Due to challenges in performing routine personalized dosimetry in radiopharmaceutical therapies, interest in single-time-point (STP) dosimetry, particularly utilizing only one SPECT scan, is on the rise.Meanwhile, there are questions about reliability of STP dosimetry, with limited independent validations.In the present work, we analyze two STP dosimetry methods and evaluate dose errors for a number of radiopharmaceuticals based on effective half-life distributions. Method:We first challenged the common assumption that radiopharmaceutical effective half-lives across the population are Gaussian (normal) distributed. Then, dose accuracy was estimated based on two STP dosimetry methods for a wide range of potential scan-times post-injection (p.i.), for different radiopharmaceuticals applied to neuroendocrine tumors and prostate cancer. The accuracy and limitations of using each of the STP methods were discussed.Results: Log-normal distribution was shown as more appropriate to capture effective half-life distributions. The STP framework was shown as promising for dosimetry of 177 Lu-DOTATATE, and for kidney dosimetry of different radiopharmaceuticals (errors<30%). Meanwhile, for some radiopharmaceuticals, STP accuracy is compromised (e.g. in bone marrow and tumors for 177 Lu-PSMA therapies). Optimal SPECT scanning time for 177 Lu-DOTATATE is at ~72 h p.i., while 48 h p.i. would be better for 177 Lu-PSMA compounds. Conclusion:Our results demonstrate that simplified STP dosimetry methods may compromise the accuracy of dose estimates, with some exceptions such as for 177 Lu-DOTATATE and for kidney dosimetry in different radiopharmaceuticals. Simplified personalized dosimetry in the clinic continues to be a challenging task. Based on these results, we make suggestions and recommendations for improved personalized dosimetry using simplified imaging schemes. * The data of effective half-lives were published in the format of median and range only. For Studies 3 and 9, their corresponding values of mean and SD were then calculated based on method by Hozo et al 2005 (19). For Study 4, we had access to complete listing of effective half-lives. † The 95% CI of range was estimated assuming log-normal statistics, as described in the text. ‡ T eff of each individual ROI (organ or lesion) was available (i.e. complete listing of effective half-lives for all patients). § This overall dataset (29 patients) consisted primarily of 177 Lu-DOTATATE (22 patients) but also included some 177 Lu-DOTATOC ( 7patients).

Introduction: Prostate-specific membrane antigen (PSMA) is a promising novel molecular target for imaging diagnostics and therapeutics (theranostics). There has been a growing body of evidence supporting PSMA theranostics approaches in optimizing the management of prostate cancer and potentially altering its natural history. Methods: We utilized PubMed and Google Scholar for published studies, and clinicaltrials.gov for planned, ongoing, and completed clinical trials in PSMA theranostics as of June 2021. We presented evolving evidence for various PSMA-targeted radiopharmaceutical agents in the treatment paradigm for prostate cancer, as well as combination treatment strategies with other targeted therapy and immunotherapy. We highlighted the emerging evidence of PSMA and fluorodeoxyglucose (FDG) PET/CT as a predictive biomarker for PSMA radioligand therapy. We identified seven ongoing clinical trials in oligometastatic-directed therapy using PSMA PET imaging. We also presented a schematic overview of 17 key PSMA theranostic clinical trials throughout the various stages of prostate cancer. Conclusions: In this review, we presented the contemporary and future landscape of theranostic applications in prostate cancer with a focus on PSMA ligands. As PSMA theranostics will soon become the standard of care for the management of prostate cancer, we underscore the importance of integrating nuclear medicine physicians into the multidisciplinary team.

