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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 FROM AUTHOR]

Objectives: Transjugular intrahepatic portosystemic shunt (TIPS) is a catheter-based, minimally invasive procedure to reduce portal hypertension. The aim of the study was to investigate dysfunction and mortality after TIPS and to identify factors associated with these events., Methods: A retrospective analysis of 834 patients undergoing TIPS implantation in a single center from 1993-2018 was performed. Cumulative incidence curves were estimated, and frailty models were used to assess associations between potentially influential variables and time to dysfunction or death., Results: 1-, 2-, and 5-year mortality rates were 20.9% (confidence interval (CI) 17.7-24.1), 22.5% (CI 19.1-25.8), and 25.0% (CI: 21.1-28.8), 1-year, 2-year, and 5-year dysfunction rates were 28.4% (CI 24.6-32.3), 38.9% (CI 34.5-43.3), and 52.4% (CI 47.2-57.6). The use of covered stents is a protective factor regarding TIPS dysfunction (hazard ratio (HR) 0.47, CI 0.33-0.68) but does not play a major role in survival (HR 0.95, CI 0.58-1.56). Risk factors for mortality are rather TIPS in an emergency setting (HR 2.78, CI 1.19-6.50), a previous TIPS dysfunction (HR 2.43, CI 1.28-4.62), and an increased Freiburg score (HR 1.45, CI 0.93-2.28)., Conclusion: The use of covered stents is an important protective factor regarding TIPS dysfunction. Whereas previous TIPS dysfunction, emergency TIPS implantation, and an elevated Freiburg score are associated with increased mortality. Awareness of risk factors could contribute to a better selection of patients who may benefit from a TIPS procedure and improve clinical follow-up with regard to early detection of thrombosis/stenosis., Critical Relevance Statement: The use of covered stents reduces the risk of dysfunction after transjugular intrahepatic portosystemic shunt (TIPS). TIPS dysfunction, emergency TIPS placement, and a high Freiburg score are linked to higher mortality rates in TIPS patients., Key Points: The risk of dysfunction is higher for uncovered stents compared to covered stents. Transjugular intrahepatic portosystemic shunt dysfunction increases the risk of instantaneous death after the intervention. A higher Freiburg score increases the rate of death after the intervention. Transjugular intrahepatic portosystemic shunt implantations in emergency settings reduce survival rates., (© 2024. The Author(s).)

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 [ 177 Lu]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 [ 177 Lu]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., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Metal artifacts notoriously pose significant challenge in computed tomography (CT), leading to inaccuracies in image formation and interpretation. Artifact reduction tools have been designed to improve cone beam computed tomography (CBCT) image quality by reducing artifacts caused by certain high-density materials. Metal artifact reduction (MAR) tools are specific algorithms that are applied during image reconstruction to minimize or eliminate artifacts degrading CBCT images. The purpose of the study is to evaluate the effect of a MAR algorithm on image quality in CBCT performed for evaluating patients before transarterial radioembolization (TARE). We retrospectively included 40 consecutive patients (aged 65 ± 13 years; 23 males) who underwent 45 CBCT examinations (Allura FD 20, XperCT Roll protocol, Philips Healthcare, Best, The Netherlands) in the setting of evaluation for TARE between January 2017 and December 2018. Artifacts caused by coils, catheters, and surgical clips were scored subjectively by four readers on a 5-point scale (1 = artifacts affecting diagnostic information to 5 = no artifacts) using a side-by-side display of uncorrected and MAR-corrected images. In addition, readers scored tumor visibility and vessel discrimination. MAR-corrected images were assigned higher scores, indicating better image quality. The differences between the measurements with and without MAR were most impressive for coils with a mean improvement of 1.6 points (95%CI [1.5 1.8]) on the 5-point likert scale, followed by catheters 1.4 points (95%CI [1.3 1.5]) and clips 0.7 points (95%CI [0.3 1.1]). Improvements for other artifact sources were consistent but relatively small (below 0.25 points on average). Interrater agreement was good to perfect (Kendall's W coefficient = 0.68-0.95) and was higher for MAR-corrected images, indicating that MAR improves diagnostic accuracy. A metal artifact reduction algorithm can improve diagnostic and interventional accuracy of cone beam CT in patients undergoing radioembolization by reducing artifacts caused by diagnostic catheters and coils, lowering interference of metal artifacts with adjacent major structures, and improving tumor visibility., (© 2024. The Author(s).)

Marfan syndrome (MFS) is an autosomal-dominant multisystem connective tissue disorder that is based on mutations in the FBN1 gene and variably affects different organs, including the heart. In this study, we investigated cardiac function with a focus on the left atrium (LA) in a relatively large cohort of patients with MFS. After screening of 1165 patients that had been examined in our center between 2016 and 2020, 231 adult MFS patients with and without aortic operation were included in our study and compared to a healthy control group ( n = 106). Cardiac function was assessed by transthoracic echocardiography and NT-proBNP was used as a secretory marker. Most (94.8%) of the patients received genetic testing. Left ventricular function was within normal ranges and not impaired. Interestingly, we found that LA size and secretory activity were increased in MFS patients, despite normal left ventricular filling pressures. This finding was even more pronounced in MFS patients with prior aortic surgery. A correlation between LA size or NT-proBNP levels and the type of pathogenic FBN1 variant could not be identified. Right ventricular function and right atrial size were increased only in MFS patients that had undergone aortic surgery. In conclusion, these findings suggest that MFS leads to structural changes in the LA that are not solely resulting from left ventricular dysfunction, but probably can be considered a primary pathology of MFS.

Aim: Over recent years, [ 225 Ac]Ac-PSMA and [ 177 Lu]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 225 Ac compared to 177 Lu. 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 225 Ac compared to 177 Lu 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 225 Ac absorbed doses to the nucleus between 0 and 50 Gy, respectively., Conclusion: In this work, the consideration of DNA repair of the damage from [ 225 Ac]Ac-PSMA and [ 177 Lu]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., (© 2023. Springer Nature Switzerland AG.)

Background: Following resection and standard adjuvant radio- and chemotherapy, approved maintenance therapies for glioblastoma are lacking. Intracavitary radioimmunotherapy (iRIT) with 177 Lu-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 [ 99m Tc]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 [ 99m Tc]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 [ 177 Lu]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., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Radiopharmaceutical therapies (RPTs) with 177 Lu-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 177 Lu-PSMA-617 therapy. Methods: Twenty metastatic castration-resistant prostate cancer patients with MTP quantitative 177 Lu-SPECT imaging data (∼24, 48, and 72 h post injection (p.i.)) available on first and second 177 Lu-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 (STP H ) and a prior-information method (STP prior ) 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 STP H at 48 h p.i. for kidneys showed a -1.3% ± 5.6% PD from MTP, whereas STP prior showed a PD of 4.6% ± 6.2%. The smallest average PDs for the 56 investigated individual lesions were found using STP prior at 48 h p.i., at only 0.4% ± 14.9%, whereas STP H at 72 h p.i. had a smallest PD of -1.9% ± 14.8%. Conclusion: STP dosimetry for 177 Lu-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 STP H and STP prior 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., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: 177 Lu-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 177 Lu-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 177 Lu-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., (© 2023. The Author(s).)

