Publications by authors named "Alexander R Haug"

65 Publications

Active Brown Adipose Tissue is Associated With a Healthier Metabolic Phenotype in Obesity.

Diabetes 2021 Oct 18. Epub 2021 Oct 18.

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

Obesity is associated with increasing cardiometabolic morbidity and mortality worldwide. Not everyone with obesity, however, develops metabolic complications. Brown adipose tissue (BAT) has been suggested as a promoter of leanness and metabolic health. To date, little is known about the prevalence and metabolic function of BAT in subjects with severe obesity, a population at high cardiometabolic risk. In this cross-sectional study, we included 40 individuals with WHO class II-III obesity (BMI ≥ 35 kg/m2). Employing a 150-minute personalized cooling protocol and 18F-fluorodeoxyglucose positron emission tomography/computed tomography, cold-activated BAT was detectable in 14 (35%) of the participants. Cold-induced thermogenesis was significantly higher in participants with detectable BAT compared to those without. Notably, individuals with obesity and active BAT had 28.8% lower visceral fat mass despite slightly higher total fat mass compared to those without detectable BAT 18F-FDG uptake. This was accompanied by lower insulin resistance and systemic inflammation and improved NAFLD parameters, all adjusted for age, sex, and percent body fat. Contrary to previous assumptions, we show here that a significant fraction of individuals with severe obesity has active BAT. We found that decreased BAT 18F-FDG uptake was not associated with adiposity per se but with higher visceral fat mass. In summary, active BAT is linked to a healthier metabolic phenotype in obesity.
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http://dx.doi.org/10.2337/db21-0475DOI Listing
October 2021

Active Brown Adipose Tissue is Associated With a Healthier Metabolic Phenotype in Obesity.

Diabetes 2021 Oct 18. Epub 2021 Oct 18.

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

Obesity is associated with increasing cardiometabolic morbidity and mortality worldwide. Not everyone with obesity, however, develops metabolic complications. Brown adipose tissue (BAT) has been suggested as a promoter of leanness and metabolic health. To date, little is known about the prevalence and metabolic function of BAT in subjects with severe obesity, a population at high cardiometabolic risk. In this cross-sectional study, we included 40 individuals with WHO class II-III obesity (BMI ≥ 35 kg/m). Employing a 150-minute personalized cooling protocol and F-fluorodeoxyglucose positron emission tomography/computed tomography, cold-activated BAT was detectable in 14 (35%) of the participants. Cold-induced thermogenesis was significantly higher in participants with detectable BAT compared to those without. Notably, individuals with obesity and active BAT had 28.8% lower visceral fat mass despite slightly higher total fat mass compared to those without detectable BAT F-FDG uptake. This was accompanied by lower insulin resistance and systemic inflammation and improved NAFLD parameters, all adjusted for age, sex, and percent body fat. Contrary to previous assumptions, we show here that a significant fraction of individuals with severe obesity has active BAT. We found that decreased BAT F-FDG uptake was not associated with adiposity per se but with higher visceral fat mass. In summary, active BAT is linked to a healthier metabolic phenotype in obesity.
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http://dx.doi.org/10.2337/db21-0475DOI 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

Characterization of endogenous bile acid composition in individuals with cold-activated brown adipose tissue.

Mol Cell Endocrinol 2021 10 28;536:111403. Epub 2021 Jul 28.

Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address:

Introduction: Bile acid signaling has been suggested to promote BAT activity in various experimental models. However, little is known if and how physiologic bile acid metabolism is linked to BAT function in humans. Here we investigated the association between BAT activity and circulating bile acid concentrations in lean and obese individuals.

Methods: BAT F-fluorodeoxyglucose uptake was measured after a standardized cooling protocol by positron emission tomography/computed tomography. Cold-induced thermogenesis was assessed by indirect calorimetry. Fasting bile acid concentrations were determined by high performance liquid chromatography-high-resolution mass spectrometry.

Results: In a cohort of 24 BAT-negative and 20 BAT-positive individuals matched by age, sex, and body mass index, circulating bile acid levels were similar between groups except for higher ursodeoxycholic acid and a trend towards a lower 12α-OH/non-12α-OH bile acid ratio in lean participants with active BAT compared to those without. Moreover, the 12α-OH/non-12α-OH ratio, a marker of CYP8B1 activity, correlated negatively with BAT volume and activity.

Conclusion: Fasting concentrations of major bile acids are not associated with cold-induced BAT activity in humans. However, the inverse association between BAT activity and 12α-OH/non-12α-OH ratio may suggest CYP8B1 as a potential new target in BAT function and warrants additional investigation.
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http://dx.doi.org/10.1016/j.mce.2021.111403DOI Listing
October 2021

Sex differences in brown adipose tissue activity and cold-induced thermogenesis.

Mol Cell Endocrinol 2021 08 11;534:111365. Epub 2021 Jun 11.

Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address:

Introduction: Brown adipose tissue (BAT) is suggested to exhibit a sexual dimorphism and thus contributes to the observed sex differences in cardiometabolic risk observed between women and men. Clinical data supporting this hypothesis are however scarce. The aim of this study was to investigate the relationship between BAT activity and sex using positron emission tomography (PET) - the current gold-standard for BAT quantification.

