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Open access

Gudmundur Johannsson, Ulla Feldt-Rasmussen, Ida Holme Håkonsson, Henrik Biering, Patrice Rodien, Shigeyuki Tahara, Andrew Toogood, Michael Højby Rasmussen and the REAL 2 Study Group

Objective

Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin®. Local tolerability and treatment satisfaction were also assessed.

Design

26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939).

Methods

Male or female patients aged 18–79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan (n = 61) or once-daily Norditropin (n = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9).

Results

Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin (P = 0.0171).

Conclusions

In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin.

Open access

Zhaoyun Zhang, Qin Li, Wenqiang He, Huijia Qiu, Hongying Ye, Yongfei Wang, Ming Shen, Min He, Yifei Yu, Xuefei Shou, Chuanxin Huang, Huan Yu, Guoqian Huang, Weijun Tang, Daoying Geng, Chaowei Fu, Congjin Liu, Zengyi Ma, Zhao Ye, Qilin Zhang, Yichao Zhang, Yue Shen, Yeping Yang, Meng Wang, Xingdang Liu, Yun Lu, Renming Hu, Ying Mao, Liangfu Zhou, Yiming Li, Shiqi Li, Nicholas A Tritos and Yao Zhao

Context

Chronic excess of growth hormone (GH) often leads to systemic complications. The reversibility of these complications after GH resolution is not fully understood.

Objective

To investigate when and to what extent will the comorbidities be ameliorated.

Design

We conducted a prospective study comprising 24 patients with acromegaly, who achieved remission after transsphenoidal surgery. The dynamic changes of endocrine, cardiovascular, respiratory, sleep, bone and morphology parameters were evaluated at enrollment and 1 week, 1 month, 3 months, 6 months and 12 months after surgery.

Results

Random GH dropped by 98.4% at the first day postoperatively. IGF-I index dropped by 50% and 64% at 1 week and 1 month respectively and remained unchanged onwards. Glucose metabolism improved significantly at 1 week and stabilized at 1 month. Testosterone in male patients recovered to normal range since 1 month. Systolic blood pressures dropped markedly at 3 months while diastolic blood pressures fell mildly at later visits. Abnormal lung function showed no improvement. The decrease of bone formation and resorption markers occurred at 1 week and 3 months, respectively. At 1 month, the tongue area declined while the airway volume increased significantly, accompanied with improved obstructive sleep apnea syndrome. Extremities, lips and nasal ala became smaller since 1 week. Liver, kidney and spleen volumes declined by 6.4, 15.9, 9.2%, respectively at 1 month. The volumes of pancreas and adrenal showed no change.

Conclusions

The rapid resolution of excessive GH led to the reversible changes of systemic comorbidities in a time-dependent and organ-specific manner.

Open access

Daniele Cassatella, Sasha R Howard, James S Acierno, Cheng Xu, Georgios E Papadakis, Federico A Santoni, Andrew A Dwyer, Sara Santini, Gerasimos P Sykiotis, Caroline Chambion, Jenny Meylan, Laura Marino, Lucie Favre, Jiankang Li, Xuanzhu Liu, Jianguo Zhang, Pierre-Marc Bouloux, Christian De Geyter, Anne De Paepe, Waljit S Dhillo, Jean-Marc Ferrara, Michael Hauschild, Mariarosaria Lang-Muritano, Johannes R Lemke, Christa Flück, Attila Nemeth, Franziska Phan-Hug, Duarte Pignatelli, Vera Popovic, Sandra Pekic, Richard Quinton, Gabor Szinnai, Dagmar l’Allemand, Daniel Konrad, Saba Sharif, Özlem Turhan Iyidir, Brian J Stevenson, Huanming Yang, Leo Dunkel and Nelly Pitteloud

Objective

Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood.

Design

We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders.

Methods

Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus).

Results

Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10−11) or controls (18%, P = 5.5 × 10−12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10−7).

