Predictive value of C-X-C motif chemokine receptor 4-directed molecular imaging in patients with advanced adrenocortical carcinoma.

BACKGROUND: In patients affected with adrenocortical carcinoma (ACC), C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in sites of disease in an ex-vivo setting. We aimed to determine the predictive value of CXCR4-targeting [68Ga]Ga-PentixaFor PET/CT for outcome when compared to clinical parameters. METHODS: We identified 41 metastasized ACC patients imaged with [68Ga]Ga-PentixaFor PET/CT. Scans were assessed visually and on a quantitative level by manually segmenting the tumor burden (providing tumor volume [TV], peak/mean/maximum standardized uptake values [SUV] and tumor chemokine receptor binding on the cell surface [TRB], defined as SUVmean multiplied by tumor volume). Clinical parameters included sex, previous therapies, age, Weiss-Score, and Ki67 index. Following imaging, overall survival (OS) was recorded. RESULTS: After [68Ga]Ga-PentixaFor PET/CT, median OS was 9 months (range, 1-96 months). On univariable analysis, only higher TRB (per 10 ml, HR 1.004, 95%CI: 1.0001-1.007, P = 0.005) and presence of CXCR4-positive peritoneal metastases (PM) were associated with shorter OS (HR 2.03, 95%CI: 1.03-4.02, P = 0.04). Presence of CXCR4-positive liver metastases (LM) trended towards significance (HR 1.85, 0.9-4.1, P = 0.11), while all other parameters failed to predict survival. On multivariable analysis, only TRB was an independent predictor for OS (HR 1.0, 95%CI: 1.00-1.001, P = 0.02). On Kaplan-Meier analysis, TRB above median (13.3 months vs. below median, 6.4 months) and presence of CXCR4-positive PM (6.4 months, vs. no PM, 11.4 months) were associated with shorter survival (P < 0.05, respectively). Presence of LM, however, was also linked to less favorable outcome (8.5 months vs. no LM, 18.1 months), without reaching significance (P = 0.07). CONCLUSIONS: In advanced ACC, elevated tumor chemokine receptor binding on the tumor cell surface detected through [68Ga]Ga-PentixaFor PET/CT is an independent predictor for OS, while other imaging and clinical parameters failed to provide relevant prognostic information.

Chemokine receptor-targeted PET/CT provides superior diagnostic performance in newly diagnosed marginal zone lymphoma patients: a head-to-head comparison with [18F]FDG.

BACKGROUND: In patients with marginal zone lymphoma (MZL), [18F]FDG PET/CT provided inconsistent diagnostic accuracy. C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in MZL and thus, may emerge as novel theranostic target. We aimed to evaluate the diagnostic performance of CXCR4-targeting [68Ga]Ga-PentixaFor when compared to [18F]FDG PET/CT in MZL. METHODS: Thirty-two untreated MZL patients (nodal, n = 17; extranodal, n = 13; splenic, n = 2) received [68Ga]Ga-PentixaFor and [18F]FDG PET/CT within median 2 days. We performed a visual and quantitative analysis of the total lymphoma volume by measuring maximum/peak standardized uptake values (SUVmax/peak), and calculating target-to-background ratios (TBR, defined as lesion-based SUVpeak divided by SUVmean from blood pool). Visual comparisons for both radiotracers were carried out for all target lesions (TL), and quantitative analysis of concordant TL evident on both scans. Last, MZL subtype analyses were also conducted. RESULTS: On a patient-based level, [68Ga]Ga-PentixaFor identified MZL manifestations in 32 (100%) subjects (vs. [18F]FDG, 25/32 [78.1%]). Of the 256 identified TL, 127/256 (49.6%) manifestations were evident only on CXCR4-directed imaging, while only 7/256 (2.7%) were identified on [18F]FDG but missed by [68Ga]Ga-PentixaFor. In the remaining 122/256 (47.7%) concordant TL, [68Ga]Ga-PentixaFor consistently provided increased metrics when compared to [18F]FDG: SUVmax, 10.3 (range, 2.53-37.2) vs. 5.72 (2.32-37.0); SUVpeak, 6.23 (1.58-25.7) vs. 3.87 (1.54-27.7); P < 0.01, respectively. Concordant TL TBR on [68Ga]Ga-PentixaFor (median, 3.85; range, 1.05-16.0) was also approximately 1.8-fold higher relative to [18F]FDG (median, 2.08; range, 0.81-28.8; P < 0.01). Those findings on image contrast, however, were driven by nodal MZL (P < 0.01), and just missed significance for extranodal MZL (P = 0.06). CONCLUSIONS: In newly diagnosed MZL patients, [68Ga]Ga-PentixaFor identified more sites of disease when compared to [18F]FDG, irrespective of MZL subtype. Quantitative PET parameters including TBR were also higher on [68Ga]Ga-PentixaFor PET/CT, suggesting improved diagnostic read-out using chemokine receptor-targeted imaging.

Test-retest repeatability of organ uptake on PSMA-targeted 18 F-DCFPyL PET/CT in patients with prostate cancer.

