Publications by authors named "Matthias M Weber"

95 Publications

The Diagnosis and Management of Endocrine Side Effects of Immune Checkpoint Inhibitors.

Dtsch Arztebl Int 2021 Jun 11;118(Forthcoming). Epub 2021 Jun 11.

Background: The immunologically mediated side effects of immune checkpoint inhibitors (CPI) often involve the endocrine system as well, and they can even be fatal, as in the case of unrecognized hypophysitis. Distinguishing such side effects from tumor-related changes is often difficult, because their clinical features can be nonspecific.

Methods: This review is based on publications retrieved by a selective search in PubMed, with special attention to international recommendations.

Results: Depending on their target molecules, the CPI now in use differ from one another in the incidence of side effects such as autoimmune thyroid disease (4-16%), hypophysitis (0.1- 18%), adrenalitis (0.7-8%), and autoimmune diabetes mellitus (0.5-2%). The typical clinical warning signs and laboratory constellations of hypophysitis include exhaustion, hyponatremia, and headache. Hypo- and hyperthyroidism and primary adrenocortical insufficiency likewise have nonspecific manifestations. Autoimmune diabetes mellitus often takes a fulminant course. Patients being treated with CPI should be monitored at close intervals, at least as frequently as the administration of the drug, so that endocrine side effects can be recognized in time. In case of doubt, glucocorticoid supplementation should be given whenever hypocortisolism is suspected, even before endocrine evaluation is completed and the results are available. Interrupting or discontinuing CPI treatment is rarely indicated.

Conclusion: With the increasing number of patients being treated with CPI, more and more physicians from a wide variety of specialties, not necessarily working in specialized centers, now have to consider immunologically mediated endocrine side effects in the differential diagnosis, and treat them properly when they arise. These things should be done in collaboration with endocrinologists. The ongoing study of such side effects of the CPI now in use, and of those that will be introduced in the future, is important and will lead to improved understanding.
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http://dx.doi.org/10.3238/arztebl.m2021.0143DOI Listing
June 2021

Pregnancy outcomes in women receiving growth hormone replacement therapy enrolled in the NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program.

Pituitary 2021 Mar 12. Epub 2021 Mar 12.

Unit of Endocrinology, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Germany.

Purpose: Data on the safety of growth hormone (GH) replacement therapy during pregnancy are limited. We report a combined analysis of data from pregnant women treated with GH while enrolled in two non-interventional, multicenter studies: NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program.

Methods: Pregnancy data were pooled from NordiNet® IOS and the ANSWER Program. Data were collected during routine clinic visits by participating physicians using a web-based system. Patients exposed to GH replacement therapy during pregnancy were included in the analysis.

Results: The study population included 40 female patients with typical causes of adult GH deficiency (GHD). Overall, there were 54 pregnancies. Of these, 47 were exposed to GH between conception and delivery. In 48.9% of pregnancies exposed to GH, the dose was > 0.6 mg/day. GH was continued past conception and then stopped during the first, second, and third trimester, in 27.7%, 17.0%, and 2.1% of pregnancies, respectively. In 29.8%, GH was continued throughout pregnancy, with an unchanged dose in most cases. Of the 47 GH-exposed pregnancies, 37 (78.7%) progressed to normal delivery. There were three adverse events reported in two pregnancies.

Conclusion: These real-world data suggest that there were no new safety signals related to GH exposure in women with GHD during pregnancy. These results are consistent with findings from previous studies reporting data in pregnancies exposed to GH at conception or throughout pregnancy. This observational study in additional pregnancies provides further evidence that GH exposure does not adversely affect pregnancy outcome.

Clinical Trial Registration: ClinicalTrials.gov NCT00960128 (date of registration: August 13, 2009) and NCT01009905 (date of registration: November 5, 2009).
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http://dx.doi.org/10.1007/s11102-021-01138-3DOI Listing
March 2021

Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine?

Gut 2021 Mar 10. Epub 2021 Mar 10.

Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg and Philipps University, Marburg, Germany.

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 of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in the poor prognosis NEN G3 group, though associated with acceptable response rates, only leads to short-term tumour control and their molecular biology requires delineation to provide new and more specific treatment options.The future requires an exploration of the NEN tumour genome, its microenvironment and an identification of critical oncologic checkpoints for precise drug targeting. In the advance to personalised medical treatment of patients with GEPNEN, clinical trials need to be based on mechanistic and multidimensional characterisation of each tumour in order to identify the therapeutic agent effective for the individual tumour.This review surveys advances in NEN research and delineates the current status of translation with a view to laying the basis for a genome-based personalised medicine management of advanced GEPNEN.
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http://dx.doi.org/10.1136/gutjnl-2020-321300DOI Listing
March 2021

First German Guideline on Diagnostics and Therapy of Clinically Non-Functioning Pituitary Tumors.

Exp Clin Endocrinol Diabetes 2021 Mar 9;129(3):250-264. Epub 2021 Mar 9.

Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.

Although 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 the visual system. Asymptomatic, hormonally inactive tumors allow for a 'wait and scan' strategy. In contrast, surgical treatment by an experienced pituitary surgeon is standard of care in case of (impending) visual impairment. Therapeutic options for incompletely resected or recurrent tumors include re-operation, radiotherapy, and observation; the individual treatment plan should be developed multidisciplinary. Irrespective of the therapeutic approach applied, patients require long-term follow-up. Patient with larger pituitary tumors or former surgery/radiotherapy should be regularly counseled regarding potential symptoms of hormonal deficiency states.
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http://dx.doi.org/10.1055/a-1373-4087DOI Listing
March 2021

Pilot Study on Malnutrition and DNA Damage in Patients with Newly Diagnosed Gastrointestinal Tumors: Is DNA Damage Reversible by Early Individualized Nutritional Support?