Conclusions

Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.

Open access

Christian J Strasburger, Anders Mattsson, Patrick Wilton, Ferah Aydin, Judith Hey-Hadavi and Beverly M K Biller

Pegvisomant monotherapy is effective and safe in treatment of acromegaly. However, some clinicians combine pegvisomant with somatostatin analogues (SSA) or dopamine agonist (DA). In this analysis of ACROSTUDY, a long-term non-interventional study, the use of combination regimens was evaluated. Based on their baseline treatment, 2043 patients were retrospectively categorized as: long-acting SSA combined with pegvisomant, ‘Combo SSA’ 768 patients (38%); DA combined with pegvisomant, ‘Combo DA’ 123 (6%); pegvisomant monotherapy, ‘Peg mono’ 1128 (55%). Treatment patterns changed over the 10-year period, with recent patients more likely to receive any combination (20% in 2003 vs 54% in 2012). Combo SSA use varied widely among countries from 22% to 78%. Exposure periods of the three treatment modalities were defined from pegvisomant start until the last visit in ACROSTUDY; patients could switch treatment categories. At year 4, IGF-I was normal in 62% of Combo SSA, 63% of Combo DA and 65% of Peg mono groups. Pegvisomant was initiated as daily injections in 94% of patients in the Peg mono group, 66% of Combo SSA and 91% of Combo DA patients. During 6169 years of treatment exposure, 3424 adverse events (AEs) were reported in 946 (51%) patients, of which 617 (18%) were serious and 401 (12%) were considered treatment related. The reported incidence of serious AEs and treatment-related non-serious AEs were similar among the three treatment modalities. This analysis describes real-world clinical care and shows favorable efficacy and safety for Peg mono and combinations. Novel findings include an increased use of combination therapy over time and variability in treatment modalities between countries.

Open access

Eylem Levelt, Gaurav Gulsin, Stefan Neubauer and Gerry P McCann

Heart failure is a major cause of morbidity and mortality in type 2 diabetes. Type 2 diabetes contributes to the development of heart failure through a variety of mechanisms, including disease-specific myocardial structural, functional and metabolic changes. This review will focus on the contemporary contributions of state of the art non-invasive technologies to our understanding of diabetic cardiomyopathy, including data on cardiac disease phenotype, cardiac energy metabolism and energetic deficiency, ectopic and visceral adiposity, diabetic liver disease, metabolic modulation strategies and cardiovascular outcomes with new classes of glucose-lowering therapies.

Open access

Vasileios Chortis, Nicholas J Johal, Irina Bancos, Matthew Evans, Kassiani Skordilis, Peter Guest, Michael H Cullen, Emilio Porfiri and Wiebke Arlt

Mitotane (o,p′DDD) is established in the adjuvant and advanced-stage treatment of adrenocortical carcinoma and counteracts both tumor growth and tumor-related steroid production. Both the adrenal glands and the gonads are steroidogenically active organs and share a common embryogenic origin. Here, we describe the effects of mitotane in two patients with metastatic Leydig cell tumor (LCT) of the testes and associated severe androgen excess (serum testosterone 93 and 88 nmol/L, respectively; male reference range 7–27 nmol/L). Both men suffered from severe restlessness, insomnia and irritability, which they described as intolerable and disrupting normal life activities. Urinary steroid profiling by gas chromatography–mass spectrometry (GC–MS) confirmed excess androgen production and revealed concurrent overproduction of glucocorticoids and glucocorticoid precursors, which under physiological conditions are produced only by the adrenal glands but not by the gonads. In a palliative approach, they were commenced on mitotane, which achieved swift control of the hormone excess and the debilitating clinical symptoms, restoring normal quality of life. GC–MS demonstrated normalization of steroid production and decreased 5α-reductase activity, resulting in decreased androgen activation, and imaging demonstrated disease stabilization for 4–10 months. In conclusion, mitotane can be highly effective in controlling steroid excess in metastatic LCTs, with anti-tumor activity in some cases.

