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CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination andpoor prognosis. We evaluated the novel CXCR4 probe [\(^{68}\)Ga]Pentixafor for invivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [\(^{68}\)Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [\(^{68}\)Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [\(^{18}\)F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34\(^{+}\) flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [\(^{68}\)Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4-directed therapeutic approaches in MM and other diseases.
Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of \(^{99m}\)Tc-mercaptoacetyltriglycine (\(^{99m}\)Tc-MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq \(^{177}\)Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m² before PRRT (baseline) and 221 ± 45 ml/min/1.73 m² after a median follow-up of 370 days. The age-corrected decrease (mean: -3%, range: -27% to +19%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=-0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by \(^{99m}\)Tc-MAG3clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy.
Diagnosis of cardiac sarcoidosis is often challenging. Whereas cardiac magnetic resonance imaging (CMR) and positron emission tomography/computed tomography (PET/CT) with \(^{18}\)F-fluorodeoxyglucose (FDG) are most commonly used to evaluate patients, PET/CT using radiolabeled somatostatin receptor (SSTR) ligands for visualization of inflammation might represent a more specific alternative. This study aimed to investigate the feasibility of SSTR–PET/CT for detecting cardiac sarcoidosis in comparison to CMR.
15 patients (6 males, 9 females) with sarcoidosis and suspicion on cardiac involvement underwent SSTR-PET/CT imaging and CMR. Images were visually scored. The AHA 17-segment model of the left myocardium was used for localization and comparison of inflamed myocardium for both imaging modalities. In semi-quantitative analysis, mean (SUV\(_{mean}\)) and maximum standardized uptake values (SUV\(_{max}\)) of affected myocardium were calculated and compared with both remote myocardium and left ventricular (LV) cavity.
SSTR-PET was positive in 7/15, CMR in 10/15 patients. Of the 3 CMR+/PET- subjects, one patient with minor involvement (<25% of wall thickness in CMR) was missed by PET. The remaining two CMR+/PET- patients displayed no adverse cardiac events during follow-up.
In the 17-segment model, PET/CT yielded 27 and CMR 29 positive segments. Overall concordance of the 2 modalities was 96.1% (245/255 segments analyzed). SUV\(_{mean}\) and SUV\(_{max}\) in inflamed areas were 2.0±1.2 and 2.6±1.2, respectively. The lesion-to-remote myocardium and lesion-to-LV cavity ratios were 1.8±0.2 and 1.9±0.2 for SUV\(_{mean}\) and 2.0±0.3 and 1.7±0.3 for SUV\(_{max}\), respectively.
Detection of cardiac sarcoidosis by SSTR-PET/CT is feasible. Our data warrant further analysis in larger prospective series.
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 (SUV\(_{max}\), SUV\(_{mean}\)). 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 SUV\(_{mean}\) and SUV\(_{max}\) of 3.0±1.5 and 3.9±2.0 respectively. Respective values for \(^{18}\)F-FET were 4.4±2.0 (SUV\(_{mean}\)) and 5.3±2.3 (SUV\(_{max}\)). TBR for SUV\(_{mean}\) and SUV\(_{max}\) were higher for \(^{68}\)Ga-Pentixafor than for \(^{18}\)F-FET (SUV\(_{mean}\) 154.0±90.7 vs. 4.1±1.3; SUV\(_{max}\) 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.
Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and obesity, we aimed to investigate glucose utilization of BAT by \(^{18}\)F-FDG PET imaging. Male Zucker diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction (ZDF-CR) group. Dynamic \(^{18}\)F-FDG PET using a dedicated small animal PET system was performed under hyperinsulinemic-euglycemic clamp. \(^{18}\)F-FDG PET identified intense inter-scapular BAT glucose uptake in all ZL control rats, while no focally increased \(^{18}\)F-FDG uptake was detected in all ZDF-ND rats. Mild but significant improved BAT tracer uptake was identified after calorie restriction in diabetic rats (ZDF-CR). The weight of BAT tissue and fat deposits were significantly increased in ZDF-CR and ZDF-ND rats as compared to ZL controls, while UCP-1 and mitochondrial concentrations were significantly decreased. Whitening and severely impaired insulin-stimulated glucose uptake in BAT was confirmed in a rat model of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake.
