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Open access

Ailsa Maria Main, Maria Rossing, Line Borgwardt, Birgitte Grønkær Toft, Åse Krogh Rasmussen and Ulla Feldt-Rasmussen

Phaeochromocytomas and paragangliomas (PPGLs) are tumours of the adrenal medulla and extra-adrenal sympathetic nervous system which often secrete catecholamines. Variants of the SDHX (SDHA, -AF2, -B, -C, -D) genes are a frequent cause of familial PPGLs. In this study from a single tertiary centre we aimed to characterize the genotype-phenotype associations in patients diagnosed with germline variants in SDHX genes. We also assessed whether systematic screening of family members resulted in earlier detection of tumours. The study cohort comprised all individuals (n=59) diagnosed with a rare variant in SDHX during a thirteen-year period. Patient- and pathology records were checked for clinical characteristics and histopathological findings. We found distinct differences in the clinical and histopathological characteristics between genetic variants in SDHB. We identified two SDHB variants with distinct phenotypical patterns. Family screening for SDHB variants resulted in earlier detection of tumours in two families. Patients with SDHA, SDHC and SDHD variants also had malignant phenotypes, underlining the necessity for a broad genetic screening of the proband. Our study corroborates previous findings of poor prognostic markers and found that the genetic variants and clinical phenotype are linked and therefore useful in the decision of clinical follow-up. Regular tumour screening of carriers of pathogenic variants may lead to an earlier diagnosis and expected better prognosis. The development of a combined algorithm with clinical, genetic, morphological, and biochemical factors may be the future for improved clinical risk stratification, and forming a basis for larger multi-centre follow up studies.

Open access

Yuka Goto, Yoshie Otsuka, Kenji Ashida, Ayako Nagayama, Nao Hasuzawa, Shimpei Iwata, Kento Hara, Munehisa Tsuruta, Nobuhiko Wada, Seiichi Motomura, Yuji Tajiri and Masatoshi Nomura

Background and Aims:

It is currently unclear whether sodium–glucose co-transporter 2 (SGLT2) inhibitor administration can improve the insulin sensitivity as well as rapidly reduce plasma glucose concentrations in humans during the early phase of treatment initiation. This study aimed to investigate the effect of SGLT2 inhibitor on insulin sensitivity in the early phase of treatment initiation.

Methods and Results

This single-center, open label, and single-arm prospective study recruited 20 patients (14 men) with type 2 diabetes mellitus (T2DM). We examined the patients’ metabolic parameters before and 1 week after SGLT2 inhibitor (10 mg/day of empagliflozin) administration. The glucose infusion rate (GIR) was evaluated using the euglycemic hyperinsulinemic glucose clamp technique. Changes in laboratory and anthropometric parameters before and after SGLT2 inhibitor administration were analyzed according to the change in the GIR. The BMI, body fat amount, skeletal muscle amount, systolic blood pressure, and triglyceride level significantly decreased along with the treatment, while urinary glucose level and log GIR value significantly increased. Notably, changes in the GIR after SGLT2 inhibitor administration, which indicated improvement in peripheral insulin sensitivity, were negatively correlated with T2DM duration and positively with reduction in fluctuation of daily plasma glucose profiles before and after treatment.


SGLT2 inhibitor improved insulin sensitivity in the skeletal muscle independent of anthropometric changes. Patients with short duration of T2DM and insulin resistance can be good candidates for short-term SGLT2 inhibitor administration to improve insulin sensitivity in the skeletal muscle.

Open access

Ferdinand Roelfsema, Peter Y Liu, Rebecca Yang, Paul Takahashi and Johannes D Veldhuis


Interleukin-2 (IL-2), one of the proinflammatory cytokines, is used in the treatment of certain malignancies. In some studies, transient increases in cortisol and ACTH secretion occurred. Thus, this agent may be used as an experimental probe of adrenal cortisol secretion.


This study quantifies the effects of low and moderate doses of IL-2 on cortisol secretion and assesses the modulation by age, dose and body composition.