Open access

Marloes Nies, Bernadette L Dekker, Esther Sulkers, Gea A Huizinga, Mariëlle S Klein Hesselink, Heleen Maurice-Stam, Martha A Grootenhuis, Adrienne H Brouwers, Johannes G M Burgerhof, Eveline W C M van Dam, Bas Havekes, Marry M van den Heuvel-Eibrink, Eleonora P M Corssmit, Leontien C M Kremer, Romana T Netea-Maier, Heleen J H van der Pal, Robin P Peeters, John T M Plukker, Cécile M Ronckers, Hanneke M van Santen, Anouk N A van der Horst-Schrivers, Wim J E Tissing, Gianni Bocca and Thera P Links

Objective

The impact of childhood differentiated thyroid carcinoma (DTC) on psychosocial development has not yet been studied. The aim of this study was to evaluate the achievement of psychosocial developmental milestones in long-term survivors of childhood DTC.

Design and methods

Survivors of childhood DTC diagnosed between 1970 and 2013 were included. Reasons for exclusion were age <18 or >35 years at follow-up, a follow-up period <5 years or diagnosis with DTC as a second malignant neoplasm. Survivors gathered peer controls of similar age and sex (n = 30). A comparison group non-affected with cancer (n = 508) and other childhood cancer survivors (CCS) were also used to compare psychosocial development. To assess the achievement of psychosocial milestones (social, autonomy and psychosexual development), the course of life questionnaire (CoLQ) was used.

Results

We included 39 survivors of childhood DTC (response rate 83.0%, mean age at diagnosis 15.6 years, and mean age at evaluation 26.1 years). CoLQ scores did not significantly differ between survivors of childhood DTC and the two non-affected groups. CoLQ scores of childhood DTC survivors were compared to scores of other CCS diagnosed at similar ages (n = 76). DTC survivors scored significantly higher on social development than other CCS, but scores were similar on autonomy and psychosexual developmental scales.

Conclusions

Survivors of childhood DTC showed similar development on social, autonomy, and psychosexual domains compared to non-affected individuals. Social development was slightly more favorable in DTC survivors than in other CCS, but was similar on autonomy and psychosexual domains.

Open access

Felix Haglund, Björn M Hallström, Inga-Lena Nilsson, Anders Höög, C Christofer Juhlin and Catharina Larsson

Context

Inflammatory infiltrates are sometimes present in solid tumors and may be coupled to clinical behavior or etiology. Infectious viruses contribute to tumorigenesis in a significant fraction of human neoplasias.

Objective

Characterize inflammatory infiltrates and possible viral transcription in primary hyperparathyroidism.

Design

From the period 2007 to 2016, a total of 55 parathyroid tumors (51 adenomas and 4 hyperplasias) with prominent inflammatory infiltrates were identified from more than 2000 parathyroid tumors in the pathology archives, and investigated by immunohistochemistry for CD4, CD8, CD20 and CD45 and scored as +0, +1 or +2. Clinicopathological data were compared to 142 parathyroid adenomas without histological evidence of inflammation. Transcriptome sequencing was performed for 13 parathyroid tumors (four inflammatory, 9 non-inflammatory) to identify potential viral transcripts.

Results

Tumors had prominent germinal center-like nodular (+2) lymphocytic infiltrates consisting of T and B lymphocytes (31%) and/or diffuse (+1–2) infiltrates of predominantly CD8+ T lymphocytes (84%). In the majority of cases with adjacent normal parathyroid tissue, the normal rim was unaffected by the inflammatory infiltrates (96%). Presence of inflammatory infiltrates was associated with higher levels of serum-PTH (P = 0.007) and oxyphilic differentiation (P = 0.002). Co-existent autoimmune disease was observed in 27% of patients with inflammatory infiltrates, which in turn was associated with oxyphilic differentiation (P = 0.041). Additionally, prescription of anti-inflammatory drugs was associated with lower serum ionized calcium (P = 0.037).