Purpose: To compare the effectivity and toxicity of monotherapy with computed tomography-guided high-dose-rate brachytherapy (CT-HDRBT) vs. combination therapy of transarterial chemoembolization with irinotecan (irinotecan-TACE) and CT-HDRBT in patients with large unresectable colorectal liver metastases (CRLM) with a diameter of > 3 cm., Material and Methods: Forty-four retrospectively matched patients with unresectable CRLM were treated either with mono-CT-HDRBT or with a combination of irinotecan-TACE and CT-HDRBT ( n = 22 in each group). Matching parameters included treatment, disease, and baseline characteristics. National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0) were used to evaluate treatment toxicity and the Society of Interventional Radiology classification was applied to analyze catheter-related adverse events. Statistical analysis involved Cox regression, Kaplan-Meier estimator, log-rank test, receiver operating characteristic curve analysis, Shapiro-Wilk test, Wilcoxon test, paired sample t -test, and McNemar test. P -values < 0.05 were deemed significant., Results: Combination therapy ensued longer median progression-free survival (PFS: 5/2 months, p = 0.002) and significantly lower local (23%/68%, p < 0.001) and intrahepatic (50%/95%, p < 0.001) progress rates compared with mono-CT-HDRBT after a median follow-up time of 10 months. Additionally, tendencies for longer local tumor control (LTC: 17/9 months, p = 0.052) were found in patients undergoing both interventions. After combination therapy, aspartate and alanine aminotransferase toxicity levels increased significantly, while total bilirubin toxicity levels showed significantly higher increases after monotherapy. No catheter-associated major or minor complications were identified in each cohort., Conclusions: Combining irinotecan-TACE with CT-HDRBT can improve LTC rates and PFS compared with mono-CT-HDRBT in patients with unresectable CRLM. The combination of irinotecan-TACE and CT-HDRBT shows satisfying safety profiles., Competing Interests: Outside of the submitted work, MJ reports personal fees from Boston Scientific (Marlborough, Massachusetts, USA). BG reports honoraria and travel support in the last 10 years from Parexel/ CALYX, C.R. BARD/ BD, SIRTex Medical, St. Jude Medical, COOK, AngioDynamics, Pharmcept, Guerbet, Ewimed, Terumo, Roche, Merck, 3M, Beacon Bioscience/ ICON, IPSEN, Bayer, Pfizer, Eisai, MSD, and INARI. All other authors report no conflicts of interest.The authors report no conflict of interest., (Copyright © 2023 Termedia.)

Spectral computed tomography (SCT) allows iodine content (IC) calculation for characterization of hypervascularized neoplasms and thus might help in the staging of neuroendocrine tumors (NETs). This single-center prospective study analyzed the association between SCT-derived IC and tumor response in the follow-up of metastasized NETs. Twenty-six patients with a median age of 70 years (range 51-85) with histologically proven NETs and a total of 78 lesions underwent SCT for staging. Because NETS are rare, no primary NET types were excluded. Lesions and intralesional hotspots were measured in virtual images and iodine maps. Tumor response was classified as progressive or nonprogressive at study endpoint. Generalized estimating equations served to estimate associations between IC and tumor response, additionally stratified by lesion location. Most commonly affected sites were the lymph nodes, liver, pancreas, and bones. Median time between SCT and endpoint was 64 weeks (range 5-260). Despite statistical imprecision in the estimate, patients with higher IC in lymphonodular metastases had lower odds for disease progression (adjusted OR = 0.21, 95% CI: 0.02-2.02). Opposite tendencies were observed in hepatic and pancreatic metastases in unadjusted analyses, which vanished after adjusting for therapy and primary tumor grade.

Therapy options for advanced pancreatic neuroendocrine tumors (pNETs) include the mTOR inhibitor everolimus and peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-TATE, however further optimization in the therapeutic landscape is required as response rates are still low. In this study, we investigated the synergistic and potentially enhanced efficacy of a combined treatment with everolimus and [177Lu]Lu-DOTA-TATE in a mouse model. Baseline [68Ga]Ga-DOTA-TATE PET scans were obtained five days after athymic CD1 mice were inoculated with AR42J tumor cells, before separating the animals into four groups. Group 1 received a placebo, group 2 everolimus, group 3 a placebo and PRRT, and group 4 everolimus and PRRT. The treatment response was monitored by manually measuring the tumor volumes (manual tumor volume, MTV) and conducting sequential [68Ga]Ga-DOTA-TATE PET scans at one, two, and four weeks after treatment induction. The biological tumor volume (BTV) was derived from PET scans using threshold-based volume of interest (VOI) measurements. Tracer uptake was measured semi-quantitatively as a tumor to background ratio (TBR). Mice were euthanized due to excessive tumor growth according to the ethics protocol; blood samples were drawn for the preparation of full blood counts and kidneys were obtained for histological analysis. For the histological assessment, a standardized score (renal damage score, RDS) was used. Full blood counts showed significantly increased numbers of neutrophils and lymphocytes in the groups receiving PRRT. All other parameters did not differ relevantly. In the histological analysis, groups receiving PRRT had a significantly higher RDS, whereas everolimus only tended to cause an increase in the RDS. Mice in groups 1 and 2 had to be euthanized due to excessive tumor growth two weeks after the start of the therapy, whereas follow-up in groups 3 and 4 comprised four weeks. PRRT significantly inhibited tumor growth; the administration of everolimus did not induce an additional effect. A good correlation existed between MTV and BTV. PRRT significantly reduced the TBR. [68Ga]Ga-DOTA-TATE PET is suitable for monitoring tumor growth in the applied model. The high efficacy of [177Lu]Lu-DOTA-TATE is not enhanced by the combination with everolimus.

Purpose: To evaluate a commercially available mobile device for the highly specialized task of detection of intracranial arterial aneurysm in telemedicine. Methods: Six radiologists with three different levels of experience retrospectively interpreted 60 computed tomography (CT) angiographies for the presence of intracranial arterial aneurysm, among them 30 cases with confirmed positive findings. Each radiologist reviewed the angiography datasets twice: once on a dedicated medical-grade workstation and on a commercially available mobile consumer-grade tablet with an interval of 3 months. Diagnostic performance, reading efficiency and subjective scorings including diagnostic confidence were analyzed and compared. Results: Diagnostic performance was comparable on both devices regardless of readers' experience, and no significant differences in sensitivity (66-87.5%) and specificity (79.4-87%) were found. Results obtained with tablets and medical workstations were also comparable in terms of subjective assessment across all reader groups. Conclusions: There was no significant difference between tablet and workstation readings of angiography datasets for the presence of intracranial arterial aneurysm. Sensitivity, specificity, efficiency and subjective scorings were similar with the two devices for all three reader groups. While medical workstations are 10 times more expensive, tablets allow higher mobility especially for radiologists on call.

Background: TIPS is an established treatment for portal hypertension. The aim was to analyze how patient selection for TIPS implantation and procedural aspects have changed over 25 years. Routinely collected demographic, clinical, laboratory, and procedural data of 835 patients treated with TIPS in a single center were used. Time trends over the observational period from 1993 to 2018 were retrospectively analyzed. Descriptive statistical analysis was performed., Results: The most common indication for TIPS implantation has changed significantly from secondary prevention of variceal hemorrhage in the early years to treatment of recurrent ascites. During the observation period, increasingly more severely ill patients became TIPS candidates. There was little change in MELD scores over this period (in total median 13.00; IQR 10.00-18.00). The proportion of patients with Child-Pugh C cirrhosis increased. The most frequent underlying diseases in total were alcohol-related liver disease (66.5%) and viral hepatitis (11.9%). However, shares of cryptogenic liver cirrhosis, autoimmune hepatitis, and NASH increased over time. The proportion of patients post liver transplant also increased. While bare metal stents were standard in the past, use of covered stents increased. The success rate of TIPS (defined by successful implantation and a decrease in the portosystemic pressure gradient ≤ 12 mmHg) increased significantly over time. The total success rate according to this definition was 84.9%., Conclusion: The results of our analysis reflect technical developments in TIPS, especially in terms of stent material and gains in clinical experience, particularly regarding indications and patient selection for TIPS implantation., (© 2022. The Author(s).)