Methods: In this study, we included 95 subjects with a wide BMI range (20-55 kg/m) aged from 18 to 50 years. Avoiding shivering, participants were cooled with a water-perfused vest to achieve adequate BAT activation. BAT activity was determined by F-fluorodeoxyglucose PET/computed tomography (F-FDG PET/CT). Cold-induced thermogenesis (CIT) was quantified by indirect calorimetry.

Results: BAT was present in 44.6% of pre-menopausal women and in 35.9% of men (p = 0.394). CIT was significantly higher in women (p = 0.024). Estradiol levels were positively associated with CIT independent of age, sex, body fat and other sex hormones (b = 0.360, p = 0.016). In women, CIT decreased during the menstrual cycle, with lower levels in the luteal phase similar to median concentrations in men.

Conclusion: The prevalence of cold-activated BAT is slightly but non-significantly higher in pre-menopausal women than men. CIT is increased in females and independently associated with estradiol, suggesting that sex hormones may play a role in different thermogenic responses between men and women.
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http://dx.doi.org/10.1016/j.mce.2021.111365DOI Listing
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

Optimizing PSMA Radioligand Therapy for Patients with Metastatic Castration-Resistant Prostate Cancer. A Systematic Review and Meta-Analysis.

Int J Mol Sci 2020 Nov 28;21(23). Epub 2020 Nov 28.

Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori (IRST) IRCCS, 7014 Meldola, Italy.

The aim of the review was to evaluate patient and treatment characteristics for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with PSMA radioligand therapy (PRLT) associated with above-average outcome. The systematic review and meta-analysis followed recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). We searched for publications in PubMed, Embase, and ClinicalTrials.gov up to 31 September 2020. Thirty-six publications and four duplicates reported 2346 patients. Nearly two-thirds of the patients had bone metastases. Median overall survival (OS) was 16 months. Asymptomatic patients and patients with only lymph node metastases lived longer than symptomatic patients and patients with more extensive metastases. Patients treated with an intensified schedule of Lu PRLT lived longer than those treated with a conventional schedule. Half of the patients obtained a PSA decline ≥ 50% and these patients lived longer than those with less PSA decline. Approximately 10% of the patients developed hematologic toxicity with anemia grade 3 as the most severe adverse effect. Characteristics for patients, cancer, restaging, and PRLT predict above average overall survival following treatment with PRLT.
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http://dx.doi.org/10.3390/ijms21239054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730994PMC
November 2020

Assessment of Central Nervous System Lymphoma Based on CXCR4 Expression In Vivo Using 68Ga-Pentixafor PET/MRI.

Clin Nucl Med 2021 Jan;46(1):16-20

From the Division of Oncology, Department of Medicine I.

Purpose Of The Report: F-FDG PET is limited for assessment of central nervous system lymphoma (CNSL) due to physiologic tracer accumulation in the brain. We prospectively evaluated the novel PET tracer Ga-pentixafor, which targets the C-X-C chemokine receptor 4 (CXCR4), for lesion visualization and response assessment of CNSL.

Materials And Methods: Seven CNSL patients underwent Ga-pentixafor PET/MRI with contrast enhancement (CE-MRI) and diffusion-weighted sequences. The accuracy of Ga-pentixafor PET for CNSL lesion detection relative to the CE-MRI reference standard was determined. Standardized uptake values (SUVmean and SUVmax), PET-based (PTV) and MRI-based (VOLMRI) tumor volumes, and apparent diffusion coefficients (ADCs) were assessed, and correlation coefficients were calculated. Three SUVmax thresholds (41%, 50%, and 70%) were evaluated for PTV definitions (PTV41%, PTV50%, and PTV70%) and tested against VOLMRI using paired sample t tests.

Results: Twelve Ga-pentixafor PET/MRI examinations (including 5 follow-up scans) of 7 patients were evaluated. Ga-pentixafor PET demonstrated 18 lesions, all of which were confirmed by CE-MRI; there were no false-positive lesions on PET (accuracy, 100%). PTV41% showed the highest concordance with lesion morphology, with no significant difference compared with VOLMRI (mean difference, -0.24 cm; P = 0.45). The correlation between ADCmean and SUVmean41% (r = 0.68) was moderate. Changes in PTV41% on follow-up PET/MRI showed the same trend as VOLMRI changes, including progression of 1 lesion each in patient 1 (+456.0% PTV41% and +350.8% VOLMRI) and patient 3 (+110.4% PTV41% and +85.1% VOLMRI).

Conclusions: Ga-pentixafor PET may be feasible for assessment and follow-up of CNSL. Future studies need to focus on testing its clinical value to distinguish between glioma and CNSL, and between radiation-induced inflammation and viable residual tumor.
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http://dx.doi.org/10.1097/RLU.0000000000003404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385649PMC
January 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

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

A Microdosing Study with Tc-PHC-102 for the SPECT/CT Imaging of Primary and Metastatic Lesions in Renal Cell Carcinoma Patients.

J Nucl Med 2021 03 17;62(3):360-365. Epub 2020 Jul 17.

