Harnessing 64Cu/67Cu for a theranostic approach to pretargeted radioimmunotherapy.

Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of copper: positron-emitting copper-64 (64Cu, t1/2 = 12.7 h) and beta particle-emitting copper-67 (67Cu, t1/2 = 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels-Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a 67Cu-labeled Tz radioligand ([67Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [67Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [67Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [64Cu]Cu-MeCOSar-Tz and [67Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz.

Dual Radionuclide Theranostic Pretargeting.

Recent years have played witness to the advent of nuclear theranostics: the synergistic use of "matched pair" radiopharmaceuticals for diagnostic imaging and targeted radiotherapy. In this investigation, we report the extension of this concept to in vivo pretargeting based on the rapid and bioorthogonal inverse electron demand Diels-Alder reaction between tetrazine (Tz) and trans-cyclooctene (TCO). We demonstrate that a single injection of a TCO-modified immunoconjugate can be used as a platform for pretargeted PET imaging and radiotherapy via the sequential administration of a pair of Tz-bearing radioligands labeled with the positron-emitting radiometal copper-64 (t1/2 ≈ 12.7 h) and the beta-emitting radiometal lutetium-177 (t1/2 ≈ 6.7 days). More specifically, a mouse model of human colorectal carcinoma received a dose of the A33 antigen-targeting immunoconjugate huA33-TCO, followed 24 and 48 h later by injections of [64Cu]Cu-SarAr-Tz and [177Lu]Lu-DOTA-PEG7-Tz, respectively. This approach produces high activity concentrations of both radioligands in tumor tissue (16.4 ± 2.7 %ID/g for [64Cu]Cu-SarAr-Tz at 48 h post-injection and 18.1 ± 2.1 %ID/g for [177Lu]Lu-DOTA-PEG7-Tz at 120 h post-injection) as well as promising tumor-to-healthy organ activity concentration ratios. Ultimately, we believe that this work could not only have important implications in nuclear theranostics-most excitingly with isotopologue-based radioligand pairs such as [64Cu]Cu-SarAr-Tz and [67Cu]Cu-SarAr-Tz-but also in the delivery of fractionated doses during pretargeted radioimmunotherapy.

Complete versus culprit-only revascularisation in ST elevation myocardial infarction with multi-vessel disease.