Objectives: Data from radiological departments provide important information on overall quantities of medical care provided. With this study we used a comprehensive analysis of radiological examinations as a surrogate marker to quantify the effect of the different COVID-19 waves on medical care provided., Methods: Radiological examination volumes during the different waves of infection were compared among each other as well as to time-matched control periods from pre-pandemic years using a locally weighted scatterplot smoothing as well as negative binominal regression models., Results: A total of 1,321,119 radiological examinations were analyzed. Examination volumes were reduced by about 10% over the whole study period (IRR = 0.90; 95% CI 0.89-0.92), with a focus on acute medical care (0.84; 0.83-0.85) and outpatients (0.93: 0.90-0.97). When compared to wave 1, examination volumes were about 17% higher during wave 2 (1.17; 1.10-1.25), and 33% higher in wave 3 of the pandemic (1.33; 1.24-1.42)., Conclusions: This study shows the severe effect of COVID-19 pandemic and related shutdown measures on overall provided medical care as measured by radiological examinations. When compared, the decrease of medical care was more pronounced in the earlier waves of the pandemic., (© 2022. The Author(s).)

Background: Aim of this study was to investigate short-term and long-term treatment outcome, complication rates, and patient satisfaction after MRI-guided laser ablation (LA) of osteoid osteoma (OO)., Methods: Thirty-five patients with OO in typical and atypical localizations were treated by MRI-guided LA with MRI thermometry in an open 1.0 T system. Twenty-nine patients underwent a standardized telephone interview including questions about recurrence, residual pain or functional symptoms, and satisfaction for short-term follow-up after a mean of 31 months. Twenty-one of these patients were available for long-term telephone follow-up after a mean of 116 months., Results: Technical success of MRI-guided LA was 100% without major complications. Two minor complications included transient local inflammation and transient damage of the peroneal nerve associated with improper patient positioning during the procedure. Primary clinical success was 92% (11/12) in typically located OO and 82% (14/17) in atypically located OO. Secondary clinical success after repeat ablation was 100% regardless of OO location. Patient satisfaction and acceptance of the intervention were very good at both short-term (97%) and long-term (100%) follow-up., Conclusions: MRI-guided LA of OO is a safe and effective treatment option resulting in high short-term and long-term patient satisfaction and acceptance rates. Recurrence and adverse events were more common in patients with atypically located OO. Level of Evidence: Level 3, non-randomized follow-up study., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-21-3343/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: During the ongoing global SARS-CoV-2 pandemic, there is a high demand for quick and reliable methods for early identification of infected patients. Due to its widespread availability, chest-CT is commonly used to detect early pulmonary manifestations and for follow-ups., Purpose: This study aims to analyze image quality and reproducibility of readings of scans using low-dose chest CT protocols in patients suspected of SARS-CoV-2 infection., Materials and Methods: Two radiologists retrospectively analyzed 100 low-dose chest CT scans of patients suspected of SARS-CoV-2 infection using two protocols on devices from two vendors regarding image quality based on a Likert scale. After 3 weeks, quality ratings were repeated to allow for analysis of intra-reader in addition to the inter-reader agreement. Furthermore, radiation dose and presence as well as distribution of radiological features were noted., Results: The exams' effective radiation doses were in median in the submillisievert range (median of 0.53 mSv, IQR: 0.35 mSv). While most scans were rated as being of optimal quality, 38% of scans were scored as suboptimal, yet only one scan was non-diagnostic. Inter-reader and intra-reader reliability showed almost perfect agreement with Cohen's kappa of 0.82 and 0.87., Conclusion: Overall, in this study, we present two protocols for submillisievert low-dose chest CT demonstrating appropriate or better image quality with almost perfect inter-reader and intra-reader agreement in patients suspected of SARS-CoV-2 infection., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Stefan Markus Niehues declares relationships with the following companies: Vital Images, CanonMedical Systems, Guerbet, Bracco Imaging, Teleflex/Vidacare., (© The Author(s) 2022.)

Purpose: Treatment of patients with primary and secondary liver tumors remains challenging. This study analyzes the efficacy and safety of transarterial radioembolization (TARE) combined with CT-guided high-dose-rate interstitial brachytherapy (CT-HDRBT) for the treatment of primary and secondary liver tumors., Patients and Methods: A total of 77 patients (30 female) with various liver malignancies were treated. Primary endpoints were median overall survival (OS) and time to untreatable progression (TTUP). Additionally, subgroup analyses were performed in consideration of diagnosis and procedure sequence. Median OS and TTUP prediction were estimated using Kaplan-Meier analysis and hazard ratios (HR) were calculated using a multivariate Cox proportional hazard model., Results: A total of 115 CT-HDRBT and 96 TARE procedures were performed with no significant complications recorded. Median OS and TTUP were 29.8 (95% CI 18.1-41.4) and 23.8 (95% CI 9.6-37.9) months. Median OS for hepatocellular carcinoma (HCC)-, cholangiocarcinoma carcinoma (CCA) and colorectal cancer (CRC) patients was 29.8, 29.6 and 34.4 months. Patients starting with TARE had a median OS of 26.0 (95% CI 14.5-37.5) compared to 33.7 (95% CI 21.6-45.8) months for patients starting with CT-HDRBT. Hazard ratio of 1.094 per month was shown for patients starting with CT-HDRBT., Conclusion: Combining TARE and CT-HDRBT is effective and safe for the treatment of advanced stage primary and secondary liver tumors. Our data indicate that early TARE during the disease progression may have a positive effect on survival.

In this study, dual PET and contrast enhanced MRI were combined to investigate their correlation per voxel in patients at initial diagnosis with suspected glioblastoma. Correlation with contrast enhancement (CE) as an indicator of BBB leakage was further used to evaluate whether PET signal is likely caused by BBB disruption alone, or rather attributable to specific binding after BBB passage. PET images with [ 18 F]GE180 and the amino acid [ 18 F]FET were acquired and normalized to healthy background (tumor-to-background ratio, TBR). Contrast enhanced images were normalized voxel by voxel with the pre-contrast T1-weighted MRI to generate relative CE values (rCE). Voxel-wise analysis revealed a high PET signal even within the sub-volumes without detectable CE. No to moderate correlation of rCE with TBR voxel-values and a small overlap as well as a larger distance of the hotspots delineated in rCE and TBR-PET images were detected. In contrast, voxel-wise correlation between both PET modalities was strong for most patients and hotspots showed a moderate overlap and distance. The high PET signal in tumor sub-volumes without CE observed in voxel-wise analysis as well as the discordant hotspots emphasize the specificity of the PET signals and the relevance of combined differential information from dual PET and MRI images.

