Quantitative and Qualitative Analyses of Biodistribution and PET Image Quality of a Novel Radiohybrid PSMA, 18F-rhPSMA-7, in Patients with Prostate Cancer.

Radiohybrid PSMA (rhPSMA) ligands, a new class of theranostic prostate-specific membrane antigen (PSMA)-targeting agents, feature fast 18F synthesis and utility for labeling with radiometals. Here, we assessed the biodistribution and image quality of 18F-rhPSMA-7 to determine the best imaging time point for patients with prostate cancer. Methods: In total, 202 prostate cancer patients who underwent a clinically indicated 18F-rhPSMA-7 PET/CT were retrospectively analyzed, and 12 groups based on the administered activity and uptake time of PET scanning were created: 3 administered activities (low, 222-296 MBq; moderate, 297-370 MBq; and high, 371-444 MBq) and 4 uptake time points (short, 50-70 min; intermediate, 71-90 min; long, 91-110 min; and extra long, ≥111 min). For quantitative analyses, SUVmean and organ- or tumor-to-background ratio were determined for background, healthy organs, and 3 representative tumor lesions. Qualitative analyses assessed overall image quality, nonspecific blood-pool activity, and background uptake in bone or marrow using 3- or 4-point scales. Results: In quantitative analyses, SUVmean showed a significant decrease in the blood pool and lungs and an increase in the kidneys, bladder, and bones as the uptake time increased. SUVmean showed a trend to increase in the blood pool and bones as the administered activity increased. However, no significant differences were found in 377 tumor lesions with respect to the administered activity or uptake time. In qualitative analyses, the overall image quality was stable along with the uptake time, but the proportion rated to have good image quality decreased as the administered activity increased. All other qualitative image parameters showed no significant differences for the administered activities, but they showed significant trends with increasing uptake time: less nonspecific blood activity, more frequent background uptake in the bone marrow, and increased negative impact on clinical decision making. Conclusion: The biodistribution of 18F-rhPSMA-7 was similar to that of established PSMA ligands, and tumor uptake of 18F-rhPSMA-7 was stable across the administered activities and uptake times. An early imaging time point (50-70 min) is recommended for 18F-rhPSMA-7 PET/CT to achieve the highest overall image quality.

[68Ga]Pentixafor PET/MR imaging of chemokine receptor 4 expression in the human carotid artery.

PURPOSE: Type 4 chemokine receptor (CXCR4) plays an important role in immune cell migration during the atherosclerosis progression. We aimed to evaluate [68Ga]Pentixafor positron emission tomography (PET) in combination magnetic resonance imaging (MRI) for in vivo quantification of CXCR4 expression in carotid plaques. METHODS: Seventy-two patients with lymphoma were prospectively scheduled for whole body [68Ga]Pentixafor PET/MRI with an additional T2-weighted carotid sequence. Volumes of interest (VOIs) were drawn along the carotid bifurcation regions, and the maximum tissue-to-blood ratios (TBR) of [68Ga]Pentixafor uptake were calculated. Lesions were categorized into non-eccentric (n = 27), mild eccentric (n = 67), moderately (n = 41) and severely (n = 19) eccentric carotid atherosclerosis. A different cohort of symptomatic patients (n = 10) with carotid stenosis scheduled for thrombendarterectomy (TEA) was separately imaged with 3T MRI with dedicated plaque sequences (time of flight, T1-, and T2-weighted). MRI findings were correlated with histochemical assessment of intact carotid plaques. RESULTS: At hybrid PET/MRI, we observed significantly increased [68Ga]Pentixafor uptake in mildly (mean TBRmax = 1.57 ± 0.27, mean SUVmax = 2.51 ± 0.39), moderately (mean TBRmax = 1.64 ± 0.37, mean SUVmax = 2.61 ± 0.55) and severely eccentric carotids (mean TBRmax = 1.55 ± 0.26, mean SUVmax = 2.40 ± 0.44) as compared to non-eccentric carotids (mean TBRmax = 1.29 ± 0.21, mean SUVmax = 1.77 ± 0.42) (p ≤ 0.05). Histological findings from TEA confirmed that prominent CXCR4 expression was localized within inflamed atheromas and preatheromas. Co-localization of cellular CXCR4 and CD68 expression in the plaque was observed by immunofluorescence staining. CONCLUSIONS: In vivo evaluation of CXCR4 expression in carotid atherosclerotic lesions is feasible using [68Ga]Pentixafor PET/MRI. In atherosclerotic plaque tissue, CXCR4 expression might be used as a surrogate marker for inflammatory atherosclerosis.

