Microfluidic modules for pre-concentration of [¹⁸F]fluoride in positron emission tomography (PET) radiotracer synthesis

lPositron Emission Tomography (PET) is a non-invasive imaging method which enables to obtain both molecular and biochemical information of physiological processes in vivo, which means that PET imaging shows the chemical functioning of organs and tissues in a living subject. In recent years microfluidic lab-on-a-chip devices have been explored as a promising alternative for radiotracer synthesis due to benefits such as (i) superior control over reaction conditions leading to high yields and conversion rates, (ii) reduced reagent consumption and radioactive waste production as well as (iii) potential for automation with minimised shielding requirement. That said, most devices presented so far have focused on the synthesis of the radiotracer, with relatively little emphasis on the integrated devices that perform activation, synthesis and purification steps in an automated fashion. FDG (fluorodeoxyglucose) is one of the most widely used radiopharmaceuticals in Positron Emission Tomography (PET). Moreover the availability of several other PET radionuclides makes fluorine-18 (¹⁸F) the most predominant in the fields of oncology and neuroscience. The aim of the Radiochemistry On Chip (ROC) project was to develop such an integrated lab-on-chip device and, in particular, here results for on-chip pre-concentration of fluoride, together with some preliminary results on the removal of Kryptofix (K2.2.2) and the purification of fluoroethyl-dimethyl-2-hydroxy-ethylammonium (FECH) are presented. Here in, three microfluidic modules for fluoride pre-concentration are described, the first employs a dam structure, the second and the third magnetic forces. In the final part of the thesis, preliminary results on the purification of fluoroethylcholine (FECH) and a suitable detection method for Kryptofix (K2.2.2) are reported. Firstly, the design, fabrication and implementation of a glass microfluidic device for recovery of [¹⁸F] and [¹⁹F]fluoride ions is described. The device was initially tested with non radioactive [¹⁹F]fluoride ions and shown to repeatedly trap and elute > 95% fluoride over 40 successive experimental runs with no decrease in efficiency. The same device was then tested for the trapping and release of [18F]fluoride ions, again over 20 experiments were executed with no measurable decrease in performance. Finally, the [¹⁸F]fluoride ions were eluted as a K¹⁸F/K2.2.2 complex, dried by repeated dissolution in acetonitrile and evaporation of residual water, and reacted with EtDT leading to the formation of the desired product ([¹⁸F]fluoroethyltosylate) with 96 ± 3 % yield (RCY). The overall time needed for conditioning, trapping, elution and regeneration was less than 6 minutes. This approach will be of great benefit towards an integrated platform able to perform faster and safer radiochemical synthesis on the micro-scale. In the following chapter, magnetic microparticles are described as a method for the trapping and elution of [¹⁸/¹⁹F]fluoride ions via formation of a magnetic plug inside a glass microdevice. Even though the method was found to be not as fast and efficient as the packed bed of microparticles (Chapter 3), and still requires several manual steps which are time and labour consuming, the proof of principle illustrates an alternative process not yet reported in the literature, with potential for future on-chip pre-concentration of fluoride. The results showed that by employing positively charged magnetic particles, fluoride could be trapped in yield of > 50 % and elution achieved with approximately 90 % recovery of fluoride. A subsequent method for reducing the inefficiencies of the plug of magnetic particles is described where a multilaminar flow microreactor was investigated in which functionalised magnetic particles can be deflecte

Concorrenza e ambiente: “conflitto” o “concorso”? Alcune riflessioni sui sustainability agreements di cui all’art. 101, par. 3 TFUE

L’articolo prende spunto dall’analisi dell’art. 101 TFUE. Tale norma nel porre la regola generale del divieto degli accordi tra imprese che possono falsare il gioco della concorrenza prevede un’eccezione per quegli accordi che contribuiscono a migliorare la produzione di prodotti. L’A. richiama le norme di diritto internazionale e di diritto europeo che legittimano la lettura di tale miglioramento della produzione anche in senso ambientale. Tale lettura consente di confermare le interpretazioni che legittimano accordi tra imprese che, pur contrari all’applicazione dei principi concorrenziali, si muovono nella direzione della produzione sostenibile (cd. sustainability agreements). L’A. ritiene che il principio di concorrenza che emerge ormai chiaramente nel Testo Unico Ambientale (TUA) e che viene applicato nella regolazione dei rifiuti e nei sistemi di Responsabilità Estesa del Produttore (EPR), da una parte, sia determinante per incentivare la produzione sostenibile e l'efficienza economica ma, dall’altra, allo stesso tempo non debba essere considerato come principio assoluto. La produzione sostenibile porta, infatti, ad ammettere deroghe al principio stesso ma solo nella misura in cui sia strettamente necessario.The article is based on an analysis of Article 101 of the Treaty on the Functioning of the European Union (TFEU). This provision, sets out the general rule of the prohibition of agreements between companies that may distort competition, with an exception for agreements that contribute to improving the production of products. The author, based on international and European provisions, proposes an interpretation of “production improvement” also in an environmental sense. This interpretation could justify agreements between companies that, while contrary to the application of competition principles, move towards sustainable production (so-called sustainability agreements), even if they do not reflect the application of the competition principle. The competition principle, emerges clearly in the Italian Environmental Code and is applied in waste regulation and Extended Producer Responsibility (EPR) systems. The author believes that this principle, on the one hand, is crucial to encourage sustainable production and economic efficiency but, on the other hand, should not be considered an absolute principle. Indeed, sustainable production requires exceptions to the principle itself, but only to the strict extent necessary

