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.

Prostate cancer can be targeted by ligands to the prostate-specific membrane antigen (PSMA). We aimed to evaluate dosimetry, safety and efficacy of 177Lu-PSMA-617 radioligand therapy (RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC).Fifteen patients each received two cycles of 3.7 GBq (n = 5) or 6.0 GBq (n = 10) 177Lu-PSMA-617 at an eight to ten weeks interval. For safety monitoring, each treatment was followed by dosimetry with serial quantitative SPECT as well as inpatient and outpatient recording of adverse events. Response to RLT was primarily determined by baseline to follow-up change in 68Ga-PSMA PET/CT (RECIST1.1), as well as change in prostate-specific antigen (PSA), quality of life (QoL, FACT-P scale), and pain (Brief Pain Inventory) as secondary endpoints.Radiation dose delivered to the tumor (6.1 Gy/GBq) was six to twelve-fold higher than to critical organs (kidney left/right 0.5/0.6 Gy/GBq each, salivary glands 1.0 Gy/GBq). Total radiation dose per kidney did not exceed 23 Gy in any patient. Three patients had sub-acute and latent grade 3 events, i.e. anemia, leukocytopenia, and nausea. No acute events, grade ≥4 events or high grade events for salivary gland or kidney function were observed. After two RLT cycles, 4 (27%) patients had partial response, 6 (40%) had stable disease, and 5 (33%) had progressive disease according to RECIST. Any PSA decline was observed in 12/15 (80%) patients during RLT. Significant pain relief was documented in 7/10 (70%) symptomatic patients and QoL improved in 9/15 (60%) patients.177Lu-PSMA-617 therapy proved safe and indicated promising response rates for both objective and patient-reported outcomes in our small group of mCRPC patients.

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Preclinical PET studies of β-amyloid (Aβ) accumulation are of growing importance, but comparisons between research sites require standardized and optimized methods for quantitation. Therefore, we aimed to evaluate systematically the (1) impact of an automated algorithm for spatial brain normalization, and (2) intensity scaling methods of different reference regions for Aβ-PET in a large dataset of transgenic mice. PS2APP mice in a 6 week longitudinal setting (N = 37) and another set of PS2APP mice at a histologically assessed narrow range of Aβ burden (N = 40) were investigated by [18F]-florbetaben PET. Manual spatial normalization by three readers at different training levels was performed prior to application of an automated brain spatial normalization and inter-reader agreement was assessed by Fleiss Kappa (κ). For this method the impact of templates at different pathology stages was investigated. Four different reference regions on brain uptake normalization were used to calculate frontal cortical standardized uptake value ratios (SUVRCTX∕REF), relative to raw SUVCTX. Results were compared on the basis of longitudinal stability (Cohen's d), and in reference to gold standard histopathological quantitation (Pearson's R). Application of an automated brain spatial normalization resulted in nearly perfect agreement (all κ≥0.99) between different readers, with constant or improved correlation with histology. Templates based on inappropriate pathology stage resulted in up to 2.9% systematic bias for SUVRCTX∕REF. All SUVRCTX∕REF methods performed better than SUVCTX both with regard to longitudinal stability (d≥1.21 vs. d = 0.23) and histological gold standard agreement (R≥0.66 vs. R≥0.31). Voxel-wise analysis suggested a physiologically implausible longitudinal decrease by global mean scaling. The hindbrain white matter reference (Rmean = 0.75) was slightly superior to the brainstem (Rmean = 0.74) and the cerebellum (Rmean = 0.73). Automated brain normalization with reference region templates presents an excellent method to avoid the inter-reader variability in preclinical Aβ-PET scans. Intracerebral reference regions lacking Aβ pathology serve for precise longitudinal in vivo quantification of [18F]-florbetaben PET. Hindbrain white matter reference performed best when considering the composite of quality criteria.