Immunohistochemical detection of chemokine receptor 4 expression in chronic osteomyelitis confirms specific uptake in 68Ga-Pentixafor-PET/CT.

Previous findings of our group showed the chemokine receptor CXCR4 as a suitable target in PET/CT-imaging of axial bone infections, early postoperative osteomyelitis and periprosthetic infections. The aim of this study was to verify specific uptake of 68Ga-Pentixafor in chronic osteomyelitis. METHODS: 29 consecutive patients who underwent 68Ga-Pentixafor-PET/CT with clinically suspected osteomyelitis were evaluated retrospectively. Bone tissues of 6 patients were available and evaluated by immunohistochemical staining for CXCR4 and autoradiography with 68Ga-Pentixafor. Staining was performed with an anti-CXCR4 antibody. In order to detect lymphocytic infiltration and CXCR4-expressing lymphocytes double immunofluorescence with an anti-CD3 and anti-CXCR4 antibody was performed. RESULTS: 68Ga-Pentixafor-PET/ CT was true positive in 16 and true negative in 13 patients. In available bone tissue samples, immunohistochemical staining of CXCR4 expression and autoradiography with 68Ga-Pentixafor was highly positive. Double immunofluorescence was able to detect CXCR4-expressing T-lymphocytes within all bone samples while a control sample of noninfected tibial bone was negative for CXCR4. CONCLUSION: 68Ga-Pentixafor-PET/CT specifically shows CXCR4-expressing immune cells in chronic osteomyelitis and is therefore a suitable method for imaging chronic infection of the skeleton.Der Chemokinrezeptor CXCR4 konnte in einer Pilotstudie unserer Arbeitsgruppe als geeignete Zielstruktur zur PET/CT-Bildgebung von frühen postoperativen und periprothetischen Osteomyelitiden sowie Osteomyelitiden im Stammskelett identifiziert werden. In dieser Studie haben wir untersucht, ob 68Ga-Pentixafor spezifisch CXCR4-exprimierende Entzündungszellen in einer chronischen Osteomyelitis darstellen kann. METHODEN: Es erfolgte eine retrospektive Auswertung von 29 Patienten mit klinischem Verdacht einer chronischen Osteomyelitis, die mittels 68Ga-Pentixafor-PET/CT untersucht wurden. Hiervon lagen uns in 6 Fällen Knochengewebe zur immunhistochemischen und autoradiographischen Evaluation vor. Die Immunhistochemie wurde mit einem anti-CXCR4 Antikörper durchgeführt. Des Weiteren wurden ein anti-CD3 und der anti-CXCR4-Antikörper zur Detektion CXCR4-exprimierender Lymphozyten am Ort der Entzündung mittels Doppel- Immunfluoreszenz verwendet. ERGEBNISSE: Die 68Ga-Pentixafor-PET/CT war bei 16 Patienten richtig positiv und bei 13 Patienten richtig negativ. Die Färbungen der verfügbaren Knochenpräparate waren sowohl in der Immunhistochemie als auch in der Autoradiographie deutlich positiv. In der Immunfluoreszenz konnten zudem CXCR4-exprimierende Lymphozyten am Ort der Entzündung in allen Proben nachgewiesen werden. Die Kontrolle eines Präparats einer nicht infizierten distalen Tibia zeigte dagegen keine CXCR4-oder CD3-Expression. FAZIT: Mit der 68Ga-Pentixafor-PET/CT können spezifisch CXCR4-exprimierende Lymphozyten am Ort der Entzündung nachgewiesen werden. Die 68Ga-Pentixafor-PET/CT stellt eine geeignete Methode in der Diagnostik chronischer Osteomyeltiden dar.

Imaging of chemokine receptor CXCR4 expression in culprit and nonculprit coronary atherosclerotic plaque using motion-corrected [68Ga]pentixafor PET/CT.

