Cost-effectiveness of [18F] fluoroethyl-L-tyrosine for temozolomide therapy assessment in patients with glioblastoma

Background and Purpose: Glioblastomas are the most aggressive of all gliomas. The prognosis of these gliomas, which are classified as grade IV tumors by the World Health Organization (WHO), is poor. Combination therapy, including surgery, radiotherapy, and chemotherapy has variable outcomes and is expensive. In light of rising healthcare costs, there are societal demands for the justification of medical expenses. Therefore, we calculated the cost-effectiveness of follow-up [F-18] fluoroethyl-L-tyrosine ([F-18] FET) positron emission tomography (PET) scans performed on patients with glioblastoma after surgery and before commencing temozolomide maintenance treatment. Materials and Methods: To determine the cost-effectiveness of follow-up [F-18] FET PET procedures, we examined published clinical data and calculated the associated costs in the context of Belgian healthcare. We subsequently performed one-way deterministic sensitivity analysis and Monte Carlo analysis on the calculated ratios. Results: The decision tree based on overall survival rates showed that the number of non-responders identified using PET was 57.14% higher than the number of non-responders identified using conventional MRI. Further, the decision tree based on progression-free survival rates revealed a comparable increase of 57.50% non-responders identified. The calculated cost of two required PET scans per patient during the follow-up treatment phase was 780.50 euros. Two cost-effectiveness ratios were determined for overall survival and progression-free survival rates. Both of these calculations yielded very similar results: incremental cost-effectiveness ratios of 1,365.86 and 1,357.38 euros, respectively, for each identified non-responder. The findings of the sensitivity analysis supported the calculated results, confirming that the obtained data were robust. Conclusion: Our comparative study of conventional MRI and [F-18] FET PET revealed that the latter is a valuable tool for predicting the treatment responses of patients with glioblastomas to follow-up temozolomide maintenance treatment while considering its cost-effectiveness. Thus, [F-18] FET PET scans enable clinical outcomes to be predicted accurately and at a low cost. Moreover, given the robustness of the data in the sensitivity analyses, the level of certainty of this outcome is acceptable

Review of periodical articles

Historians are held hostage by the sources that are available to them, and for that reason, the historiography of medieval towns is dominated by research on thirteenth-, fourteenth- or fifteenth-century case-studies. In preceding centuries, literacy was largely the monopoly of ecclesiastical milieus, who were often hostile or simply not interested in describing the urban settlements which then emerged all over Europe. An interesting exception, however, is the Breton town of Redon, which took shape around an abbey that was established in 832 with support of the Carolingian Emperor Louis the Pious. By navigating the unusually extensive set of Carolingian cartularies of this abbey, as well as the available cartographic and archaeological evidence, Julien Bachelier has developed an incisive sketch of the development of a town in the shadow of the Carolingian abbey in the eleventh and twelfth centuries (‘Une ville abbatiale bretonne. Redon du IXe au XIVe siècle’, Histoire Urbaine, 48 (2017), 133–54). This case-study confirms once again that the urbanization of medieval Europe was more than a side-effect of the rebirth of long-distance trade as the canonical Pirenne thesis would have it. The Redon case provides a valuable contribution to the revisionist perspective that stresses the importance of local demand from abbeys, episcopal palaces and castles as a stimulus for urban development (see esp. the seminal work of A. Verhulst, The Rise of Cities in North-West Europe (Cambridge, 1999))

Synthesis, in vitro and in vivo evaluation of 3β-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice

Introduction : Drug-induced cholestasis is a liver disorder that might be caused by interference of drugs with the hepatobiliary bile acid transporters. It is important to identify this interference early on in drug development. In this work, Positron Emission Tomography (PET)-imaging with a F-18 labeled bile acid analogue was introduced to detect disturbed hepatobiliary transport of bile acids. Methods : 3 beta-[F-18]fluorocholic acid ([F-18]FCA) was prepared by nucleophilic substitution of a mesylated precursor with [F-18]fluoride, followed by deprotection with sodium hydroxide. Transport of [F-18]FCA was assessed in vitro using CHO-NTCP, HEK-OATP1B1, HEK-OATP1B3 transfected cells and BSEP & MRP2 membrane vesicles. Investigation of [F-18]FCA metabolites was performed with primary mouse hepatocytes. Hepatobiliary transport of [F-18]FCA was evaluated in vivo in wild-type, rifampicin and bosentan pretreated FVB-mice by dynamic mu PET scanning. Results : Radiosynthesis of [F-18] FCA was achieved in a moderate radiochemical yield (8.11-1.94%; non-decay corrected; n = 10) and high radiochemical purity (>99%). FCA was transported by the basolateral bile acid uptake transporters NTCP, OATP1B1 and OATP1B3. For canalicular efflux, BSEP and MRP2 are the relevant bile acid transporters. [F-18]FCA was found to be metabolically stable. In vivo, [F-18]FCA showed fast hepatic uptake (4.5-0.5 min to reach 71.8-1.2% maximum % ID) and subsequent efflux to the gallbladder and intestines (93.3-6.0% ID after 1 hour). Hepatobiliary transport of [F-18]FCA was significantly inhibited by both rifampicin and bosentan. Conclusion : A F-18 labeled bile acid analogue, [F-18]FCA, has been developed that shows transport by NTCP, OATP, MRP2 and BSEP. [F-18]FCA can be used as a probe to monitor disturbed hepatobiliary transport in vivo and accumulation of bile acids in blood and liver during drug development

