Performance evaluation of the DrugWipe<Superscript>®</Superscript> 5/5<Superscript>+</Superscript> on-site oral fluid screening device

This study presents a retrospective performance evaluation of an on-site oral fluid drug screening device DrugWipe® 5/5⁺ (Securetec). The results obtained by the device were compared with gas chromatography–mass spectrometry confirmation analysis results in whole blood. Data used in the comparison were based on 1,807 real cases in which the Finnish police had conducted an on-site drug test on persons suspected of driving under the influence of drugs. The present data cover only cases wherein the DrugWipe device has shown a positive result for at least one substance. The data were compiled from the databases of Alcohol and Drug Analytics Unit at the National Institute for Health and Welfare. The performance of the DrugWipe was evaluated for its relevant drug groups: amphetamines, cannabis, opiates, and cocaine. The evaluation was carried out by calculating the sensitivity, specificity, and accuracy as well as the positive and negative predictive values. These calculations were based on the classification of the results as true positives, false positives, true negatives, and false negatives. Additionally, the demographics of the cases and analytical findings in whole blood are discussed. According to this study, the DrugWipe device performed quite well in detecting amphetamines, the most frequently encountered group of illicit drugs in Finnish traffic. The performance of the cannabis, opiate, and cocaine tests was not at the same level.     

Bio-effect model applied to <Superscript>131</Superscript>I radioimmunotherapy of refractory non-Hodgkin’s lymphoma

Purpose  

Improved data collection methods have improved absorbed dose estimation by tracking activity distributions and tumor extent at multiple time points, allowing individualized absorbed dose estimation. Treatment with tositumomab and ¹³¹I-tositumomab anti-CD20 radioimmunotherapy (BEXXAR) yields a cold antibody antitumor response (cold protein effect) and a radiation response. Biologically effective contributions, including the cold protein effect, are included in an equivalent biological effect model that was fit to patient data.     

Urinary cannabinoid levels during nabiximols (Sativex<Superscript>®</Superscript>)-medicated inpatient cannabis withdrawal

Nabiximols (Sativex^®) is a buccal spray containing both ?⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). It has shown promise as an agonist substitution therapy for treating cannabis withdrawal and dependence. Monitoring urinary cannabinoid levels during treatment is important for determination of cannabinoid pharmacokinetics and for treatment adherence during clinical trials. Here, we use a recently described hydrolysis method to liberate urinary CBD from its glucuronide conjugate, and describe the trajectory of urinary CBD, THC, 11-nor-9-carboxy-THC (THC-COOH), and 11-hydroxy-THC (11-OH-THC) in patients receiving nabiximols treatment (or placebo) during cannabis withdrawal. Urine and plasma samples were taken before and during a 6-day inpatient treatment regime and during a 3-day drug-free washout. Urine was hydrolysed with red abalone β-glucuronidase, and CBD, THC, THC-COOH, and 11-OH-THC were quantified in daily urine using liquid chromatography-tandem mass spectrometry. Overall, urine and plasma cannabinoid levels followed similar trajectories and closely reflected the dosing schedule. During nabiximols treatment, CBD levels in urine and plasma rose markedly, while concentrations of THC and its metabolites remained at, or slightly above, pre-treatment levels. Following hydrolysis, urinary CBD was detected at levels 50 and 200 times as high as those in non-hydrolysed plasma and non-hydrolysed urine, respectively. THC, THC-COOH, and 11-OH-THC concentrations were also amplified by urinary hydrolysis. This method allows sensitive assessment of urinary CBD, and may prove useful in clinical studies involving nabiximols or other cannabinoid therapies.     

<Superscript>68</Superscript>Ga- and <Superscript>111</Superscript>In-labelled DOTA-RGD peptides for imaging of αvβ3 integrin expression

