Publications by authors named "Sazan Rasul"

34 Publications

First-in-human brain PET imaging of the GluN2B-containing N-methyl-D-aspartate receptor with ()-C-Me-NB1.

J Nucl Med 2021 Oct 7. Epub 2021 Oct 7.

Animal Imaging Center-PET, Switzerland.

The N-methyl-D-aspartate receptor (NMDAR) plays a crucial role in neurodegenerative diseases such as Alzheimer's disease and in the treatment of major depression by new fast-acting antidepressants such as ketamine. Given their broad implications, GluN2B-containing NMDARs have been of large interest as diagnostic and therapeutic targets. Recently, ()-C-Me-NB1 was investigated preclinically and shown to be a promising radioligand for imaging GluN2B subunits. Here, we report on the performance characteristics of this novel radioligand in a first-in-human PET study. Six healthy male subjects were scanned twice on a fully-integrated PET/MR scanner with ()-C-Me-NB1 for 120 min. Brain uptake and tracer distribution over time were investigated by standardized uptake values (SUV). Test-retest reliability was assessed with the absolute percentage difference (APD) and the coefficient of variation (COV). Exploratory total volumes of distribution (VT) were computed using an arterial input function and the Logan plot as well as a constrained two-tissue compartment model with K1/k2 coupled (2TCM). SUV was correlated with VT to investigate its potential as a surrogate marker of GluN2B expression. High and heterogeneous radioligand uptake was observed across the entire gray matter with reversible kinetics within the scan time. SUV APD ranged from 6.8 - 8.5% and COV from 4.9 - 6.0%, indicating a high test-retest reliability. A moderate correlation was found between SUV averaged from 70-90 min and VT using Logan plot (Spearman's rho = 0.44). Correlation between VT Logan and 2TCM was r= 0.76. The novel radioligand, ()-C-Me-NB1, was highly effective in mapping GluN2B-enriched NMDARs in the human brain. With a heterogeneous uptake and a high test-retest reliability, this radioligand offers promise to deepen our understanding of the GluN2B-containing NMDA receptor in the pathophysiology and treatment of neuropsychiatric disease such as Alzheimer's disease and major depression. Additionally, it could help in the selection of appropriate doses of GluN2B-targeting drugs.
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http://dx.doi.org/10.2967/jnumed.121.262427DOI Listing
October 2021

Renal and Salivary Gland Functions after Three Cycles of PSMA-617 Therapy Every Four Weeks in Patients with Metastatic Castration-Resistant Prostate Cancer.

Curr Oncol 2021 09 23;28(5):3692-3704. Epub 2021 Sep 23.

Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, 1090 Vienna, Austria.

Background: [Lu]Lu-PSMA-617 radioligand therapy (PSMA-RLT) could affect kidney and salivary gland functions in metastatic castration-resistant prostate cancer (mCRPC) patients.

Methods: We retrospectively analyzed clinical, renal, and salivary scintigraphy data and salivary [Ga]Ga-PSMA-11 ligand PET scan measures such as metabolic volume and SUVmax values of 27 mCRPC men (mean age 71 ± 7 years) before and 4 weeks after receiving three cycles of PSMA-RLT every 4 weeks. Twenty-two patients additionally obtained renal and salivary scintigraphy prior to each cycle. A one-way ANOVA, post-hoc Scheffé test and Cochran's Q test were applied to assess organ toxicity.

Results: In total, 54 PSMA PET scans, 98 kidney, and 98 salivary scintigraphy results were evaluated. There were no significant differences for the ejection fraction, peak time, and residual activity after 5 min for both parotid and submandibular glands prior to each cycle and 4 weeks after the last cycle. Similarly, no significant differences in serum creatinine and renal scintigraphy parameters were observed prior to each cycle and 4 weeks after the last treatment. Despite there being no changes in the metabolic volume of both submandibular glands, SUVmax values dropped significantly ( < 0.05).

Conclusion: Results evidenced no alterations in renal function and only minimal impairment of salivary function of mCRPC patients who acquired an intense PSMA-RLT regimen every 4 weeks.
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http://dx.doi.org/10.3390/curroncol28050315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482282PMC
September 2021

Single-lesion Prostate-specific Membrane Antigen Protein Expression (PSMA) and Response to [Lu]-PSMA-ligand Therapy in Patients with Castration-resistant Prostate Cancer.

Eur Urol Open Sci 2021 Aug 30;30:63-66. Epub 2021 Jun 30.

Department of Urology, Medical University of Vienna, Vienna, Austria.

Initial reports of a clinical response in patients treated with the radioligand [Lu]-PSMA-617 for castration-resistant prostate cancer (CRPC) are promising, despite known inter- and intrapatient heterogeneity. In metastatic CRPC, we examined the association of baseline immunohistochemical (IHC) expression of prostate-specific membrane antigen (PSMA) in a single lesion and responsiveness to [Lu]-PSMA-617 therapy, measured as the PSMA maximum standardized uptake value (SUV). Between 2015 and 2020, 19 patients with multiple metastases underwent single-lesion biopsy, [Ga]-PSMA positron emission tomography (PET) imaging, and treatment with [Lu]-PSMA-617. A monoclonal anti-PSMA antibody was used to semiquantitatively assess PSMA IHC in the biopsy specimen. Imaging evaluation of the biopsied single lesion and overall response was performed according to Positron Emission Tomography Response Criteria in Solid Tumors. The PSMA IHC histoscore correlated positively with pretreatment same-site PSMA SUV (  = 0.6). Nine patients had imaging after three cycles of [Lu]-PSMA-617 and were included in the lesion-specific analysis. Of these, five patients (55.6%) had an SUV response at the biopsy site, but three experienced overall progression. The histoscore was unable to predict the lesion-specific change in SUV (95% confidence interval [CI] -44.2 to 69.2) or PSA (95% CI-125.2 to 17.2). There was no correlation between single-lesion SUV and overall progression (  = 0.1) on [Ga]-PSMA PET imaging. Additional studies need to interrogate the clinical consequence of PSMA expression heterogeneity in metastases and the association with response to [Lu]-PSMA-671.

Patient Summary: Treatment with a radioactive binding molecule called [Lu]-PSMA-617 for men with prostate cancer resistant to castration (CRPC) is showing promise. We investigated the association between the presence of PSMA protein in metastatic lesions at biopsy and response to [Lu]-PSMA-617 among men with metastatic CRPC. We found that assessment of PSMA presence at biopsy is not a reliable predictor of response to [Lu]-PSMA-617. Additional studies are needed to better determine which CRPC metastatic sites will respond to this therapy.
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http://dx.doi.org/10.1016/j.euros.2021.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317820PMC
August 2021

Response and Toxicity to the Second Course of 3 Cycles of Lu-PSMA Therapy Every 4 Weeks in Patients with Metastatic Castration-Resistant Prostate Cancer.

Cancers (Basel) 2021 May 20;13(10). Epub 2021 May 20.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, 1090 Vienna, Austria.

Background: We investigated the response rate and degree of toxicity of a second course of three cycles of [Lu]Lu-PSMA radioligand therapy (PSMA-RLT) every 4 weeks in mCRPC patients.

Methods: Forty-three men (71.5 ± 6.6 years, median PSA 40.8 (0.87-1358 µg/L)) were studied. The response was based on the PSA level 4 weeks after the third cycle. The laboratory parameters before and one month after the last cycle were compared. Kaplan-Meier methods were used to estimate the progression-free survival (PFS) and overall survival (OS), and the Cox regression model was performed to find predictors of survival.

