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Abstract Background The introduction of quantitative SPECT/CT allows more objective assessments of tracer accumulation in SPECT. However standardized uptake values (SUV) still do not play a big role for orthopedic or oncologic questions. With a more reliable normalization, the use of quantitative measures might also be of use for a more objective assessment of lesions. We retrospectively included patients that received a quantitative [99mTc]-HDP bone SPECT/CT scan of the lumbar spine for 4 body weight (BW) categories. Measurements of bone activity (kBq/cc) and bone density in Hounsfield Units (HU) in a standard volume of interest in the femur, the first and the fifth lumbar vertebra of all patients, without active disease within these regions was made. Correlations between tracer uptake and clinical parameters (BW, height, age, gender) were assessed with a multiple regression and based on the model coefficients, a correction formula was calculated and applied. Results The strongest correlation between measured activity in L1 and patient parameters was found for BW (r= -0.64, p

Abstract Background Liver uptake in [68Ga]Ga-PSMA-11 PET is used as an internal reference in addition to clinical parameters to select patients for [177Lu]Lu-PSMA-617 radioligand therapy (RLT). Due to increased demand, [68Ga]Ga-PSMA-11 was replaced by [18F]F-PSMA-1007, a more lipophilic tracer with different biodistribution and splenic uptake was suggested as a new internal reference. We compared the intra-patient tracer distribution between [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007. Methods Fifty patients who underwent PET examinations in two centers with both [18F]F-PSMA-1007 and [68Ga]Ga-PSMA-11 within one year were included. Mean standardized uptake values (SUVmean) were obtained for liver, spleen, salivary glands, blood pool, and bone. Primary tumor, local recurrence, lymph node, bone or visceral metastasis were also assessed for intra- and inter-individual comparison. Results Liver SUVmean was significantly higher with [18F]F-PSMA-1007 (11.7 ± 3.9) compared to [68Ga]Ga-PSMA-11 (5.4 ± 1.7, p

Abstract Background Endometriosis is characterized by the ectopic occurrence of endometrial tissue. Though considered benign, endometriotic lesions possess tumor-like properties such as tissue invasion and remodeling of the extracellular matrix. One major clinical hurdle concerning endometriosis is its diagnosis. The diagnostic modalities ultrasound and MRI are often unable to detect all lesions, and a clear correlation between imaging and clinical symptoms is still controversial. Therefore, it was our aim to identify a potential target to image active endometriotic lesions. Results For our studies, we employed the preclinical radiotracer [111In]In-FnBPA5, which specifically binds to relaxed fibronectin–an extracellular matrix protein with key functions in homeostasis that has been implicated in the pathogenesis of diseases such as cancer and fibrosis. We employed this tracer in biodistribution as well as SPECT/CT studies in mice and conducted immunohistochemical stainings on mouse uterine tissue as well as on patient-derived endometriosis tissue. In biodistribution and SPECT/CT studies using the radiotracer [111In]In-FnBPA5, we found that radiotracer uptake in the myometrium varies with the estrous cycle of the mouse, leading to higher uptake of [111In]In-FnBPA5 during estrogen-dependent phases, which indicates an increased abundance of relaxed fibronectin when estrogen levels are high. Finally, immunohistochemical analysis of patient samples demonstrated that there is preferential relaxation of fibronectin in the proximity of the endometriotic stroma. Conclusion Estrous cycle stages characterized by high estrogen levels result in a higher abundance of relaxed fibronectin in the murine myometrium. This finding together with a first proof-of-concept study employing human endometriosis tissues suggests that relaxed fibronectin could be a potential target for the development of a diagnostic radiotracer targeting endometriotic lesions. With [111In]In-FnBPA5, the matching targeting molecule is in preclinical development.

There are few randomized trials to evaluate the use of PSMA-PET in the planning of post-prostatectomy radiotherapy. There are two unresolved questions 1) should we increase the dose to lesions visible on PSMA-PET 2) can we reduce dose in the case of a negative PSMA-PET. In this review, we summarize and discuss the available evidence in the literature. We found that in general, there seems to be an advantage for dose-increase, but ta large recent study from the pre-PSMA era didn’t show an advantage for dose escalation. Retrospective studies have shown that conventional doses to PSMA-PET-positive lesions seem sufficient. On the other hand, in the case of a negative PSMA-PET, there is no evidence that dose-reduction is possible. In the future, the combination of PSMA-PET with genomic classifiers could help in better identify patients who might benefit from either dose- de-or -increase. We further need to identify intraindividual references to help identify lesions with higher aggressiveness.

For prostate cancer (PCa) biochemical recurrence (BCR), the primarily suggested imaging technique by the European Association of Urology (EAU) guidelines is prostate-specific membrane antigen (PSMA) positron emission tomography/computer tomography (PET/CT). Indeed, the increased detection rate of PSMA PET/CT for early BCR has led to a fast and wide acceptance of this novel technology. However, PCa is a very heterogeneous disease, not always easily assessable with the highly specific PSMA PET with around 10% of cases occuring without PSMA expression. In this paper, we present the case of a patient with PCa BCR that resulted negative on [68Ga]Ga-PSMA-11 PET/CT, but positive on [18F]Fluoromethylcholine (Choline) PET/CT.

The management of prostate cancer is undergoing rapid changes in all disease settings. Novel imaging tools for diagnosis have been introduced, and the treatment of high-risk localized, locally advanced and metastatic disease has changed considerably in recent years. From clinical and health-economic perspectives, a rational and optimal use of the available options is of the utmost importance. While international guidelines list relevant pivotal trials and give recommendations for a variety of clinical scenarios, there is much room for interpretation, and several important questions remain highly debated. The goal of developing a national consensus on the use of these novel diagnostic and therapeutic strategies in order to improve disease management and eventually patient outcomes has prompted a Swiss consensus meeting. Experts from several specialties, including urology, medical oncology, radiation oncology, pathology and nuclear medicine, discussed and voted on questions of the current most important areas of uncertainty, including the staging and treatment of high-risk localized disease, treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and use of new options to treat metastatic castration-resistant prostate cancer (mCRPC).