J Gastrointestin Liver Dis 2020 Oct 27;29(4):569-577. Epub 2020 Oct 27.

1 st Clinic and Polyclinic of Internal Medicine, University Medical Center Mainz; Medical Clinic 2, Dept. of Diabetology and Endocrinology, Clinic of Worms, Germany.

Background And Aims: Nutritional support (NS) in patients with malignancies and malnutrition improves outcome and treatment tolerance. The underlying mechanisms are not completely understood. We aimed to investigate for the first time the influence of an early individualized NS in newly diagnosed patients with gastrointestinal/hepato-pancreatic malignancies and malnutrition on DNA damage, oxidative stress and subclinical inflammation.

Methods: This prospective case-control study included 43 patients with newly diagnosed malignancies and malnutrition. At baseline (F0), we documented patients' data, oncological diagnosis, comorbidities, alcohol/ nicotine consume. Nutritional parameters, DNA damage [histone-variant H2AX phosphorylated on the 139-serine residue (γ-H2AX) foci/cell], oxidative status, subclinical inflammation were measured. During diagnostic workup, patients received an individualized NS, and got a follow-up before the start of treatment (F1), (n=21). Healthy controls (n=21) were included for comparison of DNA damage at baseline.

Results: γ-H2AX-values at baseline were higher than in controls (p<0.001) and higher than after the NS at F1 (p=0.011). Patients with severe gastrointestinal symptoms (SGS) had higher baseline foci compared to patients with mild gastrointestinal symptoms (MGS) at F0 (p<0.001) and showed a stronger decrease of DNA damage under NS (p=0.002). Laboratory data were stable, with tendential reduction in oxidative stress, without progression of subclinical inflammation. The number of γ-H2AX foci did not differ among patients divided by sex, age, nicotine or alcohol intake or the presence of distant metastases.

Conclusion: Increased baseline DNA damage in patients with newly diagnosed tumors and malnutrition decreased under pretherapeutic NS, independent of other known genotoxic factors. This contributes towards understanding the positive effects of early NS in cancer management.
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http://dx.doi.org/10.15403/jgld-2589DOI Listing
October 2020

Multiple modes of cell death in neuroendocrine tumors induced by artesunate.

Phytomedicine 2020 Dec 3;79:153332. Epub 2020 Sep 3.

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany. Electronic address:

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 sensitivities presented on the three cell lines also associated with a differential regulation of p21 on the long run. Co-treatment with p21 inhibitor UC2288 showed an additive effect on QGP-1 and NCI-H727 cell lines indicating p21 upregulation in these two cell lines might confer resistance towards ART treatment.

Conclusions: It is possible to include ART in the treatment of NETs in the future.
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http://dx.doi.org/10.1016/j.phymed.2020.153332DOI Listing
December 2020

Growth hormone replacement in adults: Real-world data from two large studies in US and Europe.

Growth Horm IGF Res 2020 02 26;50:71-82. Epub 2019 Oct 26.

Neuroendocrine Unit, Massachusetts General Hospital, Bulfinch 457B, Massachusetts General Hospital, Fruit St., Boston, MA 02114, USA.

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 circumference, body mass index and bioimpedance (NordiNet® IOS only).

Results: Mean (SD) baseline characteristics (effectiveness analysis set) in NordiNet® IOS (n = 971) and ANSWER (n = 304): females, 45%; 69%; mean growth hormone dose (mg/day) (female, 0.338 [0.177]; male, 0.289 [0.157]); (female, 0.501 [0.313]; male, 0.505 [0.351]). Most patients had BMI ≥25 kg/m. Median (P10,P90) exposure (females, 3.5 [0.42,11.0]; 1.6 [3.2; 0.3,8.6]; males, 4.1 [0.33,10.8]; 2.3 [2.9; 0.0,7.5] years). Mean (SD) change from baseline for waist circumference (-0.46 [6.38] cm [n = 403], BMI (0.30 [3.30] kg/m [n = 857]) and bioimpedance (-17.4 (59.19) ohm [n = 239]) were associated with growth hormone dose (waist/bioimpedance) and duration of follow-up (BMI/bioimpedance). No new safety signals were observed among patients in the full analysis set (NordiNet® IOS, n = 2321; ANSWER, n = 859).

Conclusions: Long-term growth hormone replacement is associated with an improvement in body composition. The accumulated data from >10 years of follow-up support the long-term effectiveness and safety of growth hormone replacement as prescribed in clinical practice.
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http://dx.doi.org/10.1016/j.ghir.2019.09.002DOI Listing
February 2020

[Hypoparathyroidism - un underestimated problem?]

MMW Fortschr Med 2019 12;161(Suppl 7):12-20

MVZ Endokrinologikum Göttingen, Zentrum für Hormon- und Stoffwechselerkrankungen, Nuklearmedizin und Humangenetik, Göttingen, Deutschland.

Background: Hypoparathyroidism is a rare and disabilitating disorder characterized by hypocalcemia and low parathyroid hormone levels. Most of the cases occur as a result of the removal of parathyroid glands or damage to the glands during neck surgery. More rare causes include nonsurgical causes such as autoimmune or genetic diseases.

Method: In this review, a panel of experts presents the current state of diagnosis and therapy of hypoparathyroidism and explains practical aspects of caring for the affected patients.