Results: Twenty-six patients (60.5%) exhibited a PSA reduction (median PSA declined from 40.8 to 20.2, range 0.6-1926 µg/L, = 0.002); 18 (42%) and 8 (19%) patients showed a PSA decline of ≥50% and ≥80%, respectively. The median OS and PFS were 136 and 31 weeks, respectively. The patients with only lymph node metastases survived longer ( = 0.02), whereas the patients with bone metastases had a shorter survival ( = 0.03). In the multivariate analysis, only the levels of PSA prior to the therapy remained significant for OS ( < 0.05, hazard ratio 2.43, 95% CI 1.01-5.87). The levels of hemoglobin (11.5 ± 1.7 g/dL vs. 11 ± 1.6 g/dL, = 0.006) and platelets (208 ± 63 g/L vs. 185 ± 63 g/L, = 0.002) significantly decreased one month after cycle three, though only two grade 3 anemia and one grade 3 thrombocytopenia were recorded.

Conclusion: A further intensive PSMA-RLT course is well tolerated in mCRPC patients and associated with promising response rates and OS.
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http://dx.doi.org/10.3390/cancers13102489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160614PMC
May 2021

Diagnostic Role of PET/CT Tracers in the Detection and Localization of Tumours Responsible for Ectopic Cushing's Syndrome.

Anticancer Res 2021 May;41(5):2477-2484

Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.

Background/aim: Positron emission tomography/computed tomography (PET/CT) plays an important role in cancer localization in ectopic Cushing's syndrome (ECS). However, the choice of the optimal tracer for investigation of this disease is still unclear. We aimed to evaluate the diagnostic feasibility of [F]fluoro-2-deoxyglucose ([F]FDG), [F]fluoro-L-dihydroxyphenylalanine ([F] FDOPA), and [Ga]-DOTA-1-Nal3-octreotide ([Ga]-DOTANOC) in ECS.

Patients And Methods: All PET/CT scans of patients admitted to our department for suspected ECS between 2010 and 2020 were retrospectively analysed.

Results: Collectively, 30 PET/CT examinations, 11 with [F]FDOPA, 11 with [F]FDG and 8 with [Ga]GaDOTANOC were conducted for 18 patients eligible for analysis. [F]FDG detected the tumour in 3/6 of the cases, [F]FDOPA in 3/4, and [Ga]GaDOTANOC in 3/3. [F]FDOPA was the only tracer without false positive results.

Conclusion: [Ga]GaDOTANOC and [F]FDOPA showed superior results compared to [F]FDG, although the sensitivity of the tracers might be influenced by the aetiology of the tumour underlying the ECS.
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http://dx.doi.org/10.21873/anticanres.15024DOI Listing
May 2021

Prediction of response and survival after standardized treatment with 7400 MBq Lu-PSMA-617 every 4 weeks in patients with metastatic castration-resistant prostate cancer.

Eur J Nucl Med Mol Imaging 2021 05 30;48(5):1650-1657. Epub 2020 Oct 30.

Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.

Background And Aims: [Lu]Lu-PSMA-617 radioligand therapy (PSMA-RLT) is a new therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). However, identification of reliable prognostic factors is hampered by heterogeneous treatment regimens applied in previous studies. Hence, we sought clinical factors able to predict response and survival to PSMA-RLT in a homogenous group of patients, all receiving 7400 MBq every 4 weeks.

Patients And Methods: Data of 61 patients (mean age 71.6 ± 6.9 years, median basal PSA 70.7 [range 1.0-4890 μg/L]), pretreated with abiraterone/enzalutamide (75.4%) and docetaxel/cabazitaxel (68.9%), received three cycles of PSMA-RLT (mean 7321 ± 592 MBq) at four weekly intervals and were analyzed retrospectively. General medical conditions and laboratory parameters of every patients were regularly assessed. Response to therapy was based on PSA levels 1 month after the 3rd cycle. Binary logistic regression test and Kaplan-Meier estimates were used to evaluate predictors and overall survival (OS).

Results: Forty-nine (80.3%) patients demonstrated a therapy response in terms of any PSA decline, while 21 (19.7%) patients showed increase or no changes in their PSA levels. Baseline hemoglobin (Hb) significantly predicted PSA reductions of ≥ 50% 4 weeks after receiving the 3rd PSMA-RLT (P = 0.01, 95% CI: 1.09-2.09) with an AUC of 0.68 (95% CI: 0.54-0.81). The levels of basal Hb and basal PSA were able to predict survival of patients, both P < 0.05 (relative risk 1.51 and 0.79, 95% CI: 1.09-2.09 and 0.43-1.46), respectively. In comparison to patients with reduced basal Hb, patients with normal basal Hb levels lived significantly longer (median survival not reached vs. 89 weeks, P = 0.016). Also, patients with basal PSA levels ≤ 650 μg/L had a significantly longer survival than patients with basal PSA levels > 650 μg/L (median survival not reached vs. 97 weeks, P = 0.031). Neither pretreatments with abiraterone/enzalutamide or docetaxel/cabazitaxel nor distribution of metastasis affected survival and rate of response to PSMA-RLT.

Conclusion: Basal Hb level is an independent predictor for therapy response and survival in patients receiving PSMA-RLT every 4 weeks. Both baseline PSA ≤ 650 μg/L and normal Hb levels were associated with longer survival.
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http://dx.doi.org/10.1007/s00259-020-05082-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113146PMC
May 2021

In Vivo Quantification of Myocardial Amyloid Deposits in Patients with Suspected Transthyretin-Related Amyloidosis (ATTR).

J Clin Med 2020 Oct 27;9(11). Epub 2020 Oct 27.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria.

Background: Current diagnosis of Transthyretin-related Amyloidosis (ATTR) using bone scintigraphy is primarily based on visual scoring and semi-quantitative indices. With the introduction of new potential life-prolonging drugs for ATTR, a more precise quantification of myocardial amyloid burden is desirable for improved response prediction and therapy monitoring.

Methods: At first, quantification experiments using an anthropomorphic thorax phantom were performed. Second, 32 patients underwent both planar whole body [Tc]- 3,3-Diphosphono-1,2-Propanodicarboxylic Acid (DPD)-scintigraphy and quantitative Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) of the thorax. SPECT/CT standardized myocardial uptake values SUVpeak and SUVpeak normalized to bone uptake (nSUVpeak) were determined.

Results: Phantom measurements showed a strong linear relationship between the activity in the myocardial insert and the measured activity (r = 0.9998, = 0.01), but the measured activity was systematically underestimated by approximately 30%. Receiver operating characteristics (ROC) analysis revealed a 100% sensitivity and specificity at a cut-off of 3.1 for SUVpeak for the differentiation of both patient groups.

Conclusion: SUV quantification of ATTR amyloid burden is feasible using novel SPECT/CT technology. With a SUVpeak cut-off of 3.1, patients with Perugini grade 2 and 3 could be clearly separated from those with Perugini grade 0 and 1. Besides ATTR diagnostics, quantification of amyloid deposits could potentially be used for therapy monitoring and prognostication in patients with cardiac ATTR.
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http://dx.doi.org/10.3390/jcm9113446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693120PMC
October 2020

Assessment of left and right ventricular functional parameters using dynamic dual-tracer [N]NH3 and [F]FDG PET/MRI.

