Safety, biodistribution and radiation dosimetry of 18 F-rhPSMA-7.3 in healthy adult volunteers

This first-in-human study investigated the safety, biodistribution and radiation dosimetry of the novel 18F-labeled radiohybrid prostate-specific membrane antigen (rhPSMA) positron emission tomography (PET) imaging agent, 18F-rhPSMA-7.3. Methods: Six healthy volunteer subjects (3 males, 3 females) underwent multiple whole-body PET acquisitions at scheduled time points up to 248 minutes after the administration of 18F-rhPSMA-7.3 (mean activity 220; range, 210-228 MBq). PET scans were conducted in three separate sessions and subjects were encouraged to void between sessions. Blood and urine samples were collected for up to 4 hours post-injection to assess metabolite-corrected radioactivity in whole blood, plasma and urine. Quantitative measurements of 18F radioactivity in volumes of interest (VOIs) over target organs were determined directly from the PET images at 8 time points and normalized time-activity concentration curves were generated. These normalized cumulated activities were then inputted into the OLINDA/EXM package to calculate the internal radiation dosimetry and the subjects' effective dose. Results: 18F-rhPSMA-7.3 was well tolerated. One adverse event (mild headache, not requiring medication) was considered possibly related to 18F-rhPSMA-7.3: because of the temporal association with 18F-rhPSMA-7.3 injection, a causal relationship could not be excluded. The calculated effective dose was 0.0141 mSv/MBq when using a 3.5-hour voiding interval. The organs with the highest absorbed dose per unit of administered radioactivity were the adrenals (mean absorbed dose, 0.1835 mSv/MBq), the kidneys (mean absorbed dose, 0.1722 mSv/MBq), the submandibular glands (mean absorbed dose, 0.1479 mSv) and the parotid glands (mean absorbed dose, 0.1137 mSv/MBq). At the end of the first scanning session (mean time, 111 min post-injection), an average of 7.2% (range, 4.4-9.0%) of the injected radioactivity of 18F-rhPSMA-7.3 was excreted into urine. Conclusion: The safety, biodistribution and internal radiation dosimetry 18F-rhPSMA-7.3 are considered favorable for PET imaging

A Randomised Controlled Trial Assessing the Effect of Oral Diazepam on F-18-FDG Uptake in the Neck and Upper Chest Region

A distinctive pattern of physiological symmetrical uptake of F-18-fluorodeoxyglucose (F-18-FDG) in the neck and upper chest region is a phenomenon that is sometimes observed on positron emission tomography (PET) scans of some oncologic patients. Initially, it was assumed to be muscle uptake secondary to patient anxiety or tension, which could be prevented by diazepam treatment. However, PET-computed tomography data have shown that F-18-FDG uptake is not restricted to the musculature but is also localised within the non-muscular soft tissue, such as brown adipose tissue. The efficacy of benzodiazepine treatment to reduce this uptake has not been well established. Therefore, a randomised controlled trial was conducted to decide whether diazepam would decrease physiological F-18-FDG uptake in the neck and upper chest region (FDG-NUC). A randomised, double-blind, placebo-controlled trial was conducted to assess the effect on FDG-NUC of 5 mg diazepam, given orally 1 h before F-18-FDG injection. Patients younger than 40 years, having or suspected to have a malignancy, were eligible for inclusion. The primary endpoint was FDG-NUC, as assessed by visual analysis of whole-body PET scans by two independent observers. The secondary endpoint was clinical relevance of FDG-NUC. Fifty-two patients were included between September 2003 and January 2005. Twenty-eight patients (54%) received placebo; 24 (46%) received diazepam. FDG-NUC was seen in 25% of the patients in the diazepam group versus 29% in the placebo group. This difference was not statistically significant. No beneficial effect of administration of diazepam could be established. Pre-medication with benzodiazepines to diminish physiological uptake of F-18-FDG in the neck and upper chest region is not indicate

Kinetic analysis and optimisation of 18F-rhPSMA-7.3 PET imaging of prostate cancer

