68Ga-EMP-100 PET/CT-a novel ligand for visualizing c-MET expression in metastatic renal cell carcinoma-first in-human biodistribution and imaging results

BACKGROUND 68Ga-EMP-100 is a novel positron emission tomography (PET) ligand that directly targets tumoral c-MET expression. Upregulation of the receptor tyrosin kinase c-MET in renal cell carcinoma (RCC) is correlated with overall survival in metastatic disease (mRCC). Clinicopathological staging of c-MET expression could improve patient management prior to systemic therapy with for instance inhibitors targeting c-MET such as cabozantinib. We present the first in-human data of 68Ga-EMP-100 in mRCC patients evaluating uptake characteristics in metastases and primary RCC. METHODS Twelve patients with mRCC prior to anticipated cabozantinib therapy underwent 68Ga-EMP-100 PET/CT imaging. We compared the biodistribution in normal organs and tumor uptake of mRCC lesions by standard uptake value (SUVmean) and SUVmax measurements. Additionally, metastatic sites on PET were compared to contrast-enhanced computed tomography (CT) and the respective, quantitative PET parameters were assessed and then compared inter- and intra-individually. RESULTS Overall, 87 tumor lesions were analyzed. Of these, 68/87 (79.3%) were visually rated c-MET-positive comprising a median SUVmax of 4.35 and SUVmean of 2.52. Comparing different tumor sites, the highest uptake intensity was found in tumor burden at the primary site (SUVmax 9.05 (4.86-29.16)), followed by bone metastases (SUVmax 5.56 (0.97-15.85)), and lymph node metastases (SUVmax 3.90 (2.13-6.28)) and visceral metastases (SUVmax 3.82 (0.11-16.18)). The occurrence of visually PET-negative lesions (20.7%) was distributed heterogeneously on an intra- and inter-individual level; the largest proportion of PET-negative metastatic lesions were lung and liver metastases. The highest physiological 68Ga-EMP-100 accumulation besides the urinary bladder content was seen in the kidneys, followed by moderate uptake in the liver and the spleen, whereas significantly lower uptake intensity was observed in the pancreas and the intestines. CONCLUSION Targeting c-MET expression, 68Ga-EMP-100 shows distinctly elevated uptake in mRCC patients with partially high inter- and intra-individual differences comprising both c-MET-positive and c-MET-negative lesions. Our first clinical results warrant further systemic studies investigating the clinical use of 68Ga-EMP-100 as a biomarker in mRCC patients

Actions of enflurane, isoflurane, vecuronium, atracurium, and pancuronium on pulmonary resistance in dogs.

peer reviewedThe effects of enflurane, isoflurane, vecuronium, atracurium, and pancuronium on pulmonary resistance and heart rate were studied in 30 vagotomized dogs lying supine and anesthetized with chloralose-urethane. None of the five drugs affected pulmonary resistance when the airway was unstimulated. Enflurane and isoflurane significantly attenuated the increase in pulmonary resistance induced by electrical stimulation of the vagus nerves. This effect was dose-dependent and similar for both anesthetics at equivalent multiples of their minimum alveolar concentration. Atracurium significantly (P less than 0.05) enhanced the increase in pulmonary resistance induced by vagus nerve stimulation; vecuronium had no significant effect. Pancuronium, up to a cumulative dose of 0.14 mg/kg, also significantly (P less than 0.05) enhanced the increase in pulmonary resistance induced by vagus nerve stimulation; but this effect was reversed by further increasing the dose. Pancuronium also attenuated the cardiodecelerator response to vagus nerve stimulation in a dose-dependent fashion. The underlying mechanisms for the attenuation of responses to vagus nerve stimulation by enflurane or isoflurane or for the increase in response with atracurium are unknown. Pancuronium at lower doses increases the response most likely by blocking prejunctional muscarinic receptors (M2) that physiologically inhibit vagally mediated increases in pulmonary resistance

Changes of serotonin transporter (SERT) availability in human obesity prior and 6 month after an integrative treatment approach

