Exploring the role of combined external beam radiotherapy and targeted radioligand therapy with [177Lu]Lu-PSMA-617 for prostate cancer - from bench to bedside.

Management of prostate cancer (PC) might be improved by combining external beam radiotherapy (EBRT) and prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with lutetium-177 (177Lu)-labeled PSMA inhibitors. We hypothesized a higher efficacy of the combination due to augmentation of the radiation dose to the tumor and interactions of EBRT with PSMA expression potentially increasing radiopharmaceutical uptake. Therefore, this study analyzed the influence of radiation on PSMA expression levels in vitro. The results were translated to evaluate the efficacy of the combination of photon EBRT and [177Lu]Lu-PSMA-617 in a murine PC xenograft model. Finally, a clinical case report on a combined elective field EBRT with RLT dose escalation illustrates a proof-of-concept. Methods: PSMA gene and protein expression were assessed in human PSMA-overexpressing LNCaP cells after irradiation using reverse transcription quantitative polymerase chain reaction (RT-qPCR), flow cytometry and On-Cell Western assays. In the in vivo therapy study, LNCaP tumor-bearing BALB/c nu/nu mice were irradiated once with 2 Gy X-ray EBRT and injected with 40 MBq [177Lu]Lu-PSMA-617 after 4 h or received single or no treatment (n = 10 each). Tumor-absorbed doses by [177Lu]Lu-PSMA-617 were calculated according to the Medical Internal Radiation Dosimetry (MIRD) formalism after deriving time-activity curves using a gamma probe. An exemplified patient case is demonstrated where fractionated EBRT (54 Gy to prostate; 45 Gy to pelvic lymphatics) and three cycles of [177Lu]Lu-PSMA-617 (3.4-6.0 GBq per cycle) were sequentially combined under concurrent androgen deprivation for treating locally advanced PC. Results: At 4 h following irradiation with 2-8 Gy, LNCaP cells displayed a PSMA protein upregulation by around 18% relative to non-irradiated cells, and a stronger upregulation on mRNA level (up to 2.6-fold). This effect was reversed by 24 h when PSMA protein levels were downregulated by up to 22%. Mice treated with the combination therapy showed significantly improved outcomes regarding tumor control and median survival (p < 0.0001) as compared to single or no treatment. Relative to monotherapy with PSMA-RLT or EBRT, the tumor doubling time was prolonged 1.7- or 2.7-fold and the median survival was extended by 24% or 60% with the combination, respectively. Additionally, tumors treated with EBRT exhibited a 14% higher uptake of the radiopharmaceutical as evident from the calculated tumor-absorbed dose, albeit with high variability in the data. Concerning the patient case, the tri-modality treatment was well tolerated and the patient responded with a long-lasting complete biochemical remission for five years following end of PSMA-RLT. The patient then developed a biochemical relapse with oligo-recurrent disease on follow-up imaging. Conclusion: The present preclinical and clinical data demonstrate that the combination of EBRT with dose escalation by PSMA-RLT improves tumor control and potentially prolongs survival. This may pave the way for further clinical investigations of this approach to explore the curative potential of the combination therapy.

Bone marrow disease in rhabdomyosarcoma visualized by 2-[18F]fluorodeoxyglucose positron emission tomography/computed tomography.

Bone marrow metastases-noted in 6% of patients with rhabdomyosarcoma-have been linked to very poor outcomes. Bilateral bone marrow sampling from iliac crests has been the gold standard for bone marrow examination in rhabdomyosarcoma, but sampling errors due to patchy bone marrow involvement may limit its sensitivity. Here, we report the case of a 6-year-old boy with embryonal rhabdomyosarcoma of the skull base and multiple 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG)-avid bone marrow metastases visualized by positron emission tomography and computed tomography (2-[18F]FDG PET/CT). His bone marrow aspirates were tumor-free. This case illustrates the diagnostic value of 2-[18F]FDG PET/CT in the detection of bone marrow metastases in rhabdomyosarcoma patients, which may re-shape the definition of bone marrow disease and, ultimately, alter disease staging and risk stratification.

Peptide Receptor Radionuclide Therapy Is Effective for Clinical Control of Symptomatic Metastatic Insulinoma: A Long-Term Retrospective Analysis.

