0000000001307750
AUTHOR
Matthias M. Weber
Effects on α- and β-cell function of sequentially adding empagliflozin and linagliptin to therapy in people with type 2 diabetes previously receiving metformin: An exploratory mechanistic study.
Aims The aim of the study was to investigate the effect of sequential treatment escalation with empagliflozin and linagliptin on laboratory markers of alpha- and beta cell function in patients with type 2 diabetes mellitus (T2DM) insufficiently controlled on metformin monotherapy. Methods Forty-four patients with T2DM received 25 mg empagliflozin for a duration of one month in an open-label fashion (treatment period (TP 1). Thereafter, patients were randomised to a double-blind add-on therapy with linagliptin 5 mg or placebo (TP 2) for one additional month. Alpha- and beta cell function were assessed with a standardised liquid meal test (LMT) and an intravenous (iv.) glucose challenge. Effi…
Endothelial Function and Arterial Stiffness in Uncomplicated Type 1 Diabetes and Healthy Controls and the Impact of Insulin on These Parameters during an Euglycemic Clamp
BACKGROUND In addition to its role in glucose metabolism, insulin has shown to exert numerous vascular effects, and an impaired vascular function of insulin is assumed to be a major contributor in the development of vascular complications. Arterial augmentation (AP) and the augmentation index (Aix) are surrogate parameters of arterial stiffness and are commonly used as predictors for cardiovascular risk. The aim of this study is to investigate the effect of insulin on arterial stiffness and parameters of endothelial function in patients with type 1 diabetes and healthy control subjects. METHODS Fourteen patients with type 1 diabetes (six male, eight female) with a mean age of 36.6 +/- 11.8 …
Identification and prevention of genotyping errors caused by G-quadruplex- and i-motif-like sequences.
Abstract Background: Reliable PCR amplification of DNA fragments is the prerequisite for most genetic assays. We investigated the impact of G-quadruplex– or i-motif–like sequences on the reliability of PCR-based genetic analyses. Methods: We found the sequence context of a common intronic polymorphism in the MEN1 gene (multiple endocrine neoplasia I) to be the cause of systematic genotyping errors by inducing preferential amplification of one allelic variant [allele dropout (ADO)]. Bioinformatic analyses and pyrosequencing-based allele quantification enabled the identification of the underlying DNA structures. Results: We showed that G-quadruplex– or i-motif–like sequences can reproducibly …
Elevated serum levels of IGF-binding protein 2 in patients with non-seminomatous germ cell cancer: correlation with tumor markers alpha-fetoprotein and human chorionic gonadotropin.
Background/aimsAlterations of the IGF system have been described in several different types of cancer. However, no information is available about the role of the IGF system in patients with non-seminomatous germ cell cancer.MethodsFree IGF-I, IGF-II, acid-labile subunit, and IGF-binding proteins (IGFBPs) 1–4 were analyzed by specific RIAs in 32 patients with untreated non-seminomas and compared with IGFBP levels of 38 healthy controls. Serum IGFBPs were analyzed by western ligand blotting (WLB) and immunoblotting. In 16 patients, IGFBP profiles were measured before, during, and after treatment.ResultsIn patients with testicular cancer, IGF-II levels were on average 1.44-fold higher than in …
Gene variants of osteoprotegerin, estrogen-, calcitonin- and vitamin D-receptor genes and serum markers of bone metabolism in patients with Gaucher disease type 1
Anca Zimmermann,1 Radu A Popp,2 Heidi Rossmann,3 Simona Bucerzan,4 Ioana Nascu,4 Daniel Leucuta,5 Matthias M Weber,1 Paula Grigorescu-Sido41Department of Endocrinology and Metabolic Diseases, 1st Clinic and Polyclinic of Internal Medicine, University of Mainz, Mainz, Germany; 2Department of Medical Genetics, University of Medicine and Pharmacy, Cluj-Napoca, Romania; 3Institute for Clinical Chemistry and Laboratory Medicine, University of Mainz, Mainz, Germany; 4Center of Genetic Diseases, 1st Pediatric Clinic, University of Medicine and Pharmacy, Cluj-Napoca, Romania; 5Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy, Cluj-Napoca, RomaniaPurpose: Oste…
Pioglitazone in addition to metformin improves erythrocyte deformability in patients with Type 2 diabetes mellitus