Background PET imaging of glucose metabolism has revealed presymptomatic abnormalities in genetic FTD but has not been explored in MAPT P301L mutation carriers. This study aimed to explore the patterns of presymptomatic hypometabolism and atrophy in MAPT P301L mutation carriers. Methods Eighteen asymptomatic members from five families with a P301L MAPT mutation were recruited to the study, six mutation carriers, and twelve mutation-negative controls. All participants underwent standard behavioural and cognitive assessment as well as [18F]FDG-PET and 3D T1-weighted MRI brain scans. Regional standardised uptake value ratios (SUVR) for the PET scan and volumes calculated from an automated segmentation for the MRI were obtained and compared between the mutation carrier and control groups. Results The mean (standard deviation) estimated years from symptom onset was 12.5 (3.6) in the mutation carrier group with a range of 7 to 18 years. No differences in cognition were seen between the groups, and all mutation carriers had a global CDR plus NACC FTLD of 0. Significant reduction in [18F] FDG uptake in the anterior cingulate was seen in mutation carriers (mean 1.25 [standard deviation 0.07]) compared to controls (1.36 [0.09]). A similar significant reduction was also seen in grey matter volume in the anterior cingulate in mutation carriers (0.60% [0.06%]) compared to controls (0.68% [0.08%]). No other group differences were seen in other regions. Conclusions Anterior cingulate hypometabolism and atrophy are both apparent presymptomatically in a cohort of P301L MAPT mutation carriers. Such a specific marker may prove to be helpful in stratification of presymptomatic mutation carriers in future trials.

Background: Hypometabolism of the posterior cingulate cortex (PCC) is an important diagnostic feature of late-onset, amnestic Alzheimer’s disease (AD) measured with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). However, it is unclear whether PCC hypometabolism has diagnostic value in young-onset, non-amnestic variants of AD, which exhibit less pathology in the hippocampus and default mode network. Objective: Evaluate the prevalence and diagnostic value of PCC hypometabolism in non-amnestic variants of AD. Methods: We retrospectively identified 60 patients with young-onset, atypical dementia who have undergone a detailed clinical evaluation, FDG-PET, and an amyloid biomarker (amyloid-PET or cerebrospinal fluid analysis). We quantitatively analyzed regional hypometabolism in 70 regions of interest (ROI) using the MIMneuro® software. Results: Based on a cut-off of z-score < –1.5 for significant PCC hypometabolism, the prevalence of PCC hypometabolism in non-amnestic variants of AD was 65% compared to 28% in clinical variants of frontotemporal dementia (FTD). The ROI with the maximal hypometabolism was the dominant middle temporal gyrus in the language variant of AD (mean z score –2.28), middle occipital gyrus in PCA (–3.24), middle temporal gyrus in frontal AD (–2.70), and angular gyrus in corticobasal syndrome due to AD (–2.31). The PCC was not among the 10 most discriminant regions between non-amnestic variants of AD versus clinical variants of FTD. Conclusion: We conclude that PCC hypometabolism is not a discriminant feature to distinguish non-amnestic variants of AD from clinical variants of FTD—and should be interpreted with caution in patients with young-onset, non-amnestic dementia.

Background Accurate QSPECT is crucial in dosimetry-based, personalized radiopharmaceutical therapy with 177Lu and other radionuclides. We compared the quantitative performance of three NaI(Tl)-crystal SPECT/CT systems equipped with low-energy high-resolution collimators from two vendors (Siemens Symbia T6; GE Discovery 670 and NM/CT 870 DR). Methods Using up to 14 GBq of 99mTc in planar mode, we determined the calibration factor and dead-time constant under the assumption that these systems have a paralyzable behaviour. We monitored their response when one or both detectors were activated. QSPECT capability was validated by SPECT/CT imaging of a customized NEMA phantom containing up to 17 GBq of 99mTc. Acquisitions were reconstructed with a third-party ordered subset expectation maximization algorithm. Results The Siemens system had a higher calibration factor (100.0 cps/MBq) and a lower dead-time constant (0.49 μs) than those from GE (75.4–87.5 cps/MBq; 1.74 μs). Activities of up to 3.3 vs. 2.3–2.7 GBq, respectively, were quantifiable by QSPECT before the observed count rate plateaued or decreased. When used in single-detector mode, the QSPECT capability of the former system increased to 5.1 GBq, whereas that of the latter two systems remained independent of the detectors activation mode. Conclusion Despite similar hardware, SPECT/CT systems’ response can significantly differ at high count rate, which impacts their QSPECT capability in a post-therapeutic setting.