OBJECTIVES: We evaluated 18 F-DCFPyL test-retest repeatability of uptake in normal organs. METHODS: Twenty-two prostate cancer (PC) patients underwent two 18 F-DCFPyL PET scans within 7 days within a prospective clinical trial (NCT03793543). In both PET scans, uptake in normal organs (kidneys, spleen, liver, and salivary and lacrimal glands) was quantified. Repeatability was determined by using within-subject coefficient of variation (wCOV), with lower values indicating improved repeatability. RESULTS: For SUVmean , repeatability was high for kidneys, spleen, liver, and parotid glands (wCOV, range: 9.0%-14.3%) and lower for lacrimal (23.9%) and submandibular glands (12.4%). For SUVmax , however, the lacrimal (14.4%) and submandibular glands (6.9%) achieved higher repeatability, while for large organs (kidneys, liver, spleen, and parotid glands), repeatability was low (range: 14.1%-45.2%). CONCLUSION: We found acceptable repeatability of uptake on 18 F-DCFPyL PET for normal organs, in particular for SUVmean in the liver or parotid glands. This may have implications for both PSMA-targeted imaging and treatment, as patient selection for radioligand therapy and standardized frameworks for scan interpretation (PROMISE, E-PSMA) rely on uptake in those reference organs.

Molecular imaging of arterial fibroblast activation protein: association with calcified plaque burden and cardiovascular risk factors.

PURPOSE: We aimed to assess prevalence, distribution, and intensity of in-vivo arterial wall fibroblast activation protein (FAP) uptake, and its association with calcified plaque burden, cardiovascular risk factors (CVRFs), and FAP-avid tumor burden. METHODS: We analyzed 69 oncologic patients who underwent [68 Ga]Ga-FAPI-04 PET/CT. Arterial wall FAP inhibitor (FAPI) uptake in major vessel segments was evaluated. We then investigated the associations of arterial wall uptake with calcified plaque burden (including number of plaques, plaque thickness, and calcification circumference), CVRFs, FAP-positive total tumor burden, and image noise (coefficient of variation, from normal liver parenchyma). RESULTS: High focal arterial FAPI uptake (FAPI +) was recorded in 64/69 (92.8%) scans in 800 sites, of which 377 (47.1%) exhibited concordant vessel wall calcification. The number of FAPI + sites per patient and (FAPI +)-derived target-to-background ratio (TBR) correlated significantly with the number of calcified plaques (FAPI + number: r = 0.45, P < 0.01; TBR: r = - 0.26, P = 0.04), calcified plaque thickness (FAPI + number: r = 0.33, P < 0.01; TBR: r = - 0.29, P = 0.02), and calcification circumference (FAPI + number: r = 0.34, P < 0.01; TBR: r = - 0.26, P = 0.04). In univariate analysis, only body mass index was significantly associated with the number of FAPI + sites (OR 1.06; 95% CI, 1.02 - 1.12, P < 0.01). The numbers of FAPI + sites and FAPI + TBR, however, were not associated with other investigated CVRFs in univariate and multivariate regression analyses. Image noise, however, showed significant correlations with FAPI + TBR (r = 0.30) and the number of FAPI + sites (r = 0.28; P = 0.02, respectively). In addition, there was no significant interaction between FAP-positive tumor burden and arterial wall FAPI uptake (P ≥ 0.13). CONCLUSION: [68 Ga]Ga-FAPI-04 PET identifies arterial wall lesions and is linked to marked calcification and overall calcified plaque burden, but is not consistently associated with cardiovascular risk. Apparent wall uptake may be partially explained by image noise.

mCRPC patients with PSA fluctuations under radioligand therapy have comparable survival benefits relative to patients with sustained PSA decrease.

INTRODUCTION: In men with metastatic castration-resistant prostate cancer (mCRPC) scheduled for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), biochemical response is assessed based on repeated measurements of prostate-specific antigen (PSA) levels. We aimed to determine overall survival (OS) in patients experiencing sustained PSA increase, decrease, or fluctuations during therapy. MATERIALS AND METHODS: In this bicentric study, we included 176 mCRPC patients treated with PSMA-directed RLT. PSA levels were determined using blood samples prior to the first RLT and on the admission days for the following cycles. We calculated relative changes in PSA levels compared to baseline. Kaplan-Meier curves as well as log-rank test were used to compare OS of different subgroups, including patients with sustained PSA increase, decrease, or fluctuations (defined as change after initial decrease or increase after the first cycle). RESULTS: Sixty-one out of one hundred seventy-six (34.7%) patients showed a sustained increase and 86/176 (48.8%) a sustained decrease in PSA levels. PSA fluctuations were observed in the remaining 29/176 (16.5%). In this subgroup, 22/29 experienced initial PSA decrease followed by an increase (7/29, initial increase followed by a decrease). Median OS of patients with sustained decrease in PSA levels was significantly longer when compared to patients with sustained increase of PSA levels (19 vs. 8 months; HR 0.35, 95% CI 0.22-0.56; P < 0.001). Patients with PSA fluctuations showed a significantly longer median OS compared to patients with sustained increase of PSA levels (18 vs. 8 months; HR 0.49, 95% CI 0.30-0.80; P < 0.01), but no significant difference relative to men with sustained PSA decrease (18 vs. 19 months; HR 1.4, 95% CI 0.78-2.49; P = 0.20). In addition, in men experiencing PSA fluctuations, median OS did not differ significantly between patients with initial decrease or initial increase of tumor marker levels (16 vs. 18 months; HR 1.2, 95% CI 0.38-4.05; P = 0.68). CONCLUSION: Initial increase or decrease of PSA levels is sustained in the majority of patients undergoing RLT. Sustained PSA decrease was linked to prolonged survival and men with PSA fluctuations under treatment experienced comparable survival benefits. As such, transient tumor marker oscillations under RLT should rather not lead to treatment discontinuation, especially in the absence of radiological progression.