J Nucl Cardiol 2020 Oct 22. Epub 2020 Oct 22.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Floor 5L, 1090, Vienna, Austria.

Background: Cardiac positron emission tomography/magnetic resonance imaging (PET/MRI) can assess various cardiovascular diseases. In this study, we intra-individually compared right (RV) and left ventricular (LV) parameters obtained from dual-tracer PET/MRI scan.

Methods: In 22 patients with coronary heart disease (69 ± 9 years) dynamic [N]NH (NH) and [F]FDG (FDG) PET scans were acquired. The first 2 minutes were used to calculate LV and RV first-pass ejection fraction (FPEF). Additionally, LV end-systolic (LVESV) and end-diastolic (LVEDV) volume and ejection fraction (LVEF) were calculated from the early (EP) and late-myocardial phases (LP). MRI served as a reference.

Results: RVFPEF and LVFPEF from FDG and NH as well as RVEF and LVEF from MRI were (28 ± 11%, 32 ± 15%), (32 ± 11%, 41 ± 14%) and (42 ± 16%, 45 ± 19%), respectively. LVESV, LVEDV and LVEF from EP FDG and NH in 8 and 16 gates were [71 (15 to 213 mL), 98 (16 to 241 mL), 32 ± 17%] and [50 (17 to 206 mL), 93 (13 to 219 mL), 36 ± 17%] as well as [60 (19 to 360 mL), 109 (56 to 384 mL), 41 ± 22%] and [54 (16 to 371 mL), 116 (57 to 431 mL), 46 ± 24%], respectively. Moreover, LVESV, LVEDV and LVEF acquired from LP FDG and NH were (85 ± 63 mL, 138 ± 63 mL, 47 ± 19%) and (79 ± 56 mL, 137 ± 63 mL, 47 ± 20%), respectively. The LVESV, LVEDV from MRI were 93 ± 66 mL and 153 ± 71 mL, respectively. Significant correlations were observed for RVFPEF and LVFPEF between FDG and MRI (R = .51, P = .01; R = .64, P = .001), respectively. LVESV, LVEDV, and LVEF revealed moderate to strong correlations to MRI when they acquired from EP FDG and NH in 16 gates (all R > .7, P = .000). Similarly, all LV parameters from LP FDG and NH correlated good to strongly positive with MRI (all R > .7, and P < .001), except EDV from NH3 weakly correlated to EDV of MRI (R = .54, P < .05). Generally, Bland-Altman plots showed good agreements between PET and MRI.

Conclusions: Deriving LV and RV functional values from various phases of dynamic NH and FDG PET is feasible. These results could open a new perspective for further clinical applications of the PET examinations.
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http://dx.doi.org/10.1007/s12350-020-02391-yDOI Listing
October 2020

Differential impact of radiation therapy after radical prostatectomy on recurrence patterns: an assessment using [Ga]Ga-PSMA ligand PET/CT(MRI).

Prostate Cancer Prostatic Dis 2021 06 29;24(2):439-447. Epub 2020 Sep 29.

Department of Biomedical Imaging and Image guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.

Purpose: To evaluate the differential impact of postoperative radiotherapy (RT) on recurrence patterns in patients treated with radical prostatectomy (RP) using [Ga]Ga-PSMA conjugate 11 positron emission tomography (PSMA 11-PET).

Methods: We assessed 162 consecutive patients who experienced biochemical recurrence (BCR) after RP for nonmetastatic prostate cancer (PC). All had at least one positive lesion on imaging. No patient was on androgen deprivation therapy (ADT). Patients were categorized into those who had received adjuvant/salvage RT ± ADT and those who did not (RP only). Lesion- and patient-based analyses were performed. The impact of the radiation field was assessed.

Results: Overall, 57 BCR patients underwent RP only, 105 received postoperative RT. Median PSA was 1.01 ng/ml (IQR 0.58-2). In the lesion-based analysis, compared to the RP only patients, those who had received postoperative RT, had less lymph node (LN) recurrences distal to the common iliac bifurcation (35.2 vs. 57.9%, p = 0.05), but were more likely to harbor positive LNs proximal to the iliac bifurcation and in the presacral (34.2 vs. 12.3%, p = 0.002) areas as well as bone metastases (25.7 vs. 8.8%, p = 0.01). In the patient-based analysis, the patients with postoperative RT after RP had less recurrence in the pelvis only (pelvic LNs and/or prostate bed) (52.4 vs. 79%, p = 0.002), but were more likely to harbor extrapelvic recurrence (41.9 vs. 15.8%, p = 0.001). Patients who received RT to the prostate bed only had more recurrence to the pelvic LN only (54.2% vs. 23.4%, p = 0.002), but less extrapelvic recurrence (31.3 vs. 53.2%, p = 0.03) and less bone recurrence (16.7 vs. 36.2%, p = 0.031) compared to those patients, who received RT to the prostate bed and pelvic nodes.

Conclusions: Postoperative radiation treatment alters the recurrence pattern in BCR patients after RP. Further prospective studies are needed to establish a decision tree for optimal imaging/management according to previous treatments.
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http://dx.doi.org/10.1038/s41391-020-00294-0DOI Listing
June 2021

Accuracy of PET quantification in [Ga]Ga-pentixafor PET/MR imaging of carotid plaques.

J Nucl Cardiol 2020 Jul 21. Epub 2020 Jul 21.

QIMP Team, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Aim: The aim of this study was to evaluate and correct for partial-volume-effects (PVE) on [Ga]Ga-Pentixafor uptake in atherosclerotic plaques of the carotid arteries, and the impact of ignoring bone in MR-based attenuation correction (MR-AC).

Methods: Twenty [Ga]Ga-pentixafor PET/MR examinations including a high-resolution T2-TSE MR of the neck were included in this study. Carotid plaques located at the carotid bifurcation were delineated and the anatomical information was used for partial-volume-correction (PVC). Mean and max tissue-to-background ratios (TBR) of the [Ga]Ga-Pentixafor uptake were compared for standard and PVC-PET images. A potential influence of ignoring bone in MR-AC was assessed in a subset of the data reconstructed after incorporating bone into MR-AC and a subsequent comparison of standardized-uptake values (SUV).

Results: In total, 34 atherosclerotic plaques were identified. Following PVC, mean and max TBR increased by 77 and 95%, respectively, when averaged across lesions. When accounting for bone in the MR-AC, SUV of plaque changed by 0.5%.

Conclusion: Quantitative readings of [Ga]Ga-pentixafor uptake in plaques are strongly affected by PVE, which can be reduced by PVC. Including bone information into the MR-AC yielded no clinically relevant effect on tracer quantification.
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http://dx.doi.org/10.1007/s12350-020-02257-3DOI Listing
July 2020

Dose Calculations and Dose-Effect Relationships in 177Lu-PSMA I&T Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer.

Clin Nucl Med 2020 Sep;45(9):661-667

From the Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf.

Dose response of 22 patients experiencing mCRPC (metastatic castration-resistant prostate cancer) to Lu-PSMA I&T radionuclide therapy was investigated. Dosimetry calculations are used to assess correlations between dosimetric quantities and biomarker values.

Methods: The patients' age range was 74 ± 7 years at the time of the investigated treatment cycle, and the mean injected activity was 7416 ± 218 MBq. Planar images at several time points postinjection were used for evaluation of absorbed doses to organs and lesion. Ga-PSMA PET/CT follow-up imaging enabled the determination of individual tumor molecular volume (TMV) shrinkage. Changes in 7 different biomarkers after the first treatment cycle were correlated with the calculated absorbed organ and TMV doses, resulting in a total number of 259 investigated correlations.