The aim of the present study was to compare the effect of PIO (pioglitazone) or GLIM (glimepiride) on erythrocyte deformability in T2DM (Type 2 diabetes mellitus). The study covered 23 metformin-treated T2DM patients with an HbA1c (glycated haemoglobin) >6.5%. Patients were randomized to receive either PIO (15 mg, twice a day) or GLIM (1 mg, twice a day) in combination with metformin (850 mg, twice a day) for 6 months. Blood samples were taken for the measurement of fasting glucose, HbA1c, fasting insulin, intact proinsulin, adiponectin and Hct (haematocrit). In addition, the erythrocyte EI (elongation index) was measured using laser diffractoscopy. Both treatments significantly impr…
The Effects of Self-Control on Glucose Utilization in a Hyperinsulinemic Euglycemic Glucose Clamp
Abstract. Background. The glucose hypothesis of self-control posits that acts of self-control may draw upon glucose as a source of energy, leading to a decrease in blood glucose levels after exerting self-control, mirroring the temporary depletion of self-control, but supporting evidence is mixed and inconclusive. This might partly be due to using methods that are not suitable to reliably quantify glucose utilization. Aims. We aimed at examining whether self-control exertion leads to an increase in glucose utilization. Method. In a sample of N = 30 healthy participants (50% women, age 26.5 ± 3.5 years) we combined a hyperinsulinemic euglycemic glucose clamp (a well-established and validate…
Is GH dosing optimal in female patients with adult-onset GH deficiency? An analysis from the NordiNet® International Outcome Study
SummaryObjective To evaluate gender differences in GH dosing, IGF-I and cardiovascular risk markers in adults with GH deficiency (GHD). Design NordiNet® International Outcome Study (NCT00960128), a noninterventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (Novo Nordisk A/S) in the real-life clinical setting. Patients Nondiabetic patients (n = 252; 41·7% female) with adult-onset GHD (age ≥20 years at GH start), ≥4 years’ GH therapy and glycosylated haemoglobin (HbA1c) data at baseline and 4 years. Measurements Effects of gender (adjusted for baseline age and body mass index [BMI], average GH dose, treatment duration and concomitant medication) on …
ASCO-Update 2015 – Neuigkeiten vom 51. Meeting der American Society of Clinical Oncology/ASCO 2015
The field of gastrointestinal oncology is rapidly developing, on the one hand through the identification of novel molecular targets and therapeutic principles, on the other hand through the establishment and improvement of multidisciplinary treatment strategies. The following manuscript summarizes the most important trial results of the ASCO Meeting 2015 for gastrointestinal cancers. Besides trials on perioperative treatment of esophageal-, pancreatic- and colon cancer, we will present impressive data on new therapeutic strategies such as immunotherapy in gastric-, liver and microsatellite instable colorectal cancer. The trials will be put into context by the authors.
Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine?
Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. ‘Targeted’ treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target…
21-Hydroxylase and 11beta-hydroxylase mutations in Romanian patients with classic congenital adrenal hyperplasia.
Congenital adrenal hyperplasia (CAH) comprises autosomal recessive disorders mainly due to defects in the 21-hydroxylase (CYP21) gene.The study aimed to perform molecular characterization in 43 Romanian patients with classical CAH forms diagnosed at the Center for Genetic Diseases of the Pediatric Clinic/University Cluj (38 with 21-hydroxylase deficiency, five with 11beta-hydroxylase deficiency), to determine the frequency of mutations in the CYP21A2 gene and attempt a genotype-phenotype correlation in patients with 21-hydroxylase deficiency.Molecular analysis was performed by direct sequencing of PCR amplified products of the CYP21A2 and CYP11B1 genes.The most frequent mutation in Romanian…
Interdisciplinary treatment of diabetic foot wounds in the elderly : Low risk of amputations and mortality and good chance of being mobile with good quality of life
Aims: A major proportion of patients with diabetic foot syndrome are older than 65 years. Little is known about outcomes of these elderly patients. Methods: We analysed 245 treatment cases in an observational single-centre study for comorbidities and outcomes over a 6-month period. Results: In all, 122 patients had peripheral arterial disease which was significantly increasing with age ( n = 245, df = 1, χ2 = 23.06, p ⩽ 0.0001). Increasing age correlated positively with decreasing rate of revascularisations ( n = 122, df = 1, χ2 = 4.23, p = 0.039). In total, 23 (9.3%) patients died in the observation period. In-hospital mortality was 2.8%, percentage of major amputations 2.8%. In the invasi…
Magnetic separation of encapsulated islet cells labeled with superparamagnetic iron oxide nano particles.