Combination of Iterative Metal Artifact Reduction and Virtual Monoenergetic Reconstruction Using Split-Filter Dual-Energy CT in Patients With Dental Artifact on Head and Neck CT.

BACKGROUND. Head and neck CT can be limited by dental hardware artifact. Both postprocessing-based iterative metal artifact reduction (IMAR) and virtual monoenergetic imaging (VMI) reconstruction in dual-energy CT (DECT) can reduce metal artifact. Their combination is poorly described for single-source DECT systems. OBJECTIVE. The purpose of this study was to compare metal artifact reduction between VMI, IMAR, and their combination (VMIIMAR) in split-filter single-source DECT of patients with severe dental hardware artifact. METHODS. This retrospective study included 44 patients (nine woman, 35 men; mean age, 66.0 ± 10.4 years) who underwent head and neck CT and had severe dental hardware artifact. Standard, VMI, IMAR, and VMIIMAR images were generated; VMI and VMIIMAR were performed at 40, 70, 100, 120, 150, and 190 keV. ROIs were placed to measure corrected attenuation in pronounced hyperattenuating and hypoattenuating artifacts and artifact-impaired soft tissue and to measure corrected artifact-impaired soft-tissue noise. Two radiologists independently assessed soft-tissue interpretability (1-5 scale), and pooled ratings were analyzed. Readers selected the preferred reconstruction for each patient. RESULTS. Mean hyperattenuating artifact-corrected attenuation was 521.0 HU for standard imaging, 496.4-892.2 HU for VMI, 48.2 HU for IMAR, and 32.8-91.0 HU for VMIIMAR. Mean hypoattenuating artifact-corrected attenuation was -455.1 HU for standard imaging, -408.5 to -679.9 HU for VMI, -37.3 for IMAR, and -17.8 to -36.9 HU for VMIIMAR. Mean artifact-impaired soft tissue-corrected attenuation was 10.8 HU for standard imaging, -0.6 to 24.9 HU for VMI, 4.3 HU for IMAR, and -2.0 to 7.8 HU for VMIIMAR. Mean artifact-impaired soft tissue-corrected noise was 58.7 HU for standard imaging, 38.2 to 129.7 HU for VMI, 11.0 HU for IMAR, and 5.8 to 45.6 HU for VMIIMAR. Median soft-tissue interpretability was 1.2 for standard imaging, 1.1-1.2 for VMI, 3.7 for IMAR, and 2.0-3.8 for VMIIMAR. Artifact-impaired soft tissue-corrected attenuation and soft-tissue interpretability significantly improved (p < .05) for VMIIMAR versus IMAR only at 100 keV. The two readers preferred VMIIMAR at 100 keV in 56.8% and 59.1% of examinations. CONCLUSION. For reducing severe artifact due to dental material, IMAR has greater effect than VMI. Though the results for IMAR and VMIIMAR were similar overall, VMIIMAR had a small benefit at 100 keV. CLINICAL IMPACT. VMI and IMAR techniques in split-filter DECT may be combined for clinical head and neck imaging to reduce artifact from dental hardware and improve image quality.

Accelerated aortic 4D flow MRI with wave-CAIPI.

PURPOSE: The aim of this study was to investigate the acceleration potential of wave-CAIPI (controlled aliasing in parallel imaging) for 4D flow MRI, provided that image quality and precision of flow parameters are maintained. METHODS: The 4D flow MRIs with acceleration factor R = 2 were performed on 10 healthy volunteers, using both wave-CAIPI and standard Cartesian/2D-CAIPI sampling for reference. In addition, 1 patient with known aortic valve stenosis was examined. The flow rate ( Q ), net flow ( Qnet ), peak velocity vmax , and net average through-plane velocity ( v¯âŠ¥ ) were calculated in eight analysis planes in the ascending and descending aorta. The acquisitions were retrospectively undersampled (R = 6), and deviations of flow parameters and hemodynamic flow patterns were evaluated. RESULTS: Flow parameters measured with an undersampled wave-CAIPI trajectory showed considerably smaller deviations to the references than the 2D-CAIPI images. For vmax , the mean absolute differences were 6.02±2.08 cm/s versus 14.36±5.68 cm/s; for Qnet , the mean absolute differences were 3.67±1.40 ml versus 5.87±1.91 ml for wave-CAIPI versus 2D-CAIPI, respectively. Noise calculations indicate that the 2D-CAIPI sampling exhibits a 43±38% higher average noise level than the wave-CAIPI technique. Qualitative discrepancies in hemodynamic flow patterns, visualized through streamlines, particle traces and flow velocity vectors, could be reduced by using the undersampled wave-CAIPI trajectory. CONCLUSION: Use of wave-CAIPI instead of 2D-CAIPI sampling in retrospectively 6-fold accelerated 4D flow MRI enhances the precision of flow parameters. The acquisition time of 4D flow measurements could be reduced by a factor of 3, with minimal differences in flow parameters.

