Characteristics of Patients Lost to Follow-up after Bariatric Surgery

After bariatric surgery lifelong follow-up is recommended. Evidence of the consequences and reasons for being lost to follow-up (LTFU) is sparse. In this prospective study follow-up data of all patients who underwent bariatric surgery between 2008 and 2017 at a certified obesity centre were investigated. LTFU patients were evaluated through a structured telephone interview. Overall, 573 patients (female/male 70.9%/29.1%), aged 44.1 ± 11.2 years, preoperative BMI 52.1 ± 8.4 kg/m2 underwent bariatric surgery. Out of these, 33.2% had type 2 diabetes mellitus and 74.4% had arterial hypertension. A total of 290 patients were LTFU, of those 82.1% could be reached. Baseline characteristics of patients in follow-up (IFU) and LTFU were comparable, but men were more often LTFU (p = 0.01). Reported postoperative total weight loss (%TWL) and improvements of comorbidities were comparable, but %TWL was higher in patients remaining in follow-up for at least 2 years (p = 0.013). Travel issues were mentioned as the main reason for being LTFU. A percentage of 77.6% of patients reported to regularly supplement micronutrients, while 71.0% stated regular monitoring of their micronutrient status, mostly by primary care physicians. Despite comparable reported outcomes of LTFU to IFU patients, the duration of the in-centre follow-up period affected %TWL. There is a lack of sufficient supplementation and monitoring of micronutrients in a considerable number of LTFU patients

Effect of mild cortisol cosecretion on body composition and metabolic parameters in patients with primary hyperaldosteronism

Objective To investigate the effects of simultaneous cortisol cosecretion (CCS) on body composition in computed tomography (CT)-imaging and metabolic parameters in patients with primary aldosteronism (PA) with the objective of facilitating early detection. Design Retrospective cohort study. Patients Forty-seven patients with PA and CCS confirmed by 1-mg dexamethasone suppression test (DST) with a cutoff of ≥1.8 µg/dL were compared with PA patients with excluded CCS (non-CCS, n = 47) matched by age and sex. Methods Segmentation of the fat compartments and muscle area at the third lumbar region was performed on non-contrast-enhanced CT images with dedicated segmentation software. Additionally, liver, spleen, pancreas and muscle attenuation were compared between the two groups. Results Mean cortisol after DST was 1.2 µg/dL (33.1 nmol/L) in the non-CCS group and 3.2 µg/dL (88.3 nmol/L) in the CCS group with mild autonomous cortisol excess (MACE). No difference in total, visceral and subcutaneous fat volumes was observed between the CCS and non-CCS group (p = .7, .6 and .8, respectively). However, a multivariable regression analysis revealed a significant correlation between total serum cholesterol and results of serum cortisol after 1-mg DST (p = .026). Classification of the patients based on visible lesion on CT and PA-lateralization via adrenal venous sampling also did not show any significant differences in body composition. Conclusion MACE in PA patients does not translate into body composition changes on CT-imaging. Therefore, early detection of concurrent CCS in PA is currently only attainable through biochemical tests. Further investigation of the long-term clinical adverse effects of MACE in PA is necessary

Disruptive effects of plasticizers bisphenol A, F, and S on steroidogenesis of adrenocortical cells