Results: Sixty-three TMVs were identified in the bone, lymph node, and liver tissue with an average reduction of 32.3%, 84.7%, and 72.9%, respectively. Absorbed doses per unit of administered activity for organs and lesions show good agreement with previous works (0.77, 0.71, and 0.27 mGy/MBq for parotid gland, kidneys, and liver as well as 4.38, 5.47, and 4.95 mGy/MBq for bone, lymph node, and liver malignancies, respectively). Only 37 of 259 possible correlations turned out to be statistically significant, 26 of which are associated with the absorbed dose of an organ and the decrease of alkaline phosphatases.

Conclusions: Although treatment with Lu-PSMA I&T leads to a big reduction of TMV in patients with mCRPC, the lack of correlations calls for studies using voxel-wise dosimetry based on SPECT/CTs.
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http://dx.doi.org/10.1097/RLU.0000000000003157DOI Listing
September 2020

Dynamic 2-deoxy-2[18F] fluoro-D-glucose PET/MRI in human renal allotransplant patients undergoing acute kidney injury.

Sci Rep 2020 05 19;10(1):8270. Epub 2020 May 19.

Department of Biomedical Imaging and Image- Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna. Waehringer Guertel 18-20, 1090, Vienna, Austria.

Patients after solid organ kidney transplantation (KTX) often suffer from acute kidney injury (AKI). Parameters as serum creatinine indicate a loss of kidney function, although no distinction of the cause and prognosis can be made. Imaging tools measuring kidney function have not been widely in clinical use. In this observational study we evaluated 2-deoxy-2[18F] fluoro-D-glucose (FDG) PET/MRI in thirteen patients after KTX with AKI as a functional assessment of the graft. Twenty-four healthy volunteers served as control. General kidney performance (GKP), initial flow (IF) and renal response function (RF) were calculated by standardized uptake values (SUV) and time activity curves (TAC). The GKP measured for the total kidney and medulla was significantly higher in healthy patients compared to patients after KTX (p = 0.0002 and p = 0.0004, respectively), but no difference was found for the GKP of the cortex (p = 0.59). The IF in KTX patients correlated with renal recovery, defined as change in serum creatinine 10 days after PET/MRI (r = 0.80, p = 0.001). With regard to the RF, a negative correlation for tubular damage was found (r = -0.74, p = 0.004). In conclusion, parameters obtained from FDG PET/MRI showed a possible predictive feature for renal recovery in KTX patients undergoing AKI.
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http://dx.doi.org/10.1038/s41598-020-65267-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237443PMC
May 2020

Response evaluation of SGLT2 inhibitor therapy in patients with type 2 diabetes mellitus using F-FDG PET/MRI.

BMJ Open Diabetes Res Care 2020 03;8(1)

Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.

Introduction: Inhibitors of sodium-glucose linked transporter-2 (SGLT2i) are enhancing glucose excretion in the proximal renal tubules, and thus are increasingly used to lower blood glucose levels in patients with type 2 diabetes mellitus (T2DM). The glucose analog 2-deoxy-2-(F) fluoro-D-glucose (FDG) can be used to quantify renal function in vivo, and due to an affinity for SGLT2 could also provide information about SGLT2 transporter function. Our objectives in this study were, therefore, to assess the impact of SGLT2i on renal function parameters in patients with T2DM and identify predictive parameters of long-term response to SGLT2i using dynamic FDG positron emission tomography (PET)/MRI.

Methods: PET FDG renal function measures such as mean transit time (MTT) and general renal performance (GRP) together with glomerular filtration rate (GFR) were determined in 20 patients with T2DM before (T2DM) and 2 weeks after initiation of therapy with SGLT2i (T2DM). Additionally, dynamic FDG PET data of 24 healthy subjects were used as controls.

Results: MTT in T2DM was significantly higher than in healthy controls (5.7 min vs 4.3 min, p=0.012) and significantly decreased to 4.4 min in T2DM (p=0.004). GRP of T2DM was higher than of T2DM (5.2 vs 4.7, p=0.02) and higher but not significantly than of healthy individuals (5.2 vs 5.1, p=0.34). Expectedly, GFR of healthy participants was significantly higher than of T2DM and T2DM (122 vs 92 and 86 mL/min/1.73 m², respectively; p<0.001). The higher the GRP value in kidneys of T2DM, the lower was the glycated hemoglobin level 3 months after therapy initiation.

Conclusion: MTT and GRP values of patients with T2DM shifted significantly toward values of healthy control 2 weeks after therapy with SGLT2i begins. GRP in T2DM was associated with better long-term glycemic response 3 months after initiation of therapy.

Trial Registration Number: NCT03557138.
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http://dx.doi.org/10.1136/bmjdrc-2019-001135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206902PMC
March 2020

Clinical outcome of standardized Lu-PSMA-617 therapy in metastatic prostate cancer patients receiving 7400 MBq every 4 weeks.

Eur J Nucl Med Mol Imaging 2020 03 28;47(3):713-720. Epub 2019 Nov 28.

Department of Biomedical Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.

Purpose: [Lu]Lu-PSMA-617 radio-ligand therapy (PSMA-RLT) is emerging in patients with an advanced metastatic castration-resistant prostate cancer (mCRPC). Here, we aimed to estimate the results of PSMA-RLT in terms of response, progression-free survival (PFS), and overall survival (OS) in patients receiving a highly standardized treatment regimen due to mCRPC. The toxicity of PSMA-RLT has also been evaluated.

Patients And Methods: Fifty-four patients (mean age 72 ± 7 years, median PSA at time of initial therapy 66 [range 1.0-4890 μg/L]), receiving three PSMA-RLT cycles (mean 7315 ± 573 MBq) at four weekly intervals, were included in this retrospective analysis. Hematological and biochemical parameters were regularly determined in every patient. Kaplan-Meier estimates were used to assess PFS and OS and a Cox proportional hazard model was used to analyze significant associations. Treatment response was based on PSA measurements 4 weeks after the 3rd treatment.

Results: The majority of patients were previously treated with abiraterone/enzalutamide (69%) and docetaxel/cabazitaxel (67%). In total, 79% of the patients showed a decrease in PSA (median PSA decrease from 66 to 19.8, range 0.7-4563 μg/L, P < 0.001) 1 month after the 3rd therapy cycle. Among them, 58% and 35% demonstrated a PSA-decline of > 50% and > 80%, respectively. Median OS was 119 weeks; median PFS was 25 weeks. Patients presenting with a PSA decline had significantly longer PFS (27 vs. 15 weeks, P < 0.0001) and OS (median survival not reached vs. 52 weeks, P < 0.001) than patients with no PSA reduction. Moreover, patients with reduction in PSA levels ≥ 50% (median survival not reached vs. 52 weeks, P < 0.0001) and ≥ 80% (median survival not reached vs. 87 weeks, P = 0.008) lived significantly longer. While hemoglobin did not change during treatment, levels of platelets (236 ± 71 g/L vs. 193 ± 67 g/L) and leucocytes (6.5, range 2.9-13.7 g/L vs. 4.8, range 1.5-12.3 g/L) decreased significantly, both P < 0.001. Two grade 3 leukocytopenia and one grade 3 anemia were observed.