B0 shimming of the human heart at 7T.

PURPOSE: Inhomogeneities of the static magnetic B0 field are a major limiting factor in cardiac MRI at ultrahigh field (≥ 7T), as they result in signal loss and image distortions. Different magnetic susceptibilities of the myocardium and surrounding tissue in combination with cardiac motion lead to strong spatio-temporal B0 -field inhomogeneities, and their homogenization (B0 shimming) is a prerequisite. Limitations of state-of-the-art shimming are described, regional B0 variations are measured, and a methodology for spherical harmonics shimming of the B0 field within the human myocardium is proposed. METHODS: The spatial B0 -field distribution in the heart was analyzed as well as temporal B0 -field variations in the myocardium over the cardiac cycle. Different shim region-of-interest selections were compared, and hardware limitations of spherical harmonics B0 shimming were evaluated by calibration-based B0 -field modeling. The role of third-order spherical harmonics terms was analyzed as well as potential benefits from cardiac phase-specific shimming. RESULTS: The strongest B0 -field inhomogeneities were observed in localized spots within the left-ventricular and right-ventricular myocardium and varied between systolic and diastolic cardiac phases. An anatomy-driven shim region-of-interest selection allowed for improved B0 -field homogeneity compared with a standard shim region-of-interest cuboid. Third-order spherical harmonics terms were demonstrated to be beneficial for shimming of these myocardial B0 -field inhomogeneities. Initial results from the in vivo implementation of a potential shim strategy were obtained. Simulated cardiac phase-specific shimming was performed, and a shim term-by-term analysis revealed periodic variations of required currents. CONCLUSION: Challenges in state-of-the-art B0 shimming of the human heart at 7 T were described. Cardiac phase-specific shimming strategies were found to be superior to vendor-supplied shimming.

Twin robotic x-ray system in small bone and joint trauma: impact of cone-beam computed tomography on treatment decisions.

OBJECTIVES: Trauma evaluation of extremities can be challenging in conventional radiography. A multi-use x-ray system with cone-beam CT (CBCT) option facilitates ancillary 3-D imaging without repositioning. We assessed the clinical value of CBCT scans by analyzing the influence of additional findings on therapy. METHODS: Ninety-two patients underwent radiography and subsequent CBCT imaging with the twin robotic scanner (76 wrist/hand/finger and 16 ankle/foot/toe trauma scans). Reports by on-call radiologists before and after CBCT were compared regarding fracture detection, joint affliction, comminuted injuries, and diagnostic confidence. An orthopedic surgeon recommended therapy based on reported findings. Surgical reports (N = 52) and clinical follow-up (N = 85) were used as reference standard. RESULTS: CBCT detected more fractures (83/64 of 85), joint involvements (69/53 of 71), and multi-fragment situations (68/50 of 70) than radiography (all p < 0.001). Six fractures suspected in radiographs were ruled out by CBCT. Treatment changes based on additional information from CBCT were recommended in 29 patients (31.5%). While agreement between advised therapy before CBCT and actual treatment was moderate (κ = 0.41 [95% confidence interval 0.35-0.47]; p < 0.001), agreement after CBCT was almost perfect (κ = 0.88 [0.83-0.93]; p < 0.001). Diagnostic confidence increased considerably for CBCT studies (p < 0.001). Median effective dose for CBCT was 4.3 µSv [3.3-5.3 µSv] compared to 0.2 µSv [0.1-0.2 µSv] for radiography. CONCLUSIONS: CBCT provides advantages for the evaluation of acute small bone and joint trauma by detecting and excluding extremity fractures and fracture-related findings more reliably than radiographs. Additional findings induced therapy change in one third of patients, suggesting substantial clinical impact. KEY POINTS: • With cone-beam CT, extremity fractures and fracture-related findings can be detected and ruled out more reliably than with conventional radiography. • Additional diagnostic information provided by cone-beam CT scans has substantial impact on therapy in small bone and joint trauma. • For distal extremity injury assessment, one-stop-shop imaging without repositioning is feasible with the twin robotic x-ray system.

Radiation dose of coronary CT angiography with a third-generation dual-source CT in a "real-world" patient population.

