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123/131I-MIBG scintigraphy has shown a high specificity for imaging pheochromocytoma and paraganglioma however with low sensitivity due to low spatial resolution. 124I-MIBG PET may overcome this limitation to improve the staging of patients with (suspected) pheochromocytoma. Methods: We analyzed the sensitivity, specificity, positive and negative predictive values (PPV, NPV) of 124I-MIBG PET in 43 consecutive patients with suspected (recurrence of) pheochromocytoma using histopathological (n = 25) and clinical validation (n = 18) as standard of truth. Furthermore, we compared 124I-MIBG PET versus contrast enhanced CT (CE-CT) per-patient and per-lesion detection rate of 124I-MIBG PET in 13 additional patients with known metastatic malignant pheochromocytoma (MMP). Results:124I-MIBG PET/CT was positive in 19/43 (44%) patients with suspected pheochromocytoma. Presence of pheochromocytoma was confirmed in 22/43 (51%). 124I-MIBG PET/CT sensitivity, specificity, PPV, NPV were 86%, 100%, 100%, 88%, respectively. 124I-MIBG PET was positive in 11/13 (85%) MMP patients. Combined 124I-MIBG PET and CE-CT detected 173 lesions, of which 166 (96%) and 118 (68%) were visible on 124I-MIBG PET and CE-CT, respectively. Discussion:124I-MIBG PET detects pheochromocytoma with high accuracy at initial staging and high detection rate at re-staging. Superior diagnostic performance aids guidance of surgical and medical management including personalized 131I-MIBG therapy.

Purpose The role of streptozocin-based chemotherapy (STZ CTx) in advanced, well-differentiated pancreatic neuroendocrine tumours (PanNET) and the best sequence of treatments in advanced PanNET are unclear. We examined the outcomes after STZ CTx in patients who had been selected according to the current therapeutic guidelines. Methods Data from 50 PanNET patients consecutively treated with STZ CTx between 2010 and 2018 were analysed. The endpoints of the study were the objective-response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results STZ CTx was the first-line treatment in 54% of patients. The PanNET grades were as follows: 6% G1, 88% G2, and 6% well-differentiated G3. The ORR was 38%. Stable disease was the best response in 38% of patients and 24% showed progressive disease. Treatment was discontinued because of toxicity in one patient. Median PFS and OS were 12 (95% confidence interval (CI), 8.5–15.5) and 38 months (95% CI, 20.4–55.6), respectively. In the Kaplan-Meier analysis, the median OS was 89 months (95% CI, 34.9–143.1) for STZ CTx as first-line therapy compared with 22 months (95% CI, 19.3–24.7; p = 0.001, log-rank test) for subsequent lines. Bone metastases negatively impacted survival (HR, 2.71, p = 0.009, univariate analysis, HR, 2.64, p = 0.015, multivariate analysis, and Cox regression). Conclusions In patients selected according to current guidelines, PFS, and OS after STZ CTx were lower than previously reported, whereas ORR was unchanged. First-line treatment was positively associated with OS and the presence of bone metastases was negatively associated with OS. Pre-treatment with targeted or peptide-receptor radionuclide therapy did not alter ORR, PFS, or OS.

Objective: In clinical practice, false-positive results in biochemical testing for suspected pheochromocytoma/paraganglioma (PPGL) are not infrequent and may lead to unnecessary examinations. We aimed to evaluate the role of the clonidine suppression test (CST) in the era of analyses of plasma-free metanephrines for the diagnosis or exclusion of PPGL in patients with adrenal tumours and/or arterial hypertension. Design and Methods: This single-centre, prospective trial investigated the use of CST in 60 patients with suspected PPGL associated with out-patient elevations of plasma normetanephrine (NMN) and/or metanephrine (MN), in most cases accompanied with hypertension or an adrenal mass. Measurements of plasma catecholamines and free metanephrines were performed by liquid chromatography with electrochemical detection and tandem mass spectrometry, respectively. Results: Forty-six patients entered final analysis (n = 20 with PPGL and n = 26 with a nonfunctional adrenal mass and/or hypertension). CST reliably excluded false-positive baseline NMN results with a specificity of 100%. The sensitivity of CST improved from 85% to 94% when tumours with isolated MN increase (n = 3) were not considered. In patients with elevated baseline NMN (n = 24), CST correctly identified all patients without PPGL. Patients with falsely elevated baseline NMN results (n = 7, 26.9%) exhibited increases of baseline NMN up to 1.7-fold above the upper reference limit. Conclusion: CST qualifies as a useful diagnostic tool for differential diagnosis of borderline elevated plasma-free NMN in patients with suspected PPGL. In this context, CST helps to correctly identify all false-positive NMN screening results. in press

Neuroendokrine Neoplasien (NEN) des Verdauungstrakts stellen eine heterogene Erkrankung mit variabler klinischer Manifestation dar. Sie machen etwa 1 % aller Malignome aus. Die funktionell aktiven NEN stellen aufgrund ihrer Hormonexzesssyndrome besondere Anforderungen an Diagnostik und Therapie. Die einzig kurative Therapie der NEN ist ihre vollstandige Entfernung. Weitere Optionen sind Somatostatinanaloga, molekular-zielgerichtete Therapien, Peptid-Radiorezeptor-Therapie und systemische Chemotherapie. Die Zahl der Phase-III-Studien ist limitiert, komparative Studien fehlen fur die meisten Situationen. Eine etablierte Therapiesequenz ist daher nur selten vorhanden, die Masnahmen werden individualisiert eingesetzt. Therapieziel bei fortgeschrittenen, differenzierten neuroendokrinen Tumoren ist eine Wachstumsstabilisierung. Bei undifferenzierten neuroendokrinen Karzinomen ist die objektive Ansprechrate auf eine systemische Chemotherapie hoher, jedoch statistisch von kurzer Dauer.

