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Abstract Background Histopathology is the reference standard for diagnosing liver metastases of neuroendocrine tumors (NETs). Somatostatin receptor-positron emission tomography / computed tomography (SSR-PET/CT) has emerged as a promising non-invasive imaging modality for staging NETs. We aimed to assess the diagnostic accuracy of SSR-PET/CT in the identification of liver metastases in patients with proven NETs compared to histopathology. Methods Histopathologic reports of 139 resected or biopsied liver lesions of patients with known NET were correlated with matching SSR-PET/CTs and the positive/negative predictive value (PPV/NPV), sensitivity, specificity, and diagnostic accuracy of SSR-PET/CT were evaluated. PET/CT reading was performed by one expert reader blinded to histopathology and clinical data. Results 133 of 139 (95.7%) liver lesions showed malignant SSR-uptake in PET/CT while initial histopathology reported on ‘liver metastases of NET´ in 127 (91.4%) cases, giving a PPV of 91.0%. Re-biopsy of the initially histopathologically negative lesions (reference standard) nevertheless diagnosed ‘liver metastases of NET’ in 6 cases, improving the PPV of PET/CT to 95.5%. Reasons for initial false-negative histopathology were inadequate sampling in the sense of non-target biopsies. The 6 (4.3%) SSR-negative lesions were all G2 NETs with a Ki-67 between 2–15%. Conclusion SSR-PET/CT is a highly accurate imaging modality for the diagnosis of liver metastases in patients with proven NETs. However, we found that due to the well-known tumor heterogeneity of NETs, specifically in G2 NETs approximately 4–5% are SSR-negative and may require additional imaging with [18F]FDG PET/CT.

Abstract Radiotherapy and radiation oncology play a key role in the clinical management of patients suffering from oncological diseases. In clinical routine, anatomic imaging such as contrast-enhanced CT and MRI are widely available and are usually used to improve the target volume delineation for subsequent radiotherapy. Moreover, these modalities are also used for treatment monitoring after radiotherapy. However, some diagnostic questions cannot be sufficiently addressed by the mere use standard morphological imaging. Therefore, positron emission tomography (PET) imaging gains increasing clinical significance in the management of oncological patients undergoing radiotherapy, as PET allows the visualization and quantification of tumoral features on a molecular level beyond the mere morphological extent shown by conventional imaging, such as tumor metabolism or receptor expression. The tumor metabolism or receptor expression information derived from PET can be used as tool for visualization of tumor extent, for assessing response during and after therapy, for prediction of patterns of failure and for definition of the volume in need of dose-escalation. This review focuses on recent and current advances of PET imaging within the field of clinical radiotherapy / radiation oncology in several oncological entities (neuro-oncology, head & neck cancer, lung cancer, gastrointestinal tumors and prostate cancer) with particular emphasis on radiotherapy planning, response assessment after radiotherapy and prognostication.