Results: Common signs and symptoms are abnormal sensations and increased excitability in the lower limbs, paresthesia of perioral areas and nocturnal leg cramps. Renal complications frequently occur, but also basal ganglia calcification. Treatment consists of administration of vitamin D analogs in combination with 0.5-1.0 g calcium daily. An adjunctive treatment with the in April 2017 approved recombinant human parathyroid hormone (1-84) is an option for patients whose hypoparathyroidism is difficult to control by conventional treatment alone. Initially and after dose changes follow-up controls should be performed at least every 2 weeks, in well-controlled patients or in the case of chronic progression every 3-6 months.
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http://dx.doi.org/10.1007/s15006-019-1174-4DOI Listing
December 2019

PD-L1 Expression and Immune Cell Infiltration in Gastroenteropancreatic (GEP) and Non-GEP Neuroendocrine Neoplasms With High Proliferative Activity.

Front Oncol 2019 7;9:343. Epub 2019 May 7.

Department of Endocrinology and Metabolism, I Medical Clinic, University Hospital, Johannes Gutenberg University of Mainz, Mainz, Germany.

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%) from 57 patients and in 22 samples we correlated it with TAIC density by assessing intratumoral infiltration of CD3+, CD8+, and CD68+ cells. Furthermore, the tumor microenvironment was evaluated according to the classification of Teng et al. We detected PD-L1 expression in 31.6% of NEN G3. Its expression usually was weak and more IC than TC expressed PD-L1. The proportion of tumors positive for PD-L1 was comparable in NEN from different sites of origin but varied depending on tumor differentiation and disease extension. No positive IHC staining was found in 3 well-differentiated neuroendocrine tumors (NETs) with a proliferation rate above 20% (NET G3). When analyzing TAIC, we rarely (18.2%) detected intratumoral CD8+ cells, whereas infiltration by CD3+ and CD68+ cells was more common (45.5 and 59.1%, respectively). By combining CD3+ cells and PD-L1 status, we identified the immune ignorant phenotype of tumor microenvironment as being the most common phenotype, supporting the concept of a preferably combined immunotherapeutic approach in neuroendocrine carcinoma (NEC).
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http://dx.doi.org/10.3389/fonc.2019.00343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514221PMC
May 2019

A century of sensory processing dysfunction in schizophrenia.

Eur Psychiatry 2019 06 10;59:77-79. Epub 2019 May 10.

Dept. of Psychiatry, Columbia University Medical Center, New York, NY USA; Nathan Kline Institute, Orangeburg, NY USA. Electronic address:

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http://dx.doi.org/10.1016/j.eurpsy.2019.04.006DOI Listing
June 2019

Peptide Receptor Radionuclide Therapy Combined With Chemotherapy in Patients With Neuroendocrine Tumors.

Clin Nucl Med 2019 May;44(5):e329-e335

From the Departments of Nuclear Medicine and.

Purpose: 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.

Methods: 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 (n = 12). To evaluate the effects of the combined treatment, we assessed the responses, survival, and adverse events.

Results: The cumulative administered activity of [Lu]Lu-octreotate had a median of 21.3 GBq after 3 cycles of combination therapy. The patients exhibited a median progression-free survival of 7.1 months and a median overall survival of 25.3 months. The clinical benefit (objective response and stable disease) rates were as follows: 55% of patients according to CT, 38% in [F]F-FDG PET/CT, and 44% in [Ga]Ga-DOTATOC PET/CT. One patient with rapidly progressing liver metastases experienced grade 4 liver failure according to the Common Terminology Criteria for Adverse Events (version 5.0). Four other patients (27%) experienced significantly elevated (grade 3) liver parameters.

Conclusions: According to different imaging modalities, the combination of PRRT and temozolomide +/- capecitabine led to disease control in 38% to 55% of the progressive NETs after PRRT or chemotherapy alone failed. The overall survival in this extensively pretreated group of patients was nearly 25 months. The majority of patients did not experience any serious adverse events.
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http://dx.doi.org/10.1097/RLU.0000000000002532DOI Listing
May 2019

Gene variants of osteoprotegerin, estrogen-, calcitonin- and vitamin D-receptor genes and serum markers of bone metabolism in patients with Gaucher disease type 1.

Ther Clin Risk Manag 2018 24;14:2069-2080. Epub 2018 Oct 24.

Center of Genetic Diseases, 1st Pediatric Clinic, University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Purpose: Osteopathy/osteoporosis in Gaucher disease type 1 (GD1) shows variable responses to enzyme replacement therapy (ERT); the pathogenesis is incompletely understood. We aimed to investigate the effects of several gene variants on bone mineral density (BMD) and serum markers of bone metabolism in GD1.

Patients And Methods: Fifty adult Caucasian patients with GD1/117 controls were genotyped for gene variants in the osteoprotegerin (TNFRSF11B; OPG), estrogen receptor alpha, calcitonin receptor (CALCR), and vitamin D receptor (VDR) genes. In patients and 50 matched healthy controls, we assessed clinical data, serum markers of bone metabolism, and subclinical inflammation. BMD was measured for the first time before/during ERT (median 6.7 years).

Results: Forty-two percent of patients were splenectomized. ERT led to variable improvements in BMD. Distribution of gene variants was comparable between patients/controls. The AA genotype (c.1024+283G>A gene variant; VDR gene) was associated with lower scores before ERT vs GA (=0.033), was encountered in 82.3% of patients with osteoporosis and was more frequent in patients with pathological fractures. score increases during ERT were higher in patients with the CC genotype (c.9C>G variant, TNFRSF11B; OPG gene; =0.003) compared with GC (=0.003). The CC genotype (c.1340T>C variant, CALCR gene) was associated with higher Z scores before ERT than the TT genotype (=0.041) and was absent in osteoporosis. Osteocalcin and OPG were lower in patients vs controls; beta crosslaps, interleukin-6, and ferritin were higher.