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

Tc-PHC-102 is a Tc-labeled derivative of acetazolamide, a high-affinity small organic ligand of carbonic anhydrase IX (CAIX). Tc-PHC-102 has previously shown favorable in vivo biodistribution properties in mouse models of CAIX-positive clear cell renal cell carcinoma (ccRCC) and colorectal cancer. In this study, we aimed to explore the targeting performance of Tc-PHC-102 in SPECT in patients with renal cell carcinoma while also assessing the safety and tolerability of the radiotracer. We studied 5 patients with localized or metastatic ccRCC in a microdosing regimen, after the administration of a 50-μg total of CAIX ligand and 600-800 MBq of Tc-PHC-102. Tissue distribution and residence time in normal organs and tumors were analyzed by serial SPECT/CT scans at 3 time points (30 min, 2 h, and 6 h) after intravenous administration. In the 5 patients studied, Tc-PHC-102 was well tolerated and no study drug-related adverse events were recorded. In the stomach, kidneys, and gallbladder, the radiotracer showed a rapid initial uptake, which cleared over time. Localization of the study drug in primary tumors of 5 patients was observed, with favorable tumor-to-background ratios. Tc-PHC-102 SPECT/CT allowed the identification of 4 previously unknown lung and lymph node metastases in 2 patients. Tc-PHC-102 is a promising SPECT tracer for the imaging of patients with ccRCC. This tracer has the potential to identify primary and metastatic lesions in different anatomic locations. Tc-PHC-102 might also serve as a companion diagnostic agent for future CAIX-targeting therapeutics.
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http://dx.doi.org/10.2967/jnumed.120.245530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049338PMC
March 2021

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

Particular findings on lung CT in patients undergoing immunotherapy for bronchogenic carcinoma.

Wien Klin Wochenschr 2020 Aug 20;132(15-16):467-474. Epub 2020 May 20.

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

Background: Immune checkpoint inhibitors have become a valuable tool in the therapeutic strategy against metastasized non-small cell lung cancer (NSCLC) as they represent an effective and safe treatment option for many patients; however, the treatment response and side effects of this class of drugs can considerably differ compared to classical chemotherapeutics. The aim of this study was to highlight specific radiological pulmonary findings of NSCLC patients treated with immune checkpoint inhibitors.

Methods And Results: Medical records and images of prospectively collected data from 70 patients with advanced NSCLC, treated with immune checkpoint inhibitors, were reviewed. Of the patients two experienced an initial increase in tumor size, followed by a decrease in tumor size that was described as pseudoprogression. Another patient developed a sarcoid-like reaction accompanied by clinical improvements and radiological treatment response. A further two patients developed immune checkpoint-associated pulmonary injury that was clinically and radiologically classified as pneumonitis, which responded well to anti-inflammatory treatment.

Conclusion: Management of patients with NSCLC using immune checkpoint inhibitors requires a knowledge of specific clinical and radiological findings. Both oncologists and radiologists have to be aware of the most common types, including atypical response patterns, such as a sarcoid-like reaction and pseudoprogression as well as of the pulmonary side effects that can encompass pneumonitis.
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http://dx.doi.org/10.1007/s00508-020-01667-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445205PMC
August 2020

The Presence of Active Brown Adipose Tissue Determines Cold-Induced Energy Expenditure and Oxylipin Profiles in Humans.

J Clin Endocrinol Metab 2020 07;105(7)

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

Background: Accumulating evidence links brown adipose tissue (BAT) to increased cold-induced energy expenditure (CIEE) and regulation of lipid metabolism in humans. BAT has also been proposed as a novel source for biologically active lipid mediators including polyunsaturated fatty acids (PUFAs) and oxylipins. However, little is known about cold-mediated differences in energy expenditure and various lipid species between individuals with detectable BAT positive (BATpos) and those without BAT negative (BATneg).

Methods: Here we investigated a unique cohort of matched BATpos and BATneg individuals identified by 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography ([18F]-FDG PET/CT). BAT function, CIEE, and circulating oxylipins, were analyzed before and after short-term cold exposure using [18F]-FDG PET/CT, indirect calorimetry, and high-resolution mass spectrometry, respectively.

Results: We found that active BAT is the major determinant of CIEE since only BATpos individuals experienced significantly increased energy expenditure in response to cold. A single bout of moderate cold exposure resulted in the dissipation of an additional 20 kcal excess energy in BATpos but not in BATneg individuals. The presence of BAT was associated with a unique systemic PUFA and oxylipin profile characterized by increased levels of anti-inflammatory omega-3 fatty acids as well as cytochrome P450 products but decreased concentrations of some proinflammatory hydroxyeicosatetraenoic acids when compared with BATneg individuals. Notably, cold exposure raised circulating levels of various lipids, including the recently identified BAT-derived circulating factors (BATokines) DiHOME and 12-HEPE, only in BATpos individuals.

Conclusions: In summary, our data emphasize that BAT in humans is a major contributor toward cold-mediated energy dissipation and a critical organ in the regulation of the systemic lipid pool.
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http://dx.doi.org/10.1210/clinem/dgaa183DOI Listing
July 2020

Toxicity of a combined therapy using the mTOR-inhibitor everolimus and PRRT with [Lu]Lu-DOTA-TATE in Lewis rats.

EJNMMI Res 2020 Apr 25;10(1):41. Epub 2020 Apr 25.

Department of Nuclear Medicine, University Hospital, Ludwig-Maxilimians-University Munich, Munich, Germany.

Purpose: Peptide receptor radionuclide therapy (PRRT) with [Lu]Lu-DOTA,TYR-octreotate ([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 [Lu]Lu-DOTA-TATE in female Lewis rats.