Abstract Background Magnetic resonance imaging (MRI) is recommended by the European Urology Association guidelines as the standard modality for imaging-guided biopsy. Recently positron emission tomography with prostate-specific membrane antigen (PSMA PET) has shown promising results as a tool for this purpose. The aim of this study was to compare the accuracy of positron emission tomography with prostate-specific membrane antigen/magnetic resonance imaging (PET/MRI) using the gallium-labeled prostate-specific membrane antigen (68Ga-PSMA-11) and multiparametric MRI (mpMRI) for pre-biopsy tumour localization and interreader agreement for visual and semiquantitative analysis. Semiquantitative parameters included apparent diffusion coefficient (ADC) and maximum lesion diameter for mpMRI and standardized uptake value (SUVmax) and PSMA-positive volume (PSMAvol) for PSMA PET/MRI. Results Sensitivity and specificity were 61.4% and 92.9% for mpMRI and 66.7% and 92.9% for PSMA PET/MRI for reader one, respectively. RPE was available in 23 patients and 41 of 47 quadrants with discrepant findings. Based on RPE results, the specificity for both imaging modalities increased to 98% and 99%, and the sensitivity improved to 63.9% and 72.1% for mpMRI and PSMA PET/MRI, respectively. Both modalities yielded a substantial interreader agreement for primary tumour localization (mpMRI kappa = 0.65 (0.52–0.79), PSMA PET/MRI kappa = 0.73 (0.61–0.84)). ICC for SUVmax, PSMAvol and lesion diameter were almost perfect (≥ 0.90) while for ADC it was only moderate (ICC = 0.54 (0.04–0.78)). ADC and lesion diameter did not correlate significantly with Gleason score (ρ = 0.26 and ρ = 0.16) while SUVmax and PSMAvol did (ρ = − 0.474 and ρ = − 0.468). Conclusions PSMA PET/MRI has similar accuracy and reliability to mpMRI regarding primary prostate cancer (PCa) localization. In our cohort, semiquantitative parameters from PSMA PET/MRI correlated with tumour grade and were more reliable than the ones from mpMRI.

Abstract In prostate cancer (PCa), the use of new radiopharmaceuticals has improved the accuracy of diagnosis and staging, refined surveillance strategies, and introduced specific and personalized radioreceptor therapies. Nuclear medicine, therefore, holds great promise for improving the quality of life of PCa patients, through managing and processing a vast amount of molecular imaging data and beyond, using a multi-omics approach and improving patients’ risk-stratification for tailored medicine. Artificial intelligence (AI) and radiomics may allow clinicians to improve the overall efficiency and accuracy of using these “big data” in both the diagnostic and theragnostic field: from technical aspects (such as semi-automatization of tumor segmentation, image reconstruction, and interpretation) to clinical outcomes, improving a deeper understanding of the molecular environment of PCa, refining personalized treatment strategies, and increasing the ability to predict the outcome. This systematic review aims to describe the current literature on AI and radiomics applied to molecular imaging of prostate cancer.

Abstract Objectives PSMA PET/MRI showed the potential to increase the sensitivity for extraprostatic disease (EPD) assessment over mpMRI; however, the interreader variability for EPD is still high. Therefore, we aimed to assess whether quantitative PSMA and mpMRI imaging parameters could yield a more robust EPD prediction. Methods We retrospectively evaluated PCa patients who underwent staging mpMRI and [68Ga]PSMA-PET, followed by radical prostatectomy at our institution between 01.02.2016 and 31.07.2019. Fifty-eight cases with PET/MRI and 15 cases with PET/CT were identified. EPD was determined on histopathology and correlated with quantitative PSMA and mpMRI parameters assessed by two readers: ADC (mm2/1000 s), longest capsular contact (LCC, mm), tumor volume (cm3), PSMA-SUVmax and volume-based parameters using a fixed threshold at SUV > 4 to delineate PSMAtotal (g/ml) and PSMAvol (cm3). The t test was used to compare means, Pearson’s test for categorical correlation, and ROC curve to determine the best cutoff. Interclass correlation (ICC) was performed for interreader agreement (95% CI). Results Seventy-three patients were included (64.5 ± 6.0 years; PSA 14.4 ± 17.1 ng/ml), and 31 had EPD (42.5%). From mpMRI, only LCC reached significance (p = 0.005), while both volume-based PET parameters PSMAtotal and PSMAvol were significantly associated with EPD (p = 0.008 and p = 0.004, respectively). On ROC analysis, LCC, PSMAtotal, and PSMAvol reached an AUC of 0.712 (p = 0.002), 0.709 (p = 0.002), and 0.718 (p = 0.002), respectively. ICC was moderate–good for LCC 0.727 (0.565–0.828) and excellent for PSMAtotal and PSMAvol with 0.944 (0.990–0.996) and 0.985 (0.976–0.991), respectively. Conclusions Quantitative PSMA parameters have a similar potential as mpMRI LCC to predict EPD of PCa, with a significantly higher interreader agreement.

In medical imaging, artificial intelligence (AI) can be described as the ability of a system to accurately interpret and learn from external data, acquiring knowledge to achieve specific goals and tasks through flexible adaptation. This new technology holds great promise for more personalized approaches in the future. The aim of this review is to describe the current literature on AI applied to molecular imaging for prostate cancer (PC). A comprehensive search strategy was used based on SCOPUS and PubMed databases up to October 2020. From all studies published in English, we selected the most relevant that evaluated insights of AI in the assessment of PC through positron emission tomography (PET). AI may improve PC’s patient care in many different fields, from the semi-automatization of tumor segmentation, through the technical aspect of image preparation, interpretation, the calculation of additional factors based on data obtained during scanning, to prognostic prediction and risk-group selection. The implementation of AI algorithms in PC molecular imaging can improve and ease the diagnostic, predictive process, and global patient care. Construction of standardized and large databases with complex information (clinical, imaging, laboratory) will be the essential step to creating and training automated diagnostic/prognostic models that can help clinicians make unbiased and faster decisions aimed at personalized healthcare.

