The ß- radio-guided surgery: Method to estimate the minimum injectable activity from ex-vivo test.

PURPOSE: Radio-guided surgery with ß- decays is a novel technique under investigation. One of the main advantages is its capability to detect small (⩽0.1 ml) samples after injecting the patient with low activity of radiopharmaceutical. This paper presents an experimental method to quantify this feature based on ex-vivo tests on specimens from meningioma patients. METHODS: Patients were enrolled on the basis of the standard uptake value (SUV) and the tumour-to-non-tumour activity ratio (TNR) resulted from 68Ga-DOTATOC PET exams. After injecting the patients with 93-167 MBq of 90Y-DOTATOC, 26 samples excised during surgery were analyzed with a ß- probe. The radioactivity expected on the neoplastic specimens was estimated according to the SUV found in the PET scan and the correlation with the measured counts was studied. The doses to surgeon and medical personnel were also evaluated. RESULTS: Even injecting as low as 1.4 MBq/kg of radiotracer, tumour residuals of 0.1 ml can be detected. A negligible dose to the medical personnel was confirmed. CONCLUSIONS: Radio-guided surgery with ß- decays is a feasible technique with a low radiation dose for both personnel and patient, in particular if the patient is injected with the minimum required activity. A correlation greater than 80% was observed between the measured counts and the expected activity for the lesion samples based on the individual SUV and the TNR. This makes identifiable the minimum injectable radiotracer activity for cases where 90Y is the utilized radionuclide.

Novel integrated 3D multidetector computed tomography and fluoroscopy fusion for left atrial appendage occlusion procedures.

OBJECTIVES: This report demonstrates the application and feasibility of novel 3D-MDCT real-time fusion technology with fluoroscopy, for left atrial appendage (LAA) occlusion procedures. BACKGROUND: A successful LAA occlusion procedure relies on multiple imaging modalities, including TEE or 3D-MDCT, and fluoroscopy. Effectively integrating these imaging modalities may improve implantation safety and success. To our knowledge this technique has not been previously described for LAA occlusions. METHODS: This observational study compared clinical and procedural parameters for procedures performed with or without fusion integration. All patients had a pre-procedural 3D-MDCT for LAA measurements, along with 3D analyses of LAA morphology and surrounding structures. Using the image fusion software (Valve ASSIST 2, GE Healthcare, UK), landmarks were identified on fluoroscopy, and MDCT LAA anatomy outlines were then projected onto the real-time fluoroscopy image during the procedure, to guide all steps of the intervention. RESULTS: A total of 57 patients underwent LAA occlusion, with 16 performed using fusion software. In comparison to the pre-fusion group, reductions in contrast volume (21.0 ± 11.7 vs. 95.9 ± 80.5 ml, P < 0.001), procedure time (63.0 ± 22.0 vs. 87.3 ± 43.0 min, P = 0.01), and fluoroscopy time (6.2 vs. 8.3 min, P = 0.03) were observed. Incomplete sealing (0 vs. 14.6%, P = 0.16) and device deployment success (100 vs. 92.7%, P = 0.17) were not significantly different. CONCLUSIONS: The addition of this novel fusion technology is safe and feasible. To optimize LAA procedural success, fusion integration may offer a promising addition, or alternative, to current imaging modalities. © 2017 Wiley Periodicals, Inc.

First ex vivo validation of a radioguided surgery technique with ß-radiation.

PURPOSE: A radio-guided surgery technique with ß(-)-emitting radio-tracers was suggested to overcome the effect of the large penetration of γ radiation. The feasibility studies in the case of brain tumors and abdominal neuro-endocrine tumors were based on simulations starting from PET images with several underlying assumptions. This paper reports, as proof-of-principle of this technique, an ex vivo test on a meningioma patient. This test allowed to validate the whole chain, from the evaluation of the SUV of the tumor, to the assumptions on the bio-distribution and the signal detection. METHODS: A patient affected by meningioma was administered 300MBq of (90)Y-DOTATOC. Several samples extracted from the meningioma and the nearby Dura Mater were analyzed with a ß(-) probe designed specifically for this radio-guided surgery technique. The observed signals were compared both with the evaluation from the histology and with the Monte Carlo simulation. RESULTS: we obtained a large signal on the bulk tumor (105cps) and a significant signal on residuals of ∼0.2ml (28cps). We also show that simulations predict correctly the observed yields and this allows us to estimate that the healthy tissues would return negligible signals (≈1cps). This test also demonstrated that the exposure of the medical staff is negligible and that among the biological wastes only urine has a significant activity. CONCLUSIONS: This proof-of-principle test on a patient assessed that the technique is feasible with negligible background to medical personnel and confirmed that the expectations obtained with Monte Carlo simulations starting from diagnostic PET images are correct.