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Introduction: In this study, we compared 18F-FDG-postron emission tomography/computed tomography (PET/CT) and bone scintigraphy accuracies for the detection of bone metastases for primary staging in high-grade prostate cancer (PCa) patients to determine if 18F-FDG-PET/CT could be used alone as a staging modality. Methods: Men with localized high-grade PCa (n=256, Gleason 8–10, International Society of Urological Pathology [ISUP] grades 4 or 5) were imaged with bone scintigraphy and 18F-FDG-PET/CT. We compared on a per-patient basis the accuracy of the two imaging modalities, taking intermodality agreement as the standard of truth (SOT). Results: 18F-FDG-PET/CT detected at least one bone metastasis in 33 patients compared to only 26 with bone scan. Of the seven false-negative bone scintigraphies, four (57.1%) were solitary metastases (monometastatic), three (42.9%) were oligometastatic (2–4 lesions), and none were plurimetastatic (>4 lesions). Compared to SOT, 18F-FDG-PET/CT showed higher sensitivity and accuracy than bone scintigraphy (100% vs. 78.8%, and 98.7% vs. 98.2%) for the detection of skeletal lesions. Conclusions: 18F-FDG-PET/CT appears similar or better than conventional bone scans to assess for bone metastases in patients newly diagnosed with high-grade PCa. Since intraprostatic FDG-uptake is also a biomarker of failure to radical prostatectomy and that FDG-PET/CT has been shown to be accurate in detecting PCa lymph node metastasis, FDG-PET/CT has the potential to be used as the sole preoperative staging modality in high-grade PCa.

2 Background: We conducted a randomised trial comparing 18Flourocholine-PET/CT (FCH) to Computed Tomography (abdomen and pelvis) plus 99mTc-Whole Body Bone Scan (Conventional Imaging [CIm]) to determine imaging performance in prostate cancer (PC). Methods: This prospective two-arm 1:1 randomised trial enrolled men with newly diagnosed or biochemically recurrent PC to first-line imaging (FLI) with either CIm or FCH. Participants without evidence of metastases proceeded to second-line imaging (SLI) using the alternative imaging strategy. The primary aim was to determine whether FCH was more effective as a FLI approach in changing management. Secondary endpoints included incremental utility of SLI and negative predictive value (NPV) based on progression-free survival (PFS). Australian New Zealand Clinical Trials Registry ACTRN12608000641392. Results: 108 men were enrolled; 44% were for staging of newly-diagnosed PC and median follow-up 43 months. Imaging impacted clinical management in 32.4% of men (95% CI=23.7-42.1%), mostly with FLI (n=30). High-impact management changes occurred in 27.8% (95% CI=16.5-41.6%) of FCH cases compared with 11.1% (95% CI=4.2-22.6%) in the CIm arm (p=0.032). The final management plan was derived using FCH in 98.1% (95% CI = 90.1-100%) of cases and 92.6% (95%CI = 82.1-97.9%) of CIm cases (p=0.242). FLI with FCH showed unequivocally N1 or M1 disease in 22.2% (95% CI = 12-35.6%), and 16.7% (95% CI = 7.9-29.3%; p= 0.531) of CIm cases. The overall NPV for stage TxN0M0 (from all imaging) was 26.3% (95% CI: 13.9 - 41.2%), with no significant difference between arms (p=0.9). For N1M0 cases, the NPV was 14.3% (95% CI: 7.1 - 35.7%). The identification of N1M0 by FCH resulted in a longer time to identification of progressive disease, with a median PFS of 32 months (95% CI=2-68months) compared with 3 months (95% CI=1-16 months) in the CIm N1M0 cohort (p=0.05). Conclusions: FCH-PET/CT identifies more high-clinical-impact lesions than CIm as first-line imaging. All imaging modalities were poor at predicting subsequent progressive disease. Isolated node-positive disease seen with FCH is associated with a longer time to - but similarly high rates of - recurrence, suggesting a lead-time bias. Clinical trial information: ACTRN12608000641392.