Islet cell transplantation is a promising option for the restoration of normal glucose homeostasis in patients with type 1 diabetes. Because graft volume is a crucial issue in islet transplantations for patients with diabetes, we evaluated a new method for increasing functional tissue yield in xenogeneic grafts of encapsulated islets. Islets were labeled with three different superparamagnetic iron oxide nano particles (SPIONs; dextran-coated SPION, siloxane-coated SPION, and heparin-coated SPION). Magnetic separation was performed to separate encapsulated islets from the empty capsules, and cell viability and function were tested. Islets labeled with 1000 μg Fe/ml dextran-coated SPIONs expe…
Addition of liraglutide in patients with Type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function
Diabet. Med. 29, 1115–1118 (2012) Abstract Aims The aim of this study was to investigate the vascular effects of liraglutide in patients well controlled on metformin monotherapy. Methods Forty-four patients with Type 2 diabetes were included in the study. Main inclusion criteria were: pretreatment with metformin on a stable dosage, HbA1c < 53 mmol/mol (7.0%), age 30–65 years. Patients were randomized to receive additional liraglutide or to remain on metformin monotherapy. After 6 weeks (1.2 mg) and after 12 weeks (1.8 mg), venous blood was taken for the measurement of several laboratory markers characterizing vascular and endothelial function. In addition, retinal microvascular endothelia…
Peptide Receptor Radionuclide Therapy Combined With Chemotherapy in Patients With Neuroendocrine Tumors
Combinations of therapies may enhance therapeutic effects without significantly increasing the incidence of adverse events. However, there are few data regarding survival after concomitant chemotherapy and peptide receptor radionuclide therapy (PRRT) with [Lu]Lu-octreotate in patients with neuroendocrine tumors (NETs). Thus, we explored the outcome of this combination of therapies.Fifteen patients with somatostatin receptor-positive, rapidly progressive G2/G3 NETs during chemotherapy or PRRT alone from 2 German cancer centers were included in the retrospective analysis. The patients received a combination of PRRT and chemotherapy with temozolomide (n = 3) or temozolomide plus capecitabine (…
Encapsulation of Langerhans' islets: Microtechnological developments for transplantation
There is an increasing trend to apply microsystems and microfluidics to solve medical and biomedical tasks. Microfluidic modules are used to modify and manipulate cells and cell clusters for therapeutic applications. Specifically, a method and technical system for encapsulation of Langerhans' islets as an option for the future treatment of diabetes mellitus is described. Type-1 diabetes patients suffer from an absolute lack of the hormone insulin caused by an autoimmune process destroying the Langerhans' islets. One way to restore glucose-dependent insulin secretion is the transplantation of human pancreatic islet cells (85% beta cells) from cadaveric donors. However, to prevent the rejecti…
Pilot study for the evaluation of morphological and functional changes in retinal blood flow in patients with insulin resistance and/or type 2 diabetes mellitus.
Background: The aim of this study was to investigate early morphological and functional pathology in the retinal micro-circulation in patients with insulin resistance and/or type 2 diabetes mellitus (T2DM). Methods: Fifty-four subjects, without features of retinopathy under ophthalmological investigation, were recruited for study participation and were classifed into three study groups according to their metabolic staging: (1) Group C comprised nondiabetic, insulin-sensitive subjects with a BMI <28kg/m2; (2) Group IR comprised nondiabetic, insulin-resistant, obese subjects with a BMI ≥28 kg/m2; and (3) Group DM comprised patients with manifested T2DM. Retinal microvascular blood flow was…
The Divergent Effect of Insulin-Like Growth Factor Binding Protein (IGFBP) - 1 on IGF-induced Steroidogenesis in Bovine Adrenocortical Cells is not due to its Phosphorylation Status
In previous studies we have shown that insulin-like growth factor (IGF)-II stimulates basal as well as ACTH-induced cortisol secretion from bovine adrenocortical cells more potently than IGF-I. The steroidogenic effect of both, IGF-I and IGF-II, is mediated through the IGF-I receptor and modified by locally produced IGF binding proteins. Further studies demonstrate that bovine adrenocortical cells do synthesize IGFBP-1 to -4 and that their secretion is regulated differentially by IGFs and ACTH. Since IGFBP-1 selectively is induced 3- to 4- fold by ACTH, the aim of the following studies was to evaluate the effect of IGFBP-1 on IGF-induced cortisol secretion from bovine adrenocortical cells i…
Alterations in lipid, carbohydrate and iron metabolism in patients with non-alcoholic steatohepatitis (NASH) and metabolic syndrome
NASH (non-alcoholic steatohepatitis) is considered the hepatic manifestation of the metabolic syndrome (MS). We aimed to analyze lipid, carbohydrate, and iron metabolism in NASH.37 patients with MS (17 M/20 F, 51+/-15 years), elevated transaminases; 25 patients had histologically proven NASH (NAS score≥5), 12 patients had toxic background (nonNASH). 37 age, sex, BMI-matched healthy controls. Lipid variables, LDL-subfractions, iron, ferritin, transferrin (T), transferrin saturation (TS), and hepcidin (H) were measured in patients/controls. Oral glucose tolerance tests were performed.NASH patients with steatosis gr. 2 and 3 (33% hepatic fat) had higher sd-LDL (mg/dl) concentrations than patie…
Long-term graft function of adult rat and human islets encapsulated in novel alginate-based microcapsules after transplantation in immunocompetent diabetic mice.