Metastatic insulinoma is a rare malignant neuroendocrine tumor characterized by inappropriate insulin secretion, resulting in life-threatening hypoglycemia, which is often difficult to treat. There is currently very limited information about the efficacy of peptide receptor radionuclide therapy (PRRT) for clinical control of hypoglycemia. The aim of this long-term retrospective study was to evaluate the therapeutic efficacy of PRRT for improving hypoglycemia, to evaluate the change of medication after PRRT, and to calculate progression-free survival (PFS) and overall survival (OS). Methods: Inclusion criteria were histologically proven somatostatin receptor-positive metastatic malignant insulinoma and at least 2 cycles of [90Y]Y-DOTATOC or [177Lu]Lu-DOTATOC therapy from early 2000 to early 2022. A semiquantitative scoring system was used to quantify the severity and frequency of hypoglycemic episodes under background antihypoglycemic therapy (somatostatin analog, diazoxide, everolimus, corticosteroids): score 0, no hypoglycemic episodes; score 1, hypoglycemic events requiring additional conservative treatment with optimization of nutrition; score 2, severe hypoglycemia necessitating hospitalization and combined medication or history of hypoglycemic coma. Hypoglycemic score before and after PRRT was analyzed. Time of benefit was defined as a time range of fewer hypoglycemic episodes in the observation period than at baseline. Information on antihypoglycemic medication before and after therapy, PFS, and OS was recorded. Results: Twenty-six of 32 patients with a total of 106 [90Y]Y-DOTATOC/[177Lu]Lu-DOTATOC cycles were included. The average observation period was 21.5 mo (range, 2.3-107.4 mo). Before therapy, 81% (n = 21) of the patients had a hypoglycemia score of 2 and 19% (n = 5) had a score of 1. After PRRT, 81% of patients (n = 21) had a decreased score, and the remaining 5 patients showed a stable situation. There was temporary worsening of hypoglycemia just after injection of [90Y]Y-DOTATOC/[177Lu]Lu-DOTATOC in 19% of patients. The average time of benefit in the observation period was 17.2 mo (range, 0-70.2 mo). Antihypoglycemic medication reduction was achieved in 58% (n = 15) of patients. The median OS and PFS after the start of PRRT were 19.7 mo (95% CI, 6.5-32.9 mo) and 11.7 mo (95% CI, 4.9-18.5 mo), respectively. Conclusion: To our knowledge, our study included the largest cohort of patients with malignant insulinoma to be evaluated. Long-lasting symptom control and reduction of antihypoglycemic medications were shown in most patients after late-line PRRT.

Adult-onset nesidioblastosis: a challenging diagnosis revealed by glucagon-like-peptide-1 receptor imaging.

Summary: A 52-year-old female presented with recurrent episodes of fasting or post-absorptive hypoglycemia. A 72-h fasting test confirmed endogenous hyperinsulinemia. Conventional imaging was unremarkable. Selective pancreatic arterial calcium stimulation and hepatic venous sampling showed a maximum calcium-stimulated insulin concentration from several pancreatic areas, mainly the proximal splenic artery and the proximal gastroduodenal artery, suggesting the presence of one or more occult insulinoma(s) in the region of the pancreatic body. 68Ga-DOTA-exendin-4 PET/CT showed however generalized increased uptake in the pancreas and a diagnosis of nesidioblastosis was therefore suspected. The patient has been since successfully treated with dietetic measures and diazoxide. Treatment efficacy was confirmed by a flash glucose monitoring system with a follow-up of 7 months. Learning points: Adult nesidioblastosis is a rare cause of endogenous hyperinsulinemic hypoglycemia. The distinction between insulinoma and nesidioblastosis is essential since the therapeutic strategies are different. 68Ga-DOTA-exendin-4 PET/CT emerges as a new noninvasive diagnostic tool for the localization of an endogenous source of hyperinsulinemic hypoglycemia. Medical management with dietetic measures and diazoxide need to be considered as a valuable option to treat patients with adult nesidioblastosis. Flash glucose monitoring system is helpful for the evaluation of treatment efficacy.

Quantitative myocardial perfusion 82Rb-PET assessed by hybrid PET/coronary-CT: Normal values and diagnostic performance.