Methods: Animals received 200 MBq of [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 + [Lu]Lu-DOTA-TATE; group 4, everolimus + [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 [Tc]Tc-mercaptoacetyltriglycine ([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 [Lu]Lu-DOTA-TATE. Functional renal scintigraphies using [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 [Lu]Lu-DOTA-TATE.
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http://dx.doi.org/10.1186/s13550-020-00628-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183514PMC
April 2020

PRRT of neuroendocrine tumors: individualized dosimetry or fixed dose scheme?

Authors:
Alexander R Haug

EJNMMI Res 2020 Apr 15;10(1):35. Epub 2020 Apr 15.

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

Great efforts have been made in dosimetry for individualizing PRRT. However, many centers do not use dosimetry and its results hardly influence treatment. A reason for that is that reliable thresholds for organs-at-risk, kidneys and bone marrow, and treatment response are lacking. The nuclear medicine community must provide solid data from large trials delivering reliable thresholds, which then help to tailor PRRT according to organ doses (in order to reduce toxicity or increase treatment activity) or tumor doses (in order to increase activity to meet the response-threshold). Otherwise, development of radionuclide therapies will be done like big pharmaceutical companies do it currently: classical dose escalation studies and agreement on acceptable toxicity probabilities. Therapeutic radiopharmaceuticals will then be handled like other drugs, which on the other hand will increase availability of radionuclide therapies.
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http://dx.doi.org/10.1186/s13550-020-00623-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158965PMC
April 2020

Cold Exposure Distinctively Modulates Parathyroid and Thyroid Hormones in Cold-Acclimatized and Non-Acclimatized Humans.

Endocrinology 2020 07;161(7)

Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.

Cold-induced activation of thermogenesis modulates energy metabolism, but the role of humoral mediators is not completely understood. We aimed to investigate the role of parathyroid and thyroid hormones in acute and adaptive response to cold in humans. Examinations were performed before/after 15 minutes of ice-water swimming (n = 15) or 120 to 150 minutes of cold-induced nonshivering thermogenesis (NST) applied to cold-acclimatized (n = 6) or non-acclimatized (n = 11) individuals. Deep-neck brown adipose tissue (BAT) was collected from non-acclimatized patients undergoing elective neck surgery (n = 36). Seasonal variations in metabolic/hormonal parameters of ice-water swimmers were evaluated. We found that in ice-water swimmers, PTH and TSH increased and free T3, T4 decreased after a 15-minute winter swim, whereas NST-inducing cold exposure failed to regulate PTH and free T4 and lowered TSH and free T3. Ice-water swimming-induced increase in PTH correlated negatively with systemic calcium and positively with phosphorus. In non-acclimatized men, NST-inducing cold decreased PTH and TSH. Positive correlation between systemic levels of PTH and whole-body metabolic preference for lipids as well as BAT volume was found across the 2 populations. Moreover, NST-cooling protocol-induced changes in metabolic preference for lipids correlated positively with changes in PTH. Finally, variability in circulating PTH correlated positively with UCP1/UCP1, PPARGC1A, and DIO2 in BAT from neck surgery patients. Our data suggest that regulation of PTH and thyroid hormones during cold exposure in humans varies by cold acclimatization level and/or cold stimulus intensity. Possible role of PTH in NST is indicated by its positive relationships with whole-body metabolic preference for lipids, BAT volume, and UCP1 content.
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http://dx.doi.org/10.1210/endocr/bqaa051DOI Listing
July 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

PET/MRI versus PET/CT in oncology: a prospective single-center study of 330 examinations focusing on implications for patient management and cost considerations.

Eur J Nucl Med Mol Imaging 2020 01 13;47(1):51-60. Epub 2019 Aug 13.

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

Purpose: PET/MRI has recently been introduced into clinical practice. We prospectively investigated the clinical impact of PET/MRI compared with PET/CT, in a mixed population of cancer patients, and performed an economic evaluation of PET/MRI.

Methods: Cancer patients referred for routine staging or follow-up by PET/CT underwent consecutive PET/CT and PET/MRI, using single applications of [F]FDG, [Ga]Ga-DOTANOC, or [F]FDOPA, depending on tumor histology. PET/MRI and PET/CT were rated separately, and lesions were assessed per anatomic region; based on regions, per-examination and per-patient accuracies were determined. A simulated, multidisciplinary team meeting served as reference standard and determined whether differences between PET/CT and PET/MRI affected patient management. The McNemar tests were used to compare accuracies, and incremental cost-effectiveness ratios (ICERs) for PET/MRI were calculated.

Results: Two hundred sixty-three patients (330 same-day PET/CT and PET/MRI examinations) were included. PET/MRI was accurate in 319/330 examinations and PET/CT in 277/330 examinations; the respective accuracies of 97.3% and 83.9% differed significantly (P < 0.001). The additional findings on PET/MRI-mainly liver and brain metastases-had implications for patient management in 21/263 patients (8.0%). The per-examination cost was 596.97 EUR for PET/MRI and 405.95 EUR for PET/CT. ICERs for PET/MRI were 14.26 EUR per percent of diagnostic accuracy and 23.88 EUR per percent of correctly managed patients.

Conclusions: PET/MRI enables more appropriate management than PET/CT in a nonnegligible fraction of cancer patients. Since the per-examination cost is about 50% higher for PET/MRI than for PET/CT, a histology-based triage of patients to either PET/MRI or PET/CT may be meaningful.
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http://dx.doi.org/10.1007/s00259-019-04452-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885019PMC
January 2020

Whole-Body [F]FDG-PET/MRI vs. [F]FDG-PET/CT in Malignant Melanoma.