We describe the results of the first study to show that adult rat and human islets can be protected against xenogenic rejection in immunocompetent diabetic mice by encapsulating them in a novel alginate-based microcapsule system with no additional permselective membrane. Nonencapsulated islets lost function within 4–8 days after being transplanted into diabetic Balb/c mice, whereas transplanted encapsulated adult rat or human islets resulted in normoglycemia for &gt;7 months. When rat islet grafts were removed 10 and 36 weeks after transplantation, the mice became immediately hyperglycemic, thus demonstrating the efficacy of the encapsulated islets. The explanted capsules showed only a …
MRI findings and genotype analysis in patients with childhood onset growth hormone deficiency--correlation with severity of hypopituitarism.
Aim: To evaluate the relationship between pituitary size, PIT1 and PROP1 genotype, and the severity of childhood onset growth hormone deficiency (coGHD). Patients: Forty-four patients with coGHD (34 M; 9.7 ± 4.1 years): severe isolated (SI) GHD (n = 14); partial isolated (PI) GHD (n = 13); multiple pituitary hormone deficiencies (MPHD) (n=17). Results: Pituitary abnormalities were found in 7/14 patients with SIGHD (50%), 16/17 patients with MPHD (94.1%), and no patient with PIGHD. Mean pituitary height (PHT SDS) was significantly lower in MPHD than in SIGHD and PIGHD. Pituitary height SDS and pituitary volume (PV) SDS correlated with IGF-I SDS and stimulated GH peaks in the SIGHD and MPHD g…
Alterations in Lipid and Carbohydrate Metabolism in Patients with Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
<i>Background:</i> Classic 21-hydroxylase deficiency (21HD) presents some traits of the metabolic syndrome. <i>Aim:</i> To characterize discrete alterations of lipid and carbohydrate metabolism in children and young adults with classic 21HD, which could predict early atherogenesis. <i>Patients and Methods:</i> Twenty-seven Caucasian patients with classic 21HD (4–31 years); 27 sex-, age- and BMI-matched controls. Clinical parameters, hormonal status and genotype were assessed in all patients. Lipid parameters, including relative (%) and absolute (mg/dl) small-dense low-density lipoproteins subfractions (sd-LDL) were measured in patients and controls. Oral …
Multiple modes of cell death in neuroendocrine tumors induced by artesunate.
