bluuebunny/crossref_metadata_2025 huggingface dataset:
11C-Methionine Positron Emission Tomographic Imaging of Biologic Activity of a Recurrent Glioblastoma Treated with Stereotaxy-Guided Laser-Induced Interstitial Thermotherapy
Authors: Galldiks Norbert , von Tempelhoff Wernholt , Kahraman Deniz , Kracht Lutz W. , Vollmar Stefan , Fink Gereon R. , Schroeter Michael , Goldbrunner Roland , Schmidt Matthias , Maarouf Mohammad
Published: March 2018

In patients with recurrent glioblastoma multiforme (GBM), local minimally invasive treatment modalities have gained increasing interest recently because they are associated with fewer side effects than open surgery. For example, local tumor coagulation by laser-induced interstitial thermotherapy (LITT) is such a minimally invasive technique. We monitored the metabolic effects of stereotaxy-guided LITT in a patient with a recurrent GBM using amino acid positron emission tomography (PET). Serial 11C-methyl-L-methionine positron emission tomography (MET-PET) and contrast-enhanced computed tomography (CT) were performed using a hybrid PET/CT system in a patient with recurrent GBM before and after LITT. To monitor the biologic activity of the effects of stereotaxy-guided LITT, a threshold-based volume of interest analysis of the metabolically active tumor volume (MET uptake index of ≥ 1.3) was performed. A continuous decline in metabolically active tumor volume after LITT could be observed. MET-PET seems to be useful for monitoring the short-term therapeutic effects of LITT, especially when patients have been pretreated with a multistep therapeutic regimen. MET-PET seems to be an appropriate tool to monitor and guide experimental LITT regimens and should be studied in a larger patient group to confirm its clinical value.
Contrast Enhancement of the Brain by Folate-Conjugated Gadolinium–Diethylenetriaminepentaacetic Acid–Human Serum Albumin Nanoparticles by Magnetic Resonance Imaging
Authors: Korkusuz Huedayi , Ulbrich Karsten , Bihrer Verena , Welzel Katerina , Chernikov Valery , Knobloch Thomas , Petersen Sabine , Huebner Frank , Ackermann Hanns , Gelperina Svetlana , Korkusuz Yuecel , Kromen Wolfgang , Hammerstingl Renate , Haupenthal Jörg , Fiehler Jens , Zeuzem Stefan , Kreuter Jörg , Vogl Thomas J. , Piiper Albrecht
Published: March 2018

Different from regular small molecule contrast agents, nanoparticle-based contrast agents have a longer circulation time and can be modified with ligands to confer tissue-specific contrasting properties. We evaluated the tissue distribution of polymeric nanoparticles (NPs) prepared from human serum albumin (HSA), loaded with gadolinium–diethylenetriaminepentaacetic acid (Gd-DTPA) (Gd-HSA-NP), and coated with folic acid (FA) (Gd-HSA-NP-FA) in mice by magnetic resonance imaging (MRI). FA increases the affinity of the Gd-HSA-NP to FA receptor–expressing cells. Clinical 3 T MRI was used to evaluate the signal intensities in the different organs of mice injected with Gd-DTPA, Gd-HSA-NP, or Gd-HSA-NP-FA. Signal intensities were measured and standardized by calculating the signal to noise ratios. In general, the NP-based contrast agents provided stronger contrasting than Gd-DTPA. Gd-HSA-NP-FA provided a significant contrast enhancement (CE) in the brain ( p = .0032), whereas Gd-DTPA or Gd-HSA-NP did not. All studied MRI contrast agents showed significant CE in the blood, kidney, and liver ( p < .05). Gd-HSA-NP-FA elicited significantly higher CE in the blood than Gd-HSA-NP ( p = .0069); Gd-HSA-NP and Gd-HSA-NP-FA did not show CE in skeletal muscle and gallbladder; Gd-HSA-NP, but not Gd-HSA-NP-FA, showed CE in the cardiac muscle. Gd-HSA-NP-FA has potential as an MRI contrast agent in the brain.
Combined in Situ Zymography, Immunofluorescence, and Staining of Iron Oxide Particles in Paraffin-Embedded, Zinc-Fixed Tissue Sections
Authors: Schellenberger Eyk , Haeckel Akvile , Schoenzart Lena , Appler Franziska , Schnorr Joerg , Taupitz Matthias , Hamm Bernd
Published: March 2018

Superparamagnetic iron oxide particles are used as potent contrast agents in magnetic resonance imaging. In histology, these particles are frequently visualized by Prussian blue iron staining of aldehyde-fixed, paraffin-embedded tissues. Recently, zinc salt-based fixative was shown to preserve enzyme activity in paraffin-embedded tissues. In this study, we demonstrate that zinc fixation allows combining in situ zymography with fluorescence immunohistochemistry (IHC) and iron staining for advanced biologic investigation of iron oxide particle accumulation. Very small iron oxide particles, developed for magnetic resonance angiography, were applied intravenously to BALB/c nude mice. After 3 hours, spleens were explanted and subjected to zinc fixation and paraffin embedding. Cut tissue sections were further processed to in situ zymography, IHC, and Prussian blue staining procedures. The combination of in situ zymography as well as IHC with subsequent Prussian blue iron staining on zinc-fixed paraffin-embedded tissues resulted in excellent histologic images of enzyme activity, protease distribution, and iron oxide particle accumulation. The combination of all three stains on a single section allowed direct comparison with only moderate degradation of fluorescein isothiocyanate–labeled substrate. This protocol is useful for investigating the biologic environment of accumulating iron oxide particles, with excellent preservation of morphology.
Imaging Depths of Near-Infrared Quantum Dots in First and Second Optical Windows
Authors: Won Nayoun , Jeong Sanghwa , Kim Kangwook , Kwag Jungheon , Park Joonhyuck , Kim Sang Geol , Kim Sungjee
Published: March 2018

