First-in-Human Study of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET for Integrin αvß3 Imaging in Patients with Breast Cancer and Neuroendocrine Neoplasms: Safety, Dosimetry and Tumor Imaging Ability.

Arginine-Glycine-Aspartate (RGD)-recognizing cell surface integrins are involved in tumor growth, invasiveness/metastases, and angiogenesis, and are therefore an attractive treatment target in cancers. The subtype integrin αvß3 is upregulated on endothelial cells during angiogenesis and on tumor cells. In vivo assessment of integrin αvß3 is possible with positron emission tomography (PET). Preclinical data on radiochemical properties, tumor uptake and radiation exposure identified [68Ga]Ga-NODAGA-E[c(RGDyK)]2 as a promising candidate for clinical translation. In this first-in-human phase I study, we evaluate [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET in patients with neuroendocrine neoplasms (NEN) and breast cancer (BC). The aim was to investigate safety, biodistribution and dosimetry as well as tracer uptake in tumor lesions. A total of 10 patients (5 breast cancer, 5 neuroendocrine neoplasm) received a single intravenous dose of approximately 200 MBq [68Ga]Ga-NODAGA-E[c(RGDyK)]2. Biodistribution profile and dosimetry were assessed by whole-body PET/CT performed at 10 min, 1 h and 2 h after injection. Safety assessment with vital parameters, electrocardiograms and blood tests were performed before and after injection. In vivo stability of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 was determined by analysis of blood and urine. PET images were analyzed for tracer uptake in tumors and background organs. No adverse events or pharmacologic effects were observed in the 10 patients. [68Ga]Ga-NODAGA-E[c(RGDyK)]2 exhibited good in vivo stability and fast clearance, primarily by renal excretion. The effective dose was 0.022 mSv/MBq, equaling a radiation exposure of 4.4 mSv at an injected activity of 200 MBq. The tracer demonstrated stable tumor retention and good image contrast. In conclusion, this first-in-human phase I trial demonstrated safe use of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 for integrin αvß3 imaging in cancer patients, low radiation exposure and favorable uptake in tumors. Further studies are warranted to establish whether [68Ga]Ga-NODAGA-E[c(RGDyK)]2 may become a tool for early identification of patients eligible for treatments targeting integrin αvß3 and for risk stratification of patients.

Very Early Response Evaluation by PET/MR in Patients with Lung Cancer-Timing and Feasibility.

Purpose: With the increasing number of therapy options available for patients with lung cancer, early response evaluation is needed. We performed this pilot study to assess the feasibility of early, repeated Positron emission tomography-magnetic resonance (PET/MR), the impact of timing and the capability for response prediction in lung tumors during chemotherapy. Methods: Patients with stage IV non-small cell lung cancer referred for chemotherapy were prospectively recruited. Fluorine-18-Fluorodeoxyglucose(18F-FDG)-PET/MR scans were performed prior to, during and after the first or second cycle of chemotherapy. Primary tumors were defined on all scans and size, FDG-uptake and apparent diffusion coefficient (ADC) were measured. Early response was described over time and a Standard Linear Mixed Model was applied to analyze changes over time. Results: 45 FDG-PET/MR scans were performed in 11 patients. Whereas the overall changes measured by ADC did not change significantly, there was an overall significant decrease in FDG-uptake from pre to post treatment scans. There was no difference in the FDG-uptake measured 1 or 3 weeks after therapy, but uptake measured 2 weeks after therapy differed from measurements at week 3. Changes measured in patients scanned during the first treatment cycle appeared more pronounced than during the second cycle. Conclusions: This pilot study indicates that response evaluation shortly after initiation of chemotherapy appears concordant with later evaluation and probably more reliable than evaluation midway between cycles. Responses during or after the first cycle of chemotherapy rather than during subsequent cycles are likely to be more readily measured.

Radioactive seed localization of renal cell carcinoma in a patient with Von Hippel-Lindau disease.

This report describes the case of a patient, who had successful radioactive seed localization (RSL) performed to improve the identification and excision of a renal cell carcinoma. RSL is a new method of preoperative localization, which can ease the surgical procedure, minimize tissue trauma, and ultimately benefit the patient.

Safety, Dosimetry, and Tumor Detection Ability of 68Ga-NOTA-AE105: First-in-Human Study of a Novel Radioligand for uPAR PET Imaging.