Martina Morokutti-Kurz, 1 Nicole Unger-Manhart, 1 Philipp Graf, 1 Pia Rauch, 2 Julia Kodnar, 1 Maximilian Große, 2 Christian Setz, 2 Markus Savli, 3 Friedrich Ehrenreich, 4 Andreas Grassauer, 1 Eva Prieschl-Grassauer, 1 Ulrich Schubert 2 1Marinomed Biotech AG, Korneuburg, 2100, Austria; 2Institute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany; 3Biostatistik & Consulting Savli, Hartberg, 8230, Austria; 4Practice Dr. Friedrich Ehrenreich, Vienna, 1170, AustriaCorrespondence: Martina Morokutti-KurzMarinomed Biotech AG, Korneuburg, 2100, AustriaEmail martina.morokutti-kurz@marinomed.comUlrich SchubertInstitute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, GermanyEmail ulrich.schubert@fau.dePurpose: The aim of this study was to investigate whether sucking of an iota-carrageenan containing lozenge releases sufficient iota-carrageenan into the saliva of healthy subjects to neutralize representatives of the most common respiratory virus families causing common cold and SARS-CoV-2.Patients and Methods: In this monocentric, open label, prospective clinical trial, 31 healthy subjects were included to suck a commercially available iota-carrageenan containing lozenge. Saliva samples from 27 subjects were used for ex vivo efficacy analysis. The study’s primary objective was to assess if the mean iota-carrageenan concentration of the saliva samples exceeded 5 μg/mL, which is the concentration known to reduce replication of human rhinovirus (hRV) 1a and 8 by 90%. The iota-carrageenan concentration of the saliva samples was analyzed by UV-Vis spectroscopy. The antiviral effectiveness of the individual saliva samples was determined in vitro against a panel of respiratory viruses including hRV1a, hRV8, human coronavirus OC43, influenza virus A H1N1pdm09, coxsackievirus A10, parainfluenza virus 3 and SARS-CoV-2 using standard virological assays.Results: The mean iota-carrageenan concentration detected in the saliva exceeds the concentration needed to inhibit 90% of hRV1a and hRV8 replication by 134-fold (95% CI 116.3– 160.8-fold; p < 0.001). Thus, the study met the primary endpoint. Furthermore, the iota-carrageenan saliva concentration was 60 to 30,351-fold higher than needed to reduce viral replication/binding of all tested viruses by at least 90% (p < 0.001). The effect was most pronounced in hCoV OC43; in case of SARS-CoV-2, the IC 90 was exceeded by 121-fold (p < 0.001).Conclusion: Sucking an iota-carrageenan containing lozenge releases sufficient iota-carrageenan to neutralize and inactivate the most abundant respiratory viruses as well as pandemic SARS-CoV-2. The lozenges are therefore an appropriate measure to reduce the viral load at the site of infection, hereby presumably limiting transmission within a population as well as translocation to the lower respiratory tract.Trial Registration: NCT04533906.Keywords: iota-carrageenan, respiratory viruses, corona virus, lozenges, antiviral, clinical study, SARS-CoV-2

(123/131)I-metaiodobenzylguanidine (MIBG) scintigraphy has shown a high specificity for imaging pheochromocytoma and paraganglioma, but with low sensitivity because of low spatial resolution. (124)I-MIBG PET may be able to overcome this limitation and improve the staging of patients with (suspected) pheochromocytoma. Methods: We analyzed the sensitivity, specificity, and positive and negative predictive values of (124)I-MIBG PET in 43 consecutive patients with suspected (recurrence of) pheochromocytoma using histopathologic (n = 25) and clinical validation (n = 18) as the standard of truth. Furthermore, we compared the detection rate of (124)I-MIBG PET versus contrast-enhanced (CE) CT on a per-patient and per-lesion basis in 13 additional patients with known metastatic malignant pheochromocytoma. Results: (124)I-MIBG PET/CT was positive in 19 (44%) of 43 patients with suspected pheochromocytoma. The presence of pheochromocytoma was confirmed in 22 (51%) of 43. (124)I-MIBG PET/CT sensitivity, specificity, and positive and negative predictive values were 86%, 100%, 100%, and 88%, respectively. (124)I-MIBG PET was positive in 11 (85%) of 13 patients with malignant pheochromocytoma. Combined (124)I-MIBG PET and CE CT detected 173 lesions, of which 166 (96%) and 118 (68%) were visible on (124)I-MIBG PET and CE CT, respectively. Conclusion: (124)I-MIBG PET detects pheochromocytoma with high accuracy at initial staging and a high detection rate at restaging. Future assessment of (124)I-MIBG PET for treatment guidance, including personalized (131)I-MIBG therapy, is warranted.

Corticosteroids and macrolide immunomodulators such as tacrolimus are effective drugs for the topical treatment of inflammatory eye diseases like allergic conjunctivitis or dry eye. However, tacrolimus is practically insoluble in aqueous solutions and is therefore currently formulated as dispersion. This leads to low bioavailability. Here, we present a novel pharmacologically acceptable, aqueous formulation of tacrolimus based on the "Marinosolv formulation platform". Marinosolv allows the solubilization and thereby improvement of the bioavailability of many otherwise practically insoluble drugs, since dissolved drugs permeate faster into tissues, including ocular tissues. To visualize the benefits of Marinosolv in ophthalmic formulations, we investigated the permeation of a fluorescently labeled estradiol dissolved in Marinosolv compared to a formulation containing the compound as dispersion. Permeation was studied ex-vivo and in-vivo in porcine eyes. Further, we evaluated the improved permeation of topically applied tacrolimus dissolved in Marinosolv compared to a commercially available topically applied tacrolimus dispersion. The Marinosolv formulation was also compared to oral tacrolimus treatment, the standard application route for this drug in case of severe posterior uveitis. Finally, the ocular tissue levels of tacrolimus in all groups were determined using HPLC/MS. We demonstrated that tacrolimus dissolved in Marinosolv reached significantly higher levels in ocular tissues compared to the marketed topical product or after oral application and thus may be a suitable novel option for the treatment of several eye diseases, such as allergic conjunctivitis or uveitis. Thus, Marinosolv may be considered as a new vehicle for tacrolimus eye drops.