Abstract Background NETTER-1 trial demonstrated high efficacy and low toxicity of four cycles of Peptide Receptor Radionuclide Therapy (PRRT) in patients with metastasized NET. The present study evaluates the outcome of further PRRT cycles in the so called salvage setting in patients after initial response to four therapy cycles and later progression. Methods Thirty five patients (pat.) (25 male, 10 female, 63 ± 9 years) with progressive, metastasized NET (23 small intestinal, 5 lung, 4 CUP, 1 rectal, 1 gastric and 1 paraganglioma) were included. All patients previously received 4 PRRT cycles with 177Lu-DOTATATE and showed initial response. SPECT based dosimetry was applied to determine kidney and tumor doses. Therapy response was evaluated using 68Ga-DOTATATE PET/CT (with high dose CT), CT alone or MRI (RECIST 1.1), toxicity was defined using CTCAE 5.0 criteria. 99mTc99-MAG3 scintigraphy was used to assess potential renal tubular damage. Progression free survival (PFS) and Overall survival (OS) analysis was performed with the Kaplan-Meier-method. Results The median PFS after initial PRRT was 33 months (95% CI: 30–36). The mean cumulative dose for including salvage PRRT was 44 GBq (range 33.5–47). One pat. (2.9%) showed grade 3 hematotoxicity. Kidney dosimetry revealed a mean cumulative kidney dose after a median of 6 PRRT cycles of 23.8 Gy. No grade 3 / 4 nephrotoxicity or relevant decrease in renal function was observed. Follow-up imaging was available in 32 patients after salvage therapy. Best response according to RECIST 1.1. was PR in one patient (3.1%), SD in 26 patients (81.3%) and PD in 5 patients (15.6%). PFS after salvage therapy was 6 months (95% CI: 0–16; 8 patients censored). Mean OS after initial PRRT was 105 months (95% CI: 92–119) and 51 months (95% CI: 41–61) after start of salvage therapy. Median OS was not reached within a follow-up of 71 months after initial PRRT and 25 months after start of salvage PRRT, respectively. Conclusions Salvage therapy with 177Lu-DOTATATE is safe and effective even in patients with extensive previous multimodal therapies during disease progression and represents a feasible and valuable therapy option for progressive NET.

Abstract Background Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. Methods To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Results Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Conclusion Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.

PURPOSE: The proPSMA trial at ten Australian centers demonstrated increased sensitivity and specificity for PSMA PET/CT compared to conventional imaging regarding metastatic status in primary high-risk prostate cancer patients. A cost-effectiveness analysis showed benefits of PSMA PET/CT over conventional imaging for the Australian setting. However, comparable data for other countries are lacking. Therefore, we aimed to verify the cost-effectiveness of PSMA PET/CT in several European countries as well as the USA. METHODS: Clinical data on diagnostic accuracy were derived from the proPSMA trial. Costs for PSMA PET/CT and conventional imaging were taken from reimbursements of national health systems and individual billing information of selected centers in Belgium, Germany, Italy, the Netherlands, and the USA. For comparability, scan duration and the decision tree of the analysis were adopted from the Australian cost-effectiveness study. RESULTS: In contrast to the Australian setting, PSMA PET/CT was primarily associated with increased costs in the studied centers in Europe and the USA. Mainly, the scan duration had an impact on the cost-effectiveness. However, costs for an accurate diagnosis using PSMA PET/CT seemed reasonably low compared to the potential consequential costs of an inaccurate diagnosis. CONCLUSION: We assume that the use of PSMA PET/CT is appropriate from a health economic perspective, but this will need to be verified by a prospective evaluation of patients at initial diagnosis.

Introduction: Neuroinflammation evaluation after acute ischemic stroke is a promising option for selecting an appropriate post-stroke treatment strategy. To assess neuroinflammation in vivo, translocator protein PET (TSPO PET) can be used. However, the gold standard TSPO PET quantification method includes a 90 min scan and continuous arterial blood sampling, which is challenging to perform on a routine basis. In this work, we determine what information is required for a simplified quantification approach using a machine learning algorithm. Materials and Methods: We analyzed data from 18 patients with ischemic stroke who received 0–90 min [18F]GE-180 PET as well as T1-weigted (T1w), FLAIR, and arterial spin labeling (ASL) MRI scans. During PET scans, five manual venous blood samples at 5, 15, 30, 60, and 85 min post injection (p.i.) were drawn, and plasma activity concentration was measured. Total distribution volume (VT) was calculated using Logan plot with the full dynamic PET and an image-derived input function (IDIF) from the carotid arteries. IDIF was scaled by a calibration factor derived from all the measured plasma activity concentrations. The calculated VT values were used for training a random forest regressor. As input features for the model, we used three late PET frames (60–70, 70–80, and 80–90 min p.i.), the ASL image reflecting perfusion, the voxel coordinates, the lesion mask, and the five plasma activity concentrations. The algorithm was validated with the leave-one-out approach. To estimate the impact of the individual features on the algorithm’s performance, we used Shapley Additive Explanations (SHAP). Having determined that the three late PET frames and the plasma activity concentrations were the most important features, we tested a simplified quantification approach consisting of dividing a late PET frame by a plasma activity concentration. All the combinations of frames/samples were compared by means of concordance correlation coefficient and Bland-Altman plots. Results: When using all the input features, the algorithm predicted VT values with high accuracy (87.8 ± 8.3%) for both lesion and non-lesion voxels. The SHAP values demonstrated high impact of the late PET frames (60–70, 70–80, and 80–90 min p.i.) and plasma activity concentrations on the VT prediction, while the influence of the ASL-derived perfusion, voxel coordinates, and the lesion mask was low. Among all the combinations of the late PET frames and plasma activity concentrations, the 70–80 min p.i. frame divided by the 30 min p.i. plasma sample produced the closest VT estimate in the ischemic lesion. Conclusion: Reliable TSPO PET quantification is achievable by using a single late PET frame divided by a late blood sample activity concentration.

