Potential Imaging Targets Research Articles

Potential imaging targets in primary head and neck squamous cell carcinoma and lymph node metastases

PurposeTo investigate glycoprotein nonmetastatic melanoma protein B (GPNMB) and vascular endothelial growth factor (VEGF) as potential fluorescent imaging markers by comparing their protein expression to epidermal growth factor receptor (EGFR). Materials and methodsThirty-eight paired samples of untreated head and neck squamous cell carcinoma (HNSCC) primary tumours (PT) and corresponding synchronous lymph node metastases (LNM) were selected. After immunohistochemical staining, expression was assessed and compared by the percentage of positive tumour cells. Data were analysed using the Mann-Whitney test, effect sizes (ESr) and Spearman's correlation coefficient (r). ResultsGPNMB expression was observed in 100 % of PT, and median 80 % (range 5–100 %) of tumour cells, VEGF in 92 % and 60 % (0–100 %), EGFR in 87 % and 60 % (0–100 %) respectively. In corresponding LNM, GPNMB expression was observed in 100 % of LNM and median 90 % (20–100 %) of tumour cells, VEGF in 87 % and 65 % (0–100 %), and EGFR in 84 % and 35 % (0–100 %). A positive correlation was found between expression in PT and LNM for GPNMB (r = 0.548) and EGFR (r = 0.618) (p < 0.001), but not for VEGF (r = −0.020; p = 0.905). GPNMB expression was present in a higher percentage of tumour cells compared to EGFR in PT (p = 0.015, ESr = −0.320) and in LNM (p < 0.001, ESr = −0.478), while VEGF was not (p = 1.00, ESr = −0.109 and − 0.152, respectively). ConclusionGPNMB expression is higher than EGFR in untreated HNSCC PT and corresponding LNM, while VEGF expression is comparable to EGFR. GPNMB is a promising target for fluorescent imaging in HNSCC.

Preclinical validation of a novel brain-penetrant PET ligand for visualization of histone deacetylase 6: a potential imaging target for neurodegenerative diseases.

Histone deacetylase 6 (HDAC6) has emerged as a therapeutic target for neurodegenerative diseases such as Alzheimer's disease. Noninvasive imaging of HDAC6 in the brain by positron emission tomography (PET) would accelerate research into its roles in these diseases. We recently discovered an 18F-labeled derivative of the selective HDAC6 inhibitor SW-100 ([18F]FSW-100) as a potential candidate for brain HDAC6 radioligand. As a mandatory step prior to clinical translation, we performed preclinical validation of [18F]FSW-100. Process validation of [18F]FSW-100 radiosynthesis for clinical use and assessment of preclinical toxicity and radiation dosimetry estimated from mouse distribution data were performed. In vitro selectivity of FSW-100 for 28 common receptors in the brain and HDAC isoforms was characterized. [18F]FSW-100 PET imaging was performed in non-human primates in a conscious state to estimate the feasibility of HDAC6 imaging in humans. Three consecutive validation runs of the automated radiosynthesis gave [18F]FSW-100 injections with radiochemical yields of 12%, and the injections conformed to specified quality control criteria for batch release. No acute toxicity was observed for non-radiolabeled FSW-100 or radioactivity decayed [18F]FSW-100 injection, and the former was negative in the Ames test. The whole-body effective dose estimated from biodistribution in mice was within the range of that of previously reported 18F-radioligands in humans. In vitro selectivity against common receptors and other HDAC isoforms was confirmed. [18F]FSW-100 demonstrated good penetration in monkey brain, and in vivo blocking studies suggested that the uptake was specific. These results support the clinical utility of [18F]FSW-100 for in vivo imaging of HDAC6 in the brain.

