Image-based dosimetry for [225Ac]Ac-PSMA-I&T therapy and the effect of daughter-specific pharmacokinetics.

PURPOSE: Although 221Fr and 213Bi have sufficient gamma emission probabilities, quantitative SPECT after [225Ac]Ac-PSMA-I&T therapy remains challenging due to low therapeutic activities. Furthermore, 221Fr and 213Bi may underlie a different pharmacokinetics due to alpha recoil. We conducted a quantitative SPECT study and a urine analysis to investigate the pharmacokinetics of 221Fr and 213Bi and the impact on image-based lesion and kidney dosimetry. METHODS: Five patients (7.7 ± 0.2 MBq [225Ac]Ac-PSMA-I&T) underwent an abdominal SPECT/CT (1 h) at 24 and 48 h (Siemens Symbia T2, high-energy collimator, 440 keV/218 keV (width 20%), 78 keV (width 50%)). Quantitative SPECT was reconstructed using MAP-EM with attenuation and transmission-dependent scatter corrections and resolution modelling. Time-activity curves for kidneys (CT-based) and lesions (80% isocontour 24 h) were fitted mono-exponentially. Urine samples collected along with each SPECT/CT were measured in a gamma counter until secular equilibrium was reached. RESULTS: Mean kidney and lesion effective half-lives were as follows: 213Bi, 27 ± 6/38 ± 10 h; 221Fr, 24 ± 6/38 ± 11 h; 78 keV, 23 ± 7/39 ± 13 h. The 213Bi-to-221Fr kidney SUV ratio increased by an average of 9% from 24 to 48 h. Urine analysis revealed an increasing 213Bi-to-225Ac ratio (24 h, 0.98 ± 0.15; 48 h, 1.08 ± 0.09). Mean kidney and lesion absorbed doses were 0.17 ± 0.06 and 0.36 ± 0.1 Sv RBE = 5 /MBq using 221Fr and 213Bi SPECT images, compared to 0.16 ± 0.05/0.18 ± 0.06 and 0.36 ± 0.1/0.38 ± 0.1 Sv RBE = 5 /MBq considering either the 221Fr or 213Bi SPECT. CONCLUSION: SPECT/CT imaging and urine analysis showed minor differences of up to 10% in the daughter-specific pharmacokinetics. These variances had a minimal impact on the lesion and kidney dosimetry which remained within 8%.

Proliferation and apoptosis after whole-body irradiation: longitudinal PET study in a mouse model.

PURPOSE: A reliable method for regional in vivo imaging of radiation-induced cellular damage would be of great importance for the detection of therapy-induced injury to healthy tissue and the choice of adequate treatment of radiation emergency patients in both civilian and military events. This study aimed to investigate in a mouse model if positron emission tomography (PET) imaging with proliferation and apoptosis markers is potentially suitable for this purpose. METHODS: Four groups, including twenty mice (wild-type C57BL/6) each, were whole-body irradiated with 0 Gy, 0.5 Gy, 1 Gy, and 3 Gy and examined by PET over a six-month period at defined time points. 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) and 2-(5-[18F]fluoropentyl)-2-methyl malonic acid ([18F]ML-10) were used to visualise proliferation and apoptosis. Regional standard uptake values were compared with respect to irradiation dose over time. Histologic data and peripheral blood cell values were correlated with the PET results. RESULTS: The hematopoietic bone marrow showed a significantly increased [18F]FLT signal at early time points after radiation exposure (day 3 and day 7). This correlated with blood parameters, especially leukocytes, and histological data. A significantly increased [18F]FLT signal also occurred in the gastrointestinal tract and thymus at early time points. An increased [18F]ML-10 signal related to irradiation doses was observed in the bone marrow on day 8, but there was a high variability of standard uptake values and no correlation with histological data. CONCLUSION: [18F]FLT showed potential to visualise the extent, regional distribution and recovery from radiation-induced cellular damage in the bone marrow, gastrointestinal tract and thymus. The potential of [18F]FLT imaging to assess the extent of bone marrow affected by irradiation might be especially useful to predict the subsequent severity of hematopoietic impairment and to adapt the therapy of the bone marrow reserve. [18F]ML-10 PET proved to be not sensitive enough for the reliable detection of radiation induced apoptosis.

Biodistribution and dosimetry for combined [177Lu]Lu-PSMA-I&T/[225Ac]Ac-PSMA-I&T therapy using multi-isotope quantitative SPECT imaging.

