Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy.

BACKGROUND: Somatostatin receptor-2 (SSTR2) is expressed on cell surface of neuroendocrine neoplasias; its presence is exploited for the delivery of peptide receptor radionuclide therapy (PRRT). Patients with no or low expression of SSTR2 are not candidates for PRRT. SSTR2 promotor undergoes epigenetic modification, known to regulate gene expression. We investigated whether the demethylation agent, guadecitabine, could enhance the expression of SSTR2 in NET models, using radioligand uptake/PET imaging as a biomarker of epigenetic modification. METHODS: The effects of guadecitabine on the transcriptional, translational, and functional regulation of SSTR2 both in vitro and in vivo using low (QGP-1) and high (BON-1) methylated neuroendocrine neoplasia models was characterised. Promotor region methylation profiling of clinical samples (n = 61) was undertaken. Safety of combination guadecitabine and PRRT was assessed in vivo. RESULTS: Pyrosequencing of cell lines illustrated differential methylation indices - BON: 1 94%, QGP: 1 21%. Following guadecitabine treatment, a dose-dependent increase in SSTR2 in BON-1 at a transcriptional, translational, and functional levels using the SSTR2-directed radioligand, 18F-FET-ßAG-TOCA ([18F]-FETO) (150% increase [18F]-FETO uptake, p < 0.05) was observed. In vivo, guadecitabine treatment resulted in a 70% increase in [18F]-FETO uptake in BON-1 tumour models compared models with low baseline percentage methylation (p < 0.05). No additive toxicity was observed with the combination treatment of PRRT and guadecitabine in vivo. Methylation index in clinical samples was 10.5% compared to 5.2% in controls (p = 0.03) and correlated with SSTR2 expression (Wilcoxon rank sign -3.75,p < 0.01). CONCLUSION: Guadecitabine increases SSTR2 expression both in vitro and in vivo. The combination of demethylation agents with PRRT warrants further investigation.

Use of non-Gaussian time-of-flight kernels for image reconstruction of Monte Carlo simulated data of ultra-fast PET scanners.

INTRODUCTION: Time-of-flight (TOF) positron emission tomography (PET) scanners can provide significant benefits by improving the noise properties of reconstructed images. In order to achieve this, the timing response of the scanner needs to be modelled as part of the reconstruction process. This is currently achieved using Gaussian TOF kernels. However, the timing measurements do not necessarily follow a Gaussian distribution. In ultra-fast timing resolutions, the depth of interaction of the γ-photon and the photon travel spread (PTS) in the crystal volume become increasingly significant factors for the timing performance. The PTS of a single photon can be approximated better by a truncated exponential distribution. Therefore, we computed the corresponding TOF kernel as a modified Laplace distribution for long crystals. The obtained (CTR) kernels could be more appropriate to model the joint probability of the two in-coincidenceγ-photons. In this paper, we investigate the impact of using a CTR kernel vs. Gaussian kernels in TOF reconstruction using Monte Carlo generated data. MATERIALS AND METHODS: The geometry and physics of a PET scanner with two timing configurations, (a) idealised timing resolution, in which only the PTS contributed in the CTR, and (b) with a range of ultra-fast timings, were simulated. In order to assess the role of the crystal thickness, different crystal lengths were considered. The evaluation took place in terms of Kullback-Leibler (K-L) distance between the proposed model and the simulated timing response, contrast recovery (CRC) and spatial resolution. The reconstructions were performed using STIR image reconstruction toolbox. RESULTS: Results for the idealised scanner showed that the CTR kernel was in excellent agreement with the simulated time differences. In terms of K-L distance outperformed the a fitted normal distribution for all tested crystal sizes. In the case of the ultra-fast configurations, a convolution kernel between the CTR and a Gaussian showed the best agreement with the simulated data below 40 ps timing resolution. In terms of CRC, the CTR kernel demonstrated improvements, with values that ranged up to 3.8% better CRC for the thickest crystal. In terms of spatial resolution, evaluated at the 60th iteration, the use of CTR kernel showed a modest improvement of the peek-to-valley ratios up to 1% for the 10-mm crystal, while for larger crystals, a clear trend was not observed. In addition, we showed that edge artefacts can appear in the reconstructed images when the timing kernel used for the reconstruction is not carefully optimised. Further iterations, can help improve the edge artefacts.