Purpose This phase 1 open-label study evaluated the uptake kinetics of a novel theranostic PET radiopharmaceutical, F-18-rhPSMA-7.3, to optimise its use for imaging of prostate cancer. Methods Nine men, three with high-risk localised prostate cancer, three with treatment-naive hormone-sensitive metastatic disease and three with castration-resistant metastatic disease, underwent dynamic 45-min PET scanning of a target area immediately post-injection of 300 MBq F-18-rhPSMA-7.3, followed by two whole-body PET/CT scans acquired from 60 and 90 min post-injection. Volumes of interest (VoIs) corresponding to prostate cancer lesions and reference tissues were recorded. Standardised uptake values (SUV) and lesion-to-reference ratios were calculated for 3 time frames: 35-45, 60-88 and 90-118 min. Net influx rates (K-i) were calculated using Patlak plots.Results Altogether, 44 lesions from the target area were identified. Optimal visual lesion detection started 60 min post-injection. The F-18-rhPSMA-7.3 signal from prostate cancer lesions increased over time, while reference tissue signals remained stable or decreased. The mean (SD) SUV (g/mL) at the 3 time frames were 8.4 (5.6), 10.1 (7) and 10.6 (7.5), respectively, for prostate lesions, 11.2 (4.3), 13 (4.8) and 14 (5.2) for lymph node metastases, and 4.6 (2.6), 5.7 (3.1) and 6.4 (3.5) for bone metastases. The mean (SD) lesion-to-reference ratio increases from the earliest to the 2 later time frames were 40% (10) and 59% (9), respectively, for the prostate, 65% (27) and 125% (47) for metastatic lymph nodes and 25% (19) and 32% (30) for bone lesions. Patlak plots from lesion VoIs signified almost irreversible uptake kinetics. K-i, SUV and lesion-to-reference ratio estimates showed good agreement. Conclusion F-18-rhPSMA-7.3 uptake in prostate cancer lesions was high. Lesion-to-background ratios increased over time, with optimal visual detection starting from 60 min post-injection. Thus, F-18-rhPSMA-7.3 emerges as a very promising PET radiopharmaceutical for diagnostic imaging of prostate cancer.</p

The Influence of Manga on the Graphic Novel

This material has been published in The Cambridge History of the Graphic Novel edited by Jan Baetens, Hugo Frey, Stephen E. Tabachnick. This version is free to view and download for personal use only. Not for re-distribution, re-sale or use in derivative works. © Cambridge University PressProviding a range of cogent examples, this chapter describes the influences of the Manga genre of comics strip on the Graphic Novel genre, over the last 35 years, considering the functions of domestication, foreignisation and transmedia on readers, markets and forms

Software package for integrated data processing for internal dose assessment in nuclear medicine (SPRIND).

Contains fulltext : 52046.pdf (publisher's version ) (Closed access)PURPOSE: Internal radiation dose calculations are normally carried out using the Medical Internal Radiation Dose (MIRD) schema. This requires residence times of radiopharmaceutical activity and S-values for all organs of interest. Residence times can be obtained by quantitative nuclear imaging modalities. For dealing with S-values, the freeware packages MIRDOSE and, more recently, OLINDA/EXM are available. However, these software packages do not calculate residence times from image data. METHODS AND RESULTS: For this purpose, we developed an IDL-based software package for integrated data processing for internal dose assessment in nuclear medicine (SPRIND). SPRIND allows reading and viewing of planar whole-body scintigrams. Organ and background regions of interest (ROIs) can be drawn and are automatically mirrored from the anterior to the posterior view. ROI statistics are used to obtain anterior-posterior averaged counts for each organ, corrected for background activity and attenuation. Residence times for each organ are calculated based on effective decay. The total body biological half-time is calculated for use in the voiding bladder model. Red bone marrow absorbed dose can be calculated using bone regions in the scintigrams or by a blood-derived method. Finally, the results are written to a file in MIRDOSE-OLINDA/EXM format. Using scintigrams in DICOM, the complete analysis is gamma camera vendor independent, and can be performed on any computer using an IDL virtual machine. CONCLUSION: SPRIND is an easy-to-use software package for radiation dose assessment studies. It has made these studies less time consuming and less error prone

Improved detection of acute myocardial infarction by magnetic resonance imaging using Gadolinium-DTPA