Purpose Late-life depression (LLD) even in subsyndromal stages revealed strong associations with Alzheimer’s disease (AD). Furthermore brain amyloidosis depicts an early biomarker in subjects subsequently suffering from AD and is sensitively detectable by amyloid-PET. Therefore we aimed to compare amyloid-load and glucose metabolism in subsyndromally depressed mild cognitive impaired (MCI) subjects. Methods 371 MCI subjects from ADNI underwent [18F]-AV45-, [18F]-FDG-PET, and MRI. Subjects were judged β-amyloid positive (Aß(+); N=206) or negative (Aß(−); N=165) according to [18F]-AV45-PET. Depressive symptoms were assessed by the Neuropsychiatric Inventory Questionnaire (NPI-Q) depression-item. 65 Aß(+) and 41 Aß(−) subjects with depressive symptoms (DEP) were contrasted against their non-depressed (NON-DEP) counterparts. Conversion rates to AD were analysed (mean follow-up time: 21.5±9.1 months) with regard to coexisting depressive symptoms and brain amyloid-load. Results Aß(+) DEP subjects showed large clusters with higher amyloid-load in frontotemporal and insular cortices (p<0.001) and coincident hypermetabolism (p<0.001) in frontal cortices when contrasted against NON-DEP. Faster progression to AD was observed in subjects with either depressive symptoms (p<0.005) or Aß(+) status (p<0.001). Coincident depressive symptoms additionally shortened the conversion time in all Aß(+) subjects (p<0.005) and to a greater extent in a subgroup with high amyloid-load (p<0.001). Conclusions Our results clearly indicate that Aß(+) MCI subjects with depressive symptoms suffer from elevated amyloid-load combined with relative hypermetabolism of connected brain areas when contrasted against cognitively-matched non-depressed individuals. MCI subjects with high amyloid-load and coexistent depressive symptoms represent a high-risk group for faster conversion to AD.

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Kinetic analysis of renal uptake using dynamic planar scans from the first hour after injection revealed a fast and a slow washout phase. Although the fast phase did not contribute substantially to the estimated renal dose, it could influence planar measurements performed within the first hours. We found that the presence of two clearance phases can hamper accurate dose estimation based on a single-phase model, resulting in approximately 12.4% dose underestimation, thus potentially resulting in overtreatment. In the absence of dynamic initial recordings, the first dosimetry measurements should therefore be obtained later than 3-5 h after [(177)Lu]DOTATATE injection. Omitting the early whole-body image reduced the dose estimation error to 3.1%.

BackgroundThe bone marrow (BM) is a main organ at risk in Lu-177-PSMA-617 therapy of prostate cancer and Lu-177-Octreotate therapy of neuroendocrine tumours. BM dosimetry is challenging and time-consuming, as different sequential quantitative measurements must be combined. The BM absorbed dose from the remainder of the body (ROB) can be determined from sequential whole-body planar (WB-P) imaging, while quantitative Lu-177-SPECT allows for more robust tumour and organ absorbed doses. The aim was to investigate a time-efficient and patient-friendly hybrid protocol (HP) for the ROB absorbed dose to the BM. It combines three abdominal quantitative SPECT (QSPECT) scans with a single WB-P acquisition and was compared with a reference protocol (RP) using sequential WB-P in combination with sequential QSPECT images. We investigated five patients receiving 7.4 GBq Lu-177-Octreotate and five patients treated with 3.7 GBq Lu-177-PSMA-617. Each patient had WB-P and abdominal SPECT acquisitions 24 (+ CT), 48, and 72 h post-injection. Blood samples were drawn 30 min, 80 min, 24 h, 48 h, and 72 h post-injection. BM absorbed doses from the ROB were estimated from sequential WB-P images (RP), via a mono-exponential fit and mass-scaled organ-level S values. For the HP, a mono-exponential fit on the QSPECT data was scaled with the activity of one WB-P image acquired either 24, 48, or 72 h post-injection (HP24, HP48, HP72). Total BM absorbed doses were determined as a sum of ROB, blood, major organ, and tumour contributions.ResultsCompared with the RP and for Lu-177-Octreotate therapy, median differences of the total BM absorbed doses were 13% (9–17%), 8% (4–15%), and 1% (0–5%) for the HP24, HP48, and HP72, respectively. For Lu-177-PSMA-617 therapy, total BM absorbed doses deviated 10% (2–20%), 3% (0–6%), and 2% (0–6%).ConclusionFor both Lu-177-Octreotate and Lu-177-PSMA-617 therapy, BM dosimetry via sequential QSPECT imaging and a single WB-P acquisition is feasible, if this WB-P image is acquired at a late time point (48 or 72 h post-injection). The reliability of the HP can be well accepted considering the uncertainties of quantitative Lu-177 imaging and BM dosimetry using standardised organ-level S values.