Due to high morbidity and mortality of untreated hypercortisolism, a prompt diagnosis is essential. Measurement of late-night salivary cortisol provides a simple and non-invasive method. However, thresholds and reference ranges differ among studies. The goal of this study was to define a threshold of late-night salivary cortisol for the diagnosis of hypercortisolism based on the used assay. Moreover, the influence of different aetiologies of hypercortisolism and individual comorbidities were investigated. Prospective analyses of 217 patients, including 36 patients with proven hypercortisolism were carried out. A sum of 149 patients with suspicion of hypercortisolism but negative endocrine testing and 32 patients with hypercortisolism in remission served as control group. Late-night salivary cortisol was measured using an automated chemiluminescence immunoassay. Cut-off values were calculated by ROC analysis. The calculated cut-off value for the diagnosis of hypercortisolism was 10.1 nmol/l (sensitivity 94%; specificity 84%). Only slightly lower thresholds were obtained in patients with suspected hypercortisolism due to weight gain/obesity (9.1 nmol/l), hypertension or adrenal tumours (both 9.8 nmol/l) or pituitary adenomas (9.5 nmol/l). The late-night salivary cortisol threshold to distinguish between Cushing’s disease and Cushing’s disease in remission was 9.2 nmol/l. The cut-off value for the diagnosis of ectopic ACTH-production was 109.0 nmol/l (sensitivity 50%, specificity 92%). Late-night salivary cortisol is a convenient and reliable parameter for the diagnosis of hypercortisolism. Except for ectopic ACTH-production, thresholds considering different indications for evaluation of hypercortisolism were only slightly different. Therefore, they might only be useful if late-night salivary cortisol results near the established cut-off value are present.

Introduction: Aggressive atypical pituitary tumors are characterized by invasive growth, recurrence and resistance to standard therapies. We present two female patients with pituitary adenomas in whom multiple other therapies had failed, who presented with significant response to temozolomide. Case presentations: In patient #1 (w, 78y), the diagnosis of macroprolactinoma had been made in a community hospital and dopaminagonistic treatment with bromocriptin had been initiated. After failure to achieve significant tumor reduction under this treatment and persisting visual field disturbances, first transnasal-transphenoidal surgery (TSS) was performed in 07/2011, followed by cabergoline exposure in increasing dose due to failure to control prolactin levels. Repeat TSS and stereotactic radiosurgery were performed in both 2014 and 2018 because of invasive tumor growth and double vision. She was then put on temozolomide. Patient #2 (w, 58y) presented with apoplectic gonadotropinoma in 2013. She also underwent 3 courses of TSS as well as stereotactic radiosurgery because of repeated tumor growth leading to visual field disturbances and double vision. Despite these measures, the tumor could not be controlled and she, as well, was put on temozolomide in 2018. In both cases costs were reimbursed by the patient’s health care insurance and in both the first cycle was conducted with 150 mg/ body surface area (BSA) with escalation to 200 mg/BSA in the second. After only 2 cycles, double vision resolved in both patients and the tumor had shrunk by approximately 20% on MRI in patient #1 and even more in patient #2. In both patients, temozolomide dose was reduced again to 150 mg/BSA due to side effects. Nevertheless, in both patients tumor volume further continued to decrease under therapy. Conclusion: This promising clinical course after exposure to temozolomide with early, significant tumor shrinkage in two heavily pretreated patients with aggressive pituitary adenomas indicates that this therapy can be considered also in older patients and may yield astonishing results. Although temozolomide is increasingly becoming a therapeutic option for those patients whose pituitary tumors are refractory to standard therapies, further research and observance over time of temozolomide therapy in aggressive pituitary adenomas and carcinomas is indicated.

Introduction While reasons for non-adherence in children requiring growth hormone (GH) replacement (GH-Rx) are well researched, few studies have investigated adherence in adult GH deficient patients. Against the background of the adverse medical sequelae of untreated severe GH deficiency (GHD) in adults, we explored adherence to GH-Rx and associated factors in this patient group. Method Cross-sectional analysis including 107 adult patients with severe GHD on GH-Rx, 15 untreated GDH patients and 19 who had discontinued therapy. Patients completed self-developed ad hoc surveys on adherence to medication and GH-Rx, specific beliefs about GH-Rx, side effects and burden of injection, reasons for never receiving or dropping out of therapy, respectively. Results Adherence to GH-Rx was high (mean 15.8/18 points on the self-developed adherence score) and significantly correlated with general medication adherence. Higher age was significantly associated with better adherence to GH-Rx, while injection side effects, duration of treatment or device used were not. The most frequent reasons for not being on GH-Rx apart from medical reasons included fear of side effects, lack of belief in treatment effects and dislike of injections. In patients not on GH-Rx, the proportion of patients in employment was significantly smaller than in the treatment group, despite similar age and comorbidities. Conclusions Adherence to GH-Rx was high for those patients on therapy. Instead of focusing on improving adherence in those adults already on GH-Rx, efforts should be undertaken to ally fear of side effects and provide education on positive treatment effects for those eligible but not receiving therapy.