PURPOSE: alphavbeta3 integrins are important cell adhesion receptors involved in angiogenic processes. Recently, we demonstrated using [(18)F]Galacto-RGD that monitoring of alphavbeta3 expression is feasible. Here, we introduce (68)Ga- and (111)In-labelled derivatives and compare them with [(18)F]Galacto-RGD. METHODS: For radiolabelling, cyclo(RGDfK(DOTA)) was synthesised using SPPS. For in vitro characterisation determination of partition coefficients, protein binding, metabolic stability, alphavbeta3 affinity and cell uptake and for in vivo characterization, biodistribution studies and micro positron emission tomography (PET) imaging were carried out. For in vivo and in vitro studies, human melanoma M21 (alphavbeta3 positive) and M21-L (alphavbeta3 negative) cells were used. RESULTS: Both tracers can be synthesised straightforward. The compounds showed hydrophilic properties and high metabolic stability. Up to 23% protein-bound activity for [(68)Ga]DOTA-RGD and only up to 1.4% for [(111)In]DOTA-RGD was found. Cell uptake studies indicate receptor-specific accumulation. This is confirmed by the biodistribution data. One hour p.i. accumulation in alphavbeta3-positive tumours was 2.9 +/- 0.3%ID/g and in alphavbeta3-negative tumours 0.8 +/- 0.1%ID/g for [(68)Ga]DOTA-RGD ([(111)In]DOTA-RGD: 1.9 +/- 0.3%ID/g and 0.5 +/- 0.2%ID/g; [(18)F]Galacto-RGD: 1.6 +/- 0.2%ID/g and 0.4 +/- 0.1%ID/g). Thus, tumour uptake ratios were comparable. Due to approx. 3-fold higher blood pool activities for [(68)Ga]DOTA-RGD, tumour/blood ratios were higher for [(111)In]DOTA-RGD and [(18)F]Galacto-RGD. However, microPET studies demonstrated that visualisation of alphavbeta3-positive tumours using [(68)Ga]DOTA-RGD is possible. CONCLUSIONS: Our data indicate that [(68)Ga]DOTA-RGD allows monitoring of alphavbeta3 expression. Especially, the much easier radiosynthesis compared to [(18)F]Galacto-RGD would make it an attractive alternative. However, due to higher blood pool activity, [(18)F]Galacto-RGD remains superior for imaging alphavbeta3 expression. Introduction of alternative chelator systems may overcome the disadvantages.     

Clinical results of radionuclide therapy of neuroendocrine tumours with <Superscript>90</Superscript>Y-DOTATATE and tandem <Superscript>90</Superscript>Y/<Superscript>177</Superscript>Lu-DOTATATE: which is a better therapy option?

Purpose  

Peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues is a treatment option for patients with disseminated neuroendocrine tumours (NET). A combination treatment using the high-energy ⁹⁰Y beta emitter for larger lesions and the lower energy ¹⁷⁷Lu for smaller lesions has been postulated in the literature.The aim of the study was to evaluate combined ⁹⁰Y/¹⁷⁷Lu-DOTATATE therapy in comparison to ⁹⁰Y-DOTATATE alone.     

Comparison of <Superscript>99m</Superscript>Tc-annexin A5 with <Superscript>18</Superscript>F-FDG for the detection of atherosclerosis in ApoE−/− mice

Purpose ^99mTc-annexin A5, a marker of ongoing apoptosis, and ¹⁸F-FDG, a marker of the increased metabolism of inflammatory cells, are supposed to be useful in the detection of metabolically active atheroma. This study reports a comparison of the intralesional distribution of these tracers in relation to lesion development in ApoE−/− mice. Methods Male ApoE−/− mice (n = 12–14/group) were maintained on a Western-type diet after the age of 5 weeks. At 25 weeks, ^99mTc-annexin A5 or ¹⁸F-FDG was injected and the aortas were harvested for autoradiography (ARG) and Oil Red O staining. Regional radioactivity accumulation was compared in relation to the Oil Red O staining score (ranging from 0 to 3, a semiquantitative parameter for evaluating lesion development). Results Both ^99mTc-annexin A5 and ¹⁸F-FDG showed preferential uptake into atherosclerotic lesions, with higher uptake levels for ¹⁸F-FDG (mean, 56.07 %ID×kg/m²) than for ^99mTc-annexin A5 (mean, 10.38 %ID×kg/m²). The regional uptake levels of each tracer correlated with the Oil Red O staining score (r = 0.65, p < 0.05 for ^99mTc-annexin A5; r = 0.56, p < 0.05 for ¹⁸F-FDG). The uptake ratios of advanced lesions (score >0.5) to early lesions (score <0.5) were significantly higher for ^99mTc-annexin A5 than for ¹⁸F-FDG (f = 4.73, p = 0.03). Conclusion Both ^99mTc-annexin A5 and ¹⁸F-FDG accumulate in atherosclerotic lesions and correlate with the severity of each lesion. The higher absolute uptake levels of ¹⁸F-FDG may be advantageous for lesion detection, whereas the preferential uptake of ^99mTc-annexin A5 in advanced lesions may be a useful indicator of late-stage lesions or vulnerable plaque transformation.     

Do androgens control the uptake of <Superscript>18</Superscript>F-FDG, <Superscript>11</Superscript>C-choline and <Superscript>11</Superscript>C-acetate in human prostate cancer cell lines?