PURPOSE: Quantitative SPECT for patient-specific dosimetry is a valuable tool in the scope of radionuclide therapy, although its clinical application for 225Ac-based treatments may be limited due to low therapeutic activities. Therefore, the aim of this study was to demonstrate the feasibility of clinical quantitative low-count SPECT imaging during [177Lu]Lu-PSMA-I&T/[225Ac]Ac-PSMA-I&T treatment. METHODS: Eight prostate cancer patients (1000 MBq/8 MBq [177Lu]Lu-PSMA-I&T/[225Ac]Ac-PSMA-I&T) received a single-bed quantitative 177Lu/225Ac SPECT/CT acquisition (1 h) at 24 h post treatment (high-energy collimator, 16 projections p. head à 3.5 min, 128 × 128 pixel). The gamma peak at 440 keV (width: 10%) of the progeny 213Bi was imaged along with the peak at 208 keV (width: 15%) of 177Lu. Quantification included CT-based attenuation and window-based scatter correction plus resolution modelling. Gaussian post-filtering with a full-width-half-maximum of 30 mm and 40-45 mm was employed to match the signal-to-noise ratio of 225Ac and 177Lu, respectively. RESULTS: Kidney (r = 0.96, p < 0.01) and lesion (r = 0.94, p < 0.01) SUV for [177Lu]Lu-PSMA-I&T and [225Ac]Ac-PSMA-I&T showed a strong and significant correlation. Kidney SUV were significantly higher (p < 0.01) for [225Ac]Ac-PSMA-I&T (2.5 ± 0.8 vs. 2.1 ± 0.9), while for [177Lu]Lu-PSMA-I&T lesion SUV were significantly higher (p = 0.03; 1.8 ± 1.1 vs. 2.1 ± 1.5). For absorbed dose estimates, significant differences regarding the kidneys remained, while no significant differences for lesion dosimetry were found. CONCLUSION: Quantitative low-count SPECT imaging of the peak at 440 keV during [225Ac]Ac-PSMA-I&T therapy is feasible. Multi-isotope imaging for [177Lu]Lu-PSMA-I&T/[225Ac]Ac-PSMA-I&T therapy indicates accumulation of free 213Bi in the kidneys.

[68Ga]DOTA-TATE PET for the detection of early transplant rejection in a heterotopic allograft heart transplantation model of the rat: a pilot study.

BACKGROUND: The most important cause of heart transplant loss is early acute allograft rejection, caused by the infiltration of lymphocytes, development of edema and myocardial necrosis. It has been propagated that [68Ga]DOTA-TATE PET might be suitable to quantify the presence of SSTR over-expressing lymphocytes. With heterotopic allogenic heart transplant models in the rat readily available, we aimed to investigate, if monitoring and quantification of acute allograft rejection after heterotopic allogenic heart transplantation was feasible by non-invasive serial [68Ga]DOTA-TATE PET. METHODS: Seventeen Lewis rats (9 for serial PET imaging, 8 for histological correlation) received allogenic heterotopic heart transplants from 17 Brown-Norway rats. On days 4, 6 and 7 a [68Ga]DOTA-TATE PET scan was performed. RESULTS: Imaging of acute transplant rejection until 7 days after allogenic heart transplantation in the rat is feasible. Heterotopic allografts showed significantly increased tracer uptake on day 4 until day 7 after transplantation, reflecting the process of histologically detected myocardial lymphocytic infiltration. Both the area of infarction and the amount of necrosis increased over the course of 7 days, with necrosis reaching statistical significance. CONCLUSIONS: We purport that the detected PET signal is primarily a specific marker of lymphocyte infiltration and only to a lesser extent an unspecific marker of infarction and necrosis. Thus, [68Ga]DOTA-TATE PET might be a suitable tool for serial imaging and quantification of lymphocyte infiltration as a direct mediator of acute allograft rejection at an early stage after heart transplantation.

Dosimetry and optimal scan time of [18F]SiTATE-PET/CT in patients with neuroendocrine tumours.

