Hongcheng Shi

Differential diagnostic value of single-photon emission computed tomography/spiral computed tomography with Tc-99m-methylene diphosphonate in patients with spinal lesions.

PurposeThe objective of this study was to compare the diagnostic value obtained using single-photon emission computed tomography (SPECT)/spiral computed tomography (CT) with Tc-99m methylene-diphosphonate with that obtained using SPECT alone in patients with spinal lesions. MethodsThis was a retrospective study of 56 patients who underwent planar whole-body scintigraphy because of bone pain or osseous lesions that had been detected by other imaging techniques, or for the investigation of bone metastasis in patients with extraskeletal malignancies. Only patients who had hot spots detected in their spine and who had undergone single-photon emission computed tomography/computed tomography (SPECT/CT) imaging were included. One lesion from each patient was resected or biopsied for pathological diagnosis, and lesions for which a pathological diagnosis could be made were included in this study. Single-photon emission computed tomography (SPECT) and SPECT/CT images were independently interpreted by two experienced nuclear medicine physicians who had not been involved in the selection of data for the study. The physicians were aware of patients’ sex, age, history of histologically confirmed extraskeletal malignancy, and whole-body scintigraphy results, but were unaware of the results of other investigations, such as X-ray, MRI, and laboratory tests. SPECT images were analyzed first, followed by SPECT/CT images. Each lesion was graded on a 4-point diagnostic scale (1, benign; 2, likely benign; 3, likely malignant; 4, malignant), and the inter-reviewer agreement and the agreement of the SPECT and SPECT/CT diagnoses with the pathology results were evaluated by &kgr; scores. ResultsThe pathology results revealed 39 malignant bone tumors and 17 benign lesions. In the malignant cases, 20 were bone metastases and 19 were malignant tumors of another histological type. The reviewers rated 67.9% of lesions as equivocal (grade 2–3) by SPECT, but only 19.6% as equivocal by SPECT/CT. The &kgr; scores for inter-reviewer agreement were 0.467 for SPECT and 0.905 for SPECT/CT (both P<0.0001). The &kgr; scores for the agreement of the interpretation of SPECT and SPECT/CT with the pathology results were 0.493 and 0.689, respectively (both P<0.0001). ConclusionCompared with SPECT imaging, SPECT/spiral CT hybrid imaging significantly reduced the number of lesions judged to be equivocal. This reduction allowed for a definitive diagnosis to be made by imaging in the majority of patients.

64Cu-Labeled Divalent Cystine Knot Peptide for Imaging Carotid Atherosclerotic Plaques

The rupture of vulnerable atherosclerotic plaques that lead to stroke and myocardial infarction may be induced by macrophage infiltration and augmented by the expression of integrin αvβ3. Indeed, atherosclerotic angiogenesis may be a promising marker of inflammation. In this study, an engineered integrin αvβ3–targeting PET probe, 64Cu-NOTA-3-4A, derived from a divalent knottin miniprotein was evaluated in a mouse model for carotid atherosclerotic plaques. Methods: Atherosclerotic plaques in BALB/C mice, maintained on a high-fat diet, were induced with streptozotocin injection and carotid artery ligation and verified by MR imaging. Knottin 3-4A was synthesized by solid-phase peptide synthesis chemistry and coupled to 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) before radiolabeling with 64Cu. PET probe stability in mouse serum was evaluated. Mice with carotid atherosclerotic plaques were injected via the tail vein with 64Cu-NOTA-3-4A or 18F-FDG, followed by small-animal PET/CT imaging at different time points. Receptor targeting specificity of the probe was verified by coinjection of c(RGDyK) administered in molar excess. Subsequently, carotid artery dissection and immunofluorescence staining were performed to evaluate target expression. Results: 64Cu-NOTA-3-4A was synthesized in high radiochemical purity and yield and demonstrated molecular stability in both phosphate-buffered saline and mouse serum at 4 h. Small-animal PET/CT showed that 64Cu-NOTA-3-4A accumulated at significantly higher levels in the neovasculature of carotid atherosclerotic plaques (7.41 ± 1.44 vs. 0.67 ± 0.23 percentage injected dose/gram, P < 0.05) than healthy or normal vessels at 1 h after injection. 18F-FDG also accumulated in atherosclerotic lesions at 0.5 and 1 h after injection but at lower plaque–to–normal tissue ratios than 64Cu-NOTA-3-4A. For example, plaque–to–normal carotid artery ratios for 18F-FDG and 64Cu-NOTA-3-4A at 1 h after injection were 3.75 and 14.71 (P < 0.05), respectively. Furthermore, uptake of 64Cu-NOTA-3-4A in atherosclerotic plaques was effectively blocked (∼90% at 1 h after injection) by coinjection of c(RGDyK). Immunostaining confirmed integrin αvβ3 expression in both the infiltrating macrophages and the neovasculature of atherosclerotic plaques. Conclusion: 64Cu-NOTA-3-4A demonstrates specific accumulation in carotid atherosclerotic plaques in which macrophage infiltration and angiogenesis are responsible for elevated integrin αvβ3 levels. Therefore, 64Cu-NOTA-3-4A may demonstrate clinical utility as a PET probe for atherosclerosis imaging or for the evaluation of therapies used to treat atherosclerosis.