Purpose  

The aim of this study was to evaluate the impact of androgen ablation therapy in different prostate cancer (PCa) cell lines—reflecting different stages of the disease—on ¹⁸F-fluorodeoxyglucose (FDG), ¹¹C-choline and ¹¹C-acetate uptake.     

<Superscript>99m</Superscript>Tc-tetrofosmin or <Superscript>99m</Superscript>Tc-sestamibi for double-phase parathyroid scintigraphy?

Several years ago technetium-99m tetrofosmin was reported to localise parathyroid adenomas. The aim of this study was to compare the sensitivity of this radiopharmaceutical with that of (99m)Tc-sestamibi using a double-phase parathyroid scintigraphy protocol. Scans of 12 patients were evaluated visually and lesion to thyroid ratios were calculated. Nine of the patients were subsequently operated on; a total of eight parathyroid adenomas or hyperplastic glands were histologically confirmed in seven of the patients, while in one patient a parathyroid carcinoma was histologically proven. All of these patients had positive (99m)Tc-sestamibi scintigrams, whereas only two (99m)Tc-tetrofosmin scintigrams were positive. With (99m)Tc-sestamibi there was a significant increase in the lesion to thyroid ratio from 10 min to 90 min and 150 min p.i. which was not seen on scintigraphy with (99m)Tc-tetrofosmin. This makes (99m)Tc-tetrofosmin less suitable for double-phase parathyroid scintigraphy.     

<Superscript>18</Superscript>F-labeled mini-PEG spacered RGD dimer (<Superscript>18</Superscript>F-FPRGD2): synthesis and microPET imaging of α<Subscript>v</Subscript>β<Subscript>3</Subscript> integrin expression

Purpose We have previously reported that ¹⁸F-FB-E[c(RGDyK)]₂ (¹⁸F-FRGD2) allows quantitative PET imaging of integrin α_vβ₃ expression. However, the potential clinical translation was hampered by the relatively low radiochemical yield. The goal of this study was to improve the radiolabeling yield, without compromising the tumor targeting efficiency and in vivo kinetics, by incorporating a hydrophilic bifunctional mini-PEG spacer. Methods ¹⁸F-FB-mini-PEG-E[c(RGDyK)]₂ (¹⁸F-FPRGD2) was synthesized by coupling N-succinimidyl-4-¹⁸F-fluorobenzoate (¹⁸F-SFB) with NH₂-mini-PEG-E[c(RGDyK)]₂ (denoted as PRGD2). In vitro receptor binding affinity, metabolic stability, and integrin α_vβ₃ specificity of the new tracer ¹⁸F-FPRGD2 were assessed. The diagnostic value of ¹⁸F-FPRGD2 was evaluated in subcutaneous U87MG glioblastoma xenografted mice and in c-neu transgenic mice by quantitative microPET imaging studies. Results The decay-corrected radiochemical yield based on ¹⁸F-SFB was more than 60% with radiochemical purity of >99%. ¹⁸F-FPRGD2 had high receptor binding affinity, metabolic stability, and integrin α_vβ₃-specific tumor uptake in the U87MG glioma xenograft model comparable to those of ¹⁸F-FRGD2. The kidney uptake was appreciably lower for ¹⁸F-FPRGD2 compared with ¹⁸F-FRGD2 [2.0 ± 0.2%ID/g for ¹⁸F-FPRGD2 vs 3.0 ± 0.2%ID/g for ¹⁸F-FRGD2 at 1 h post injection (p.i.)]. The uptake in all the other organs except the urinary bladder was at background level. ¹⁸F-FPRGD2 also exhibited excellent tumor uptake in c-neu oncomice (3.6 ± 0.1%ID/g at 30 min p.i.). Conclusion Incorporation of a mini-PEG spacer significantly improved the overall radiolabeling yield of ¹⁸F-FPRGD2. ¹⁸F-FPRGD2 also had reduced renal uptake and similar tumor targeting efficacy as compared with ¹⁸F-FRGD2. Further testing and clinical translation of ¹⁸F-FPRGD2 are warranted. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Zhanhong Wu and Zi-Bo Li contributed equally to this work.     

Occlusion of a Long-Term Transpleural Biliary Drainage Tract Using a Gelatin Pledget (Hep-Plug<Superscript>™</Superscript>)

This case describes a technique used to close a long-term 14F transpleural biliary drainage catheter tract to prevent biliopleural fistula and further complications. We deployed a compressed gelatin foam pledget provided in a pre-loaded delivery device (Hep-Plug?) along the intrahepatic tissue tract for sealing it against the pleural cavity. The device used is easy to handle and gives the Interventional Radiologist the possibility to safely manage and prevent complications after percutaneous transhepatic interventions.     