Objectives: Central serotonergic systems comprise important neuromodulatory capacity and participate in regulating appetite and satiety, thus contributing to obesogenic mechanism. Especially presynaptic SERT are target structures for modern antidepressants and interventions aiming to reduce weight. The aim of our study was to quantitatively assess SERT availability in obese, non-depressed humans at baseline and following a 6 months integrative treatment program. SERT was compared with changes in body mass index (BMI) as the outcome parameter. This study investigates SERT levels in obese individuals(OB) and normal-weight, healthy control subjects (NW). Methods: Twenty-two OB (BMI 41±5kg/m2, age 38±11yrs, 14♀) and 15 NW (BMI 23±2 kg/m2, age 36±7yrs, 10♀) were investigated prior and after a 6 month of treatment program including diet, physical and psychological intervention by using C-11-DASB and PET. Parametric images of binding potential BPND (MRTM2) were generated from atlas-based analysis of VOI after coregistration with individual 3D MRI data. Results: In OB, BPND and BMI were negatively associated (P<0.05) in the left medial prefrontal cortex (PFC) (R=-0.37), the left dorso-lateral PFC (R=-0.38), the right hippocampus (R=-0.37) and the left amygdala (R=-0.39, p=0.037). All of these regions showed a significant BPND increase after the OB lost weight (delta BMI -1.02±2.1kg/m2). No significant BPND changes over time were found in the NW. Conclusions: Changes of SERT availability in obese are evident in regions thought to be relevant of eating control. Furthermore, correlation between losing weight and higher SERT mainly in the PFC after the 6 month program suggest that the PFC likely has an essential role in feeding behavior modulated by the serotonin system and SERT availability in those brain areas may serve as a predictor for treatment response

Schaffung von Grundlagen zur stofflichen Verwertung von Miscanthus sinensis. T. 1

Renewable feedstocks like Miscanthus sinensis are more and more becoming the most viable solution for the conservation of the environment and constitute the basic requisite for the continued existence of a healthy climate and life. Already within a relatively brief and foreseeable period of time, the constant consumption of fossil energy sources, combined at present with irreversible structural changes, causes serious problems for the continuance of living conditions. By current standards, renewable feedstocks offer the best solution to this problem. - Processed into intermediate and end-use products, they form a closed biological cycle. Carbon dioxide required for plant growth is taken from the atmosphere and converted into hydrocarbon-hydrogen structures, a process causing the formation of oxygen. Composting or combustion results again in the release of carbon dioxide. Fast-growing varieties with effective C4-photosynthesis like Miscanthus sinensis seem particularly suited. Consequently, the utilization of renewable feedstocks does not aggravate atmospheric carbon dioxide pollution and thus is the most urgent demand of our time. (EF)Nachwachsende Rohstoffe wie Miscanthus sinensis sind in zunehmendem Masse die brauchbarste Loesung fuer die Schonung der Umwelt und die existentielle Basis fuer das Fortbestehen eines gesunden Klimas und des Lebens. Der staendige Verbrauch fossiler Rohstoffe in Verbindung mit derzeit irreversibler Strukturwandlung bringt bereits in relativ kurzer und ueberschaubarer Zeit schwere Probleme bei der Reproduktion der Lebensbedingungen. Nachwachsende Rohstoffe bieten nach dem derzeitigen Erkenntnisstand den optimalen Ausweg aus diesem Problem. Sie bieten bei entsprechender Verarbeitung zu Zwischen- und Endprodukten die Moeglichkeit eines biologisch geschlossenen Kreislaufes. Das beim Pflanzenwachstum aus der Atmosphaere entzogene Kohlendioxid wird unter Freisetzung von Sauerstoff in Kohlenstoff- Wasserstoff-Strukturen umgewandelt und bei der Kompostierung oder Verbrennung wieder freigesetzt. Dabei erscheinen schnellwachsende Arten mit effektiver C4-Photosynthese, wie Miscanthus sinensis, besonders geeignet. Die stoffliche Nutzung belastet demzufolge nicht die Kohlendioxyd-Bilanz der Atmosphaere und ist somit gleichzeitig die dringendste Forderung der heutigen Zeit. (EF)SIGLEAvailable from TIB Hannover: F95B91+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany); Bundesministerium fuer Ernaehrung, Landwirtschaft und Forsten, Bonn (Germany)DEGerman

Photopenic defects on O-(2-18F-fluoroethyl)-L-tyrosine PET - clinical relevance in glioma patients.