PURPOSE: We aimed to assess normal values for quantified myocardial blood flow (MBF) on a hybrid PET/coronary-CT scanner and to test their diagnostic performance in patients with suspected CAD. MATERIALS AND METHODS: Patients underwent 82Rb-PET/CT and integrated CT-based coronary angiography (CCTA) and were classified as normal (no stenosis), with non-obstructive stenosis (< 50%) and with CAD (≥ 50%). Global and regional stress MBF (sMBF), rest MBF and myocardial flow reserve (MFR) were calculated. Ischemia was defined as SDS ≥ 2, severe ischemia as SDS ≥ 7. RESULTS: 357 consecutive patients were included. Global sMBF and MFR were higher in normal patients than in patients with CAD (3.61 ± 0.71 vs 3.04 ± 0.77, P < 0.0001; 3.08 ± 0.84 vs 2.68 ± 0.79, P = 0.0001), but not different compared to patients with non-obstructive stenosis (3.61 ± 0.71 vs 3.43 ± 0.69, P = 0.052; 3.08 ± 0.84 vs 2.99 ± 0.82, P = 0.45). sMBF yielded superior accuracy over MFR in identifying both ischemia (AUC 0.74 vs 0.62, P = 0.003) and severe ischemia (AUC 0.88 vs 0.78, P = 0.012). Optimal threshold for global sMBF to rule out myocardial ischemia was 3.5 mL g-1 min-1. CONCLUSIONS: Normal quantitative values are provided. Global sMBF provided higher diagnostic accuracy than MFR. Using sMBF-threshold of 3.5 mL·g-1·min-1 on 82Rb-PET/CT yielded similar NPV (96%) as CCTA to rule out CAD. Hence, resting scan could be omitted in patients with sMBF values above reference.

Assessment of Melanin Content and its Influence on Susceptibility Contrast in Melanoma Metastases.

PURPOSE: To quantify the influence of melanin content on magnetic susceptibility of cerebral melanoma metastases. METHODS: Patients with non-hemorrhagic metastases were included based on the absence of susceptibility blooming artifacts. Susceptibility maps were calculated from 3D gradient echo data, using Laplacian-based phase unwrapping, sophisticated harmonic artefact reduction for phase data (V-SHARP) with varying spherical kernel sizes for background field removal and the iLSQR algorithm for the inversion of phase data. Susceptibility maps were referenced to cerebrospinal fluid. Non-hemorrhagic metastases were identified on contrast-enhanced T1-weighted images and susceptibility weighted images. Metastases masks were drawn on T1-weighted post-contrast images and used to compute mean susceptibility values of each metastasis. RESULTS: A total of 33 non-hemorrhagic melanoma brain metastases in 20 patients were quantitatively evaluated. Metastases without and with hyperintense signal on T1-weighted images, which corresponds to the melanin content, showed median susceptibility values of -0.028 ppm and -0.020 ppm, respectively. The susceptibility differences between metastases without and with T1-weighted hyperintense signal was not statistically significant (p ≥ 0.05). CONCLUSION: Non-hemorrhagic cerebral melanoma metastases showed weak diamagnetic susceptibility values and susceptibility did not significantly correlate to T1-weighted signals. Therefore, melanin does not seem to be a major contributor to susceptibility in cerebral melanoma metastases.

De-masking oxytocin-deficiency in craniopharyngioma and assessing its link with affective function.