Conclusions: We suggest for the first time a protective role against osteoporosis in GD1 patients for the CC genotype of the c.9C>G gene variant in the TNFRSFB11 (OPG) gene and for the CC genotype of the c.1340T>C gene variant (CALCR gene), while the AA genotype of the c.1024+283G>A gene variant in the VDR gene appears as a risk factor for lower BMDs. Serum markers suggest decreased osteosynthesis, reduced inhibition of osteoclast activation, increased bone resorption, and subclinical inflammation during ERT.
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http://dx.doi.org/10.2147/TCRM.S177480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207091PMC
October 2018

Personality Traits and Physical Complaints in Patients With Acromegaly: A Cross Sectional Multi-Center Study With Analysis of Influencing Factors.

Front Endocrinol (Lausanne) 2018 17;9:391. Epub 2018 Jul 17.

Department of Endocrinology and Metabolic Diseases, 1. Medical Clinic, University Medical Center, Mainz, Germany.

Acromegalic patients display a distinct neuropsychological profile and suffer from chronic physical complaints. We aimed to investigate in more detail these aspects in acromegalic patients, dependent on influencing factors like disease activity, age, sex, chronic medication, surgery, pituitary radiation, pituitary insufficiency and comorbidities. Cross sectional, multicentric. 129 patients (M/W 65/64, 58.3 ± 12.7 years, 53/76 with active/controlled disease). Acromegalic patients completed the following inventories: NEO-FFI, IIP-D, and the Giessen Complaints List (GBB-24), after written informed consent. Age, sex, IGF-1 concentrations, comorbidities, treatment modalities and pituitary insufficiency were documented. Acromegalic patients or specific patient-subgroups were more agreeable, neurotic, exploitable/permissive, introverted/socially avoidant, non-assertive/insecure, nurturant and less open to experience, cold/denying, domineering, compared to normal values from the healthy population (controls). Multivariable analysis demonstrated that these overall results were due to the specific patient subgroups as patients on chronic medication, with arthrosis and pituitary insufficiency. Disease activity was only associated with the trait nurturant. Higher scores for introversion were associated with arthrosis. Lower domineering was independent of any disease- or treatment related variable or comorbidity. The GBB inventory showed overall higher scores in patients, with higher scores for exhaustion and general complaints being associated with pituitary insufficiency, coronary heart disease and history of malignancy in the multivariable analysis. Joint complaints were independent of any disease- or treatment- related variable. We define new aspects of a distinct neuropsychological profile in patients with acromegaly, which are largely independent of disease activity. Chronic physical complaints are more pronounced in patients than in controls, with exhaustion and general complaints showing no association with disease activity.
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http://dx.doi.org/10.3389/fendo.2018.00391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056634PMC
July 2018

Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia.

Oncol Res Treat 2018 26;41(5):306-312. Epub 2018 Apr 26.

Background: Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited.

Method: Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs.

Results: Evidence points to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastroenteropancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs.

Conclusion: Immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load.
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http://dx.doi.org/10.1159/000488996DOI Listing
August 2019

Sequential Treatment Escalation with Dapagliflozin and Saxagliptin Improves Beta Cell Function in Type 2 Diabetic Patients on Previous Metformin Treatment: An Exploratory Mechanistic Study.

Horm Metab Res 2018 May 4;50(5):403-407. Epub 2018 May 4.

Profil Mainz GmbH & Co. KG, Mainz, Germany.

We 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 clamp with the measurement of plasma C-peptide, insulin, proinsulin, and glucagon was performed. Treatment with dapagliflozin reduced fasting glucose levels and insulin resistance (TP1). Within the hyperglycaemic clamp, C-peptide and insulin concentrations increased after the addition of dapagliflozin in TP1 (0.48±0.45 nmol*h/l; 6.24±17.9 mU*h/l) and further improved after the addition of saxagliptin in TP2 (0.38±0.34 nmol*h/l; 6.59±10.15 mU*h/l). Acute insulin response did not change after the addition of dapagliflozin (TP1), but significantly improved after the addition of saxagliptin in TP2 (0.89±0.76 mU*h/l). Both drugs improved the C-peptide/proinsulin ratio. After the addition of saxagliptin, the glucagon/insulin ratio significantly declined (TP2). Treatment escalation with dapagliflozin and saxagliptin exhibit additive effects on beta cell capacity, and improves alpha and beta cell integrity.
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http://dx.doi.org/10.1055/a-0591-9442DOI Listing
May 2018

The impact of the IGF-1 system of cancer cells on radiation response - An study.

Clin Transl Radiat Oncol 2017 Dec 5;7:1-8. Epub 2017 Oct 5.

Department of Endocrinology and Metabolic Diseases, University Medical Center, Mainz, Germany.

Background: Overexpression of the insulin-like growth factor-1 receptor (IGF-1R) is associated with increased cell proliferation, differentiation, transformation, and tumorigenicity. Additionally, signaling involved in the resistance of cancer cells to radiotherapy originates from IGF-1R. The purpose of this study was to investigate the role of the IGF-1 system in the radiation response and further evaluate its effect on the expression of DNA repair pathway genes.

Methods: To inhibit the IGF-1 system, we stably transfected the Caco-2 cell line to express a kinase-deficient IGF-1R mutant. We then studied the effects of this mutation on cell growth, the response to radiation, and clonogenic survival, as well as using a cell viability assay to examine DNA damage and repair. Finally, we performed immunofluorescence for γ-H2AX to examine double-strand DNA breaks and evaluated the expression of 84 key genes involved in DNA repair with a real-time PCR array.