PURPOSE: Radiolabelled somatostatin analogues targeting somatostatin receptors (SSR) are well established for combined positron emission tomography/computer tomography (PET/CT) imaging of neuroendocrine tumours (NET). [18F]SiTATE has recently been introduced showing high image quality, promising clinical performance and improved logistics compared to the clinical reference standard 68Ga-DOTA-TOC. Here we present the first dosimetry and optimal scan time analysis. METHODS: Eight NET patients received a [18F]SiTATE-PET/CT (250 ± 66 MBq) with repeated emission scans (10, 30, 60, 120, 180 min after injection). Biodistribution in normal organs and SSR-positive tumour uptake were assessed. Dosimetry estimates for risk organs were determined using a combined linear-monoexponential model, and by applying 18F S-values and reference target masses for the ICRP89 adult male or female (OLINDA 2.0). Tumour-to-background ratios were compared quantitatively and visually between different scan times. RESULTS: After 1 h, normal organs showed similar tracer uptake with only negligible changes until 3 h post-injection. In contrast, tracer uptake by tumours increased progressively for almost all types of metastases, thus increasing tumour-to-background ratios over time. Dosimetry resulted in a total effective dose of 0.015 ± 0.004 mSv/MBq. Visual evaluation revealed no clinically relevant discrepancies between later scan times, but image quality was rated highest in 60 and 120 min images. CONCLUSION: [18F]SiTATE-PET/CT in NET shows overall high tumour-to-background ratios from 60 to 180 min after injection and an effective dose comparable to 68Ga-labelled alternatives. For clinical use of [18F]SiTATE, the best compromise between image quality and tumour-to-background contrast is reached at 120 min, followed by 60 min after injection.

Intracavitary radioimmunotherapy of high-grade gliomas: present status and future developments.

There is a distinct need for new and second-line therapies to delay or prevent local tumor regrowth after current standard of care therapy. Intracavitary radioimmunotherapy, in combination with radiotherapy, is discussed in the present review as a therapeutic strategy of high potential. We performed a systematic literature search following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The available body of literature on intracavitary radioimmunotherapy (iRIT) in glioblastoma and anaplastic astrocytomas is presented. Several past and current phase I and II clinical trials, using mostly an anti-tenascin monoclonal antibody labeled with I-131, have shown median overall survival of 19-25 months in glioblastoma, while adverse events remain low. Tenascin, followed by EGFR and variants, or smaller peptides have been used as targets, and most clinical studies were performed with I-131 or Y-90 as radionuclides while only recently Re-188, I-125, and Bi-213 were applied. The pharmacokinetics of iRIT, as well as the challenges encountered with this therapy, is comprehensively discussed. This promising approach deserves further exploration in future studies by incorporating several innovative modifications.

Dosimetry for (177)Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer.

PURPOSE: Dosimetry is critical to achieve the optimal therapeutic effect of radioligand therapy (RLT) with limited side effects. Our aim was to perform image-based absorbed dose calculation for the new PSMA ligand (177)Lu-DKFZ-PSMA-617 in support of its use for the treatment of metastatic prostate cancer. METHODS: Whole-body planar images and SPECT/CT images of the abdomen were acquired in five patients (mean age 68 years) for during two treatment cycles at approximately 1, 24, 48 and 72 h after administration of 3.6 GBq (range 3.4 to 3.9 GBq) (177)Lu-DKFZ-PSMA-617. Quantitative 3D SPECT OSEM reconstruction was performed with corrections for photon scatter, photon attenuation and detector blurring. A camera-specific calibration factor derived from phantom measurements was used for quantitation. Absorbed doses were calculated for various organs from the images using a combination of linear approximation, exponential fit, and target-specific S values, in accordance with the MIRD scheme. Absorbed doses to bone marrow were estimated from planar and SPECT images and with consideration of the blood sampling method according to the EANM guidelines. RESULTS: The average (± SD) absorbed doses per cycle were 2.2 ± 0.6 Gy for the kidneys (0.6 Gy/GBq), 5.1 ± 1.8 Gy for the salivary glands (1.4 Gy/GBq), 0.4 ± 0.2 Gy for the liver (0.1 Gy/GBq), 0.4 ± 0.1 Gy for the spleen (0.1 Gy/GBq), and 44 ± 19 mGy for the bone marrow (0.012 Gy/GBq). The organ absorbed doses did not differ significantly between cycles. The critical absorbed dose reported for the kidneys (23 Gy) was not reached in any patient. At 24 h there was increased uptake in the colon with 50 - 70 % overlap to the kidneys on planar images. Absorbed doses for tumour lesions ranged between 1.2 and 47.5 Gy (13.1 Gy/GBq) per cycle. CONCLUSION: The salivary glands and kidneys showed high, but not critical, absorbed doses after RLT with (177)Lu-DKFZ-PSMA-617. We suggest that (177)Lu-DKFZ-PSMA-617 is suitable for radiotherapy, offering tumour-to-kidney ratios comparable to those with RLT agents currently available for the treatment of neuroendocrine tumours. Our dosimetry results suggest that (177)Lu-DKFZ-PSMA-617 treatment with higher activities and more cycles is possible without the risk of damaging the kidneys.