PURPOSE: The chemokine receptor CXCR4 is a promising target for molecular imaging of CXCR4+ cell types, e.g. inflammatory cells, in cardiovascular diseases. We speculated that a specific CXCR4 ligand, [68Ga]pentixafor, along with novel techniques for motion correction, would facilitate the in vivo characterization of CXCR4 expression in small culprit and nonculprit coronary atherosclerotic lesions after acute myocardial infarction by motion-corrected targeted PET/CT. METHODS: CXCR4 expression was analysed ex vivo in separately obtained arterial wall specimens. [68Ga]Pentixafor PET/CT was performed in 37 patients after stent-based reperfusion for a first acute ST-segment elevation myocardial infarction. List-mode PET data were reconstructed to five different datasets using cardiac and/or respiratory gating. Guided by CT for localization, the PET signals of culprit and various groups of nonculprit coronary lesions were analysed and compared. RESULTS: Ex vivo, CXCR4 was upregulated in atherosclerotic lesions, and mainly colocalized with CD68+ inflammatory cells. In vivo, elevated CXCR4 expression was detected in culprit and nonculprit lesions, and the strongest CXCR4 PET signal (median SUVmax 1.96; interquartile range, IQR, 1.55-2.31) was observed in culprit coronary artery lesions. Stented nonculprit lesions (median SUVmax 1.45, IQR 1.23-1.88; P = 0.048) and hot spots in naive remote coronary segments (median SUVmax 1.34, IQR 1.23-1.74; P = 0.0005) showed significantly lower levels of CXCR4 expression. Dual cardiac/respiratory gating provided the strongest CXCR4 PET signal and the highest lesion detectability. CONCLUSION: We demonstrated the basic feasibility of motion-corrected targeted PET/CT imaging of CXCR4 expression in coronary artery lesions, which was triggered by vessel wall inflammation but also by stent-induced injury. This novel methodology may serve as a platform for future diagnostic and therapeutic clinical studies targeting the biology of coronary atherosclerotic plaque.

Isolated metastasis of an EGFR-L858R-mutated NSCLC of the meninges: the potential impact of CXCL12/CXCR4 axis in EGFRmut NSCLC in diagnosis, follow-up and treatment.

Brain and leptomeningeal metastasis (LMM) of non-small cell lung cancer is still associated with poor prognosis. Moreover, the current diagnostic standard for LMM often yields false negative results and the scientific progress in this field is still unsatisfying. We present a case of a 71-year old patient with an isolated LMM. While standard diagnostics could only diagnose a cancer of unknown primary, the use of [68Ga]-Pentixafor-PET/CT (CXCR4-PET/CT, a radiotracer targeting CXCR4) and a liquid biopsy of the cerebrospinal fluid revealed the primary NSCLC. The detection of L858R-EGFR, a common driver mutation in NSCLC, enabled us to treat the patient with Afatinib and monitor treatment using [68Ga]-Pentixafor PET/CT. To estimate the impact of CXCR4 signaling and its ligands in NSCLC brain metastasis we looked at their expression and correlation with EGFR mutations in a primary and brain metastasis data set and investigated the previously described binding of extracellular ubiquitin to CXCR4. In conclusion, we describe a novel approach to improve diagnostics towards LMM and underline the impact of the CXCL12/CXCR4 axis in brain metastasis in a subset of NSCLC patients. We cannot confirm a correlation of CXCR4 expression with EGFR mutations or the binding of extracellular ubiquitin as previously reported.

[68Ga]Pentixafor-PET/MRI for the detection of Chemokine receptor 4 expression in atherosclerotic plaques.

