Journal of Nuclear Medicine最新文献

The purpose of this study was to determine the impact of [¹⁸F]FDG PET/CT on the initial staging, restaging, clinical management, and outcomes of patients with soft-tissue and bone sarcomas. Methods: This single-arm, prospective multicenter registry enrolled 304 patients with 320 [¹⁸F]FDG PET/CT scans (November 2018 to October 2021). Eligibility included the initial staging of a grade 2 or higher or ungradable soft-tissue or bone sarcoma, with negative or equivocal findings for nodal or distant metastases on conventional imaging before curative-intent therapy, or restaging of patients with a history of treated sarcoma with a suspicion or confirmation of local recurrence or limited metastatic disease who were being considered for curative-intent or salvage therapy. The presence of local recurrence or metastases on [¹⁸F]FDG PET/CT was recorded. Clinical management after [¹⁸F]FDG PET/CT compared with pre-[¹⁸F]FDG PET/CT planned management and quantitative metabolic tumor parameters (SUV_max, metabolic tumor volume, total lesion glycolysis) were correlated with the outcome data for 171 patients. Results: At the initial staging, [¹⁸F]FDG PET/CT detected metastases in 17 of 105 patients (16.2%) with no metastases on conventional work-up and confirmed metastases in 44 of 92 patients (47.8%) with equivocal findings for metastases. At the time of restaging, [¹⁸F]FDG PET/CT detected local recurrence in 37 of 123 patients (30.1%) and distant metastases in 71 of 123 patients (57.7%). Overall, the change in treatment intent and treatment type was recorded in 64 of 171 cases (37.4%) and 56 of 171 cases (32.8%), respectively. The presence of metastases on [¹⁸F]FDG PET/CT was associated with shorter progression-free survival at the initial staging (P = 0.04) and shorter overall survival at the time of recurrence (P = 0.002). All quantitative metabolic tumor parameters correlated with progression-free survival and overall survival. Conclusion: [¹⁸F]FDG PET/CT frequently detects additional sites of disease compared with conventional imaging in patients with sarcomas that were being considered for curative-intent or salvage therapy. This increased detection impacts the clinical management in a third of patients referred for initial staging or presumed limited recurrence after primary therapy. The presence of metastases on [¹⁸F]FDG PET/CT is associated with poorer outcomes.

Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted α-therapy with the α-particle-emitting radionuclide ²²⁵Ac (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2) ²²⁵Ac-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). Methods: On day 0, 10⁵ SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2 ²²⁵Ac-PRIT (37 kBq/cycle as ²²⁵Ac-Proteus DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Results: Untreated PC-tumor-bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of ²²⁵Ac-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel-Cox] P = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups (P = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness-weighted dose, where relative biological effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to α-toxicity were observed in both therapeutic groups. Conclusion: Treatment of EOC PC-tumor-bearing mice with anti-HER2 ²²⁵Ac-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted α-therapy using the anti-HER2 ²²⁵Ac-PRIT system is a potential treatment for otherwise incurable EOC.

Estimation of the time-integrated activity (TIA) for dosimetry from imaging at a single time point (STP) facilitates the clinical translation of dosimetry-guided radiopharmaceutical therapy. However, the accuracy of the STP methods for TIA estimation varies on the basis of time-point selection. We constructed patient data-driven regression models to reduce the sensitivity to time-point selection and to compare these new models with commonly used STP methods. Methods: SPECT/CT performed at time period (TP) 1 (3-5 h), TP2 (days 1-2), TP3 (days 3-5), and TP4 (days 6-8) after cycle 1 of [¹⁷⁷Lu]Lu-DOTATATE therapy involved 27 patients with 100 segmented tumors and 54 kidneys. Influenced by the previous physics-based STP models of Madsen et al. and Hänscheid et al., we constructed an STP prediction expression, TIA = A(t) × g(t), in a SPECT data-driven way (model 1), in which A(t) is the observed activity at imaging time t, and the curve, g(t), is estimated with a nonparametric generalized additive model by minimizing the normalized mean square error relative to the TIA derived from 4-time-point SPECT (reference TIA). Furthermore, we fit a generalized additive model that incorporates baseline biomarkers as auxiliary data in addition to the single activity measurement (model 2). Leave-one-out cross validation was performed to evaluate STP models using mean absolute error (MAE) and mean square error between the predicted and reference TIA. Results: At days 3-5, all evaluated STP methods performed very well, with an MAE of less than 7% (between-patient SD of <10%) for both kidneys and tumors. At other TPs, the Madsen method and data-driven models 1 and 2 performed reasonably well (MAEs < 17% for kidneys and < 32% for tumors), whereas the error with the Hänscheid method was substantially higher. The proof of concept of adding baseline biomarkers to the prediction model was demonstrated and showed a moderate enhancement at TP1, especially for estimating kidney TIA (MAE ± SD from 15.6% ± 1.3% to 11.8% ± 1.0%). Evaluations on 500 virtual patients using clinically relevant time-activity simulations showed a similar performance. Conclusion: The performance of the Madsen method and proposed data-driven models is less sensitive to TP selection than is the Hänscheid method. At the earliest TP, which is the most practical, the model incorporating baseline biomarkers outperforms other methods that rely only on the single activity measurement.