Potential advantages of quantum dot (QD) imaging in the second optical window (SOW) at 1,000 to 1,400 nm over the first optical window (FOW) at 700 to 900 nm have attracted much interest. QDs that emit at 800 nm (800QDs) and QDs that emit at 1,300 nm (1,300QDs) are used to investigate the imaging depths at the FOW and SOW. QD images in biologic tissues are processed binarized via global thresholding method, and the imaging depths are determined using the criteria of contrast to noise ratio and relative apparent size. Owing to the reduced scattering in the SOW, imaging depth in skin can be extended by approximately three times for 1,300QD/SOW over 800QD/FOW. In liver, excitation of 1,300QD/SOW can be shifted to longer wavelengths; thus, the imaging depth can be extended by 1.4 times. Effects of quantum yield (QY), concentration, incidence angle, polarization, and fluence rate F on imaging depth are comprehensively studied. Under F approved by the Food and Drug Administration, 1,300QDs with 50% QY can reach imaging depths of 29.7 mm in liver and 17.5 mm in skin. A time-gated excitation using 1,000 times higher F pulses can obtain the imaging depth of ≈ 5 cm. To validate our estimates, in vivo whole-body imaging experiments are performed using small-animal models.
In Vitro and In Vivo Characterization of Three 68Ga- and 111In-Labeled Peptides for Cholecystokinin Receptor Imaging
Authors: Roosenburg Susan , Laverman Peter , Joosten Lieke , Eek Annemarie , Rutjes Floris P.J.T. , van Delft Floris L. , Boerman Otto C.
Published: March 2018

Cholecystokinin (CCK) receptors are overexpressed in several human tumor types, such as medullary thyroid carcinomas and small cell lung cancers. Several ligands for the CCK2 receptor (CCK2R) have been developed for radionuclide targeting of these tumors. In this study, we evaluated whether radiolabeled DOTA-sCCK8 and its stabilized derivative, DOTA-sCCK8[Phe2(p-CH2SO3H), Nle3,6], are suitable for imaging of CCK2R-positive tumors, using DOTA-MG0 as a reference. In vivo targeting of CCK2R-positive tumors with DOTA-sCCK8, DOTA-sCCK8[Phe2( p-CH2SO3H), Nle3,6], and DOTA-MG0, labeled with 111In or 68Ga, was evaluated in BALB/c nude mice with a subcutaneous A431-CCK2R tumor. Biodistribution studies and single-photon emission computed tomography (SPECT) and positron emission tomography (PET) were performed at 1 hour postinjection. All peptides specifically accreted in the CCK2R-expressing tumors. Both 111In-DOTA-sCCK8 and 111In-DOTA-sCCK8[Phe2( p-CH2SO3H), Nle3,6] showed good tumor retention (4.65% ID/g and 5.44% ID/g, respectively, at 4 hours postinjection). On PET/computed tomographic (CT) and SPECT/CT scans, subcutaneous A431-CCK2R tumors were clearly visualized with low uptake of sCCK8 peptides in the intestines. Whereas radiolabeled DOTA-MG0 showed high kidney uptake (70% ID/g), the sCCK8 peptides showed low uptake in the kidneys. Sulfated CCK8 analogues combined high tumor uptake with low retention in the kidney and are therefore promising tracers for imaging of CCK2R-positive tumors.
[18F]-2′ -Fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (18F-FMAU) in Prostate Cancer: Initial Preclinical Observations
Authors: Jadvar Hossein , Yap Li-Peng , Park Ryan , Li Zibo , Chen Kai , Hughes Lindsey , Kouhi Aida , Conti Peter
Published: March 2018

We hypothesized that imaging-based assessment of cellular proliferation in prostate cancer may improve tumor characterization. We therefore evaluated the biodistribution and effect of androgen on tumor uptake of the cellular proliferation imaging marker [18F]-2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (18F-FMAU) in xenograft mouse models of human prostate cancer. Castrated and noncastrated athymic male mice were implanted with androgen-independent PC3 and androgen-sensitive CWR22 human prostate cancer cells. Dynamic micro–positron emission tomography (PET)/computed tomography was performed for 1 hour followed by 10-minute static scans at 2 and 3 hours. Animals were sacrificed after imaging for biodistribution studies and immunohistochemical staining of tumors for androgen receptor and Ki-67/MIB expression. 18F-FMAU uptake was significantly higher in all major organs of the castrated animals in comparison with noncastrated mice, with the highest uptake in liver and the lowest uptake in muscle and bone. When compared to PC3 tumors, CWR22 xenografts showed significantly higher tumor to muscle (2.56 ± 0.30 vs 1.99 ± 0.30, p 5.008) and tumor to liver (1.72 ± 0.12 vs 1.26 ± 0.17, p = .0003) uptake ratios in the noncastrated animal at the 3-hour time point. Androgen receptor and Ki-67/MIB expressions were higher in CWR22 than in PC3 xenografts. Our initial preclinical observations suggest that there may be an association between androgen signaling and thymidine metabolism and that 18F-FMAU PET may be useful in prostate tumor characterization.
Tracking Tumor Cells in Lymphatics in a Mice Xenograft Model by Magnetic Resonance Imaging
Authors: Liu Ting , Zhou Haijun , Xia Rui , Liao Jichun , Wu Changqiang , Wang Hui , Ai Hua , Bi Feng , Gao Fabao
Published: March 2018

