Although the overall risk of cancer is not increased in Turner syndrome, the pattern of cancer occurrence differs from the general population. We aim to describe the cancer morbidity pattern in Turner syndrome and evaluate the effect of long-term hormone replacement therapy (HRT).

Design

Nationwide epidemiological study.

Methods

1156 females with Turner syndrome diagnosed during 1960–2014, were linked with data from the Danish National Patient Registry. Statistics Denmark randomly identified 115 578 female controls. Stratified Cox regression was used to analyze cancer morbidity, mortality and effect of HRT.

Results

Overall risk of cancer was not elevated (hazard ratio 1.04 (95% CI: 0.80–1.36)). The risk of skin cancer and benign skin neoplasms was two-fold increased, while the risk of breast cancer was decreased (hazard ratio 0.4 (0.2–0.9)). Turner syndrome (45,X) had a two- to five-fold increased risk of benign CNS tumors, colon and rectal cancers, benign skin neoplasms and skin cancer. Turner syndrome women with a 45,X/46,XX karyotype had an increased risk of tongue cancer. HRT had no impact on the risk of any cancer investigated in this study.

Conclusions

The lack of one X chromosome might play a role in skin neoplasms, CNS tumors, colon and rectal cancers. The risk of breast cancer is lower than in the general population. Long-term HRT during the premenopausal age range seems not to exert a cancerous effect in Turner syndrome. Increased vigilance concerning specific types of cancer in Tuner syndrome harboring a 45,X karyotype is needed.

Open access

Carmina Teresa Fuss, Katharina Brohm, Max Kurlbaum, Anke Hannemann, Sabine Kendl, Martin Fassnacht, Timo Deutschbein, Stefanie Hahner, and Matthias Kroiss

Objective

Saline infusion testing (SIT) for confirmation of primary aldosteronism (PA) is based on impaired aldosterone suppression in PA compared to essential hypertension (EH). In the past, aldosterone was quantified using immunoassays (IA). Liquid chromatography tandem mass spectrometry (LC-MS/MS) is increasingly used in clinical routine. We aimed at a method-specific aldosterone threshold for the diagnosis of PA during SIT and explored the diagnostic utility of steroid panel analysis.

Design

Retrospective cohort study of 187 paired SIT samples (2009–2018). Diagnosis of PA (n = 103) and EH (n = 84) was established based on clinical routine workup without using LC-MS/MS values.

Setting

Tertiary care center.

Methods

LC-MS/MS using a commercial steroid panel. Receiver operator characteristics analysis was used to determine method-specific cut-offs using a positive predictive value (PPV) of 90% as criterion.

Results

Aldosterone measured by IA was on average 31 ng/L higher than with LC-MS/MS. The cut-offs for PA confirmation were 54 ng/L for IA (sensitivity: 95%, 95% CI: 89.0–98.4; specificity: 87%, 95% CI: 77.8–93.3; area under the curve (AUC): 0.955, 95% CI: 0.924–0.986; PPV: 90%, 95% CI: 83.7–93.9) and 69 ng/L for LC-MS/MS (79%, 95% CI: 69.5–86.1; 89%, 95% CI: 80.6–95.0; 0.902, 95% CI: 0.857–0.947; 90%, 95% CI: 82.8–94.4). Other steroids did not improve SIT.

Conclusions

Aldosterone quantification with LC-MS/MS and IA yields comparable SIT-cut-offs. Lower AUC for LC-MS/MS is likely due to the spectrum of disease in PA and previous decision making based on IA results. Until data of a prospective trial with clinical endpoints are available, the suggested cut-off can be used in clinical routine.

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Hao Jin, Weidong Lin, Ligong Lu, and Min Cui

Objective

The complications and treatment effects of conventional thyroidectomy and thyroid thermal ablation should be compared in order to identify the best intervention for patients with benign thyroid nodules.