The overexpression of urokinase-type plasminogen activator receptors (uPARs) represents an established biomarker for aggressiveness in most common malignant diseases, including breast cancer (BC), prostate cancer (PC), and urinary bladder cancer (UBC), and is therefore an important target for new cancer therapeutic and diagnostic strategies. In this study, uPAR PET imaging using a 68Ga-labeled version of the uPAR-targeting peptide (AE105) was investigated in a group of patients with BC, PC, and UBC. The aim of this first-in-human, phase I clinical trial was to investigate the safety and biodistribution in normal tissues and uptake in tumor lesions. Methods: Ten patients (6 PC, 2 BC, and 2 UBC) received a single intravenous dose of 68Ga-NOTA-AE105 (154 ± 59 MBq; range, 48-208 MBq). The biodistribution and radiation dosimetry were assessed by serial whole-body PET/CT scans (10 min, 1 h, and 2 h after injection). Safety assessment included measurements of vital signs with regular intervals during the imaging sessions and laboratory blood screening tests performed before and after injection. In a subgroup of patients, the in vivo stability of 68Ga-NOTA-AE105 was determined in collected blood and urine. PET images were visually analyzed for visible tumor uptake of 68Ga-NOTA-AE105, and SUVs were obtained from tumor lesions by manually drawing volumes of interest in the malignant tissue. Results: No adverse events or clinically detectable pharmacologic effects were found. The radioligand exhibited good in vivo stability and fast clearance from tissue compartments primarily by renal excretion. The effective dose was 0.015 mSv/MBq, leading to a radiation burden of 3 mSv when the clinical target dose of 200 MBq was used. In addition, radioligand accumulation was seen in primary tumor lesions as well as in metastases. Conclusion: This first-in-human, phase I clinical trial demonstrates the safe use and clinical potential of 68Ga-NOTA-AE105 as a new radioligand for uPAR PET imaging in cancer patients.

Radioguided Surgery for Localization of Nonpalpable Breast Lesions A Mini-Review.

The majority of patients with nonpalpable breast lesions are eligible for breast conserving surgery guided by some kind of lesion localization. The current standard is wire-guided localization (WGL) even though it has several disadvantages, the most important one being the considerable proportion of patients with insufficient resection margin. These patients require a reoperation. New methods in the field of radioguided surgery (RGS) have been developed including radioguided occult lesion localization (ROLL) and radioactive seed localization (RSL). Especially RSL is a very promising technique. Guided by ultrasound a small titanium seed containing typically 1-10 MBq of radioactive iodine-125 is placed in the centre of the nonpalpable breast lesion. During the operation the seed is located with a hand-held gamma probe. To date, only few cohort studies exist on the feasibility of RSL, and the method has only been tested in one randomized trial. The results are either equal to or superior to those obtained with WGL, with regards to achieving free margins and low reoperation rates. Additionally, the RSL technique is less unpleasant for the patient and more flexible regarding preoperative logistics. The seed can be placed a few days before surgery, in contrast to the wire used in WGL, which has to be placed within few hours of surgery. RSL has quickly become popular in surgical and radiological teams that have used the technique and will probably become an important tool for preoperative localization of nonpalpable breast lesions in the near future.

Preparation and Administration of I-125 Labeled Seeds for Localization of Nonpalpable Breast Lesions.

UNLABELLED: Radioactive seed localization (RSL) is a new technique for surgical identification of non-palpable breast lesions. We describe the preparation of the needle with I-125 seeds for ultrasound-guided deposition in breast lesions. In a feasibility study we investigated the minimum activity amount needed for reliable gamma probe identification of the seeds and the levels of exposure to the staff. METHODS: 11 patients received a seed, which was manually placed in an 18 gauge needle with bone wax occluding the tip, and the radiologist introduced it into the breast tissue guided by ultra-sound. The seed was located during the operation with a handheld gamma probe. The activity amount required was studied in a water bath. Radiation exposure to the fingertips of pathologists was measured by a thermoluminescent dosemeter. RESULTS: All seeds were successfully prepared, positioned in the breast lesion, and easily identified. The surgeon removed the seeds together with the breast lesions, and they were identified by the pathologist. There were no unexpected adverse drug reactions. Water bath studies suggest that 1-3 MBq I-125 was sufficient for precise identification, regardless of the presence of conventional Tc- 99m activity from sentinel node injection. The total finger dose exposure to the pathologists for the 8 procedures was below the detection limit of 0.1 mSv. CONCLUSION: I-125 seeds for ultrasound-guided deployment and surgical identification of breast lesions were successfully prepared and identified for this promising new radioguided surgical technique. The radiation exposure to staff involved is considerably below the permissible limits and almost negligible.