To enrich our understanding of the mechanism of tumor lymphatic metastasis, we developed a model system for tracking metastatic tumor cells in the lymphatic system with cellular magnetic resonance imaging (MRI) in live mice to observe the interaction between tumor cells and the lymphatic system. Nude mice were inoculated subcutaneously with superparamagnetic iron oxide (SPIO)-labeled and unlabeled LOVO cells in the foot pad, groin, or axillary area. Serial 7 T MRI of the tumors and surrounding regions was performed in the following 2 weeks. After imaging, tumor tissues and regional lymph nodes were collected and subjected to immunohistologic analysis. T2/T2*-weighted MRIs showed the primary tumor growth and the draining lymphatic architecture, as well as the SPIO-labeled tumor cells metastasized into the regional lymph node at 8 days. MRIs also revealed information on sentinel lymph node mapping with high-resolution anatomic information. Histologic findings confirmed the in vivo MRI results and revealed lymphangiogenesis, angiogenesis, infiltration of macrophages, and expression of vascular endothelial growth factor C in tumor and draining lymph nodes as well. This technology provides a powerful tool for tracking SPIO-labeled cancer cells in the lymphatics by cellular MRI. There was a close relationship between tumor lymphatic metastasis and lymphangiogenesis.
Basic Studies on Radioimmunotargeting of CD133-Positive HCT116 Cancer Stem Cells
Authors: Jin Zhao-Hui , Sogawa Chizuru , Furukawa Takako , Saito Yuriko , Aung Winn , Fujibayashi Yasuhisa , Saga Tsuneo
Published: March 2018

As cancer stem cells (CSCs) are postulated to play critical roles in cancer development, including metastasis and recurrence, CSC imaging would provide valuable information for cancer treatment and lead to CSC-targeted therapy. To assess the possibility of in vivo CSC targeting, we conducted basic studies on radioimmunotargeting of cancer cells positive for CD133, a CSC marker recognized in various cancers. Antibodies against CD133 were labeled with 125I, and their in vitro cell binding properties were tested. Using the same isotype IgG as a control, in vivo biodistribution of the labeled antibody retaining immunoreactivity was examined in mice bearing an HCT116 xenograft in which a population of the cancer cells expressed CD133. Intratumoral distribution of the labeled antibody was examined and compared to the CD133 expression pattern. The 125I-labeled anti-CD133 antibody showed a modest but significantly higher accumulation in the HCT116 xenograft compared to the control IgG. The intratumoral distribution of the labeled antibody mostly overlapped with the CD133 expression, whereas the control IgG was found in the area close to the necrotic tumor center. Our results indicate that noninvasive in vivo targeting of CSCs could be possible with radiolabeled antibodies against cell membrane markers.
Molecular Imaging of Gastric Neoplasia with Near-Infrared Fluorescent Activatable Probes
Authors: Ding Shengli , Blue Randall Eric , Chen Yijing , Scull Brooks , Lund Pauline Kay , Morgan Douglas
Published: March 2018

Gastric cancer is the second leading cause of cancer mortality worldwide and is projected to rise to tenth in all-cause mortality in the near term. Early detection requires improved sensitivity and specificity of endoscopic imaging with novel methods. The objective of this study was to evaluate the utility of activatable molecular probes for the detection of gastric cancer both in vivo and ex vivo in a preclinical model. Smad4+/− mice, which develop spontaneous gastric neoplasia, were compared to normal wild-type controls. Cathepsin-activatable and matrix metalloproteinase (MMP)-activatable molecular probes were injected 24 hours and 6 hours before imaging, respectively. In vivo imaging was performed using quantitative tomographic near-infrared fluorescence (NIRF) imaging. For validation, ex vivo imaging and histologic examination were performed. Molecular imaging in vivo of Smad4+/− gastric cancer murine models revealed intense activation of both cathepsin B and MMP probes. Ex vivo imaging and histology confirmed that the detected neoplasms were adenocarcinomas and hyperplastic lesions. This study provides proof of principle that the cathepsin- and MMP-activatable molecular probes are activated in the Smad4+/− murine model of spontaneous gastric adenocarcinoma and can be imaged by both in vivo and ex vivo NIRF methods. The cathepsin probe also detects hyperplastic lesions.
Novel Fluorescent Dyes for Single DNA Molecule Techniques
Authors: Zarkov Alexander , Vasilev Aleksey , Deligeorgiev Todor , Stoynov Stoyno , Nedelcheva-Veleva Marina
Published: March 2018

To answer the demands of scientific and medical imaging issues, the family of nucleic acid fluorescent dyes is constantly enlarging. Most of the developed dyes reveal high qualities in bulk solution assays but are inefficient to produce a strong and sufficiently stable signal to enable the application of single-molecule techniques. Therefore, we tested 12 novel monomeric and homodimeric cyanine dyes for potential single DNA molecule imaging. Although their qualities in bulk solutions have already been described, nothing was known about their behavior on a single-molecule level. All 12 dyes demonstrated strong emission when intercalated into single DNA molecules and stretched on a silanized surface, which makes them the perfect choice for fluorescent microscopy imaging. A comparison of their fluorescence intensity and photostability with the most applicable dyes in single-molecule techniques, fluorescent dyes YOYO-1 and POPO-3, was carried out. They all exhibited a strong signal, comparable to that of YOYO-1. However, in contrast to YOYO-1, which is visualized under a green filter only, their emission permits red filter visualization. As their photostability highly exceeds that of similar spectrum POPO-3 dye, the studied dyes stand out as the best choice for a broad range of solid surface single-molecule applications when yellow to red DNA backbone fluorescence is needed.
[18F]Fluoroethyltyrosine–Positron Emission Tomography-Based Therapy Monitoring after Stereotactic Iodine-125 Brachytherapy in Patients with Recurrent High-Grade Glioma
Authors: Jansen Nathalie L. , Suchorska Bogdana , Schwarz Silke B. , Eigenbrod Sabina , Lutz Juergen , Graute Vera , Bartenstein Peter , Belka Claus , Kreth Friedrich W. , Fougère Christian la
Published: March 2018