In vitro and in vivo activities of novel, semisynthetic thiopeptide inhibitors of bacterial elongation factor Tu.

Recently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here the in vitro and in vivo activities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC(90) ≤ 0.25 µg/ml) but weaker against the streptococci (MIC(90) ≥ 4 µg/ml). Like GE2270 A, the derivatives inhibited bacterial protein synthesis and selected for spontaneous loss of susceptibility via mutations in the tuf gene, encoding EF-Tu. The mutants were not cross-resistant to other antibiotic classes. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethal S. aureus infections with 50% effective doses (ED(50)) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemic E. faecalis infections with ED(50) of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are active in vitro and in vivo activity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy.

Interactions between ephrin-B and metabotropic glutamate 1 receptors in brain tissue and cultured neurons.

We examined the interaction between ephrins and metabotropic glutamate (mGlu) receptors in the developing brain and cultured neurons. EphrinB2 coimmunoprecipitated with mGlu1a receptors, in all of the brain regions examined, and with mGlu5 receptors in the corpus striatum. In striatal slices, activation of ephrinB2 by a clustered form of its target receptor, EphB1, amplified the mGlu receptor-mediated stimulation of polyphosphoinositide (PI) hydrolysis. This effect was abolished in slices treated with mGlu1 or NMDA receptor antagonists but was not affected by pharmacological blockade of mGlu5 receptors. An interaction among ephrinB2, mGlu1 receptor, and NMDA was supported by the following observations: (1) the NR1 subunit of NMDA receptors coimmunoprecipitated with mGlu1a receptors and ephrinB2 in striatal lysates; (2) clustered EphB1 amplified excitatory amino acid-stimulated PI hydrolysis in cultured granule cells grown under conditions that favored the expression of mGlu1a receptors; and (3) clustered EphB1 amplified the enhancing effect of mGlu receptor agonists on NMDA toxicity in cortical cultures, and its action was sensitive to mGlu1 receptor antagonists. Finally, fluorescence resonance energy transfer and coclustering analysis in human embryonic kidney 293 cells excluded a physical interaction between ephrinB2 and mGlu1a (or mGlu5 receptors). A functional interaction between ephrinB and mGlu1 receptors, which likely involves adaptor or scaffolding proteins, might have an important role in the regulation of developmental plasticity.

Selective alpha-1a adrenergic receptor antagonists. Effects of pharmacophore regio- and stereochemistry on potency and selectivity.

The anti-anxiety agent ipsapirone has been shown to have modest affinity for alpha-1 receptors. We disclose the discovery of potent alpha-1a receptor subtype selective antagonists based on the ipsapirone structure which possess selectivity versus the 5-HT receptors tested. These antagonists were obtained by tethering a saccharin ring to 4-phenyl-3-carboxyethyl piperidines. The design principles which led to this structural motif are discussed. The synthesis of key analogs, their SAR, as well as results of selected in vitro and in vivo studies are described.

Design, synthesis and evaluation of bouvardin, deoxybouvardin and RA-I-XIV pharmacophore analogs.

The synthesis and in vitro cytotoxic evaluation of a key set of cycloisodityrosine subunit analogs of deoxybouvardin and RA-VII are detailed and constitute a complete investigation of the natural product pharmacophore. The studies illustrate that the 18-membered ring tetrapeptide potentiation of the cytotoxic activity of cycloisodityrosine is not likely to be due to simple alteration or constraint of the conformation of the 14-membered cycloisodityrosine subunit and that simple derivatization of cycloisodityrosine may not provide the same potentiation.