BACKGROUND: Multi-vessel coronary disease in people with ST elevation myocardial infarction (STEMI) is common and is associated with worse prognosis after STEMI. Based on limited evidence, international guidelines recommend intervention on only the culprit vessel during STEMI. This, in turn, leaves other significantly stenosed coronary arteries for medical therapy or revascularisation based on inducible ischaemia on provocative testing. Newer data suggest that intervention on both the culprit and non-culprit stenotic coronary arteries (complete intervention) may yield better results compared with culprit-only intervention. OBJECTIVES: To assess the effects of early complete revascularisation compared with culprit vessel only intervention strategy in people with STEMI and multi-vessel coronary disease. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, World Health Organization International Clinical Trials Registry Platform Search Portal, and ClinicalTrials.gov. The date of the last search was 4 January 2017. We applied no language restrictions. We handsearched conference proceedings to December 2016, and contacted authors and companies related to the field. SELECTION CRITERIA: We included only randomised controlled trials (RCTs), wherein complete revascularisation strategy was compared with a culprit-only percutaneous coronary intervention (PCI) for the treatment of people with STEMI and multi-vessel coronary disease. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of each trial using the Cochrane 'Risk of bias' tool. We resolved the disagreements by discussion among review authors. We followed standard methodological approaches recommended by Cochrane. The primary outcomes were long-term (one year or greater after the index intervention) all-cause mortality, long-term cardiovascular mortality, long-term non-fatal myocardial infarction, and adverse events. The secondary outcomes were short-term (within the first 30 days after the index intervention) all-cause mortality, short-term cardiovascular mortality, short-term non-fatal myocardial infarction, revascularisation, health-related quality of life, and cost. We analysed data using fixed-effect models, and expressed results as risk ratios (RR) with 95% confidence intervals (CI). We used GRADE criteria to assess the quality of evidence and we conducted Trial Sequential Analysis (TSA) to control risks of random errors. MAIN RESULTS: We included nine RCTs, that involved 2633 people with STEMI and multi-vessel coronary disease randomly assigned to either a complete (n = 1381) versus culprit-only (n = 1252) revascularisation strategy. The complete and the culprit-only revascularisation strategies did not differ for long-term all-cause mortality (65/1274 (5.1%) in complete group versus 72/1143 (6.3%) in culprit-only group; RR 0.80, 95% CI 0.58 to 1.11; participants = 2417; studies = 8; I2 = 0%; very low quality evidence). Compared with culprit-only intervention, the complete revascularisation strategy was associated with a lower proportion of long-term cardiovascular mortality (28/1143 (2.4%) in complete group versus 51/1086 (4.7%) in culprit-only group; RR 0.50, 95% CI 0.32 to 0.79; participants = 2229; studies = 6; I2 = 0%; very low quality evidence) and long-term non-fatal myocardial infarction (47/1095 (4.3%) in complete group versus 70/1004 (7.0%) in culprit-only group; RR 0.62, 95% CI 0.44 to 0.89; participants = 2099; studies = 6; I2 = 0%; very low quality evidence). The complete and the culprit-only revascularisation strategies did not differ in combined adverse events (51/2096 (2.4%) in complete group versus 57/1990 (2.9%) in culprit-only group; RR 0.84, 95% CI 0.58 to 1.21; participants = 4086; I2 = 0%; very low quality evidence). Complete revascularisation was associated with lower proportion of long-term revascularisation (145/1374 (10.6%) in complete group versus 258/1242 (20.8%) in culprit-only group; RR 0.47, 95% CI 0.39 to 0.57; participants = 2616; studies = 9; I2 = 31%; very low quality evidence). TSA of long-term all-cause mortality, long-term cardiovascular mortality, and long-term non-fatal myocardial infarction showed that more RCTs are needed to reach more conclusive results on these outcomes. Regarding long-term repeat revascularisation more RCTs may not change our present result. The quality of the evidence was judged to be very low for all primary and the majority of the secondary outcomes mainly due to risk of bias, imprecision, and indirectness. AUTHORS' CONCLUSIONS: Compared with culprit-only intervention, the complete revascularisation strategy may be superior due to lower proportions of long-term cardiovascular mortality, long-term revascularisation, and long-term non-fatal myocardial infarction, but these findings are based on evidence of very low quality. TSA also supports the need for more RCTs in order to draw stronger conclusions regarding the effects of complete revascularisation on long-term all-cause mortality, long-term cardiovascular mortality, and long-term non-fatal myocardial infarction.

Association of Volume and Outcomes in 234 556 Patients Undergoing Surgical Aortic Valve Replacement.

BACKGROUND: The relationship between institutional volume and operative mortality after surgical aortic valve replacement (SAVR) remains unclear. METHODS: From January 2013 to June 2018, 234 556 patients underwent isolated SAVR (n = 144 177) or SAVR with coronary artery bypass grafting (CABG) (n = 90 379) within the Society of Thoracic Surgeons Adult Cardiac Surgery Database. The association between annualized SAVR volume (group 1 [1-25 SAVRs], group 2 [26-50 SAVRs], group 3 [51-100 SAVRs], and group 4 [>100 SAVRs]) and operative mortality and composite major morbidity or mortality was assessed. Random effects models were used to evaluate whether historical (2013-2015) SAVR volume or risk-adjusted outcomes explained future (2016-2018) risk-adjusted outcomes. RESULTS: The annualized median number of SAVRs per site was 35 (interquartile range, 22-59; isolated aortic valve replacement [AVR], 20; AVR with CABG, 13). Among isolated SAVR cases, the mean operative mortality and composite morbidity or mortality were 1.5% and 9.7%, respectively, at the highest-volume sites (group 4), with significantly higher rates among progressively lower-volume groups (P trend < .001). After adjustment, lower-volume centers had increased odds of operative mortality (group 1 vs group 4 [reference]: adjusted odds ratio [AOR] for SAVR, 2.24 [95% CI, 1.91-2.64]; AOR for SAVR with CABG, 1.96 [95% CI, 1.67-2.30]) and major morbidity or mortality (AOR for SAVR, 1.53 [95% CI, 1.39-1.69]; AOR for SAVR with CABG, 1.46 [95% CI, 1.32-1.61]) compared with the highest-volume institutions. Substantial variation in outcomes was observed across hospitals within each volume category, and prior outcomes explained a greater proportion of hospital operative outcomes than did prior volume. CONCLUSIONS: Operative outcomes after SAVR with or without CABG is inversely associated with institutional procedure volumes; however, prior outcomes are more predictive of future outcomes than is prior volume. Given the excellent outcomes observed at many lower-volume hospitals, procedural outcomes may be preferable to procedural volumes as a quality metric.