Purpose: 2-Fluorodeoxyglucose-PET (FDG-PET) is a powerful tool to study glucose metabolism in mammalian brains, but cellular sources of glucose uptake and metabolic connectivity during aging are not yet understood. Methods: Healthy wild-type mice of both sexes (2–21 months of age) received FDG-PET and cell sorting after in vivo tracer injection (scRadiotracing). FDG uptake per cell was quantified in isolated microglia, astrocytes and neurons. Cerebral FDG uptake and metabolic connectivity were determined by PET. A subset of mice received measurement of blood glucose levels to study associations with cellular FDG uptake during aging. Results: Cerebral FDG-PET signals in healthy mice increased linearly with age. Cellular FDG uptake of neurons increased between 2 and 12 months of age, followed by a strong decrease towards late ages. Contrarily, FDG uptake in microglia and astrocytes exhibited a U-shaped function with respect to age, comprising the predominant cellular source of higher cerebral FDG uptake in the later stages. Metabolic connectivity was closely associated with the ratio of glucose uptake in astroglial cells relative to neurons. Cellular FDG uptake was not associated with blood glucose levels and increasing FDG brain uptake as a function of age was still observed after adjusting for blood glucose levels. Conclusion: Trajectories of astroglial glucose uptake drive brain FDG-PET alterations and metabolic connectivity during aging.

BackgroundSalvage radiation therapy (sRT) is often the sole curative option in patients with biochemical recurrence after radical prostatectomy. After sRT, we developed and validated a nomogram to predict freedom from biochemical failure. ObjectiveThis study aims to evaluate prostate-specific membrane antigen–positron emission tomography (PSMA-PET)–based sRT efficacy for postprostatectomy prostate-specific antigen (PSA) persistence or recurrence. Objectives include developing a random survival forest (RSF) model for predicting biochemical failure, comparing it with a Cox model, and assessing predictive accuracy over time. Multinational cohort data will validate the model’s performance, aiming to improve clinical management of recurrent prostate cancer. MethodsThis multicenter retrospective study collected data from 13 medical facilities across 5 countries: Germany, Cyprus, Australia, Italy, and Switzerland. A total of 1029 patients who underwent sRT following PSMA-PET–based assessment for PSA persistence or recurrence were included. Patients were treated between July 2013 and June 2020, with clinical decisions guided by PSMA-PET results and contemporary standards. The primary end point was freedom from biochemical failure, defined as 2 consecutive PSA rises >0.2 ng/mL after treatment. Data were divided into training (708 patients), testing (271 patients), and external validation (50 patients) sets for machine learning algorithm development and validation. RSF models were used, with 1000 trees per model, optimizing predictive performance using the Harrell concordance index and Brier score. Statistical analysis used R Statistical Software (R Foundation for Statistical Computing), and ethical approval was obtained from participating institutions. ResultsBaseline characteristics of 1029 patients undergoing sRT PSMA-PET–based assessment were analyzed. The median age at sRT was 70 (IQR 64-74) years. PSMA-PET scans revealed local recurrences in 43.9% (430/979) and nodal recurrences in 27.2% (266/979) of patients. Treatment included dose-escalated sRT to pelvic lymphatics in 35.6% (349/979) of cases. The external outlier validation set showed distinct features, including higher rates of positive lymph nodes (47/50, 94% vs 266/979, 27.2% in the learning cohort) and lower delivered sRT doses (