FGF19-Based Mini Probe Targeting FGFR4 for Diagnosis and Surgical Navigation of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a frequent malignancy that has a high death rate and a high rate of recurrence following surgery, owing to insufficient surgical resection. Furthermore, HCC is prone to peritoneal metastasis (HCC-PM), resulting in a significant number of tiny cancer lesions, making surgical removal more challenging. As a potential imaging target, FGFR4 is highly expressed in tumors, especially in HCC, but is less expressed in the normal liver. In this study, we used computational simulation approaches to develop peptide I0 derived from FGF19, a particular ligand of FGFR4, and labeled it with the NIRF dye, MPA, for HCC detection. In surgical navigation, the TBR was 9.31 ± 1.36 and 8.57 ± 1.15 in HepG2 in situ tumor and HCC-PM models, respectively, indicating considerable tumor uptake. As a result, peptide I0 is an excellent clinical diagnostic reagent for HCC, as well as a tool for surgically resecting HCC peritoneal metastases.

Cross-species evaluation of fibroblast activation protein alpha as potential imaging target for soft tissue sarcoma: a comparative immunohistochemical study in humans, dogs, and cats.

Complete surgical tumor resection is paramount in the management of soft tissue sarcoma (STS) in humans, dogs, and cats alike. Near-infrared targeted tracers for fluorescence-guided surgery (FGS) could facilitate intraoperative visualization of the tumor and improve resection accuracy. Target identification is complicated in STS due to the rarity and heterogeneity of the disease. This study aims to validate the expression of fibroblast activation protein alpha (FAP) in selected human, canine, and feline STS subtypes to assess the value of FAP as a target for FGS and to validate companion animals as a translational model. Formalin-fixed and paraffin-embedded tissue samples from 53 canine STSs (perivascular wall tumor (PWT), canine fibrosarcoma (cFS), and STS not further specified (NOS)), 24 feline fibrosarcomas, and 39 human STSs (myxofibrosarcoma, undifferentiated pleomorphic sarcoma, dermatofibrosarcoma protuberans, and malignant peripheral nerve sheath tumor) as well as six canine and seven feline healthy controls and 10 inflamed tissue samples were immunohistochemically stained for their FAP expression. FAP labeling in tumor, peritumoral, healthy skin, and inflamed tissue samples was quantified using a visually assessed semiquantitative expression score and digital image analysis. Target selection criteria (TASC) scoring was subsequently performed as previously described. Eighty-five percent (85%) of human (33/39), 76% of canine (40/53), and 92% of feline (22/24) STSs showed FAP positivity in over 10% of the tumor cells. A high expression was determined in 53% canine (28/53), 67% feline (16/24), and 44% human STSs (17/39). The average FAP-labeled area of canine, feline, and human STSs was 31%, 33%, and 42%, respectively (p > 0.8990). The FAP-positive tumor area was larger in STS compared to healthy and peritumoral tissue samples (p < 0.0001). TASC scores were above 18 for all feline and human STS subtypes and canine PWTs but not for canine STS NOS and cFS. This study represents the first cross-species target evaluation of FAP for STS. Our results demonstrate that FAP expression is increased in various STS subtypes compared to non-cancerous tissues across species, thereby validating dogs and cats as suitable animal models. Based on a TASC score, FAP could be considered a target for FGS.

Abstract 6261: Comparison of glycoprotein nonmetastatic melanoma protein b, epidermal growth factor receptor and vascular endothelial growth factor expression in head and neck squamous cell carcinoma, and untreated and residual lymph node metastases