Abstract Background The paucity of effective treatment in neuroendocrine tumors (NETs) encouraged us to investigate the therapeutic value of artesunate (ART) promised by its inhibitory effect against various tumors and broad safety profile. Methods We evaluated the impact of ART on three NET cell lines, BON-1, QGP-1 and NCI-H727 on cellular and molecular levels. Results Our results showed that ART induced endoplasmic reticulum (ER) stress through phosphorylation of eIF2α, which further gave rise to autophagy in all three NET cell lines. Specifically, apoptosis and ferroptosis were also observed in BON-1 cells, which made BON-1 cell line more vulnerable upon ART treatment. The different sens…
Retinal Microcirculation in Type 1 Diabetic Patients With and Without Peripheral Sensory Neuropathy
In patients with diabetes mellitus (DM), early retinal microvascular alterations can be observed even before the clinical diagnosis of diabetic retinopathy. This study aimed to investigate morphological and functional changes in retinal microvascular blood flow in type 1 diabetic patients with and without peripheral neuropathy (PNP) as compared to nondiabetic controls. Retinal microvascular blood flow (RBF) was assessed using scanning laser Doppler flowmetry (Heidelberg Retina Flowmeter, Heidelberg Engineering, Germany) before and after stimulation with flicker light. PNP was assessed using the neuropathy disability score (NDS) and by the evaluation of the vibration perception threshold (V…
Evaluation of CGMS® During Rapid Blood Glucose Changes in Patients with Type 1 Diabetes
CGMS (Medtronic Minimed, Duesseldorf, Germany) allows continuous glucose monitoring. Recent studies with invasive monitoring techniques revealed discrepancies in blood glucose measurements obtained from different anatomical sites compared with those from the fingertip. The aim of this study was to investigate the CGMS and a device for alternative site testing (AST) during dynamic blood glucose changes and to compare these results with fingertip measurements.Twelve patients with type 1 diabetes (seven women, five men; age, 33.3 +/- 8.7 years) received a 75-g oral glucose load. Insulin was applied intravenously (rapid glucose decline) or subcutaneously (moderate glucose decline) in a dosage b…
Alginate encapsulation improves viability and integrity of cryopreserved pancreatic islets and multicellular spheroids: combined fluorescence, scanning and block-face scanning electron microscopy
Extended abstract of a paper presented at MC 2007, 33rd DGE Conference in Saarbrücken, Germany, September 2 – September 7, 2007
The effect of growth hormone ( GH ) replacement on blood glucose homeostasis in adult nondiabetic patients with GH deficiency: real‐life data from the NordiNet ® International Outcome Study
SummaryObjective To assess the effect of 4 years’ growth hormone (GH) replacement on glucose homeostasis and evaluate factors affecting glycosylated haemoglobin (HbA1c) in adults with growth hormone deficiency (GHD). Design NordiNet® International Outcome Study, a noninterventional study, monitors long-term effectiveness and safety of GH replacement [Norditropin® (somatropin), Novo Nordisk A/S] in real-life clinical practice. Patients Nondiabetic patients (n = 245) with adult-onset GHD (age ≥20 years at GH start), ≥4 years’ GH replacement and HbA1c values at baseline and 4 years were included in the analysis. Measurements Changes from baseline (∆) to 4 years in HbA1c, fasting plasma glucose…
Molecular imaging of gastroenteropancreatic neuroendocrine tumors.
Somatostatin-receptor scintigraphy has become an obligatory molecular imaging method in the management of patients with neuroendocrine tumors when metastatic disease is suspected. Using positron emission tomography and new somatostatin analogues, sensitivity of somatostatin receptor imaging has further increased. With a combination of morphologic imaging methods, such as hybrid imaging by PET/CT, this method represents the method of choice in many centers and efforts are under way to translate somatostatin receptor imaging onto a cellular level by endoscopic confocal microscopy. Other clinically relevant functional pathways in neuroendocrine tumors that are accessible by PET imaging are glu…
First German Guideline on Diagnostics and Therapy of Clinically Non-Functioning Pituitary Tumors
AbstractAlthough non-functioning pituitary tumors are frequent, diagnostic and therapeutic concepts are not well standardized. We here present the first German multidisciplinary guideline on this topic. The single most important message is to manage the patients by a multidisciplinary team (consisting at least of an endocrinologist, a neurosurgeon, and a (neuro-) radiologist). The initial diagnostic work-up comprises a detailed characterization of both biochemical (focusing on hormonal excess or deficiency states) and morphological aspects (with magnetic resonance imaging of the sellar region). An ophthalmological examination is only needed in presence of symptoms or large tumors affecting …
Increased Arterial Augmentation and Augmentation Index as Surrogate Parameters for Arteriosclerosis in Subjects with Diabetes Mellitus and Nondiabetic Subjects with Cardiovascular Disease
Background: Arterial augmentation (AP) and the augmentation index (Aix) are surrogate parameters of arterial stiffness and are commonly used as predictors for cardiovascular risk. The aim of this study is to compare these parameters in diabetic subjects and nondiabetic cardiovascular risk subjects with healthy control subjects. Methods: One hundred sixty-six nonsmoking subjects aged between 35 and 70 years were included in the study, which included 100 subjects with cardiovascular disease but not diabetes (mean age 62.73±8.75 years), 33 subjects with type 2 diabetes (66.58±2.69 years), and 33 healthy controls (51.89±8.91 years). In these subjects, arterial stiffness was measured by the diff…
The gut–liver-axis: Endotoxemia, inflammation, insulin resistance and NASH
Metabolic endotoxemia initiates obesity and insulin resistance. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R. Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a…
Quality of Life and Occupational Disability in Endocrine Orbitopathy
SUMMARY Background: In endocrine orbitopathy (EO), disfiguring proptosis and diplopia impair patients' quality of life both at home and at work. Methods: From late 2006 to the beginning of 2008, 250 outpatients in an interdisciplinary thyroid and eye clinic filled out a questionnaire about their quality of life, occupational disability, and use of psychotherapy. 400 physicians who referred their EO patients to the clinic also participated in a survey on these issues. Results: 45% of the patients complained of restrictions in their daily activities, and 38% reported impaired selfperception. 36% were on sick leave because of EO. 28% were disabled, 5% had retired early, and 3% had lost their j…
Malignant paraganglioma caused by a novel germline mutation of the succinate dehydrogenase D-gene--a case report.