IntroductionEndocrine disrupting chemicals (EDCs) are known to interfere with endocrine homeostasis. Their impact on the adrenal cortex and steroidogenesis has not yet been sufficiently elucidated. This applies in particular to the ubiquitously available bisphenols A (BPA), F (BPF), and S (BPS).MethodsNCI-H295R adrenocortical cells were exposed to different concentrations (1nM-1mM) of BPA, BPF, BPS, and an equimolar mixture of them (BPmix). After 72 hours, 15 endogenous steroids were measured using LC-MS/MS. Ratios of substrate and product of CYP-regulated steps were calculated to identify most influenced steps of steroidogenesis. mRNA expression of steroidogenic enzymes was determined by real-time PCR.ResultsCell viability remained unaffected at bisphenol concentrations lower than 250 µM. All tested bisphenols and their combination led to extensive alterations in the quantified steroid levels. The most profound fold changes (FC) in steroid concentrations after exposure to BPA (>10µM) were seen for androstenedione, e.g. a 0.37±0.11-fold decrease at 25µM (p≤0.0001) compared to vehicle-treated controls. For BPF, levels of 17-hydroxyprogesterone were significantly increased by 25µM (FC 2.57±0.49, p≤0.001) and 50µM (FC 2.65±0.61, p≤0.0001). BPS treatment led to a dose-dependent decrease of 11-deoxycorticosterone at >1µM (e.g. FC 0.24±0.14, p≤0.0001 at 10µM). However, when combining all three bisphenols, additive effects were detected: e.g. 11-deoxycortisosterone was decreased at doses >10µM (FC 0.27±0.04, p≤0.0001, at 25µM), whereas 21-deoxycortisol was increased by 2.92±0.20 (p≤0.01) at 10µM, and by 3.21±0.45 (p≤0.001) at 50µM. While every measured androgen (DHEA, DHEAS, androstenedione, testosterone, DHT) was lowered in all experiments, estradiol levels were significantly increased by BPA, BPF, BPS, and BPmix (e.g. FC 3.60±0.54, p≤0.0001 at 100µM BPF). Calculated substrate-product ratios indicated an inhibition of CYP17A1-, and CYP21A2 mediated conversions, whereas CYP11B1 and CYP19A1 showed higher activity in the presence of bisphenols. Based on these findings, most relevant mRNA expression of CYP genes were analysed. mRNA levels of StAR, CYP11B1, and CYP17A1 were significantly increased by BPF, BPS, and BPmix.DiscussionIn cell culture, bisphenols interfere with steroidogenesis at non-cytotoxic levels, leading to compound-specific patterns of significantly altered hormone levels. These results justify and call for additional in-vivo studies to evaluate effects of EDCs on adrenal gland functionality

Metabolic heterogeneity in adrenocortical carcinoma impacts patient outcomes

Spatially resolved metabolomics enables the investigation of tumoral metabolites in situ. Inter- and intratumor heterogeneity are key factors associated with patient outcomes. Adrenocortical carcinoma (ACC) is an exceedingly rare tumor associated with poor survival. Its clinical prognosis is highly variable, but the contributions of tumor metabolic heterogeneity have not been investigated thus far to our knowledge. An in-depth understanding of tumor heterogeneity requires molecular feature-based identification of tumor subpopulations associated with tumor aggressiveness. Here, using spatial metabolomics by high-mass resolution MALDI Fourier transform ion cyclotron resonance mass spectrometry imaging, we assessed metabolic heterogeneity by de novo discovery of metabolic subpopulations and Simpson's diversity index. After identification of tumor subpopulations in 72 patients with ACC, we additionally performed a comparison with 25 tissue sections of normal adrenal cortex to identify their common and unique metabolic subpopulations. We observed variability of ACC tumor heterogeneity and correlation of high metabolic heterogeneity with worse clinical outcome. Moreover, we identified tumor subpopulations that served as independent prognostic factors and, furthermore, discovered 4 associated anticancer drug action pathways. Our research may facilitate comprehensive understanding of the biological implications of tumor subpopulations in ACC and showed that metabolic heterogeneity might impact chemotherapy

What Is the Optimal Duration of Adjuvant Mitotane Therapy in Adrenocortical Carcinoma? An Unanswered Question

A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence

Responses to systemic therapy in metastatic pheochromocytoma/paraganglioma: a retrospective multicenter cohort study

OBJECTIVE The therapeutic options for metastatic pheochromocytomas/paragangliomas (mPPGLs) include chemotherapy with cyclophosphamide/vincristine/dacarbazine (CVD), temozolomide monotherapy, radionuclide therapies, and tyrosine kinase inhibitors such as sunitinib. The objective of this multicenter retrospective study was to evaluate and compare the responses of mPPGLs including those with pathogenic variants in succinate dehydrogenase subunit B (SDHB), to different systemic treatments. DESIGN This is a retrospective analysis of treatment responses of mPPGL patients (n = 74) to systemic therapies. METHODS Patients with mPPGLs treated at 6 specialized national centers were selected based on participation in the ENSAT registry. Survival until detected progression (SDP) and disease-control rates (DCRs) at 3 months were evaluated based on imaging reports. RESULTS For the group of patients with progressive disease at baseline (83.8% of 74 patients), the DCR with first-line CVD chemotherapy was 75.0% (n = 4, SDP 11 months; SDHB [n = 1]: DCR 100%, SDP 30 months), with somatostatin peptide receptor-based radionuclide therapy (PPRT) 85.7% (n = 21, SDP 17 months; SDHB [n = 10]: DCR 100%, SDP 14 months), with 131I-meta-iodobenzylguanidine (131I-MIBG) 82.6% (n = 23, SDP 43 months; SDHB [n = 4]: DCR 100%, SDP 24 months), with sunitinib 100% (n = 7, SDP 18 months; SDHB [n = 3]: DCR 100%, SDP 18 months), and with somatostatin analogs 100% (n = 4, SDP not reached). The DCR with temozolomide as second-line therapy was 60.0% (n = 5, SDP 10 months; SDHB [n = 4]: DCR 75%, SDP 10 months). CONCLUSIONS We demonstrate in a real-life clinical setting that all current therapies show reasonable efficacy in preventing disease progression, and this is equally true for patients with germline SDHB mutations