Abstract Objective: To evaluate expression of the potential molecular imaging targets glycoprotein nonmetastatic melanoma protein B (GPNMB) and vascular endothelial growth factor (VEGF) in comparison to classical epidermal growth factor receptor (EGFR) in previously untreated head and neck cancer primary tumors and corresponding lymph node metastases, and in lymph node metastases after initial (chemo)radiotherapy. Methods: Primary tumors and lymph node metastases of 38 patients who underwent primary resection of head and neck squamous cell carcinoma (HNSCC) were selected. In addition, lymph node metastases from salvage surgery after (chemo)radiotherapy from 22 patients with HNSCC were selected. Immunohistochemical staining for EGFR, VEGF and GPNMB was performed, after which protein expression was scored using H-scores (percentage of positive tumor cells multiplied by staining intensity ranging from 0 to 2). Primary tumors and lymph node metastases with an H-score ≥5 were considered positive, after which sensitivity rates were calculated. Groups were compared using the Mann-Whitney U test for non-parametric data with post-hoc Bonferroni corrections. Results: In untreated primary HNSCC the sensitivity was 86.8% for EGFR (median H-score 60), 92.1% for VEGF (median 60), and 100% for GPNMB (median 100). In previously untreated lymph node metastases the sensitivity was 81.6% for EGFR (median 30), 86.8% for VEGF (median 65), and 100% for GPNMB (median 118). In lymph node metastases after initial (chemo)radiotherapy, sensitivity was 86.4% for EGFR (median 95) and 100% for GPMB (median 100). VEGF sensitivity could not reliably be evaluated in these lymph nodes due to nonspecific staining in all tissue slides. GPNMB expression was significantly higher compared to EGFR in untreated primary HNSCC (p = .009 and p &amp;lt; .001, respectively) and lymph node metastases (p &amp;lt; .001 for both). Conclusion: GPNMB shows better tumor-specific receptor expression in both sensitivity and H-scores compared to EGFR and VEGF in immunohistochemistry. VEGF performed comparable to EGFR in untreated HNSCC and lymph node metastases. GPNMB could therefore be a new potential imaging target based on these immunohistochemical results. Citation Format: Jeroen E. van Schaik, Bert van der Vegt, Saskia H. Hanemaaijer, Gyorgy B. Halmos, Max J. Witjes, Bernard F.A.M. van der Laan, Rudolf S. Fehrmann, Sjoukje F. Oosting, Boudewijn E. Plaat. Comparison of glycoprotein nonmetastatic melanoma protein b, epidermal growth factor receptor and vascular endothelial growth factor expression in head and neck squamous cell carcinoma, and untreated and residual lymph node metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6261.

Visualization of Macrophase Separation and Transformation in Immiscible Polymer Blends

Visualization of Macrophase Separation and Transformation in Immiscible Polymer Blends

Fully Automated Synthesis of Novel TSPO PET Imaging Ligand [18F]Fluoroethyltemazepam.

Introduction: Benzodiazepines, including temazepam are described as TSPO antagonists. In fact, TSPO was initially described as a peripheral benzodiazepine receptor (PBR) with a secondary binding site for diazepam. TSPO is a potential imaging target of neuroinflammation because there is an amplification of the expression of this receptor. Objectives: Herein, we developed a novel fluorinated benzodiazepine ligand, [18F]Fluoroethyltemazepam ([18F]F-FETEM), for positron emission tomography (PET) imaging of translocator protein (18 kDa). Methods: [18F]F-FETEM was radiolabelled with an automated synthesizer via a one-pot procedure. We conducted a [18F]F-aliphatic nucleophilic substitution of a tosylated precursor followed by purification on C18 and Alumina N SPE cartridges. Quality control tests was also carried out. Results: We obtained 2.0–3.0% decay-uncorrected radiochemical activity yield (3.7% decay-corrected) within the whole synthesis time about 33 min. The radiochemical purity of [18F]F-FETEM was over 90% by TLC analysis. Conclusions: This automated procedure may be used as basis for future production of [18F]F-FETEM for preclinical PET imaging studies.

Nuclear Imaging of Post-infarction Inflammation in Ischemic Cardiac Diseases - New Radiotracers for Potential Clinical Applications.