Background Budesonide, a poorly water‐soluble corticosteroid, is currently marketed as a suspension. Budesolv is a novel aqueous formulation containing dissolved budesonide showing increased local availability in preclinical models. Budesolv contains ~85% less corticosteroid than the marketed comparator. Objective The study (EudraCT:2018‐001324‐19) was designed to assess non‐inferiority of Budesolv compared to Rhinocort® Aqua 64 (RA) and early onset of action. Methods In a three‐way cross‐over double‐blinded randomized trial, Budesolv 10 was compared to RA and placebo in grass pollen allergic rhinoconjunctivitis volunteers (n = 83 (ITT); n = 75 (PP)). On day 1, participants entered the Vienna Challenge Chamber (VCC) for 6 hours; first treatment took place at 1:45 hours after entry. Participants treated themselves for further 6 days; on day 8, the last treatment was applied before entering the VCC. Subjective symptom scores, nasal airflow and nasal secretion were measured regularly during allergen challenge. Results Budesolv 10 was equally effective compared to RA with respect to TNSS and nasal airflow after eight days of treatment with a strongly reduced dose (more than 80% reduction). After first dose, only Budesolv 10 showed a significant reduction of nasal and respiratory symptoms starting 90 minutes (P

About one third of global edible food is lost or wasted along the supply chain, causing the wastage of embedded natural and economic resources. Life cycle methodologies can be applied to identify sustainable and viable prevention and valorization routes needed to prevent such inefficiencies. However, no systemic approach has been developed so far to guide practitioners and stakeholders. Specifically, the goal and scoping phase (e.g. problem assessed or system function) can be characterized by a large flexibility, and the comparability between food waste scenarios could be not ensured. Within the Horizon2020 project Resource Efficient Food and dRink for the Entire Supply cHain, this study aimed to provide practitioners with guidance on how to combine life cycle assessment and environmental life cycle costing in the context of food waste. Recent literature was reviewed to identify relevant methodological aspects, possible commonly adopted approaches, main differences among studies and standards and protocols, main challenges, and knowledge gaps. Basing on this review, an analytical framework with a set of recommendations was developed encompassing different assessment situations. The framework intends to provide a step by step guidance for food waste practitioners, and it is composed of a preliminary section on study purpose definition, three decision trees—respectively on assessment situation(s), costing approach, and type of study (footprint vs. intervention)—and two sets of recommendations. Recommendations can be applied to all levels of the food waste hierarchy, stating a generic order of preference for handling food chain side flows. This consistent and integrated life cycle approach should ensure a better understanding of the impact of specific interventions, thus supporting informed private and public decision making and promoting the design of sustainable and cost-efficient interventions and a more efficient food supply chains.

The increase in recycling targets is seen as an important contribution towards a circular economy as envisioned by the European Union. Waste Electrical and Electronic Equipment (WEEE) is highly complex and heterogeneous and one of the fastest growing waste streams in the EU. Its recycling typically consists of pre-treatment, recovery of secondary resources (materials and energy), and disposal. Legal recycling targets, stated by the European Commission, are exceeded by leading pre-treatment operators driven by economic needs. While recycling has been shown in the past to have greenhouse gas benefits, no study could be found that compares WEEE recycling at two different recycling rates using industry data. Therefore, this study investigates: (1) How much secondary material is recovered from WEEE at a certain recycling rate and (2) what is the associated greenhouse gas impact of the WEEE end-of-life system? The results of two end-of-life systems operating at different recycling rates are compared and analysed. A leading Austrian pre-treatment facility provided data and know-how for this case study. One system describes the current practice at the pre-treatment facility (recycling rate: 80.5%) and the other system operates at the same facility close to the legally required minimum target set by the European WEEE directive (62.5% for this specific input material). In terms of secondary material recovery, the study shows that a recycling rate of 80.5% enables recovery of just above halve of the input material, while for recycling close to the legal target the amount of recovered material is around 45%. The differences are due to less recycling of plastics, ferrous materials and copper. Regarding the greenhouse gas impact, recycling at a rate of 80.5%, the Austrian pre-treatment site proves to avoid at least 215 kg of CO2 equivalents per ton WEEE input compared to recycling WEEE at the same facility close to the legal minimum recycling target. In the authors’ view a mandatory recycling rate above 80% would be difficult to fulfil as, according to the pre-treatment facility operator, additional costs of better separation would outweigh any additional revenues from secondary material.

Background: Metyrapone is a steroidogenesis inhibitor approved in Europe for the treatment of endogenous Cushing’s syndrome (CS) based on observational retrospective studies published over more than 50 years. We present data from the first prospective study designed to confirm metyrapone efficacy and good tolerance in patients with CS. Methods: This single arm, open-label, multicenter, international trial enrolled 50 patients with CS who had three baseline 24 hours urine free cortisol (UFC) values at least 50% above the upper limit of normal (ULN=165 nmol/24h). Metyrapone was titrated over 12 weeks (W12) to achieve normal urine (mean of 3 values, mUFC) and serum cortisol levels. Patients whose mUFC did not exceed 2-fold the ULN could enter a 6-month extension period. The primary efficacy endpoint was the proportion of patients with mUFC ≤ ULN at W12 assessed in a central laboratory using LC-MS/MS. The most important secondary endpoint was mUFC decrease of ≥ 50% at W12. Results: At baseline: mean age was 47 years, median mUFC (range) was 570 (291 - 8476) nmol/24h (3.5 x ULN). Hypercortisolism was in 96% of patients either moderate (mUFC ≥ 2xULN; < 5x ULN) in 63% or severe (≥5 x ULN) in 33%. Hypertension (69%) and diabetes mellitus (47%) were the most common comorbidities. At W12: 47% (23/ 49) met primary endpoint. Another 40% (19 / 49) had mUFC ≤ 2xULN. Median percentage decrease in mUFC from baseline to W12 was -74%. Secondary endpoint was met by 80% of patients who had a mUFC decrease of 50%. Final median metyrapone dose was 1500 (250; 5500) mg/day. Physical signs and symptoms were normalized or improved in 66% of patients. Circulating cholesterol, HbA1C and fasting glucose and insulin improved with median decrease of 12%, 3%, 5% and 9% respectively and median systolic and diastolic blood pressure also decreased by 4 and 5mmHg respectively. Among patients with antihypertensive treatments, 10 (31%) had a decrease in number of drugs and 5 (16%) had an increase in number of drugs during the study. Median ACTH increased by 11 % from baseline. Twenty six (52%) patients experienced mild to moderate study drug related adverse events (AEs). One patient discontinued before W12 because of an unrelated SAE on day 2 (pneumonia with septic shock). The most common AEs were nausea (24%), decreased appetite (18%), fatigue (14%), headache (10%), peripheral edema (6.0%), hypokalemia (6.0%) and hypertension (6.0%). Reversible adrenal insufficiency occurred in 6 (12%) patients. Few patients 14% (7/50) experienced at least one AE that led to a dose interruption or dose adjustment. Cushing Quality of Life Questionnaire increased of 10 points from baseline which is close to minimal clinically important difference = 10.1. Conclusions: This prospective study in patients with CS confirms that metyrapone effectively lowers UFC levels with a tolerability profile similar to the previously reported safety profile and improves QoL, at Week 12.