PURPOSE: The expression of chemokine receptor type 4 (CXCR4) was found co-localized with macrophages on the atherosclerotic vessel wall and participated in the initial emigration of leukocytes. Gallium-68 [68Ga]Pentixafor has recently been introduced for the imaging of atherosclerosis by targeting CXCR4. We sought to evaluate human atherosclerotic lesions using [68Ga]Pentixafor PET/MRI. METHODS: Thirty-eight oncology patients underwent [68Ga]Pentixafor PET/MR imaging at baseline. Maximum standardized uptake values (SUVmax) were derived from hot lesions in seven arterial segments and target-to-blood ratios (TBR) were calculated. ANOVA post-hoc and paired t test were performed for statistical comparison, Spearman's correlation coefficient between uptake ratios and cardiovascular risk factors were assessed. The reproducibility of [68Ga]Pentixafor PET/MRI was assessed in seven patients with a follow-up exanimation by Pearson's regression and Bland-Altman plots analysis. RESULTS: Thirty-four of 38 patients showed 611 focal [68Ga]Pentixafor uptake that followed the contours of the large arteries. Both prevalence and mean TBRmax were highest in the descending aorta. There were significantly higher TBR values found in men (1.9 ± 0.3) as compared to women (1.7 ± 0.2; p < 0.05). Patients with mean TBRmax > 1.7 showed a significantly higher incidence of diabetes, hypertension hypercholesterolemia and history of cardiovascular disease than patients with mean TBRmax ≤ 1.7. [68Ga]Pentixafor uptake showed a good reproducibility (r = 0.6, p < 0.01), and there was no difference between the mean TBRmax values of plaque lesions (TBRbaseline1.8 ± 0.3 vs TBRfollow-up1.8 ± 0.3) (p = 0.9). CONCLUSION: Patients with high arterial uptake showed increased incidence of cardiovascular risk factors, suggesting a potential role of [68Ga]Pentixafor in characterization of atherosclerosis.

Clinical Molecular Imaging of Chemokine Receptor CXCR4 Expression in Atherosclerotic Plaque Using 68Ga-Pentixafor PET: Correlation with Cardiovascular Risk Factors and Calcified Plaque Burden.

The CXC-motif chemokine receptor 4 (CXCR4) represents a promising target for molecular imaging of different CXCR4-positive cell types in cardiovascular diseases such as atherosclerosis and arterial wall injury. The aim of this study was to assess the prevalence, pattern, and clinical correlates of arterial wall accumulation of 68Ga-pentixafor, a specific CXCR4 ligand for PET. Methods: The data for 51 patients who underwent 68Ga-pentixafor PET/CT for noncardiovascular indications were retrospectively analyzed. Tracer accumulation in the vessel wall of major arteries was analyzed qualitatively and semiquantitatively by blood-pool-corrected target-to-background ratios. Tracer uptake was compared with calcified plaque burden and cardiovascular risk factors. Results: Focal arterial uptake of 68Ga-pentixafor was seen at 1,411 sites in 51 (100%) of patients. 68Ga-pentixafor uptake was significantly associated with calcified plaque burden (P < 0.0001) and cardiovascular risk factors including age (P < 0.0001), arterial hypertension (P < 0.0001), hypercholesterolemia (P = 0.0005), history of smoking (P = 0.01), and prior cardiovascular events (P = 0.0004). Both the prevalence (P < 0.0001) and the signal intensity (P = 0.009) of 68Ga-pentixafor uptake increased as the number of risk factors increased. Conclusion:68Ga-pentixafor PET/CT is suitable for noninvasive, highly specific PET imaging of CXCR4 expression in the atherosclerotic arterial wall. Arterial wall 68Ga-pentixafor uptake is significantly associated with surrogate markers of atherosclerosis and is linked to the presence of cardiovascular risk factors. 68Ga-pentixafor signal is higher in patients with a high-risk profile and may hold promise for identification of vulnerable plaque.

Targeting CXCR4 (CXC Chemokine Receptor Type 4) for Molecular Imaging of Aldosterone-Producing Adenoma.

Primary aldosteronism is the most frequent cause of secondary hypertension and is associated with increased morbidity and mortality compared with hypertensive controls. The central diagnostic challenge is the differentiation between bilateral and unilateral disease, which determines treatment options. Bilateral adrenal venous sampling, currently recommended for differential diagnosis, is an invasive procedure with several drawbacks, making it desirable to develop novel noninvasive diagnostic tools. When investigating the expression pattern of chemokine receptors by quantitative real-time polymerase chain reaction and immunohistochemistry, we observed high expression of CXCR4 (CXC chemokine receptor type 4) in aldosterone-producing tissue in normal adrenals, adjacent adrenal cortex from adrenocortical adenomas, and in aldosterone-producing adenomas (APA), correlating strongly with the expression of CYP11B2 (aldosterone synthase). In contrast, CXCR4 was not detected in the majority of nonfunctioning adenomas that are frequently found coincidently. The specific CXCR4 ligand 68Ga-pentixafor has recently been established as radiotracer for molecular imaging of CXCR4 expression and showed strong and specific binding to cryosections of APAs in our study. We further investigated 9 patients with primary aldosteronism because of APA by 68Ga-pentixafor-positron emission tomography. The tracer uptake was significantly higher on the side of increased adrenocortical aldosterone secretion in patients with APAs compared with patients investigated by 68Ga-pentixafor-positron emission tomography for other causes. Molecular imaging of aldosterone-producing tissue by a CXCR4-specific ligand may, therefore, be a highly promising tool for noninvasive characterization of patients with APAs.