Derivation of a respiration trigger signal in small animal list-mode PET based on respiration-induced variations of the ECG signal.

BACKGROUND: Raw PET list-mode data contains motion artifacts causing image blurring and decreased spatial resolution. Unless corrected, this leads to underestimation of the tracer uptake and overestimation of the lesion size, as well as inaccuracies with regard to left ventricular volume and ejection fraction (LVEF), especially in small animal imaging. METHODS AND RESULTS: A respiratory trigger signal from respiration-induced variations in the electro-cardiogram (ECG) was detected. Original and revised list-mode PET data were used for calculation of left ventricular function parameters using both respiratory gating techniques. For adequately triggered datasets we saw no difference in mean respiratory cycle period between the reference standard (RRS) and the ECG-based (ERS) methods (1120 ± 159 ms vs 1120 ± 159 ms; P = n.s.). While the ECG-based method showed somewhat higher signal noise (66 ± 22 ms vs 51 ± 29 ms; P < .001), both respiratory triggering techniques yielded similar estimates for EDV, ESV, LVEF (RRS: 387 ± 56 µL, 162 ± 34 µL, 59 ± 5%; ERS: 389 ± 59 µL, 163 ± 35 µL, 59 ± 4%; P = n.s.). CONCLUSIONS: This study showed that respiratory gating signals can be accurately derived from cardiac trigger information alone, without the additional requirement for dedicated measurement of the respiratory motion in rats.

Impact of partial volume effect correction on cerebral ß-amyloid imaging in APP-Swe mice using [(18)F]-florbetaben PET.

We previously investigated the progression of ß-amyloid deposition in brain of mice over-expressing amyloid-precursor protein (APP-Swe), a model of Alzheimer's disease (AD), in a longitudinal PET study with the novel ß-amyloid tracer [(18)F]-florbetaben. There were certain discrepancies between PET and autoradiographic findings, which seemed to arise from partial volume effects (PVE). Since this phenomenon can lead to bias, most especially in the quantitation of brain microPET studies of mice, we aimed in the present study to investigate the magnitude of PVE on [(18)F]-florbetaben quantitation in murine brain, and to establish and validate a useful correction method (PVEC). Phantom studies with solutions of known radioactivity concentration were performed to measure the full-width-at-half-maximum (FWHM) resolution of the Siemens Inveon DPET and to validate a volume-of-interest (VOI)-based PVEC algorithm. Several VOI-brain-masks were applied to perform in vivo PVEC on [(18)F]-florbetaben data from C57BL/6(N=6) mice, while uncorrected and PVE-corrected data were cross-validated with gamma counting and autoradiography. Next, PVEC was performed on longitudinal PET data set consisting of 43 PET scans in APP-Swe (13-20months) and age-matched wild-type (WT) mice using the previously defined masks. VOI-based cortex-to-cerebellum ratios (SUVR) were compared for uncorrected and PVE-corrected results. Brains from a subset of transgenic mice were ultimately examined by autoradiography ex vivo and histochemistry in vitro as gold standard assessments, and compared to VOI-based PET results. The phantom study indicated a FWHM of 1.72mm. Applying a VOI-brain-mask including extracerebral regions gave robust PVEC, with increased precision of the SUVR results. Cortical SUVR increased with age in APP-Swe mice compared to baseline measurements (16months: +5.5%, p<0.005; 20months: +15.5%, p<0.05) with uncorrected data, and to a substantially greater extent with PVEC (16months: +12.2% p<0.005; 20months: +36.4% p<0.05). WT animals showed no binding changes, irrespective of PVEC. Relative to autoradiographic results, the error [%] for uncorrected cortical SUVR was 18.9% for native PET data, and declined to 4.8% upon PVEC, in high correlation with histochemistry results. We calculate that PVEC increases by 10% statistical power for detecting altered [(18)F]-florbetaben uptake in aging APP-Swe mice in planned studies of disease modifying treatments on amyloidogenesis.

In vivo monitoring of parathyroid hormone treatment after myocardial infarction in mice with [68Ga]annexin A5 and [18F]fluorodeoxyglucose positron emission tomography.