OBJECTIVES: To assess radiation dose and image quality of coronary computed tomography angiography (cCTA) with a third-generation dual-source scanner in a real-world patient population. METHODS: Scans of otherwise unselected, consecutive patients referred for clinically indicated cCTA between June 2015 and November 2017 were included for retrospective analysis. Scan protocol was based on heart rate: prospectively ECG-gated high-pitch spiral below 60 beats per minute (bpm), prospectively ECG-gated sequential scan between 61 and 70 bpm, and retrospective spiral above 70 bmp or at irregular heart rates. Objective image quality was measured as signal-to-noise (SNR) and contrast-to-noise ratio (CNR); subjective image quality was evaluated using a five-point Likert scale by two independent readers. For radiation dose analysis, effective dose, size-specific dose estimates, and volume CT dose index were assessed. RESULTS: Two hundred seventy-eight patients (median age, 60 years; 155 men) with a median body mass index of 26.6 kg/m2 (range, 16.7-60.9 kg/m2; 180 (64.7%) overweight or obese) were included (122 in the high-pitch spiral group, 60 in the prospective sequence group, and 96 in the retrospective spiral group). Median effective dose was 0.63 mSv (interquartile range [IQR], 0.51-0.90 mSv) for high-pitch spiral, 1.32 mSv (IQR, 0.79-2.46 mSv) for prospective sequence, and 4.77 (IQR, 3.02-8.27 mSv) for retrospective spiral (p < 0.001). Most studies had at least very good image quality (91.4/88.8% R1/R2), with highest SNR and CNR in the high-pitch spiral group. CONCLUSIONS: cCTA with sufficient image quality is achievable at reasonably low radiation exposure in a real-world patient collective with a high proportion of overweight or obese patients. KEY POINTS: • Submillisievert radiation dose coronary CT angiography with good diagnostic image quality is feasible in the majority of cases in a real-world patient using high-pitch spiral. • Prospective sequence results in about double median effective dose compared to the high-pitch protocol. • To optimize individual radiation exposure, lowering the heart rate is paramount, as it allows for choosing a dose-optimized (high-pitch spiral) scan protocol.

Multiple Myeloma and Dual-Energy CT: Diagnostic Accuracy of Virtual Noncalcium Technique for Detection of Bone Marrow Infiltration of the Spine and Pelvis.

Purpose To determine the diagnostic performance of dual-energy computed tomography (CT) for detection of bone marrow (BM) infiltration in patients with multiple myeloma by using a virtual noncalcium (VNCa) technique. Materials and Methods In this prospective study, 34 consecutive patients with multiple myeloma or monoclonal gammopathy of unknown significance sequentially underwent dual-energy CT and magnetic resonance (MR) imaging of the axial skeleton. Two independent readers visually evaluated standard CT and color-coded VNCa images for the presence of BM involvement. MR imaging served as the reference standard. Analysis on the basis of the region of interest (ROI) of VNCa CT numbers of infiltrated (n = 75) and normal (n = 170) BM was performed and CT numbers were subjected to receiver operating characteristic analysis to calculate cutoff values. Results In the visual analysis, VNCa images had an overall sensitivity of 91.3% (21 of 23), specificity of 90.9% (10 of 11), accuracy of 91.2% (31 of 34), positive predictive value of 95.5% (21 of 22), and a negative predictive value of 83.3% (10 of 12). ROI-based analysis of VNCa CT numbers showed a significant difference between infiltrated and normal BM (P < .001). Receiver operating characteristic analysis revealed an area under the curve of 0.978. A cutoff of -44.9 HU provided a sensitivity of 93.3% (70 of 75), specificity of 92.4% (157 of 170), accuracy of 92.7% (227 of 245), positive predictive value of 84.3% (70 of 83), and negative predictive value of 96.9% (157 of 162) for the detection of BM infiltration. Conclusion Visual and ROI-based analyses of dual-energy VNCa images had excellent diagnostic performance for assessing BM infiltration in patients with multiple myeloma with precision comparable to that of MR imaging. © RSNA, 2017 Online supplemental material is available for this article.

Dual-energy CT of the bone marrow in multiple myeloma: diagnostic accuracy for quantitative differentiation of infiltration patterns.

OBJECTIVES: Bone marrow imaging patterns in patients with multiple myeloma possess prognostic and potential therapeutic relevance. We aim to evaluate whether different magnetic resonance imaging (MRI) patterns also result in different bone marrow dual-energy computed tomography (DECT) virtual non-calcium (VNCa) attenuation values. METHODS: The institutional review board approved this study. Written informed consent was obtained from all participants. 53 patients with plasma cell disorders (24 with normal imaging pattern, 24 with focal infiltration, 5 with diffuse infiltration) and 21 control subjects sequentially underwent DECT and MRI of the axial skeleton. MRI served as reference standard for imaging pattern assessment. Bone marrow VNCa attenuation numbers were obtained according to pattern allocation. Generalised estimating equations and a receiver operating characteristic (ROC) analysis were performed. RESULTS: Mean VNCa attenuation numbers in patients with normal, focal and diffuse imaging patterns were - 65.8 HU, 3.3 HU and - 13.3 HU, respectively. We found significant differences between diffuse vs. normal (p < 0.001), diffuse vs. focal (p = 0.002) and normal vs. focal (p < 0.001) patterns. A cut-off of - 35.7 HU showed a sensitivity of 100% (24/24) and specificity of 97% (116/120) for the identification of a diffuse pattern vs. normal pattern, with an area under the ROC curve of 0.997. CONCLUSIONS: Bone marrow VNCa attenuation numbers of various imaging patterns in patients with plasma cell disorders differ significantly and a diffuse imaging pattern can be determined confidently using DECT, when ROIs are carefully selected on the basis of MRI findings. KEY POINTS: • DECT allows for imaging pattern allocation similar to MRI. • Bone marrow VNCa attenuation numbers differ significantly depending on the imaging pattern. • A diffuse imaging pattern can be determined confidently using DECT.

Vertebral Compression Fractures: Third-Generation Dual-Energy CT for Detection of Bone Marrow Edema at Visual and Quantitative Analyses.