To assess the value of the paramagnetic contrast agent Gadolinium (Gd)-DTPA in Magnetic Resonance Imaging (MRI) of acute myocardial infarction (AMI), we studied 20 patients with a first AMI by ECG-gated MRI before and after intravenous administration of 0.15mmol/kg Gd-DTPA. The MRI studies were performed after a mean of 98 hours (range 15-241) after the acute onset of AMI. Spin-echo measurements (TE 30 msec) were made using a Philips Gyroscan (0.5 Tesla). After performing the baseline MRI scans, the MRI procedure was repeated every 10 minutes for up to 40 minutes following injection of Gd-DTPA. In 18 (90%) patients contrast enhancement in the infarcted myocardial areas was observed after Gd-DTPA. In these patients intensity versus region curves, derived from 9 to 11 adjacent myocardial regions of interest, showed increased signal intensities in the infarcted areas after administration of Gd-DTPA. The precontrast signal intensity ratio between infarcted and normal myocardium was 1.14±0.15 (mean±SD); the postcontrast ratios at 10 minutes were 1.41±0.21 (P <0.05), at 20 minutes 1.61±0.19 (P <0.01), at 30 minutes 1.43±0.20 (P < 0.05), and at 40 minutes 1.33±0.20 (P=NS). It is concluded that MRI using the contrast agent Gd-DTPA significantly improves the visualization and detection of infarcted myocardial areas in patients with AMI and that optimal contrast enhancement is obtained 20 minutes after administration of Gd-DTPA

Phase I therapy study with 186Re-labeled humanized monoclonal antibody BIWA 4 (Bivatuzumab) in patients with head and neck squamous cell carcinoma

Purpose: In previous studies, we have shown the potential of radioimmunotherapy (RIT) with 186Re-labeled chimeric monoclonal antibody (MAb) U36 for treatment of head and neck cancer. A limitation of this anti-CD44v6 MAb, however, appeared to be its immunogenicity, resulting in human antichimeric antibodies in 40% of the patients. Aiming for a less immunogenic anti-CD44v6 MAb, the humanized MAb BIWA 4 (bivatuzumab) was introduced. In the present Phase I RIT study, we determined the safety, maximum tolerated dose (MTD), pharmacokinetics, immunogenicity, and therapeutic potential of 186Re-labeled BIWA 4 in patients with squamous cell carcinoma of the head and neck. Experimental Design: Twenty patients with inoperable recurrent and/or metastatic head and neck squamous cell carcinoma received a single dose of 186Re-labeled BIWA 4 in radiation dose-escalation steps of 20, 30, 40, 50, and 60 mCi/m2. Three patients received a second dose at least 3 months after the initial dose. After each administration, whole-body images as well as planar and tomographic images of the head and neck region were obtained, and the pharmacokinetics and the development of human antihuman antibody responses were determined. Radiation absorbed doses were calculated for whole body, red marrow, organs, and tumor. Results: First and second administrations were all well tolerated, and targeting of tumor lesions proved to be excellent. The only significant manifestations of toxicity were dose-limiting myelotoxicity consisting of thrombo- and leukocytopenia and, to a lesser extent, oral mucositis (grade 2). Grade 4 myelotoxicity was seen in two patients treated with 60 mCi/m2. The MTD was established at 50 mCi/m2, at which level dose-limiting myelotoxicity was seen in one of six patients. Stable disease, varying between 6 and 21 weeks, was observed in three of six patients treated at the MTD level. The median tumor dose, recalculated to MTD level, was 12.4 Gy. The absorbed dose in red marrow was 1. 82 ± 0.11 cGy/mCi for males and 2.35 ± 0.10 for females. Two patients experienced a human antihuman antibody response. Pharmacokinetics showed consistency across patients and within the three patients receiving 186Re-BIWA 4 on two occasions. Conclusions: This study shows that 186Re-labeled BIWA 4 can safely be administered, also in a repeated way. The MTD was established at 50 mCi/m2. In comparison with the previously described anti-CD44v6 MAb U36, the humanized MAb BIWA 4 seems to be less immunogenic. The fact that antitumor effects were seen in incurable patients with bulky disease justifies the evaluation of RIT with 186Relabeled BIWA 4 in an adjuvant setting