Harnessing PET to track micro- and nanoplastics in vivo.

The proliferation of plastics in the environment continues at an alarming rate. Plastic particles have been found to be persistent and ubiquitous pollutants in a variety of environments, including sea water, fresh water, soil, and air. In light of this phenomenon, the scientific and medical communities have become increasingly wary of the dangers posed to human health by chronic exposure to microplastics (< 5 mm diameter) and nanoplastics (< 100 nm diameter). A critical component of the study of the health effects of these pollutants is the accurate determination of their pharmacokinetic behavior in vivo. Herein, we report the first use of molecular imaging to track polystyrene (PS) micro- and nanoplastic particles in mammals. To this end, we have modified PS particles of several sizes-diameters of 20 nm, 220 nm, 1 µm, and 6 µm-with the chelator desferrioxamine (DFO) and radiolabeled these DFO-bearing particles with the positron-emitting radiometal zirconium-89 (89Zr; t1/2 ~ 3.3 d). Subsequently, positron emission tomography (PET) was used to visualize the biodistribution of these radioplastics in C57BL/6J mice at 6, 12, 24, and 48 h after ingestion. The imaging data reveal that the majority of the radioplastics remain in the gastrointestinal tract and are eliminated through the feces by 48 h post-ingestion, a result reinforced by acute biodistribution studies. Ultimately, this work suggests that nuclear imaging-and PET in particular-can be a sensitive and effective tool in the urgent and rapidly growing effort to study the in vivo behavior and potential toxicity of micro- and nanoplastics.

Concurrent induction and mechanism-based inactivation of CYP3A4 by an L-valinamide derivative.

DPC 681 (N-[(3-fluorophenyl)methyl]glycyl-N-[3-[((3-aminophenyl) sulfonyl)-2-(aminophenyl)amino]-(1S,2S)-2-hydroxy-1-(phenyl-methyl)propyl]-3-methyl-l-valinamide) is a potent peptide-like human immunodeficiency virus protease inhibitor that was evaluated in phase I clinical trials. In primary cultures of hepatocytes, DPC 681 significantly induced the testosterone 6beta-hydroxylase activity of rat CYP3A, but not human CYP3A4. Western blot analysis, however, demonstrated a 3-fold increase in expression of CYP3A4 protein by 20 microM DPC 681 in primary cultures of human hepatocytes. Subsequent studies showed that DPC 681 was a potent inhibitor of human CYP3A4 (IC50 = 0.039 microM) and rat CYP3A (IC50 = 1.62 microM). Moreover, DPC 681 was a mechanism-based inactivator of CYP3A4 with KI and kinact of 0.24 microM and 0.22 min-1, respectively. Thus, DPC 681 is both a potent inhibitor and a strong inducer of CYP3A4. Induction of CYP3A4 by DPC 681 was masked in vitro by autoinactivation, similar to the protease inhibitor ritonavir. In pharmacokinetic studies in healthy human volunteers and rats, DPC 681 was found to highly autoinduce its metabolism. Human volunteers dosed with DPC 681 at 600 mg twice daily for 14 days had a 75% decrease in the mean area under the concentration-time curve and a more than 3-fold increase in apparent clearance as compared with that on day 1. Because the primary route of DPC 681 clearance is via CYP3A metabolism, the increased clearance observed in clinical studies is due to induction of human CYP3A4 expression.