Acute myocardial infarction is one of the leading causes of death in the western world. Despite major improvements in myocardial reperfusion with sophisticated percutaneous coronary intervention technologies and new antithrombotic agents, there is still no effective therapy for preventing post- infarction myocardial injury and remodeling. Death of cardiomyocytes following ischemia results in "danger signals" that elicit an inflammatory reaction to remove cell debris and form scar tissue. Optimal healing of the damaged myocardial tissue requires a coordinated cellular response for sufficient wound healing and scar formation. However, if this inflammatory reaction is overactive or incompletely resolved, adverse left ventricular remodeling and heart failure may occur. Treatment aimed at the modulation of the post-MI inflammatory response has been widely pursued and investigated. Although improved infarct healing was shown in many experimental preclinical studies, to date, clinical trials using anti-inflammatory treatment strategies have been far less successful. Clearly, a need exists for predicting and selecting patients at risk and selecting the most appropriate therapy for individual patients. To this end, imaging of the post-MI response has been a topic of significant interest. In this review, we first discuss the clinical complications resulting from myocardial inflammation following AMI and the need for non-invasive imaging techniques using radiolabeled tracers. We then discuss the inflammatory reaction cascade following acute myocardial infarction, the inflammatory reaction cascade following acute myocardial infarction focusing on inflammatory cell types involved herein, and potential imaging targets for identifying these cells during the inflammatory process. In addition, we discuss specific characteristics and limitations of various preclinical animal models for ischemic heart disease since they are crucial in the development and evaluation of the imaging techniques. Finally, we discuss the need for non-invasive imaging approaches using radiolabeled tracers.

Glycoprotein Nonmetastatic Melanoma Protein B as Potential Imaging Marker in Posttherapeutic Metastatic Head and Neck Cancer.

ObjectiveTo evaluate expression of potential molecular imaging targets epidermal growth factor receptor (EGFR), glycoprotein nonmetastatic melanoma protein B (GPNMB), and vascular endothelial growth factor (VEGF) in lymph nodes (LNs) with or without head and neck squamous cell carcinoma (HNSCC) metastases after (chemo)radiation.Study DesignRetrospective study comparing receptor expression in paired lymph nodes after initial treatment.SettingA tertiary referral hospital.Subjects and MethodsSalvage neck dissection specimens of 40 patients treated with (chemo)radiation were selected. LNs that contained viable tumor, reactive changes after initial treatment, and normal LNs were analyzed using immunohistochemically determined H-scores and by calculating sensitivity and specificity rates and positive/negative predictive values (PPVs/NPVs).ResultsEGFR expression was found in 86% and GPNMB expression in 100% of the LNs with viable tumor. VEGF expression was present in all lymph node types. For EGFR, the sensitivity rate was 86%, and specificity rate was 81%. For GPNMB, these were 100% and 75%, respectively. PPV of EGFR was 61.8% and NPV was 98.2%. These were 56.4% and 100% for GPNMB, respectively.ConclusionIn residual or recurrent HNSCC lymph node metastases, both EGFR and GPNMB show tumor-specific expression in immunohistochemistry, which may prove useful in future molecular imaging in salvage neck dissections. Immunohistochemically detected VEGF expression indicates that this target is not feasible for imaging purposes in salvage surgery. Therefore, GPNMB could be a new potential imaging target showing comparable results to EGFR in immunohistochemistry.

Advances in Diagnostic and Intraoperative Molecular Imaging of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. To improve outcomes, there is a critical need for improved tools for detection, accurate staging, and resectability assessment. This could improve patient stratification for the most optimal primary treatment modality. Molecular imaging, used in combination with tumor-specific imaging agents, can improve established imaging methods for PDAC. These novel, tumor-specific imaging agents developed to target specific biomarkers have the potential to specifically differentiate between malignant and benign diseases, such as pancreatitis. When these agents are coupled to various types of labels, this type of molecular imaging can provide integrated diagnostic, noninvasive imaging of PDAC as well as image-guided pancreatic surgery. This review provides a detailed overview of the current clinical imaging applications, upcoming molecular imaging strategies for PDAC, and potential targets for imaging, with an emphasis on intraoperative imaging applications.