[68Ga]Annexin A5 positron emission tomography (PET) reveals the externalization of phosphatidylserine as a surrogate marker for apoptosis. We tested this technique for therapy monitoring in a murine model of myocardial infarction (MI) including parathyroid hormone (PTH) treatment. MI was induced in mice, and they were assigned to the saline or the PTH group. On day 2, they received [68Ga]annexin A5 PET or histofluorescence TUNEL staining. Mice had 2-deoxy-2-[18F]fluoro-d-glucose (FDG)-PET examinations on days 6 and 30 for calculation of the left ventricular ejection fraction and infarct area. [68Ga]Annexin A5 uptake was 7.4 ± 1.3 %ID/g within the infarction for the controls and 4.5 ± 1.9 %ID/g for the PTH group (p  =  .013). TUNEL staining revealed significantly more apoptotic cells in the infarct area on day 2 in the controls (64 ± 9%) compared to the treatment group (52 ± 4%; p  =  .045). FDG-PET revealed a significant decrease in infarct size in the treatment group and an increase in the controls. Examinations of left ventricular ejection fraction on days 6 and 30 did not reveal treatment effects. [68Ga]Annexin A5 PET can detect the effects of PTH treatment as a marker of apoptosis 2 days after MI; ex vivo examination confirmed significant rescue of myocardiocytes. FDG-PET showed a small but significant reduction in infarct size but no functional improvement.

In-vivo monitoring of erythropoietin treatment after myocardial infarction in mice with [68Ga]Annexin A5 and [¹8F]FDG PET.

BACKGROUND: Several studies substantiate the cardioprotective effects of erythropoietin (EPO). Our goal was to quantify the effects of EPO treatment on the early expression of the apoptosis marker phosphatidylserine as well as on the left ventricular volumes and function by means of small animal PET. METHODS AND RESULTS: Myocardial infarction (MI) was induced in C57BL/6 mice. Animals were assigned to saline or EPO groups and underwent Annexin PET (day 2) and gated FDG PET (days 6 and 30). Annexin uptake was significantly higher in the infarction than in remote myocardium, with no differences between treatment groups. Infarct size showed a slight decrease in the EPO group and a slight increase in the controls, which did not reach statistical significance. Follow-up analyses revealed a significant increase of end-diastolic and end-systolic volumes in the EPO group, in which a stable left ventricular ejection fraction (LVEF) was maintained. CONCLUSION: We find that deleterious effects of EPO can outweigh cardioprotective effects. The present EPO treatment did not significantly reduce apoptosis after MI, but seemingly provoked significant myocardial dilation while maintaining a stable LVEF. Molecular mechanisms of EPO treatment may need further elucidation to optimize therapy regimens.

Impact of the Reference Multiple-Time-Point Dosimetry Protocol on the Validity of Single-Time-Point Dosimetry for [177Lu]Lu-PSMA-I&T Therapy.

Internal dosimetry supports safe and effective patient management during radionuclide therapy. Yet, it is associated with high clinical workload, costs, and patient burden, as patient scans at multiple time points (MTPs) must be acquired. Dosimetry based on imaging at a single time point (STP) has continuously gained popularity. However, MTP protocols, used as a reference to judge the validity of STP dosimetry, differ depending on local requirements and deviate from the unknown patient-specific ground truth pharmacokinetics. The aim of this study was to compare the error and optimum time point for different STP approaches using different reference MTP protocols. Methods: Whole-body SPECT/CT scans of 7 patients (7.4-8.9 GBq of [177Lu]Lu-PSMA-I&T) were scheduled at 24, 48, 72, and 168 h after injection. Sixty lesions, 14 kidneys, and 10 submandibular glands were delineated in the SPECT/CT data. Two curve models, that is, a mono- and a biexponential model, were fitted to the MTP data, in accordance with goodness-of-fit analysis (coefficients of variation, sum of squared errors). Three population-based STP approaches were compared: one method published by Hänscheid et al., one by Jackson et al., and one using population-based effective half-lives in the mono- or biexponential curve models. Percentage differences between STP and MTP dosimetry were evaluated. Results: Goodness-of-fit parameters show that a monoexponential function and a biexponential function with shared population-based parameters and physical tail are reasonable reference models. When comparing both reference models, we observed maximum differences of -44%, -19%, and -28% in the estimated absorbed doses for lesions, kidneys, and salivary glands, respectively. STP dosimetry with an average deviation of less than 10% from MTP dosimetry may be feasible; however, this deviation and the optimum imaging time point showed a dependence on the chosen reference protocol. Conclusion: STP dosimetry for [177Lu]Lu-PSMA therapy is promising to boost the integration of dosimetry into clinical routine. According to our patient cohort, 48 h after injection may be regarded as a compromise for STP dosimetry for lesions and at-risk organs. The results from this analysis show that a common gold standard for dosimetry is desirable to allow for reliable and comparable STP dosimetry.