Results: Mutant IGF-1R cells exhibited significantly blunted cell growth and viability, compared to wild-type cells, as well as reduced clonogenic survival after γ-irradiation. However, mutant IGF-1R cells did not show any significant delays in the repair of radiation-induced DNA double-strand breaks. Furthermore, expression of mutant IGF-1R significantly down-regulated the mRNA levels of BRCA2, a major protein involved in homologous recombination DNA repair.

Conclusion: These results indicate that blocking the IGF-1R-mediated signaling cascade, through the expression of a kinase-deficient IGF-1R mutant, reduces cell growth and sensitizes cancer cells to ionizing radiation. Therefore, the IGF-1R system could be a potential target to enhance radio-sensitivity and the efficacy of cancer treatments.
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http://dx.doi.org/10.1016/j.ctro.2017.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862664PMC
December 2017

Design of the Growth hormone deficiency and Efficacy of Treatment (GET) score and non-interventional proof of concept study.

BMC Endocr Disord 2018 Feb 13;18(1):10. Epub 2018 Feb 13.

Clinical, Medical & Regulatory Department, Novo Nordisk Pharma GmbH, 55127, Mainz, Germany.

Background: The adverse effects of growth hormone (GH) deficiency (GHD) in adults (AGHD) on metabolism and health-related quality of life (HRQoL) can be improved with GH substitution. This investigation aimed to design a score summarising the features of GHD and evaluate its ability to measure the effect of GH substitution in AGHD.

Methods: The Growth hormone deficiency and Efficacy of Treatment (GET) score (0-100 points) assessed (weighting): HRQoL (40%), disease-related days off work (10%), bone mineral density (20%), waist circumference (10%), low-density lipoprotein cholesterol (10%) and body fat mass (10%). A prospective, non-interventional, multicentre proof-of-concept study investigated whether the score could distinguish between untreated and GH-treated patients with AGHD. A 10-point difference in GET score during a 2-year study period was expected based on pre-existing knowledge of the effect of GH substitution in AGHD.

Results: Of 106 patients eligible for analysis, 22 were untreated GHD controls (9 females, mean ± SD age 52 ± 17 years; 13 males, 57 ± 13 years) and 84 were GH-treated (31 females, age 45 ± 13 years, GH dose 0.30 ± 0.16 mg/day; 53 males, age 49 ± 15 years, GH dose 0.25 ± 0.10 mg/day). Follow-up was 706 ± 258 days in females and 653 ± 242 days in males. The GET score differed between the untreated control and treated groups with a least squares mean difference of + 10.01 ± 4.01 (p = 0.0145).

Conclusions: The GET score appeared to be a suitable integrative instrument to summarise the clinical features of GHD and measure the effects of GH substitution in adults. Exercise capacity and muscle strength/body muscle mass could be included in the GET score.

Trial Registration: NCT number: NCT00934063 . Date of registration: 02 July 2009.
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http://dx.doi.org/10.1186/s12902-018-0237-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810096PMC
February 2018

Hormone secreting gastro-entero-pancreatic neuroendocrine neoplasias (GEP-NEN): When to consider, how to diagnose?

Rev Endocr Metab Disord 2017 12;18(4):393-410

Schwerpunkt Endokrinologie und Stoffwechselerkrankungen, I. Medizinischen Klinik und Poliklinik; ENETS center of excellence, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany.

Neuroendocrine neoplasms of the digestive system (GEP-NEN) represent a heterogeneous group of malignancies with various clinical presentation and prognosis. GEP-NENs can potentially affect all organs of the gastrointestinal tract; characteristically they share the biological property to produce and secrete peptides and neuroamines. About 30% of GEP-NENs are hormonally active and can cause specific clinical syndromes. The clinical presentation mainly depends on the primary site of the tumor and its functionality. Because of the wide spectrum of clinical symptoms and their misperceived rarity, diagnosis of GEP-NENs is often delayed for years and tumors are detected first in an advanced stage. Early identification of a specific hormonal syndrome can significantly impact tumor diagnosis and treatment, moreover the preoperative management of NEN hormonal release avoids potential life threatening hormonal crisis. However, GEP-NEN diagnostic work-up is challenging, it requires a multidisciplinary team and needs particular experience; standardized protocols and clinical experience are essential for a proper endocrine diagnostic work-up. In addition to the biochemical diagnostic, further radiologic and endoscopic imaging modalities are required moreover, somatostatin-receptor based functional imaging, using either Octreotide-scintigraphy or novel PET-based techniques with specific isotopes like Ga-DOTA-octreotate, plays an important role for the detection of the primary tumor as well as for the evaluation of the tumor extent.
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http://dx.doi.org/10.1007/s11154-017-9438-8DOI Listing
December 2017

Is GH dosing optimal in female patients with adult-onset GH deficiency? An analysis from the NordiNet International Outcome Study.

Clin Endocrinol (Oxf) 2017 Jun 19;86(6):798-805. Epub 2017 Apr 19.

Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, USA.

Objective: 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 (HbA ) 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 change from baseline to 4 years (∆) in HbA , fasting plasma glucose (FPG), IGF-I, lipids and waist circumference were evaluated.

Results: GH dose (mean [SE]; mg/day) was similar between females (0·22 [0·02]) and males (0·21 [0·01]) at baseline, but higher in females from year 1 (year 4, females, 0·45 [0·03]; males, 0·32 [0·02]). Mean IGF-I standard deviation score [SDS] was lower in females vs males at each treatment year; more than one-third of females still had an IGF-I SDS below 0 at year 4, compared with only 21·8% of men. An adverse lipid profile at baseline remained poor in more females than males at 4 years. Improvement in total cholesterol was significantly associated with gender (P < 0·0001), improving less in females than in males.