New CHARMM force field parameters for dehydrated amino acid residues, the key to lantibiotic molecular dynamics simulations

Lantibiotics are an important class of naturally occurring antimicrobial peptides containing unusual dehydrated amino acid residues. In order to enable molecular dynamics simulations of lantibiotics, we have developed empirical force field parameters for dehydroalanine and dehydrobutyrine, which are compatible with the CHARMM all-atom force field. The parameters reproduce the geometries and energy barriers from MP2/6-31G*//MP2/cc-pVTZ quantum chemistry calculations. Experimental, predicted and calculated NMR chemical shifts for the amino protons and alpha-, beta- and carbonyl carbon atoms of the dehydrated residues are consistent with a significant charge redistribution. The new parameters are used to perform the first molecular dynamics simulations of nisin, a widely used but poorly understood lantibiotic, in an aqueous environment and in a phospholipid bilayer. The simulations show surface association of the peptide with membranes in agreement with solid state NMR data and formation of beta-turns in agreement with solution NMR

Effects of different environmental conditions on phenotype and gene expression in the mouse model

In zahlreichen Untersuchungen konnte gezeigt werden, dass Umweltbedingungen im frühen Lebensalter einerseits die Entwicklung von Resilienz, d.h. Widerstandsfähigkeit gegenüber Stressoren, andererseits aber auch die Entwicklung physischer und psychischer Erkrankungen im weiteren Lebensverlauf beeinflussen können. Dabei wird angenommen, dass sich sowohl dezidiert positive als auch in Maßen aversive Umweltbedingungen mit rezidivierender Stressbelastung günstig auf die Resilienz im späteren Leben auswirken können. Auf neurobiologischer Ebene scheinen dabei das CRH und seine Rezeptoren (CRHR1 und CRHR2), das NPY-System sowie das NPS-System (insbesondere NPS-Rezeptor) eine besondere Rolle zu spielen. Jedoch sind die exakten Zusammenhänge und neurobiologischen Grundlagen weiterhin nur unzureichend aufgeklärt. Dies ist insbesondere insofern bedauernswert, da weiterer Erkenntnisgewinn auf diesem Gebiet möglicherweise Präventionsstrategien und Therapieoptionen für den Menschen begründen könnte. Um die Auswirkung der Umweltbedingungen im frühkindlichen Lebensalter auf die Resilienz im späteren Leben weiter aufzuklären, wurden im Rahmen dieser Arbeit insgesamt 310 Cd1-Mäuse den Haltungsbedingungen "Environmental Enrichment" (EE, Stimulation durch Spielobjekte) und "Maternal separation" (MS, wiederholte Stressbelastung durch Separation der Nachkommen vom Muttertier) sowie Standardhaltungsbedingungen unterworfen. Insgesamt 31 männlichen Tieren wurde im Alter von vier Wochen die Gehirne entnommen und aus diesen jeweils die Regionen Frontalcortex, Striatum, Nucleus accumbens, Hippocampus, Amygdala, dorsale Nuclei raphes und Hypothalamus herauspräpariert. Aus den gewonnenen Proben wurde RNA extrahiert, hieraus cDNA synthetisiert und abschließend - nach Ausschluss von Kontamination und Integritätsprüfung - die Expressionsraten der untersuchten Gene mittels RT-qPCR quantifiziert. Um auch verhaltensbiologische Konsequenzen der unterschiedlichen Haltungsbedingungen zu erfassen, wurden außerdem 30 weibliche sowie 30 männliche Tiere im weiteren Lebensverlauf verschiedenen Verhaltenstests zugeführt. In den Sucrose-Präferenz-Tests zeigten sich Effekte der Haltungsbedingung auf Sucrose-Konsum und Präferenz mit signifikant geringeren Werten der Haltungsgruppe EE. Bei der Auswertung der Openfield-Tests fanden sich Gruppen-Geschlechter-Interaktionseffekte mit signifikant geringeren Werten (Gesamtstrecke, Strecke und Aufenthaltsdauer im zentralen Bereich, Eintritte in den zentralen Bereich) der weiblichen EE-Tiere. In den Barnes Maze-Tests benötigten die Tiere der Haltungsgruppe EE an den meisten Testtagen signifikant weniger Zeit, um in die Escape-Box zu "entkommen". Auf neurobiologischer Ebene fanden sich signifikante Unterschiede der CRH-Expressionsraten in Amygdalae und Frontalcortex, der CRHR 1-Expressionsraten in Amygdalae und Hypothalamus sowie der CRHR2-Expressionsraten in Amygdalae und Hippocampus. Demgegenüber konnte kein signifikanter Effekt der Haltungsbedingung auf das NPY-System gefunden werden. Jedoch ließen sich signifikante Unterschiede der NPSR1-Expressionsraten in Amygdalae, Frontalcortex, dorsalen Nuclei raphes und Hypothalamus feststellen. Es kann also grundsätzlich von Auswirkungen unterschiedlich aversiver Haltungsbedingungen auf die Stress-Resilienz von Versuchstieren ausgegangen werden. Dies ist einerseits für Tierversuche allgemein von grundsätzlicher Bedeutung. Andererseits legen die Resultate eine entsprechende frühkindliche "Programmierung" auch im Menschen nahe.Chronic stress leads to several somatic and psychiatric diseases. Especially chronic stress in early stages of life predisposes to psychiatric disease in later life due to plasticity and therefore adaptability of the human brain in early life. On the other side repeated stress as well as decidedly positive conditions in early life potentially lead to resilience against stressors in later life. Data from animal studies suggest both options. Further insight into this matter could establish new prevention strategies in humans. The aim of this paper was to further examine the consequences of repeated stress on behaviour and gene expression in later life compared to decidedly positive conditions in a mouse model. Several genes, which play a role in stress processing, were examined, the CRH system, the NPY system and the NPS receptor. We found several effects of repeated stress vs. decidedly positive conditions in early life on behaviour and gene expression in later life, which were unfortunately not consistent. Further studies should be undertaken to gain further insight into this matter