Background Paragangliomas of the head and neck are rare, mostly benign tumors. Approximately 10% to 15% of paragangliomas are caused by mutations in the succinate dehydrogenase (SDH) genes B, C, or D. These are often multifocal as part of paraganglioma syndromes and hormone secreting, and malignant particularly associated with mutations in SDHB. Methods and Results A 29-year-old man was seen with recurrent paraganglioma. The patient's father reportedly suffered from bilateral carotid body tumors. Imaging studies showed metastases in both lungs and the liver. There was no increased hormone production by the tumor. Sequence analysis of the SDH genes revealed a novel C to T nonsense mutation i…
Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues
Edward M Wolin,1 Barbara Jarzab,2 Barbro Eriksson,3 Thomas Walter,4 Christos Toumpanakis,5 Michael A Morse,6 Paola Tomassetti,7 Matthias M Weber,8 David R Fogelman,9 John Ramage,10 Donald Poon,11 Brian Gadbaw,12 Jiang Li,12 Janice L Pasieka,13 Abakar Mahamat,14 Fredrik Swahn,15 John Newell-Price,16 Wasat Mansoor,17 Kjell &Ouml;berg3 1Markey Cancer Center, University of Kentucky, Lexington, KY, USA; 2Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland; 3Department of Medical Sciences, Endocrine Oncology Unit, University Hospital, Uppsala, Sweden; 4Department of Medical Oncology, Ed…
Growth hormone replacement in adults:Real-world data from two large studies in US and Europe
Objective: This report describes the effectiveness and safety of growth hormone replacement in 3180 adult patients with growth hormone deficiency followed-up for 0.0–12.2 years in two completed, complementary, non-interventional, multicentre studies, NordiNet® International Outcome Study (IOS) (NCT00960128) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program (NCT01009905). Design: In both studies, Norditropin® (somatropin; Novo Nordisk A/S, Denmark) was administered at the discretion of the treating physician and according to routine practice. We present data on baseline characteristics, growth hormone dose, safety data and change from baseline in waist circumferenc…
Sequential Treatment Escalation with Dapagliflozin and Saxagliptin Improves Beta Cell Function in Type 2 Diabetic Patients on Previous Metformin Treatment: An Exploratory Mechanistic Study
AbstractWe investigated the effect of sequential treatment escalation with dapagliflozin and saxagliptin on beta cell function in patients with T2DM insufficiently controlled on metformin monotherapy during a hyperglycaemic clamp investigation. Twenty-six patients (19 males, age 63.5±7.0 years; duration of diabetes 8.8±4.7 years; HbA1c 63.9±15.8 mmol/mol; mean±SD) were enrolled in the study. During a first treatment period (TP1) all patients received 10 mg dapagliflozin for one month, followed by the addition of 5 mg saxagliptin or placebo for another month (TP2). At baseline and at the end of each treatment period, fasting glucose and insulin levels were analysed, and a hyperglycaemic clam…
Role of the insulin-like growth factor system in adrenocortical growth control and carcinogenesis.