Intravenous contrast-enhanced CT can be used for CT-based attenuation correction in clinical (111)In-octreotide SPECT/CT.

BACKGROUND: CT-based attenuation correction (CT-AC) using contrast-enhancement CT impacts (111)In-SPECT image quality and quantification. In this study we assessed and evaluated the effect. METHODS: A phantom (5.15 L) was filled with an aqueous solution of In-111. Three SPECT/CT scans were performed: (A) no IV contrast, (B) with 100-mL IV contrast, and (C) with 200-mL IV contrast added. Scan protocol included a localization CT, a low-dose CT (LD), and a full-dose CT (FD). Phantom, LD and FD scan series were performed at 90, 120, and 140 kVp. Phantom data were evaluated looking at mean counts in a central volume. Ten patients referred for (111)In-octreotide scintigraphy were scanned according to our clinical (111)In-SPECT/CT protocol including a topogram, a LD (140 kVp), and a FD (120 kVp). The FD/contrast-enhanced CT was acquired in both arterial (FDAP) and venous phase (FDVP) following a mono-phasic IV injection of 125-mL Optiray (4.5 mL/s). For patient data, we report image quality, Krenning scores, and mean/max values for liver and tumor regions. RESULTS: Phantoms: in uncorrected emission data, mean counts (average ± SD) decreased with increasing IV concentration: (A) 119 ± 9, (B) 113 ± 8, and (C) 110 ± 9. For all attenuation correction (AC) scans, the mean values increased with increasing iodine concentration. PATIENTS: there were no visible artifacts in single photon emission computed tomography (SPECT) following CT-AC with contrast-enhanced CT. The average score of image quality was 4.1 ± 0.3, 3.8 ± 0.4, and 4.2 ± 0.4 for LD, arterial phase, and venous phase, respectively. A total of 16 lesions were detected. The Krenning scores of 13/16 lesions were identical across all scan series. The max pixel values for the 16 lesions showed generally lower values for LD than for contrast-enhanced CT. CONCLUSIONS: In (111)In-SPECT/CT imaging of phantoms and patients, the use of IV CT contrast did neither degrade the SPECT image quality nor affect the clinical Krenning score. Reconstructed counts in healthy liver tissues were unaffected, and there was a generally lower count value in lesions following CT-AC based on the LD non-enhanced images. Overall, for clinical interpretation, no separate low-dose CT is required for CT-AC in (111)In-SPECT/CT.

First-in-human uPAR PET: Imaging of Cancer Aggressiveness.

A first-in-human clinical trial with Positron Emission Tomography (PET) imaging of the urokinase-type plasminogen activator receptor (uPAR) in patients with breast, prostate and bladder cancer, is described. uPAR is expressed in many types of human cancers and the expression is predictive of invasion, metastasis and indicates poor prognosis. uPAR PET imaging therefore holds promise to be a new and innovative method for improved cancer diagnosis, staging and individual risk stratification. The uPAR specific peptide AE105 was conjugated to the macrocyclic chelator DOTA and labeled with (64)Cu for targeted molecular imaging with PET. The safety, pharmacokinetic, biodistribution profile and radiation dosimetry after a single intravenous dose of (64)Cu-DOTA-AE105 were assessed by serial PET and computed tomography (CT) in 4 prostate, 3 breast and 3 bladder cancer patients. Safety assessment with laboratory blood screening tests was performed before and after PET ligand injection. In a subgroup of the patients, the in vivo stability of our targeted PET ligand was determined in collected blood and urine. No adverse or clinically detectable side effects in any of the 10 patients were found. The ligand exhibited good in vivo stability and fast clearance from plasma and tissue compartments by renal excretion. In addition, high uptake in both primary tumor lesions and lymph node metastases was seen and paralleled high uPAR expression in excised tumor tissue. Overall, this first-in-human study therefore provides promising evidence for safe use of (64)Cu-DOTA-AE105 for uPAR PET imaging in cancer patients.

Clinical evaluation of PET image reconstruction using a spatial resolution model.