Purpose To assess the diagnostic performance of a third-generation dual-energy computed tomographic (CT) virtual noncalcium (VNCa) technique for detection of traumatic bone marrow edema in patients with vertebral compression fractures. Materials and Methods This prospective study was approved by the institutional review board. Informed consent was obtained from all participants. Twenty-two consecutive patients with 37 morphologic vertebral fractures were studied between October 2015 and May 2016. All patients underwent dual-energy CT (90 kV and 150 kV with a tin filter) and 3-T magnetic resonance (MR) imaging. Two independent readers visually evaluated all vertebral bodies (n = 163) for the presence of abnormal bone marrow attenuation on VNCa images by using color-coded maps and performed a quantitative analysis of CT numbers on VNCa images. MR images served as the reference standard. CT numbers were subjected to receiver operating characteristic analysis to calculate cutoff values. Results In the visual analysis, VNCa images had an overall sensitivity of 64.0%, specificity of 99.3%, accuracy of 93.9%, positive predictive value of 94.1%, and negative predictive value of 93.8%. The interobserver agreement was excellent (κ = 0.85). CT numbers obtained from VNCa images were significantly different in vertebral bodies with and without edema (P < .001). Receiver operating characteristic analysis revealed an area under the curve of 0.922. A cutoff value of -47 provided sensitivity of 92.0%, specificity of 82.6%, accuracy of 84.0%, positive predictive value of 48.9%, and negative predictive value of 98.3% for the differentiation of edematous vertebral bodies. Conclusion Visual and quantitative analyses of dual-energy VNCa images showed excellent diagnostic performance for assessing traumatic bone marrow edema in vertebral compression fractures. © RSNA, 2017 Online supplemental material is available for this article.

Comparison of PET/CT-based eligibility according to VISION and TheraP trial criteria in end-stage prostate cancer patients undergoing radioligand therapy.

BACKGROUND: Two randomized clinical trials demonstrated the efficacy of prostate-specific membrane antigen (PSMA) radioligand therapy (PSMA RLT) in metastatic castration-resistant prostate cancer (mCRPC). While the VISION trial used criteria within PSMA PET/CT for inclusion, the TheraP trial used dual tracer imaging including FDG PET/CT. Therefore, we investigated whether the application of the VISION criteria leads to a benefit in overall survival (OS) or progression-free survival (PFS) for men with mCRPC after PSMA RLT. METHODS: Thirty-five men with mCRPC who had received PSMA RLT as a last-line option and who had undergone pretherapeutic imaging with FDG and [68Ga]Ga-PSMA I&T or [18F]PSMA-1007 were studied. Therapeutic eligibility was retrospectively evaluated using the VISION and TheraP study criteria. RESULTS: 26 of 35 (74%) treated patients fulfilled the VISION criteria (= VISION+) and only 17 of 35 (49%) fulfilled the TheraP criteria (= TheraP+). Significantly reduced OS and PFS after PSMA RLT was observed in patients rated VISION- compared to VISION+ (OS: VISION-: 3 vs. VISION+: 12 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.0-9.1, p < 0.01; PFS: VISION-: 1 vs. VISION+: 5 months, HR 2.7, 95% CI 1.0-7.8, p < 0.01). For patients rated TheraP-, no significant difference in OS but in PFS was observed compared to TheraP+ patients (OS: TheraP-: 5.5 vs. TheraP+: 11 months, HR 1.6, 95% CI 0.8-3.3, p = 0.2; PFS: TheraP-: 1 vs. TheraP+: 6 months, HR 2.2, 95% CI 1.0-4.5, p < 0.01). CONCLUSION: Retrospective application of the inclusion criteria of the VISION study leads to a benefit in OS and PFS after PSMA RL, whereas TheraP criteria appear to be too strict in patients with end-stage prostate cancer. Thus, performing PSMA PET/CT including a contrast-enhanced CT as proposed in the VISION trial might be sufficient for treatment eligibility of end-stage prostate cancer patients.

Volumetric Parameters Derived from CXCR4-Directed PET/CT Predict Outcome in Patients with Gastrointestinal Neuroendocrine Carcinomas.

BACKGROUND: Gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs) are an aggressive subgroup of neuroendocrine neoplasms (NENs). In patients affected with NEN, there is a growing body of evidence that increased C-X-C motif chemokine receptor (CXCR4) expression is linked to decreasing overall survival (OS) in an ex-vivo setting. Thus, we aimed to determine whether the in-vivo-derived CXCR4-directed whole-body PET signal can also determine GEP-NEC patients with shorter OS. METHODS: We retrospectively included 16 patients with histologically proven GEP-NEC, who underwent CXCR4-directed PET/CT for staging and therapy planning. We assessed maximum, peak, and mean standardized uptake values as well as whole-body tumor volume (TV) and total-lesion uptake (TLU = SUVmean × TV) using a semi-automatic segmentation tool with a 50% threshold. Association of PET-based biomarkers and OS or radiographic progression-free survival (rPFS; according to RECIST 1.1 criteria) was analyzed using univariable and multivariable cox regression. RESULTS: Median OS and rPFS was 7.5 and 7 months, respectively. A significant correlation between TV and TLU was found for OS (TV: hazard ratio (HR) 1.007 95% confidence interval (CI) 1.000-1.014, p = 0.0309; TLU: HR 1.002 95% CI 1.000-1.003, p = 0.0350) and rPFS (TV: HR 1.010 95% CI 1.002-1.021; p = 0.0275; TLU: HR 1.002 95% CI 1.000-1.004, p = 0.0329), respectively. No significant correlation with OS or rPFS was found for non-volumetric parameters (p > 0.4). TV remained a significant predictive marker for OS and rPFS in multivariable analysis (OS: HR 1.012 95%, CI 1.003-1.022, p = 0.0084; rPFS: HR 1.009, 95% CI 0.9999-1.019, p = 0.0491), whereas TLU remained only prognostic for OS (HR 1.009, 95% CI 0.9999-1.019, p = 0.0194) but narrowly failed significance for rPFS (p = 0.0559). CONCLUSION: In-vivo assessment of CXCR4 PET-derived volumetric parameters is predictive for outcome of patients with GEP-NEC and could be used as a risk stratification tool, which detects patients prone to early progression.