A comparative study of quantitative assessment with fluorine-18-fluorodeoxyglucose positron-emission tomography and endoscopic ultrasound in oesophageal cancer.

OBJECTIVES: This study aims to assess the correlation between PET/CT and endoscopic ultrasound (EUS) parameters in patients with oesophageal cancer. PATIENTS AND METHODS: All patients who had complete PET/CT and EUS staging performed for oesophageal cancer at our centre between 2010 and 2016 were included. Images were retrieved and analysed for a range of parameters including tumour length, volume and position relative to the aortic arch. RESULTS: Seventy patients were included in the main analysis. A strong correlation was found between EUS and PET/CT in the tumour length, the volume and the position of the tumour relative to the aortic arch. Regression modelling showed a reasonable predictive value for PET/CT in calculating EUS parameters, with r higher than 0.585 in some cases. CONCLUSION: Given the strong correlation between EUS and PET parameters, fluorine-18 fluorodeoxyglucose (F-FDG) PET can provide accurate information on the length and the volume of tumour in patients who either cannot tolerate EUS or have impassable strictures.

An alternative synthesis of Vandetanib (Caprelsa™) via a microwave accelerated Dimroth rearrangement.

Vandetanib is an orally available tyrosine kinase inhibitor used in the treatment of cancer. The current synthesis proceeds via an unstable 4-chloroquinazoline, using harsh reagents, in addition to requiring sequential protection and deprotection steps. In the present work, use of the Dimroth rearrangement in the key quinazoline forming step enabled the synthesis of Vandetanib in nine steps (compared to the previously reported 12-14).

Mapping arginine methylation in the human body and cardiac disease.

PURPOSE: Arginine methylation (ArgMe) is one of the most ubiquitous PTMs, and hundreds of proteins undergo ArgMe in, for example, brain. However, the scope of ArgMe in many tissues, including the heart, is currently underexplored. Here, we aimed to (i) identify proteins undergoing ArgMe in human organs, and (ii) expose the relevance of ArgMe in cardiac disease. EXPERIMENTAL DESIGN: The publicly available proteomic data is used to search for ArgMe in 13 human tissues. To induce H9c2 cardiac-like cell hypertrophy glucose is used. RESULTS: The results show that ArgMe is mainly tissue-specific; nevertheless, the authors suggest an embryonic origin of core ArgMe events. In the heart, 103 mostly novel ArgMe sites in 58 nonhistone proteins are found. The authors provide compelling evidence that cardiac protein ArgMe is relevant to cardiomyocyte ontology, and important for proper cardiac function. This is highlighted by the fact that genetic mutations affecting methylated arginine positions are often associated with cardiac disease, including hypertrophic cardiomyopathy. The pilot experimental data suggesting significant changes in ArgMe profiles of H9c2 cells upon induction of cell hypertrophy using glucose is provided. CONCLUSIONS AND CLINICAL RELEVANCE: The work calls for in-depth investigation of ArgMe in normal and diseased tissues using methods including clinical proteomics.

Development of PDT/PET Theranostics: Synthesis and Biological Evaluation of an (18)F-Radiolabeled Water-Soluble Porphyrin.

Synthesis of the first water-soluble porphyrin radiolabeled with fluorine-18 is described: a new molecular theranostic agent which integrates the therapeutic selectivity of photodynamic therapy (PDT) with the imaging efficacy of positron emission tomography (PET). Generation of the theranostic was carried out through the conjugation of a cationic water-soluble porphyrin bearing an azide functionality to a fluorine-18 radiolabeled prosthetic bearing an alkyne functionality through click conjugation, with excellent yields obtained in both cold and hot synthesis. Biological evaluation of the synthesized structures shows the first example of an (18)F-radiolabeled porphyrin retaining photocytotoxicity following radiolabeling and demonstrable conjugate uptake and potential application as a radiotracer in vivo. The promising results gained from biological evaluation demonstrate the potential of this structure as a clinically relevant theranostic agent, offering exciting possibilities for the simultaneous imaging and photodynamic treatment of tumors.