Methods

Patients (18–50 years old) who had benign thyroid nodules and were eligible for both thyroidectomy and thyroid thermal ablation were randomly allocated (1:1) to either conventional thyroidectomy group or thyroid thermal ablation group. Patients’ satisfaction and condition-specific quality of life were measured with the Thyroid-Specific Quality-of-Life Questionnaire Scale (QoL) at the 15th post-randomization month and were set as the co-primary outcome.

Results

A total of 450 patients were enrolled and randomized (225 patients in each group). At the 15th month after randomization, more patients in the thyroid thermal ablation group were satisfied with the treatment effects compared to those in the conventional thyroidectomy group. More patients in the thyroid thermal ablation group have a QoL score of 410 (QOL scores ranges from 0 to 410) than patients in conventional thyroidectomy. Eight (4%) of the 209 patients in conventional thyroidectomy group and 6 (3%) of the 208 patients in thyroid thermal ablation group had at least one severe postoperative complication. The time to achieve volume reduction was longer in the thermal ablation group.

Conclusion

Thyroid thermal ablation is superior to conventional thyroidectomy in terms of patients satisfaction, post-operative quality of life, and shorter hospital stay but takes longer to achieve BTNs volume reduction. The complication rates between the two groups were similar.

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Martin Reincke, Adriana Albani, Guillaume Assie, Irina Bancos, Thierry Brue, Michael Buchfelder, Olivier Chabre, Filippo Ceccato, Andrea Daniele, Mario Detomas, Guido Di Dalmazi, Atanaska Elenkova, James Findling, Ashley B. Grossman, Celso E Gomez-Sanchez, Anthony P Heaney, Juergen Honegger, Niki Karavitaki, Andre Lacroix, Edward R Laws, Marco Losa, Masanori Murakami, John Newell-Price, Francesca Pecori Giraldi, Luis G. Pérez‐Rivas, Rosario Pivonello, William E Rainey, Silviu Sbiera, Jochen Schopohl, Constantine A Stratakis, Marily Theodoropoulou, Elisabeth F.C. van Rossum, Elena Valassi, Sabina Zacharieva, German Rubinstein, and Katrin Ritzel

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

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

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

CONCLUSIONS: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.

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Maxim S Petrov and Marina Basina

Diabetes in the setting of diseases of the exocrine pancreas has long existed as a known, but underdiagnosed or misdiagnosed, disorder. It currently finds itself in a state of taxonomic dereliction and requires a long overdue refurbishment. Correct conceptualisation is a key precondition for knowledge development in this disorder. This article lays out the epistemiological foundation for diabetes of the exocrine pancreas (DEP) and presents a synthesis of the current interdisciplinary discourse on diagnosing and classifying DEP. The diagnosis of DEP is generally based on the most up-to-date biochemical criteria endorsed by the American Diabetes Association and European Association for the Study of Diabetes. The presence of exocrine pancreatic dysfunction is not considered a mandatory diagnostic criterion for DEP but is rather a significant risk factor for developing DEP. DEP principally comprises post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes, which are mutually exclusive with autoimmune diabetes and type 2 diabetes. Other exclusions and stipulations apply. The DEP criteria will be instrumental in aiding optimal design and conduct of clinical studies, uniform collection of health utilisation data, meaningful comparison of scientific findings across countries, and clear communication among stakeholders (healthcare providers, patients, health regulatory authorities, pharmaceutical industry).