Elektroaltgerate stellen mit einem jahrlichen Zuwachs von 3 bis 5 % einen der am schnellsten wachsenden Abfallstrome in Europa dar. Vorgaben und Ambitionen der Europaischen Union zielen auf die Vermeidung des Anfalls von Elektroaltgeraten, eine nachhaltige Ressourcennutzung sowie eine Beschrankung von gefahrlichen Stoffen ab. Im Rahmen eines FFG-Forschungsprojekts wurden die Materialstrome von Elektrokleingeraten entlang der gesamten Verwertungskette und die dabei auftretenden Materialverluste von der Sammlung bis zur Sekundarressource untersucht. Dabei wurden neue Ansatze zur Sammlung von Elektrokleingeraten aus Haushalten recherchiert sowie ein stochastisches Modell zur Abschatzung der Materialzusammensetzung des Outputs einer mechanischen Behandlungsanlage basierend auf dem Inputmaterial (Sammelware) entwickelt. Primardaten wurden in Kooperation mit dem Betreiber einer osterreichischen mechanischen Aufbereitungsanlage im Rahmen von Batchversuchen sowohl fur das Inputmaterial in die Anlage wie auch fur die Outputstrome erhoben. Die prognostizierte Zusammensetzung des Anlagenoutputs wurde mit den tatsachlichen Outputstromen verglichen. Die Verwertungskette zeigt, dass bei derzeitigen osterreichischen Sammelmengen und stofflichem Recycling am Stand der Technik 28 bis 31 % der in Verkehr gebrachten Geratematerialien zuruckgewonnen werden konnen. Anders ausgedruckt bedeutet dies, dass 69 bis 72 % des Materials der in Verkehr gesetzten EKG trotz Sammlung und Recycling verloren gehen. Die grosten Materialverluste (und damit einhergehend die grosten Verbesserungspotenziale) treten in der Sammlung (41 % Verluste) und in der stofflichen Verwertung (30 bis 36 % Verluste) auf. Die Recherche von Sammelsystemen zeigt, dass die Rucknahme durch den Handel sowie die Sammlung im offentlichen Raum vielversprechende Beitrage zur Erhohung der Sammelmengen liefern konnen. Die modellbasierte Outputschatzung zeigte fur Leiterplatten, Eisen und Kunststoffe eine zufriedenstellende Genauigkeit.

Nearly 800 million people in India lack access to adequate sanitation. The choice of technology for addressing this need may have important sustainability implications. In this study, we used life cycle assessment to compare environmental impacts and nutrient recovery potentials of four different options for providing everyone in India with access to improved sanitation: (i) centralised wastewater treatment with sequential batch reactors (SBR), (ii) twin-pit latrines, (iii) latrines with source separation only and (iv) latrines with source-separation of urine and faeces connected to biogas plants. Results revealed large variability. Closing the sanitation gap through pit latrines would be expected to cause large increases of India's annual greenhouse gas (GHG) emissions, equivalent to 7% of current levels. Source separation only and centralised plants with SBR will be associated with lower GHG emissions, while the biogas scenario shows a potential to provide net emission reduction. The study revealed that source separating systems can provide significant quantities of plant available nitrogen and phosphorus at the country level. Future research should include more technological options and regions. Methodology piloted in this study can be integrated into the planning and design processes for scaling up sanitation in India and other countries.

Introduction: Juvenile Paget’s disease (JPD), an ultra-rare, debilitating bone disease due to loss of functional osteoprotegerin (OPG), is caused by recessive mutations in TNFRFSF11B. A genotype–phenotype correlation spanning from mild to very severe forms is described. Aim: This study aimed to describe the complexity of the human phenotype of OPG deficiency in more detail and to investigate heterozygous mutation carriers for clinical signs of JPD. Patients: We investigated 3 children with JPD from families of Turkish, German, and Pakistani descent and 19 family members (14 heterozygous). Results: A new disease-causing 4 bp-duplication in exon 1 was detected in the German patient, and a microdeletion including TNFRFSF11B in the Pakistani patient. Skeletal abnormalities in all affected children included bowing deformities and fractures, contractures, short stature and skull involvement. Complex malformation of the inner ear and vestibular structures (2 patients) resulted in early deafness. Patients were found to be growth hormone deficient (2), displayed nephrocalcinosis (1), and gross motor (3) and mental (1) retardation. Heterozygous family members displayed low OPG levels (12), elevated bone turnover markers (7), and osteopenia (6). Short stature (1), visual impairment (2), and hearing impairment (1) were also present. Conclusion: Diminished OPG levels cause complex changes affecting multiple organ systems, including pituitary function, in children with JPD and may cause osteopenia in heterozygous family members. Diagnostic and therapeutic measures should aim to address the complex phenotype.

Context Despite growing evidence that temozolomide (TMZ) therapy is effective for the treatment of aggressive pituitary tumors (APTs) or carcinomas (PCs), individual therapy decisions remain challenging. Objective We therefore aimed to report on clinical characteristics leading to initiation of TMZ therapy and to add evidence on TMZ long-term effectiveness. Design and subjects Retrospective survey on TMZ treatment in patients with APTs or PCs. TMZ therapy was initiated in 47 patients (22 females) with APTs (n = 34) or PCs (n = 13). Mean age at diagnosis was 45 ± 15 years. The immunohistochemical subtypes were corticotroph (n = 20), lactotroph (n = 18), and nonfunctioning (n = 9) tumors. TMZ therapy started 8 years after initial diagnosis using a standard regimen (median 6 cycles) for the majority of patients. Results Long-term radiological response to TMZ after a median follow-up of 32 months with 4 patients still on TMZ therapy was tumor regression for 9 (20%), stable disease for 8 (17%), and tumor progression for 29 patients (63%) (outcome data available for 46 patients). Progression occurred 16 months after initiation of TMZ. Median estimated progression-free survival was 23 months. Disease stabilization and median progression-free survival did not differ between patients with APTs or PCs. Predictors of tumor response were not identified. Overall, TMZ was well tolerated. Conclusion We performed a nationwide survey on TMZ therapy in patients with APTs and PCs. While early response rates to TMZ are promising, long-term outcome is less favorable. Prolonged TMZ administration should be considered. We were not able to confirm previously reported predictors of tumor response to TMZ.