V48Photopenic defects on O-(2-18F-fluoroethyl)-L-tyrosine PET - clinical relevance in glioma patientsN. Galldiks1, M. Unterrainer2, N. Judov3, G. Stoffels3, M. Rapp4, P. Lohmann3, F. Vettermann2, V. Dunkl1, B. Suchorska5, J. C. Tonn5, F. W. Kreth5, G. R. Fink1, P. Bartenstein2, K. J. Langen3, N. L. Albert21Uniklinik Köln, Klinik für Neurologie, Köln; 2Uniklinik München (LMU), Klinik für Nuklearmedizin, München; 3Forschungszentrum Jülich, Inst. für Neurowissenschaften und Medizin (INM-4), Jülich; 4Uniklinik Düsseldorf, Klinik für Neurochirurgie, Düsseldorf; 5Uniklinik München (LMU), Klinik für Neurochirurgie, MünchenZiel/Aim:In PET imaging, a fraction of approximately 5-10% of cerebral gliomas show no increased accumulation of O-(2-18F-fluoroethyl)-L-tyrosine (FET) compared to the normal brain. Some of these lesions present even as photopenic defects. The clinical relevance of this phenomenon remains to be elucidated.Methodik/Methods:Glioma patients with a negative FET PET scan prior to histological confirmation were retrospectively identified in three university centers. Gliomas were visually rated as having indifferent FET uptake or as photopenic when FET uptake was below background acitivity. For quantitative analysis, FET uptake in the area of signal hyperintensity on the T2-/FLAIR-weighted MRI was evaluated by mean standardized uptake values (SUV) and mean tumor-to-brain ratios (TBR). In patients without treatment (“watch and wait” strategy), the progression-free survival (PFS) of photopenic gliomas was compared with that of gliomas with indifferent FET uptake.Ergebnisse/Results:Of 104 FET-negative gliomas (2 WHO grade I, 75 WHO grade II, 23 WHO grade III, and 4 WHO grade IV), 36 cases with photopenic defects (35%) were identified (23 WHO grade II, 12 WHO grade III, and one glioblastoma). FET uptake in photopenic defects was significantly decreased compared to both the healthy-appearing brain tissue (SUV, 0.88±0.23 vs. 1.10±0.26; P0.05).Schlussfolgerungen/Conclusions:Around one-third of FET-negative gliomas exhibit photopenic defects. These photopenic gliomas should be managed more actively as they might have a higher risk for harboring a higher-grade glioma and an unfavorable outcome compared to gliomas with indifferent FET uptake

Inverse relationship between central serotonin and noradrenaline transporter availability in humans with high BMI range - a potential biological mechanism in obesity

Objective The brain neurotransmitters serotonin (5-HT) and noradrenaline (NA) are both implicated in the regulation of appetite and energy balance. Disturbances of these systems, i.e. in key areas of feeding control such as the hypothalamus, lead to eating disorders and obesity. The mechanism by which an impaired 5-HT/NA signalling contributes is still unclear. Methods A PET study using either central 5-HT transporter (5-HTT)- or NA transporter (NAT)-selective [11C]DASB/[11C]MRB in 65 lean-to-highly obese individuals (BMI range: 19.1–54.1 kg/m2). 5-HTT/NAT binding potential BPND was obtained as PET outcome measures and correlated with BMI. Results 5-HTT BPND and NAT BPND tend towards an inverse relationship with increasing BMI (e.g., in the midbrain: Fig. 1A; p = 0.13 and p = 0.06, respectively). Such an opponent association is supported by correlative data with neurobehavioral scores (Y-FAS, FEV II), pharmacological stress test results, and follow-up BPND after 6-months diet. Although the participants were free of major depressive disorder (as assessed by structured clinical interview), correlative analyses showed a relationship between midbrain NAT BPND and Beck Depression Inventory (BDI) as an index for sub-threshold depression (r = −0.408; p = 0.07) as well as a correlation between BMI and BDI in both groups (5-HTT: p < 0.01; NAT: p = 0.19; Fig. 1B). Conclusion High 5-HTT and low NAT are associated with high BMI. This indicates a potential mechanism in the pathogenesis of human obesity reflecting high NA tone and low 5-HT levels. Together with certain eating behaviours and other biomarkers (pharmacogenotypes) the hypothesized association may lead to more individualised approaches if confirmed. It also questioned the presumed mechanism of action of the drug sibutramine, which is a combined NAT and 5-HTT inhibitor. Sub-threshold depression is an important modulator but may not explain the findings alone

Discursively ‘Undoing’ and ‘Doing Europe’ the Austrian Way

Literature on European and national identities displays a tension between occasional observations of an emerging ‘banal Europeanism’ (Cram, 2009) and a dominant strand (e.g. Guibernau, 2007; Toplak & Šumi, 2012) that questions the viability of European identifications vis-à-vis historically entrenched nationalisms, particularly in the context of the debt crisis and the resulting (re)nationalization of European politics. This chapter builds on recent work on Austrian European Union (EU) scepticism and its contestation (Karner, 2013) to examine instances – in diverse media coverage, readers’ letters to the editor of Austria’s most widely read newspaper, internet platforms, political essays and party political positions – of national identity negotiations in relation to the EU and as articulated in the context of successive European crises and the most recent elections to the European Parliament. The qualitative, thematic analysis of these wide-ranging materials developed here draws on two key concepts in critical discourse analysis, the notions of deixis (Billig, 1995) or ‘rhetorical pointing’ and of the topos or ‘structure of argument’ (e.g. Reisigl & Wodak, 2001), which are complemented by a third theoretical tool, namely the anthropological concept of ‘grammars of identity’ (Baumann & Gingrich, 2004). The resulting discussion reveals the uneasy coexistence of (critical) Europeanisms and various national reassertions in Austria’s public sphere and their respective discursive features. Further, the theoretical approaches synthesized cast light on internal diversities within political positions that are often too monolithicly classified as being ‘simply’ pro- or anti-European respectively. Instead, the analysis presented here reveals a spectrum of (at least five) competing positions