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.

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.

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.

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.

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.

Early Detection of Malignant Transformation in Resected WHO II Low-Grade Glioma Using Diffusion Tensor-Derived Quantitative Measures.

OBJECTIVE: Here, we retrospectively investigate the value of voxel-wisely plotted diffusion tensor-derived (DTI) axial, radial and mean diffusivity for the early detection of malignant transformation (MT) in WHO II glioma compared to contrast-enhanced images. MATERIALS AND METHODS: Forty-seven patients underwent brain magnetic resonance imaging follow-up between 2006-2014 after gross-tumor resection of intra-axial WHO II glioma. Axial/Mean/Radial diffusivity maps (AD/MD/RD) were generated from DTI data. ADmin/MDmin/RDmin values were quantified within tumor regions-of-interest generated by two independent readers including tumor contrast-to-noise (CNR). Sensitivity/specificity and area-under-the-curve (AUC) were calculated using receiver-operating-characteristic analysis. Inter-reader agreement was assessed (Cohen's kappa). RESULTS: Eighteen patients demonstrated malignant transformation (MT) confirmed in 8/18 by histopathology and in 10/18 through imaging follow-up. Twelve of 18 patients (66.6%) with MT showed diffusion restriction timely coincidental with contrast-enhancement (CE). In the remaining six patients (33.3%), the diffusion restriction preceded the CE. The mean gain in detection time using DTI was (0.8±0.5 years, p = 0.028). Compared to MDmin and RDmin, ROC-analysis showed best diagnostic value for ADmin (sensitivity/specificity 94.94%/89.7%, AUC 0.96; p<0.0001) to detect MT. CNR was highest for AD (1.83±0.14), compared to MD (1.31±0.19; p<0.003) and RD (0.90±0.23; p<0.0001). Cohen's Kappa was 0.77 for ADmin, 0.71 for MDmin and 0.65 for RDmin (p<0.0001, respectively). CONCLUSION: MT is detectable at the same time point or earlier compared to T1w-CE by diffusion restriction in diffusion-tensor-derived maps. AD demonstrated highest sensitivity/specificity/tumor-contrast compared to radial or mean diffusivity (= apparent diffusion coefficient) to detect MT.

68Ga-PSMA-11 Dynamic PET/CT Imaging in Primary Prostate Cancer.

PURPOSE: The aim of our study is to assess the pharmacokinetics and biodistribution of Ga-PSMA-11 in patients suffering from primary prostate cancer (PC) by means of dynamic and whole-body PET/CT. MATERIALS AND METHODS: Twenty-four patients with primary, previously untreated PC were enrolled in the study. All patients underwent dynamic PET/CT (dPET/CT) scanning of the pelvis and whole-body PET/CT studies with Ga-PSMA-11. The evaluation of dPET/CT studies was based on qualitative evaluation, SUV calculation, and quantitative analysis based on two-tissue compartment modeling and a noncompartmental approach leading to the extraction of fractal dimension (FD). RESULTS: A total of 23/24 patients (95.8%) were Ga-PSMA-11 positive. In 9/24 patients (37.5%), metastatic lesions were detected. PC-associated lesions demonstrated the following mean values: SUVaverage = 14.3, SUVmax = 23.4, K1 = 0.24 (1/min), k3 = 0.34 (1/min), influx = 0.15 (1/min), and FD = 1.27. The parameters SUVaverage, SUVmax, k3, influx, and FD derived from PC-associated lesions were significantly higher than respective values derived from reference prostate tissue. Time-activity curves derived from PC-associated lesions revealed an increasing Ga-PSMA-11 accumulation during dynamic PET acquisition. Correlation analysis revealed a moderate but significant correlation between PSA levels and SUVaverage (r = 0.60) and SUVmax (r = 0.57), and a weak but significant correlation between Gleason score and SUVaverage (r = 0.33) and SUVmax (r = 0.28). CONCLUSION: Ga-PSMA-11 PET/CT confirmed its capacity in detecting primary PC with a detection rate of 95.8%. Dynamic PET/CT studies of the pelvis revealed an increase in tracer uptake in PC-associated lesions during the 60 minutes of dynamic PET acquisition, a finding with potential applications in anti-PSMA approaches.

Multiparametric Magnetic Resonance Imaging (MRI) and MRI-Transrectal Ultrasound Fusion Biopsy for Index Tumor Detection: Correlation with Radical Prostatectomy Specimen.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) and MRI fusion targeted biopsy (FTB) detect significant prostate cancer (sPCa) more accurately than conventional biopsies alone. OBJECTIVE: To evaluate the detection accuracy of mpMRI and FTB on radical prostatectomy (RP) specimen. DESIGN, SETTING AND PARTICIPANTS: From a cohort of 755 men who underwent transperineal MRI and transrectal ultrasound fusion biopsy under general anesthesia between 2012 and 2014, we retrospectively analyzed 120 consecutive patients who had subsequent RP. All received saturation biopsy (SB) in addition to FTB of lesions with Prostate Imaging Reporting and Data System (PI-RADS) score ≥2. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The index lesion was defined as the lesion with extraprostatic extension, the highest Gleason score (GS), or the largest tumor volume (TV) if GS were the same, in order of priority. GS 3+3 and TV ≥1.3ml or GS ≥3+4 and TV ≥0.55ml were considered sPCa. We assessed the detection accuracy by mpMRI and different biopsy approaches and analyzed lesion agreement between mpMRI and RP specimen. RESULTS AND LIMITATIONS: Overall, 120 index and 71 nonindex lesions were detected. Overall, 107 (89%) index and 51 (72%) nonindex lesions harbored sPCa. MpMRI detected 110 of 120 (92%) index lesions, FTB (two cores per lesion) alone diagnosed 96 of 120 (80%) index lesions, and SB alone diagnosed 110 of 120 (92%) index lesions. Combined SB and FTB detected 115 of 120 (96%) index foci. FTB performed significantly less accurately compared with mpMRI (p=0.02) and the combination for index lesion detection (p=0.002). Combined FTB and SB detected 97% of all sPCa lesions and was superior to mpMRI (85%), FTB (79%), and SB (88%) alone (p<0.001 each). Spearman's rank correlation coefficient for index lesion agreement between mpMRI and RP was 0.87 (p<0.001). Limitations included the retrospective design, multiple operators, and nonblinding of radiologists. CONCLUSIONS: MpMRI identified 92% of index lesions compared with RP histopathology. The combination of FTB and SB was superior to both approaches alone, reliably detecting 97% of sPCa lesions. PATIENT SUMMARY: Multiparametric magnetic resonance imaging detects the index lesion accurately in 9 of 10 patients; however, the combined biopsy approach, while missing less significant cancer, comes at the cost of detecting more insignificant cancer.