Targeting CXCR4 with [68Ga]Pentixafor: a suitable theranostic approach in pleural mesothelioma?

C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [68Ga]Pentixafor in malignant pleural mesothelioma. Six patients with pleural mesothelioma underwent [68Ga]Pentixafor-PET/CT. 2'-[18F]fluoro-2'-deoxy-D-glucose ([18F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up. Whereas [18F]FDG-PET depicted active lesions in all patients, [68Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [68Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed. In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy.

[177Lu]pentixather: Comprehensive Preclinical Characterization of a First CXCR4-directed Endoradiotherapeutic Agent.

Purpose: Based on the clinical relevance of the chemokine receptor 4 (CXCR4) as a molecular target in cancer and on the success of [68Ga]pentixafor as an imaging probe for high-contrast visualization of CXCR4-expression, the spectrum of clinical CXCR4-targeting was expanded towards peptide receptor radionuclide therapy (PRRT) by the development of [177Lu]pentixather. Experimental design: CXCR4 affinity, binding specificity, hCXCR4 selectivity and internalization efficiency of [177Lu]pentixather were evaluated using different human and murine cancer cell lines. Biodistribution studies (1, 6, 48, 96h and 7d p.i.) and in vivo metabolite analyses were performed using Daudi-lymphoma bearing SCID mice. Extrapolated organ doses were cross-validated with human dosimetry (pre-therapeutic and during [177Lu]pentixather PRRT) in a patient with multiple myeloma (MM). Results: [177Lu]pentixather binds with high affinity, specificity and selectivity to hCXCR4 and shows excellent in vivo stability. Consequently, and supported by >96% plasma protein binding and a logP=-1.76, delaying whole-body clearance of [177Lu]pentixather, tumor accumulation was high and persistent, both in the Daudi model and the MM patient. Tumor/background ratios (7d p.i.) in mice were 499±202, 33±7, 4.0±0.8 and 116±22 for blood, intestine, kidney and muscle, respectively. In the patient, high tumor/kidney and tumor/liver dose ratios of 3.1 and 6.4 were observed during [177Lu]pentixather PRRT (7.8 GBq), with the kidneys being the dose-limiting organs. Conclusions: [177Lu]pentixather shows excellent in vivo CXCR4-targeting characteristics and a suitable pharmacokinetic profile, leading to high tumor uptake and retention and thus high radiation doses to tumor tissue during PRRT, suggesting high clinical potential of this [68Ga]pentixafor/[177Lu]pentixather based CXCR4-targeted theranostic concept.

Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach.

C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [68Ga]Pentixafor in comparison to 68Ga-DOTA-D-Phe-Tyr3-octreotide ([68Ga]DOTATOC) and 18F-fluorodeoxyglucose ([18F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [68Ga]DOTATOC, [18F]FDG, and [68Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [68Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [18F]FDG revealed sites of disease in 10/12 and [68Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [68Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [68Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors.

CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed Multiple Myeloma.

C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM). Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival. ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive. CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted.

[68Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - Comparison to [18F]FDG and laboratory values.

Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [68Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies. Thirty-five patients with MM underwent [68Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [18F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity. [68Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [18F]FDG was available, [68Ga]Pentixafor-PET detected more lesions in 4/19 (21%) subjects, [18F]FDG proved superior in 7/19 (37%). In the remaining 8/19 (42%) patients, both tracers detected an equal number of lesions. [18F]FDG-PET positivity correlated with [68Ga]Pentixafor-PET positivity (p=0.018). [68Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.

Investigating the Chemokine Receptor 4 as Potential Theranostic Target in Adrenocortical Cancer Patients.