Evaluating the Patterns of FAPI Uptake in the Shoulder Joint: a Preliminary Study Comparing with FDG Uptake in Oncological Studies.

BACKGROUND: Fibroblast activation protein inhibitor (FAPI) targeting PET has been introduced as a novel molecular imaging modality for visualizing cancer-associated fibroblasts. There have also been reports suggesting incidental findings of localized accumulation in the shoulder joints. However, further characterization in a larger patient cohort is still lacking. METHODS: 77 consecutive patients (28 females; mean age, 63.1 ± 11.6) who underwent Ga-68 FAPI-04 PET/CT for diagnosis of solid tumors were included. The incidence and localization of tracer uptake in shoulder joints were investigated and compared with available F-18 FDG scans serving as reference. RESULTS: Ga-68 FAPI-04 uptake was evaluated in 77 patients (154 shoulder joints), of whom 54 subjects (108 shoulder joints) also had available F-18 FDG scans for head-to-head comparison. On FAPI-targeted imaging, 67/154 shoulders (43.5%) demonstrated increased radiotracer accumulation in target lesions, which were distributed as follows: acromioclavicular (AC) joints in 25/67 (37.3%), followed by glenohumeral and subacromial (GH + SA) joints in 23/67 (34.3%), or both (AC and GH + SA joints) in the remaining 19/67 (28.4%). Ga-68 FAPI-04 correlated with quantified F-18 FDG uptake (r = 0.69, p < 0.0001). Relative to the latter radiotracer, however, in-vivo FAP expression in the shoulders was significantly increased (Ga-68 FAPI-04, 4.7 ± 3.2 vs F-18 FDG, 3.6 ± 1.3, p < 0.001). CONCLUSION: Our study revealed focal accumulation of Ga-68 FAPI-04 in the shoulders, particularly in the AC joints, with higher uptake compared to the inflammatory-directed PET radiotracer F-18 FDG in oncological studies. As a result, further trials are warranted to investigate the potential of FAPI-directed molecular imaging in identifying chronic remodeling in shoulder joints. This could have implications for initiating anti-FAP targeted photodynamic therapy based on PET signal strength.

Prognostic role of quantitative [18F]FDG PET/CT parameters in adrenocortical carcinoma.

PURPOSE: We aimed to evaluate the prognostic potential of baseline [18F]FDG PET/CT for overall survival (OS) in patients with adrenocortical carcinoma (ACC). METHODS: We performed a retrospective analysis of 67 treatment-naïve ACC patients with available [18F]FDG PET/CT at time of initial diagnosis. Pretherapeutic PETs of primary tumors were manually segmented and quantitative parameters (maximum/mean/peak standardized uptake value (SUVmax/mean/peak), metabolic tumor volume (MTV) and tumor lesion glycolysis (TLG, defined as TV*SUVmean) were derived. Based on a visual read, absence (M0) or presence of metastatic disease (M1) were evaluated. Kaplan-Meier and Cox regression analyses were used to determine the prognostic value of the above mentioned markers on overall survival adjusted for established prognostic markers. RESULTS: 24/67 patients (36%) presented with M0 based on PET/CT, while the remaining 43/67 (64%) had M1-status. 32/67 patients died during follow-up and median OS was 48 months. In 12% of patients FDG-PET detected additional metastatic lesion not clearly visible by CT only. In univariable analysis, all quantitatively derived PET parameters failed to reach significance (P ≥ 0.1), and only PET/CT-based M1-status and Ki-67 were associated with increased mortality (M1: HR 13.89, 95% CI 4.15-86.32, P < 0.001; Ki-67 HR 1.29, 95% CI 1.16-1.42; P < 0.0001). Using multivariable Cox regression analyses, M1-status (HR 9.69, 95% CI 2.82-60.99) and Ki-67 index (HR 1.29, 95% CI 1.13-1.04; P < 0.05) remained significant associated with OS. CONCLUSION: In treatment-naïve ACC patients, the quantitative PET parameter failed to predict OS, but presence of metastases detected by [18F]FDG PET/CT and Ki-67 index were independently associated with shorter OS. Therefore, a simple visual PET-based read-out is of prognostic value at initial diagnosis, while time-consuming PET-based quantification can be omitted.