Therapy monitoring of glioma after stereotactic iodine-125 brachytherapy (SBT) remains challenging because posttherapeutic changes in magnetic resonance imaging can mimic tumor progression. We evaluated the prognostic value of serial [18F]fluoroethyltyrosine (FET)-positron emission tomographic (PET) scans for therapy monitoring of high-grade glioma (HGG) after SBT. Thirty-three patients with recurrent HGG were included. Serial FET-PET scans were performed prior to therapeutic intervention and at 3-month intervals during the first year after SBT. FET-PET evaluation was performed by both conventional data analysis and kinetic analysis. Prognostic factors were obtained from proportional hazard models. Median local progression-free survival (LPFS) was 11.1 months. Maximal standardized background uptake value (SUVmax/BG) and biologic tumor volume (BTV) differentiated accurately between therapeutic effects and local tumor progression at the 6-month and subsequent examinations. Increasing uptake kinetics at baseline ( p < .05) and during follow-up ( p < .01) were stringently associated with a longer LPFS. Early increase in FET uptake after SBT is not unequivocally associated with tumor progression; it might be induced by reactive changes and could easily lead to a misclassification of the tumor status (pseudoprogression). Six months after SBT (or later), however, increased SUVmax/BG and BTV values are associated with a worse prognosis. Multivariate analysis stresses the prognostic importance of dynamic studies.
Comparison of Computed Tomography– and Optical Image–Based Assessment of Liposome Distribution
Authors: Huang Huang , Dunne Michael , Lo John , Jaffray David A. , Allen Christine
Published: March 2018

The use of multimodal imaging as a tool to assess the in vivo pharmacokinetics and biodistribution of nanocarriers is important in understanding the nature of their in vivo transport. The current study reports the development of a nano-sized liposomal computed tomographic (CT)/optical imaging probe carrying iohexol and Cy5.5 and its use in micro-CT and optical imaging to quantitatively assess the whole-body (macroscopic), intratumoral, and microscopic distribution over a period of 8 days. These multimodal liposomes have a vascular half-life of 30.3 ± 8.9 hours in mice bearing subcutaneous H520 non-small cell lung cancer tumors, with the maximum liposome accumulation in tumor achieved 48 hours postinjection. The in vivo liposome distribution and stability were quantitatively assessed using both micro-CT and fluorescence molecular tomography. The combination of CT and optical imaging enables visualization of the liposomes at the whole-body, tumor, and cellular scales with high sensitivity. Such noninvasive tracking of therapeutic vehicles at the macro- and microscale is important for informed and rational development of novel nanocarrier systems.
In Vivo Bioluminescence Imaging Validation of a Human Biopsy–Derived Orthotopic Mouse Model of Glioblastoma Multiforme
Authors: Jarzabek Monika A. , Huszthy Peter C. , Skaftnesmo Kai O. , McCormack Emmet , Dicker Patrick , Prehn Jochen H.M. , Bjerkvig Rolf , Byrne Annette T.
Published: March 2018

Glioblastoma multiforme (GBM), the most aggressive brain malignancy, is characterized by extensive cellular proliferation, angiogenesis, and single-cell infiltration into the brain. We have previously shown that a xenograft model based on serial xenotransplantation of human biopsy spheroids in immunodeficient rodents maintains the genotype and phenotype of the original patient tumor. The present work further extends this model for optical assessment of tumor engraftment and growth using bioluminescence imaging (BLI). A method for successful lentiviral transduction of the firefly luciferase gene into multicellular spheroids was developed and implemented to generate optically active patient tumor cells. Luciferase-expressing spheroids were injected into the brains of immunodeficient mice. BLI photon counts and tumor volumes from magnetic resonance imaging (MRI) were correlated. Luciferase-expressing tumors recapitulated the histopathologic hallmarks of human GBMs and showed proliferation rates and microvessel density counts similar to those of wild-type xenografts. Moreover, we detected widespread invasion of luciferase-positive tumor cells in the mouse brains. Herein we describe a novel optically active model of GBM that closely mimics human pathology with respect to invasion, angiogenesis, and proliferation indices. The model may thus be routinely used for the assessment of novel anti-GBM therapeutic approaches implementing well-established and cost-effective optical imaging strategies.
In Vivo Visualization and Monitoring of Viable Neural Stem Cells Using Noninvasive Bioluminescence Imaging in the 6-Hydroxydopamine-Induced Mouse Model of Parkinson Disease
Authors: Im Hyung-Jun , Hwang Do Won , Lee Han Kyu , Jang Jaeho , Lee Song , Youn Hyewon , Jin Yeona , Kim Seung U. , Kim E. Edmund , Kim Yong Sik , Lee Dong Soo
Published: March 2018

Transplantation of neural stem cells (NSCs) has been proposed as a treatment for Parkinson disease (PD). The aim of this study was to monitor the viability of transplanted NSCs expressing the enhanced luciferase gene in a mouse model of PD in vivo. The PD animal model was induced by unilateral injection of 6-hydroxydopamine (6-OHDA). The behavioral test using apomorphine-induced rotation and positron emission tomography with [18F]N-(3-fluoropropyl)-2′-carbomethoxy-3′-(4-iodophenyl)nortropane ([18F]FP-CIT) were conducted. HB1.F3 cells transduced with an enhanced firefly luciferase retroviral vector (F3-effLuc cells) were transplanted into the right striatum. In vivo bioluminescence imaging was repeated for 2 weeks. Four weeks after transplantation, [18F]FP-CIT PET and the rotation test were repeated. All 6-OHDA-injected mice showed markedly decreased [18F]FP-CIT uptake in the right striatum. Transplanted F3-effLuc cells were visualized on the right side of the brain in all mice by bioluminescence imaging. The bioluminescence intensity of the transplanted F3-effLuc cells gradually decreased until it was undetectable by 10 days. The behavioral test showed that stem cell transplantation attenuated the motor symptoms of PD. No significant change was found in [18F]FP-CIT imaging after cell transplantation. We successfully established an in vivo bioluminescence imaging system for the detection of transplanted NSCs in a mouse model of PD. NSC transplantation induced behavioral improvement in PD model mice.
Imaging of Integrin αvβ3 Expression Using 68Ga-RGD Positron Emission Tomography in Pediatric Cerebral Infarct
Authors: Choi Hongyoon , Phi Ji Hoon , Paeng Jin Chul , Kim Seung-Ki , Lee Yun-Sang , Jeong Jae Min , Chung June-Key , Lee Dong Soo , Wang Kyu-Chang
Published: March 2018