Conclusions: These data highlight that, even after 4 years, GH dose is suboptimal in many female patients, which may impact clinical outcomes; therefore, GH titration for women requires further improvement.
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http://dx.doi.org/10.1111/cen.13330DOI Listing
June 2017

Gender-, age- and time-dependent dosing of growth hormone in adults - real-world data from a decade of clinical practice in Germany.

Gynecol Endocrinol 2017 Jul 5;33(7):564-569. Epub 2017 Mar 5.

e Novo Nordisk Pharma GmbH , Mainz , 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 dose increased more in females than males during treatment; this was statistically significant in years 2-6 (p < 0.05). Over the 10-year study period, a time trend of an overall estimated GH dose increase by 0.06 mg/day (females) and decrease by 0.07 mg/day (males) was shown; this interaction of gender and calendar year was significant (p < 0.0001). In both genders, overall GH dose decreased with increasing age (p < 0.0001). Our study confirms that females and younger patients require higher GH doses compared with males and older patients.
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http://dx.doi.org/10.1080/09513590.2017.1296130DOI Listing
July 2017

The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review.

Oncologist 2017 03 20;22(3):272-285. Epub 2017 Feb 20.

Cancer Imaging & Neuroendocrine Service & Molecular Imaging and Targeted Therapeutics Laboratory, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Australia.

Background: Neuroendocrine tumors (NETs) are a heterogeneous group of tumors, with >50% of cases involving the gastrointestinal system or pancreas. Somatostatin analogs (SSAs) are used for treating NET-related secretory syndromes and, more recently, for their antiproliferative effects. We conducted a systematic review of published literature on the antiproliferative efficacy and safety of the SSA lanreotide Autogel in the management of NETs to gain a fuller understanding of the evidence and identify future areas of research.

Methods: Searches were conducted in PubMed up to March 16, 2016, and in the proceedings of four congresses from 2013 to 2016.

Results: Screening of 1,132 publications identified in the searches found 40 relevant publications, including 27 full-length publications and 13 congress abstracts. Twenty-four of these publications reported antiproliferative efficacy data for lanreotide Autogel. The CLARINET study showed that 120 mg lanreotide Autogel every 4 weeks improves progression-free survival (PFS) in patients with gastroenteropancreatic (GEP)-NETs, with grade 1 or grade 2 (Ki-67 <10%) disease, providing class I evidence of its antiproliferative effects. The CLARINET open-label extension study reported a median PFS of 32.8 months with lanreotide Autogel. Other smaller studies generally support CLARINET.

Conclusion: Current clinical evidence shows that lanreotide Autogel has good antiproliferative activity with favorable safety and tolerability in patients with GEP-NETs, suggesting it should be considered as an early first-line treatment in this population. Further studies are needed to assess the potential benefits of higher doses and the use of lanreotide Autogel in combination therapy and as maintenance therapy in the absence of disease progression following other therapies. 2017;22:272-285 IMPLICATIONS FOR PRACTICE: This review presents the current clinical evidence for the antiproliferative activity of lanreotide Autogel in patients with midgut or pancreatic neuroendocrine tumors (NETs) and shows its effectiveness, safety, and tolerability in these patient populations. By systematically presenting all the clinical evidence, the review adds to existing publications by discussing results in a broad range of settings. The review also indicates future directions for investigation of the use of lanreotide Autogel in NETs originating in other locations, in combination therapy, or as maintenance therapy in progressive disease.
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http://dx.doi.org/10.1634/theoncologist.2016-0305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344642PMC
March 2017

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.

Diabetes Obes Metab 2017 04 10;19(4):489-495. Epub 2017 Jan 10.

Profil, Mainz, Germany.

Aims: To investigate the effect of sequential treatment escalation with empagliflozin and linagliptin on laboratory markers of α- and β-cell function in people with type 2 diabetes mellitus (T2DM) insufficiently controlled on metformin monotherapy.

Research Design And Methods: A total of 44 people with T2DM received 25 mg empagliflozin for a duration of 1 month in an open-label fashion (treatment period 1 [TP1]). Thereafter, they were randomized to a double-blind add-on therapy with linagliptin 5 mg or placebo (treatment period 2 [TP2]) for 1 additional month. α- and β-cell function was assessed using a standardized liquid meal test and an intravenous (i.v.) glucose challenge. Efficacy measures comprised the areas under the curve for glucose, insulin, proinsulin and glucagon after the liquid meal test and the assessment of fast and late-phase insulin release after an i.v. glucose load with a subsequent hyperglycaemic clamp.

Results: Empagliflozin reduced fasting and postprandial plasma glucose levels, associated with a significant reduction in postprandial insulin levels and an improvement in the conversion rate of proinsulin (TP1). The addition of linagliptin during TP2 further improved postprandial glucose levels, probably as a result of a marked reduction in postprandial glucagon concentrations (TP2). The insulin response to an i.v. glucose load increased during treatment with empagliflozin (TP1), and further improved after the addition of linagliptin (TP2).

Conclusion: After metformin failure, sequential treatment escalation with empagliflozin and linagliptin is an attractive treatment option because of the additive effects on postprandial glucose control, probably mediated by complementary effects on α- and β-cell function.
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http://dx.doi.org/10.1111/dom.12838DOI Listing
April 2017

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.

Diab Vasc Dis Res 2017 01 20;14(1):55-58. Epub 2016 Oct 20.

Department of Gastroenterology and Diabetology, Klinikum Worms, Worms, Germany.