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Maxim S Petrov

While most people with diabetes have type 2 disease, a non-negligible minority develops a secondary diabetes. Post-pancreatitis diabetes mellitus (PPDM) is an exemplar secondary diabetes that represents a sequela of pancreatitis - the most common disease of the exocrine pancreas. Although this type of diabetes has been known as a clinical entity since the late 19th century, early 21st century high-quality epidemiological, clinical, and translational studies from around the world have amassed a sizeable body of knowledge that have led to a renewed understanding of PPDM. People have at least two-fold higher lifetime risk of developing diabetes after an attack of pancreatitis than those in the general population without history of diseases of the exocrine pancreas. PPDM is caused by acute pancreatitis (including non-necrotising pancreatitis, which constitutes the majority of acute pancreatitis) in four-fifth of cases and chronic pancreatitis in one-fifth of cases. Moreover, the frequency of incident diabetes is not considerably lower after acute pancreatitis than after chronic pancreatitis. Recurrent attacks of pancreatitis and exocrine pancreatic dysfunction portend high risk for PPDM, but are not mandatory for its development. Further, young- or middle-aged non-obese men have an increased risk of developing PPDM. In comparison with type 2 diabetes, PPDM is characterised by poorer glycaemic control, higher risk of developing cancer (in particular, pancreatic cancer), younger age at death, and higher risk of mortality. Metformin monotherapy is recommended as first-line therapy for PPDM. Appropriate screening of individuals after an attack of pancreatitis, correct identification of PPDM, and apposite management is crucial with a view to improving the outcomes of this secondary but not inappreciable disease.

Free access

A B Hansen, D Wøjdemann, C H Renault, A T Pedersen, K M Main, L L Raket, R B Jensen, and A Juul

Abstract

This review aims to cover the subject of sex steroid action in adolescence. It will include situations with too little sex steroid action, as seen in for example, Turners syndrome and androgen insensitivity issues, too much sex steroid action as seen in adolescent PCOS, CAH and gynecomastia, too late sex steroid action as seen in constitutional delay of growth and puberty and too early sex steroid action as seen in precocious puberty. This review will cover the etiology, the signs and symptoms which the clinician should be attentive to, important differential diagnoses to know and be able to distinguish, long-term health and social consequences of these hormonal disorders and the course of action with regards to medical treatment in the pediatric endocrinological department and for the general practitioner. This review also covers situations with exogenous sex steroid application for therapeutic purposes in the adolescent and young adult. This includes gender-affirming therapy in the transgender child and hormone treatment of tall statured children. It gives some background information of the cause of treatment, the patient’s motivation for medicating (or self-medicating), long-term consequences of exogenous sex steroid treatment and clinical outcome of this treatment.

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Mototsugu Nagao, Izumi Fukuda, Akira Asai, Jonathan L S Esguerra, Naomi Hizuka, Lena Eliasson, and Hitoshi Sugihara

Objective

In insulin-like growth factor II (IGF-II) producing non-islet cell tumor hypoglycemia (NICTH), high molecular weight forms of IGF-II (big IGF-II) are produced as a cause of spontaneous hypoglycemia. MicroRNA (miRNA)-483 family, encoded in an intron lesion of IGF2 gene, is suggested to be co-expressed with IGF-II. Here, we tested whether serum miR-483-5p and -3p levels are associated with the presence of big IGF-II in NICTH.

Design

Serum samples from patients who were suspected to have IGF-II producing NICTH (n = 42) were tested. MiR-483-5p and -3p levels were evaluated using quantitative PCR. IGF-II level was analyzed using ELISA. The presence of big IGF-II was identified by Western blotting.

Results

Big IGF-II was detected in the sera of 32 patients. MiR-483-5p (P = 0.0015) and -3p (P = 0.027) levels were significantly higher in sera with big IGF-II (n = 32) than in those without (n = 10), whereas serum IGF-II level (P = 0.055) was not significantly different between the groups. The median serum concentration of miR-483-5p was ~10 times higher than that of miR-483-3p. Although a strong correlation was observed between the two miRNAs (r = 0.844, P < 0.0001), but neither of which was correlated with serum IGF-II level. The areas under the receiver operating characteristic curves of miR-483-5p (0.853) and -3p (0.722) were higher than that of IGF-II (0.694) for detecting the presence of big IGF-II.

Conclusion

The associations of serum miR-483-5p and -3p levels with the presence of big IGF-II suggest the diagnostic potential of these miRNAs for IGF-II producing NICTH.