Aim: β-amyloid (Aβ) small animal PET facilitates quantification of fibrillar amyloidosis in Alzheimer's disease (AD) mouse models. Thus, the methodology is receiving growing interest as a monitoring tool in preclinical drug trials. In this regard, harmonization of data from different scanners at multiple sites would allow the establishment large collaborative cohorts and may facilitate efficacy comparison of different treatments. Therefore, we objected to determine the level of agreement of Aβ-PET quantification by a head-to-head comparison of three different state-of-the-art small animal PET scanners, which could help pave the way for future multicenter studies. Methods: Within a timeframe of 5 ± 2 weeks, transgenic APPPS1 (n = 9) and wild-type (WT) (n = 8) mice (age range: 13–16 months) were examined three times by Aβ-PET ([18F]florbetaben) using a Siemens Inveon DPET, a MedisonanoScan PET/MR, and a MedisonanoScan PET/CT with harmonized reconstruction protocols. Cortex-to-white-matter 30–60 min p.i. standardized uptake value ratios (SUVRCTX/WM) were calculated to compare binding differences, effect sizes (Cohen's d) and z-score values of APPPS1 relative to WT mice. Correlation coefficients (Pearson's r) were calculated for the agreement of individual SUVR between different scanners. Voxel-wise analysis was used to determine the agreement of spatial pathology patterns. For validation of PET imaging against the histological gold standard, individual SUVR values were subject to a correlation analysis with area occupancy of methoxy‑X04 staining. Results: All three small animal PET scanners yielded comparable group differences between APPPS1 and WT mice (∆PET=20.4 % ± 2.9 %, ∆PET/MR=18.4 % ± 4.5 %, ∆PET/CT=18.1 % ± 3.3 %). Voxel-wise analysis confirmed a high degree of congruency of the spatial pattern (Dice coefficient (DC)PETvs.PET/MR=83.0 %, DCPETvs.PET/CT=69.3 %, DCPET/MRvs.PET/CT=81.9 %). Differences in the group level variance of the three scanners resulted in divergent z-scores (zPET=11.5 ± 1.6; zPET/MR=5.3 ± 1.3; zPET/CT=3.4 ± 0.6) and effect sizes (dPET=8.5, dPET/MR=4.5, dPET/CT=4.1). However, correlations at the individual mouse level were still strong between scanners (rPETvs.PET/MR=0.96, rPETvs.PET/CT=0.91, rPET/MRvs.PET/CT=0.87; all p ≤ 0.0001). Methoxy-X04 staining exhibited a significant correlation across all three PET machines combined (r = 0.76, p < 0.0001) but also at individual level (PET: r = 0.81, p = 0.026; PET/MR: r = 0.89, p = 0.0074; PET/CT: r = 0.93, p = 0.0028). Conclusions: Our comparison of standardized small animal Aβ-PET acquired by three different scanners substantiates the possibility of moving towards a multicentric approach in preclinical AD research. The alignment of image acquisition and analysis methods achieved good overall comparability between data sets. Nevertheless, differences in variance of sensitivity and specificity of different scanners may limit data interpretation at the individual mouse level and deserves methodological optimization.