Auger electron (AE) radiopharmaceutical therapy (RPT) may have the same therapeutic efficacy as α-particles for oncologic small disease, with lower risks of normal-tissue toxicity. The seeds of using AE emitters for RPT were planted several decades ago. Much knowledge has been gathered about the potency of the biologic effects caused by the intense shower of these low-energy AEs. Given their short range, AEs deposit much of their energy in the immediate vicinity of their site of decay. However, the promise of AE RPT has not yet been realized, with few agents evaluated in clinical trials and none becoming part of routine treatment so far. Instigated by the 2022 "Technical Meeting on Auger Electron Emitters for Radiopharmaceutical Developments" at the International Atomic Energy Agency, this review presents the current status of AE RPT based on the discussions by experts in the field. A scoring system was applied to illustrate hurdles in the development of AE RPT, and we present a selected list of well-studied and emerging AE-emitting radionuclides. Based on the number of AEs and other emissions, physical half-life, radionuclide production, radiochemical approaches, dosimetry, and vector availability, recommendations are put forward to enhance and impact future efforts in AE RPT research.

The current study aimed to compare ⁶⁸Ga-NODAGA-Cpa-cyclo(d-Cys-amino-Phe-hydroorotic acid-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)-d-Tyr-NH₂ (JR11) and ⁶⁸Ga-DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors. Methods: A prospective bicenter study aimed at enrolling 100 patients with histologically proven, metastatic or unresectable, well-differentiated neuroendocrine tumors was conducted. The first 48 patients represented the study cohort. Each patient received ⁶⁸Ga-DOTATATE on the first day and ⁶⁸Ga-NODAGA-JR11 on the second day. Whole-body PET/CT scans were performed at 40-60 min after injection. Normal-organ uptake, lesion numbers, lesion uptake, and sensitivity were compared. The potential impact on clinical management was also determined. Results: Overall, ⁶⁸Ga-NODAGA-JR11 demonstrated lower background uptake in normal organs. Compared with ⁶⁸Ga-DOTATATE, ⁶⁸Ga-NODAGA-JR11 detected significantly more liver lesions (673 vs. 584, P = 0.002). The target-to-background ratio of liver lesions was significantly higher on ⁶⁸Ga-NODAGA-JR11 (6.4 ± 8.7 vs. 3.1 ±2.6, P = 0.000). Comparable uptake was observed for primary tumors, bone lesions, and lymph node metastases. In total, 180 lesions were detected on conventional imaging in 15 patients; 165 and 139 lesions of them were positive on ⁶⁸Ga-NODAGA-JR11 and ⁶⁸Ga-DOTATATE, leading to a sensitivity of 91.7% and 77.2%, respectively. In 14.5% (7/48) of patients, ⁶⁸Ga-NODAGA-JR11 PET might have a potential impact on clinical management. Conclusion: ⁶⁸Ga-NODAGA-JR11 shows better sensitivity and a higher target-to-background ratio than ⁶⁸Ga-DOTATATE. The detection of more lesions by the antagonist may have a potential impact on clinical management in a subgroup of patients.

Calcific aortic valve disease (CAVD) is a prevailing disease with increasing occurrence and no known medical therapy. Dcbld2^-/- mice have a high prevalence of bicuspid aortic valve (BAV), spontaneous aortic valve calcification, and aortic stenosis (AS). ¹⁸F-NaF PET/CT can detect the aortic valve calcification process in humans. However, its feasibility in preclinical models of CAVD remains to be determined. Here, we sought to validate ¹⁸F-NaF PET/CT for tracking murine aortic valve calcification and leveraged it to examine the development of calcification with aging and its interdependence with BAV and AS in Dcbld2^-/- mice. Methods: Dcbld2^-/- mice at 3-4 mo, 10-16 mo, and 18-24 mo underwent echocardiography, ¹⁸F-NaF PET/CT (n = 34, or autoradiography (n = 45)), and tissue analysis. A subset of mice underwent both PET/CT and autoradiography (n = 12). The aortic valve signal was quantified as SUV_max on PET/CT and as percentage injected dose per square centimeter on autoradiography. The valve tissue sections were analyzed by microscopy to identify tricuspid and bicuspid aortic valves. Results: The aortic valve ¹⁸F-NaF signal on PET/CT was significantly higher at 18-24 mo (P < 0.0001) and 10-16 mo (P < 0.05) than at 3-4 mo. Additionally, at 18-24 mo BAV had a higher ¹⁸F-NaF signal than tricuspid aortic valves (P < 0.05). These findings were confirmed by autoradiography, with BAV having significantly higher ¹⁸F-NaF uptake in each age group. A significant correlation between PET and autoradiography data (Pearson r = 0.79, P < 0.01) established the accuracy of PET quantification. The rate of calcification with aging was significantly faster for BAV (P < 0.05). Transaortic valve flow velocity was significantly higher in animals with BAV at all ages. Finally, there was a significant correlation between transaortic valve flow velocity and aortic valve calcification by both PET/CT (r = 0.55, P < 0.001) and autoradiography (r = 0.45, P < 0.01). Conclusion: ¹⁸F-NaF PET/CT links valvular calcification to BAV and aging in Dcbld2^-/- mice and suggests that AS may promote calcification. In addition to addressing the pathobiology of valvular calcification, ¹⁸F-NaF PET/CT may be a valuable tool for evaluation of emerging therapeutic interventions in CAVD.