Conclusion: Intense PSMA-RLT regime with four weekly intervals between the cycles is well-tolerated and offers favorable response rates, PFS, and survival rates for patients with mCRPC.
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http://dx.doi.org/10.1007/s00259-019-04584-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005080PMC
March 2020

Response assessment using [ Ga]Ga-PSMA ligand PET in patients undergoing systemic therapy for metastatic castration-resistant prostate cancer.

Prostate 2020 01 15;80(1):74-82. Epub 2019 Oct 15.

Working Group of Diagnostic Imaging in Urology, Austrian Society of Urology, Vienna, Austria.

Background: To assess which parameters of [ Ga]Ga-PSMA-11 positron emission tomography (PSMA-PET) predict response to systemic therapies in metastatic (m) castration-resistant prostate cancer (CRPC). In addition, to investigate which of these factors are associated with overall survival (OS).

Methods: We retrospectively assessed the following PSMA-PET parameters in 43 patients before and after systemic therapies for mCRPC: PSMA total tumor volume (TTV), mean standardized uptake value (SUVmean), SUVmax, and SUVpeak. prostate-specific antigen (PSA) levels and PSMA-PET/CT(magnetic resonance imaging [MRI]) imaging were both performed within 8 weeks before and 6 weeks after systemic therapy. PSMA-PET and CT (MRI) images were reviewed according to the modified PET Response Criteria in Solid Tumors (PERCIST) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Results were compared to PSA response. Univariable survival analyses were performed.

Results: Overall, 43 patients undergoing 67 systemic therapies were included (9 patients radium-223, 12 cabazitaxel, 22 docetaxel, 6 abiraterone, and 18 enzalutamide). Median serum PSA level before any therapy was 11.3 ng/mL (interquartile range [IQR] = 3.3, 30.1). Delta (d) PSA after systemic therapies was -41%, dTTV 10.5%, dSUVmean -7.5%, dSUVmax -13.3%, dSUVpeak -12%, and dRECIST -13.3%. Overall, 31 patients had dPSA response (46.3%), 12 stable disease (17.9%), and 24 progressive disease (35.8%). All observed PET parameters, as well as the RECIST evaluation, were significantly associated with PSA response (dTTV P = .003, dSUVmean P = .003, dSUVmax P = .011, dSUVpeak P < 0001, dRECIST P = .012), while RECIST assessment was applicable in 37 out of 67 patients (55.2%). Within a median follow-up of 33 months (IQR = 26, 38), 10 patients (23.3%) died of PC. On univariable survival analyses, neither the investigated PET parameters nor PSA level or RECIST criteria were associated with OS.

Conclusion: PSMA-PET provides reliable parameters for prediction of response to systemic therapies for mCRPC. These parameters, if confirmed, could enhance RECIST criteria, specifically concerning its limitations for sclerotic bone lesions.
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http://dx.doi.org/10.1002/pros.23919DOI Listing
January 2020

Renal Cell Carcinoma: the Oncologist Asks, Can PSMA PET/CT Answer?

Curr Urol Rep 2019 Oct 11;20(11):68. Epub 2019 Oct 11.

Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Purpose Of Review: To critically review the potential clinical applications of prostate-specific membrane antigen (PSMA) radioactive ligands in renal cell carcinoma (RCC).

Recent Findings: Radioactive probes targeting PSMA hold promise in several malignancies in addition to prostate cancer, owing to the expression of PSMA by tumor neovasculature. The majority of clear cell RCCs (ccRCC), the most malignant RCC subtype, express PSMA on tumor-associated neovasculature. The endothelium of less aggressive RCC subtypes is PSMA positive in a lower, but still significant percentage of cases. PSMA might therefore represent an interesting theragnostic target in RCC. The preliminary data available suggest a potential role for PSMA-targeting radiopharmaceuticals in complementing conventional imaging for staging ccRCC patients at risk of nodal involvement and oligometastatic disease. Additional applications of PSMA imaging may be the selection and the response assessment of patients receiving anti-angiogenic treatments. The effectiveness of PSMA-targeting radionuclide therapy should also be investigated.
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http://dx.doi.org/10.1007/s11934-019-0938-9DOI Listing
October 2019

Assessment of Myocardial Viability in Ischemic Heart Disease by PET/MRI: Comparison of Left Ventricular Perfusion, Hibernation, and Scar Burden.

Acad Radiol 2020 02 30;27(2):188-197. Epub 2019 Apr 30.

Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Waehringer Gürtel 18-20, 1090 Vienna, Austria. Electronic address:

Rationale And Objectives: Hybrid positron emission tomography-magnetic resonance (PET-MR) is a novel imaging technology that enables a comprehensive assessment of myocardial viability. The aim of this study was to intra-individually compare simultaneously acquired viability parameters from MRI and PET to determine complementary and redundant information.

Materials And Methods: Thirty-nine patients with ischemic heart disease (IHD) underwent cardiac PET-MR for myocardial viability assessment. Cardiac magnetic resonance (CMR), including late gadolinium enhancement (LGE), and PET, including a dynamic dual-tracer acquisition of [N]ammonia ([N]NH)/[F]fluorodeoxyglucose ([F]FDG), were performed simultaneously. Allocation, extent, and transmural degree of left ventricular (LV) scars were measured from LGE. Perfusion, viability, and hibernation were assessed by PET.

Results: A comparison of scar location revealed six more areas of infarction on MR than on PET. Mean LV scarring by CMR was 14% (range, 2% to 42%) and 14% (range, 1% to 46%) by PET (CMR vs. PET: p = 0.9). An intra-individual comparison of scarring showed a good inter-method correlation (r = 0.7), which was also evident in the subgroup with low ejection fraction (EF) (r = 0.6). Hibernation and transmural degree of scars showed a moderate to weak correlation (r = 0.4), which was even worse in the low EF group (r = 0.1).

Conclusions: In patients with IHD, there was a good correlation between PET and CMR for the LV scar extent using hybrid cardiac PET-MR. The degree of transmural scarring by CMR showed no correlation to PET hibernation. Therefore, cardiac PET-MR might be a suitable tool for a comprehensive assessment of myocardial viability if used to predict response to cardiac reperfusion strategies.
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http://dx.doi.org/10.1016/j.acra.2019.03.021DOI Listing
February 2020

Data-driven, projection-based respiratory motion compensation of PET data for cardiac PET/CT and PET/MR imaging.

J Nucl Cardiol 2020 12 13;27(6):2216-2230. Epub 2019 Feb 13.

QIMP Team, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.

Background: Respiratory patient motion causes blurring of the PET images that may impact accurate quantification of perfusion and infarction extents in PET myocardial viability studies. In this study, we investigate the feasibility of correcting for respiratory motion directly in the PET-listmode data prior to image reconstruction using a data-driven, projection-based, respiratory motion compensation (DPR-MoCo) technique.

Methods: The DPR-MoCo method was validated using simulations of a XCAT phantom (Biograph mMR PET/MR) as well as experimental phantom acquisitions (Biograph mCT PET/CT). Seven patient studies following a dual-tracer (F-FDG/N-NH) imaging-protocol using a PET/MR-system were also evaluated. The performance of the DPR-MoCo method was compared against reconstructions of the acquired data (No-MoCo), a reference gate method (gated) and an image-based MoCo method using the standard reconstruction-transform-average (RTA-MoCo) approach. The target-to-background ratio (TBR) in the myocardium and the noise in the liver (CoV) were evaluated for all acquisitions. For all patients, the clinical effect of the DPR-MoCo was assessed based on the end-systolic (ESV), the end-diastolic volumes (EDV) and the left ventricular ejection fraction (EF) which were compared to functional values obtained from the cardiac MR.