Introduction: Given the metachronous and multifocal occurrence of hepatocellular carcinoma (HCC) and colorectal cancer metastases in the liver (CRLM), this study aimed to compare intrahepatic progression patterns after computed tomography (CT)-guided high dose-rate brachytherapy., Patients and Methods: This retrospective analysis included 164 patients (114 HCC, 50 CRLM) treated with brachytherapy between January 2016 and January 2018. Patients received multiparametric magnetic resonance imaging (MRI) before, and about 8 weeks after brachytherapy, then every 3 months for the first, and every 6 months for the following years, until progression or death. MRI scans were assessed for local or distant intrahepatic tumor progression according to RECIST 1.1 and electronic medical records were reviewed prior to therapy. The primary endpoint was progression-free survival (PFS). Specifically, local and distant intra-hepatic PFS were assessed to determine differences between the intrahepatic progression patterns of HCC and CRLM. Secondary endpoints included the identification of predictors of PFS, time to progression (TTP), and overall survival (OS). Statistics included Kaplan-Meier analysis and univariate and multivariate Cox regression modeling., Results: PFS was longer in HCC [11.30 (1.33-35.37) months] than in CRLM patients [8.03 (0.73-19.80) months, p  = 0.048], respectively. Specifically, local recurrence occurred later in HCC [PFS: 36.83 (1.33-40.27) months] than CRLM patients [PFS: 12.43 (0.73-21.90) months, p  = 0.001]. In contrast, distant intrahepatic progression occurred earlier in HCC [PFS: 13.50 (1.33-27.80) months] than in CRLM patients [PFS: 19.80 (1.43-19.80) months, p  = 0.456] but without statistical significance. Multivariate Cox regression confirmed tumor type and patient age as independent predictors for PFS., Conclusion: Brachytherapy proved to achieve better local tumor control and overall PFS in patients with unresectable HCC as compared to those with CRLM. However, distant progression preceded local recurrence in HCC. As a result, these findings may help design disease-specific surveillance strategies and personalized treatment planning that highlights the strengths of brachytherapy. They may also help elucidate the potential benefits of combinations with other loco-regional or systemic therapies., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

We evaluated a simple semi-quantitative (SSQ) method for determining pulmonary involvement in computed tomography (CT) scans of COVID-19 patients. The extent of lung involvement in the first available CT was assessed with the SSQ method and subjectively. We identified risk factors for the need of invasive ventilation, intensive care unit (ICU) admission and for time to death after infection. Additionally, the diagnostic performance of both methods was evaluated. With the SSQ method, a 10% increase in the affected lung area was found to significantly increase the risk for need of ICU treatment with an odds ratio (OR) of 1.68 and for invasive ventilation with an OR of 1.35. Male sex, age, and pre-existing chronic lung disease were also associated with higher risks. A larger affected lung area was associated with a higher instantaneous risk of dying (hazard ratio (HR) of 1.11) independently of other risk factors. SSQ measurement was slightly superior to the subjective approach with an AUC of 73.5% for need of ICU treatment and 72.7% for invasive ventilation. SSQ assessment of the affected lung in the first available CT scans of COVID-19 patients may support early identification of those with higher risks for need of ICU treatment, invasive ventilation, or death.

Background: This study aimed to investigate the use of spectral computed tomography (SCT) hybrid images combining virtual monoenergetic images (VMIs) and iodine maps (IMs) as a potentially efficient search series for routine clinical imaging in patients with hypervascular abdominal tumors., Methods: A total of 69 patients with hypervascular abdominal tumors including neuroendocrine neoplasms (NENs, n = 48), renal cell carcinoma (RCC, n = 10), and primary hepatocellular carcinoma (HCC, n = 11) were analyzed retrospectively. Two radiological readers (blinded to clinical data) read three CT image sets (1st a reference set with 70 keV; 2nd a 50:50 hybrid 140 keV/40 keV set; 3rd a 50:50 hybrid 140 keV/IM set). They assessed images subjectively by rating several parameters including image contrast, visibility of suspicious lesions, and diagnostic confidence on five-point Likert scales. In addition, reading time was estimated., Results: Median subjective Likert scores were highest for the 1st set, except for image contrast, for which the 2nd set was rated highest. Scores for diagnostic confidence, artifacts, noise, and visibility of suspicious lesions or small structures were significantly higher for the 1st set than for the 2nd or 3rd set ( p < 0.001). Regarding image contrast, the 2nd set was rated significantly higher than the 3rd set ( p < 0.001), while the median did not differ significantly compared with the 1st set. Agreement between the two readers was high for all sets. Estimated potential reading time was the same for hybrid and reference sets., Conclusions: Hybrid images have the potential to efficiently exploit the additional information provided by SCT in patients with hypervascular abdominal tumors. However, the use of rigid weighting did not significantly improve diagnostic performance in this study.

Because of challenges in performing routine personalized dosimetry in radiopharmaceutical therapies, interest in single-time-point (STP) dosimetry, particularly using only a single SPECT scan, is on the rise. Meanwhile, there are questions about the reliability of STP dosimetry, with limited independent validations. In the present work, we analyzed 2 STP dosimetry methods and evaluated dose errors for several radiopharmaceuticals based on effective half-life distributions. Methods: We first challenged the common assumption that radiopharmaceutical effective half-lives across the population are gaussian-distributed (i.e., follow a normal distribution). Then, dose accuracy was estimated using 2 STP dosimetry methods for a wide range of potential post injection (p.i.) scan time points for different radiopharmaceuticals applied to neuroendocrine tumors and prostate cancer. The accuracy and limitations of each of the STP methods were discussed. Results: A lognormal distribution was more appropriate for capturing effective half-life distributions. The STP framework was promising for dosimetry of 177 Lu-DOTATATE and for kidney dosimetry of different radiopharmaceuticals (errors < 30%). Meanwhile, for some radiopharmaceuticals, STP accuracy was compromised (e.g., in bone marrow and tumors for 177 -labeled prostate-specific membrane antigen [PSMA])). The optimal SPECT scanning time for 177 Lu-DOTATATE was approximately 72 h p.i., whereas 48 h p.i. was better for 177 Lu-PSMA. Conclusion: 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 challenging. On the basis of our results, we make suggestions and recommendations for improved personalized dosimetry using simplified imaging schemes., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: To evaluate the feasibility, safety and efficacy of magnetic resonance imaging (MRI)-guided lumbar facet joint radiofrequency denervation (FRD) in patients with chronic low back pain., Methods: The study consisted of two parts. First, a preclinical analysis using an ex vivo animal model was performed to define optimal technical parameters for ablation. Then, 17 patients with chronic lumbar facet joint pain syndrome were prospectively included and underwent MRI-guided FRD in an open 1.0-Tesla MRI. We analyzed technical feasibility and complications as well as clinical outcome in terms of subjective pain assessed on a numerical visual analogue scale (VAS) before and after 1 week/6 months after FRD. Clinical assessment was complemented by measurement of paravertebral muscle volume and fat content before the intervention and at 6-month follow-up., Results: All interventions were technically successful without major complications. Initial VAS scores (median: 8, IQR: 1, range: 6-9, CI: 7.14-8.04) decreased significantly both after one week (median: 4, IQR: 5, range: 0-7, CI: 1.9-4.69, P=0.003) and after 6 months (median: 1, IQR: 6, range: 0-7, CI: 1.06-4.23, P<0.001). Mean multifidus muscle volume increased significantly in the patient population (from 366.8±130.8 cm 3 before to 435.4±146.7 cm 3 after FRD, P=0.031)., Conclusions: This proof of principle study shows MRI-guided FRD in an open 1.0-Tesla MRI system to be a potential therapy option for patients with chronic low back pain., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-633). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Treatment of advanced metastatic castration-resistant prostate cancer after failure of approved therapy options remains challenging. Prostate-specific membrane antigen (PSMA)-targeting β- and α-emitters have been introduced, with promising response rates. Here, we present the first-to our knowledge-clinical data for PSMA-targeted α-therapy (TAT) using 225 Ac-PSMA imaging and therapy (I&T). Methods: Fourteen patients receiving 225 Ac-PSMA-I&T were included in this retrospective analysis. Eleven of the 14 had prior second-line antiandrogen treatment with abiraterone or enzalutamide, prior chemotherapy, and prior 177 Lu-PSMA treatment. Patients were treated at bimonthly intervals until progression or intolerable side effects. Prostate-specific antigen (PSA) was measured for response assessment. Hematologic and nonhematologic side effects were recorded according to the Common Terminology Criteria for Adverse Events, version 5.0. Results: Thirty-four cycles of 225 Ac-PSMA-I&T were applied (median dose, 7.8 MBq; range, 6.0-8.5), with 1 cycle in 3 patients, 2 cycles in 7 patients, 4 cycles in 3 patients, and 5 cycles in 1 patient. No acute toxicity was observed during hospitalization. Baseline PSA was 112 ng/mL (range, 20.5-818 ng/mL). The best PSA response after TAT (a PSA decline ≥ 50%) was observed in 7 patients, and a PSA decline of any amount was observed in 11 patients. Three patients had no PSA decline at any time. A subgroup analysis of 11 patients with prior 177 Lu-PSMA treatment showed any PSA decline in 8 patients and a decline of at least 50% in 5 patients. After TAT, grade 3 anemia was observed in 3 of the 14 patients, with 2 of them presenting with grade 2 anemia already at baseline. Grade 3 leukopenia was observed in 1 patient. Eight patients with preexisting xerostomia after 177 Lu-PSMA showed no worsening after TAT. Newly diagnosed grade 1 or 2 xerostomia after TAT was observed in 5 patients. One patient reported no xerostomia at all. Conclusion: Our first clinical data for TAT using 225 Ac-PSMA-I&T showed a promising antitumor effect in advanced metastatic castration-resistant prostate cancer. These results are highly comparable to data on 225 Ac-PSMA-617 TAT., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Patients with metastatic, castration-resistant prostate cancer (mCRPC) present with an increased tumor burden in the skeleton. For these patients, Lutetium-177 (Lu-177) radioligand therapy targeting the prostate-specific membrane antigen (PSMA) has gained increasing interest with promising outcome data. Patient-individualized dosimetry enables improvement of therapy success with the aim of minimizing absorbed dose to organs at risk while maximizing absorbed dose to tumors. Different dosimetric approaches with varying complexity and accuracy exist for this purpose. The Medical Internal Radiation Dose (MIRD) formalism applied to tumors assumes a homogeneous activity distribution in a sphere with unit density for derivation of tumor S values (TSV). Voxel S value (VSV) approaches can account for heterogeneous activities but are simulated for a specific tissue. Full patient-individual Monte Carlo (MC) absorbed dose simulation addresses both, heterogeneous activity and density distributions. Subsequent CT-based density weighting has the potential to overcome the assumption of homogeneous density in the MIRD formalism with TSV and VSV methods, which could be a major limitation for the application in bone metastases with heterogeneous density. The aim of this investigation is a comparison of these methods for bone lesion dosimetry in mCRPC patients receiving Lu-177-PSMA therapy., Results: In total, 289 bone lesions in 15 mCRPC patients were analyzed. Percentage difference (PD) of average absorbed dose per lesion compared to MC, averaged over all lesions, was + 14 ± 10% (min: - 21%; max: + 56%) for TSVs. With lesion-individual density weighting using Hounsfield Unit (HU)-to-density conversion on the patient's CT image, PD was reduced to - 8 ± 1% (min: - 10%; max: - 3%). PD on a voxel level for three-dimensional (3D) voxel-wise dosimetry methods, averaged per lesion, revealed large PDs of + 18 ± 11% (min: - 27%; max: + 58%) for a soft tissue VSV approach compared to MC; after voxel-wise density correction, this was reduced to - 5 ± 1% (min: - 12%; max: - 2%)., Conclusion: Patient-individual MC absorbed dose simulation is capable to account for heterogeneous densities in bone lesions. Since the computational effort prevents its routine clinical application, TSV or VSV dosimetry approaches are used. This study showed the necessity of lesion-individual density weighting for TSV or VSV in Lu-177-PSMA therapy bone lesion dosimetry.