Efficacia, sicurezza e valutazione farmaco-economica dei farmaci biotecnologici per il trattamento dell´artrite reumatoide: revisione della letteratura e contributo casistico

Background. Rheumatoid Arthritis (RA) is a highly invalidating, chronic, progressive disease; it represents the 2% of all rheumatic diseases and it is related to very high costs for both civil society and health systems. Since many efficacious therapeutic options are now available (in particular the so-called biologic drugs) and because of the high costs related to these therapies, pharmaco-economic studies are becoming a useful tool for the optimization of health system-related budgets. Methods. Review of the literature for pharmaco-economic studies in RA. Efficacy, safety and pharmaco-economic retrospective analysis in a large monocentric cohort of patients treated with a TNF-inhibitor (first biologic line with infliximab - IFX), etanercept – ETN, or adalimumab - ADA); the database covers a follow-up of 10 years. Results. The review of the literature reported that annual direct costs for managing a patient with RA in Italy range from € 1.643 (1st stage of disease) to € 5.697 (4th stage of disease), while indirect costs range from € 2.705 to € 17.249. ADA monotherapy at the standard 40 mg every other week dose costed € 13.451/year while costs raised up to € 26.369 when the drug was administred at the dose 40 mg/week. The cost of ETN was € 13.582. In the case of combination therapy with methotrexate (MTX) the costs were € 13.637 for ADA and € 13.855 for ETN. The 3 TNF-inhibitors were highly efficacious in significantly reducing disease activity and were well tolerated (with no significant difference for the 3 molecules). Conclusion. In our experience, TNF-alfa inhibitors demonstrated to be an efficacious and safe therapeutic option, in particular in patients with moderate-to-severe disease activity. In the future, prospectic studies implementing extensive quality of life assessment (e.g. calculation of QALY) must be warranted, in order to produced detailed real-life pharmaco-economic evaluations

Investigation of refractive index sensing based on Fano resonance in fiber Bragg grating ring resonators.

In this paper we theoretically investigate a ring resonant cavity obtained by closing on itself a pi-shifted fiber Bragg grating, to be used for refractive index sensing applications. Differently from a conventional pi-shifted fiber Bragg grating, the spectral structure of this cavity is characterized by an asymmetric splitting doublet composed by a right side resonance having an asymmetric Fano profile and a left side resonance having a symmetric Lorentzian profile. The right side resonance shows a narrower and sharper peak than all the other kinds of resonance achievable with both conventional ring resonators and pi-shifted fiber Bragg gratings. A reduction of the resonant linewidth with respect to a conventional pi-shifted Fiber Bragg grating and a fiber ring resonator, having the same physical parameters, is theoretically proved, achieving up to five orders of magnitude improvement with respect to the usual ring resonator. Due to these resonance features, the pi-shifted Bragg grating ring resonator results suitable for RI sensing applications requiring extremely narrow resonances for high resolution measurements. In particular, by assuming a refractive index sensing to detect the presence of sugar in water, the sensor can show a theoretical resolution better than 10(-9) RIU. (C)2015 Optical Society of Americ

A Unique Case of Bilateral Thalamic High-Grade Glioma in a Pediatric Patient with LI-Fraumeni Syndrome: Case Presentation and Review of the Literature

Li-Fraumeni syndrome (LFS) is a rare high-penetrance and autosomal-dominant pathological condition caused by the germline mutation of the TP53 gene, predisposing to the development of tumors from pediatric age. We conducted a qualitative systematic review following the ENTREQ (Enhancing Transparency in Reporting the Synthesis of Qualitative Research) framework. A search was made in MEDLINE/Pubmed and MeSH Database using the terms “Li-Fraumeni” AND “pediatric high-grade glioma (HGG)”, identifying six cases of HGGs in pediatric patients with LFS. We added a further case with peculiar features such as no familiar history of LFS, association of embryonal rhabdomyosarcoma and bithalamic HGG, whose immunohistochemical profile was accurately defined by Next Generation Sequencing. Knowledge synthesis and case analysis grounded the discussion about challenges in the management of this pathology in pediatric age