Results: The DPR-MoCo and the No-MoCo images presented with similar noise-properties (CoV) (P = .12), while the RTA-MoCo and reference-gate images showed increased noise levels (P = .05). TBR values increased for the motion limited reconstructions when compared to the No-MoCo reconstructions (P > .05). DPR-MoCo results showed higher correlation with the functional values obtained from the cardiac MR than the No-MoCo results, though non-significant (P > .05).

Conclusion: The projection-based DPR-MoCo method helps to improve PET image quality of the myocardium without the need for external devices for motion tracking.
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http://dx.doi.org/10.1007/s12350-019-01613-2DOI Listing
December 2020

Assessment of the kidney function parameters split function, mean transit time, and outflow efficiency using dynamic FDG-PET/MRI in healthy subjects.

Eur J Hybrid Imaging 2019 Feb 15;3(1). Epub 2019 Feb 15.

Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: Traditionally, isotope nephrography is considered as the method of choice to assess kidney function parameters in nuclear medicine. We propose a novel approach to determine the split function (SF), mean transit time (MTT), and outflow efficiency (OE) with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) dynamic positron emission tomography (PET).

Materials And Methods: Healthy adult subjects underwent dynamic simultaneous FDG-PET and magnetic resonance imaging (PET/MRI). Time-activity curves (TACs) of total kidneys, renal cortices, and the aorta were prospectively obtained from dynamic PET series. MRI images were used for anatomical correlation. The same individuals were subjected to dynamic renal Technetium-99 m-mercaptoacetyltriglycine (MAG3) scintigraphy and TACs of kidneys; the perirenal background and the left ventricle were determined. SF was calculated on the basis of integrals over the TACs, MTT was determined from renal retention functions after deconvolution analysis, and OE was determined from MTT. Values obtained from PET series were compared with scintigraphic parameters, which served as the reference.

Results: Twenty-four subjects underwent both examinations. Total kidney SF, MTT, and OE as estimated by dynamic PET/MRI correlated to their reference values by r = 0.75, r = 0.74 and r = 0.81, respectively, with significant difference (p < 0.0001) between the means of MTT and OE. No correlations were found for cortex FDG values.

Conclusions: The study proofs the concept that SF, MTT, and OE can be estimated with dynamic FDG PET/MRI scans in healthy kidneys. This has advantages for patients receiving a routine PET/MRI scan, as kidney parameters can be estimated simultaneously to functional and morphological imaging with high accuracy.
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http://dx.doi.org/10.1186/s41824-019-0051-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212313PMC
February 2019

[F]DOPA PET/ceCT in diagnosis and staging of primary medullary thyroid carcinoma prior to surgery.

Eur J Nucl Med Mol Imaging 2018 11 15;45(12):2159-2169. Epub 2018 May 15.

Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Waehringer-Guertel 18-20, A-1090, Vienna, Austria.

Purpose: Medullary thyroid carcinoma (MTC) is characterized by a high rate of metastasis. In this study we evaluated the ability of [F]DOPA PET/ceCT to stage MTC in patients with suspicious thyroid nodules and pathologically elevated serum calcitonin (Ctn) levels prior to total thyroidectomy and lymph node (LN) dissection.

Methods: A group of 32 patients with sonographically suspicious thyroid nodules and pathologically elevated basal Ctn (bCtn) and stimulated Ctn (sCtn) levels underwent DOPA PET/ceCT prior to surgery. Postoperative histology served as the standard of reference for ultrasonography and DOPA PET/ceCT region-based LN staging. Univariate and multivariate regression analyses as well as receiver operating characteristic analysis were used to evaluate the correlations between preoperative and histological parameters and postoperative tumour persistence or relapse.

Results: Primary MTC was histologically verified in all patients. Of the 32 patients, 28 showed increased DOPA decarboxylase activity in the primary tumour (sensitivity 88%, mean SUVmax 10.5). Undetected tumours were exclusively staged pT1a. The sensitivities of DOPA PET in the detection of central and lateral metastatic neck LN were 53% and 73%, in contrast to 20% and 39%, respectively, for neck ultrasonography. Preoperative bCtn and carcinoembryonic antigen levels as well as cN1b status and the number of involved neck regions on DOPA PET/ceCT were predictive of postoperative tumour persistence/relapse in the univariate regression analysis (P < 0.05). Only DOPA PET/ceCT cN1b status remained significant in the multivariate analysis (P = 0.016, relative risk 4.02).

Conclusion: This study revealed that DOPA PET/ceCT has high sensitivity in the detection of primary MTC and superior sensitivity in the detection of LN metastases compared to ultrasonography. DOPA PET/ceCT identification of N1b status predicts postoperative tumour persistence. Thus, implementation of a DOPA-guided LN dissection might improve surgical success.
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http://dx.doi.org/10.1007/s00259-018-4045-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182401PMC
November 2018

Assessing the kidney function parameters glomerular filtration rate and effective renal plasma flow with dynamic FDG-PET/MRI in healthy subjects.

EJNMMI Res 2018 May 9;8(1):37. Epub 2018 May 9.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: A method was developed to assess the kidney parameters glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) from 2-deoxy-2-[F]fluoro-D-glucose (FDG) concentration behavior in kidneys, measured with positron emission tomography (PET) scans. Twenty-four healthy adult subjects prospectively underwent dynamic simultaneous PET/magnetic resonance imaging (MRI) examination. Time activity curves (TACs) were obtained from the dynamic PET series, with the guidance of MR information. Patlak analysis was performed to determine the GFR, and based on integrals, ERPF was calculated. Results were compared to intra-individually obtained reference values determined from venous blood samples.

Results: Total kidney GFR and ERPF as estimated by dynamic PET/MRI were highly correlated to their reference values (r = 0.88/p < 0.0001 and r = 0.82/p < 0.0001, respectively) with no significant difference between their means.

Conclusions: The study is a proof of concept that GFR and ERPF can be assessed with dynamic FDG PET/MRI scans in healthy kidneys. This has advantages for patients getting a routine scan, where additional examinations for kidney function estimation could be avoided. Further studies are required for transferring this PET/MRI method to PET/CT applications.
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http://dx.doi.org/10.1186/s13550-018-0389-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943199PMC
May 2018

Hybrid cardiac imaging using PET/MRI: a joint position statement by the European Society of Cardiovascular Radiology (ESCR) and the European Association of Nuclear Medicine (EANM).

Eur Radiol 2018 Oct 2;28(10):4086-4101. Epub 2018 May 2.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University Vienna, Währinger Gürtel 18-20, Floor 5L, 1090, Vienna, Austria.

Positron emission tomography (PET) and magnetic resonance imaging (MRI) have both been used for decades in cardiovascular imaging. Since 2010, hybrid PET/MRI using sequential and integrated scanner platforms has been available, with hybrid cardiac PET/MR imaging protocols increasingly incorporated into clinical workflows. Given the range of complementary information provided by each method, the use of hybrid PET/MRI may be justified and beneficial in particular clinical settings for the evaluation of different disease entities. In the present joint position statement, we critically review the role and value of integrated PET/MRI in cardiovascular imaging, provide a technical overview of cardiac PET/MRI and practical advice related to the cardiac PET/MRI workflow, identify cardiovascular applications that can potentially benefit from hybrid PET/MRI, and describe the needs for future development and research. In order to encourage its wide dissemination, this article is freely accessible on the European Radiology and European Journal of Hybrid Imaging web sites.