Despite the high prevalence of panhypopituitarism and diabetes insipidus in patients with craniopharyngioma (CP), little is known about the functioning of the neuropeptide oxytocin in these patients. This is of special interest as tumor-associated lesions often impair sites critical for oxytocin production and release, and affective dysfunction in CP links with elsewhere reported prosocial, antidepressant and anxiolytic oxytocin effects. Using a prospective study-design, we tested whether oxytocin is reduced in CP-patients, and whether altered oxytocin levels account for affective and emotional dysfunction. 26 adult CP-patients and 26 healthy controls matched in sex and age underwent physical exercise, a stimulus previously shown to induce oxytocin release. Baseline and stimulated salivary oxytocin levels, as well as empathy, depression and anxiety scores were measured. Results showed that patients overall did not present with lower baseline oxytocin levels than controls (F[1,30]=0.21, p=0.649), but baseline oxytocin levels were indeed reduced in patients with hypothalamic damage, as assessed by MRI-based grading (F[2,9.79]=4.54, p=0.040). In response to exercise-induced stimulation, all CP-patients showed a blunted oxytocin-release compared to controls (F[1,30]=9.36, p=0.005). DI was not associated with oxytocin levels. Regarding affective function, unexpectedly, higher baseline oxytocin was related to higher trait anxiety (b=2.885, t(43)=2.421, p=0.020, CI[.478; 5.292]); the positive link with higher depression failed to reach statistical significance (b=1.928, t(43)=1.949, p=0.058, CI[-0.070; 3.927]). A blunted oxytocin-release was linked with higher state anxiety (b=-0.133, t(43)=-2.797, p=0.008, CI[-0.230; -0.037]). Empathy was not associated with oxytocin measures. In conclusion, we observed reduced baseline oxytocin levels only in CP-patients with hypothalamic damage. Exercise-induced stimulation de-masked an oxytocin-deficiency in all CP-patients. Baseline oxytocin levels and stimulated OT-responses might have different effects on affective function, which should be considered in future substitution paradigms.

Simultaneous whole-body 18F-PSMA-1007-PET/MRI with integrated high-resolution multiparametric imaging of the prostatic fossa for comprehensive oncological staging of patients with prostate cancer: a pilot study.

INTRODUCTION: The aim of the present study was to explore the clinical feasibility and reproducibility of a comprehensive whole-body 18F-PSMA-1007-PET/MRI protocol for imaging prostate cancer (PC) patients. METHODS: Eight patients with high-risk biopsy-proven PC underwent a whole-body PET/MRI (3 h p.i.) including a multi-parametric prostate MRI after 18F-PSMA-1007-PET/CT (1 h p.i.) which served as reference. Seven patients presented with non-treated PC, whereas one patient presented with biochemical recurrence. SUVmean-quantification was performed using a 3D-isocontour volume-of-interest. Imaging data was consulted for TNM-staging and compared with histopathology. PC was confirmed in 4/7 patients additionally by histopathology after surgery. PET-artifacts, co-registration of pelvic PET/MRI and MRI-data were assessed (PI-RADS 2.0). RESULTS: The examinations were well accepted by patients and comprised 1 h. SUVmean-values between PET/CT (1 h p.i.) and PET/MRI (3 h p.i.) were significantly correlated (p < 0.0001, respectively) and similar to literature of 18F-PSMA-1007-PET/CT 1 h vs 3 h p.i. The dominant intraprostatic lesion could be detected in all seven patients in both PET and MRI. T2c, T3a, T3b and T4 features were detected complimentarily by PET and MRI in five patients. PET/MRI demonstrated moderate photopenic PET-artifacts surrounding liver and kidneys representing high-contrast areas, no PET-artifacts were observed for PET/CT. Simultaneous PET-readout during prostate MRI achieved optimal co-registration results. CONCLUSIONS: The presented 18F-PSMA-1007-PET/MRI protocol combines efficient whole-body assessment with high-resolution co-registered PET/MRI of the prostatic fossa for comprehensive oncological staging of patients with PC.

Integration of CT urography improves diagnostic confidence of 68Ga-PSMA-11 PET/CT in prostate cancer patients.

BACKGROUND: To prove the feasibility of integrating CT urography (CTU) into 68Ga-PSMA-11 PET/CT and to analyze the impact of CTU on assigning focal tracer accumulation in the ureteric space to either ureteric excretion or metastatic disease concerning topographic attribution and diagnostic confidence. METHODS: Ten prostate cancer patients who underwent 68Ga-PSMA-11 PET/CT including CTU because of biochemical relapse or known metastatic disease were retrospectively analyzed. CTU consisted of an excretory phase 10 min after injection of 80 mL iodinated contrast material. Ureter opacification at CTU was evaluated using the following score: 0, 0% opacification; 1, < 50%; 2, 50-99%; 3, 100%. Topographic attribution and confidence of topographic attribution of focal tracer accumulation in the ureteric space were separately assessed for 68Ga-PSMA-11 PET/CT without and with CTU. Diagnostic confidence was evaluated using the following score: 0, < 25% confidence; 1, 26-50%; 2, 51-75%; 3, 76-100%. RESULTS: At CTU, mean ureter opacification score was 2.6 ± 0.7. At 68Ga-PSMA-11 PET/CT without CTU, mean confidence of topographic attribution of focal tracer accumulation was 2.5 ± 0.7 in total and 2.6 ± 0.7 for metastatic disease. At 68Ga-PSMA-11 PET/CT with CTU, mean confidence of topographic attribution of focal areas of tracer accumulation was significantly higher with 2.9 ± 0.2 in total and 2.7 ± 0.9 for metastatic disease (p < 0.001). In 4 of 34 findings (12%) attribution to either ureteric excretion or metastatic disease was discrepant between 68Ga-PSMA-11 PET/CT without and with CTU (n.s). CONCLUSIONS: Integration of CTU into 68Ga-PSMA-11 PET/CT is feasible and increases diagnostic confidence of assigning focal areas of tracer accumulation in the ureteric space to either metastatic disease or ureteric excretion.