PURPOSE: Adrenocortical carcinoma (ACC) is a rare but aggressive endocrine tumor with limited treatment options. Preclinical studies confirmed overexpression of the chemokine receptor 4 (CXCR4) in this cancer type. This study aimed to analyze the role of CXCR4 imaging using Ga-pentixafor for ACC staging and selection of patients for CXCR4-directed endoradiotherapy. METHODS: Thirty patients with histologically proven advanced, metastasized ACC underwent F-FDG PET/CT and Ga-pentixafor PET/CT within a time interval of 3 ± 4 days to evaluate suitability for CXCR4-directed endoradiotherapy. Scans were analyzed retrospectively for visual extent of ACC and SUVmax/mean of the tumor lesions. Ga-pentixafor PET was compared with F-FDG PET, the reference imaging standard. All patients were rated for suitability of CXCR4-directed endoradiotherapy considering patient's history, previous treatment, and CXCR4 expression of FDG-positive lesions compared with background activity within the same organ. RESULTS: All patients had lesions that were positive for both F-FDG and Ga-pentixafor PET and were rated as positive for disease. In 2 patients (7%), Ga-pentixafor PET identified more lesions compared with F-FDG PET. In 5 patients (17%) and 10 patients (33%), complementary and comparable information, respectively, was provided by dual-tracer imaging. In 13 patients (43%), more tumor lesions were identified by F-FDG PET compared with Ga-pentixafor PET. The F-FDG uptake of the malignant lesions was significantly higher (P < 0.01) than the SUVmax/mean for Ga-pentixafor. Overall, 70% of the patients were rated as suitable or potentially suitable for CXCR4-directed treatment. CONCLUSIONS: Ga-pentixafor allows in vivo imaging of CXCR4 expression in patients with advanced ACC and may serve as companion diagnostic tool in selecting patients for potential CXCR4-directed endoradiotherapy. Seventy percent of the patients with advanced, metastasized ACC may be suitable for a CXCR4-directed treatment after failure of standard treatment options.

68Ga-TRAP-(RGD)3 Hybrid Imaging for the In Vivo Monitoring of αvß3-Integrin Expression as Biomarker of Anti-Angiogenic Therapy Effects in Experimental Breast Cancer.

OBJECTIVES: To investigate 68Ga-TRAP-(RGD)3 hybrid imaging for the in vivo monitoring of αvß3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer. MATERIALS AND METHODS: Human breast cancer (MDA-MB-231) xenografts were implanted orthotopically into the mammary fat pads of n = 25 SCID mice. Transmission/emission scans (53 min to 90 min after i.v. injection of 20 MBq 68Ga-TRAP-(RGD)3) were performed on a dedicated small animal PET before (day 0, baseline) and after (day 7, follow-up) a 1-week therapy with the VEGF antibody bevacizumab or placebo (imaging cohort n = 13; therapy n = 7, control n = 6). The target-to-background ratio (TBR, VOImaxtumor/VOImeanmuscle) served as semiquantitative measure of tumor radiotracer uptake. Unenhanced CT data sets were subsequently acquired for anatomic coregistration and morphology-based tumor response assessments (CT volumetry). The imaging results were validated by multiparametric ex vivo immunohistochemistry (αvß3-integrin, microvascular density-CD31, proliferation-Ki-67, apoptosis-TUNEL) conducted in a dedicated immunohistochemistry cohort (n = 12). RESULTS: 68Ga-TRAP-(RGD)3 binding was significantly reduced under VEGF inhibition and decreased in all bevacizumab-treated animals (ΔTBRfollow-up/baseline: therapy -1.07±0.83, control +0.32±1.01, p = 0.022). No intergroup difference in tumor volume development between day 0 and day 7 was observed (Δvolumetherapy 134±77 µL, Δvolumecontrol 132±56 µL, p = 1.000). Immunohistochemistry revealed a significant reduction of αvß3-integrin expression (308±135 vs. 635±325, p = 0.03), microvascular density (CD31, 168±108 vs. 432±70, p = 0.002), proliferation (Ki-67, 5,195±1,002 vs. 7,574±418, p = 0.004) and significantly higher apoptosis (TUNEL, 14,432±1,974 vs. 3,776±1,378, p = 0.002) in the therapy compared to the control group. CONCLUSIONS: 68Ga-TRAP-(RGD)3 hybrid imaging allows for the in vivo assessment of αvß3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer.