Background: Dosimetry can tailor prostate-specific membrane-antigen-targeted radioligand therapy (PSMA-RLT) for metastatic castration-resistant prostate cancer (mCRPC). However, whole-body tumor dosimetry is challenging in patients with a high tumor burden. We evaluate a simplified index-lesion-based single-photon emission computed tomography (SPECT) dosimetry method in correlation with clinical outcome., Methods: 30 mCRPC patients were included (median 71 years). The dosimetry was performed for the first cycle using quantitative 177 Lu-SPECT. The response was evaluated using RECIST 1.1 and PERCIST criteria, as well as changes in PSMA-positive tumor volume (PSMA-TV) in post-therapy PSMA-PET and biochemical response according to PSA changes after two RLT cycles., Results: Mean tumor doses as well as index-lesion doses were significantly higher in PERCIST responders compared to non-responders (10.2 ± 12.0 Gy/GBq vs. 4.0 ± 2.9 Gy/GBq, p = 0.03 and 13.7 ± 14.2 Gy/GBq vs. 5.9 ± 4.4 Gy/GBq, p = 0.04, respectively). No significant differences in mean tumor and index lesion doses were observed between responders and non-responders according to RECIST 1.1, PSMA-TV, and biochemical response criteria., Conclusion: Compared to mean tumor doses on a patient level, single index-lesion-based SPECT dosimetry correlates equally well with the response to PSMA-RLT according to PERCIST criteria and may represent a fast and feasible dosimetry approach for clinical routine.

Open injuries bear the risk of foreign body contamination. Commonly encountered materials include gravel debris, glass fragments, wooden splinters or metal particles. While foreign body incorporation is obvious in some injury patterns, other injuries may not display hints of being contaminated with foreign body materials. Foreign objects that have not been detected and removed bear the risk of leading to severe wound infections and chronic wound healing disorders. Besides these severe health issues, medicolegal consequences should be considered. While an accurate clinical examination is the first step for the detection of foreign body materials, choosing the appropriate radiological imaging is decisive for the detection or non-detection of the foreign material. Especially in cases of impaired wound healing over time, the existence of an undetected foreign object needs to be considered.Here, we would like to give a practical radiological guide for the assessment of foreign objects in head and neck injuries by a special selection of patients with different injury patterns and various foreign body materials with regard to the present literature.

Purpose: Besides diagnostic imaging devices, in particular computed tomography (CT) and magnetic resonance imaging (MRI), numerous reading workstations contribute to the high energy consumption of radiological departments. It was investigated whether switching off workstations after core working hours can relevantly lower energy consumption considering both ecological and economical aspects., Methods: Besides calculating different theoretical energy consumption scenarios, we measured power consumption of 3 workstations in our department over a 6-month period under routine working conditions and another 6-month period during which users were asked to switch off workstations after work. Staff costs arising from restarting workstations manually were calculated., Results: Our approach to switching off workstations after core working hours reduced energy consumption by about 5.6 %, corresponding to an extrapolated saving of 3.2 tons in carbon dioxide (CO 2 ) emissions and 2100.70 USD/year in electricity costs for 227 workstations. Theoretical calculations indicate that consistent automatic shutdown after core working hours could result in a potential total reduction of energy consumption of 38.6 %, equaling 22.2 tons of CO 2 and 14,388.28 USD/year. However, staff costs resulting from waiting times after manually restarting workstations would amount to 36,280.02 USD/year., Conclusions: Switching off workstations after core working hours can considerably reduce energy consumption and costs, but varies with user adherence. Staff costs caused by waiting time after manually starting up workstations outweigh energy savings by far. Therefore, an energy-saving plan with automated shutdown/restart besides enabling an energy-saving mode would be the most effective way of saving both energy and costs., Competing Interests: The authors report no declarations of interest., (© 2020 The Authors.)

Computed tomography (CT) plays an important role in the diagnosis of COVID-19. The aim of this study was to evaluate a simple, semi-quantitative method that can be used for identifying patients in need of subsequent intensive care unit (ICU) treatment and intubation. We retrospectively analyzed the initial CT scans of 28 patients who tested positive for SARS-CoV-2 at our Level-I center. The extent of lung involvement on CT was classified both subjectively and with a simple semi-quantitative method measuring the affected area at three lung levels. Competing risks Cox regression was used to identify factors associated with the time to ICU admission and intubation. Their potential diagnostic ability was assessed with receiver operating characteristic (ROC)/area under the ROC curves (AUC) analysis. A 10% increase in the affected lung parenchyma area increased the instantaneous risk of intubation (hazard ratio (HR) = 2.00) and the instantaneous risk of ICU admission (HR 1.73). The semi-quantitative measurement outperformed the subjective assessment diagnostic ability (AUC = 85.6% for ICU treatment, 71.9% for intubation). This simple measurement of the involved lung area in initial CT scans of COVID-19 patients may allow early identification of patients in need of ICU treatment/intubation and thus help make optimal use of limited ICU/ventilation resources in hospitals.