Improved clinical workflow for simultaneous whole-body PET/MRI using high-resolution CAIPIRINHA-accelerated MR-based attenuation correction.

PURPOSE: To explore the value and reproducibility of a novel magnetic resonance based attenuation correction (MRAC) using a CAIPIRINHA-accelerated T1-weighted Dixon 3D-VIBE sequence for whole-body PET/MRI compared to the clinical standard. METHODS: The PET raw data of 19 patients from clinical routine were reconstructed with standard MRAC (MRACstd) and the novel MRAC (MRACcaipi), a prototype CAIPIRINHA accelerated Dixon 3D-VIBE sequence, both acquired in 19 s/bed position. Volume of interests (VOIs) for liver, lung and all voxels of the total image stack were created to calculate standardized uptake values (SUVmean) followed by inter-method agreement (Passing-Bablok regression, Bland-Altman analysis). A voxel-wise SUV comparison per patient was performed for intra-individual correlation between MRACstd and MRACcaipi. Difference images (MRACstd-MRACcaipi) of attenuation maps and SUV images were calculated. The image quality of in/opposed-phase water and fat images obtained from MRACcaipi was assessed by two readers on a 5-point Likert-scale including intra-class coefficients for inter-reader agreement. RESULTS: SUVmean correlations of VOIs demonstrated high linearity (0.95

Investigation of the halo-artifact in 68Ga-PSMA-11-PET/MRI.

OBJECTIVES: Combined positron emission tomography (PET) and magnetic resonance imaging (MRI) targeting the prostate-specific membrane antigen (PSMA) with a 68Ga-labelled PSMA-analog (68Ga-PSMA-11) is discussed as a promising diagnostic method for patients with suspicion or history of prostate cancer. One potential drawback of this method are severe photopenic (halo-) artifacts surrounding the bladder and the kidneys in the scatter-corrected PET images, which have been reported to occur frequently in clinical practice. The goal of this work was to investigate the occurrence and impact of these artifacts and, secondly, to evaluate variants of the standard scatter correction method with regard to halo-artifact suppression. METHODS: Experiments using a dedicated pelvis phantom were conducted to investigate whether the halo-artifact is modality-, tracer-, and/or concentration-dependent. Furthermore, 31 patients with history of prostate cancer were selected from an ongoing 68Ga-PSMA-11-PET/MRI study. For each patient, PET raw data were reconstructed employing six different variants of PET scatter correction: absolute scatter scaling, relative scatter scaling, and relative scatter scaling combined with prompt gamma correction, each of which was combined with a maximum scatter fraction (MaxSF) of MaxSF = 75% or MaxSF = 40%. Evaluation of the reconstructed images with regard to halo-artifact suppression was performed both quantitatively using statistical analysis and qualitatively by two independent readers. RESULTS: The phantom experiments did not reveal any modality-dependency (PET/MRI vs. PET/CT) or tracer-dependency (68Ga vs. 18F-FDG). Patient- and phantom-based data indicated that halo-artifacts derive from high organ-to-background activity ratios (OBR) between bladder/kidneys and surrounding soft tissue, with a positive correlation between OBR and halo size. Comparing different variants of scatter correction, reducing the maximum scatter fraction from the default value MaxSF = 75% to MaxSF = 40% was found to efficiently suppress halo-artifacts in both phantom and patient data. In 1 of 31 patients, reducing the maximum scatter fraction provided new PET-based information changing the patient's diagnosis. CONCLUSION: Halo-artifacts are particularly observed for 68Ga-PSMA-11-PET/MRI due to 1) the biodistribution of the PSMA-11-tracer resulting in large OBRs for bladder and kidneys and 2) inaccurate scatter correction methods currently used in clinical routine, which tend to overestimate the scatter contribution. If not compensated for, 68Ga-PSMA-11 uptake pathologies may be masked by halo-artifacts leading to false-negative diagnoses. Reducing the maximum scatter fraction was found to efficiently suppress halo-artifacts.