Clinically silent adrenocortical adenomas are the most frequent abnormalities in the adrenal gland. In contrast, adrenocortical carcinoma is a rare tumor with an extremely poor prognosis. The factors responsible for the frequent occurrence of benign adrenocortical tumors on one hand and the rare malignant transformation on the other are not known. Several genetic alterations such as loss of imprinting or loss of heterozygosity of the 11p15 gene locus causing a strong IGF-II overexpression have been demonstrated in the majority of adrenocortical carcinomas. In addition to IGF-II overexpression, increased levels of the IGF-I-receptor and IGFBP-2 have been found in advanced human adrenocortica…
Psychische Komorbidität, Inanspruchnahme- und Gesundheitsverhalten bei Übergewichtigen und Adipösen - am Beispiel einer repräsentativen Stichprobe der deutschen Allgemeinbevölkerung
Obesity is associated with an increased somatic morbidity and mortality. This paper focuses on the controversial issue of mental co-morbidity in various populations of overweight and obese persons and the relationship to the utilization of medical care and health behaviour. Therefore, this paper focuses on health care utilization and health behaviour in overweight/obese with mental co-morbidity. In a representative German community sample with n = 1281 we administered valid self-rating scales on depression and anxiety. Using established cut-off scores we identified 61 subjects with both overweight/obesity and at least one mental disorder. Compared to the overweight/obese without mental co-m…
Overexpression of the insulin-like growth factor I receptor in human pheochromocytomas.
In order to determine the role of the IGF-I receptor (IGF-IR) in human pheochromocytomas we have compared the expression of the IGF-IR in normal tissues and in pheochromocytomas with regard to the IGF-IR mRNA levels and ligand binding. By semiquantitative reverse transcription polymerase chain reaction (RT-PCR), the mRNA of the IGF-IR could be detected in all samples of normal adrenomedullary cells (n=13) and pheochromocytomas (n=16). However, pheochromocytomas exhibited 2.8-fold higher mean IGF-IR mRNA levels than normal adrenomedullary cells (2.8±0.5×105 molecules/μg RNA vs 7.8±1.2×105 molecules/μg RNA; P < 0.001). This overexpression of the IGF-IR in pheochromocytomas could be confirm…
A phase II, open label, multicenter trial of avelumab in patients with advanced, metastatic high-grade neuroendocrine carcinomas NEC G3 (WHO 2010) progressive after first-line chemotherapy (AVENEC).
4103 Background: High grade Neuroendocrine Neoplasias (NEN) are rare tumors with a poor prognosis and no established second line therapy when progressive after first line platinum-based chemotherapy resulting in a median overall survival (OS) of 5 months. This study aims to evaluate the efficacy and safety of the anti-programmed death ligand-1 (PD-L1) antibody Avelumab in patients (pts) with NEN G3 progressing after first-line chemotherapy. Methods: In a multicenter, national, single-arm, open-label, phase II trial the efficacy and safety of Avelumab was evaluated in patients with metastatic progressive Neuroendocrine Carcinomas (NEC G3) according to WHO 2010, excluding Merkel cell carcino…
PD-L1 Expression and Immune Cell Infiltration in Gastroenteropancreatic (GEP) and Non-GEP Neuroendocrine Neoplasms With High Proliferative Activity
The potential of neuroendocrine neoplasms (NEN) to respond to checkpoint inhibitors is largely unknown and full of great expectations. Immunohistochemical (IHC) studies of programmed cell death ligand 1 (PD-L1) expression in the tumor microenvironment and its implications in predicting the response to checkpoint inhibition is a very active subject. Currently, the combined analysis of PD-L1 expression and tumor-associated immune cell (TAIC) infiltration is considered the best predictive marker of therapeutic response. Here we investigated the expression of PD-L1 on tumor cells (TC) and tumor-infiltrating immune cells (IC) by IHC in 68 NEN samples with a high proliferation rate (Ki-67 >20%…
Multicenter, Observational Study of Lanreotide Autogel for the Treatment of Patients with Neuroendocrine Tumors in Routine Clinical Practice in Germany and Austria
Abstract Background The long-acting somatostatin analog lanreotide autogel is effective in the treatment of patients with neuroendocrine tumors. Objective To evaluate the long-term treatment response in patients with neuroendocrine tumors receiving lanreotide autogel in routine clinical practice. Methods Non-interventional, 24-month study in patients with neuroendocrine tumors treated with lanreotide autogel (NCT01840449). Results Patients (n=80) from 26 centers in Germany and Austria were enrolled. Neuroendocrine tumors were mainly grade 1/2, metastasized, intestinal, and associated with carcinoid syndrome; 88.9% had received previous neuroendocrine tumor treatment. Of those, 84.4% had pre…
Binostril versus mononostril approaches in endoscopic transsphenoidal pituitary surgery: clinical evaluation and cadaver study.