Enhanced expression of integrin αvβ3 is commonly used as a biomarker for angiogenesis, which is one of the key pathophysiologic processes in cerebral infarct. Integrin αvβ3 can be imaged with arginine-glycine-aspartic acid (RGD) peptide agents. In this study, characteristics of positron emission tomography (PET) using a 68Ga-labeled RGD were investigated in pediatric cerebral infarct. Pediatric patients with moyamoya disease underwent 68Ga-RGD PET in a research protocol for neovascularization evaluation. In these patients, 17 cerebral infarct lesions of 10 patients were included in the analysis. On 68Ga-RGD PET, the infarct lesion to contralateral brain ratio (LCR) of the infarct lesion was measured and analyzed with regard to postinfarct time interval (PTI) and perfusion single-photon emission computed tomography (SPECT) findings. An increase in 68Ga-RGD uptake was observed in cerebral infarct, particularly in recent lesions. The LCR was significantly higher in the recent than in the chronic lesions, and a significant correlation existed between the LCR and PTI. Additionally, the LCR was significantly higher in the lesions with hyperperfusion on SPECT. This study, as the first human study using an RGD agent for in vivo cerebral infarct imaging, demonstrated that 68Ga-RGD PET has a potential for molecular imaging of integrin αvβ3 expression in cerebral infarct as a biomarker of angiogenesis.
Differentiation of Glioblastomas from Metastatic Brain Tumors by Tryptophan Uptake and Kinetic Analysis: A Positron Emission Tomographic Study with Magnetic Resonance Imaging Comparison
Authors: Kamson David O. , Mittal Sandeep , Buth Amy , Muzik Otto , Kupsky William J. , Robinette Natasha L. , Barger Geoffrey R. , Juhász Csaba
Published: March 2018

Differentiating high-grade gliomas from solitary brain metastases is often difficult by conventional magnetic resonance imaging (MRI); molecular imaging may facilitate such discrimination. We tested the accuracy of α[11C]methyl-L-tryptophan (AMT)–positron emission tomography (PET) to differentiate newly diagnosed glioblastomas from brain metastases. AMT-PET was performed in 36 adults with suspected brain malignancy. Tumoral AMT accumulation was measured by standardized uptake values (SUVs). Tracer kinetic analysis was also performed to separate tumoral net tryptophan transport (by AMT volume of distribution [VD]) from unidirectional uptake rates using dynamic PET and blood input function. Differentiating the accuracy of these PET variables was evaluated and compared to conventional MRI. For glioblastoma/metastasis differentiation, tumoral AMT SUV showed the highest accuracy (74%) and the tumor/cortex VD ratio had the highest positive predictive value (82%). The combined accuracy of MRI (size of contrast-enhancing lesion) and AMT-PET reached up to 93%. For ring-enhancing lesions, tumor/cortex SUV ratios were higher in glioblastomas than in metastatic tumors and could differentiate these two tumor types with > 90% accuracy. These results demonstrate that evaluation of tryptophan accumulation by PET can enhance pretreatment differentiation of glioblastomas and metastatic brain tumors. This approach may be particularly useful in patients with a newly diagnosed solitary ring-enhancing mass.
Molecular Imaging of β-Amyloid Plaques with Near-Infrared Boron Dipyrromethane (BODIPY)-Based Fluorescent Probes
Authors: Watanabe Hiroyuki , Ono Masahiro , Matsumura Kenji , Yoshimura Masashi , Kimura Hiroyuki , Saji Hideo
Published: March 2018

The formation of β-amyloid (Aβ) plaques is a critical neurodegenerative change in Alzheimer disease (AD). We designed and synthesized novel boron dipyrromethane (BODIPY)-based Aβ probes (BAPs) and evaluated their utility for near-infrared fluorescence imaging of Aβ plaques in the brain. In binding experiments in vitro, BAPs showed high affinity for synthetic Aβ aggregates ( Kd = 18–149 nM). Furthermore, BAPs clearly stained Aβ plaques in sections of Tg2576 mice. In mouse brain tissue, BAPs showed sufficient uptake for optical imaging. In addition, ex vivo fluorescent staining of brain sections from Tg2576 mice after the injection of BAP-2 showed selective binding of Aβ plaques with little nonspecific binding. BAPs may be useful as a near-infrared fluorescent probe for imaging Aβ plaques.
Use of eXIA 160 XL for Contrast Studies in Micro–Computed Tomography: Experimental Observations
Authors: Willekens Inneke , Buls Nico , Maeseneer Michel De , Lahoutte Tony , de Mey Johan
Published: March 2018

The purpose of this study was to evaluate the time course of contrast enhancement of spleen, liver, and blood using eXIA 160 XL in healthy mice. eXIA 160 XL was intravenously injected in C57bl/6 mice ( n = 12) at a dose of 0.1 mL/20 g (16 mg iodine [I]/20 g) ( n = 6) or 0.2 mL/20 g (32 mg I/20 g) ( n = 6). The distribution was analyzed by repeated micro–computed tomographic scans up to 48 hours after contrast administration. Images were analyzed using Amide software. Regions of interest were drawn in the spleen, liver, and left ventricle. Contrast enhancement was measured and expressed as a function of time. Peak contrast enhancement of the spleen was reached at 30 minutes, and peak contrast enhancement of the liver occurred 45 minutes after 16 mg I/20 g. Given that this contrast was found to be rather low in the spleen in comparison with former eXIA 160 products, experiments were done at a higher dose. However, the 32 mg I/20 g dose was lethal for mice. Enhancement inside the heart lasts for 1 hour. Administration of eXIA 160 XL results in long-lasting blood pool contrast with higher contrast enhancement in heart and liver in comparison with eXIA 160; however, the administered dose should be limited to 16 mg I/20 g.
Age-Dependent Small-Animal Internal Radiation Dosimetry
Authors: Xie Tianwu , Zaidi Habib
Published: March 2018