Positron emission tomography in the assessment of left ventricular function in healthy rats: a comparison of four imaging methods.

OBJECTIVE: To measure left ventricular (LV) function parameters in heart of healthy rats by three different positron emission tomography (PET) imaging techniques and by magnetic resonance imaging (MRI). METHODS: ECG-gated microPET examinations were obtained in seven healthy rats with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) for calculation of LV-function from the blood-pool phase of the dynamic recording (FDGBP), and also from the later myocardial uptake (FDGMyo). On subsequent days, we re-measured LV-function using the novel blood-pool tracer (68)Ga-albumin (AlbBP) and again by FDG (FDGMyo2) in one setting. Cine-MRI examination provided the reference standard measurement. RESULTS: The mean LV ejection fractions (LVEF) were 56 ± 3 (FDGBP), 55 ± 3 (FDGMyo), 56 ± 3 (FDGMyo2), 57 ± 3 (AlbBP), and 57 ± 2 (MRI). There were good to excellent correlations found between the LVEF-values as compared to MRI reference standard for FDGBP (r = 0.71), FDGMyo (r = 0.86) and AlbBP (r = 0.88). Both of the blood-pool methods significantly overestimated the magnitudes of end-diastolic-volume and end-systolic-volume, whereas FDGMyo matched closely to the MRI reference standard. There was no significant bias for both blood-pool methods and a minor negative bias for FDGMyo regarding the LV ejection fraction (LVEF) when compared to cine-MRI results. There was no significant difference between the means of FDGMyo and FDGMyo2 (P = .50). CONCLUSIONS: Relative to reference standard MRI measurements of LVEF, there was excellent agreement between PET-based measurements, notably for the novel blood-pool tracer (68)Ga-albumin.

Toward Single-Time-Point Image-Based Dosimetry of 177Lu-PSMA-617 Therapy.

Radiopharmaceutical therapies (RPTs) with 177Lu-prostate-specific membrane antigen (PSMA) ligands have demonstrated promising results for the treatment of metastatic castration-resistant prostate cancer. The lack of absorbed-dose-effect relationships currently prevents patient-specific activity personalization. To ease the implementation of dosimetry in the routine clinical workflow for RPT, simplified methods such as single-time-point (STP) instead of multiple-time-point (MTP) imaging protocols are required. This work aimed at assessing differences in the time-integrated activity (TIA) of STP versus MTP image-based dosimetry for 177Lu-PSMA-617 therapy. Methods: Twenty metastatic castration-resistant prostate cancer patients with MTP quantitative 177Lu-SPECT imaging data (∼24, 48, and 72 h post injection (p.i.)) available on first and second 177Lu-PSMA-617 therapy cycles were included in this study. Time-activity curves were fitted for kidneys and lesions to derive effective half-lives and yield a reference TIA. STP approaches involved the formula by Hänscheid (STPH) and a prior-information method (STPprior) that uses the effective half-lives from the first therapy cycle. All time points were considered for the STP approaches. Percentage differences (PDs) in TIA between STP and MTP were compared for the second therapy cycle. Results: Using STPH at 48 h p.i. for kidneys showed a -1.3% ± 5.6% PD from MTP, whereas STPprior showed a PD of 4.6% ± 6.2%. The smallest average PDs for the 56 investigated individual lesions were found using STPprior at 48 h p.i., at only 0.4% ± 14.9%, whereas STPH at 72 h p.i. had a smallest PD of -1.9% ± 14.8%. Conclusion: STP dosimetry for 177Lu-PSMA-617 therapy using a single SPECT/CT scan at 48 or 72 h p.i. is feasible, with a PD of less than ±20% compared with MTP. The validity of both STPH and STPprior has been demonstrated. We believe this finding can increase the adoption of dosimetry and facilitate implementation in routine clinical RPT workflows. Doing so will ultimately enable the finding of dose-effect relationships based on fixed therapy activities that may, in future, allow for absorbed-dose-based RPT activity personalization.

Estimation of relative biological effectiveness of 225Ac compared to 177Lu during [225Ac]Ac-PSMA and [177Lu]Lu-PSMA radiopharmaceutical therapy using TOPAS/TOPAS-nBio/MEDRAS.