Mol Imaging Biol 2020 06;22(3):739-744

Department of Biomedical Imaging and Image-guided Therapy, Division of General and Pediatric Radiology, Medical University of Vienna, Vienna, Austria.

Purpose: To assess the diagnostic performance of simultaneous whole-body 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) compared to [F]FDG PET/x-ray computed tomography (CT) for detection of distant metastatic disease in patients with malignant melanoma.

Procedures: We included patients with malignant melanoma who underwent a single injection [F]FDG dual-imaging protocol that included whole-body PET/CT and subsequent whole-body PET/MRI for staging or restaging purposes in a prospective setting. Images from both modalities were analyzed by two rater teams for the presence of metastatic lesions. PET/CT-PET/MRI overall agreement as well as region-based accuracies, sensitivities (Se), and specificities (Sp) were computed.

Results: Between July 2014 and December 2018, 22 patients were enrolled. Interrater agreement and overall accuracy (consensus reading) were 78.8 % (95 % CI 71-84.9) and 96.1 % (95 % CI 92.3-98) for PET/MRI and 78 % (70.2-84.3) and 97.4 % (95 % CI 93.7-98.9) for PET/CT, respectively (P = 0.42). PET/MRI reached a region-based Se of 89.1 % (95 % CI 79.4-94.5) and a Sp of 100 %, whereas PET/CT showed a region-based Se of 92.7 % (95 % CI 84-96.9) and a Sp of 100 % for the detection of metastatic disease in malignant melanoma.

Conclusions: Whole-body [F]FDG-PET/MRI appears to be comparable to [F]FDG-PET/CT for lesion detection in patients with malignant melanoma.
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http://dx.doi.org/10.1007/s11307-019-01413-7DOI Listing
June 2020

Prospective non-invasive evaluation of CXCR4 expression for the diagnosis of MALT lymphoma using [Ga]Ga-Pentixafor-PET/MRI.

Theranostics 2019 27;9(12):3653-3658. Epub 2019 May 27.

Department of Biomedical Imaging and Image-guided Therapy, Division of General and Paediatric Radiology, Medical University of Vienna, Austria.

MALT lymphomas express the chemokine receptor CXCR4 on a regular basis, and [68Ga]Ga-Pentixafor-PET has been shown to quantify CXCR4 expression non-invasively. We, therefore, aimed to evaluate [68Ga]Ga-Pentixafor-PET/MRI for the non-invasive assessment of MALT lymphomas.

Methods: We included 36 MALT lymphoma patients, who had not undergone previous systemic or radiation therapy, in our prospective, IRB-approved, proof-of-concept study. Involved anatomic regions were the orbit (n=14), stomach (n=10), lungs (n=5), and other sites (soft-tissues n=3; adrenal gland, tonsils, parotid gland, and urinary bladder n=1, respectively). MRI sequences included an axial 2-point Dixon T1 VIBE SPAIR 3D sequence for PET attenuation correction; a coronal T2 HASTE sequence; and an axial echo-planar imaging SPAIR-based diffusion-weighted sequence (DWI) obtained during free-breathing (b-values, 50 and 800), with corresponding ADC (apparent diffusion coefficient) maps.

Results: In 33/36 patients, there were MALT lymphomas with an increased uptake of [68Ga]Ga-Pentixafor; all current lymphoma manifestations showed an increased uptake and, accordingly, were positive on the PET/MRI. The remaining three patients had undergone surgery for their orbital MALT lymphomas prior to PET/MRI. Mean SUVmax was 8.6 ± 4.7, mean SUVmean was 4.7 ± 1.8, and mean SUVpeak was 8.0 ± 4.2. The mean SUVmax of the liver was 1.8, and the mean tumor-to-liver ratio was 2.9 ± 2.0. There were no significant differences in SUVmax (P=0.22), SUVmean (P=0.53), SUVpeak (P=0.29), or SUVt/l (P=0.92) between the four anatomic regions (orbit, stomach, lungs, other). The mean tumor volume was 146 ± 499.

Conclusions: Our results thus indicate that [68Ga]Ga-Pentixafor-PET is feasible for the assessment of MALT lymphomas, with a good tumor-to-background ratio in terms of radiotracer uptake.
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http://dx.doi.org/10.7150/thno.31032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587159PMC
July 2020

(R)-[F]NEBIFQUINIDE: A promising new PET tracer for TSPO imaging.

Eur J Med Chem 2019 Aug 10;176:410-418. Epub 2019 May 10.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria; Ludwig Boltzmann Institute Applied Diagnostics, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), has a high diagnostic potential in neurodegenerative disorders and cancer. However, TSPO is considered a challenge for molecular imaging due to the poor availability of suitable radiotracers with adequate pharmacokinetic properties. Here, we describe the development of a radiofluorinated pyridinyl isoquinoline analogue of the established TSPO PET tracer (R)-[C]PK11195 with improved binding properties in all known human TSPO phenotypes. We conducted a complete preclinical evaluation using in vitro, in vivo and ex vivo methods to assess the performance of this novel radiotracer and observed high specific binding of the radiotracer to TSPO, as well as high metabolic stability. Therefore, we propose this radiolabeled compound for further evaluation in animal models as well as in clinical trials.
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http://dx.doi.org/10.1016/j.ejmech.2019.05.008DOI Listing
August 2019

Comparison of RECIST, iRECIST, and PERCIST for the Evaluation of Response to PD-1/PD-L1 Blockade Therapy in Patients With Non-Small Cell Lung Cancer.