Radiopharmaceuticals for Treatment of Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) represents a rare tumor entity with limited treatment options and usually rapid tumor progression in case of metastatic disease. As further treatment options are needed and ACC metastases are sensitive to external beam radiation, novel theranostic approaches could complement established therapeutic concepts. Recent developments focus on targeting adrenal cortex-specific enzymes like the theranostic twin [123/131I]IMAZA that shows a good image quality and a promising therapeutic effect in selected patients. But other established molecular targets in nuclear medicine such as the C-X-C motif chemokine receptor 4 (CXCR4) could possibly enhance the therapeutic regimen as well in a subgroup of patients. The aims of this review are to give an overview of innovative radiopharmaceuticals for the treatment of ACC and to present the different molecular targets, as well as to show future perspectives for further developments since a radiopharmaceutical with a broad application range is still warranted.

Wnt/ß-catenin modulating drugs regulate somatostatin receptor expression and internalization of radiolabelled octreotide in neuroendocrine tumor cells.

BACKGROUND: Differentiated neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs), targets for therapy with either unlabeled or radioactively labeled somatostatin analogs (SSA). Associated with worse prognosis, dedifferentiated NET loose SSTR expression, which may be linked to deregulation of Wnt/ß-catenin signaling on an intracellular level. The aim of the present study was to investigate the effect of Wnt/ß-catenin signaling pathway alterations on SSTR expression and its function in NET. METHODS: The NET cell lines BON-1 and QGP-1 were incubated with the Wnt-inhibitors 5-aza-2'-deoxycytidine (5-aza-CdR), Quercetin, or Niclosamide, or the Wnt activator lithium chloride (LiCl). Expression of SSTR1, SSTR2, and SSTR5 was determined by quantitative RT-PCR (qRT-PCR), immunocytomicroscopy and western blot. Changes in the Wnt pathway were analyzed by qRT-PCR of selected target genes and the TaqMan Array Human WNT Pathway. Receptor-associated function was determined by measuring the cellular uptake of [125I-Tyr3] octreotide. RESULTS: The mRNAs of SSTRs 1-5 were expressed in both cell lines. Wnt inhibitors caused downregulation of Wnt target genes, while 5-aza-CdR had the highest inhibitory effect. LiCl lead to an upregulation of Wnt genes, which was more marked in QGP-1 cells. SSTR expression increased in both cell lines upon Wnt inhibition. All three Wnt inhibitors lead to a marked increase in the specific uptake of [125I-Tyr3]octreotide, with 5-aza-CdR showing the greatest effect (increase by more than 50% in BON-1 cells), while a decreased uptake of [125I-Tyr3]octreotide was seen upon activation of Wnt signaling by LiCl. CONCLUSIONS: We demonstrate here that Wnt signaling orchestrates SSTR expression and function in a preclinical NET model. Wnt inhibition increases [125I-Tyr3]octreotide uptake offering an opportunity to enhance the efficacy of SSTR-targeted theranostic approaches.

Somatostatin Receptor-Directed PET/CT for Therapeutic Decision-Making and Disease Control in Patients Affected With Small Cell Lung Cancer.

BACKGROUND: Somatostatin receptor (SSTR)-targeted PET/CT is used for patients affected with small cell lung cancer (SCLC), but the clinical impact has not been elucidated yet. We aimed to determine whether SSTR PET/CT can trigger relevant therapeutic management changes in patients with SCLC and whether those modifications achieve disease control and are associated with prolonged survival. METHODS: One hundred patients with SCLC received SSTR PET/CT. In a retrospective setting, we evaluated the diagnostic performance of PET versus CT and compared therapies before and after PET/CT to determine the impact of molecular imaging on treatment decision. We also determined the rate of disease control after therapeutic modifications and assessed survival in patients with and without changes in the therapeutic regimen. RESULTS: Relative to CT, SSTR PET alone was superior for assessing bone lesions in 19 of 39 instances (49%). Treatment was modified in 59 of 100 (59%) after SSTR PET/CT. Forty of 59 (74.6%) received systemic treatment after hybrid imaging, with the remaining 15 of 59 (25.4%) scheduled for nonsystemic therapy. In the latter group, 13 of 15 (86.7%) received local radiation therapy or active surveillance (2/15 [13.3%]). Individuals scheduled for systemic treatment after imaging received peptide receptor radionuclide therapy (PRRT) in 28 of 44 (63.6%), followed by chemotherapy in 10 of 44 (22.7%), change in chemotherapy regimen in 3 of 44 (6.8%), and initiation of tyrosine kinase inhibitor in the remaining 3 of 44 (6.8%). Among patients with modified treatment, follow-up was available in 53 subjects, and disease control was achieved in 14 of 53 (26.4%). However, neither change to systemic treatment (155 days; hazard ratio, 0.94; 95% confidence interval, 0.53-1.67) nor change to nonsystemic treatment (210 days; hazard ratio, 0.67; 95% confidence interval, 0.34-1.34) led to a prolonged survival when compared with subjects with no change (171 days, P ≥ 0.22, respectively). CONCLUSIONS: In patients with SCLC, SSTR-targeted hybrid imaging provides complementary information on the disease status. PET/CT led to management changes in 59% (mainly PRRT), achieving disease control in >26%. The high fraction of patients scheduled for PRRT may lay the foundation for combination strategies to achieve synergistic antitumor effects, for example, by combining PRRT plus recently introduced RNA polymerase II inhibitors.