Introduction:Traditional patient-clinician relationships are paternalistic in the sense that the clinician makes the decision of what is best for the patient. However, modern medicine requires a paradigm shift away from this type of interaction and a drive towards more patient-centered care, implying that physicians must gain a broader knowledge about the patients’ view of their illness. This also hold true for neuroendocrine disorders such as acromegaly. Here, we present the results of a focus group with acromegaly patients on their perceptions and needs concerning their illness. Patients and method:As a pre-project for a larger questionnaire study, a focus group research was conducted. Six patients with acromegaly who could not be cured by neurosurgery but required further therapies such as medical treatment and/or radiotherapy took part in this group, which was moderated by an external medical communication company (SDMed. Cologne, Germany). The group discussion focused on topics such as impact of the illness on everyday life and support needs. Results: The patients reported that the diagnosis “acromegaly” was experienced as a nightmare but also a relief after a long medical odyssey. The management of numerous doctors’ visits, procuring and applying medication (“illness as a part-time job”), the irreversible bodily changes due to acromegaly (“buying shoes ruins my day”, “I cannot look at photographs of myself”, “buying work gloves is simply impossible”), treating physicians’ lack of knowledge about the disease, but also a lack of reliable information for patients and relatives, maintaining the cold chain for medication when travelling and fears of the results of medical investigations were named as chronic stressors of living with acromegaly. Patients’ coping strategies included family support, sport, activities to balance out work and everyday life, and humor. The participants wished for a more interdisciplinary treatment of their illness, medical rehabilitation services with special knowledge on acromegaly-related morbidity, a stable contact person in the medical process and reliable information material about their illness for themselves and their relatives. Conclusion: Next to traditional medical care, a successful management of acromegaly requires knowledge about the everyday illness-related stressors and patients’ desires for successful treatment. Placing the focus solely on normalization of IGF-I levels does not seem to be adequate. This study was sponsored under a grant from Ipsen. Ipsen had no input into the study design, analysis or interpretation of results.

Pseudohypoparathyroidism 1A (PHP1A) consists of signs of Albright hereditary osteodystrophy (AHO) and multiple, variable hormonal resistances. Elevated PTH levels are the biochemical hallmark of the disease. Short stature in PHP1A may be caused by a form of accelerated chondrocyte differentiation leading to premature growth plate closure, possibly in combination with GH deficiency in some patients. Treatment of short stature with recombinant growth hormone (rhGH) in pediatric patients may improve final height if started during childhood. The 10 11/12-year-old boy with clinical signs of AHO presented for evaluation of short stature [height standard deviation score (SDS) −2.72]. Clinically his mother was affected by AHO as well. A heterozygous mutation c.505G>A (p.E169K) in exon 6 of the GNAS gene confirmed a diagnosis of PHP1A in the boy. However, hormonal assessment was unremarkable except for low serum IGF-1 (SDS −2.67). On follow-up, GH deficiency due to GHRH resistance was suspected and confirmed by clonidine and arginine stimulation tests. Treatment with rhGH (0.035 mg/kg) for 2 years resulted in catch-up growth (height SDS −1.52). At age 15 years the PTH levels and bone age of the patient remain within the normal range. In patients with PHP1A, short stature is caused by the effects of Gs-α deficiency on the growth plate. However, resistance to GHRH and the resulting GH deficiency might also contribute. Recombinant GH treatment increases growth in these patients. Diagnostic workup for GH deficiency as a factor contributing to short stature is recommended even in the absence of other hormonal resistances.

Food waste prevention and valorization are needed to reduce environmental and economic costs of food systems. However, these measures will have different environmental and economic effects and tradeoffs. Therefore, a consistent and integrated life cycle framework is needed to generate reliable information for both individual stakeholders and policy makers. Within the H2020 project REFRESH (Resource Efficient Food and dRink for the Entire Supply cHain), this study aimed to provide practitioners with guidance on how to combine Life Cycle Assessment (LCA) and Life Cycle Costing (E-LCC) methodologies, with a focus on the impact of food waste, its prevention, and valorization. Building on existing standards, protocols and scientific literature, a framework, consisting of methodologically structured recommendations was developed for clearly defined assessment situations. The framework is composed of a section on study purpose definition, three decision trees - on assessment situation(s), costing approach, and type of study (footprint vs. intervention) - and two sets of recommendations. The framework will be tested in the next phase of the project on selected food chain side flows.

Due to fast nasal mucociliary clearance, only the dissolved drug content can effectively permeate the mucosa and be pharmaceutically active after intranasal application of suspensions. Therefore, the aim of this study was to increase the budesonide concentration in solution of a nasal spray formulation. Budesonide, a highly water-insoluble corticosteroid, was successfully solubilized using a micellar formulation comprising escin, propylene glycol and dexpanthenol in an aqueous buffered environment (&ldquo, Budesolv&rdquo, ). A formulation based on this micellar system was well-tolerated in the nasal cavity as shown in a good laboratory practice (GLP) local tolerance study in rabbits. Ex vivo permeation studies into porcine nasal mucosa revealed a faster and more efficient absorption. Budesolv with 300 &micro, g/mL solubilized budesonide resulted in a budesonide concentration of 42 &micro, g/g tissue after only 15 min incubation. In comparison, incubation with the marketed product Rhinocort&reg, aqua 64 (1.28 mg/mL budesonide as suspension) led to 15 &micro, g/g tissue. The in vivo tumor-necrosis-factor (TNF)-&alpha, secretion in an acute lung inflammation mouse model was significantly reduced (p &lt, 0.001) following a prophylactic treatment with Budesolv compared to Rhinocort&reg, aqua 64. Successful treatment 15 min after the challenge was only possible with Budesolv (40% reduction of TNF-&alpha, p = 0.0012) suggesting a faster onset of action. The data reveal that solubilization based on saponin micelles presents an opportunity for the development of products containing hardly soluble substances that result in a faster onset and a better topical treatment effect.