Clin Nucl Med 2019 Jul;44(7):535-543

Respiratory Oncology Unit, Otto-Wagner Hospital, Vienna.

Purpose: The aim of this study was to compare the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the immune RECIST (iRECIST) criteria, and the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 in patients with advanced non-small cell lung cancer treated with programmed cell death protein 1 (PD-1)/programmed cell death protein 1 ligand (PD-L1) inhibitors.

Methods: This prospective study of 42 patients treated with a PD-1/PD-L1 inhibitor was approved by our institutional review board, and all patients gave written, informed consent. Tumor burden dynamics were assessed on F-FDG PET/CT before and after treatment initiation. Immunotherapeutic responses were evaluated according to RECIST 1.1, iRECIST, and PERCIST 1.0 for the dichotomous groups, responders versus nonresponders. Cohen κ and Wilcoxon signed rank tests were used to evaluate concordance among these criteria. We assessed progression-free survival and overall survival using the Kaplan-Meier estimator.

Results: The RECIST 1.1 and PERCIST 1.0 response classifications were discordant in 6 patients (14.2%; κ = 0.581). RECIST 1.1 and iRECIST were discordant in 2 patients, who evidenced pseudoprogression after treatment initiation. Median progression-free survival, as well as overall survival, was significantly longer for responders compared with nonresponders for all criteria (P < 0.001), with no significant difference between the 3 criteria (P > 0.05).

Conclusions: RECIST 1.1 and PERCIST 1.0 show only moderate agreement, but both can predict treatment response to PD-1/PD-L1 inhibitor therapy. In case of pseudoprogression, metabolic tumor activity may help to correctly classify treatment response.
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http://dx.doi.org/10.1097/RLU.0000000000002603DOI Listing
July 2019

[Ga]Pentixafor PET/MR imaging of chemokine receptor 4 expression in the human carotid artery.

Eur J Nucl Med Mol Imaging 2019 Jul 19;46(8):1616-1625. Epub 2019 Apr 19.

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

Purpose: Type 4 chemokine receptor (CXCR4) plays an important role in immune cell migration during the atherosclerosis progression. We aimed to evaluate [Ga]Pentixafor positron emission tomography (PET) in combination magnetic resonance imaging (MRI) for in vivo quantification of CXCR4 expression in carotid plaques.

Methods: Seventy-two patients with lymphoma were prospectively scheduled for whole body [Ga]Pentixafor PET/MRI with an additional T2-weighted carotid sequence. Volumes of interest (VOIs) were drawn along the carotid bifurcation regions, and the maximum tissue-to-blood ratios (TBR) of [Ga]Pentixafor uptake were calculated. Lesions were categorized into non-eccentric (n = 27), mild eccentric (n = 67), moderately (n = 41) and severely (n = 19) eccentric carotid atherosclerosis. A different cohort of symptomatic patients (n = 10) with carotid stenosis scheduled for thrombendarterectomy (TEA) was separately imaged with 3T MRI with dedicated plaque sequences (time of flight, T1-, and T2-weighted). MRI findings were correlated with histochemical assessment of intact carotid plaques.

Results: At hybrid PET/MRI, we observed significantly increased [Ga]Pentixafor uptake in mildly (mean TBR = 1.57 ± 0.27, mean SUV = 2.51 ± 0.39), moderately (mean TBR = 1.64 ± 0.37, mean SUV = 2.61 ± 0.55) and severely eccentric carotids (mean TBR = 1.55 ± 0.26, mean SUV = 2.40 ± 0.44) as compared to non-eccentric carotids (mean TBR = 1.29 ± 0.21, mean SUV = 1.77 ± 0.42) (p ≤ 0.05). Histological findings from TEA confirmed that prominent CXCR4 expression was localized within inflamed atheromas and preatheromas. Co-localization of cellular CXCR4 and CD68 expression in the plaque was observed by immunofluorescence staining.

Conclusions: In vivo evaluation of CXCR4 expression in carotid atherosclerotic lesions is feasible using [Ga]Pentixafor PET/MRI. In atherosclerotic plaque tissue, CXCR4 expression might be used as a surrogate marker for inflammatory atherosclerosis.
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http://dx.doi.org/10.1007/s00259-019-04322-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584241PMC
July 2019

Is there a reliable size cut-off for splenic involvement in lymphoma? A [18F]FDG-PET controlled study.

PLoS One 2019 8;14(3):e0213551. Epub 2019 Mar 8.

Department of Biomedical Imaging and Image-guided Therapy, Division of General and Pediatric Radiology, Medical University of Vienna, Vienna, Austria.

Purpose: Aim of present study was to determine whether the currently recommended 13-cm cranio-caudal diameter cut-off on CT for assessment of splenic involvement in lymphoma offers adequate sensitivity and specificity.

Materials And Methods: Patients with histologically proven lymphoma who had undergone [18F]FDG-PET/CT before therapy were included. Cranio-caudal diameters of the spleen were measured on the CT component of PET/CT, and ROC analyses with calculation of respective areas under the curve (AUC) were used to determine cut-off values of cranio-caudal measurements with their respective sensitivities and specificities, using [18F]FDG-PET as the reference standard.