Effects of arm truncation on the appearance of the halo artifact in 68Ga-PSMA-11 (HBED-CC) PET/MRI.

PURPOSE: PSMA ligand imaging with hybrid PET/MRI scanners could be an integral part of the clinical routine in the future. However, the first study about this novel method revealed a severe photopenic artifact ("halo artifact") around the urinary bladder causing significantly reduced tumor visibility. The aim of this evaluation was to analyze the role of arm truncation on the appearance of the halo artifact in 68Ga-PSMA-11 PET/MRI hypothesizing that this influences the appearance. METHODS: Twenty-seven consecutive patients were subjected to 68Ga-PSMA-11 PET/CT (1 h p.i.) followed by PET/MRI (3 h p.i.). PET/MRI was first started with scans of the abdomen to pelvis with arms positioned up above the head. Immediately thereafter, additional scans from the pelvis to abdomen were conducted with arms positioned down beside the trunk. All investigations were first analyzed separately and then compared with respect to tumor detection and tumor uptake (SUV) as well as the presence and intensity of the halo artifact. The Wilcoxon signed rank test was used to determine statistical differences including Bonferroni correction. RESULTS: The halo was significantly reduced if the arms were elevated. Lesions inside the halo artifact (n = 16) demonstrated significantly increased SUVmean (p = 0.0007) and SUVmax (p = 0.0024) with arms positioned up. The halo appearance and intensity was not dependent on the total activity and activity concentration of the urinary bladder. CONCLUSION: Positioning the arms down was shown to be significantly associated with the appearance of the halo artifact in PET/MRI. Positioning the arms up above the head can significantly reduce the halo artifact, thereby detecting more tumor lesions.

Combined Clinical Parameters and Multiparametric Magnetic Resonance Imaging for Advanced Risk Modeling of Prostate Cancer-Patient-tailored Risk Stratification Can Reduce Unnecessary Biopsies.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) is gaining widespread acceptance in prostate cancer (PC) diagnosis and improves significant PC (sPC; Gleason score≥3+4) detection. Decision making based on European Randomised Study of Screening for PC (ERSPC) risk-calculator (RC) parameters may overcome prostate-specific antigen (PSA) limitations. OBJECTIVE: We added pre-biopsy mpMRI to ERSPC-RC parameters and developed risk models (RMs) to predict individual sPC risk for biopsy-naïve men and men after previous biopsy. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed clinical parameters of 1159 men who underwent mpMRI prior to MRI/transrectal ultrasound fusion biopsy between 2012 and 2015. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariate regression analyses were used to determine significant sPC predictors for RM development. The prediction performance was compared with ERSPC-RCs, RCs refitted on our cohort, Prostate Imaging Reporting and Data System (PI-RADS) v1.0, and ERSPC-RC plus PI-RADSv1.0 using receiver-operating characteristics (ROCs). Discrimination and calibration of the RM, as well as net decision and reduction curve analyses were evaluated based on resampling methods. RESULTS AND LIMITATIONS: PSA, prostate volume, digital-rectal examination, and PI-RADS were significant sPC predictors and included in the RMs together with age. The ROC area under the curve of the RM for biopsy-naïve men was comparable with ERSPC-RC3 plus PI-RADSv1.0 (0.83 vs 0.84) but larger compared with ERSPC-RC3 (0.81), refitted RC3 (0.80), and PI-RADS (0.76). For postbiopsy men, the novel RM's discrimination (0.81) was higher, compared with PI-RADS (0.78), ERSPC-RC4 (0.66), refitted RC4 (0.76), and ERSPC-RC4 plus PI-RADSv1.0 (0.78). Both RM benefits exceeded those of ERSPC-RCs and PI-RADS in the decision regarding which patient to receive biopsy and enabled the highest reduction rate of unnecessary biopsies. Limitations include a monocentric design and a lack of PI-RADSv2.0. CONCLUSIONS: The novel RMs, incorporating clinical parameters and PI-RADS, performed significantly better compared with RMs without PI-RADS and provided measurable benefit in making the decision to biopsy men at a suspicion of PC. For biopsy-naïve patients, both our RM and ERSPC-RC3 plus PI-RADSv1.0 exceeded the prediction performance compared with clinical parameters alone. PATIENT SUMMARY: Combined risk models including clinical and imaging parameters predict clinically relevant prostate cancer significantly better than clinical risk calculators and multiparametric magnetic resonance imaging alone. The risk models demonstrate a benefit in making a decision about which patient needs a biopsy and concurrently help avoid unnecessary biopsies.