Evaluating hepatobiliary transport with 18F-labeled bile acids : the effect of radiolabel position and bile acid structure on radiosynthesis and in vitro and in vivo performance

Introduction. An in vivo determination of bile acid hepatobiliary transport efficiency can be of use in liver disease and preclinical drug development. Given the increased interest in bile acid Positron Emission Tomography- (PET-) imaging, a further understanding of the impact of 18-fluorine substitution on bile acid handling in vitro and in vivo can be of significance. Methods. A number of bile acid analogues were conceived for nucleophilic substitution with [18F]fluoride: cholic acid analogues of which the 3-, 7-, or 12-OH function is substituted with a fluorine atom (3α-[18F]FCA; 7β-[18F]FCA; 12β-[18F]FCA); a glycocholic and chenodeoxycholic acid analogue, substituted on the 3-position (3β-[18F]FGCA and 3β-[18F]FCDCA, resp.). Uptake by the bile acid transporters NTCP and OATP1B1 was evaluated with competition assays in transfected CHO and HEK cell lines and efflux by BSEP in membrane vesicles. PET-scans with the tracers were performed in wild-type mice (n=3 per group): hepatobiliary transport was monitored and compared to a reference tracer, namely, 3β-[18F]FCA. Results. Compounds 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA were synthesized in moderate radiochemical yields (4–10% n.d.c.) and high radiochemical purity (>99%); 7β-[18F]FCA and 12β-[18F]FCA could not be synthesized and included further in this study. In vitro evaluation showed that 3α-FCA, 3β-FGCA, and 3β-FCDCA all had a low micromolar Ki-value for NTCP, OATP1B1, and BSEP. In vivo, 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA displayed hepatobiliary transport with varying efficiency. A slight yet significant difference in uptake and efflux rate was noticed between the 3α-[18F]FCA and 3β-[18F]FCA epimers. Conjugation of 3β-[18F]FCA with glycine had no significant effect in vivo. Compound 3β-[18F]FCDCA showed a significantly slower hepatic uptake and efflux towards gallbladder and intestines. Conclusion. A set of 18F labeled bile acids was synthesized that are substrates of the bile acid transporters in vitro and in vivo and can serve as PET-biomarkers for hepatobiliary transport of bile acids

Interpretation of results from on-farm experiments: manure-nitrogen recovery on grassland as affected by manure quality and application technique. 1. An agronomic analysis

In a 5-year field experiment, a comparison was made between the manure application practices of two adjacent dairy farms in the north of the Netherlands. Grassland management systems at Drogeham and Harkema contrasted in manure application technique (surface application versus shallow injection, respectively), quality of applied manure (slurry + MX: slurry with Euromestmix® clay mineral additive versus regular slurry), and some relevant site characteristics (high versus low soil organic matter content and soil moisture supply). Effects of manure types and application techniques, and treatment of the soil with a micro-organism supplement, were tested in a factorial experiment at the two sites, two blocks per site, one with and one without additional application of 157 kg N ha–1 year–1 inorganic fertilizer. Apparent N recovery was higher after shallow injection than after surface application. For plots receiving no additional inorganic fertilizer, this difference was largest for slurry + MX applied at site Harkema, since this slurry–site combination resulted in the highest observed average apparent N recovery following shallow injection (47%) and the lowest N recovery following surface application (20%). For plots receiving additional inorganic fertilizer N the contrasts between treatments were less pronounced. Year effects on N uptake and dry matter production could be related to cumulative temperature and precipitation surplus over the growing season. A simple comparison between the grassland management systems was carried out based on the response curves derived from the experiment. This demonstrated that the grassland system where slurry was applied by shallow injection is not necessarily the lowest in actual amount of N not accounted for (i.e., potentially lost). The efficiency of the Harkema system strongly depended on high N recovery, but showed high potential losses in some years and a high herbage crude protein content in other years, due to the low DM production capacity. On the other hand, the Drogeham system was tuned to high DM production and was characterized by higher system stability, as reflected by more stable relationships between DM production and N not accounted for and herbage crude protein content. These differences between the systems were probably to a large extent caused by differences in water balance and soil organic matter content

Interpretation of results from on-farm experiments: manure-nitrogen recovery on grassland as affected by manure quality and application technique. 2. A sociological analysis