Abstract Infective native aortic aneurysms (INAA) are aneurysms arising from infection of the aortic wall. Treatment is demanding with 5-year survival rates between 53 and 55%. The aim of our study was to evaluate the usefulness of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in the long-term monitoring of patients with proven INAA. Fifty-three PET/CT were performed in 15 patients with INAA in this single-center retrospective cohort study and retrospective analysis of prospectively collected Vascular Graft Cohort Study (VASGRA) data. Median metabolic activity (as measured by maximum standardized uptake value, SUVmax) of the aneurysms at the initial PET/CT was high (6.8 (IQR 5.7–21.8)), and lower at the last PET/CT prior to the end of antimicrobial therapy (3.9 (IQR 2.7–6.8); n = 11) as well as in the first PET/CT after the end of the treatment (3.9 (IQR 3.0–4.4);n = 6). Compared to the course of C-reactive protein alone, PET/CT provided different (> 20% difference in trend) or altering (opposed trend) information on the course of disease in at least 14 comparisons (56%) in 11 patients (73%). The one-year and five-year freedom from all-cause lethality was 92% (95% confidence interval 57%-99%). As compared to the course of C-reactive protein, PET/CT provides different and occasionally altering information in therapy control of INAA.

Abstract Purpose Prostate-specific membrane antigen positron emission tomography (PSMA-PET) has shown promise for detecting nodal and distant prostate cancer (PCa) metastases. However, its performance for local tumor staging is not as well established. The purpose of this study was to review the diagnostic performance of PSMA-PET for determining seminal vesical invasion (SVI) and extraprostatic extension (EPE). Methods Pubmed and Embase databases were searched until January 12, 2020. Studies assessing accuracy of PSMA-PET in determining SVI and EPE were included. Study quality was evaluated with the revised Quality Assessment of Diagnostic Accuracy Studies-2 tool. Pooled sensitivity and specificity were calculated using hierarchical summary receiver operating characteristics modeling. Heterogeneity was explored using meta-regression analyses for anatomical imaging component (MRI vs CT) and by testing for a threshold effect. Results Twelve studies (615 patients) were included. Pooled sensitivity and specificity were 0.68 (95% CI 0.53-0.81) and 0.94 (95% CI 0.90-0.96) for SVI and 0.72 (95% CI 0.56-0.84) and 0.87 (95% CI 0.72-0.94) for EPE. Meta-regression analyses showed that for SVI, PET/MRI demonstrated greater sensitivity than PET/CT (0.87 [95% CI 0.75-0.98] vs 0.60 [95% CI 0.47-0.74]; p = 0.02 for joint model) while specificity was comparable (0.91 [95% CI 0.84-0.97] vs. 0.96 [95% CI 0.93-0.99]) but not for EPE (p = 0.08). A threshold effect was present for studies assessing EPE (correlation coefficient = 0.563 [95% CI, −0.234-0.908] between sensitivity and false-positive rate). Conclusion PSMA-PET has moderate sensitivity and excellent specificity for assessing local tumor extent in patients with PCa. PET/MRI showed potential for greater sensitivity than PET/CT in assessing SVI.

Abstract Background The folate receptor alpha (FRα) is an interesting target for imaging and therapy of different cancers. We present the first in-human radiation dosimetry and radiation safety results acquired within a prospective, multicentric trial (NCT03242993) evaluating the 18F-AzaFol (3′-aza-2′-[18F]fluorofolic acid) as the first clinically assessed PET tracer targeting the FRα. Material and methods Six eligible patients presented a histologically confirmed adenocarcinoma of the lung with measurable lesions (≥ 10 mm according to RECIST 1.1). TOF-PET images were acquired at 3, 11, 18, 30, 40, 50, and 60 min after the intravenous injection of 327 MBq (range 299–399 MBq) of 18F-AzaFol to establish dosimetry. Organ absorbed doses (AD), tumor AD, and patient effective doses (E) were assessed using the OLINDA/EXM v.2.0 software and compared with pre-clinical results. Results No serious related adverse events were observed. The highest AD were in the liver, the kidneys, the urinary bladder, and the spleen (51.9, 45.8, 39.1, and 35.4 μGy/MBq, respectively). Estimated patient and gender-averaged E were 18.0 ± 2.6 and 19.7 ± 1.4 μSv/MBq, respectively. E in-human exceeded the value of 14.0 μSv/MBq extrapolated from pre-clinical data. Average tumor AD was 34.8 μGy/MBq (range 13.6–60.5 μGy/MBq). Conclusions 18F-Azafol is a PET agent with favorable dosimetric properties and a reasonable radiation dose burden for patients which merits further evaluation to assess its performance. Trial registration ClinicalTrial.gov , NCT03242993 , posted on August 8, 2017

Abstract Background PET/MRI has a high potential in oncology imaging, especially for tumor indications where high soft tissue contrast is crucial such as genitourinary tumors. One of the challenges for PET/MRI acquisition is handling of metal implants. In addition to conventional methods, more innovative techniques have been developed to reduce artifacts caused by those implants such as the selective multiacquisition variable-image combination (MAVRIC-SL). The aim of this study is to perform a quantitative and qualitative assessment of metal artifact reduction in 68Ga-PSMA-11 PET/MRI for prostate cancer patients with hip joint replacement using a selective MAVRIC-SL sequence for the whole pelvis. Methods We retrospectively analyzed data of 20 men with 37 metal hip implants diagnosed with PCA, staged or restaged by 68Ga-PSMA-11 PET/MRI from June 2016 to December 2017. Each signal cancellation per side or metal implant was analyzed on the reference sequence LAVA-FLEX, as well as T1-weighted fast spin echo (T1w-FSE) sequence and MAVRIC-SL. Two independent reviewers reported on a four-point scale whether abnormal pelvic 68Ga-PSMA-11 uptake could be assigned to an anatomical structure in the tested sequences. Results The smallest averaged signal void was observed on MAVRIC-SL sequences with a mean artifact size of 26.17 cm2 (range 12.63 to 42.93 cm2, p < 0.001). The best image quality regarding anatomical assignment of pathological PSMA uptakes in the pelvis by two independent readers was noted for MAVRIC-SL sequences, followed by T1w-FSE with excellent interreader agreement. Conclusions MAVRIC-SL sequence allows better image quality in the surrounding of hip implants by reducing MR signal voids and increasing so the accuracy of anatomical assignment of pathological 68Ga-PSMA-11 uptake in the pelvis over LAVA-FLEX and T1w-FSE sequences.