Purpose: Peptide receptor radionuclide therapy (PRRT) with [ 177 Lu]Lu-DOTA 0 ,TYR 3 -octreotate ([ 177 Lu]Lu-DOTA-TATE) and the mechanistic target of rapamycin (mTOR) inhibitor everolimus are both approved for the treatment of neuroendocrine tumours (NET). However, tumour progression is still frequent, and treatment strategies need further improvement. One possible approach could be to combine different therapy options. In this study, we investigated the toxicity of a combined treatment with everolimus and [ 177 Lu]Lu-DOTA-TATE in female Lewis rats., Methods: Animals received 200 MBq of [ 177 Lu]Lu-DOTA-TATE once and/or 5 mg/kg body weight everolimus or placebo weekly for 16 weeks and were divided into four groups (group 1, placebo; group 2, everolimus; group 3, placebo + [ 177 Lu]Lu-DOTA-TATE; group 4, everolimus + [ 177 Lu]Lu-DOTA-TATE). Blood levels of creatinine and blood urea nitrogen (BUN) were assessed weekly to monitor nephrotoxicity, and a full blood count was performed at the time of euthanasia to monitor myelotoxicity. Additionally, renal function was analysed by sequential [ 99m Tc]Tc-mercaptoacetyltriglycine ([ 99m Tc]Tc-MAG3) scintigraphies. Histopathological examination was performed in all the kidneys using a standardized renal damage score (RDS)., Results: Rats receiving everolimus showed a significantly lower increase in creatinine levels than those receiving placebo. Everolimus therapy reduced white blood count significantly, which was not observed for [ 177 Lu]Lu-DOTA-TATE. Functional renal scintigraphies using [ 99m Tc]Tc-MAG3 showed a compromised initial tracer uptake after PRRT and slower but still preserved excretion after everolimus. Histology showed no significant RDS differences between groups., Conclusion: Renal scintigraphy is a highly sensitive tool for the detection of renal function impairment after a combination of everolimus and PRRT. Additional treatment with everolimus does not increase renal and haematological toxicity of PRRT with [ 177 Lu]Lu-DOTA-TATE.

Purpose: Computed tomography (CT) is used for initial diagnosis and therapy monitoring of patients with coronavirus disease 2019 (COVID-19). As patients of all ages are affected, radiation dose is a concern. While follow-up CT examinations lead to high cumulative radiation doses, the ALARA principle states that the applied dose should be as low as possible while maintaining adequate image quality. The aim of this study was to evaluate parameter settings for two commonly used CT scanners to ensure sufficient image quality/diagnostic confidence at a submillisievert dose., Materials and Methods: We retrospectively analyzed 36 proven COVID-19 cases examined on two different scanners. Image quality was evaluated objectively as signal-to-noise ratio (SNR)/contrast-to-noise ratio (CNR) measurement and subjectively by two experienced, independent readers using 3-point Likert scales. CT dose index volume (CTDIvol) and dose-length product (DLP) were extracted from dose reports, and effective dose was calculated., Results: With the tested parameter settings we achieved effective doses below 1 mSv (median 0.5 mSv, IQR: 0.2 mSv, range: 0.3-0.9 mSv) in all 36 patients. Thirty-four patients had typical COVID-19 findings. Both readers were confident regarding the typical COVID-19 CT-characteristics in all cases (3 ± 0). Objective image quality parameters were: SNR normal lung : 17.0 ± 5.9, CNR GGO/normal lung : 7.5 ± 5.0, and CNR consolidation/normal lung : 15.3 ± 6.1., Conclusion: With the tested parameters, we achieved applied doses in the submillisievert range, on two different CT scanners without sacrificing diagnostic confidence regarding COVID-19 findings., Competing Interests: The authors declare no conflict of interest., (© 2020 The Author(s).)

Patients with increased liver stiffness have a higher risk of developing cancer, however, the role of fluid-solid tissue interactions and their contribution to liver tumor malignancy remains elusive. Tomoelastography is a novel imaging method for mapping quantitatively the solid-fluid tissue properties of soft tissues in vivo . It provides high resolution and thus has clear clinical applications. In this work we used tomoelastography in 77 participants, with a total of 141 focal liver lesions of different etiologies, to investigate the contributions of tissue stiffness and fluidity to the malignancy of liver tumors. Shear-wave speed (c) as surrogate for tissue stiffness and phase-angle (φ) of the complex shear modulus reflecting tissue fluidity were abnormally high in malignant tumors and allowed them to be distinguished from nontumorous liver tissue with high accuracy [c: AUC = 0.88 with 95% confidence interval (CI) = 0.83-0.94; φ: AUC = 0.95, 95% CI = 0.92-0.98]. Benign focal nodular hyperplasia and hepatocellular adenoma could be distinguished from malignant lesions on the basis of tumor stiffness (AUC = 0.85, 95% CI = 0.72-0.98; sensitivity = 94%, 95% CI = 89-100; and specificity = 85%, 95% CI = 62-100), tumor fluidity (AUC = 0.86, 95% CI = 0.77-0.96; sensitivity = 83%, 95% CI = 72-93; and specificity = 92%, 95% CI = 77-100) and liver stiffness (AUC = 0.84, 95% CI = 0.74-0.94; sensitivity = 72%, 95% CI = 59-83; and specificity = 88%, 95% CI = 69-100), but not on the basis of liver fluidity. Together, hepatic malignancies are characterized by stiff, yet fluid tissue properties, whereas surrounding nontumorous tissue is dominated by solid properties. Tomoelastography can inform noninvasively on the malignancy of suspicious liver lesions by differentiating between benign and malignant lesions with high sensitivity based on stiffness and with high specificity based on fluidity. SIGNIFICANCE: Solid-fluid tissue properties measured by tomoelastography can distinguish malignant from benign masses with high accuracy and provide quantitative noninvasive imaging biomarkers for liver tumors., (©2019 American Association for Cancer Research.)