AIM: Over recent years, [225Ac]Ac-PSMA and [177Lu]Lu-PSMA radiopharmaceutical therapy have evolved as a promising treatment option for advanced prostate cancer. Especially for alpha particle emitter treatments, there is still a need for improving dosimetry, which requires accurate values of relative biological effectiveness (RBE). To achieve that, consideration of DNA damages in the cell nucleus and knowledge of the energy deposition in the location of the DNA at the nanometer scale are required. Monte Carlo particle track structure simulations provide access to interactions at this level. The aim of this study was to estimate the RBE of 225Ac compared to 177Lu. The initial damage distribution after radionuclide decay and the residual damage after DNA repair were considered. METHODS: This study employed the TOol for PArtcile Simulation (TOPAS) based on the Geant4 simulation toolkit. Simulation of the nuclear DNA and damage scoring were performed using the TOPAS-nBio extension of TOPAS. DNA repair was modeled utilizing the Python-based program MEDRAS (Mechanistic DNA Repair and Survival). Five different cell geometries of equal volume and two radionuclide internalization assumptions as well as two cell arrangement scenarios were investigated. The radionuclide activity (number of source points) was adopted based on SPECT images of patients undergoing the above-mentioned therapies. RESULTS: Based on the simulated dose-effect curves, the RBE of 225Ac compared to 177Lu was determined in a wide range of absorbed doses to the nucleus. In the case of spherical geometry, 3D cell arrangement and full radionuclide internalization, the RBE based on the initial damage had a constant value of approximately 2.14. Accounting for damage repair resulted in RBE values ranging between 9.38 and 1.46 for 225Ac absorbed doses to the nucleus between 0 and 50 Gy, respectively. CONCLUSION: In this work, the consideration of DNA repair of the damage from [225Ac]Ac-PSMA and [177Lu]Lu-PSMA revealed a dose dependency of the RBE. Hence, this work suggested that DNA repair is an important aspect to understand response to different radiation qualities.

First clinical experience with fractionated intracavitary radioimmunotherapy using [177Lu]Lu-6A10-Fab fragments in patients with glioblastoma: a pilot study.

BACKGROUND: Following resection and standard adjuvant radio- and chemotherapy, approved maintenance therapies for glioblastoma are lacking. Intracavitary radioimmunotherapy (iRIT) with 177Lu-labeled 6A10-Fab fragments targeting tumor-associated carbonic anhydrase XII and injected into the resection cavity offers a novel and promising strategy for improved tumor control. METHODS: Three glioblastoma patients underwent tumor resection followed by standard radio- and chemotherapy. These patients with stable disease following completion of standard therapy underwent iRIT on compassionate grounds. After surgical implantation of a subcutaneous injection reservoir with a catheter into the resection cavity, a leakage test with [99mTc]Tc-DTPA was performed to rule out leakage into other cerebral compartments. IRIT comprised three consecutive applications over three months for each patient, with 25%, 50%, 25% of the total activity injected. A dosimetry protocol was included with blood sampling and SPECT/CT of the abdomen to calculate doses for the bone marrow and kidneys as potential organs at risk. RESULTS: All three patients presented without relevant leakage after application of [99mTc]Tc-DTPA. Two patients underwent three full cycles of iRIT (592 MBq and 1228 MBq total activity). One patient showed histologically proven tumor progression after the second cycle (526 MBq total activity). No relevant therapy-associated toxicities or adverse events were observed. Dosimetry did not reveal absorbed doses above upper dose limits for organs at risk. CONCLUSIONS: In first individual cases, iRIT with [177Lu]Lu-6A10-Fab appears to be feasible and safe, without therapy-related side effects. A confirmatory multicenter phase-I-trial was recently opened and is currently recruiting.

Investigation of image-based lesion and kidney dosimetry protocols for 177Lu-PSMA-I&T therapy with and without a late SPECT/CT acquisition.