Abstract Background A substantial number of patients will develop further biochemical progression after radical prostatectomy (RP) and salvage radiotherapy (sRT). Recently published data using prostate-specific membrane antigen ligand positron emission tomography (PSMA - PET) for re-staging suggest that those recurrences are often located outside the prostate fossa and most of the patients have a limited number of metastases, making them amenable to metastasis-directed treatment (MDT). Methods We analyzed 78 patients with biochemical progression after RP and sRT from a retrospective European multicenter database and assessed the biochemical recurrence-free survival (bRFS; PSA

Prostate cancer (PCa) is the most frequently diagnosed cancer worldwide and the second most common cause of cancer-related deaths among men. Progress in molecular imaging has magnified its clinical management; however, an unmet clinical need involves the identification of new imaging biomarkers that complement the gold standard of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) in cases of clinically significant PCa that do not express PSMA. Fibroblast activation protein (FAP) is a type II transmembrane serine overexpressed in many solid cancers that can be imaged through quinoline-based PET tracers derived from an FAP inhibitor (FAPi). Preliminary results of FAPi application in PCa (in PSMA-negative lesions, and in comparison with fluorodeoxyglucose—FDG) are now available in the literature. FAP-targeting ligands for PCa are not limited to detection, but could also include therapeutic applications. In this preliminary review, we provide an overview of the clinical applications of FAPi ligands in PCa, summarising the main results and highlighting contemporary strengths and limitations.

Abstract Background Dutasteride has been shown to increase expression of the prostate‐specific membrane antigen (PSMA) in prostate cancer cells in previous in vitro studies. This 5‐alpha‐reductase inhibitor is commonly used for the treatment of symptomatic benign prostatic enlargement. The modulation of PSMA expression might affect PSMA‐based prostate cancer imaging and therapy. Aim The purpose of this work was to further analyze concentration‐dependent effects of Dutasteride on PSMA expression in a mouse xenograft model. Methods and results Four groups of mice bearing LNCaP xenografts were treated for 14 days with daily intraperitoneal injections of either vehicle control or different concentrations of Dutasteride (0.1, 1, 10 mg/kg). Total expression of PSMA, androgen receptor (AR), and caspase‐3 protein was analyzed using immunoblotting (WES). In addition, PSMA, cleaved caspase‐3 and Ki‐67 expression was assessed and quantified by immunohistochemistry. Tumor size was measured by caliper on day 7 and 14, tumor weight was assessed following tissue harvesting. The mean PSMA protein expression in mice increased significantly after treatment with 1 mg/kg (10‐fold) or 10 mg/kg (sixfold) of Dutasteride compared to vehicle control. The mean fluorescence intensity significantly increased by daily injections of 0.1 mg/kg Dutasteride (1.6‐fold) as well as 1 and 10 mg/kg Dutasteride (twofold). While the reduction in tumor volume following treatment with high concentrations of 10 mg/kg Dutasteride was nonsignificant, no changes in AR, caspase‐3, cleaved caspase‐3, and Ki‐67 expression were observed. Conclusion Short‐term Dutasteride treatments with concentrations of 1 and 10 mg/kg significantly increase the total PSMA protein expression in a mouse LNCaP xenograft model. PSMA fluorescence intensity increases significantly even using lower daily concentrations of 0.1 mg/kg Dutasteride. Further investigations are needed to elucidate the impact of Dutasteride treatment on PSMA expression in patients.

BackgroundStatins are commonly prescribed for primary and secondary prevention of atherosclerotic disease. They reduce cholesterol biosynthesis by inhibiting hydroxymethylglutaryl-coenzyme A-reductase (HMG-CoA-reductase) and therefore mevalonate synthesis. Several studies reported a small, but significant increase in the diagnosis of diabetes mellitus with statin treatment. The molecular mechanisms behind this adverse effect are not yet fully understood. Brown adipose tissue (BAT), which plays a role in thermogenesis, has been associated with a reduced risk of insulin resistance. Statins inhibit adipose tissue browning and have been negatively linked to the presence of BAT in humans. We therefore speculated that inhibition of BAT by statins contributes to increased insulin resistance in humans.MethodsA prospective study was conducted in 17 young, healthy men. After screening whether significant cold-induced thermogenesis (CIT) was present, participants underwent glucose tolerance testing (oGTT) and assessment of BAT activity by FDG-PET/MRI after cold-exposure and treatment with a β3-agonist. Fluvastatin 2x40mg per day was then administered for two weeks and oGTT and FDG-PET/MRI were repeated.ResultsTwo weeks of fluvastatin treatment led to a significant increase in glucose area under the curve (AUC) during oGTT (p=0.02), reduction in total cholesterol and LDL cholesterol (both p