Results: In 93 patients, we found a sensitivity of 74.1% and a specificity of 47% for the 13-cm splenic diameter cut-off.

Conclusions: Our results show reasonable, though far from perfect sensitivities and specificities for the currently recommend 13-cm splenic diameter cut-off.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213551PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407760PMC
December 2019

Dynamic [18F]FET-PET/MRI using standard MRI-based attenuation correction methods.

Eur Radiol 2019 Aug 11;29(8):4276-4285. Epub 2019 Jan 11.

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

Aim: To assess if tumour grading based on dynamic [18F]FET positron emission tomography/magnetic resonance imaging (PET/MRI) studies is affected by different MRI-based attenuation correction (AC) methods.

Methods: Twenty-four patients with suspected brain tumours underwent dynamic [18F]FET-PET/MRI examinations and subsequent low-dose computed tomography (CT) scans of the head. The dynamic PET data was reconstructed using the following AC methods: standard Dixon-based AC and ultra-short echo time MRI-based AC (MR-AC) and a model-based AC approach. All data were reconstructed also using CT-based AC (reference). For all lesions and reconstructions, time-activity curves (TACs) and time to peak (TTP) were extracted using different region-of-interest (ROI) and volume-of-interest (VOI) definitions. According to the most common evaluation approaches, TACs were categorised into two or three distinct curve patterns. Changes in TTP and TAC patterns compared to PET using CT-based AC were reported.

Results: In the majority of cases, TAC patterns did not change. However, TAC pattern changes as well as changes in TTP were observed in up to 8% and 17% of the cases when using different MR-AC methods and ROI/VOI definitions, respectively. However, these changes in TTP and TAC pattern were attributed to different delineations of the ROIs/VOIs in PET corrected with different AC methods.

Conclusion: PET/MRI using different MR-AC methods can be used for the assessment of TAC patterns in dynamic [18F]FET studies, as long as a meaningful delineation of the area of interest within the tumour is ensured.

Key Points: • PET/MRI using different MR-AC methods can be used for dynamic [18F]FET studies. • A meaningful segmentation of the area of interest needs to be ensured, mandating a visual validation of the delineation by an experienced reader.
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http://dx.doi.org/10.1007/s00330-018-5942-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610265PMC
August 2019

Response assessment using Ga-PSMA ligand PET in patients undergoing Lu-PSMA radioligand therapy for metastatic castration-resistant prostate cancer.

Eur J Nucl Med Mol Imaging 2019 May 19;46(5):1063-1072. Epub 2018 Dec 19.

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

Purpose: The first aim of this study was to evaluate Ga-PSMA conjugate 11 positron emission tomography (PSMA PET) parameters for assessment of response to Lu-PSMA-617 radioligand therapy (RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC). The second aim was to investigate factors associated with overall survival (OS).

Methods: We retrospectively assessed mean standardized uptake values (SUVmean) and total tumor volumes (TTV) on PSMA PET in 38 of 55 mCRPC patients before and after RLT. PSA testing and PSMA PET/CT(MRI) imaging were performed during the 8 weeks before and the 6 weeks after RLT. PSMA PET and CT(MRI) images were reviewed separately according to the modified PET Response Criteria in Solid Tumors (mPERCIST) and RECIST1.1. The results were compared with PSA responses. Associations between OS and the RECIST evaluation and changes in SUVmean, TTV, and PSA, CRP, LDH, hemoglobin and ALP levels were determined in a univariable survival analysis.

Results: The median PSA level at the time of pretherapy PSMA PET/CT(MRI) was 60.8 ng/ml (IQR 15.4, 264.2 ng/ml). After RLT the median PSA level decreased by 44%, TTV by 45.1%, SUVmean by 25.8% and RECIST by 11.3%. A PSA response was seen in 18 patients (47.4%), stable disease in 12 (31.6%) and progressive disease in 8 (21.1%). Contrary to the changes in SUVmean and the RECIST evaluation, the change in TTV was significantly associated with PSA response (p = 0.15, p = 0.58, and p < 0.001, respectively). After a median follow-up of 17 months (IQR 8.0, 24.2 months), 11 patients (28.9%) had died of their prostate cancer. The changes in both TTV and PSA levels were associated with OS (HR 1.001, 95% CI 1-1.003, p = 0.04, and HR 1.004, 95% CI 1.001-1.008, p = 0.01, respectively), while the changes in SUVmean and the RECIST evaluation were not. The pre-therapy CRP level was also associated with OS (HR 1.07, 95% CI 1.009-1.14, p = 0.02).

Conclusion: TTV on PSMA PET seems to be a reliable parameter for response assessment in mCRPC patients undergoing RLT and might overcome the limitations of RECIST in prostate cancer. Furthermore, the change in TTV was significantly associated with OS in our cohort.
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http://dx.doi.org/10.1007/s00259-018-4236-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451716PMC
May 2019

PSMA Ligand PET/MRI for Primary Prostate Cancer: Staging Performance and Clinical Impact.

Clin Cancer Res 2018 12 23;24(24):6300-6307. Epub 2018 Aug 23.

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

Purpose: Primary staging of prostate cancer relies on modalities, which are limited. We evaluate simultaneous [Ga]Ga-PSMA-11 PET (PSMA-PET)/MRI as a new diagnostic method for primary tumor-node-metastasis staging compared with histology and its impact on therapeutic decisions.