Mayo Clinical Translational Research Unit.


Study comprised 35 healthy men, 17 young and 18 older.


Randomized prospective double-blind saline-controlled study of IL-2 administration in two doses with concurrent 10-min blood sampling for 24 h.

Outcome measures:

Deconvolution analysis and approximate entropy of cortisol secretion.


Low-dose IL-2 administration increased nocturnal pulsatile cortisol secretion from 1460 ± 160 to 2120 ± 220 nmol/L/8 h in young subjects and from 1680 ± 105 to 1960 ± 125 nmol/L/8 h (treatment P < 0.0001, but more in young than older, P = 0.02). Comparable results were obtained for total cortisol secretion (P treatment <0.0001, age effect P = 0.005). The higher IL-2 dose caused a large increase in young (P < 0.0001), but not in older (P = 0.90) subjects. This dose also increased approximate entropy from 0.877 ± 0.041 to 1.024 ± 0.049 (P = 0.008), pointing to reduced secretory orderliness. Incremental cortisol (nocturnal) secretion correlated negatively with visceral fat mass (R = −0.41, P = 0.019).


In healthy men, IL-2 injection drives pulsatile cortisol secretion in a dose-dependent way in young, but not older, individuals and erodes cortisol secretory orderliness at a higher dose in young subjects. Cortisol responses are diminished with increasing abdominal visceral fat mass.

Open access

Anne Jouinot, Juliane Lippert, Martin Fassnacht, Bruno de La Villeon, Amandine Septier, Mario Neou, Karine Perlemoine, Silke Appenzeller, Mathilde Sibony, Sébastien Gaujoux, Bertrand Dousset, Rossella Libe, Lionel Groussin, Cristina L Ronchi, Guillaume Assié and Jérôme Bertherat


The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level.


Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n = 26), chromosome alteration profiles were determined using SNP arrays (n = 14) and methylation profiles were determined using four-gene bisulfite pyrosequencing (n = 12).


Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients, respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were ‘Noisy’ (numerous and anarchic alterations) in 8/14 and ‘Chromosomal’ (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%).


Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable and might be more robust for the prognostic assessment.

Open access

Salem A Beshyah, Khawla F. Ali and Hussein F Saadi

Introduction: Appropriate dose adjustments of glucocorticoids replacement therapy for adrenal insufficiency (AI) is vital.

Objective: We sought to scope physicians’ perceptions, and practices regarding Ramadan fasting (RF) impact on the management of AI.

Methods: A web-based survey of a convenience sample of endocrinologists.

Results: Nearly two-thirds of 145 respondents (64.1%) were adult endocrinologists and almost half (49%) saw more than 10 hypoadrenal patients per year. Most respondents (78.6%) prescribed hydrocortisone, while the minority prescribed other preparations. The glucocorticoid doses were reportedly divided twice daily by 70.8% and thrice daily by 22.2% of respondents. Respondents recognized RF as having potential consequences in adrenal insufficiency patients included causing hypoglycaemia, undue tiredness, and fatigue, hypotension, feeling dizzy, and light-headedness. Symptoms of under-replacement were thought to happen in the late afternoon by 59.3% of respondents. Almost half (45.5%) of respondents thought that RF has some probable or definite impact on glucocorticoid therapy that certainly warrants specific concern and possible action. Three quarters (76.4%) of respondents confirmed providing specific management recommendations during RF. The most frequently reported recommendation was taking in the usual morning dose of hydrocortisone just before pre-dawn meal (Suhor) (57.8%). A third switch patients from hydrocortisone to prednisolone/prednisone. Half reported providing patients with specific recommendations regarding breaking their fast and/or seeking help if hypoadrenal symptoms occur.

Conclusions: There is a remarkable variation in the physicians’ perceptions and practices regarding the management of AI during Ramadan. This warrants professional effort to increase the awareness and dissemination of evidence-based guidelines.

Open access

Lijuan Fu, Jinhuan Ma, Sumei Yan and Qijun Si

Background: Whether polymorphisms in VDR gene affect the risk of postmenopausal osteoporosis or not remain unclear. Thus, the authors performed a meta-analysis to more robustly assess associations between polymorphisms in VDR gene and the risk of postmenopausal osteoporosis by integrating the results of previous literature.

Methods: Medline, Embase, Wanfang, VIP and CNKI were searched comprehensively for eligible literatures, and sixty-seven genetic association studies were finally selected to be included in this meta-analysis.

Results: We found that ApaI rs7975232 (dominant comparison: OR = 0.77, p = 0.007; allele comparison: OR = 0.81, p = 0.04), BsmI rs1544410 (dominant comparison: OR = 0.69, p = 0.002; allele comparison: OR = 0.78, p = 0.008) and TaqI rs731236 (recessive comparison: OR = 1.32 , p = 0.01) polymorphisms were significantly associated with the risk of postmenopausal osteoporosis in Caucasians, whereas FokI rs10735810 polymorphism was significantly associated with the risk of postmenopausal osteoporosis in Asians (dominant comparison: OR = 0.61, p = 0.0001; recessive comparison: OR = 2.02, p = 0.001; allele comparison: OR = 0.68, p = 0.002).

Conclusions: This meta-analysis shows that ApaI rs7975232, BsmI rs1544410 and TaqI rs731236 polymorphisms may affect the risk of postmenopausal osteoporosis in Caucasians, while BsmI rs1544410 polymorphism may affect the risk of postmenopausal osteoporosis in Asians.

Open access

V G Pluimakers, M van Waas, C W N Looman, M P de Maat, R de Jonge, P Delhanty, M Huisman, F U S Mattace-Raso, M M van den Heuvel-Eibrink and S J C M M Neggers


Augmented survival of childhood nephroblastoma and neuroblastoma has increased long-term side effects such as metabolic syndrome (MetS). Risk stratification is difficult after abdominal radiation because waist circumference underestimates adiposity. We aimed to develop a strategy for determining MetS in irradiated survivors using an integrated biomarker profile and vascular ultrasonography.


The NCEP-ATPIII MetS-components, 14 additional serum biomarkers and 9 vascular measurements were assessed in a single-centre cohort of childhood nephroblastoma (n = 67) and neuroblastoma (n = 36) survivors and controls (n = 61). Multivariable regression models were used to study treatment effects. Principal component analysis (PCA) was used to study all biomarkers in a combined analysis, to identify patterns and correlations.


After 27.5 years of follow-up, MetS occurred more often in survivors (14%) than controls (3%). Abdominal radiotherapy and nephrectomy, to a lesser extent, were associated with MetS and separate components and with several biomarker abnormalities. PCA of biomarkers revealed a pattern on PC1 from favourable lipid markers (HDL-cholesterol, adiponectin) towards unfavourable markers (triglycerides, LDL-cholesterol, apoB, uric acid). Abdominal radiotherapy was associated with the unfavourable biomarker profile (β = 1.45, P = 0.001). Vascular measurements were not of added diagnostic value.


Long-term childhood nephro- and neuroblastoma survivors frequently develop MetS. Additional assessment of biomarkers identified in PCA – adiponectin, LDL, apoB, and uric acid – may be used especially in abdominally irradiated survivors, to classify MetS as alternative for waist circumference. Vascular ultrasonography was not of added value.

Open access

Xue-Jiao Yang, Le-Yang Zhang, Qing-Hua Ma, Hong-Peng Sun, Yong Xu, Xing Chen and Chen-Wei Pan


We aimed to examine the associations of platelet parameters with the presence of metabolic syndrome in community-dwelling older Chinese adults.


Study sample was from the Weitang Geriatric Diseases Study, which included 4338 individuals aged 60 years or above. The mean age of the participants was 68 years. Metabolic syndrome was defined based on the Adult Treatment Panel III criteria. Platelet parameters were assessed using an automated hematology analyzer. Multiple logistic regression models were fitted to examine relationships between the platelet parameters and the presence of metabolic syndrome after adjusting for potential confounders.


The adjusted odds ratio (95% CI) of metabolic syndrome for the highest quartile of platelet parameters (platelet count, mean platelet volume, plateletcrit, platelet distribution width, platelet larger cell ratio) when compared to the lowest quartile were 1.32 (1.06, 1.64), 1.00 (0.81, 1.24), 1.37 (1.10, 1.71), 1.45 (1.14, 1.83), 1.11 (0.89, 1.39), respectively. Hypertension and diabetes modified the relationship between platelet distribution width and metabolic syndrome with the associations being significant in hypertensive and non-diabetic groups. The levels of platelet distribution width increased with the risk of metabolic syndrome in men but not in women.


The levels of platelet count, plateletcrit and platelet distribution width increased in older adults with metabolic syndrome, suggesting that these parameters may be useful biomarkers for further risk appraisal of metabolic syndrome in aged population.

Open access

David T Broome, Gauri B Gadre, Ehsan Fayazzadeh, James F Bena and Christian Nasr

Objective: To identify novel prognostic risk factors and compare them with other known prognostic risk factors in follicular cell derived thyroid carcinoma (FDTC) with distant metastases.

Methods: A retrospective review was conducted of adult patients with metastatic FDTC seen at a tertiary care center between January 1990 and December 2010. A 15-year Kaplan-Meier survival estimate was created for overall survival (OS) and cancer-specific survival (CSS). Hazard ratios (HR) and P values from Cox proportional hazard models were used with a 95% confidence interval (CI).

Results: There were 143 patients (60.1% male, 39.9% female), of whom 104 (72.7%) patients had papillary, 30 (21.0%) had follicular, 5 (3.5%) had poorly differentiated, and 4 (2.8%) had Hürthle cell cancers. Median length of follow-up was 80.0 months (range 1.0-564.0). The 15-year mortality rate was 32.2% and cancer-specific mortality was 25.2%, with OS and CSS having the same risk factors. Lung was the most common site of metastases in 53 patients (37.1%), and patients with pleural effusions had significantly lower CSS (HR = 5.21, CI = 1.79-15.12). Additional risk factors for a decreased CSS included: older age upon diagnosis (>45 years, HR = 4.15, CI = 1.43-12.02), multiple metastatic locations (HR = 3.75, CI = 1.32-10.67), and incomplete/unknown tumor resection (HR = 2.35, CI = 1.18-4.67).

Conclusion: This study is the first to demonstrate that pleural effusion is a poor prognostic sign in patients with FDTC with distant metastases and compare this risk with other accepted prognostic variables.

Open access

Ya-Fen Hu, Lin Hua, Xiu Tuo, Ting-Ting Shi, Yi-Lin Yang, Yun-Fu Liu, Zhong-Yu Yan and Zhong Xin


The pathogenesis underlying the alterations of orbital architecture in Graves’ orbitopathy (GO) is not yet fully understood. The present study aimed to investigate the association of DNA methylation in peripheral blood and orbital volumetry in Chinese patients with GO.


A total of 35 GO subjects (70 orbits) were subjected to CT scan. The total cross-sectional area of the extraocular muscles (orbital muscles, OM), total orbit area (TOA), and the exophthalmometry were measured and OM/TOA ratio was calculated. Targeted bisulfite sequencing was performed on seven candidate genes.


No significant correlation was established between the DNA methylation levels of these genes and exophthalmometry. The MBP methylation level was found to be correlated with OM/TOA ratio (P < 0.05). Multiple linear regression analysis on parameters including age, sex, TRAb, duration of GO, and DNA methylation levels of seven genes with OM/TOA ratio confirmed that MBP and OM/TOA ratio had a significant correlation (P < 0.05). The partial least squares analysis showed that the top three genes with the highest loadings were MBP, BOLL, and BECN1 and that OM/TOA ratio affected the DNA methylation block than exophthalmometry.


This study provided preliminary evidence that MBP is a potential gene associated with OM enlargement in GO patients according to the combination of DNA methylation sequencing and orbital CT measurement.