Abstract Background Positron emission tomography (PET) is increasingly applied for in vivo brown adipose tissue (BAT) research in healthy volunteers. To limit the radiation exposure, the injected 18F-FDG tracer dose should be as low as possible. With simultaneous PET/MR imaging, the radiation exposure due to computed tomography (CT) can be avoided, but more importantly, the PET acquisition time can often be increased to match the more extensive magnetic resonance (MR) imaging protocol. The potential gain in detected coincidence counts, due to the longer acquisition time, can then be applied to decrease the injected tracer dose. The aim of this study was to investigate the minimal 18F-FDG dose for a 10-min time-of-flight (TOF) PET/MR acquisition that would still allow accurate quantification of supraclavicular BAT volume and activity. Methods Twenty datasets from 13 volunteers were retrospectively included from a prospective clinical study. PET emission datasets were modified to simulate step-wise reductions of the original 75 MBq injected dose. The resulting PET images were visually and quantitatively assessed and compared to a 4-min reference scan. For the visual assessment, the image quality and artifacts were scored using a 5-point and a 3-point Likert scale. For the quantitative analysis, image noise and artifacts, BAT metabolic activity, BAT metabolic volume (BMV), and total BAT glycolysis (TBG) were investigated. Results The visual assessment showed still good image quality for the 35%, 30%, and 25% activity reconstructions with no artifacts. Quantitatively, the background noise was similar to the reference for the 35% and 30% activity reconstructions and the artifacts started to increase significantly in the 25% and lower activity reconstructions. There was no significant difference in supraclavicular BAT metabolic activity, BMV, and TBG between the reference and the 35% to 20% activity reconstructions. Conclusions This study indicates that when the PET acquisition time is matched to the 10-min MRI protocol, the injected 18F-FDG tracer dose can be reduced to approximately 19 MBq (25%) while maintaining image quality and accurate supraclavicular BAT quantification. This could decrease the effective dose from 1.4 mSv to 0.36 mSv.

Thyroid hormone (TH) is an important regulator of mammalian metabolism and facilitates cold induced thermogenesis (CIT) in brown adipose tissue (BAT). Profound hypothyroidism or hyperthyroidism lead to alterations in BAT function and CIT. In euthyroid humans the inter-individual variation of thyroid hormones is relatively large. Therefore, we investigated whether levels of free thyroxine (T4) or free triiodothyronine (T3) are positively associated with CIT in euthyroid individuals. We performed an observational study in 79 healthy, euthyroid volunteers (mean age 25.6 years, mean BMI 23.0 kg · m-2). Resting energy expenditure (REE) was measured by indirect calorimetry during warm conditions (EEwarm) and after a mild cold stimulus of two hours (EEcold). CIT was calculated as the difference between EEcold and EEwarm. BAT activity was assessed by 18F-FDG-PET after a mild cold stimulus in a subset of 26 participants. EEcold and CIT were significantly related to levels of free T4 (R2 = 0.11, p=0.0025 and R2 = 0.13, p=0.0011, respectively) but not to free T3 and TSH. Cold induced BAT activity was also associated with levels of free T4 (R2 = 0.21, p=0.018). CIT was approximately fourfold higher in participants in the highest tertile of free T4 as compared to the lowest tertile. Additionally, free T4 was weakly, albeit significantly associated with outdoor temperature seven days prior to the respective study visit (R2 = 0.06, p=0.037). These finding suggests that variations in thyroid hormone levels within the euthyroid range are related to the capability to adapt to cool temperatures and affect energy balance.

Background: Investigation of the clinical feasibility of dynamic whole-body (WB) [18F]FDG PET, including standardized uptake value (SUV), rate of irreversible uptake (Ki), and apparent distribution volume (Vd) in physiologic tissues, and comparison between inflammatory/infectious and cancer lesions. Methods: Twenty-four patients were prospectively included to undergo dynamic WB [18F]FDG PET/CT for clinically indicated re-/staging of oncological diseases. Parametric maps of Ki and Vd were generated using Patlak analysis alongside SUV images. Maximum parameter values (SUVmax, Kimax, and Vdmax) were measured in liver parenchyma and in malignant or inflammatory/infectious lesions. Lesion-to-background ratios (LBRs) were calculated by dividing the measurements by their respective mean in the liver tissue. Results: Seventy-seven clinical target lesions were identified, 60 malignant and 17 inflammatory/infectious. Kimax was significantly higher in cancer than in inflammatory/infections lesions (3.0 vs. 2.0, p = 0.002) while LBRs of SUVmax, Kimax, and Vdmax did not differ significantly between the etiologies: LBR (SUVmax) 3.3 vs. 2.9, p = 0.06; LBR (Kimax) 5.0 vs. 4.4, p = 0.05, LBR (Vdmax) 1.1 vs. 1.0, p = 0.18). LBR of inflammatory/infectious and cancer lesions was higher in Kimax than in SUVmax (4.5 vs. 3.2, p < 0.001). LBRs of Kimax and SUVmax showed a strong correlation (Spearman’s rho = 0.83, p < 0.001). Conclusions: Dynamic WB [18F]FDG PET/CT is feasible in a clinical setting. LBRs of Kimax were higher than SUVmax. Kimax was higher in malignant than in inflammatory/infectious lesions but demonstrated a large overlap between the etiologies.

The aim of this study was to investigate the application of [18F]FDG PET/CT images-based textural features analysis to propose radiomics models able to early predict disease progression (PD) and survival outcome in metastatic colorectal cancer (MCC) patients after first adjuvant therapy. For this purpose, 52 MCC patients who underwent [18F]FDGPET/CT during the disease restaging process after the first adjuvant therapy were analyzed. Follow-up data were recorded for a minimum of 12 months after PET/CT. Radiomics features from each avid lesion in PET and low-dose CT images were extracted. A hybrid descriptive-inferential method and the discriminant analysis (DA) were used for feature selection and for predictive model implementation, respectively. The performance of the features in predicting PD was performed for per-lesion analysis, per-patient analysis, and liver lesions analysis. All lesions were again considered to assess the diagnostic performance of the features in discriminating liver lesions. In predicting PD in the whole group of patients, on PET features radiomics analysis, among per-lesion analysis, only the GLZLM_GLNU feature was selected, while three features were selected from PET/CT images data set. The same features resulted more accurately by associating CT features with PET features (AUROC 65.22%). In per-patient analysis, three features for stand-alone PET images and one feature (i.e., HUKurtosis) for the PET/CT data set were selected. Focusing on liver metastasis, in per-lesion analysis, the same analysis recognized one PET feature (GLZLM_GLNU) from PET images and three features from PET/CT data set. Similarly, in liver lesions per-patient analysis, we found three PET features and a PET/CT feature (HUKurtosis). In discrimination of liver metastasis from the rest of the other lesions, optimal results of stand-alone PET imaging were found for one feature (SUVbwmin; AUROC 88.91%) and two features for merged PET/CT features analysis (AUROC 95.33%). In conclusion, our machine learning model on restaging [18F]FDGPET/CT was demonstrated to be feasible and potentially useful in the predictive evaluation of disease progression in MCC.