P and S Wave Receiver Function Imaging of Subduction With Scattering Kernels

AbstractA method for scattered wave imaging in 3‐D with both teleseismic P and S wave receiver function data is introduced. The approach relies on body‐wave scattering kernels that are derived from the adjoint data sensitivity kernels which are typically used for full waveform tomography. The forward problem is approximated using ray theory, yielding a computationally efficient imaging algorithm that can resolve dipping and discontinuous interfaces using both P and S wave receiver functions. Traveltime fields for the incident teleseismic arrivals and the receiver point‐sources are obtained by solving the Eikonal equation using a Fast Marching code which can handle a 3‐D reference velocity model. An energy stable finite‐difference method is used to simulate elastic wave propagation in a 2‐D hypothetical subduction zone model. The resulting synthetic P and S wave receiver function data sets are used to validate the imaging method. The kernel images are compared with those generated by the Generalized Radon Transform and Common Conversion Point Stacking methods. These results demonstrate the potential of the kernel imaging approach for constraining lithospheric structure in complex geologic environments with sufficiently dense recordings of teleseismic data. Potential imaging targets include short‐wavelength compositional variations in the mantle wedge and the slab's lithosphere‐asthenosphere boundary.

Leukocyte trafficking-associated vascular adhesion protein 1 is expressed and functionally active in atherosclerotic plaques.

Given the important role of inflammation and the potential association of the leukocyte trafficking-associated adhesion molecule vascular adhesion protein 1 (VAP-1) with atherosclerosis, this study examined whether functional VAP-1 is expressed in atherosclerotic lesions and, if so, whether it could be targeted by positron emission tomography (PET). First, immunohistochemistry revealed that VAP-1 localized to endothelial cells of intra-plaque neovessels in human carotid endarterectomy samples from patients with recent ischemic symptoms. In low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 (LDLR−/−ApoB100/100), VAP-1 was expressed on endothelial cells lining inflamed atherosclerotic lesions; normal vessel walls in aortas of C57BL/6N control mice were VAP-1-negative. Second, we discovered that the focal uptake of VAP-1 targeting sialic acid-binding immunoglobulin-like lectin 9 based PET tracer [68Ga]DOTA-Siglec-9 in atherosclerotic plaques was associated with the density of activated macrophages (r = 0.58, P = 0.022). As a final point, we found that the inhibition of VAP-1 activity with small molecule LJP1586 decreased the density of macrophages in inflamed atherosclerotic plaques in mice. Our results suggest for the first time VAP-1 as a potential imaging target for inflamed atherosclerotic plaques, and corroborate VAP-1 inhibition as a therapeutic approach in the treatment of atherosclerosis.

Synthesis and Biologic Evaluation of Novel 18F-Labeled Probes Targeting Prostate-Specific Membrane Antigen for PET of Prostate Cancer.

Four 18F-labeled probes, 18F-8a, 18F-8b, 18F-10a, and 18F-10b, were synthesized using 18F-SFB, and their affinity for PSMA and partition coefficients (log D) were evaluated in vitro. Biodistribution studies were performed in human prostate cancer xenograft-bearing mice. PET images were obtained using 2 compounds, 18F-8a and 18F-10a, and a toxicologic study of 18F-10a was performed. Four 18F-labeled asymmetric urea compounds, conjugated with 18F-SFB, were synthesized at a radiochemical yield of 30%-50% (decay-corrected), with a radiochemical purity greater than 95%. The radiochemical yield was 10-15 times higher than that of 18F-DCFPyL, the probe currently used in clinical studies. All 4 compounds showed high affinity for PSMA. 18F-8a and 18F-10a had a particularly high binding affinity (Ki values of 3.35 and 2.23 nM, respectively). In the biodistribution study, the accumulation of 18F-8a (13.3 ± 2.2 percentage injected dose per gram [%ID/g]) and 18F-10a (14.0 ± 3.1 %ID/g) in PSMA-positive human prostate (LNCaP) tumors was higher than that of the other 2 compounds and similar to that of 18F-DCFPyL (16.0 ± 2.9 %ID/g). 18F-10a showed the lowest hepatic and intestinal accumulation among the 4 compounds and slightly slower blood clearance than others. In the PET imaging studies, 18F-8a and 18F-10a were clearly visualized in LNCaP in xenograft-bearing mice. 18F-10a showed higher LNCaP-to-liver ratios than 18F-8a. We confirmed the safety profiles of 18F-10a; the no-observed-adverse-effects level was larger than 13.2 μg/kg. A novel 18F-labeled asymmetric urea compound, 18F-10a, had a high radiochemical yield, high binding affinity for PSMA, and pharmacokinetic profiles suitable for a PSMA imaging probe. We believe that 18F-10a can be effectively and safely used in this type of imaging.