Rats at various ages were observed to present with different radiosensitivity and bioavailability for radiotracers commonly used in preclinical research. We evaluated the effect of age-induced changes in body weight on radiation dose calculations. A series of rat models at different age periods were constructed based on the realistic four-dimensional digital rat whole-body (ROBY) computational model. Particle transport was simulated using the MCNPX Monte Carlo code. Absorbed fractions (AFs) and specific absorbed fraction (SAFs) of monoenergetic photons/electrons and S values of eight positron-emitting radionuclides were calculated. The SAFs and S values for most source-target pairs were inversely correlated with body weight. Differences between F-18 S values for most source-target pairs were between −1.5% and −2%/10 g difference in bodyweight for different computational models. For specific radiotracers, the radiation dose to organs presents a negative correlation with rat body weight. The SAFs for monoenergetic photons/electrons and S values for common positron-emitting radionuclides can be exploited in the assessment of radiation dose delivered to rats at different ages and weights. The absorbed dose to organs is significantly higher in the low-weight young rat model than in the adult model, which would result in steep secondary effects and might be a noteworthy issue in laboratory animal internal dosimetry.
Shear Forces from Flow Are Responsible for a Distinct Statistical Signature of Adherent Microbubbles in Large Vessels
Authors: Wang Shiying , Mauldin F. William , Klibanov Alexander L. , Hossack John A.
Published: March 2018

Real-time ultrasound-based targeted molecular imaging in large blood vessels holds promise for early detection and diagnosis of stroke risk by identifying early markers for atherosclerosis prior to plaque formation. Singular spectrum-based targeted molecular (SiSTM) imaging is a recently proposed method that uses changes in statistical dimensionality—quantified by a normalized singular spectrum area (NSSA)—to image receptor-ligand–bound adherent microbubbles. However, the precise physical mechanism responsible for the distinct statistical signature was previously unknown. In this study, in vitro flow phantom experiments were performed to elucidate the physical mechanism in large blood vessel environments. In the absence of flow, an increase in the NSSA of adherent microbubbles with respect to tissue was not observed with increased microbubble concentration or pulse length ( p > .23; n = 5) but was observed with increased flow rate ( p < .01; n = 10). When observing the dynamics of the adherent microbubble statistics, a good correlation was observed between the NSSA and the derivative of image intensity ( R2 > .97). In addition, a monotonic relationship between the NSSA and decorrelation was demonstrated. These findings confirm the hypothesis that the statistical signature of adherent microbubbles is derived from frame-to-frame decorrelation, which is induced by flow shear forces.
Somatostatin Receptor Type 2–Based Reporter Expression after Plasmid-Based in Vivo Gene Delivery to Non–Small Cell Lung Cancer
Authors: Han Lin , Ravoori Murali , Wu Guanglin , Sakai Ryo , Yan Shaoyu , Singh Sheela , Xu Kai , Roth Jack A. , Ji Lin , Kundra Vikas
Published: March 2018

Plasmids tend to have much lower expression than viruses. Gene expression after systemic administration of plasmid vectors has not been assessed using somatostatin receptor type 2 ( SSTR2)-based reporters. The purpose of this work was to identify gene expression in non–small cell lung cancer (NSCLC) after systemic liposomal nanoparticle delivery of plasmid containing SSTR2-based reporter gene. In vitro, Western blotting was performed after transient transfection with the plasmid cytomegalovirus (CMV)-SSTR2, CMV-TUSC2-IRES-SSTR2, or CMV-TUSC2. SSTR2 is the reporter gene, and TUSC2 is a therapeutic gene. Mice with A549 NSCLC lung tumors were injected intravenously with CMV-SSTR2, CMV-TUSC2-IRES-SSTR2, or CMV-TUSC2 plasmids in DOTAP:cholesterolliposomal nanoparticles. Two days later, mice were injected intravenously with 111In-octreotide. The next day, biodistribution was performed. The experiment was repeated including single-photon emission computed tomography/computed tomography (SPECT/CT). Immunohistochemistry was performed. In vitro, SSTR2 expression was similar in cells transfected with CMV-SSTR2 or CMV-TUSC2-IRES-SSTR2. TUSC2 expression was similar in cells transfected with CMV-TUSC2 or CMV-TUSC2-SSTR2. Biodistribution demonstrated significantly greater 111In-octreotide uptake in tumors from mice injected with CMV-TUSC2-IRES-SSTR2 or CMV-SSTR2 than the control plasmid, CMV-TUSC2 ( p < .05). Gamma-camera and SPECT/CT imaging illustrated SSTR2 expression in tumors in mice injected with CMV-TUSC2-IRES-SSTR2 or CMV-SSTR2 versus background with control plasmid. Immunohistochemistry corresponded with imaging. SSTR2-based reporter imaging can visualize gene expression in lung tumors after systemic liposomal nanoparticle delivery of plasmid containing SSTR2-based reporter gene or SSTR2 linked to a second therapeutic gene, such as TUSC2.
Folate Receptor–Targeted Single-Photon Emission Computed Tomography/Computed Tomography to Detect Activated Macrophages in Atherosclerosis: Can It Distinguish Vulnerable from Stable Atherosclerotic Plaques?
Authors: Winkel Leah C.J. , Groen Harald C. , van Thiel Bibi S. , Müller Cristina , van der Steen Antonius F.W. , Wentzel Jolanda J. , de Jong Marion , Van der Heiden Kim
Published: March 2018