Abstract Background Locoregional recurrence is a critical factor in the prognosis of sinonasal malignancies. Due to the rarity of these tumours, as well as the heterogeneity of histologies and anatomical subsites, there is little evidence regarding the rate and location of regional metastases in sinonasal malignancies. Elective regional lymph node dissection in the therapy of sinonasal malignancies has become controversial. On the one hand, elective regional lymph node dissection is considered to be an overtreatment in the cN0 cases. On the other hand, undetected occult lymphatic metastases are associated with a poor prognosis. In this study, we discuss the role of sentinel lymph node biopsy as a minimally invasive procedure in the treatment of sinonasal malignancies based on our two years of practical experience and the currently available data. Results This is a descriptive, monocentric, retrospective study, including 20 cases of cN0 malignant sinonasal neoplasm, that underwent a surgical therapy between 2020 and 2022. The following aspects were investigated: tumour entity, localisation of the primary tumour, tumoral stage, localisation of the sentinel lymph nodes, and postoperative complications. Squamous cell carcinoma was the most frequently diagnosed tumour entity (50%), followed by adenocarcinoma (20%) and malignant melanoma (15%), adenoid cystic carcinoma and mucoepidermoid carcinoma. Sentinel lymph nodes were most frequently found in the ipsilateral neck region I (45%), followed by the ipsilateral neck region II (40%). In all cases, the removed lymph nodes were free of malignancy. There were no postoperative complications due to lymph node biopsy. There were no recurrences during the study period. Conclusion Sentinel node biopsy could add more safety to the management of cN0 sinonasal malignancies due to its low morbidity. Whether SNB could provide an alternative to elective neck dissection in the management of SNM should be investigated in further studies.

Abstract Background and objectives 18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer’s disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between β-amyloid-accumulation and microglial activation in AD. Methods 49 patients with AD (29 females, all Aβ-positive) and 15 Aβ-negative CN (8 female) underwent TSPO-PET ([18F]GE-180) and β-amyloid-PET ([18F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([18F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional Aβ-PET on TSPO-PET was used to determine the Aβ-plaque-dependent microglial response (slope) and the Aβ-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI). Results In AD, females showed higher mean cortical TSPO-PET z-scores (0.91 ± 0.49; males 0.30 ± 0.75; p = 0.002), while Aβ-PET z-scores were similar. The Aβ-plaque-independent microglial response was stronger in females with AD (+ 0.37 ± 0.38; males with AD − 0.33 ± 0.87; p = 0.006), pronounced at the prodromal stage. On the contrary, the Aβ-plaque-dependent microglial response was not different between sexes. The Aβ-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the Aβ-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F (3,52) = 3.077, p = 0.005). Conclusion While microglia response to fibrillar Aβ is similar between sexes, women with AD show a stronger Aβ-plaque-independent microglia response. This sex difference in Aβ-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the Aβ-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD.

Among functional imaging methods, metabolic connectivity (MC) is increasingly used for investigation of regional network changes to examine the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD) or movement disorders. Hitherto, MC was mostly used in clinical studies, but only a few studies demonstrated the usefulness of MC in the rodent brain. The goal of the current work was to analyze and validate metabolic regional network alterations in three different mouse models of neurodegenerative diseases (β-amyloid and tau) by use of 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) imaging. We compared the results of FDG-µPET MC with conventional VOI-based analysis and behavioral assessment in the Morris water maze (MWM). The impact of awake versus anesthesia conditions on MC read-outs was studied and the robustness of MC data deriving from different scanners was tested. MC proved to be an accurate and robust indicator of functional connectivity loss when sample sizes ≥12 were considered. MC readouts were robust across scanners and in awake/ anesthesia conditions. MC loss was observed throughout all brain regions in tauopathy mice, whereas β-amyloid indicated MC loss mainly in spatial learning areas and subcortical networks. This study established a methodological basis for the utilization of MC in different β-amyloid and tau mouse models. MC has the potential to serve as a read-out of pathological changes within neuronal networks in these models.

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2nd generation 18F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples (n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.