Selecting Tumor-Specific Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery.

PurposeThe purpose of this study was to identify suitable molecular targets for tumor-specific imaging of pancreatic adenocarcinoma.ProceduresThe expression of eight potential imaging targets was assessed by the target selection criteria (TASC)—score and immunohistochemical analysis in normal pancreatic tissue (n = 9), pancreatic (n = 137), and periampullary (n = 28) adenocarcinoma.ResultsIntegrin αvβ6, carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), and urokinase plasminogen activator receptor (uPAR) showed a significantly higher (all p < 0.001) expression in pancreatic adenocarcinoma compared to normal pancreatic tissue and were confirmed by the TASC score as promising imaging targets. Furthermore, these biomarkers were expressed in respectively 88 %, 71 %, 69 %, and 67 % of the pancreatic adenocarcinoma patients.ConclusionsThe results of this study show that integrin αvβ6, CEA, EGFR, and uPAR are suitable targets for tumor-specific imaging of pancreatic adenocarcinoma.

Use of somatostatin receptor PET to differentiate between high-risk and low-risk atherosclerotic lesions: a prospective clinical study

BackgroundInflammation drives atherosclerotic plaque rupture that underlies most myocardial infarctions and strokes. Upregulation of somatostatin receptor subtype-2 (SST2) occurs on the cell surface of activated macrophages, offering a potential imaging target for tracking vascular inflammation. We tested the hypothesis that SST2 PET-CT imaging with 68Ga-DOTATATE can detect high-risk carotid and coronary plaque inflammation. We then compared its efficacy with 18F-fludeoxyglucose (18F-FDG), which has limited use in coronary imaging. MethodsProspective sequential 68Ga-DOTATATE PET and 18F-FDG PET imaging, plus CT angiography, were performed in 42 patients with either a recent cardiovascular event (within 3 months of imaging) or stable atherosclerosis, and at least 30% carotid or coronary artery stenosis. Images were analysed, with investigators masked to clinical details, to derive median (IQR) maximum arterial tissue-to-background ratio (TBR). Arterial TBRs were statistically evaluated against clinical and biochemical data, as well as CT-derived plaque morphology. Findings70 carotid arteries and 230 coronary segments were included. 24 patients (57%) had a recent cardiovascular event. 68Ga-DOTATATE TBR (1·98 [1·67–2·14]) was higher in symptomatic carotid arteries than in contralateral arteries (1·77 [1·46–2·08], p=0·0031) and asymptomatic plaques (1·49 [1·36–1·66], p=0·0012). 18F-FDG TBR was also higher on the symptomatic side (1·68 [1·49–1·97] vs 1·51 [1·44–1·80], p=0·0081). The two PET tracers were moderately correlated (r=0·40, p=0·0007). Coronary SST2 signals were visible in all patients, but high myocardial muscle 18F-FDG uptake was prohibitive in 27 patients (64%). Culprit coronary arteries had higher 68Ga-DOTATATE TBR (2·91 [2·69–4·08]) than the highest non-culprit segment (2·61 [1·94–3·01], p=0·0078), stable stented (2·00 [1·51–2·70], p=0·0063), and calcified (1·64 [1·33–2·04], p<0·0001) plaques. SST2 signal from culprit and high-risk coronary arteries was correlated with total cholesterol (r=0·44, p=0·042). InterpretationWe have shown that measurement of vascular inflammation with SST2 PET is feasible and differentiates high-risk and low-risk carotid and coronary lesions. High target specificity, low myocardial binding, and lower cost owing to generator-production give advantage to 68Ga-DOTATATE over 18F-FDG for atherosclerosis imaging. Correlations with 18F-FDG TBR and serum cholesterol further support the vascular SST2 signal as a potential prognostic biomarker to identify patients most at risk of future cardiovascular events. FundingWellcome Trust.