PURPOSE: PET image resolution is variable across the measured field-of-view and described by the point spread function (PSF). When accounting for the PSF during PET image reconstruction image resolution is improved and partial volume effects are reduced. Here, we evaluate the effect of PSF-based reconstruction on lesion quantification in routine clinical whole-body (WB) PET/CT imaging. MATERIALS AND METHODS: 41 oncology patients were referred for a WB-PET/CT examination (Biograph 40 TruePoint). Emission data were acquired at 2.5 min/bed at 1 hpi of 400 MBq [18F]-FDG. Attenuation-corrected PET images were reconstructed on 336 × 336-matrices using: (R1) standard AW-OSEM (4 iter, 8 subsets, 4 mm Gaussian) and (R2) AW-OSEM with PSF (3 iter, 21 subsets, 2 mm). Blinded and randomised reading of R1- and R2-PET images was performed. Individual lesions were located and counted independently on both sets of images. The relative change in PET quantification (SUVmax, SUVmean, volume) of lesions seen on R1 and R2 is reported as (R2-R1)/R1. Furthermore, SUVmax and SUVmean was measured for a 3 cm spherical norm region in the right lobe of the healthy liver for R1 and R2. RESULTS: Clinical reading revealed 91 and 103 positive lesions for R1 and R2, respectively. For all lesions SUVmax (R2) was higher than SUVmax (R1). Regression analysis indicated that the relative increase in SUVmax (and SUVmean) decreased with lesion size, whilst it increased with increasing radial distance from the centre of the field of view (FOV). There was no significant difference in SUVmean in homogenous liver tissue between R1 and R2. CONCLUSION: In whole-body FDG-PET/CT using routine clinical protocols, PSF-based PET reconstruction increases lesion detection and affects SUVmax measurements compared to standard AW-OSEM PET reconstruction.

Clinical PET of neuroendocrine tumors using 64Cu-DOTATATE: first-in-humans study.

UNLABELLED: The use of positron emitter-labeled compounds for somatostatin receptor imaging (SRI) has become attractive because of the prospect of improved spatial resolution, accelerated imaging procedures, and the ability to quantify tissue radioactivity concentrations. This paper provides results from first-in-humans use of (64)Cu-DOTATATE, an avidly binding somatostatin receptor ligand linked to a radioisotope with intermediate half-life and favorable positron energy (half-life, 12.7 h; maximum positron energy, 0.653 MeV). METHODS: In a prospective setup, 14 patients with a history of neuroendocrine tumors underwent both PET/CT with (64)Cu-DOTATATE and SPECT/CT with our current routine imaging agent (111)In-diethylenetriaminepentaacetic acid-octreotide. After intravenous injection of 193-232 MBq of (64)Cu-DOTATATE, whole-body PET scans were acquired at 1 h (n = 14), 3 h (n = 12), and 24 h (n = 5) after administration. Tissue radioactivity concentrations for normal organs and lesions were quantified, and standardized uptake values were calculated for the early (1 h) and delayed (3 h) scans. Using the data for 5 patients, we assessed the radiation dose with OLINDA/EXM software. Furthermore, the clinical performance of (64)Cu-DOTATATE with respect to lesion detection was compared with conventional SRI. RESULTS: SRI with (64)Cu-DOTATATE produced images of excellent quality and high spatial resolution. Images were characterized by high and stable tumor-to-background ratios over an imaging time window of at least 3 h. Compared with conventional scintigraphy, (64)Cu-DOTATATE PET identified additional lesions in 6 of 14 patients (43%). In 5 patients, lesions were localized in organs and organ systems not previously known as metastatic sites, including the early-stage detection of a secondary neuroendocrine tumor in a patient with a known mutation in the multiple endocrine neoplasia type I gene. All major additional findings seen only on PET could be confirmed on the basis of a clinical follow-up interval of 18 mo. Calculated radiation dose estimates yielded an effective dose of 6.3 mSv for an injected activity of 200 MBq of (64)Cu-DOTATATE, with the liver being the organ with the highest absorbed radiation dose (0.16 mGy/MBq). CONCLUSION: This first-in-humans study supports the clinical use of (64)Cu-DOTATATE for SRI with excellent imaging quality, reduced radiation burden, and increased lesion detection rate when compared with (111)In-diethylenetriaminepentaacetic acid-octreotide.

Variability and reproducibility of hepatic FDG uptake measured as SUV as well as tissue-to-blood background ratio using positron emission tomography in healthy humans.