OBJECTIVE Over the past 2 decades, endoscopy has become an integral part of the surgical repertoire for skull base procedures. The present clinical evaluation and cadaver study compare binostril and mononostril endoscopic transnasal approaches and the surgical techniques involved. METHODS Forty patients with pituitary adenomas were treated with either binostril or mononostril endoscopic surgery. Neurosurgical, endocrinological, ophthalmological, and neuroradiological examinations were performed. Ten cadaver specimens were prepared, and surgical aspects of the preparation and neuroradiological examination were documented. RESULTS In the clinical evaluation, 0° optics were optimal in the nas…
Bone mineral density and bone turnover in Romanian children and young adults with classical 21-hydroxylase deficiency are influenced by glucocorticoid replacement therapy
Summary Objective It remains controversial if glucocorticoid replacement therapy impairs bone mineral density (BMD) in young patients with 21-hydroxylase deficiency. We aimed to analyze the impact of treatment variables, phenotype and genotype on BMD and bone metabolism in these patients. Design Cross-sectional study. Measurements Twenty-eight Caucasian patients with classical 21-hydroxylase deficiency (5–39 years). Clinical parameters, hormonal status, osteocalcin (OC), C-terminal telopeptide of type I collagen (CTX), genotype and lumbar BMD (Z-scores) were assessed. Cumulative and mean hydrocortisone equivalent doses were calculated for the entire treatment period. Results Patients wi…
Gender-, age- and time-dependent dosing of growth hormone in adults - real-world data from a decade of clinical practice in Germany.
We evaluated treatment patterns and gender-dependent dosing of growth hormone (GH) substitution in adults with GH deficiency (AGHD). Data on GH dose were collected (2003-2013) from 509 GH-treated patients (mean age: 48.9 years; 47% female) enroled in the observational German NordiWin study (NCT01543880). The impact of gender, age, treatment duration and calendar year on GH treatment patterns was evaluated by multiple regression analysis. Mean (SD) baseline GH dose (mg/day) was similar between females (0.25 [0.19] and males (0.24 [0.15]), but increased with treatment duration (at year 10, 0.55 [0.48] and 0.31 [0.09] in females and males, respectively), reflecting patient dose titration. GH d…
In-vivo confocal real-time mini-microscopy in animal models of human inflammatory and neoplastic diseases
Background and study aims Although various improvements in tissue imaging modalities have recently been achieved, in-vivo molecular and subsurface imaging in the field of gastroenterology remains a technical challenge. In this study we evaluated a newly developed, handheld, miniaturized confocal laser microscopy probe for real-time in-vivo molecular and subsurface imaging in rodent models of human disease. Materials and methods The minimicroscope uses a 488-nm, single line laser for fluorophore excitation. The optical slice thickness is 7 microm, the lateral resolution 0.7 microm. The range of the z-axis is 0-250 microm below the tissue surface. Imaging was performed using different fluores…
Gastroenterologische Palliativmedizin
On consideration of current medical and socio-economical factors, palliative care is becoming an increasingly important aspect of modern medicine in Germany. The German Society for Digestive and Metabolic Disorders (DGVS) has taken this into account by founding the working group "Palliative Gastroenterology". Patients with gastrointestinal malignancies or advanced non-malignant liver disease represent an important group that benefits from palliative care. Approximately 80 % of all palliative care patients suffer from gastrointestinal symptoms and endoscopic procedures performed by gastroenterologists play an important role in relieving symptoms such as obstruction. It is the object of this …
Gender-, age- and time-dependent dosing of growth hormone in adults – real-world data from a decade of clinical practice in Germany
We evaluated treatment patterns and gender-dependent dosing of growth hormone (GH) substitution in adults with GH deficiency (AGHD). Data on GH dose were collected (2003–2013) from 509 GH-treated patients (mean age: 48.9 years; 47% female) enroled in the observational German NordiWin study (NCT01543880). The impact of gender, age, treatment duration and calendar year on GH treatment patterns was evaluated by multiple regression analysis. Mean (SD) baseline GH dose (mg/day) was similar between females (0.25 [0.19] and males (0.24 [0.15]), but increased with treatment duration (at year 10, 0.55 [0.48] and 0.31 [0.09] in females and males, respectively), reflecting patient dose titration. GH d…