68Ga-PSMA-PET/CT in Patients With Biochemical Prostate Cancer Recurrence and Negative 18F-Choline-PET/CT.

PURPOSE: Investigating the value of Ga-PSMA-PET/CT in biochemically recurring prostate cancer patients with negative F-choline-PET/CT. PATIENTS AND METHODS: One hundred thirty-nine consecutive patients with biochemical recurrence after curative (surgery and/or radiotherapy) therapy were offered participation in this sequential clinical imaging approach. Patients first underwent an F-choline-PET/CT. If negative, an additional Ga-PSMA-PET/CT was offered. One hundred twenty-five of 139 eligible patients were included in the study; 32 patients underwent additional Ga-PSMA-PET/CT. Patients with equivocal findings (n = 5) on F-choline-PET/CT and those who declined the additional Ga-PSMA-PET/CT (n = 9) were excluded. Images were analyzed visually for the presence of suspicious lesions. Findings on PET/CT were correlated with PSA level, PSA doubling time (dt), and PSA velocity (vel). RESULTS: The overall detection rates were 85.6% (107/125) for the sequential imaging approach and 74.4% (93/125) for F-choline-PET/CT alone. Ga-PSMA-PET/CT detected sites of recurrence in 43.8% (14/32) of the choline-negative patients. Detection rates of the sequential imaging approach and F-choline-PET/CT alone increased with higher serum PSA levels and PSA vel. Subgroup analysis of Ga-PSMA-PET/CT in F-choline negative patients revealed detection rates of 28.6%, 45.5%, and 71.4% for PSA levels of 0.2 or greater to less than 1 ng/mL, 1 to 2 ng/mL, and greater than 2 ng/mL, respectively. CONCLUSIONS: The sequential imaging approach designed to limit Ga-PSMA imaging to patients with negative choline scans resulted in high detection rates. Ga-PSMA-PET/CT identified sites of recurrent disease in 43.8% of the patients with negative F-choline PET/CT scans.

[68Ga]Pentixafor-PET/CT for imaging of chemokine receptor 4 expression in small cell lung cancer--initial experience.

Chemokine receptor CXCR4 is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging of small cell lung cancer (SCLC) with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine ligand [68Ga]Pentixafor. 10 patients with primarily diagnosed (n=3) or pre-treated (n=7) SCLC (n=9) or large cell neuroendocrine carcinoma of the lung (LCNEC, n=1) underwent [68Ga]Pentixafor-PET/CT. 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG, n=6) and/or somatostatin receptor (SSTR)-directed PET/CT with [68Ga]DOTATOC (n=5) and immunohistochemistry (n=10) served as standards of reference. CXCR4-PET was positive in 8/10 patients and revealed more lesions with significantly higher tumor-to-background ratios than SSTR-PET. Two patients who were positive on [18F]FDG-PET were missed by CXCR4-PET, in the remainder [68Ga]Pentixafor detected an equal (n=2) or higher (n=2) number of lesions. CXCR4 expression of tumor lesions could be confirmed by immunohistochemistry. Non-invasive imaging of CXCR4 expression in SCLC is feasible. [68Ga]Pentixafor as a novel PET tracer might serve as readout for confirmation of CXCR4 expression as prerequisite for potential CXCR4-directed treatment including receptor-radio(drug)peptide therapy.

(68)Ga-Pentixafor-PET/CT for Imaging of Chemokine Receptor 4 Expression in Glioblastoma.

Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand (68)Ga-Pentixafor. 15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent (68)Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUVmax, SUVmean). Tumor-to-background ratios (TBR) were calculated for both PET probes. (68)Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples. (68)Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUVmean and SUVmax of 3.0±1.5 and 3.9±2.0 respectively. Respective values for (18)F-FET were 4.4±2.0 (SUVmean) and 5.3±2.3 (SUVmax). TBR for SUVmean and SUVmax were higher for (68)Ga-Pentixafor than for (18)F-FET (SUVmean 154.0±90.7 vs. 4.1±1.3; SUVmax 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high (68)Ga-Pentixafor uptake; regions of the same tumor without apparent (68)Ga-Pentixafor uptake showed no or low receptor expression. In this pilot study, (68)Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, (68)Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy.