What is the value of regional cerebral saturation in post-cardiac arrest patients? A prospective observational study.

BACKGROUND: The aim of this study was to elucidate the possible role of cerebral saturation monitoring in the post-cardiac arrest setting. METHODS: Cerebral tissue saturation (SctO2) was measured in 107 successfully resuscitated out-of-hospital cardiac arrest patients for 48 hours between 2011 and 2015. All patients were treated with targeted temperature management, 24 hours at 33 °C and rewarming at 0.3 °C per hour. A threshold analysis was performed as well as a linear mixed models analysis for continuous SctO2 data to compare the relation between SctO2 and favorable (cerebral performance category (CPC) 1-2) and unfavorable outcome (CPC 3-4-5) at 180 days post-cardiac arrest in OHCA patients. RESULTS: Of the 107 patients, 50 (47 %) had a favorable neurological outcome at 180 days post-cardiac arrest. Mean SctO2 over 48 hours was 68 % ± 4 in patients with a favorable outcome compared to 66 % ± 5 for patients with an unfavorable outcome (p = 0.035). No reliable SctO2 threshold was able to predict favorable neurological outcome. A significant different course of SctO2 was observed, represented by a logarithmic and linear course of SctO2 in patients with favorable outcome and unfavorable outcome, respectively (p < 0.001). During the rewarming phase, significant higher SctO2 values were observed in patients with a favorable neurological outcome (p = 0.046). CONCLUSIONS: This study represents the largest post-resuscitation cohort evaluated using NIRS technology, including a sizeable cohort of balloon-assisted patients. Although a significant difference was observed in the overall course of SctO2 between OHCA patients with a favorable and unfavorable outcome, the margin was too small to likely represent functional outcome differentiation based on SctO2 alone. As such, these results given such methodology as performed in this study suggest that NIRS is insufficient by itself to serve in outcome prognostication, but there may remain benefit when incorporated into a multi-neuromonitoring bedside assessment algorithm.

Exploring the Potential of High-Molar-Activity Samarium-153 for Targeted Radionuclide Therapy with [153Sm]Sm-DOTA-TATE.

Samarium-153 is a promising theranostic radionuclide, but low molar activities (Am) resulting from its current production route render it unsuitable for targeted radionuclide therapy (TRNT). Recent efforts combining neutron activation of 152Sm in the SCK CEN BR2 reactor with mass separation at CERN/MEDICIS yielded high-Am 153Sm. In this proof-of-concept study, we further evaluated the potential of high-Am 153Sm for TRNT by radiolabeling to DOTA-TATE, a well-established carrier molecule binding the somatostatin receptor 2 (SSTR2) that is highly expressed in gastroenteropancreatic neuroendocrine tumors. DOTA-TATE was labeled with 153Sm and remained stable up to 7 days in relevant media. The binding specificity and high internalization rate were validated on SSTR2-expressing CA20948 cells. In vitro biological evaluation showed that [153Sm]Sm-DOTA-TATE was able to reduce CA20948 cell viability and clonogenic potential in an activity-dependent manner. Biodistribution studies in healthy and CA20948 xenografted mice revealed that [153Sm]Sm-DOTA-TATE was rapidly cleared and profound tumor uptake and retention was observed whilst these were limited in normal tissues. This proof-of-concept study showed the potential of mass-separated 153Sm for TRNT and could open doors towards wider applications of mass separation in medical isotope production.

Gold nanoparticles meet medical radionuclides.

Thanks to their unique optical and physicochemical properties, gold nanoparticles have gained increased interest as radiosensitizing, photothermal therapy and optical imaging agents to enhance the effectiveness of cancer detection and therapy. Furthermore, their ability to carry multiple medically relevant radionuclides broadens their use to nuclear medicine SPECT and PET imaging as well as targeted radionuclide therapy. In this review, we discuss the radiolabeling process of gold nanoparticles and their use in (multimodal) nuclear medicine imaging to better understand their specific distribution, uptake and retention in different in vivo cancer models. In addition, radiolabeled gold nanoparticles enable image-guided therapy is reviewed as well as the enhancement of targeted radionuclide therapy and nanobrachytherapy through an increased dose deposition and radiosensitization, as demonstrated by multiple Monte Carlo studies and experimental in vitro and in vivo studies.

In Vivo Pharmacokinetics, Biodistribution and Toxicity of Antibody-Conjugated Gold Nanoparticles in Healthy Mice.

Cetuximab-conjugated gold nanoparticles are known to target cancer cells, but display toxicity towards normal kidney, liver and endothelial cells in vitro. In this study, we investigated their pharmacokinetics, biodistribution and toxicity after intravenous administration in healthy mice. Our data showed that these nanoparticles were rapidly cleared from the blood and accumulated mainly in the liver and spleen with long-term retention. Acute liver injury, inflammatory activity and vascular damage were transient and negligible, as confirmed by the liver functionality tests and serum marker analysis. There was no sign of altered liver, kidney, lung and spleen morphology up to 4 weeks post-injection. After 6 months, kidney casts and splenic apoptosis appeared to be more prevalent than in the controls. Furthermore, occasional immune cell infiltration was observed in the lungs. Therefore, we recommend additional in vivo studies, in order to investigate the long-term toxicity and elimination of gold nanoparticles after multiple dosing in their preclinical validation as new targeted anti-cancer therapies.

Gold nanoparticles affect the antioxidant status in selected normal human cells.

Purpose: This study evaluates the cytotoxicity of AuNPs coated with polyallylamine (AuNPs-PAA) and conjugated or not to the epidermal growth factor receptor (EGFR)-targeting antibody Cetuximab (AuNPs-PAA-Ctxb) in normal human kidney (HK-2), liver (THLE-2) and microvascular endothelial (TIME) cells, and compares it with two cancer cell lines that are EGFR-overexpressing (A431) or EGFR-negative (MDA-MB-453). Results: Conjugation of Cetuximab to AuNPs-PAA increased the AuNPs-PAA-Ctxb interactions with cells, but reduced their cytotoxicity. TIME cells exhibited the strongest reduction in viability after exposure to AuNPs-PAA(±Ctxb), followed by THLE-2, MDA-MB-453, HK-2 and A431 cells. This cell type-dependent sensitivity was strongly correlated to the inhibition of thioredoxin reductase (TrxR) and glutathione reductase (GR), and to the depolarization of the mitochondrial membrane potential. Both are suggested to initiate apoptosis, which was indeed detected in a concentration- and time-dependent manner. The role of oxidative stress in AuNPs-PAA(±Ctxb)-induced cytotoxicity was demonstrated by co-incubation of the cells with N-acetyl L-cysteine (NAC), which significantly decreased apoptosis and mitochondrial membrane depolarization. Conclusion: This study helps to identify the cells and tissues that could be sensitive to AuNPs and deepens the understanding of the risks associated with the use of AuNPs in vivo.