MLAA-based attenuation correction of flexible hardware components in hybrid PET/MR imaging.

BACKGROUND: Accurate PET quantification demands attenuation correction (AC) for both patient and hardware attenuation of the 511 keV annihilation photons. In hybrid PET/MR imaging, AC for stationary hardware components such as patient table and MR head coil is straightforward, employing CT-derived attenuation templates. AC for flexible hardware components such as MR-safe headphones and MR radiofrequency (RF) surface coils is more challenging. Registration-based approaches, aligning CT-based attenuation templates with the current patient position, have been proposed but are not used in clinical routine. Ignoring headphone or RF coil attenuation has been shown to result in regional activity underestimation values of up to 18%. We propose to employ the maximum-likelihood reconstruction of attenuation and activity (MLAA) algorithm to estimate the attenuation of flexible hardware components. Starting with an initial attenuation map not including flexible hardware components, the attenuation update of MLAA is applied outside the body outline only, allowing to estimate hardware attenuation without modifying the patient attenuation map. Appropriate prior expectations on the attenuation coefficients are incorporated into MLAA. The proposed method is investigated for non-TOF PET phantom and 18F-FDG patient data acquired with a clinical PET/MR device, using headphones or RF surface coils as flexible hardware components. RESULTS: Although MLAA cannot recover the exact physical shape of the hardware attenuation maps, the overall attenuation of the hardware components is accurately estimated. Therefore, the proposed algorithm significantly improves PET quantification. Using the phantom data, local activity underestimation when neglecting hardware attenuation was reduced from up to 25% to less than 3% under- or overestimation as compared to reference scans without hardware present or to CT-derived AC. For the patient data, we found an average activity underestimation of 7.9% evaluated in the full brain and of 6.1% for the abdominal region comparing the uncorrected case with MLAA. CONCLUSIONS: MLAA is able to provide accurate estimations of the attenuation of flexible hardware components and can therefore be used to significantly improve PET quantification. The proposed approach can be readily incorporated into clinical workflow.

4D respiratory motion-compensated image reconstruction of free-breathing radial MR data with very high undersampling.

PURPOSE: To develop four-dimensional (4D) respiratory time-resolved MRI based on free-breathing acquisition of radial MR data with very high undersampling. METHODS: We propose the 4D joint motion-compensated high-dimensional total variation (4D joint MoCo-HDTV) algorithm, which alternates between motion-compensated image reconstruction and artifact-robust motion estimation at multiple resolution levels. The algorithm is applied to radial MR data of the thorax and upper abdomen of 12 free-breathing subjects with acquisition times between 37 and 41 s and undersampling factors of 16.8. Resulting images are compared with compressed sensing-based 4D motion-adaptive spatio-temporal regularization (MASTeR) and 4D high-dimensional total variation (HDTV) reconstructions. RESULTS: For all subjects, 4D joint MoCo-HDTV achieves higher similarity in terms of normalized mutual information and cross-correlation than 4D MASTeR and 4D HDTV when compared with reference 4D gated gridding reconstructions with 8.4 ± 1.1 times longer acquisition times. In a qualitative assessment of artifact level and image sharpness by two radiologists, 4D joint MoCo-HDTV reveals higher scores (P < 0.05) than 4D HDTV and 4D MASTeR at the same undersampling factor and the reference 4D gated gridding reconstructions, respectively. CONCLUSIONS: 4D joint MoCo-HDTV enables time-resolved image reconstruction of free-breathing radial MR data with undersampling factors of 16.8 while achieving low-streak artifact levels and high image sharpness. Magn Reson Med 77:1170-1183, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI.