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 [\(^{68}\)Ga]Pentixafor in malignant pleural mesothelioma.
Six patients with pleural mesothelioma underwent [\(^{68}\)Ga]Pentixafor-PET/CT. 2′-[\(^{18}\)F]fluoro-2′-deoxy-D-glucose ([\(^{18}\)F]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 [\(^{18}\)F]FDG-PET depicted active lesions in all patients, [\(^{68}\)Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [\(^{68}\)Ga]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.
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 [\(^{68}\)Ga]Pentixafor in comparison to \(^{68}\)Ga-DOTA-D-Phe-Tyr3-octreotide ([\(^{68}\)Ga]DOTATOC) and \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [\(^{68}\)Ga]DOTATOC, [\(^{18}\)F]FDG, and [\(^{68}\)Ga]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. [\(^{68}\)Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [\(^{18}\)F]FDG revealed sites of disease in 10/12 and [\(^{68}\)Ga]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 [\(^{68}\)Ga]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, [\(^{68}\)Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors.
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.
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 [\(^{68}\)Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies.
Thirty-five patients with MM underwent [\(^{68}\)Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [\(^{18}\)F]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.
[\(^{68}\)Ga]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 [\(^{18}\)F]FDG was available, [\(^{68}\)Ga]Pentixafor-PET detected more lesions in 4/19 (21%) subjects, [\(^{18}\)F]FDG proved superior in 7/19 (37%). In the remaining 8/19 (42%) patients, both tracers detected an equal number of lesions. [\(^{18}\)F]FDG-PET positivity correlated with [\(^{68}\)Ga]Pentixafor-PET positivity (p=0.018).
[\(^{68}\)Ga]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.
Objective: Radiotracers targeting prostate-specific membrane antigen (PSMA) have increasingly been recognized as showing uptake in a number of normal structures, anatomic variants, and non-prostate-cancer pathologies. We aimed to explore the frequency and degree of uptake in peripheral ganglia in patients undergoing PET with the PSMA-targeted agent \(^{18}\)F-DCFPyL.
Methods: A total of 98 patients who underwent \(^{18}\)F-DCFPyL PET/CT imaging were retrospectively analyzed. This included 76 men with prostate cancer (PCa) and 22 patients with renal cell carcinoma (RCC; 13 men, 9 women). Scans were evaluated for uptake in the cervical, stellate, celiac, lumbar and sacral ganglia. Maximum standardized uptake value corrected to body weight (SUV\(_{max}\)), and maximum standardized uptake value corrected to lean body mass (SUL\(_{max}\)) were recorded for all ganglia with visible uptake above background. Ganglia-to-background ratios were calculated by dividing the SUV\(_{max}\) and SUL\(_{max}\) values by the mean uptake in the ascending aorta (Aortamean) and the right gluteus muscle (Gluteusmean).
Results: Overall, 95 of 98 (96.9%) patients demonstrated uptake in at least one of the evaluated peripheral ganglia. With regard to the PCa cohort, the most frequent sites of radiotracer accumulation were lumbar ganglia (55/76, 72.4%), followed by the cervical ganglia (51/76, 67.1%). Bilateral uptake was found in the majority of cases [lumbar 44/55 (80%) and cervical 30/51 (58.8%)]. Additionally, discernible radiotracer uptake was recorded in 50/76 (65.8%) of the analyzed stellate ganglia and in 45/76 (59.2%) of the celiac ganglia, whereas only 5/76 (6.6%) of the sacral ganglia demonstrated \(^{18}\)F-DCFPyL accumulation. Similar findings were observed for patients with RCC, with the most frequent locations of radiotracer uptake in both the lumbar (20/22, 90.9%) and cervical ganglia (19/ 22, 86.4%). No laterality preference was found in mean PSMA-ligand uptake for either the PCa or RCC cohorts.
Conclusion: As PSMA-targeted agents become more widely disseminated, the patterns of uptake in structures that are not directly relevant to patients’ cancers must be understood. This is the first systematic evaluation of the uptake of \(^{18}\)F-DCFPyL in ganglia demonstrating a general trend with a descending frequency of radiotracer accumulation in lumbar, cervical, stellate, celiac, and sacral ganglia. The underlying biology that leads to variability of PSMA-targeted radiotracers in peripheral ganglia is not currently understood, but may provide opportunities for future research.