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Open access

Sanjeet Kumar Jaiswal, Vijaya Sarathi, Saba Samad Memon, Robin Garg, Gaurav Malhotra, Priyanka Verma, Ravikumar Shah, Manjeet Kaur Sehemby, Virendra A Patil, Swati Jadhav, Anurag Ranjan Lila, Nalini S Shah and Tushar R Bandgar

Introduction: 177Lu-DOTATATE-based peptide receptor radionuclide therapy (PRRT) is a promising therapy for metastatic and/ inoperable pheochromocytoma and paraganglioma (PPGL). We aim to evaluate the efficacy and safety of and identify predictors of response to 177Lu-DOTATATE therapy in metastatic and/ inoperable PPGL.

Methods: This retrospective study involved 15 patients of metastatic or unresectable PPGL, who received 177Lu-DOTATATE PRRT therapy. Clinical, biochemical (Plasma free normetanephrine), and radiological (anatomical and functional) responses were compared before and after the last therapy.

Results: A total of 15 patients PCC (4), sPGL (4), HNPGL (5), PCC+sPGL (1), HNPGL+sPGL (1) were included. The median duration of follow up was 27 (range: 11-62) months from the start of PRRT. Based on the RECIST (1.1) criteria, progressive disease was seen in three (20%), stable disease in eight (53 %), partial response in one (7%), and minor response in three (20%) and controlled disease in 12 (80%). On linear regression analysis presence of PGL (p= 0.044) and baseline SUVmax >21 (p < 0.0001) were significant positive predictors of early response to PRRT. Encouraging safety profiles were noted with no long term nephrotoxicity and haematotoxicity.

Conclusion: 177Lu-DOTATATE therapy is an effective and safe modality of treatment for patients with metastatic/inoperable PPGL. Although it is not prudent to withhold PRRT in metastatic PPGL with baseline SUVmax < 21, baseline SUVmax >21 can be used to predict early response to PRRT.

Open access

Roland Därr, Jonas Kater, Peggy Sekula, Birke Bausch, Tobias Krauss, Christoph Bode, Gerd Walz, Hartmut P H Neumann and Stefan Zschiedrich

The optimal treatment strategy for patients with small non-functioning VHL-related incidentalomas is unclear. We searched the Freiburg VHL registry for patients with radiologic evidence of pheochromocytoma/paraganglioma (PHEO/PGL). 176 patients with single, multiple, and recurrent tumors were identified (1.84 tumors/patient, range 1-8). Mean age at diagnosis was 32±16 years. 74% of tumors were localized to the adrenals. Mean tumor diameter was 2.42±2.27 cm, 46% were <1.5 cm. 24% of tumors were biochemically inactive. Inactive tumors were significantly smaller than active PHEO/PGL at diagnosis (4.16±2.80 cm vs. 1.43±0.45 cm; p<0.025) and before surgery (4.89±3.47 cm vs. 1.36±0.43 cm; p<0.02). Disease was stable in 67% of 21 patients with evaluable tumors ≤1.5 cm according to RECIST and progressed in 7. Time till surgery in these patients was 29.5±20.0 months. 155 patients underwent surgery. PHEO/PGL was histologically excluded in 4 and proven in 151. Of these one had additional metastatic disease, one harboured another tumor of a different type, and in 2 a second surgery for suspected disease recurrence did not confirm PHEO/PGL. Logistic regression analysis revealed 50% probability for a positive/negative biochemical test result at 1.8 cm tumor diameter. Values of a novel symptom score were positively correlated with tumor size (Rs 0.46, p<0.0001) and together with a positive biochemistry a linear size predictor (p<0.01). Results support standardized clinical assessment and measurement of tumor size and metanephrines in VHL patients non-functioning incidentalomas <1.5 cm at one year following diagnosis and at individualized intervals thereafter depending on evolving growth dynamics, secretory activity and symptomatology.

Open access

Helle Keinicke, Gao Sun, Caroline M Junker Mentzel, Merete Fredholm, Linu Mary John, Birgitte Andersen, Kirsten Raun and Marina Kjaergaard

The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased dramatically worldwide and, subsequently, also the risk of developing non-alcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis and cancer. Today, weight loss is the only available treatment, but administration of fibroblast growth factor 21 (FGF21) analogues have, in addition to weight loss, shown improvements on liver metabolic health but the mechanisms behind are not entirely clear. The aim of this study was to investigate the hepatic metabolic profile in response to FGF21 treatment. Diet-induced obese (DIO) mice were treated with s.c. administration of FGF21 or subjected to caloric restriction by switching from high fat diet (HFD) to chow to induce 20% weight loss and changes were compared to vehicle dosed DIO mice. Cumulative caloric intake was reduced by chow, while no differences were observed between FGF21 and vehicle dosed mice. The body weight loss in both treatment groups was associated with reduced body fat mass and hepatic triglycerides (TG), while hepatic cholesterol was slightly decreased by chow. Liver glycogen was decreased by FGF21 and increased by chow. The hepatic gene expression profiles suggest that FGF21 increased uptake of fatty acids and lipoproteins, channeled TGs toward the production of cholesterol and bile acid, reduced lipogenesis and increased hepatic glucose output. Furthermore, FGF21 appeared to reduce inflammation and regulate hepatic leptin receptor-a expression. In conclusion, FGF21 affected several metabolic pathways to reduce hepatic steatosis and improve hepatic health and markedly more genes than diet restriction (61 vs 16 out of 89 investigated genes).

Open access

Mai Morsi, Torben Schulze, Eike Früh, Dennis Brüning, Uwe Panten and Ingo Rustenbeck

Observing different kinetics of nutrient-induced insulin secretion in fresh and cultured islets under the same condition we compared parameters of stimulus secretion coupling in freshly isolated and 22-h-cultured NMRI mouse islets. Stimulation of fresh islets with 30 mM glucose after perifusion without nutrient gave a continuously ascending secretion rate. In 22-h-cultured islets the same protocol produced a brisk first phase followed by a moderately elevated plateau, a pattern regarded to be typical for mouse islets. This was also the response of cultured islets to the nutrient secretagogue alpha-ketoisocaproic acid, whereas the secretion of fresh islets increased similarly fast but remained strongly elevated. The responses of fresh and cultured islets to purely depolarizing stimuli (tolbutamide or KCl), however, were closely similar. Signs of apoptosis and necrosis were rare in both preparations. In cultured islets, the glucose-induced rise of the cytosolic Ca2+ concentration started from a lower value and was larger as was the increase of the ATP/ADP ratio. The prestimulatory level of mitochondrial reducing equivalents, expressed as the NAD(P)H/FAD fluorescence ratio, was lower in cultured islets, but increased more strongly than in fresh islets. When culture conditions were modified by replacing RPMI with Krebs–Ringer medium and FCS with BSA, the amount of released insulin varied widely, but the kinetics always showed a predominant first phase. In conclusion, the secretion kinetics of fresh mouse islets is more responsive to variations of nutrient stimulation than cultured islets. The more uniform kinetics of the latter may be caused by a different use of endogenous metabolites.

Open access

Kristian Almstrup, Hanne Frederiksen, Anna-Maria Andersson and Anders Juul

Puberty marks a transition period, which leads to the attainment of adult sexual maturity. Timing of puberty is a strongly heritable trait. However, large genetic association studies can only explain a fraction of the observed variability and striking secular trends suggest that lifestyle and/or environmental factors are important. Using liquid-chromatography tandem-mass-spectrometry, we measured endocrine disrupting chemicals (EDCs; triclosan, bisphenol A, benzophenone-3, 2,4-dichlorophenol, 11 metabolites from 5 phthalates) in longitudinal urine samples obtained biannually from peri-pubertal children included in the COPENHAGEN puberty cohort. EDC levels were associated with blood DNA methylation profiles from 31 boys and 20 girls measured both pre- and post-pubertally. We found little evidence of single methylation sites that on their own showed association with urinary excretion levels of EDCs obtained either the same day or measured as the yearly mean of dichotomized EDC levels. In contrast, methylation of several promoter regions was found to be associated with two or more EDCs, overlap with known gene-chemical interactions, and form a core network with genes known to be important for puberty. Furthermore, children with the highest yearly mean of dichotomized urinary phthalate metabolite levels were associated with higher promoter methylation of the thyroid hormone receptor interactor 6 gene (TRIP6), which again was mirrored by lower circulating TRIP6 protein levels. In general, the mean TRIP6 promoter methylation was mirrored by circulating TRIP6 protein levels. Our results provide a potential molecular mode of action of how exposure to environmental chemicals may modify pubertal development.

Open access

Shufei Zang, Lei Shi, Jinying Zhao, Min Yang, Jun Liu and Heyuan Ding

The aim of our study was to explore the diagnostic value of prealbumin to fibrinogen ratio (PFR) for predicting prognosis with the optimal cut-off value in diabetic peripheral neuropathy (DPN) patients. A total of 568 type 2 diabetes mellitus (T2DM) patients were enrolled in this study. The values including Toronto clinical neuropathy score (TCNS), nerve conduction velocity (NCV), vibration perception threshold (VPT), blood cells count, biochemical parameters, fibrinogen and PFR were recorded. The patients were divided into tertiles based on admission PFR value. Firstly, clinical parameters were compared among the groups. Secondly, a logistic regression and ROC analysis were performed as the statistical model. The percentage of DPN, TCNS and VPT were significantly higher in the lowest PFR tertile than in the middle PFR tertile and the highest PFR tertile (P<0.01-0.001). NCV was significantly lower in lowest PFR tertile than in the middle PFR tertile and the highest PFR tertile (P<0.01-0.001). The Spearman correlation analysis showed that PFR was negatively correlated with TCNS and VPT(P<0.001), while PFR was positively correlated with median motor NCV(P<0.001), peroneal motor NCV(P<0.001), median sensory NCV (P<0.001), and peroneal sensory NCV (P<0.001). After adjusting these potentially related factors, PFR was independently related to DPN (P=0.007). The area under ROC curve was 0.627. This study finds the first evidence to suggest PFR may be the key component associated with DPN in T2DM, while PFR might underlie the pathophysiologic features of DPN.

Open access

Myrian Velasco, Rosa Isela Ortiz-Huidobro, Carlos Larqué, Yuriko Itzel Sánchez-Zamora, José Romo-Yáñez and Marcia Hiriart

Objective: We assessed the sex-specific differences in the molecular mechanisms of insulin resistance in muscle and adipose tissue, in a MS rat model induced by a high sucrose diet.

Methods: Male, female, and ovariectomized female Wistar rats were randomly distributed in control and high-sucrose diet (HSD) groups, supplemented for 24 weeks with 20% sucrose in the drinking water. At the end, we assessed parameters related to MS, analyzing the effects of the HSD on critical nodes of the insulin signaling pathway in muscle and adipose tissue.

Results: At the end of treatment, HSD groups of both sexes developed obesity, with a 15%, 33% and 23% of body weight gain, in male, female, and OVX groups respectively, compared with controls; mainly related to hypertrophy of peripancreatic and gonadal adipose tissue. They also developed hypertriglyceridemia, and liver steatosis, with the last being worse in the HSD females. Compared to the control groups, HSD rats had higher IL-1β and TNFα levels and insulin resistance. HSD females were more intolerant to glucose than HSD males. Our observations suggest that insulin resistance mechanisms, include an increase in phosphorylated Akt(S473) form in HSD male and female groups, and a decrease in phosphorylated P70S6K1(T389) in the HSD male groups from peripancreatic adipose tissue. While in gonadal adipose tissue the phosphorylated form of Akt decreased in HSD females, but not in HSD males. Finally, HSD groups showed a reduction in p-Akt levels in gastrocnemius muscle.

Conclusion: A high-sucrose diet induces MS and insulin resistance with sex-associated differences and in a tissue-specific manner.

Open access

Julide Durmusoglu, Henri J. L. M. Timmers, Pepijn van Houten, Hans F. Langenhuijsen, Ad Hermus and Annenienke C. Van de Ven

Abstract

Background: Adrenocortical carcinoma is a rare malignancy with a poor prognosis. We hypothesized that patients with adrenocortical carcinoma are at high risk for venous thromboembolism, given the numerous risk factors such as malignancy, abdominal surgery, immobility and hormonal excess. The aim of this study was to determine retrospectively the incidence of venous thromboembolisms after surgical treatment in patients with adrenocortical carcinoma.

Materials and Methods: A retrospective study was performed, collecting data from all patients diagnosed with adrenocortical carcinoma from 2003 to 2018 at the Radboud University Medical Centre, The Netherlands.

Results: In 34 patients, 8 postoperative venous thromboembolisms, all pulmonary embolisms, were diagnosed in the first 6 months after adrenalectomy (23.5%). In addition, one patient developed pulmonary embolism just prior to surgery and one patient 7 years after surgery. Five of the 8 patients with postoperative venous thromboembolisms presented with symptomatic pulmonary embolism whereas the other 3 pulmonary embolisms were incidentally found on regular follow up CT scans. Seven of the 8 venous thromboembolisms occurred within 10 weeks after surgery. Seven of the 8 patients had advanced stage adrenocortical carcinoma and 4 patients already received low-molecular weight heparin during the development of the venous thromboembolism. There was one case of fatal pulmonary embolism in a patient with a cortisol producing tumor with pulmonary metastases, despite the use of a therapeutic dose thromboprophylaxis.

Conclusion: Patients with adrenocortical carcinoma are at high risk of developing postoperative venous thromboembolisms. Prolonged postoperative thromboprophylaxis could be considered in these patients.

Open access

Barbara J Boucher

Abstract.

Our knowledge of vitamin D has come a long way since the 100 years it took for doctors to accept, between 1860-1890, that both sunlight and cod liver oil [a well-known folk remedy] cured and prevented rickets.1]Vitamins D2/3 were discovered exactly a hundred years ago and over the last 50 years vitamin D has been found to have many effects on virtually all human tissues and not just on bone health, while mechanisms effecting the actions of vitamin D at the cellular level are increasingly understood, but deficiency persists globally.2 Observational studies in humans have shown that better provision of vitamin D is strongly associated, dose-wise, with reductions in current and future health risks in line with the known actions of vitamin D. Randomised controlled trials, commonly accepted as providing a ‘gold standard’ for assessing the efficacy of new forms of treatment, have frequently failed to provide supportive evidence for the expected health benefits of supplementation. Such RCTs, however, have used designs evolved for testing drugs while vitamin D is a nutrient; the appreciation of this difference is critical to identifying health benefits from existing RCT data and for improving future RCT design. This report aims, therefore, to provide a brief overview of the evidence for a range of non-bony health benefits of vitamin D repletion; to discuss specific aspects of vitamin D biology that can confound RCT design and how to allow for them

Open access

Jana Ernst, Katharina Gert, Frank Bernhard Kraus, Ulrike Elisabeth Rolle-Kampczyk, Martin Wabitsch, Faramarz Dehghani and Kristina Schaedlich

The rapid increase of obesity during the last decades and its future prospects are alarming. Besides the general discussed causes of obesity, the ‘Developmental Origins of Health and Disease’ (DOHaD) hypothesis received more attention in recent years. This hypothesis postulates an adverse influence during early development that programs the unborn child for metabolic dysfunctions later in life. Childhood obesity – an as much increasing problem – can be predisposed by maternal overweight and diabetes. Both, obesity and hyperinsulinemia are major causes of female hyperandrogenemia. As predicted by the DOHaD hypothesis and shown in animal models, developmental androgen excess can lead to metabolic abnormalities in offspring. In this study, we investigated, if androgen exposure adversely affects the adipogenic differentiation of preadipocytes and the endocrine function of adult adipocytes. The human SGBS preadipocyte model was used to affirm the de novo biosynthesis of steroid hormones under normal adipogenesis conditions. Normal adipogenesis was paralleled by an increase of corticosteroids and androgens, whereas estrogen remained at a steady level. Treatment with androstenedione had no effect on SGBS proliferation and differentiation, but adult adipocytes exhibited a significant higher accumulation of triglycerides. Progesterone (up to 2-fold), testosterone (up to 38-fold) and cortisone (up to 1.4-fold) – but not cortisol – were elevated by androstenedione administration in adult adipocytes. Estrogen was not altered. Data suggest that androgen does not negatively influence adipogenic differentiation, but steroidogenic function of SGBS adipocytes.