Non-invasive Assessment of Coronary Plaque Morphology

The majority of acute coronary syndromes are a result of atherosclerotic plaque rupture and subsequent occlusive luminal thrombus formation. Identification of rupture prone plaques could provide the means of reducing cardiovascular mortality and morbidity. Vulnerable plaques have distinct morphologic features which might serve as potential targets for imaging. Coronary CT angiography (CTA) is a non-invasive imaging modality which allows the visualization of the coronary artery lumen and wall with a sub-millimeter spatial and sub-second temporal resolution. Several coronary CTA plaque features have been linked to higher cardiovascular event rates, such as spotty calcification, low CT attenuation, positive remodeling, napkin-ring sign, large plaque volume, and increased plaque burden. The combined assessment of total plaque burden and single high-risk plaque features might improve cardiovascular risk stratification, and enable the early identification of vulnerable patients. Magnetic resonance angiography (MRA) with or without the use of contrast agents enables imaging of blood vessels; therefore, MRA might be an alternative to coronary CTA. However, the assessment of coronary vessel wall structure using MRA is currently limited due to breathing artifacts, heart motion artifacts, and lower spatial resolution.

Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver.

BackgroundColorectal cancer is the third most frequently diagnosed cancer and the third cause of cancer deaths in the United States. Despite the fact that tumor cell-intrinsic mechanisms controlling colorectal carcinogenesis have been identified, novel prognostic and diagnostic tools as well as novel therapeutic strategies are still needed to monitor and target colon cancer progression. We and others have previously shown, using mouse models, that the extracellular matrix (ECM), a major component of the tumor microenvironment, is an important contributor to tumor progression. In order to identify candidate biomarkers, we sought to define ECM signatures of metastatic colorectal cancers and their metastases to the liver.MethodsWe have used enrichment of extracellular matrix (ECM) from human patient samples and proteomics to define the ECM composition of primary colon carcinomas and their metastases to liver in comparison with normal colon and liver samples.ResultsWe show that robust signatures of ECM proteins characteristic of each tissue, normal and malignant, can be defined using relatively small samples from small numbers of patients. Comparisons with gene expression data from larger cohorts of patients confirm the association of subsets of the proteins identified by proteomic analysis with tumor progression and metastasis.ConclusionsThe ECM protein signatures of metastatic primary colon carcinomas and metastases to liver defined in this study, offer promise for development of diagnostic and prognostic signatures of metastatic potential of colon tumors. The ECM proteins defined here represent candidate serological or tissue biomarkers and potential targets for imaging of occult metastases and residual or recurrent tumors and conceivably for therapies. Furthermore, the methods described here can be applied to other tumor types and can be used to investigate other questions such as the role of ECM in resistance to therapy.