Abstract Background The aim of this study was to evaluate and compare PET image reconstruction algorithms on novel digital silicon photomultiplier PET/CT in patients with newly diagnosed and histopathologically confirmed lung cancer. A total of 45 patients undergoing 18F-FDG PET/CT for initial lung cancer staging were included. PET images were reconstructed using ordered subset expectation maximization (OSEM) with time-of-flight and point spread function modelling as well as Bayesian penalized likelihood reconstruction algorithm (BSREM) with different β-values yielding a total of 7 datasets per patient. Subjective and objective image assessment with all image datasets was carried out, including subgroup analyses for patients with high dose (> 2.0 MBq/kg) and low dose (≤ 2.0 MBq/kg) of 18F-FDG injection regimen. Results Subjective image quality ratings were significantly different among all different reconstruction algorithms as well as among BSREM using different β-values only (both p < 0.001). BSREM with a β-value of 600 was assigned the highest score for general image quality, image sharpness, and lesion conspicuity. BSREM reconstructions resulted in higher SUVmax of lung tumors compared to OSEM of up to + 28.0% (p < 0.001). BSREM reconstruction resulted in higher signal-/ and contrast-to-background ratios of lung tumor and higher signal-/ and contrast-to-noise ratio compared to OSEM up to a β-value of 800. Lower β-values (BSREM450) resulted in the best image quality for high dose 18F-FDG injections, whereas higher β-values (BSREM600) lead to the best image quality in low dose 18F-FDG PET/CT (p < 0.05). Conclusions BSREM reconstruction algorithm used in digital detector PET leads to significant increases of lung tumor SUVmax, signal-to-background ratio, and signal-to-noise ratio, which translates into a higher image quality, tumor conspicuity, and image sharpness.

Abstract Background In contrast to ordered subset expectation maximization (OSEM), block sequential regularized expectation maximization (BSREM) positron emission tomography (PET) reconstruction algorithms can run until full convergence while controlling image quality and noise. Recent studies with BSREM and 18F-FDG PET reported higher signal-to-noise ratios and higher standardized uptake values (SUV). In this study, we investigate the optimal regularization parameter (β) for clinical 68Ga-PSMA PET/MR reconstructions in the pelvic region applying time-of-flight (TOF) BSREM in comparison to TOF OSEM. Two-minute emission data from the pelvic region of 25 patients who underwent 68Ga-PSMA PET/MR were retrospectively reconstructed. Reference OSEM reconstructions had 28 subsets and 2 iterations. BSREM reconstructions were performed with 15 β values between 150 and 1200. Regions of interest (ROIs) were drawn around lesions and in uniform background. Background SUVmean (average) and SUVstd (standard deviation), and lesion SUVmax (average of 5 hottest voxels) were calculated. Differences were analyzed using the Wilcoxon matched pairs signed-rank test. Results A total of 40 lesions were identified in the pelvic region. Background noise (SUVstd) and lesions SUVmax decreased with increasing β. Image reconstructions with β values lower than 400 have higher (p

Abstract Background The existence of abscopal effects has been suggested already a long time ago, but only recently with the advent of immune checkpoint inhibition in clinical oncology and modern imaging techniques has it become possible to directly observe such effects in patients. They have been well described in patients with malignant melanoma being treated with immune-checkpoint inhibitors and stereotactic radiotherapy, but experience in other malignancies is very limited. Case presentation Here, we describe a case of a patient with metastatic non-small cell lung cancer, who experienced a complete response secondary to an abscopal effect on treatment with anti-PD-1 therapy and stereotactic body radiotherapy to some of the involved sites. Conclusions Our case reports confirms the existence of abscopal effects in NSCLC and suggests synergism between immune-checkpoint inhibition and local ablative RT. We suggest that this approach is now further studied in prospective clinical trials on oligo-metastatic or oligo-progressing NSCLC.

Abstract Background Accurate attenuation correction (AC) is an inherent problem of positron emission tomography magnetic resonance imaging (PET/MRI) systems. Simulation studies showed that time-of-flight (TOF) detectors can reduce PET quantification errors in MRI-based AC. However, its impact on lesion detection in a clinical setting with 18F-choline has not yet been evaluated. Therefore, we compared TOF and non-TOF 18F-choline PET for absolute and relative difference in standard uptake values (SUV) and investigated the detection rate of metastases in prostate cancer patients. Results Non-TOF SUV was significantly lower compared to TOF in all osseous structures, except the skull, in primary lesions of the prostate, and in pelvic nodal and osseous metastasis. Concerning lymph node metastases, both experienced readers detected 16/19 (84%) on TOF PET, whereas on non-TOF PET readers 1 and 2 detected 11 (58%), and 14 (73%), respectively. With TOF PET readers 1 and 2 detected 14/15 (93%) and 11/15 (73%) bone metastases, respectively, whereas detection rate with non-TOF PET was 73% (11/15) for reader 1 and 53% (8/15) for reader 2. The interreader agreement was good for osseous metastasis detection on TOF (kappa 0.636, 95% confidence interval [CI] 0.453–0.810) and moderate on non-TOF (kappa = 0.600, CI 0.438–0.780). Conclusion TOF reconstruction for 18F-choline PET/MRI shows higher SUV measurements compared to non-TOF reconstructions in physiological osseous structures as well as pelvic malignancies. Our results suggest that addition of TOF information has a positive impact on lesion detection rate for lymph node and bone metastasis in prostate cancer patients.