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, χ = 23.06, p ⩽ 0.0001). Increasing age correlated positively with decreasing rate of revascularisations (n = 122, df = 1, χ = 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 invasively treated subgroup, 13 out of 67 patients died within the observation period. Death after revascularisation was independent of age (n = 67, df = 1, χ = 2.05, p = 0.153). Mobility decreased in the whole study group with increasing age. The risk of decrease with age was not influenced by revascularisation status.

Conclusion: With careful interdisciplinary evaluation, elderly patients with diabetic foot syndrome can be treated with favourable outcome. Mobility before and after treatment deserves more attention as a predictor of treatment success and outcome parameter.
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http://dx.doi.org/10.1177/1479164116666477DOI Listing
January 2017

Impact of combined FDG-PET/CT and MRI on the detection of local recurrence and nodal metastases in thyroid cancer.

Cancer Imaging 2016 Nov 3;16(1):37. Epub 2016 Nov 3.

Department of Nuclear Medicine, Johannes Gutenberg-University Medical Center, Langenbeckstr. 1, D-55131, Mainz, Germany.

Background: Suspected recurrence of thyroid carcinoma is a diagnostic challenge when findings of both a radio iodine whole body scan and ultrasound are negative. PET/CT and MRI have shown to be feasible for detection of recurrent disease. However, the added value of a consensus reading by the radiologist and the nuclear medicine physician, which has been deemed to be helpful in clinical routines, has not been investigated. This study aimed to investigate the impact of combined FDG-PET/ldCT and MRI on detection of locally recurrent TC and nodal metastases in high-risk patients with special focus on the value of the multidisciplinary consensus reading.

Materials And Methods: Forty-six patients with suspected locally recurrent thyroid cancer or nodal metastases after thyroidectomy and radio-iodine therapy were retrospectively selected for analysis. Inclusion criteria comprised elevated thyroglobulin blood levels, a negative ultrasound, negative iodine whole body scan, as well as combined FDG-PET/ldCT and MRI examinations. Neck compartments in FDG-PET/ldCT and MRI examinations were independently analyzed by two blinded observers for local recurrence and nodal metastases of thyroid cancer. Consecutively, the scans were read in consensus. To explore a possible synergistic effect, FDG-PET/ldCT and MRI results were combined. Histopathology or long-term follow-up served as a gold standard. For method comparison, sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were calculated.

Results: FDG-PET/ldCT was substantially more sensitive and more specific than MRI in detection of both local recurrence and nodal metastases. Inter-observer agreement was substantial both for local recurrence (κ = 0.71) and nodal metastasis (κ = 0.63) detection in FDG-PET/ldCT. For MRI, inter-observer agreement was substantial for local recurrence (κ = 0.69) and moderate for nodal metastasis (κ = 0.55) detection. In contrast, FDG-PET/ldCT and MRI showed only slight agreement (κ = 0.21). However, both imaging modalities identified different true positive results. Thus, the combination created a synergistic effect. The multidisciplinary consensus reading further increased sensitivity, specificity, and diagnostic accuracy.

Conclusions: FDG-PET/ldCT and MRI are complementary imaging modalities and should be combined to improve detection of local recurrence and nodal metastases of thyroid cancer in high-risk patients. The multidisciplinary consensus reading is a key element in the diagnostic approach.
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http://dx.doi.org/10.1186/s40644-016-0096-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093960PMC
November 2016

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.

Clin Endocrinol (Oxf) 2017 Feb 21;86(2):192-198. Epub 2016 Nov 21.

Department of Endocrinology, Metabolism and Diabetology, Department of Molecular Medicine and Surgery, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.

Objective: To assess the effect of 4 years' growth hormone (GH) replacement on glucose homeostasis and evaluate factors affecting glycosylated haemoglobin (HbA ) 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 HbA values at baseline and 4 years were included in the analysis.

Measurements: Changes from baseline (∆) to 4 years in HbA , fasting plasma glucose (FPG), IGF-I, lipids (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides), waist circumference, glycaemic (HbA <5·7%; HbA , 5·7-6·5%; HbA , ≥6·5%) and metabolic health status were evaluated. Effects of baseline HbA , gender, baseline age, average GH dose and baseline body mass index (BMI) on ΔHbA were investigated. The models were adjusted for concomitant medication use.

Results: Mean (standard deviation) baseline HbA was 5·13 (0·65)% and remained at the same level at 4 years. Age at treatment start (P = 0·0094) and BMI (P = 0·0008) had a significant impact on ∆HbA . At 4 years, 85% of patients with HbA <5·7% (normal levels) at baseline and 55% of patients with HbA 5·7-6·5% (impaired glucose tolerance) at baseline remained in the same glycaemic health category. Nineteen patients improved from impaired glucose tolerance to normal HbA . Seven patients developed diabetes.

Conclusions: These data demonstrate that 4 years' GH replacement therapy did not adversely affect glucose homeostasis in the majority of adults with GHD.
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http://dx.doi.org/10.1111/cen.13256DOI Listing
February 2017

Psychiatric governance, völkisch corporatism, and the German Research Institute of Psychiatry in Munich (1912-26). Part 2.

Hist Psychiatry 2016 06 11;27(2):137-52. Epub 2016 Feb 11.

Max-Planck-Institute of Psychiatry, Munich

This is the second of two articles exploring in depth some of the early organizational strategies that were marshalled in efforts to found and develop the German Research Institute of Psychiatry (Deutsche Forschungsanstalt für Psychiatrie). The first article analysed the strategies of psychiatric governance - best understood as a form of völkisch corporatism - that mobilized a group of stakeholders in the service of higher bio-political and hygienic ends. This second article examines how post-war imperatives and biopolitical agendas shaped the institute's organization and research. It also explores the financial challenges the institute faced amidst the collapse of the German financial system in the early Weimar Republic, including efforts to recruit financial support from the Rockefeller Foundation and other philanthropists in the USA.
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http://dx.doi.org/10.1177/0957154X16629579DOI Listing
June 2016

Psychiatric governance, völkisch corporatism, and the German Research Institute of Psychiatry in Munich (1912-26). Part 1.