The need for noninvasive imaging to distinguish stable from vulnerable atherosclerotic plaques is evident. Activated macrophages play a role in atherosclerosis and express folate receptor folate receptor β (FR-β). The feasibility of folate targeting to detect atherosclerosis was demonstrated in human and mouse plaques, and it was suggested that molecular imaging of FR-β through folate conjugates might be a specific marker for plaque vulnerability. However, these studies did not allow differentiation between stable and vulnerable atherosclerotic plaques. We investigated the feasibility of a folate-based radiopharmaceutical (111In-EC0800) with high-resolution animal single-photon emission computed tomography/computed tomography (SPECT/CT) to differentiate between stable and vulnerable atherosclerotic plaques in apolipoprotein E 7 mice in which we can induce plaques with the characteristics of stable and vulnerable plaques by placing a flow-modifying cast around the common carotid artery. Both plaques showed 111In-EC0800 uptake, with higher uptake in the vulnerable plaque. However, the vulnerable plaque was larger than the stable plaque. Therefore, we determined tracer uptake per plaque volume and demonstrated higher accumulation of 111In-EC0800 in the stable plaque normalized to plaque volume. Our data show that 111In-EC0800 is not a clear-cut marker for the detection of vulnerable plaques but detects both stable and vulnerable atherosclerotic plaques in a mouse model of atherosclerosis.
Simultaneous Viewing of Individual Cells and Ambient Microvasculature Using Optical Absorption and Fluorescence Contrasts
Authors: Xie Zhixing , Chen Sung-Liang , Fabiilli Mario L. , Fowlkes J. Brian , Shung K. Kirk , Zhou Qifa , Carson Paul L. , Wang Xueding
Published: March 2018

Viewing individual cells and ambient microvasculature simultaneously is crucial for understanding tumor angiogenesis and microenvironments. We developed a confocal fluorescence microscopy (CFM) and photoacoustic microscopy (PAM) dual-modality imaging system that can assess fluorescent contrast and optical absorption contrast in biologic samples simultaneously. After staining tissues with fluorescent dye at an appropriate concentration, each laser pulse can generate not only sufficient fluorescent signals from cells for CFM but also sufficient photoacoustic signals from microvessels for PAM. To explore the potential of this system for diagnosis of bladder cancer, experiments were conducted on a rat bladder model. The CFM image depicts the morphology of individual cells, showing not only large polygonal umbrella cells but also intracellular components. The PAM image acquired at the same time provides complementary information on the microvascular distribution in the bladder wall, ranging from large vessels to capillaries. This device provides an opportunity to realize both histologic assay and microvascular characterization simultaneously. The combination of the information of individual cells and local microvasculature in the bladder offers the capability of envisioning the viability and activeness of these cells and holds promise for more comprehensive study of bladder cancer in vivo.
Noninvasive Manganese-Enhanced Magnetic Resonance Imaging for Early Detection of Breast Cancer Metastatic Potential
Authors: Nofiele Joris Tchouala , Czarnota Gregory J. , Cheng Hai-Ling Margaret
Published: March 2018

Cancer cells with a high metastatic potential will more likely escape and form distant tumors. Once the cancer has spread, a cure is rarely possible. Unfortunately, metastasis often proceeds unnoticed until a secondary tumor has formed. The culprit is that current imaging-based cancer screening and diagnosis are limited to assessing gross physical changes, not the earliest cellular changes that drive cancer progression. The purpose of this study is to develop a novel noninvasive magnetic resonance (MR) cellular imaging capability for characterizing the metastatic potential of breast cancer and enable early cancer detection. This MR method relies on imaging cell uptake of manganese, an endogenous calcium analogue and an MR contrast agent, to detect aggressive cancer cells. Studies on normal breast epithelial cells and three breast cancer cell lines, from nonmetastatic to highly metastatic, demonstrated that aggressive cancer cells appeared significantly brighter on MR as a result of altered cell uptake of manganese. In vivo results in nude rats showed that aggressive tumors that are otherwise unseen on conventional gadolinium-enhanced MR imaging are detected after manganese injection. This cellular MR imaging technology brings a critically needed, unique dimension to cancer imaging by enabling us to identify and characterize metastatic cancer cells at their earliest appearance.
The Antiangiogenic Effects of a Vascular Endothelial Growth Factor Decoy Receptor Can Be Monitored in Vivo Using Contrast-Enhanced Ultrasound Imaging
Authors: Forsberg Flemming , Ro Raymond J. , Marshall Andrew , Liu Ji-Bin , Chiou See-Ying , Merton Daniel A. , Machado Priscilla , Dicker Adam P. , Nazarian Levon N.
Published: March 2018

The development of antiangiogenic therapies has stimulated interest in noninvasive imaging methods to monitor response. We investigated whether the effects of a vascular endothelial growth factor decoy receptor (VEGF Trap, Regeneron Pharmaceuticals, Tarrytown, NY) could be monitored in vivo using contrast-enhanced ultrasonography (CEUS). Twenty nude mice (in two groups) were implanted with a human melanoma cell line (DB-1). The active group received VEGF Trap (4 × 25 mg/kg over 2 weeks), whereas the control group received an inactive protein. An ultrasound contrast agent was injected followed by power Doppler imaging (PDI) and pulse inversion harmonic imaging (PIHI; regular and intermittent). Specimens were sectioned in the same planes as the images and stained for endothelial cells (CD31), cyclooxygenase-2 (COX-2), VEGF, and hypoxia (Glut1). Measures of tumor vascularity obtained with the different imaging modes were compared to immunohistochemical markers of angiogenesis. Mean tumor volume was smaller in the active group than in the control group (656 ± 225 vs 1,160 ± 605 mm3). Overall, PDI and VEGF correlated ( r = .34; p = .037). Vascularity decreased from control to treated mice with intermittent PIHI, as did the expression of CD31 and COX-2 ( p # .02), whereas VEGF increased ( p = .05). CEUS appears to allow in vivo monitoring of the antiangiogenic effects of VEGF Trap in the DB-1 human melanoma xenograft model.
Imaging Atherosclerotic Plaque Inflammation via Folate Receptor Targeting Using a Novel 18F-Folate Radiotracer
Authors: Müller Adrienne , Beck Katharina , Rancic Zoran , Müller Cristina , Fischer Cindy R. , Betzel Thomas , Kaufmann Philipp A. , Schibli Roger , Kramer Stefanie D. , Ametamey Simon M.
Published: March 2018