PURPOSE: To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS: The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS: Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION: We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:369-380.

Suitable reference tissues for quantitative susceptibility mapping of the brain.

PURPOSE: Since quantitative susceptibility mapping (QSM) quantifies magnetic susceptibility relative to a reference value, a suitable reference tissue has to be available to compare different subjects and stages of disease. METHODS: To find such a suitable reference tissue for QSM of the brain, melanoma patients with and without brain metastases were measured. Twelve reference regions were chosen and assessed for stability of susceptibility values with respect to multiple intra-individual and inter-individual measurements, age, and stage of disease. RESULTS: Cerebrospinal fluid (CSF), the internal capsule and one region in the splenium of the corpus callosum are the regions with the smallest standard deviations of the mean susceptibility value. The mean susceptibility is 0.010 ± 0.014 ppm for CSF in the atrium of the lateral ventricles (csfpost ), -0.060 ± 0.019 ppm for the posterior limb of the internal capsule (ci2), and -0.008 ± 0.019 ppm for the splenium of the corpus callosum. csfpost and ci2 show nearly no dependence on age or stage of disease, whereas some other regions, e.g., the red nucleus, show moderate dependence on age or disease. CONCLUSION: The internal capsule and CSF appear to be the most suitable reference regions for QSM of the brain in the melanoma patients studied. Both showed virtually no dependence on age or disease and small variations among patients. Magn Reson Med 78:204-214, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Local recurrence of prostate cancer after radical prostatectomy is at risk to be missed in 68Ga-PSMA-11-PET of PET/CT and PET/MRI: comparison with mpMRI integrated in simultaneous PET/MRI.

PURPOSE: The positron emission tomography (PET) tracer 68Ga-PSMA-11, targeting the prostate-specific membrane antigen (PSMA), is rapidly excreted into the urinary tract. This leads to significant radioactivity in the bladder, which may limit the PET-detection of local recurrence (LR) of prostate cancer (PC) after radical prostatectomy (RP), developing in close proximity to the bladder. Here, we analyze if there is additional value of multi-parametric magnetic resonance imaging (mpMRI) compared to the 68Ga-PSMA-11-PET-component of PET/CT or PET/MRI to detect LR. METHODS: One hundred and nineteen patients with biochemical recurrence after prior RP underwent both hybrid 68Ga-PSMA-11-PET/CTlow-dose (1 h p.i.) and -PET/MRI (2-3 h p.i.) including a mpMRI protocol of the prostatic bed. The comparison of both methods was restricted to the abdomen with focus on LR (McNemar). Bladder-LR distance and recurrence size were measured in axial T2w-TSE. A logistic regression was performed to determine the influence of these variables on detectability in 68Ga-PSMA-11-PET. Standardized-uptake-value (SUVmean) quantification of LR was performed. RESULTS: There were 93/119 patients that had at least one pathologic finding. In addition, 18/119 Patients (15.1%) were diagnosed with a LR in mpMRI of PET/MRI but only nine were PET-positive in PET/CT and PET/MRI. This mismatch was statistically significant (p = 0.004). Detection of LR using the PET-component was significantly influenced by proximity to the bladder (p = 0.028). The PET-pattern of LR-uptake was classified into three types (1): separated from bladder; (2): fuses with bladder, and (3): obliterated by bladder). The size of LRs did not affect PET-detectability (p = 0.84), mean size was 1.7 ± 0.69 cm long axis, 1.2 ± 0.46 cm short-axis. SUVmean in nine men was 8.7 ± 3.7 (PET/CT) and 7.0 ± 4.2 (PET/MRI) but could not be quantified in the remaining nine cases (obliterated by bladder). CONCLUSION: The present study demonstrates additional value of hybrid 68Ga-PSMA-11-PET/MRI by gaining complementary diagnostic information compared to the 68Ga-PSMA-11-PET/CTlow-dose for patients with LR of PC.