BACKGROUND: 177Lu-PSMA therapy has been successfully used to prolong the survival of patients with metastatic castration-resistant prostate cancer. Patient-specific dosimetry based on serial quantitative SPECT/CT imaging can support the understanding of dose-effect relationships. However, multiple SPECT/CT measurements can be challenging for patients, which motivates the investigation of efficient sampling schedules and their impact on dosimetry. In this study, different time samplings with respect to the number and timing of SPECT/CT acquisitions with and without a late measurement were investigated. MATERIALS AND METHODS: In total, 43 lesions and 10 kidneys of 5 patients receiving 177Lu-PSMA-I&T therapy were investigated. Whole-body SPECT/CT measurements were performed at 1, 2, 3 and 7 days post-injection. For both lesions (isocontour-based segmentation) and kidneys (CT-based segmentation), a reference model was employed including all four time points. To identify the best-matching fit function out of a pre-defined set of models, visual inspection, coefficients of variation and sum of squared errors were considered as goodness-of-fit criteria. Biologically effective doses (BEDs) calculated with different time samplings (days 1, 2, 3/1, 2, 7/1, 3, 7/2, 3, 7 and 1, 2/1, 3/1, 7) were compared to the reference. RESULTS: The best-fit function was found to be a mono-exponential model for lesions and a bi-exponential model with a population-based parameter and two free parameters for kidneys. The BEDs calculated with the time sampling 1, 3, 7 days showed the lowest deviations from the reference for lesions with 4 ± 5%. Without day 7, still 86% of all lesions showed deviations from the reference < 10%. The outlier deviations showed a positive correlation with the effective half-life of the respective lesions. For kidneys, including days 1, 2, 3 achieved the best results with 0 ± 1%. Generally, deviations for kidneys were found to be small for all time samplings (max. 13%). CONCLUSIONS: For combined optimization of the SPECT/CT time sampling for kidney and lesion dosimetry during 177Lu-PSMA-I&T therapy, the sampling with days 1, 3, 7 showed the smallest deviation from the reference. Without a late acquisition, using the schedule with days 1, 2, 3 is likewise feasible.

Temporal changes in phosphatidylserine expression and glucose metabolism after myocardial infarction: an in vivo imaging study in mice.

Positron emission tomography (PET) for in vivo monitoring of phosphatidylserine externalization and glucose metabolism can potentially provide early predictors of outcome of cardioprotective therapies after myocardial infarction. We performed serial [68Ga]annexin A5 PET (annexin-PET) and [¹8F]fluorodeoxyglucose PET (FDG-PET) after myocardial infarction to determine the time of peak phosphatidylserine externalization in relation to impaired glucose metabolism in infracted tissue. Annexin- and FDG-PET recordings were obtained in female (C57BL6/N) mice on days 1 to 4 after ligation of the left anterior descending (LAD) artery. [68Ga]annexin A5 uptake (%ID/g) in the LAD artery territory increased from 1.7 ± 1.1 on day 1 to 5.0 ± 3.3 on day 2 and then declined to 2.0 ± 1.4 on day 3 (p  =  .047 vs day 2) and 1.6 ± 1.4 on day 4 (p  =  .014 vs day 2). These results matched apoptosis rates as estimated by autoradiography and fluorescein staining. FDG uptake (%ID/g) declined from 28 ± 14 on day 1 to 14 ± 3.5 on day 4 (p < .0001 vs day 1). Whereas FDG-PET revealed continuous loss of cell viability after permanent LAD artery occlusion, annexin-PET indicated peak phosphatidylserine expression at day 2, which might be the optimal time point for therapy monitoring.

Compensation for cranial spill-in into the cerebellum improves quantitation of striatal dopamine D2/3 receptors in rats with prolonged [¹8F]-DMFP infusions.

The condition of steady-state receptor binding in positron emission tomography (PET) studies is best obtained through the use of a bolus plus steady-infusion paradigm. This is a particularly important consideration in the context of in vivo competition studies, where a pharmacological challenge can be administered during the interval of steady-state ligand binding, as in the case of [¹¹C]-raclopride studies with amphetamine challenge. However, the short half-life of ¹¹C imposes limits on the practical duration of constant infusions. Therefore, we chose to test [¹8F]-DMFP as a tracer for dopamine D2/3 receptors in rat striatum in the paradigm. Using a conventional bolus injection, the [¹8F]-DMFP BP(ND) was 3.8 in striatum of anesthetized rats. When followed by a constant infusion, we obtained quasi-stable BP(ND) estimates of 4.5 within an interval of 45 min. During infusions lasting up to 4 h, BP(ND) declined progressively. This seemed due to the progressive spill-in of radioactivity from the cranium to the cerebellum reference region, despite optimized iterative reconstruction of the images. Therefore, we propose a new concept of compensation for this spill-in effect using pharmacokinetic considerations, without requiring high-resolution anatomical images. Challenge with amphetamine (1 and 4 mg/kg) evoked an ∼25% reduction in BP(ND) . There was no clear evidence of dose-dependence in the striatal-binding changes, despite the considerably greater physiological effect, as documented by ECG. Thus, the general applicability of the bolus plus infusion method with [¹8F]-DMFP for small animal studies is impeded by the substantial labeling of the cranium. The cranial uptake was linear, indicating first-order kinetics for the enzymatic defluorination of the tracer. Based on this phenomenon, we developed an analytic method compensating for the effects of progressive cranial labeling on the estimation of specific binding in striatum.