Conclusions

No evidence of virus-like sequences in the parathyroid tumors could be found by transcriptome sequencing, suggesting that other factors may contribute to attract the immune system to the parathyroid tumor tissue.

Open access

George Tharakan, Preeshila Behary, Nicolai J Wewer Albrechtsen, Harvinder Chahal, Julia Kenkre, Alexander D Miras, Ahmed R Ahmed, Jens J Holst, Stephen R Bloom and Tricia Tan

Objective

Roux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment for diabetes and obesity. An increasingly recognized and highly disabling complication of RYGB is postprandial hypoglycaemia (PPH). The pathophysiology of PPH remains unclear with multiple mechanisms suggested including nesidioblastosis, altered insulin clearance and increased glucagon-like peptide-1 (GLP-1) secretion. Whilst many PPH patients respond to dietary modification, some have severely disabling symptoms. Multiple treatments are proposed, including dietary modification, GLP-1 antagonism, GLP-1 analogues and even surgical reversal, with none showing a more decided advantage over the others. A greater understanding of the pathophysiology of PPH could guide the development of new therapeutic strategies.

Methods

We studied a cohort of PPH patients at the Imperial Weight Center. We performed continuous glucose monitoring to characterize their altered glycaemic variability. We also performed a mixed meal test (MMT) and measured gut hormone concentrations.

Results

We found increased glycaemic variability in our cohort of PPH patients, specifically a higher mean amplitude glucose excursion (MAGE) score of 4.9. We observed significantly greater and earlier increases in insulin, GLP-1 and glucagon in patients who had hypoglycaemia in response to an MMT (MMT Hypo) relative to those that did not (MMT Non-Hypo). No significant differences in oxyntomodulin, GIP or peptide YY secretion were seen between these two groups.

Conclusion

An early peak in GLP-1 and glucagon may together trigger an exaggerated insulinotropic response to eating and consequent hypoglycaemia in patients with PPH.

Open access

Michel Polak, Jo Blair, Primoz Kotnik, Effie Pournara, Birgitte Tønnes Pedersen and Tilman R Rohrer

Objective

To investigate the effect of age at growth hormone (GH) treatment start on near adult height (NAH) in children with isolated GH deficiency (GHD).

Design

NordiNet® International Outcome Study (IOS) (Nbib960128), a non-interventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (somatropin) (Novo Nordisk A/S) in the real-life clinical setting.

Methods

Patients (n = 172) treated to NAH (height at ≥18 years, or height velocity <2 cm/year at ≥16 (boys) or ≥15 (girls) years) were grouped by age (years) at treatment start (early (girls, <8; boys, <9), intermediate (girls, 8–10; boys, 9–11) or late (girls, >10; boys, >11)) and GHD severity (<3 ng/mL or 3 to ≤10 ng/mL). Multiple regression analysis was used to evaluate the effect of age at treatment start (as a categorical and continuous variable) on NAH standard deviation score (SDS).

Results

Age at treatment start had a marked effect on NAH SDS; NAH SDS achieved by patients starting treatment early (n = 40 (boys, 70.0%); least squares mean (standard error) −0.76 (0.14)) exceeded that achieved by those starting later (intermediate, n = 42 (boys, 57.1%); −1.14 (0.15); late, n = 90 (boys, 68.9%); −1.21 (0.10)). Multiple regression analysis showed a significant association between NAH SDS and age at treatment start (P < 0.0242), baseline height SDS (HSDS) (P < 0.0001), target HSDS (P < 0.0001), and GHD severity (P = 0.0012). Most (78.5%) patients achieved a normal NAH irrespective of age at treatment start.

Conclusions

Early initiation of GH treatment in children with isolated GHD improves their chance of achieving their genetic height potential.