BackgroundBrown adipose tissue (BAT) is a specialized form of adipose tissue, able to increase energy expenditure by heat generation in response to various stimuli. Recently, its pathological activation has been implicated in the pathogenesis of cancer cachexia. To establish a causal relationship, we retrospectively investigated the longitudinal changes in BAT and cancer in a large FDG-PET/CT cohort.MethodsWe retrospectively analyzed 13 461 FDG-PET/CT examinations of n = 8 409 patients at our institution from the winter months of 2007-2015. We graded the activation strength of BAT based on the anatomical location of the most caudally activated BAT depot into three tiers, and the stage of the cancer into five general grades. We validated the cancer grading by an interreader analysis and correlation with histopathological stage. Ambient temperature data (seven-day average before the examination) was obtained from a meteorological station close to the hospital. Changes of BAT, cancer, body mass index (BMI) and temperature between the different examinations were examined with Spearman's test and a mixed linear model for correlation, and with a causal inference algorithm for causality.ResultsWe found n = 283 patients with at least two examinations and active BAT in at least one of them. There was no significant interaction between the changes in BAT activation, cancer burden or BMI. Temperature changes exhibited a strong negative correlation with BAT activity (ϱ = -0.57, pConclusionsOur data did not confirm the hypothesis that BAT plays a major role in cancer-mediated weight loss. Temperature changes are the main driver of incidental BAT activity on FDG-PET scans.

Background Increasing evidence suggests a psychosomatic link between neural systems and the heart. In light of the growing burden of ischemic cardiovascular disease across the globe, a better understanding of heart‐brain interactions and their implications for cardiovascular treatment strategies is needed. Thus, we sought to investigate the interaction between myocardial injury and metabolic alterations in central neural areas in patients with suspected or known coronary artery disease. Methods and Results The association between resting metabolic activity in distinct neural structures and cardiac function was analyzed in 302 patients (aged 66.8±10.2 years; 70.9% men) undergoing fluor‐18‐deoxyglucose positron emission tomography and 99mTc‐tetrofosmin single‐photon emission computed tomography myocardial perfusion imaging. There was evidence for reduction of callosal, caudate, and brainstem fluor‐18‐deoxyglucose uptake in patients with impaired left ventricular ejection fraction (

Introduction: The role of positron-emission tomography/computed-tomography (PET/CT) in the management of sarcomas and as a prognostic tool has been studied. However, it remains unclear which metric is the most useful. We aimed to investigate if volume-based PET metrics (Tumor volume (TV) and total lesions glycolysis (TLG)) are superior to maximal standardized uptake value (SUVmax) and other metrics in predicting survival of patients with soft tissue and bone sarcomas. Materials and Methods: In this retrospective cohort study, we screened over 52′000 PET/CT scans to identify patients diagnosed with either soft tissue, bone or Ewing sarcoma and had a staging scan at our institution before initial therapy. We used a Wilcoxon signed-rank to assess which PET/CT metric was associated with survival in different patient subgroups. Receiver-Operating-Characteristic curve analysis was used to calculate cutoff values. Results: We identified a total of 88 patients with soft tissue (51), bone (26) or Ewing (11) sarcoma. Median age at presentation was 40 years (Range: 9–86 years). High SUVmax was most significantly associated with short survival (defined as p = 0.001). Similar results were seen in Ewing sarcoma (with a median and range of SUVmax 12.1 (7.6–14.7) in short (n = 6) and 3.7 (3.5–5.5) in long survival (n = 5), with (p = 0.017). However, no PET-specific metric but tumor-volume was significantly associated (p = 0.035) with survival in primary bone sarcomas (with a median and range of 217 cm3 (186–349) in short survival (n = 4) and 60 cm3 (22–104) in long survival (n = 19), with (p = 0.035). TLG was significantly inversely associated with long survival only in Ewing sarcoma (p = 0.03). Discussion: Our analysis shows that the outcome of soft tissue, bone and Ewing sarcomas is associated with different PET/CT metrics. We could not confirm the previously suggested superiority of volume-based metrics in soft tissue sarcomas, for which we found SUVmax to remain the best prognostic factor. However, bone sarcomas should probably be evaluated with tumor volume rather than FDG PET activity.

Background: The use of 18F-2-Fluor-2-desoxy-D-glucose Positron Emission Tomography/Computed Tomography FDG-PET/CT in clinical routine for staging, treatment response monitoring and post treatment surveillance in metastatic melanoma patients has noticeably increased due to significant improvement of the overall survival rate in melanoma patients. However, determining the dignity of the findings with increased metabolic activity on FDG-PET/CT can be sometimes challenging and may need further investigation. Purpose: We aimed to investigate the malignancy rate of indeterminate findings on FDG-PET/CT in metastatic cutaneous melanoma patients. Methods: This single-center retrospective study included cutaneous melanoma patients who underwent FDG-PET/CT in clinical routine between 2015 and 2017 with findings reported as indeterminate and therefore requiring further evaluation. The dignity of the included findings was determined by subsequent imaging and, if required, additional histopathology. The impact of the outcome on the clinical management was also reported. Results: A total of 842 FDG-PET/CT reports of 244 metastatic cutaneous melanoma patients were reviewed. Sixty indeterminate findings were included. Almost half of all indeterminate findings were lymph nodes, lung nodules and cerebral lesions. In total, 43.3% of all included findings proved to be malignant. 81% of all malignant lesions were metastases of cutaneous melanoma, while 19% of all malignant lesions could be attributed to other primary malignancies, such as lung, breast, thyroid and colorectal cancers. Malignant findings influenced clinical management in 60% of the cases. Conclusion: Indeterminate findings on FDG-PET/CT in metastatic cutaneous melanoma patients should be further investigated. Almost one out of every two indeterminate findings on FDG-PET/CT is malignant. The majority of the findings are melanoma manifestations, however, in a significant percentage, other primary tumors are found. Upon verification, patient management is changed in most cases.

Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic landscape in oncology and improved patient prognosis in a variety of neoplastic diseases. However, to date, the selection of the best patients eligible for these therapies, as well as the response assessment is still challenging. Patients are mainly stratified using an immunohistochemical analysis of the expression of antigens on biopsy specimens, such as PD-L1 and PD-1, on tumor cells, on peritumoral immune cells and/or in the tumor microenvironment (TME). Recently, the use and development of imaging biomarkers able to assess in-vivo cancer-related processes are becoming more important. Today, positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is used routinely to evaluate tumor metabolism, and also to predict and monitor response to immunotherapy. Although highly sensitive, FDG-PET in general is rather unspecific. Novel radiopharmaceuticals (immuno-PET radiotracers), able to identify specific immune system targets, are under investigation in pre-clinical and clinical settings to better highlight all the mechanisms involved in immunotherapy. In this review, we will provide an overview of the main new immuno-PET radiotracers in development. We will also review the main players (immune cells, tumor cells and molecular targets) involved in immunotherapy. Furthermore, we report current applications and the evidence of using [18F]FDG PET in immunotherapy, including the use of artificial intelligence (AI).

Objective: Energy expenditure (EE) increases in response to cold exposure, which is called cold induced thermogenesis (CIT). Brown adipose tissue (BAT) has been shown to contribute significantly to CIT in human adults. BAT activity and CIT are acutely influenced by ambient temperature. In the present study, we investigated the long-term effect of seasonal temperature variation on human CIT.Materials and Methods: We measured CIT in 56 healthy volunteers by indirect calorimetry. CIT was determined as difference between EE during warm conditions (EEwarm) and after a defined cold stimulus (EEcold). We recorded skin temperatures at eleven anatomically predefined locations, including the supraclavicular region, which is adjacent to the main human BAT depot. We analyzed the relation of EE, CIT and skin temperatures to the daily minimum, maximum and mean outdoor temperature averaged over 7 or 30 days, respectively, prior to the corresponding study visit by linear regression.Results: We observed a significant inverse correlation between outdoor temperatures and EEcold and CIT, respectively, while EEwarm was not influenced. The daily maximum temperature averaged over 7 days correlated best with EEcold (R2 = 0.123, p = 0.008) and CIT (R2 = 0.200, p = 0.0005). The mean skin temperatures before and after cold exposure were not related to outdoor temperatures. However, the difference between supraclavicular and parasternal skin temperature after cold exposure was inversely related to the average maximum temperature during the preceding 7 days (R2 = 0.07575, p = 0.0221).Conclusion: CIT is significantly related to outdoor temperatures indicating dynamic adaption of thermogenesis and BAT activity to environmental stimuli in adult humans.Clinical Trial Registration:www.ClinicalTrials.gov, Identifier NCT02682706.

BACKGROUND:Sexual dimorphism in cardiac sympathetic outflow has recently gained attention in the context of Takotsubo cardiomyopathy. Previous studies suggest that there are sex- and age-dependent differences in peripheral autonomic control, however, data on cardiac-specific sympathetic activation in aged women and men are lacking. METHODS AND RESULTS:Regional quantitative analysis of cardiac fluorine-18 (18F)- Dihydroxyphenylalanine (DOPA) uptake was retrospectively performed in 133 patients (69 females, mean age 52.4±17.7 years) referred for assessment of neuroendocrine tumours (NET) by Positron-Emission-Tomography. Cardiac 18F-DOPA uptake was significantly higher in women as compared to men (1.33±0.21 vs. 1.18±0.24, p55 years of age (1.39±0.25 in women vs. 1.09±0.24 in men, p

Disease bulk is an important prognostic factor in early stage Hodgkin lymphoma, but its definition is unclear in the computed tomography era. This retrospective analysis investigated the prognostic significance of bulky disease measured in transverse and coronal planes on computed tomography imaging. Early stage Hodgkin lymphoma patients (n=185) treated with chemotherapy with or without radiotherapy from 2000–2010 were included. The longest diameter of the largest lymph node mass was measured in transverse and coronal axes on pre-treatment imaging. The optimal cut off for disease bulk was maximal diameter greater than 7 cm measured in either the transverse or coronal plane. Thirty patients with maximal transverse diameter of 7 cm or under were found to have bulk in coronal axis. The 4-year overall survival was 96.5% (CI: 93.3%, 100%) and 4-year relapse-free survival was 86.8% (CI: 81.9%, 92.1%) for all patients. Relapse-free survival at four years for bulky patients was 80.5% (CI: 73%, 88.9%) compared to 94.4% (CI: 89.1%, 100%) for non-bulky; Cox HR 4.21 (CI: 1.43, 12.38) (P=0.004). In bulky patients, relapse-free survival was not impacted in patients treated with chemoradiotherapy; however, it was significantly lower in patients treated with chemotherapy alone. In an independent validation cohort of 38 patients treated with chemotherapy alone, patients with bulky disease had an inferior relapse-free survival [at 4 years, 71.1% (CI: 52.1%, 97%) vs. 94.1% (CI: 83.6%, 100%), Cox HR 5.27 (CI: 0.62, 45.16); P=0.09]. Presence of bulky disease on multidimensional computed tomography imaging is a significant prognostic factor in early stage Hodgkin lymphoma. Coronal reformations may be included for routine Hodgkin lymphoma staging evaluation. In future, our definition of disease bulk may be useful in identifying patients who are most appropriate for chemotherapy alone.

Unfortunately, after publication of this article [1], it was noticed that the name of Urs J. Muehlematter was incorrectly displayed as Urs J. Mühlematter. The corrected author list can be seen above and the original article has been corrected to reflect this.