Background: The bone marrow (BM) is a main risk organ during Lu-177-PSMA ligand therapy of metastasized castration-resistant prostate cancer (mCRPC) patients. So far, BM dosimetry relies on S values, which are pre-computed for reference anatomies, simplified activity distributions, and a physiological BM distribution. However, mCRPC patients may show a considerable bone lesion load, which leads to a heterogeneous and patient-specific activity accumulation close to BM-bearing sites. Furthermore, the patient-specific BM distribution might be significantly altered in the presence of bone lesions. The aim was to perform BM absorbed dose calculations through Monte Carlo (MC) simulations and to investigate the potential value of image-based BM localization. This study is based on 11 Lu-177-PSMA-617 therapy cycles of 10 patients (10 first cycles), who obtained a pre-therapeutic Ga-68-PSMA-11 PET/CT; quantitative Lu-177 SPECT acquisitions of the abdomen 24 (+CT), 48, and 72 h p.i.; and a Lu-177 whole-body planar acquisition at 24 h post-therapy. Patient-specific 3D volumes of interest were segmented from the Ga-68-PSMA-11 PET/CT, filled with activity information from the Lu-177 data, and imported into the FLUKA MC code together with the patient CT. MC simulations of the BM absorbed dose were performed assuming a physiological BM distribution according to the ICRP 110 reference male (MC1) or a displacement of active BM from the direct location of bone lesions (MC2). Results were compared with those from S values (SMIRD). BM absorbed doses were correlated with the decrease of lymphocytes, total white blood cells, hemoglobin level, and platelets. For two patients, an additional pre-therapeutic Tc-99m-anti-granulocyte antibody SPECT/CT was performed for BM localization., Results: Median BM absorbed doses were 130, 37, and 11 mGy/GBq for MC1, MC2, and SMIRD, respectively. Significant strong correlation with the decrease of platelet counts was found, with highest correlation for MC2 (MC1: r = - 0.63, p = 0.04; MC2: r = - 0.71, p = 0.01; SMIRD: r = - 0.62, p = 0.04). For both investigated patients, BM localization via Tc-99m-anti-granulocyte antibody SPECT/CT indicated a displacement of active BM from the direct location of lesions similar to model MC2 and led to a reduction in the BM absorbed dose of 40 and 41% compared to MC1., Conclusion: Higher BM absorbed doses were observed for MC-based models; however, for MC2, all absorbed doses were still below 2 Gy. MC1 resulted in critical values for some patients, but is suspected to yield strongly exaggerated absorbed doses by neglecting bone marrow displacement. Image-based BM localization might be beneficial, and future studies are recommended to support an improvement for the prediction of hematoxicities.

Computed tomography (CT) protocols for the detection of bleeding sources often include unenhanced CT series to distinguish contrast agent extravasation from calcification. This study evaluates whether virtual non-contrast images (VNC) can safely replace real non-contrast images (RNC) in the search for acute thoracoabdominal bleeding and whether monoenergetic imaging can improve the detection of the bleeding source.The 32 patients with active bleeding in spectral CT angiography (SCT) were retrospectively analyzed. RNC and SCT series were acquired including VNC and monoenergetic images at 40, 70, and 140 keV. CT numbers were measured in regions of interest (ROIs) in different organs and in the bleeding jet for quantitative image analysis (contrast-to-noise ratios [CNR] and signal-to-noise ratio [SNR]). Additionally, 2 radiologists rated detectability of the bleeding source in the different CT series. Wilcoxon rank test for related samples was used.VNC series suppressed iodine sufficiently but not completely (CT number of aorta: RNC: 33.3±12.3, VNC: 44.8 ± 9.5, P = .01; bleeding jet: RNC: 43.1 ± 16.9, VNC: 56.3 ± 16.7, P = .02). VNC showed significantly higher signal-to-noise ratios than RNC for all regions investigated. Contrast-to-noise ratios in the bleeding jet were significantly higher in 40 keV images than in standard 140 keV images. The 40 keV images were also assigned the best subjective ratings for bleeding source detection.VNC can safely replace RNC in a CT protocol used to search for bleeding sources, thereby reducing radiation exposure by 30%. Low-keV series may enhance diagnostic confidence in the detection of bleeding sources.

Background/aim: Thermal-ablative therapies are limited to tumors of 3-4 cm diameter. The purpose of this study was to evaluate the local tumor control (LTC) of CT-guided High-Dose-Rate-Brachytherapy (CT-HDRBT) for ablation of cholangiocarcinomas (CCA) ≥4 cm compared to smaller tumors., Patients and Methods: Sixty-one patients (tumors: 142, interventions: 91) were treated from March 2008 to January 2017. LTC, progression-free survival (PFS) and overall survival (OS) after first CT-HDRBT were identified for two subgroups (A:<4 cm, B:≥4 cm) and the influence of coverage and target-dose were evaluated. Log-Rank- and Mann-Whitney-U-Tests were performed for statistical analyses with p-values <0.05 considered as significant., Results: Better coverage was achieved for smaller tumors (A: 99.22-0.25%, B: 95.10-1.40%, p<0.001). LTC was better in subgroup A (A: 8, B: 6 months, p=0.006). Larger tumors (4-7 cm) with incomplete coverage showed the poorest LTC (p=0.032). There were no statistical significances in PFS (A: 5, B: 3 months, p=0.597) and OS (A:15.5; B:10.0 months, p=0.107)., Conclusion: CT-HDRBT is sufficient in CCA ≥4 cm, if full coverage with therapeutic doses can be achieved., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Glioma grading with dynamic 18 F-FET PET (0-40 min p.i.) is typically performed by analysing the mean time-activity curve of the entire tumour or a suspicious area within a heterogeneous tumour. This work aimed to ensure a reader-independent glioma characterisation and identification of aggressive sub-volumes by performing a voxel-based analysis with diagnostically relevant kinetic and static 18 F-FET PET parameters. One hundred sixty-two patients with a newly diagnosed glioma classified according to histologic and molecular genetic properties were evaluated. The biological tumour volume (BTV) was segmented in static 20-40 min p.i. 18 F-FET PET images using the established threshold of 1.6 × background activity. For each enclosed voxel, the time-to-peak (TTP), the late slope (Slope 15-40 ), and the tumour-to-background ratios (TBR 5-15, TBR 20-40 ) obtained from 5 to 15 min p.i. and 20 to 40 min p.i. images were determined. The percentage portion of these values within the BTV was evaluated with percentage volume fractions (PVFs) and cumulated percentage volume histograms (PVHs). The ability to differentiate histologic and molecular genetic classes was assessed and compared to volume-of-interest (VOI)-based parameters., Results: Aggressive WHO grades III and IV and IDH-wildtype gliomas were dominated by a high proportion of voxels with an early peak, negative slope, and high TBR, whereby the PVHs with TTP < 20 min p.i., Slope 15-40 < 0 SUV/h, and TBR 5-15 and TBR 20-40 > 2 yielded the most significant differences between glioma grades. We found significant differences of the parameters between WHO grades and IDH mutation status, where the effect size was predominantly higher for voxel-based PVHs compared to the corresponding VOI-based parameters. A low overlap of BTV sub-volumes defined by TTP < 20 min p.i. and negative Slope 15-40 with TBR 5-15 > 2 - and TBR 20-40 > 2 -defined hotspots was observed., Conclusions: The presented approach applying voxel-wise analysis of dynamic 18 F-FET PET enables an enhanced characterisation of gliomas and might potentially provide a fast identification of aggressive sub-volumes within the BTV. Parametric 3D 18 F-FET PET information as investigated in this study has the potential to guide individual therapy instrumentation and may be included in future biopsy studies.

Background: The 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., Results: Compared 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%)., Conclusion: For 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.

Background: PET ligands targeting the translocator protein (TSPO) represent promising tools to visualise neuroinflammation. Here, we analysed parameters obtained in dynamic and static PET images using the novel TSPO ligand [ 18 F]GE-180 in patients with relapsing remitting multiple sclerosis (RRMS) and an approach for semi-quantitative assessment of this disease in clinical routine. Seventeen dynamic [ 18 F]GE-180 PET scans of RRMS patients were evaluated (90 min). A pseudo-reference region (PRR) was defined after identification of the least disease-affected brain area by voxel-based comparison with six healthy controls (HC) and upon exclusion of voxels suspected of being affected in static 60-90 min p.i. images. Standardised uptake value ratios (SUVR) obtained from static images normalised to PRR were correlated to the distribution volume ratios (DVR) derived from dynamic data with Logan reference tissue model., Results: Group comparison with HC revealed white matter and thalamus as most affected regions. Fewest differences were found in grey matter, and normalisation to frontal cortex (FC) yielded the greatest reduction in variability of healthy grey and white matter. Hence, FC corrected for affected voxels was chosen as PRR, leading to time-activity curves of FC which were congruent to HC data (SUV 60-90 0.37, U test P = 0.42). SUVR showed a very strong correlation with DVR (Pearson ρ > 0.9). Focal MS lesions exhibited a high SUVR (range, 1.3-3.2)., Conclusions: This comparison with parameters from dynamic data suggests that SUVR normalised to corrected frontal cortex as PRR is suitable for the quantification of [ 18 F]GE-180 uptake in lesions and different brain regions of RRMS patients. This efficient diagnostic protocol based on static [ 18 F]GE-180 PET scans acquired 60-90 min p.i. allows the semi-quantitative assessment of neuroinflammation in RRMS patients in clinical routine.