<Superscript>68</Superscript>Ga-labeled multimeric RGD peptides for microPET imaging of integrin α<Subscript>v</Subscript>β<Subscript>3</Subscript> expression

PURPOSE: We and others have reported that (18)F- and (64)Cu-labeled arginine-glycine-aspartate (RGD) peptides allow positron emission tomography (PET) quantification of integrin alpha(v)beta(3) expression in vivo. However, clinical translation of these radiotracers is partially hindered by the necessity of cyclotron facility to produce the PET isotopes. Generator-based PET isotope (68)Ga, with a half-life of 68 min and 89% positron emission, deserves special attention because of its independence of an onsite cyclotron. The goal of this study was to investigate the feasibility of (68)Ga-labeled RGD peptides for tumor imaging. METHODS: Three cyclic RGD peptides, c(RGDyK) (RGD1), E[c(RGDyK)](2) (RGD2), and E{E[c(RGDyK)](2)}(2) (RGD4), were conjugated with macrocyclic chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and labeled with (68)Ga. Integrin affinity and specificity of the peptide conjugates were assessed by cell-based receptor binding assay, and the tumor targeting efficacy of (68)Ga-labeled RGD peptides was evaluated in a subcutaneous U87MG glioblastoma xenograft model. RESULTS: U87MG cell-based receptor binding assay using (125)I-echistatin as radioligand showed that integrin affinity followed the order of NOTA-RGD4 > NOTA-RGD2 > NOTA-RGD1. All three NOTA conjugates allowed nearly quantitative (68)Ga-labeling within 10 min (12-17 MBq/nmol). Quantitative microPET imaging studies showed that (68)Ga-NOTA-RGD4 had the highest tumor uptake but also prominent activity accumulation in the kidneys. (68)Ga-NOTA-RGD2 had higher tumor uptake (e.g., 2.8 +/- 0.1%ID/g at 1 h postinjection) and similar pharmacokinetics (4.4 +/- 0.4 tumor/muscle ratio, 2.0 +/- 0.1 tumor/liver ratio, and 1.1 +/- 0.1 tumor/kidney ratio) compared with (68)Ga-NOTA-RGD1. CONCLUSIONS: The dimeric RGD peptide tracer (68)Ga-NOTA-RGD2 with good tumor uptake and favorable pharmacokinetics warrants further investigation for potential clinical translation to image integrin alpha(v)beta(3).     

<Superscript>11</Superscript>C–MET PET/MRI for detection of recurrent glioma

Introduction

Radiological assessment of brain tumors is widely based on the Radiology Assessment of Neuro-Oncology (RANO) criteria that consider non-specific T1 and T2 weighted images. Limitation of the RANO criteria is that they do not include metabolic imaging techniques that have been reported to be helpful to differentiate treatment related changes from true tumor progression. In the current study, we assessed if the combined use of MRI and PET with hybrid ¹¹C–MET PET/MRI can improve diagnostic accuracy and diagnostic confidence of the readers to differentiate treatment related changes from true progression in recurrent glioma.

Methods

Fifty consecutive patients with histopathologically proven glioma were prospectively enrolled for a hybrid ¹¹C–MET PET/MRI to differentiate recurrent glioma from treatment induced changes. Sole MRI data were analyzed based on RANO. Sole PET data and in a third evaluation hybrid ¹¹C–MET-PET/MRI data were assessed for metabolic respectively metabolic and morphologic glioma recurrence. Diagnostic performance and diagnostic confidence of the reader were calculated for the different modalities, and the McNemar test and Mann-Whitney U Test were applied for statistical analysis.

Results

Hybrid ¹¹C–MET PET/MRI was successfully performed in all 50 patients. Glioma recurrence was diagnosed in 35 of the 50 patients (70%). Sensitivity and specificity were calculated for MRI (86.11% and 71.43%), for ¹¹C–MET PET (96.77% and 73.68%), and for hybrid ¹¹C–MET-PET/MRI (97.14% and 93.33%). For diagnostic accuracy hybrid ¹¹C–MET-PET/MRI (96%) showed significantly higher values than MRI alone (82%), whereas no significant difference was found for 11C–MET PET (88%). Furthermore, by rating on a five-point Likert scale significantly higher scores were found for diagnostic confidence when comparing ¹¹C–MET PET/MRI (4.26?±?0,777) to either PET alone (3.44?±?0.705) or MRI alone (3.56?±?0.733).

Conclusion

This feasibility study showed that hybrid PET/MRI might strengthen RANO classification by adding metabolic information to conventional MRI information. Future studies should evaluate the clinical utility of the combined use of ¹¹C–MET PET/MRI in larger patient cohorts.