This article discusses the outcomes of a re-analysis of a grassland experiment, by locating it within the wider institutional context composed of well-established routines used in agronomic research and the dominant epistemological tradition of agricultural sciences. It is argued that both, research routines and epistemological tradition, are strategic pillars of the reigning socio-technical regime. They contribute to path-dependency, thus reinforcing the uni-lateral development tendency centring on technological solutions that fit within the dominating regime. An important, albeit probably unintended consequence is that promising novelties are obscured within and through research, thus blocking a potentially highly effective road towards sustainability

Adjuvant therapeutic potential of tonabersat in the standard treatment of glioblastoma : a preclinical F98 glioblastoma rat model study

Purpose Even with an optimal treatment protocol, the median survival of glioblastoma (GB) patients is only 12-15 months. Hence, there is need for novel effective therapies that improve survival outcomes. Recent evidence suggests an important role for connexin (Cx) proteins (especially Cx43) in the microenvironment of malignant glioma. Cx43-mediated gap junctional communication has been observed between tumor cells, between astrocytes and between tumor cells and astrocytes. Therefore, gap junction directed therapy using a pharmacological suppressor or modulator, such as tonabersat, could be a promising target in the treatment of GB. In this preclinical study, we evaluated the possible therapeutic potential of tonabersat in the F98 model. Procedures Female Fischer rats were inoculated with +/- 25.000 F98 tumor cells in the right frontal lobe. Eight days post-inoculation contrast-enhanced T1-weighted (CE-T1w) magnetic resonance (MR) images were acquired to confirm tumor growth in the brain. After tumor confirmation, rats were randomized into a Control Group, a Connexin Modulation Group (CM), a Standard Medical Treatment Group (ST), and a Standard Medical Treatment with adjuvant Connexin Modulation Group (STCM). To evaluate therapy response, T2-weighted (T2w) and CE-T1w sequences were acquired at several time points. Tumor volume analysis was performed on CE-T1w images and statistical analysis was performed using a linear mixed model. Results Significant differences in estimated geometric mean tumor volumes were found between the ST Group and the Control Group and also between the STCM Group and the Control Group. In addition, significant differences in estimated geometric mean tumor volumes between the ST Group and the STCM Group were demonstrated. No significant differences in estimated geometric mean tumor volumes were found between the Control Group and the CM Group. Conclusion Our results demonstrate a therapeutic potential of tonabersat for the treatment of GB when used in combination with radiotherapy and temozolomide chemotherapy

Radiosynthesis, in vitro and preliminary in vivo evaluation of the novel glutamine derived PET tracers [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine

INTRODUCTION: Glucose has been deemed the driving force of tumor growth for decades. However, research has shown that several tumors metabolically shift towards glutaminolysis. The development of radiolabeled glutamine derivatives could be a useful molecular imaging tool for visualizing these tumors. We elaborated on the glutamine-derived PET tracers by developing two novel probes, namely [(18)F]fluorophenylglutamine and [(18)F]fluorobiphenylglutamine MATERIALS AND METHODS: Both tracers were labelled with fluorine-18 using our recently reported ruthenium-based direct aromatic fluorination method. Their affinity was evaluated with a [(3)H]glutamine inhibition experiment in a human PC-3 and a rat F98 cell line. The imaging potential of [(18)F]fluorophenylglutamine and [(18)F]fluorobiphenylglutamine was tested using a mouse PC-3 and a rat F98 tumor model. RESULTS: The radiosynthesis of both tracers was successful with overall non-decay corrected yields of 18.46 ± 4.18 % (n=10) ([(18)F]fluorophenylglutamine) and 8.05 ± 3.25 % (n=5) ([(18)F]fluorobiphenylglutamine). In vitro inhibition experiments showed a moderate and low affinity of fluorophenylglutamine and fluorobiphenylglutamine, respectively, towards the human ASCT-2 transporter. Both compounds had a low affinity towards the rat ASCT-2 transporter. These results were endorsed by the in vivo experiments with low uptake of both tracers in the F98 rat xenograft, low uptake of [(18)F]FBPG in the mice PC-3 xenograft and a moderate uptake of [(18)F]FPG in the PC-3 tumors. CONCLUSION: We investigated the imaging potential of two novel PET radiotracers [(18)F]FPG and [(18)F]FBPG. [(18)F]FPG is the first example of a glutamine radiotracer derivatized with a phenyl group which enables the exploration of further derivatization of the phenyl group to increase the affinity and imaging qualities. We hypothesize that increasing the affinity of [(18)F]FPG by optimizing the substituents of the arene ring can result in a high-quality glutamine-based PET radiotracer. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: We hereby report novel glutamine-based PET-tracers. These tracers are tagged on the arene group with fluorine-18, hereby preventing in vivo defluorination, which can occur with alkyl labelled tracers (e.g. (2S,4R)4-[(18)F]fluoroglutamine). [(18)F]FPG shows clear tumor uptake in vivo, has no in vivo defluorination and has a straightforward production. We believe this tracer is a good starting point for the development of a high-quality tracer which is useful for the clinical visualization of the glutamine transport