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Open access

Shilpa Lingaiah, Laure Morin-Papunen, Terhi Piltonen, Inger Sundström-Poromaa, Elisabeth Stener-Victorin and Juha S. Tapanainen

Objective: Serum levels of retinol-binding protein 4 (RBP4), an adipokine thought to effect systemic insulin sensitivity, were compared between women with polycystic ovary syndrome (PCOS) and non-PCOS controls to evaluate the association of RBP4 with clinical, hormonal and metabolic parameters of PCOS.

Subjects and methods: Serum RBP4 levels were analysed in 278 women with PCOS (age range 18–57 years) and 191 non-PCOS controls (age 20–53 years) by enzyme-linked immunosorbent assay.

Results: Serum levels of RBP4 were increased in women with PCOS compared with control women in the whole population (45.1 ± 24.0 (SD) vs. 33.5 ± 18.3 mg/L, p<0.001). Age-stratified analysis showed that serum RBP4 levels were increased in women with PCOS aged ≤ 30 years compared with controls (47.7 ± 23.5 vs. 27.1 ± 10.4 mg/L, p<0.001), whereas no significant differences were seen in the other age groups. No significant correlations of RBP4 were seen with either steroids or indices of insulin resistance.

Conclusions: Although serum RBP4 levels were increased in younger women with PCOS compared with age-matched non-PCOS controls, RBP4 does not seem to be a good marker of insulin resistance or other metabolic derangements in women with PCOS.

Open access

Barbora Pekova, Sarka Dvorakova, Vlasta Sykorova, Gabriela Vacinova, Eliska Vaclavikova, Jitka Moravcova, Rami Katra, Petr Vlcek, Pavla Sykorova, Daniela Kodetova, Josef Včelák and Bela Bendlova

Thyroid nodules of pediatric patients occur with rising incidence. Most of them are benign tissues, but part of them represents papillary thyroid cancer (PTC). The aim of this study was to detect mutations in commonly investigated genes as well as in novel PTC-causing genes in thyroid nodules and to correlate found mutations with clinical and pathological data. The cohort of 113 pediatric samples consisted of 30 benign lesions and 83 PTCs. DNA from samples was used for next generation sequencing to identify mutations in genes: HRAS, KRAS, NRAS, BRAF, IDH1, CHEK2, PPM1D, EIF1AX, EZH1 and for capillary sequencing in case of the TERT promoter. RNA was used for Real Time PCR to detect RET/PTC1 and RET/PTC3 rearrangements. Total detection rate of mutations was 5/30 in benign tissues and 35/83 in PTCs. Mutations in RAS genes (HRAS G13R, KRAS G12D, KRAS Q61R, NRAS Q61R) were detected in benign lesions and HRAS Q61R, NRAS Q61K mutations in PTCs. The RET/PTC rearrangement was identified in 18/83 of PTCs and was significantly associated with higher frequency of local and distant metastases. The BRAF V600E mutation was identified in 15/83 of PTCs and significantly correlated with higher age of patients and classical variant of PTC. Germline variants in the genes IDH1, CHEK2 and PPM1D were found. In conclusion, RET/PTC rearrangements and BRAF mutations were associated with the different clinical and histopathological features in pediatric PTC. RAS mutations were detected with high frequency in patients with benign nodules, thus our results suggest that these patients should be intensively followed.

Open access

Aneta Gawlik, Mishael Shmoish, Michaela F Hartmann, Stefan A Wudy, Zbigniew Olczak, Katarzyna Gruszczynska and Ze'ev Hochberg

Objective: Analysis of steroids by gas chromatography-mass spectrometry (GC-MS) defines a subject’s steroidal fingerprint. Here, we compare the steroidal fingerprints of obese children with or without liver disease to identify the ’steroid metabolomic signature’ of childhood non-alcoholic fatty liver disease.

Methods: Urinary samples of 85 children age 8.5-18.0 with BMI>97% were quantified for 31 steroid metabolites by GC-MS. The fingerprints of 21 children with liver disease (L1) as assessed by sonographic steatosis (L1L), elevated alanine aminotransferases (L1A) or both (L1AL), were compared to 64 children without markers of liver disease (L0). The steroidal signature of the liver disease was generated as the difference in profiles of L1 against L0 groups.