Detection of Esophageal Squamous Cell Carcinoma by Cathepsin B Activity in Nude Mice

Background and ObjectiveDespite great progress in treatment, the prognosis for patients with esophageal squamous cell carcinoma (ESCC) remains poor, highlighting the importance of early detection. Although upper endoscopy can be used for the screening of esophagus, it has limited sensitivity for early stage disease. Thus, development of new diagnosis approach to improve diagnostic capabilities for early detection of ESCC is an important need. The aim of this study was to assess the feasibility of using cathepsin B (CB) as a novel imaging target for the detection of human ESCC by near-infrared optical imaging in nude mice.MethodsInitially, we examined specimens from normal human esophageal tissue, intraepithelial neoplasia lesions, tumor in situ, ESCC and two cell lines including one human ESCC cell line (Eca-109) and one normal human esophageal epithelial cell line (HET-1A) for CB expression by immunohistochemistry and western blot, respectively. Next, the ability of a novel CB activatable near-infrared fluorescence (NIRF) probe detecting CB activity presented in Eca-109 cells was confirmed by immunocytochemistry. We also performed in vivo imaging of tumor bearing mice injected with the CB probe and ex vivo imaging of resected tumor xenografts and visceral organs using a living imaging system. Finally, the sources of fluorescence signals in tumor tissue and CB expression in visceral organs were identified by histology.ResultsCB was absent in normal human esophageal mucosa, but it was overexpressed in ESCC and its precursor lesions. The novel probe for CB activity specifically detected ESCC xenografts in vivo and in vitro.ConclusionsCB was highly upregulated in human ESCC and its precursor lesions. The elevated CB expression in ESCC allowed in vivo and in vitro detection of ESCC xenografts in nude mice. Our results support the usefulness of CB activity as a potential imaging target for the detection of human ESCC.

Integrin αvβ3 Imaging of Radioactive Iodine–Refractory Thyroid Cancer Using 99mTc-3PRGD2

Integrin α(v)β(3) has been proposed as a potential imaging target for radiolabeled RGD peptides and a molecular marker for the estimation of tumor angiogenesis, yet it has not been applied in differentiated thyroid cancer (DTC) patients with radioactive iodine-refractory (RAIR) lesions. The current study was conducted to assess the potential of integrin α(v)β(3) imaging in the detection of RAIR DTC lesions using (99m)Tc-PEG(4)-E[PEG(4)-c(RGDfK)](2) ((99m)Tc-3PRGD2), thus providing a feasible antiangiogenetic therapeutic target. Ten DTC patients (2 men, 8 women; mean age ± SD, 56.4 ± 9.8 y; age range, 42-73 y) with multiple RAIR metastases were recruited; all patients had both elevated thyroglobulin levels (thyroglobulin-positive) and negative (131)I whole-body scan (WBS) results. Clinical data were collected including history, (131)I WBS, contemporary CT, ultrasonography, thyroid-stimulating hormone, thyroglobulin, and antithyroglobulin. One or 2 target lesions were selected on the contemporary CT images using Response Evaluation Criteria in Solid Tumors 1.0 for all patients, 7 of whom were chosen for the calculation of the rates of lesion growth within the 3 mo before the study. WBS at 30 min and regional SPECT for lesions at 1 h were performed after the intravenous injection of (99m)Tc-3PRGD2. Two experienced nuclear medicine physicians read the images in a masked fashion. The tumor-to-background ratios were calculated for further analysis. All the target RAIR metastatic lesions were identified as positive on (99m)Tc-3PRGD2 SPECT images. There was a significant correlation between the mean tumor-to-background ratios and mean growth rates of target lesions (r = 0.878, P = 0.009). The RAIR ((131)I WBS-negative/thyroglobulin-positive) metastatic lesions can be traced using (99m)Tc-3PRGD2 imaging, meaning these lesions are highly neovascularized. (99m)Tc-3PRGD2 angiogenesis imaging can be used for the localization and growth evaluation of RAIR lesions, providing a new therapeutic target and a novel imaging modality to monitor the efficacy of certain antiangiogenetic therapy.

Molecular Imaging of Prostate Cancer: PET Radiotracers

Recent advances in the fundamental understanding of the complex biology of prostate cancer have provided an increasing number of potential targets for imaging and treatment. The imaging evaluation of prostate cancer needs to be tailored to the various phases of this remarkably heterogeneous disease. In this article, I review the current state of affairs on a range of PET radiotracers for potential use in the imaging evaluation of men with prostate cancer.