Key Points: • Studies and case-reports indicate that PET/MRI is a feasible and robust technology. • Promising fields of application include a variety of cardiac conditions. • Larger studies are required to demonstrate its incremental and cost-effective value. • The translation of novel radiopharmaceuticals and MR-sequences will provide exciting new opportunities.
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http://dx.doi.org/10.1007/s00330-017-5008-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132726PMC
October 2018

Assessment of attenuation correction for myocardial PET imaging using combined PET/MRI.

J Nucl Cardiol 2019 08 22;26(4):1107-1118. Epub 2017 Nov 22.

QIMP Group, Center for Medical Physics and Biomedical Engineering, General Hospital Vienna, Medical University of Vienna, 1090, Vienna, Austria.

Objective: To evaluate the frequency of artifacts in MR-based attenuation correction (AC) maps and their impact on the quantitative accuracy of PET-based flow and metabolism measurements in a cohort of consecutive heart failure patients undergoing combined PET/MR imaging.

Methods: Myocardial viability studies were performed in 20 patients following a dual-tracer protocol involving the assessment of myocardial perfusion (N-NH: 813 ± 86 MBq) and metabolism (F-FDG: 335 ± 38 MBq). All acquisitions were performed using a fully-integrated PET/MR system, with standard DIXON-attenuation correction (DIXON-AC) mapping for each PET scan. All AC maps were examined for spatial misalignment with the emission data, total lung volume, susceptibility artifacts, and tissue inversion (TI). Misalignment and susceptibility artifacts were corrected using rigid co-registration and retrospective filling of the susceptibility-induced gaps, respectively. The effects of the AC artifacts were evaluated by relative difference measures and perceived changes in clinical interpretations.

Results: Average respiratory misalignment of (7 ± 4) mm of the PET-emission data and the AC maps was observed in 18 (90%) patients. Substantial changes in the lung volumes of the AC maps were observed in the test-retest analysis (ratio: 1.0 ± 0.2, range: 0.8-1.4). Susceptibility artifacts were observed in 10 (50%) patients, while six (30%) patients had TI artifacts. Average differences of 14 ± 10% were observed for PET images reconstructed with the artifactual AC maps. The combined artifact effects caused false-positive findings in three (15%) patients.

Conclusion: Standard DIXON-AC maps must be examined carefully for artifacts and misalignment effects prior to AC correction of cardiac PET/MRI studies in order to avoid misinterpretation of biased perfusion and metabolism readings from the PET data.
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http://dx.doi.org/10.1007/s12350-017-1118-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660490PMC
August 2019

Similarities in trabecular hypertrophy with site-specific differences in cortical morphology between men and women with type 2 diabetes mellitus.

PLoS One 2017 6;12(4):e0174664. Epub 2017 Apr 6.

Department of Internal Medicine III, Division of Endocrinology and Metabolism, Gender Medicine Unit, Medical University of Vienna, Vienna, Austria.

The goal of our study was to investigate interactions between sex and type 2 diabetes mellitus (T2DM) with regard to morphology of the peripheral skeleton. We recruited 85 subjects (mean age, 57±11.4 years): women with and without T2DM (n = 17; n = 16); and men with and without T2DM (n = 26; n = 26). All patients underwent high-resolution, peripheral, quantitative, computed tomography (HR-pQCT) imaging of the ultradistal radius (UR) and tibia (UT). Local bone geometry, bone mineral density (BMD), and bone microarchitecture were obtained by quantitative analysis of HR-pQCT images. To reduce the amount of data and avoid multi-collinearity, we performed a factor-analysis of HR-pQCT parameters. Based on factor weight, trabecular BMD, trabecular number, cortical thickness, cortical BMD, and total area were chosen for post-hoc analyses. At the radius and tibia, diabetic men and women exhibited trabecular hypertrophy, with a significant positive main effect of T2DM on trabecular number. At the radius, cortical thickness was higher in diabetic subjects (+20.1%, p = 0.003). Interestingly, there was a statistical trend that suggested attenuation of tibial cortical hypertrophy in diabetic men (cortical thickness, pinteraction = 0.052). Moreover, we found an expected sexual dichotomy, with higher trabecular BMD, Tb.N, cortical BMD, Ct.Th, and total area in men than in women (p≤ 0.003) at both measurement sites. Our results suggest that skeletal hypertrophy associated with T2DM is present in men and women, but appears attenuated at the tibial cortex in men.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174664PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383225PMC
September 2017

Association Between Osteogenesis and Inflammation During the Progression of Calcified Plaque Evaluated by F-Fluoride and F-FDG.

J Nucl Med 2017 06 23;58(6):968-974. Epub 2017 Feb 23.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria

F-FDG is the most widely validated PET tracer for the evaluation of atherosclerotic inflammation. Recently, F-NaF has also been considered a potential novel biomarker of osteogenesis in atherosclerosis. We aimed to analyze the association between inflammation and osteogenesis at different stages of atherosclerosis, as well as the interrelationship between these 2 processes during disease progression. Thirty-four myeloma patients underwent F-NaF and F-FDG PET/CT examinations. Lesions were divided into 3 groups (noncalcified, mildly calcified, and severely calcified lesions) on the basis of calcium density as measured in Hounsfield units by CT. Tissue-to-background ratios were determined from PET for both tracers. The association between inflammation and osteogenesis during atherosclerosis progression was evaluated in 19 patients who had at least 2 examinations with both tracers. There were significant correlations between the maximum tissue-to-background ratios of the 2 tracers (Spearman = 0.5 [ < 0.01]; Pearson = 0.4 [ < 0.01]) in the 221 lesions at baseline. The highest uptake of both tracers was observed in noncalcified lesions, but without any correlation between the tracers (Pearson = 0.06; = 0.76). Compared with noncalcified plaques, mildly calcified plaques showed concordant significantly lower accumulation, with good correlation between the tracers (Pearson = 0.7; < 0.01). In addition, enhanced osteogenesis-derived F-NaF uptake and regressive inflammation-derived F-FDG uptake were observed in severely calcified lesions (Pearson = 0.4; < 0.01). During follow-up, increased calcium density and increased mean F-NaF uptake were observed, whereas mean F-FDG uptake decreased. Most noncalcified (86%) and mildly calcified (81%) lesions and 47% of severely calcified lesions had concordant development of both vascular inflammation and osteogenesis. The combination of F-NaF PET imaging and F-FDG PET imaging promotes an understanding of the mechanism of plaque progression, thereby providing new insights into plaque stabilization.
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http://dx.doi.org/10.2967/jnumed.116.182790DOI Listing
June 2017

The Microtubule-Associated Protein Tau and Its Relevance for Pancreatic Beta Cells.

J Diabetes Res 2016 28;2016:1964634. Epub 2015 Dec 28.

Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.