Objective Purpose of this DBPC study was to evaluate onset of action and non-inferiority of a novel low dose aqueous solution of Budesonide (“Budesolv 10μg”) to Rhinocort® aqua 64μg (RA) in adult grass pollen allergic patients. Methods Budesonide, a poorly water-soluble corticosteroid, currently marketed as suspension, was reformulated to enhance solubility and local concentration on the target mucosa. Subjects received Budesolv, the market comparator RA and placebo once daily for 8 days. Allergic symptoms were induced by 6h grass pollen challenges in the Vienna Challenge Chamber at days 1 and 8 of each treatment period. First dose was applied after 1:45h to evaluate onset of action of either treatment. Nasal, ocular, asthma symptoms and objective measures of nasal secretion and nasal obstruction were evaluated. A 95% confidence interval (CI) was calculated for difference in means between active treatments. Non-inferiority was stated if the upper limit of the CI did not exceed 115% of the reference. Onset of action was defined as first time point when the difference in nasal symptoms change from baseline between active treatment and placebo was p Results 75 patients concluded the study per protocol. The primary endpoint (TNSS; sum of obstruction, itch, sneeze and rhinorrhoea) was met proving non-inferiority of Budesolv compared to RA. A significant difference between Budesolv and placebo was shown for TNSS 2.45 h and for total asthma score 2 h after first dose. On day 8 Budesolv 10μg was significantly better than placebo for all parameters evaluated. Conclusion Non-inferiority of Budesolv compared to Rhinocort® was shown on day 8 of treatment. Early onset of action within 3h after first dose was evident for Budesolv only.

The presentations addressed the topic of food waste management in a circular economy from various angles. Understanding the amount of food waste generated and setting measures to prevent it should be the starting point. Any not prevented food waste should be valorised aiming at a positive triple bottom line (social, economic and environmental). The huge environmental and economic potential of co-digestion of dairy manure and food wastes by linking waste producers with costumers for derived products was demonstrated for the US. Further the link between bio-waste, compost and soil quality is highlighted which contributes to food security and the wider bio-economy. Looking forward research into the application of selected agri-food wastes to produce alternative sources of protein could result in more sustainable source of proteins able to compete with industrial chicken production. Overall, the presentations and discussions showed the multi-facetted nature of food waste management emphasising that a range of measures by many stakeholders are required to move towards a circular economy society.

Whereas microglia involvement in virtually all brain diseases is well accepted their role in the control of homeostasis in the central nervous system (CNS) is mainly thought to be the maintenance of neuronal function through the formation, refinement, and monitoring of synapses in both the developing and adult brain. Although the prenatal origin as well as the neuron-centered function of cortical microglia has recently been elucidated, much less is known about a distinct amoeboid microglia population formerly described as the "fountain of microglia" that appears only postnatally in myelinated regions such as corpus callosum and cerebellum. Using large-scale transcriptional profiling, fate mapping, and genetic targeting approaches, we identified a unique molecular signature of this microglia subset that arose from a CNS endogenous microglia pool independent from circulating myeloid cells. Microglia depletion experiments revealed an essential role of postnatal microglia for the proper development and homeostasis of oligodendrocytes and their progenitors. Our data provide new cellular and molecular insights into the myelin-supporting function of microglia in the normal CNS.

Objective For secondary adrenal insufficiency (SAI), established biochemical parameters for dosage control are lacking and no optimal substitution dosage and daily distribution have been determined yet. Therefore, in clinical practice, the individual total dose is often adjusted based on patients' subjective well-being. Design Effects of three standard glucocorticoid replacement regimens on psychological variables were assessed in patients with SAI based on a randomized double-blind study design. Methods SAI patients (n=18) were treated with three different established glucocorticoid replacement regimens in a randomized, double-blind, crossover study (treatment A, hydrocortisone 10 mg-placebo-5 mg-placebo; treatment B, hydrocortisone 10 mg-5 mg-placebo-5 mg; and treatment C, prednisone 5 mg-placebo-placebo-placebo). Following each 4-week replacement regimen, quality of life (SF-36) and emotional distress (brief symptom inventory (BSI)) were assessed along with diurnal changes in current well-being (Bf-S) and alertness (Stanford Sleepiness Scale (SSS)) using validated questionnaires, and additionally compared with patient (patients with pituitary disease and adrenal sufficiency) and healthy control groups. Results SAI patients showed improvements in physical quality of life (i.e. SF-36 physical function, PPP Conclusions Although the observed improvements in psychological parameters were comparatively small, our results indicate beneficial effects of a 10-0-5-0 mg hydrocortisone replacement regimen. Nevertheless, treatment effects were insufficient to restore subjective health compared with healthy controls, indicating the need for improved replacement regimens and supportive psychosocial interventions in SAI patients.