Experimental Design: We investigated 122 patients with PSMA-PET/MRI prior to planned radical prostatectomy (RP). Primary endpoint was the accuracy of PSMA-PET/MRI in tumor staging as compared with staging-relevant histology. In addition, a multidisciplinary team reassessed the initial therapeutic approach to evaluate its impact on the therapeutic management.

Results: PSMA-PET/MRI correctly identified prostate cancer in 119 of 122 patients (97.5%). Eighty-one patients were treated with RP and pelvic lymphadenectomy. The accuracy for T staging was 82.5% [95% confidence interval (CI), 73-90; < 0.001], for T2 stage was 85% (95% CI, 71-94; < 0.001), for T3a stage was 79% (95% CI, 43-85; < 0.001), for T3b stage was 94% (95% CI, 73-100; < 0.001), and for N1 stage was 93% (95% CI, 84-98; < 0.001). PSMA-PET/MRI changed the therapeutic strategy in 28.7% of the patients with either the onset of systemic therapy/radiotherapy ( = 16) or active surveillance ( = 19).

Conclusions: PSMA-PET/MRI can provide an accurate staging of newly diagnosed prostate cancer. In addition, treatment strategies were changed in almost a third of the patients due to the information of this hybrid imaging technique.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0768DOI Listing
December 2018

Analysis of hematological parameters as prognostic markers for toxicity and survival of Radium treatment.

Oncotarget 2018 Mar 5;9(22):16197-16204. Epub 2018 Mar 5.

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

Radium (Ra) has emerged as treatment prolonging survival in patients with metastatic castration-resistant prostate cancer (CRPC). As Ra can cause hematotoxicity (HT), pre-existing hematopoiesis might influence the efficacy of Ra and the rate of hematotoxicity, but as to our knowledge such data has not been published yet, we retrospectively conducted an analysis on patients receiving Ra. 54 patients treated with Ra had a median survival of 67 weeks, which was significantly reduced in patients with pre-existing Hb toxicity (Tox) grade 2 (48 weeks = 0.008) as compared to grade 1 (67 weeks) and normal levels of Hb (not reached); survival in patients with Plt Tox grade 1 was significantly reduced (44 weeks) as compared to normal Plt counts (71 weeks, = 0.033). Patients with impaired hematopoiesis regarding Hb and Plts developed significantly more grade 3 and 4 HT (Hb < 10 g/dl: 42.9% [3/7] vs 10.6% [5/47], < 0.001; Plt < 150 G/L: 28.6% [2/7] vs 6.4% [3/47], = 0.002) and received significantly fewer treatment cycles (Hb <10 g/dl: 5.1 vs 5.8, = 0.04; Plt < 150 G/L: 3.4 vs 5.6, < 0.001). These results imply that pre-existing impaired hematopoiesis, in particular thrombocytopenia and anemia, before Ra therapy, is an important risk factor for worse outcome of treatment with Ra.
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http://dx.doi.org/10.18632/oncotarget.24610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882327PMC
March 2018

Combined [18F]-Fluoroethylcholine PET/CT and 99mTc-Macroaggregated Albumin SPECT/CT Predict Survival in Patients With Intermediate-Stage Hepatocellular Carcinoma.

Clin Nucl Med 2018 Jul;43(7):477-481

Departments of Nuclear Medicine and.

Aim: The aim of this study was to retrospectively analyze the prognostic value of combined Tc-macroaggregated albumin (MAA) SPECT/CT and [F]-fluoroethylcholine (FEC) PET/CT before radioembolization for survival of patients with intermediate-stage hepatocellular carcinoma.

Methods: Twenty-four patients with known hepatocellular carcinoma Barcelona Clinic Liver Cancer stage B were eligible for this analysis. All patients were scheduled for radioembolization and received a pretherapeutic [F]FEC PET/CT scan as well as Tc-MAA SPECT/CT for hepatopulmonary shunting. Laboratory and semiquantitative PET parameters and morphologic and metabolic (intersection) volumes of MAA and FEC were evaluated. Spearman correlation with overall survival, receiver operating curve analyses, univariate and multivariate Cox regression, and Kaplan-Meier-analysis was applied.

Results: All patients (5 female/19 male) are deceased within the observational period. Median survival was 395 days (±51 days; range, 23-1122 days). The percentage of hypervascularized metabolically active tumor volume (vascularized tumor ratio; defined as high MAA and FEC uptake) correlated significantly with survival. Vascularized tumor ratio was a significant predictor in univariate and multivariate analyses (P = 0.026; hazard ratio, 11.65; 95% confidence interval, 1.62-83.73; P = 0.015). Statistical significance was not reached by all other variables in multivariate analysis. Receiver operating curve analysis for 1-year survival revealed an area under the curve of 0.77 (P = 0.024) for vascularized tumor ratio. At a cutoff value of 9%, sensitivity, specificity, and positive and negative prediction were 83%, 67%, and 71% and 80% (P = 0.036). Patients with a higher tumor vascularization had a median survival of 274 ± 80 versus 585 ± 284 days (P = 0.015).

Conclusions: Hepatocellular carcinoma with high vascularization in metabolic active areas as assessed by combined FEC PET/CT and Tc-MAA SPECT/CT represents an unfavorable subgroup with reduced overall survival after radioembolization.
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http://dx.doi.org/10.1097/RLU.0000000000002092DOI Listing
July 2018
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