Hist Psychiatry 2016 Mar 28;27(1):38-50. Epub 2016 Jan 28.

Max-Planck-Institute of Psychiatry, Germany

This is the first of two articles exploring in depth some of the early organizational strategies that were marshalled in efforts to found and develop the German Research Institute of Psychiatry (Deutsche Forschungsanstalt für Psychiatrie) in 1917. After briefly discussing plans for a German research institute before World War I, the article examines the political strategies and networks that Emil Kraepelin used to recruit support for the institute. It argues that his efforts at psychiatric governance can best be understood as a form of völkisch corporatism which sought to mobilize and coordinate a group of players in the service of higher biopolitical and hygienic ends. The article examines the wartime arguments used to justify the institute, the list of protagonists actively engaged in recruiting financial and political support, the various social, scientific and political networks that they exploited, and the local contingencies that had to be negotiated in order to found the research institute.
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http://dx.doi.org/10.1177/0957154X15623692DOI Listing
March 2016

Binostril versus mononostril approaches in endoscopic transsphenoidal pituitary surgery: clinical evaluation and cadaver study.

J Neurosurg 2016 08 1;125(2):334-45. Epub 2016 Jan 1.

Klinik für Neurochirurgie, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.

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 nasal and sphenoidal phase of surgery for both techniques. For detection of tumor remnants, 30° optics were superior. The binostril approach was significantly more time consuming than the mononostril technique. The nasal retractor limited maneuverability of instruments during mononostril approaches in 5 of 20 patients. Endocrinological pituitary function, control of excessive hormone secretion, ophthalmological outcome, residual tumor, and rates of adverse events, such as CSF leaks and diabetes insipidus, were similar in both groups. In the cadaver study, there was no significant difference in the time required for dissection via the binostril or mononostril technique. The panoramic view was superior in the binostril group; this was due to the possibility of wider opening of the sella in the craniocaudal and horizontal directions, but the need for removal of more of the nasal septum was disadvantageous. CONCLUSIONS Because of maneuverability of instruments and a wider view in the sphenoid sinus, the binostril technique is superior for resection of large tumors with parasellar and suprasellar expansion and tumors requiring extended approaches. The mononostril technique is preferable for tumors with limited extension in the intra- and suprasellar area.
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http://dx.doi.org/10.3171/2015.6.JNS142637DOI Listing
August 2016

Elevated Intact Proinsulin Levels During an Oral Glucose Challenge Indicate Progressive ß-Cell Dysfunction and May Be Predictive for Development of Type 2 Diabetes.

J Diabetes Sci Technol 2015 Sep 29;9(6):1307-12. Epub 2015 Sep 29.

University-Hospital, Department of Endocrinology & Diabetes, Mainz, Germany.

Background: Elevated fasting intact proinsulin is a biomarker of late-stage ß-cell-dysfunction associated with clinically relevant insulin resistance. In this pilot investigation, we explored the potential value of measuring intact proinsulin as a functional predictor of ß-cell exhaustion during an oral glucose tolerance test (OGTT).

Methods: The study was performed with 31 participants, 11 of whom were healthy subjects (7 female, age: 59 ± 20 years), 10 had impaired glucose tolerance (IGT, 6 female, 62 ± 10 years), and 10 had known type 2 diabetes (T2DM, 5 female, 53 ± 11 years, HbA1c: 7.0 ± 0.6%, disease duration: 8 ± 5 years). During OGTT, blood was drawn after 0 hours, 1 hour, and 2 hours for determination of glucose and intact proinsulin. Five years later, patients were again contacted to assess their diabetes status and the association to the previous OGTT results was analyzed.

Results: The OGTT (0 hours/1 hour/2 hours) results were as follows: healthy subjects: glucose: 94 ± 8 mg/dL/140 ± 29 mg/dL/90 ± 24 mg/dL, intact proinsulin: 3 ± 2 pmol/L/10 ± 7 pmol/L/10 ± 5 pmol/L); IGT: glucose: 102 ± 9 mg/dL/158 ± 57 mg/dL/149 ± 34 mg/dL, intact proinsulin: 7 ± 4 pmol/L/23 ± 8 pmol/L/28 ± 6 pmol/L; T2DM: glucose: 121 ± 20 mg/dL/230 ± 51 mg/dL/213 ± 34 mg/dL; intact proinsulin: 7 ± 7 pmol/L/26 ± 9 pmol/L/27 ± 10 pmol/L). Five years later, all of the IGT and 2 of the healthy subjects had developed T2DM and one had devloped IGT. All of them had elevated 2-hour proinsulin values in the initial OGTT, while patients with normal intact proinsulin results did not develop diabetes.

Conclusions: Elevated 2-hour intact proinsulin levels during OGTT were predictive for later type 2 diabetes development. Further studies need to confirm our findings in larger populations.
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http://dx.doi.org/10.1177/1932296815607862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667304PMC
September 2015

Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues.

Drug Des Devel Ther 2015 3;9:5075-86. Epub 2015 Sep 3.

Department of Medical Sciences, Endocrine Oncology Unit, University Hospital, Uppsala, Sweden.

In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27-1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89-4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 - not reached) with pasireotide versus 6.8 months (5.6 - not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20-0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.
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http://dx.doi.org/10.2147/DDDT.S84177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562767PMC
July 2016