Metyrapone versus osilodrostat in the short-term therapy of endogenous Cushing’s syndrome: results from a single center cohort study

Background Although surgery is considered the first-line treatment for patients with endogenous Cushing’s syndrome (CS), medical therapy is often required to control severe hypercortisolism. Metyrapone and osilodrostat are both steroidogenic inhibitors targeting the 11β-hydroxylase, however, their therapeutic effectiveness has not yet been directly compared. This study aimed to evaluate metyrapone and osilodrostat in the short-term therapy of CS. Methods Retrospective analysis of patients with endogenous CS treated with metyrapone or osilodrostat as monotherapy for at least 4 weeks. Main outcome measures were serum cortisol and 24h urinary free cortisol (UFC) at baseline (T0) and after 2 (T1), 4 (T2), and 12 weeks (T3) of therapy. Results 16 patients with endogenous CS were identified (pituitary n=7, adrenal n=4, ectopic CS n=5). Each 8 patients were treated with metyrapone and osilodrostat. Despite heterogeneity, both groups showed comparable mean UFC levels at T0 (metyrapone: 758 µg/24h vs osilodrostat: 817 µg/24h; p=0.93). From T0 to T1, the decrease of UFC was less pronounced under metyrapone than osilodrostat (-21.3% vs -68.4%; median daily drug dose: 1000 mg vs 4 mg). This tendency persisted at T2 (-37.3% vs -50.1%; median drug dose: 1250 mg vs 6 mg) while at T3 a decrease in UFC from T0 was more pronounced in the metyrapone group (-71.5% vs -51.5%; median dose 1250 mg vs 7 mg). Under osilodrostat, a QTc-interval prolongation was identified at T3 (mean 432 ms vs 455 ms). From T0 to T2, the number of antihypertensive drugs remained comparable under metyrapone and decreased under osilodrostat (n= -0.3 vs n= -1.0). Conclusion Although both drugs show comparable therapeutic efficacy, osilodrostat seems to reduce cortisol levels and to control blood pressure faster