Folate receptor β (FR-β) is overexpressed on activated, but not resting, macrophages involved in a variety of inflammatory and autoimmune diseases. A pivotal step in atherogenesis is the subendothelial accumulation of macrophages. In nascent lesions, they coordinate the scavenging of lipids and cellular debris to define the likelihood of plaque inflammation and eventually rupture. In this study, we determined the presence of FR-β-expressing macrophages in atherosclerotic lesions by the use of a fluorine-18-labeled folate-based radiotracer. Human endarterectomized specimens were used to measure gene expression levels of FR-β and CD68. Increased FR-β and CD68 levels were found in atherosclerotic plaques compared to normal artery walls by quantitative real-time polymerase chain reaction. Western blotting and immunohistochemistry demonstrated prominent FR-β protein levels in plaques. FR- β-positive cells colocalized with activated macrophages (CD68) in plaque tissue. Carotid sections incubated with 3′-aza-2′- [18F]fluorofolic acid displayed increased accumulation in atherosclerotic plaques through in vitro autoradiography. Specific binding of the radiotracer correlated with FR-β-expressing macrophages. These results demonstrate high FR-β expression in atherosclerotic lesions of human carotid tissue correlating with CD68-positive macrophages. Areas of high 3′-aza-2′-[18F]fluorofolic acid binding within the lesions represented FR-β-expressing macrophages. Selectively targeting FR-β-positive macrophages through folate-based radiopharmaceuticals may be useful for noninvasive imaging of plaque inflammation.
Treatment with Octreotide in Patients with Well-Differentiated Neuroendocrine Tumors of the Ileum: Prognostic Stratification with Ga-68-DOTA-TATE Positron Emission Tomography
Authors: Koch Walter , Auernhammer Christoph J. , Geisler Julia , Spitzweg Christine , Cyran Clemens C. , Ilhan Harun , Bartenstein Peter , Haug Alexander R.
Published: March 2018

We investigated the use of Ga-68-DOTA-Tyr3-octreotate (Ga-68-DOTA-TATE) positron emission tomography (PET) and standardized uptake values (SUVs) to predict the effectiveness of treatment with the somatostatin analogue octreotide acetate (Sandostatin LAR) in patients with neuroendocrine tumors (NETs). Thirty patients with well-differentiated NETs of the ileum (grades G1 and G2) were studied with Ga-68-DOTA-TATE. The average SUV of a 50% isocontour volume of interest covering the lesion with maximum uptake (SUVmean) and the maximum SUV (SUVmax) were determined. Patients were followed up, and the time to progression was recorded. Twenty-one patients showed progressive disease at the end of the study; nine patients had stable disease. The median progression-free survival (PFS) was 51.0 weeks (95% confidence interval [CI] 26.4-75.6). A cutoff for the SUVmax of 29.4 and for the SUVmean of 20.3 could separate between patients with a long PFS (69.0 weeks; 95% CI 9.8-128.2) and a short PFS (26.0 weeks; 95% CI 8.7-43.3) response to octreotide acetate therapy. Patients with high radiotracer uptake had significantly higher PFS with a 2.9-fold higher chance for stable disease after 45 weeks; however, the prognostic performance of SUVmax on an individual basis was poor, with a sensitivity of 75% and a specificity of 64%. SUVmax and SUVmean of NET tumor lesions in Ga-68-DOTA-TATE PET are important prognostic indices for predicting the response to therapy with octreotide acetate.
99mTc-3PRGD2 Scintimammography in Palpable and Nonpalpable Breast Lesions
Authors: Liu Lin , Song Yan , Gao Shi , Ji Tiefeng , Zhang Haishan , Ji Bin , Chen Ben , Jia Bing , Wang Fan , Xu Zheli , Ma Qingjie
Published: March 2018

The aim of this study was to explore the diagnostic performance of 99mTc-3(poly-(ethylene glycol),PEG)4-RGD2 (99mTc-3PRGD2) scintimammography (SMM) in patients with either palpable or nonpalpable breast lesions and compare SMM to mammography to assess the possible incremental value of SMM in breast cancer detection. We also investigated the αvβ3 expression in malignant and benign breast lesions. Ninety-four patients with 110 lesions were included in this study. Mammograms were evaluated according to the Breast Imaging Reporting and Data System (BI-RADS) by a specialized imaging radiologist. Prone SMM was performed 1 hour after injection of 99mTc-3PRGD2. Scintigraphic images were interpreted independently by two experienced nuclear medicine physicians using a three-point system, and the kappa value was calculated to determine the interreader agreement. The McNemar test was used to compare SMM and mammography with respect to sensitivity, specificity, and accuracy. Diagnostic values for breast cancer detection were evaluated for each lesion. Immunohistochemistry was performed to evaluate integrin αvβ3 expression. Histopathology revealed 46 malignant lesions and 64 benign lesions. The overall sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of SMM were 83%, 73%, 77%, 69%, and 85%, respectively. The kappa value between the two reviewers was 0.63. The diagnostic values of SMM were higher than those of mammography in evaluating overall breast lesions. A sensitivity of 91% was achieved when SMM and mammography results were combined with 60% of all false-negative mammography findings classified as true-positive results by SMM. Integrin αvβ3 expression was positively identified using SMM imaging. SMM is a promising tool to avoid unnecessary biopsies when used in addition to mammography and can be used to image αvβ3 expression in breast cancer with good image quality.