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 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.