Comparison of hybrid (68)Ga-PSMA PET/MRI and (68)Ga-PSMA PET/CT in the evaluation of lymph node and bone metastases of prostate cancer.

PURPOSE: To evaluate the reproducibility of the combination of hybrid PET/MRI and the (68)Ga-PSMA-11 tracer in depicting lymph node (LN) and bone metastases of prostate cancer (PC) in comparison with that of PET/CT. MATERIALS AND METHODS: A retrospective analysis of 26 patients who were subjected to (68)Ga-PSMA PET/CTlow-dose (1 h after injection) followed by PET/MRI (3 h after injection) was performed. MRI sequences included T1-w native, T1-w contrast-enhanced, T2-w fat-saturated and diffusion-weighted sequences (DWIb800). Discordant PET-positive and morphological findings were evaluated. Standardized uptake values (SUV) of PET-positive LNs and bone lesions were quantified and their morphological size and conspicuity determined. RESULTS: Comparing the PET components, the proportion of discordant PSMA-positive suspicious findings was very low (98.5 % of 64 LNs concordant, 100 % of 28 bone lesions concordant). Two PET-positive bone metastases could not be confirmed morphologically using CTlow-dose, but could be confirmed using MRI. In 12 of 20 patients, 47 PET-positive LNs (71.9 %) were smaller than 1 cm in short axis diameter. There were significant linear correlations between PET/MRI SUVs and PET/CT SUVs in the 64 LN metastases (p < 0.0001) and in the 28 osseous metastases (p < 0.0001) for SUVmean and SUVmax, respectively. The LN SUVs were significantly higher on PET/MRI than on PET/CT (p SUVmax < 0.0001; p SUVmean < 0.0001) but there was no significant difference between the bone lesion SUVs (p SUVmax = 0.495; p SUVmean = 0.381). Visibility of LNs was significantly higher on MRI using the T1-w contrast-enhanced fat-saturated sequence (p = 0.013), the T2-w fat-saturated sequence (p < 0.0001) and the DWI sequence (p < 0.0001) compared with CTlow-dose. For bone lesions, only the overall conspicuity was higher on MRI compared with CTlow-dose (p < 0.006). CONCLUSION: Nodal and osseous metastases of PC are accurately and reliably depicted by hybrid PET/MRI using (68)Ga-PSMA-11 with very low discordance compared with PET/CT including PET-positive LNs of normal size. The correlation between PET/MRI SUVs and PET/CT SUVs was linear in LN and bone metastases but was significantly lower in control (non-metastatic) tissue.

Application of (18)F-FDG PET and diffusion weighted imaging (DWI) in multiple myeloma: comparison of functional imaging modalities.

Aim of this prospective study was to assess the sensitivity of positron emission tomography (PET) and diffusion-weighted imaging (DWI) in detecting multiple myeloma (MM) lesions, using the well-established morphologic modalities magnetic resonance imaging (MRI) and computed tomography (CT) as the standard of reference (RS). The study included 24 MM patients (15 newly diagnosed, 9 pre-treated). All underwent (18)F-FDG PET/CT and wholebody DWI. The findings in PET and DWI were compared to matching imaging findings in combined non-enhanced T1w, fat-saturated T2w (TIRM)- MRI, and low-dose CT. Patient-based analysis revealed that 15/24 patients (10 primary MM, 5 pre-treated) had myeloma lesions according to our RS. PET was positive in 13/24 patients (11 primary MM, 2 pre-treated) and DWI in 18/24 patients (12 primary MM, 6 pre-treated). Lesion-based analysis demonstrated 128 MM lesions, of which PET depicted 60/128 lesions (sensitivity 47%), while DWI depicted 99/128 lesions (sensitivity 77%). Further analysis including only the 15 untreated MM patients revealed a sensitivity of 90% for both PET and DWI and an overall concordance of PET and DWI of 72%. In conclusion, DWI was more sensitive than (18)F-FDG PET in detecting myeloma lesions in a mixed population of primary and pre-treated MM patients. However, (18)F-FDG PET and DWI demonstrated equivalent sensitivities in the sub-population of primary, untreated MM patients. This higher sensitivity of DWI in pre-treated patients may be due to the fact that (18)F-FDG PET becomes negative earlier in the course of treatment in contrary to MRI, in which already treated lesions can remain visible.