Background: PET using O-(2-[ 18 F]fluoroethyl)-L-tyrosine ( 18 F-FET) is an established method for brain tumour diagnostics, but data processing varies in different centres. This study analyses the influence of methodological differences between two centres for tumour characterization with 18 F-FET PET using the same PET scanner. Methodological differences between centres A and B in the evaluation of 18 F-FET PET data were identified for (1) framing of PET dynamic data, (2) data reconstruction, (3) cut-off values for tumour delineation to determine tumour-to-brain ratios (TBR) and tumour volume (T vol ) and (4) ROI definition to determine time activity curves (TACs) in the tumour. Based on the 18 F-FET PET data of 40 patients with untreated cerebral gliomas (20 WHO grade II, 10 WHO grade III, 10 WHO grade IV), the effect of different data processing in the two centres on TBR mean , TBR max , T vol , time-to-peak (TTP) and slope of the TAC was compared. Further, the effect on tumour grading was evaluated by ROC analysis., Results: Significant differences between centres A and B were found especially for TBR max (2.84 ± 0.99 versus 3.34 ± 1.13; p < 0.001), T vol (1.14 ± 1.28 versus 1.51 ± 1.44; p < 0.001) and TTP (22.4 ± 8.3 min versus 30.8 ± 6.3 min; p < 0.001) and minor differences for TBR mean and slope. Tumour grading was not influenced by different data processing., Conclusions: Variable data processing of 18 F-FET PET in different centres leads to significant differences especially for TBR max and T vol . A standardization of data processing and evaluation is needed to make 18 F-FET PET comparable between different centres.

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.

Noninvasive tumor growth monitoring is of particular interest for the evaluation of experimental glioma therapies. This study investigates the potential of positron emission tomography (PET) using O-(2-(18)F-fluoroethyl)-L-tyrosine ([(18)F]-FET) to determine tumor growth in a murine glioblastoma (GBM) model-including estimation of the biological tumor volume (BTV), which has hitherto not been investigated in the pre-clinical context. Fifteen GBM-bearing mice (GL261) and six control mice (shams) were investigated during 5 weeks by PET followed by autoradiographic and histological assessments. [(18)F]-FET PET was quantitated by calculation of maximum and mean standardized uptake values within a universal volume-of-interest (VOI) corrected for healthy background (SUVmax/BG, SUVmean/BG). A partial volume effect correction (PVEC) was applied in comparison to ex vivo autoradiography. BTVs obtained by predefined thresholds for VOI definition (SUV/BG: ≥1.4; ≥1.6; ≥1.8; ≥2.0) were compared to the histologically assessed tumor volume (n = 8). Finally, individual "optimal" thresholds for BTV definition best reflecting the histology were determined. In GBM mice SUVmax/BG and SUVmean/BG clearly increased with time, however at high inter-animal variability. No relevant [(18)F]-FET uptake was observed in shams. PVEC recovered signal loss of SUVmean/BG assessment in relation to autoradiography. BTV as estimated by predefined thresholds strongly differed from the histology volume. Strikingly, the individual "optimal" thresholds for BTV assessment correlated highly with SUVmax/BG (ρ = 0.97, p < 0.001), allowing SUVmax/BG-based calculation of individual thresholds. The method was verified by a subsequent validation study (n = 15, ρ = 0.88, p < 0.01) leading to extensively higher agreement of BTV estimations when compared to histology in contrast to predefined thresholds. [(18)F]-FET PET with standard SUV measurements is feasible for glioma imaging in the GBM mouse model. PVEC is beneficial to improve accuracy of [(18)F]-FET PET SUV quantification. Although SUVmax/BG and SUVmean/BG increase during the disease course, these parameters do not correlate with the respective tumor size. For the first time, we propose a histology-verified method allowing appropriate individual BTV estimation for volumetric in vivo monitoring of tumor growth with [(18)F]-FET PET and show that standardized thresholds from routine clinical practice seem to be inappropriate for BTV estimation in the GBM mouse model.

Unlabelled: The tumor-homing property of mesenchymal stem cells (MSCs) allows targeted delivery of therapeutic genes into the tumor microenvironment. The application of sodium iodide symporter (NIS) as a theranostic gene allows noninvasive imaging of MSC biodistribution and transgene expression before therapeutic radioiodine application. We have previously shown that linking therapeutic transgene expression to induction of the chemokine CCL5/RANTES allows a more focused expression within primary tumors, as the adoptively transferred MSC develop carcinoma-associated fibroblast-like characteristics. Although RANTES/CCL5-NIS targeting has shown efficacy in the treatment of primary tumors, it was not clear if it would also be effective in controlling the growth of metastatic disease., Methods: To expand the potential range of tumor targets, we investigated the biodistribution and tumor recruitment of MSCs transfected with NIS under control of the RANTES/CCL5 promoter (RANTES-NIS-MSC) in a colon cancer liver metastasis mouse model established by intrasplenic injection of the human colon cancer cell line LS174t. RANTES-NIS-MSCs were injected intravenously, followed by (123)I scintigraphy, (124)I PET imaging, and (131)I therapy., Results: Results show robust MSC recruitment with RANTES/CCL5-promoter activation within the stroma of liver metastases as evidenced by tumor-selective iodide accumulation, immunohistochemistry, and real-time polymerase chain reaction. Therapeutic application of (131)I in RANTES-NIS-MSC-treated mice resulted in a significant delay in tumor growth and improved overall survival., Conclusion: This novel gene therapy approach opens the prospect of NIS-mediated radionuclide therapy of metastatic cancer after MSC-mediated gene delivery., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: Human mesenchymal stem cells (hMSCs) represent a promising treatment approach for tissue repair and regeneration. However, little is known about the underlying mechanisms and the fate of the transplanted cells. The objective of the presented work was to determine the feasibility of PET imaging and in vivo monitoring after transplantation of dopamine type 2 receptor-expressing cells., Methods: An hMSC line constitutively expressing a mutant of the dopamine type 2 receptor (D2R80A) was generated by lentiviral gene transfer. D2R80A messenger RNA expression was confirmed by reverse transcriptase-polymerase chain reaction. Localization of the transmembrane protein was analyzed by confocal fluorescence microscopy. The stem cell character of transduced hMSCs was investigated by adipogenic and osteogenic differentiation. Migration capacity was assessed by scratch assays in time-lapse imaging. In vitro specific binding of ligands was tested by fluorescence-activated cell sorting analysis and by radioligand assay using (18)F-fallypride. Imaging of D2R80A overexpressing hMSC transplanted into athymic rats was performed by PET using (18)F-fallypride., Results: hMSCs showed long-term overexpression of D2R80A. As expected, the fluorescence signal suggested the primary localization of the protein in the membrane of the transduced cells. hMSC and D2R80A retained their stem cell character demonstrated by their osteogenic and adipogenic differentiation capacity and their proliferation and migration behavior. For in vitro hMSCs, at least 90% expressed the D2R80A transgene and hMSC-D2R80A showed specific binding of (18)F-fallypride. In vivo, a specific signal was detected at the transplantation site up to 7 d by PET., Conclusion: The mutant of the dopamine type 2 receptor (D2R80A) is a potent reporter to detect hMSCs by PET in vivo., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

[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.

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.