An open-label, multi-center, expanded access study was conducted in patients with advanced neuroendocrine tumors (NET) treated with everolimus (10 mg/day) to assess safety and health-related quality of life (HRQOL). Of the 246 patients enrolled, 126 have pancreatic NET (pNET) and 120 have non-pNET. Patients continued treatment until disease progression, unacceptable toxicity, death, until commercial availability of everolimus, or May 2012, whichever came first. Adverse events (AEs) were analyzed according to Common Terminology Criteria version 4.0. HRQOL was assessed at baseline, for three 28-day cycles, and then at every three cycles until end of treatment (EOT) with EQ-5D, EORTC QLQ-C30, and EORTC QLQ-GINET21 instruments. The most common grade 3 or 4 AEs included hyperglycemia, infections, stomatitis, fatigue, and abdominal pain. In patients with pNET, mean (± SD) EQ VAS score remained stable at EOT (baseline, 68.8 ± 19.9 vs. EOT, 66.5 ± 20.6) without clinically significant change in QLQ-C30 global health status (change from baseline, - 3.9; n = 86). For patients with non-pNET, a reduction in EQ VAS score (63.9 ± 19.0 vs. 55.3 ± 23.0) with clinically significant changes in QLQ-C30 global health status (-13.0; n = 69) was seen by EOT. EQ-5D utility scores remained stable in patients with pNET and a moderate decrease was reported by patients with non-pNET. The safety profile of everolimus was consistent with the previous studies without adversely affecting HRQOL in pNET. Lower baseline HRQOL scores and more frequent comorbidities might have contributed to the worse outcomes in non-pNET. EudraCT no. 2010-023032-17

Sunitinib treatment leads to improvement in progression-free survival in patients with advanced pancreatic neuroendocrine tumours (pNETs). However, limited data exist regarding the effectiveness, safety and tolerability in clinical practice. We present the results of the first detailed pNET cohort analysis since sunitinib was approved. Patients with advanced, differentiated pNET treated with sunitinib were retrospectively analysed. All patients had progressive disease before start of sunitinib treatment. Twenty-one patients, with a median age of 64 years (range 28-78), were included in this study. Nineteen patients could be analysed for treatment effectiveness. Twelve (57%) patients exhibited either a partial response (1 patient) or stable disease (11 patients) according to the RECIST criteria. The median progression-free survival was 7.0 months (95% CI 3.0-12.0); the probability of being event-free at 6 months was 52.6% (95% CI 28.4-72.1). Potential influencing factors as Ki-67 index, age or duration of disease did not show significant correlations with the response to sunitinib therapy. Considering the differences in patients' characteristics, sunitinib in daily practice showed effectiveness parameters similar to the phase III trial.

Adrenal pheochromocytomas are neoplasms characterized by catecholamine excess. Determination of metanephrines by high-pressure liquid chromatography has been well established for the diagnosis of pheochromocytomas, demonstrating high sensitivity and specificity. This study evaluates the diagnostic value of newly available enzyme immunoassays for metanephrines in plasma and urine. Chromogranin A was studied as a potential additional diagnostic tool. Spontaneous blood samples and 24-h urine samples were collected in 149 subjects, including 24 histologically proven pheochromocytomas, 17 aldosterone-secreting and 21 cortisol-secreting adrenal adenomas, 30 nonfunctioning adrenal masses, 15 patients with essential hypertension and 42 healthy normotensive volunteers. Plasma and urinary metanephrine and normetanephrine as well as chromogranin A were determined and putative thresholds were calculated by ROC analysis. Plasma free normetanephrine was found to be the best single parameter with the highest sensitivity (89.5%) and specificity (98.3%) using a threshold of 167 pg/ml. Analysis of the combination of plasma free metanephrines revealed a similar sensitivity with lower specificity of 90.0%. Considering both urinary parameters demonstrated a slightly higher sensitivity (92.9%) with lower specificity (77.6%). ROC analysis revealed a threshold of 215 µg/l for chromogranin A with rather low sensitivity (73.9%) and specificity (74.2%). A weak positive correlation was found between the tumor size of pheochromocytomas and plasma metanephrine (r = 0.53, p ≤ 0.05) as well as chromogranin A (r = 0.60, p ≤ 0.01). In conclusion, plasma free and urinary metanephrines measured by enzyme immunoassays are convenient and reliable parameters for the diagnosis of pheochromocytoma. In contrast, CgA demonstrated poor sensitivity and specificity.

Introduction “Food and drink” products are the basis of life. However, it is recognised that their supply also contributes to the environmental impacts associated with production and consumption. Recently, an increasing number of food chain partners and public authorities have introduced a widening range of initiatives to provide information about the environmental performance of food and drink products. These initiatives show a high degree of diversity in terms of their chosen scope, assessment methodologies and means of communication, which has the potential to confuse or even mislead consumers and other stakeholders. In this context, the European Food Sustainable Consumption and Production (SCP) Round Table was launched by food supply chain partners and the European Commission with the vision of promoting a science-based, coherent approach to sustainable consumption and production in the European food sector.

The goal of the study was to compare the environmental impact of butter and margarine. Altogether, seven products were studied in three European markets: UK, Germany and France. The approach used for the analysis is descriptive (attributional) LCA. The SimaPro software PRe 2007 was used to perform the calculations. Data for the production chain of the margarine products (production of raw materials, processing, packaging and logistics) were compiled from Unilever manufacturing sites, suppliers and from literature. The edible oil data inventories have been compared with those in proprietary databases (ecoinvent and SIK food database) and they show a high degree of similarity. For the butter products, data on milk production and butter processing were taken from various published studies for the countries of interest. Sensitivity analyses were conducted for a number of parameters (functional unit, allocation method, impact of using different oil, milk and dairy data, impact of estimating GHG emissions from land use change for certain oils) in order to evaluate their influence on the comparison between margarine and butter. The sensitivity analyses demonstrate that the initial results and conclusions are robust. The results show that margarine has significantly lower environmental impact (less than half) compared to butter for three impact categories global warming potential, eutrophication potential and acidification potential. For primary energy demand, the margarines have a lower impact than butter, but the difference is not as significant. Margarines use approximately half of the land required used for producing the butter products. For POCP, the impact is higher for the margarines due to the use of hexane in the oil extraction (no similar process occurs for butter). The margarine products analysed here are more environmentally favourable than the butter products. In all three markets (UK, DE and FR) the margarine products are significantly better than the butter products for the categories global warming potential, eutrophication potential and acidification potential. These findings are also valid when comparing margarines and butters between the markets; for this reason they are likely to be of general relevance for other Western European countries where similar margarine and butter production systems are found.