Structural and biochemical alterations of the microtubule-associated protein tau (MAPT) are associated with degenerative disorders referred to as tauopathies. We have previously shown that MAPT is present in human islets of Langerhans, human insulinomas, and pancreatic beta-cell line models, with biophysical similarities to the pathological MAPT in the brain. Here, we further studied MAPT in pancreatic endocrine tissue to better understand the mechanisms that lead to functional dysregulation of pancreatic beta cells. We found upregulation of MAPT protein expression in human insulinomas when compared to human pancreatic islets of Langerhans and an imbalance between MAPT isoforms in insulinomas tissue. We cloned one 3-repeat domain MAPT and transduced this into a beta-cell derived rodent cell line Rin-5F. Proliferation experiments showed higher growth rates and metabolic activities of cells overexpressing MAPT protein. We observed that a MAPT overexpressing cell line demonstrates altered insulin transcription, translation, and insulin secretion rates. We found the relative insulin secretion rates were significantly decreased in a MAPT overexpressing cell line and these findings could be confirmed using partial MAPT knock-down cell lines. Our findings support that MAPT may play an important role in insulin granule trafficking and indicate the importance of balanced MAPT phosphorylation and dephosphorylation for adequate insulin release.
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http://dx.doi.org/10.1155/2016/1964634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707345PMC
October 2016

Quantitative assessment of atherosclerotic plaques on (18)F-FDG PET/MRI: comparison with a PET/CT hybrid system.

Eur J Nucl Med Mol Imaging 2016 Jul 27;43(8):1503-12. Epub 2016 Jan 27.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Purpose: PET with (18)F-FDG has the potential to assess vascular macrophage metabolism. (18)F-FDG is most often used in combination with contrast-enhanced CT to localize increased metabolism to specific arterial lesions. Novel (18)F-FDG PET/MRI hybrid imaging shows high potential for the combined evaluation of atherosclerotic plaques, due to the superior morphological conspicuity of plaque lesions. The purpose of this study was to evaluate the reliability and accuracy of (18)F-FDG PET/MRI uptake quantification compared to PET/CT as a reference standard in patients with carotid atherosclerotic plaques.

Methods: The study group comprised 34 consecutive oncological patients with carotid plaques who underwent both PET/CT and PET/MRI with (18)F-FDG on the same day. The presence of atherosclerotic plaques was confirmed by 3 T MRI scans. Maximum standardized uptake values (SUVmax) for carotid plaque lesions and the average SUV of the blood pool within the adjacent internal jugular vein were determined and target-to-blood ratios (TBRs, plaque to blood pool) were calculated.

Results: Atherosclerotic lesions with maximum colocalized focal FDG uptake were assessed in each patient. SUVmax values of carotid plaque lesions were significantly lower on PET/MRI than on PET/CT (2.3 ± 0.6 vs. 3.1 ± 0.6; P < 0.01), but were significantly correlated between PET/CT and PET/MRI (Spearman's r = 0.67, P < 0.01). In contrast, TBRmax values of plaque lesions were similar on PET/MRI and on PET/CT (2.2 ± 0.3 vs. 2.2 ± 0.3; P = 0.4), and again were significantly correlated between PET/MRI and PET/CT (Spearman's r = 0.73, P < 0.01). Considering the increasing trend in SUVmax and TBRmax values from early to delayed imaging time-points on PET/CT and PET/MRI, respectively, with continuous clearance of radioactivity from the blood, a slight underestimation of TBRmax values may also be expected with PET/MRI compared with PET/CT.

Conclusion: SUVmax and TBRmax values are widely accepted reference parameters for estimation of the radioactivity of atherosclerotic plaques on PET/CT. However, due to a systematic underestimation of SUVmax and TBRmax with PET/MRI, the optimal cut-off values indicating the presence of inflamed plaque tissue need to be newly defined for PET/MRI.
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http://dx.doi.org/10.1007/s00259-016-3308-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906060PMC
July 2016

Fetuin-A and angiopoietins in obesity and type 2 diabetes mellitus.

Endocrine 2012 Dec 21;42(3):496-505. Epub 2012 Jul 21.

Unit of Gender Medicine, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Although type 2 diabetes mellitus (DM) is a chronic metabolic disorder with multiple etiologies, obesity has been constantly linked with insulin resistance and manifestation of type 2 DM. In addition, obesity is associated with hypertension, dyslipidemia, and fatty liver disease and is regarded as a subclinical inflammatory condition characterized by release of pro-inflammatory mediators such as cytokines from adipose tissue. Both, type 2 DM and obesity are considered as major risks for developing micro- and macrovascular diseases. Recent studies showed that impaired circulating levels of fetuin-A, which is involved in propagating insulin resistance as well as circulating levels of angiopoietins, which are growth factors promoting angiogenesis, were observed in patients with obesity, metabolic syndrome, and type 2 DM. However, independent of type 2 DM and obesity, defective regulation of fetuin-A and angiopoietin are playing a critical role in predisposing to coronary and peripheral vascular diseases. Therefore, mechanisms linking type 2 DM and obesity with fetuin-A and angiopoietins seem to be complex and are in need of further exploration. In this review, we aimed to present a summary concerning associations of type 2 diabetes, obesity, and vascular diseases with circulating levels of angiopoietins and fetuin-A. Furthermore, we aimed to focus on roles of fetuin-A and angiopoietins and to highlight the most plausible mechanisms that might explain their associations with type 2 DM and obesity.
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http://dx.doi.org/10.1007/s12020-012-9754-4DOI Listing
December 2012

Diabetic polyneuropathy relates to bone metabolism and markers of bone turnover in elderly patients with type 2 diabetes: greater effects in male patients.

Gend Med 2012 Jun 12;9(3):187-96. Epub 2012 Apr 12.

Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Background: There is evidence that diabetic polyneuropathy (PNP) is associated with reduced bone mineral density (BMD) in type 1 diabetes but little is known about the impact of diabetic PNP on bone metabolism in type 2 diabetes.

Objectives: The aim of this study was to evaluate differences in bone metabolism by measuring markers of bone turnover and BMD in men and postmenopausal women with type 2 diabetes and diabetic PNP compared with those without PNP. Gender differences were analyzed for both groups of patients.

Methods: One hundred twenty patients with type 2 diabetes, 68 without PNP (43 men, 25 women, mean age 62 [8] years) and 52 with PNP (28 men, 24 women, mean age 64 [8] years) were studied. Clinical parameters with bone turnover biomarkers such as osteocalcin, bone alkaline phosphatase, procollagen type 1 amino-terminal propeptide, and carboxy-terminal telopeptide of type 1 collagen were measured in all patients. Dual energy x-ray absorptiometry to evaluate BMD was performed in a subgroup of patients.

Results: After controlling for age, body mass index, duration of diabetes, smoking, glycosylated hemoglobin, homeostasis model assessment index for insulin resistance, serum C-reactive protein, creatinine, calcium, gamma-glutamyltransferase, parathyroid and sex hormones levels, presence of micro/macrovascular complications, statin- as well as diabetes-related therapies, levels of carboxy-terminal telopeptide of type 1 collagen and procollagen type 1 amino-terminal propeptide were significantly higher among patients with PNP when compared with patients without PNP (P = 0.01 and P = 0.03, respectively). Differences in bone biomarkers were more pronounced among men with diabetes. BMD did not differ significantly between patients with and without PNP, independent of gender.

Conclusions: Male patients with PNP exhibit a higher rate of bone turnover than men without PNP. High rate of bone turnover increases the susceptibility for developing osteoporosis. Prevention of diabetic PNP might also reduce the incidence of osteoporosis and fractures in patients with type 2 diabetes.
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http://dx.doi.org/10.1016/j.genm.2012.03.004DOI Listing
June 2012
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