INTRODUCTION: To investigate variability and reproducibility of hepatic [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) uptake in healthy individuals. METHODS: Static images were obtained 70 min after the injection of 160 MBq FDG in six healthy subjects at two occasions with 13 days' interval. FDG uptake was adjusted for tissue-to-blood background ratio (T/B), or measured as standardized uptake value (SUV). Small regions of interest (ROIs) of 10 cm(3) in two different hepatic regions were analysed as well as the total liver. RESULTS: Mean SUV was 1.16 +/- 0.15 and mean T/B corrected values was 1.87 +/- 0.17. The maximal values were 2.70 (SUV) and 4.67 (T/B). Reproducibility was 6.7% for the mean SUV and 0.2% for the max SUV values. The corresponding figures for the T/B corrected mean values were 6.4% and for the max T/B values 13.0%. In general, the small ROIs had a comparable or even lower CV% for SUV values, but a higher CV% for T/B corrected values. CONCLUSIONS: In normal subjects hepatic FDG-uptake is high and homogeneous with a low CV% between days. T/B corrected values are largely comparable to SUV values but not superior, probably due to the standardization of procedures and homogeneity of the subjects. The T/B corrected method is theoretically superior in a more inhomogeneous population or when using different scanners and is shown here to be easy to apply. Small ROIs of 10 cm(3) are representative with respect to mean FDG uptake in the total liver and reproducibility, but do not identify the max FDG uptake.

Nucleotide regulation of paracellular Cl- permeability in natural rabbit airway epithelium.

In this study, we demonstrate a novel regulatory mechanism by which mucosal nucleotides via P2Y receptors decrease paracellular Cl(-) ion permeability in natural rabbit airway epithelium (in addition to a decrease in active Na(+) absorption). In contrast to primary cultures, the natural airway epithelium is a low-resistance epithelium, and an equivalent circuit model predicts that changes of more than approximately 12% in transepithelial conductance (G (t)) must include an effect on paracellular conductance (G (s)). Mucosal P2Y receptor stimulation with uridine triphosphate (UTP; 200 microM) decreased G (t) by up to 50% (average, 24%) and simultaneously decreased the paracellular Cl(-) permeability (mucosa-to-serosa Cl(-) flux) by 16%, but had no effect on mannitol permeability. The G (t) response to UTP was mimicked and attenuated by ionomycin (1 microM), suggesting a dependence on Ca(2+) (i). Amiloride (100 microM) and hyperosmolarity (+75 mM mannitol) also decreased G (t), indicating a role of cell shrinkage. Elevation of cAMP with forskolin (8 microM) or isoproterenol (10 microM) increased G (t) by 55 and 32%, and forskolin increased paracellular Cl(-) permeability by 37% without affecting mannitol permeability. The opposite effects of Ca(2+) (i) and cAMP on G (t) suggest an autocrine nucleotide signaling sequence where P2Y-dependent decrease in passive, paracellular Cl(-) transport is succeeded by a reversion of this effect due to P1-receptor-stimulated cAMP formation by adenosine originating from a time-dependent breakdown of mucosal ATP.

Regulation of ion transport via apical purinergic receptors in intact rabbit airway epithelium.

We investigated purinergic receptors involved in ion transport regulation in the intact rabbit nasal airway epithelium. Stimulation of apical membrane P2Y receptors with ATP or UTP (200 microM) induced transient increases in short-circuit current (Isc) of 13 and 6% followed by sustained inhibitions to 8 and 17% below control level, respectively. Serosal application of nucleotides had no effect. The ATP-induced response appeared to involve additional activation of apical adenosine (P1) and P2X receptors. The inhibitory effect of ATP and UTP on Isc was eliminated by pretreatment with amiloride (100 microM), while the stimulatory effect was potentiated, indicating that ATP and UTP inhibit Na+ and stimulate Cl- current. Ionomycin (1 microM) induced responses similar to UTP and ATP and desensitized the epithelium to the nucleotides, indicating involvement of intracellular Ca2+ (Ca2+ i. Furthermore, ATP, UTP and ionomycin induced 21, 24, and 21% decreases, respectively, in transepithelial conductance. Measurements of unidirectional isotope fluxes showed a 39% decrease in the dominant net Na+ absorption in response to ATP, while the smaller net Cl- secretion increased only insignificantly and unidirectional Cl- fluxes decreased significantly. The results suggest that nucleotides released to the airway surface liquid exert an autocrine regulation of epithelial NaCl absorption mainly by inhibiting the amiloride-sensitive epithelial Na+ channel (ENaC) and paracellular anion conductance via a P2Y receptor-dependent increase in Ca2+ i, while stimulation of Cl- secretion is of minor importance.