Results: L1 comparing to L0 presented higher fasting triglycerides (p=0.004), insulin (p=0.002), INS/GLU (p=0.003), HOMA-IR (p=0.002), GGTP (p=0.006), AST/SGOT (p=0.002), postprandial glucose (p=0.001) and insulin (p=0.011). L1AL showed highest level of T-cholesterol and triglycerides (p=0.029; p=0.044). Fasting insulin, postprandial glucose, INS/GLU and HOMA-IR were highest in L1L and L1AL (p=0.001; p=0.017; p=0.001; p=0.001). The liver disease steroidal signature was marked by lower DHEA and its metabolites, higher glucocorticoids (mostly tetrahydrocortisone) and lower mineralocorticoid metabolites than L0. L1 patients showed higher 5α-reductase and 21-hydroxylase activity (the highest in L1A and L1AL) and lower activity of 11βHSD1 than L0 (p=0.041, p=0.009, p=0.019).

Conclusions: The ‘steroid metabolomic signature’ of liver disease in childhood obesity provides a new approach to the diagnosis and further understanding of its metabolic consequences. It reflects the derangements of steroid metabolism in NAFLD that includes enhanced glucocorticoids and deranged androgens and mineralocorticoids.

Open access

Adrian F Daly, David A Cano, Eva Venegas-Moreno, Patrick Petrossians, Elena Dios, Emilie Castermans, Alvaro Flores-Martínez, Vincent Bours, Albert Beckers and Alfonso Soto-Moreno

Background

Pituitary adenomas have a high disease burden due to tumor growth/invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset of aggressive pituitary adenomas that can be resistant to medical therapy.

Aims

We performed a retrospective screening study using published risk criteria to assess the frequency of AIP and MEN1 mutations in pituitary adenoma patients in a tertiary referral center.

Methods

Pituitary adenoma patients with pediatric/adolescent onset, macroadenomas occurring ≤30 years of age, familial isolated pituitary adenoma (FIPA) kindreds and acromegaly or prolactinoma cases that were uncontrolled by medical therapy were studied genetically. We also assessed whether immunohistochemical staining for AIP (AIP-IHC) in somatotropinomas was associated with somatostatin analogs (SSA) response.

Results

Fifty-five patients met the study criteria and underwent genetic screening for AIP/MEN1 mutations. No mutations were identified and large deletions/duplications were ruled out using MLPA. In a cohort of sporadic somatotropinomas, low AIP-IHC tumors were significantly larger (P = 0.002) and were more frequently sparsely granulated (P = 0.046) than high AIP-IHC tumors. No significant relationship between AIP-IHC and SSA responses was seen.

Conclusions

Germline mutations in AIP/MEN1 in pituitary adenoma patients are rare and the use of general risk criteria did not identify cases in a large tertiary-referral setting. In acromegaly, low AIP-IHC was related to larger tumor size and more frequent sparsely granulated subtype but no relationship with SSA responsiveness was seen. The genetics of pituitary adenomas remains largely unexplained and AIP screening criteria could be significantly refined to focus on large, aggressive tumors in young patients.

Open access

Adrian F Daly, Liliya Rostomyan, Daniela Betea, Jean-François Bonneville, Chiara Villa, Natalia S Pellegata, Beatrice Waser, Jean-Claude Reubi, Catherine Waeber Stephan, Emanuel Christ and Albert Beckers

Acromegaly is a rare disease due to chronic excess growth hormone (GH) and IGF-1. Aryl hydrocarbon receptor interacting protein (AIP) mutations are associated with an aggressive, inheritable form of acromegaly that responds poorly to SST2-specific somatostatin analogs (SSA). The role of pasireotide, an SSA with affinity for multiple SSTs, in patients with AIP mutations has not been reported. We studied two AIP mutation positive acromegaly patients with early-onset, invasive macroadenomas and inoperable residues after neurosurgery. Patient 1 came from a FIPA kindred and had uncontrolled GH/IGF-1 throughout 10 years of octreotide/lanreotide treatment. When switched to pasireotide LAR, he rapidly experienced hormonal control which was associated with marked regression of his tumor residue. Pasireotide LAR was stopped after >10 years due to low IGF-1 and he maintained hormonal control without tumor regrowth for >18 months off pasireotide LAR. Patient 2 had a pituitary adenoma diagnosed when aged 17 that was not cured by surgery. Chronic pasireotide LAR therapy produced hormonal control and marked tumor shrinkage but control was lost when switched to octreotide. Tumor immunohistochemistry showed absent AIP and SST2 staining and positive SST5. Her AIP mutation positive sister developed a 2.5 cm follicular thyroid carcinoma aged 21 with tumoral loss of heterozygosity at the AIP locus and absent AIP staining. Patients 1 and 2 required multi-modal therapy to control diabetes. On stopping pasireotide LAR after >10 years of treatment, Patient 1’s glucose metabolism returned to baseline levels. Long-term pasireotide LAR therapy can be beneficial in some AIP mutation positive acromegaly patients that are resistant to first-generation SSA.

Open access

Kosmas Daskalakis, Marina Tsoli, Anna Angelousi, Eva Kassi, Krystallenia Alexandraki, Denise Kolomodi, Gregory A Kaltsas and Anna Koumarianou

Comparisons between everolimus and sunitinib, regarding their efficacy and safety in neuroendocrine neoplasms (NENs) are scarce. We retrospectively analysed clinicopathological characteristics and outcomes in 92 patients with well-differentiated (WD) NEN of different origin (57 pancreatic NENs (PanNENs)), treated with molecular targeted therapy (MTT) with everolimus or sunitinib, first- (73:19) or second-line (sequential;12:22) for progressive disease. Disease control rates (DCR: partial response or stable disease) at first-line were higher in all patients treated with everolimus than sunitinib (64/73 vs. 12/19, P=0.012). In panNENs, DCR at first-line everolimus was 36/42 versus 9/15 with sunitinib (P=0.062). Progression-free survival (PFS) at first-line everolimus was longer than sunitinib (31 months (95%CI: 23.1-38.9) vs. 9 months (95%CI:0-18.5); log-rank P<0.0001) in the whole cohort and the subset of PanNENs (log-rank P<0.0001). Median PFS at second-line MTT was 12 months with everolimus (95%CI:4.1-19.9) vs. 13 months with sunitinib (95%CI:9.3-16.7; log-rank P=0.951). Treatment with sunitinib (HR:3.47; 95%CI: 1.5-8.3; P=0.005), Ki67>20% (HR 6.38; 95%CI 1.3-31.3; P=0.022) and prior chemotherapy (HR 2.71; 95%CI 1.2-6.3; P=0.021) were negative predictors for PFS at first-line in multivariable- and also confirmed at multi-state modelling analyses. Side-effects (SE) analysis indicated events of serious toxicities (Grades 3 and 4; n=13/85 for everolimus and n=4/41 for sunitinib). Discontinuation rate due to SE was 19% (23.5% for everolimus vs. 10% for sunitinib, P=0.065). No additive toxicity of second-line MTT was confirmed. Based on these findings, and until reliable predictors of response become available, everolimus may be preferable to sunitinib when initiating molecular targeted therapies in progressive NENs.

Open access

Vito Francic, Martin Keppel, Verena Schwetz, Christian Trummer, Marlene Pandis, Valentin Borzan, Martin Grübler, Nicolas Dominik Verheyen, Marcus E Kleber, Graciela Delgado, Angela P Moissl, Benjamin Dieplinger, Winfried Maerz, Andreas Tomaschitz, Stefan Pilz and Barbara R Obermayer-Pietsch

Objective: Cardiovascular disease manifestation and several associated surrogate markers, such as vitamin D, have shown substantial seasonal variation. A promising cardiovascular biomarker, soluble ST2 (sST2), has not been investigated in this regard - we therefore determined if systemic levels of sST2 are affected by seasonality and/or vitamin D in order to investigate their clinical interrelation and usability.

Design: sST2 levels were measured in two cohorts involving hypertensive patients at cardiovascular risk, the Styrian Vitamin D Hypertension Trial (study A; RCT design, 8 weeks 2800 IU cholecalciferol daily) and the Ludwigshafen Risk and Cardiovascular Health Study (LURIC; study B; cross-sectional design).

Methods: The effects of a vitamin D intervention on sST2 levels were determined in study A using ANCOVA, while seasonality of sST2 levels was determined in study B using ANOVA.

Results: The concentrations of sST2 remained unchanged by a vitamin D intervention in study A, with a mean treatment effect (95% confidence interval) of 0.1 (-0.6 to 0.8) ng/mL; p = 0.761), despite a rise in 25(OH)D (11.3 (9.2 to 13.5) ng/mL; p < 0.001) compared to placebo. In study B, seasonal variations were present in 25(OH)D levels in men and women with or without heart failure (p < 0.001 for all subgroups), while sST2 levels remained unaffected by the seasons in all subgroups.

Conclusions: Our study provides the first evidence that systemic sST2 levels are not interrelated with vitamin D levels or influenced by the seasons in subjects at cardiovascular risk.

Open access

Xiujuan Su, Yan Zhao, Zhijuan Cao, Yingying Yang, Tony Duan and Jing Hua

Background

The effect of isolated maternal hypothyroxinaemia (IMH) on pregnancy complications and neonatal outcomes in human beings is still controversial.

Methods

This was a retrospective cohort study based on the electronic medical register system. The records of women with a singleton pregnancy who sought antenatal examination between January 2014 and December 2015 at Shanghai First Maternity and Infant Hospital were extracted from the electronic medical records system. Thyroid-stimulating hormone (TSH), free thyroxine (fT4) and anti-thyroperoxidase autoantibody (TPO-Ab) was measured before 20 gestational weeks, and a multiple logistic regression model was used to estimate the odds ratios of pregnancy complications and neonatal outcomes between euthyroid women and those with isolated hypothyroxinaemia.

Results

A total of 8173 women were included in this study, of whom 342 (4.18%) were diagnosed with IMH. Regression analysis showed that IMH diagnosed in the second trimester (13–20 weeks) was associated with an increased risk of hypertensive disorders of pregnancy (OR = 2.66, 95% CI: 1.38–5.10) and placenta abruption (OR = 3.64, 95% CI: 1.07–12.41), but not with preterm delivery (OR = 1.09, 95% CI: 0.50–2.40), small or large gestational age of infant (OR = 0.91, 95% CI: 0.39–2.12; OR = 1.16, 95% CI: 0.72–1.86), macrosomia (OR = 1.71, 95% CI: 0.95–3.07), gestational diabetes mellitus (OR = 1.36, 95% CI: 0.86–2.15) and placenta previa (OR = 1.62, 95% CI: 0.39–7.37).

Conclusion

IMH could be a risk factor for hypertensive disorders of pregnancy.

Open access

Marko Stojanovic, Zida Wu, Craig E Stiles, Dragana Miljic, Ivan Soldatovic, Sandra Pekic, Mirjana Doknic, Milan Petakov, Vera Popovic, Christian Strasburger and Márta Korbonits

Background

Aryl hydrocarbon receptor-interacting protein (AIP) is evolutionarily conserved and expressed widely throughout the organism. Loss-of-function AIP mutations predispose to young-onset pituitary adenomas. AIP co-localizes with growth hormone in normal and tumorous somatotroph secretory vesicles. AIP protein is detectable in circulation. We aimed to investigate possible AIP and GH co-secretion, by studying serum AIP and GH levels at baseline and after GH stimulation or suppression, in GH deficiency (GHD) and in acromegaly patients.

Subjects and methods

Insulin tolerance test (ITT) was performed in GHD patients (n = 13) and age-BMI-matched normal GH axis control patients (n = 31). Oral glucose tolerance test (OGTT) was performed in active acromegaly patients (n = 26) and age-BMI-matched normal GH axis control patients (n = 18). In-house immunometric assay was developed for measuring circulating AIP.

Results

Serum AIP levels were in the 0.1 ng/mL range independently of gender, age or BMI. Baseline AIP did not differ between GHD and non-GHD or between acromegaly and patients with no acromegaly. There was no change in peak, trough or area under the curve during OGTT or ITT. Serum AIP did not correlate with GH during ITT or OGTT.

Conclusions

Human circulating serum AIP in vivo was assessed by a novel immunometric assay. AIP levels were independent of age, sex or BMI and unaffected by hypoglycaemia or hyperglycaemia. Despite co-localization in secretory vesicles, AIP and GH did not correlate at baseline or during GH stimulation or suppression tests. A platform of reliable serum AIP measurement is established for further research of its circulatory source, role and impact.

Open access

Marieke Stientje Velema, Aline de Nooijer, Ad R M M Hermus, Henri J L M Timmers, Jacques W M Lenders, Olga Husson and Jaap Deinum

Objective

To develop a primary aldosteronism (PA) disease-specific Health-Related Quality of Life (HRQoL) questionnaire.

Methods

We included newly diagnosed patients with PA (n = 26), and patients with PA after adrenalectomy (n = 25) or treated with mineralocorticoid receptor antagonists (n = 25). According to the guidelines for developing HRQoL questionnaires from the European Organization for Research and Treatment of Cancer (EORTC): Phase I: systematic literature review followed by focus group meetings with patients (n = 13) resulting in a list of 94 HRQoL issues. Relevance of issues was rated by 18 other patients and by health care professionals (n = 15), resulting in 30 remaining issues. Phase II: selected issues were converted into questions. Phase III: the provisional questionnaire was pre-tested by a third group of patients (n = 45) who also completed the EORTC core Quality of Life questionnaire (QLQ-C30). Psychometric testing resulted in a final selection of questions with their scale structure.

Results

After the collection and selection of HRQoL issues a provisional questionnaire consisting of 30 items was formed. Of these items, 26 could be assigned to one of the four scales ‘physical and mental fatigue’, ‘anxiety and stress’, ‘fluid balance’ and ‘other complaints’ cumulatively accounting for 68% of variation in all items. All scales had good reliability and validity. There was a significant correlation of all four scales with the QLQ-C30 in most cases.

Conclusions

We developed the first PA-specific HRQoL questionnaire (PA-QoL) using standard, methodologically proven guidelines. After completion of the final validation (phase IV, international field testing), the questionnaire can be implemented into clinical practice.