PET probes beyond ^18F-FDG

Abstract During the past several decades, positron emission tomography (PET) has been one of the rapidly growing areas of medical imaging; particularly, its applications in routine oncological practice have been widely recognized. At present, 18F-fluorodeoxyglucose (18F-FDG) is the most broadly used PET probe. However, 18F-FDG also suffers many limitations. Thus, scientists and clinicians are greatly interested in exploring and developing new PET imaging probes with high affinity and specificity. In this review, we briefly summarize the representative PET probes beyond 18F-FDG that are available for patients imaging in three major clinical areas (oncology, neurology and cardiology), and we also discuss the feasibility and trends in developing new PET probes for personalized medicine.

Added value of SPECT/spiral CT versus SPECT in diagnosing solitary spinal lesions in patients with extraskeletal malignancies.

PurposeThe aim of this study was to investigate the added value of single-photon emission computed tomography (SPECT)/spiral computed tomography (CT) versus SPECT alone in the differential diagnosis of solitary spinal lesions in patients with extraskeletal malignancies. Materials and methodsA total of 90 patients who had a solitary spine ‘hot spot’ that could not be definitively diagnosed using planar scintigraphy were enrolled in the study. SPECT/spiral CT was performed on the indeterminate lesions in the spine. Images were independently interpreted by two experienced nuclear medicine physicians. Each spinal lesion was graded on a four-point diagnostic scale (1, benign; 2, likely benign; 3, likely bone metastasis; 4, bone metastasis). The final diagnosis of each lesion was based on pathological confirmation or follow-up. &kgr; scores were used to evaluate inter-reviewer agreement and agreement of the SPECT and SPECT/spiral CT diagnoses with the final diagnosis. ResultsFinal diagnoses revealed 25 bone metastases and 65 benign lesions. Forty percent (36/90) of the solitary spinal lesions were diagnosed as equivocal (likely benign or likely bone metastasis) according to SPECT, whereas only 5.6% (5/90) were diagnosed as equivocal according to SPECT/spiral CT. For SPECT/spiral CT-based and SPECT-based diagnoses, the &kgr; scores for inter-reviewer agreement were 0.889 (P<0.001, 95% confidence interval 0.824–0.954) and 0.504 (P<0.001, 95% confidence interval 0.401–0.607). The diagnostic accuracies of SPECT/spiral CT and SPECT images were 91.1% (82/90) and 58.9% (53/90), respectively (&khgr;2=24.919, P<0.001). ConclusionCompared with SPECT imaging alone, SPECT/spiral CT imaging was more accurate and valuable in the differential diagnosis of solitary spinal lesions in patients with extraskeletal malignancies.

A Radiofluorinated Divalent Cystine Knot Peptide for Tumor PET Imaging

A divalent knottin containing two separate integrin binding epitopes (RGD) in the adjacent loops, 3-4A, was recently developed and reported in our previous publication. In the current study, 3-4A was radiofluorinated with a 4-nitrophenyl 2-18F-fluoropropinate (18F-NFP) group and the resulting divalent positron emission tomography (PET) probe, 18F-FP–3-4A, was evaluated as a novel imaging probe to detect integrin αvβ3 positive tumors in living animals. Knottin 3-4A was synthesized by solid phase peptide synthesis, folded, and site-specifically conjugated with 18/19F-NFP to produce the fluorinated peptide 18/19F-fluoropropinate-3-4A (18/19F-FP–3-4A). The stability of 18F-FP–3-4A was tested in both phosphate buffered saline (PBS) buffer and mouse serum. Cell uptake assays of the radiolabeled peptides were performed using U87MG cells. In addition, small animal PET imaging and biodistribution studies of 18F-FP–3-4A were performed in U87MG tumor-bearing mice. The receptor targeting specificity of the radiolabeled peptide was also verified by coinjecting the probe with a blocking peptide cyclo(RGDyK). Our study showed that 18F-FP–3-4A exhibited excellent stability in PBS buffer (pH 7.4) and mouse serum. Small animal PET imaging and biodistribution data revealed that 18F-FP–3-4A exhibited rapid and good tumor uptake (3.76 ± 0.59% ID/g and 2.22 ± 0.62% ID/g at 0.5 and 1 h, respectively). 18F-FP–3-4A was rapidly cleared from the normal tissues, resulting in excellent tumor-to-normal tissue contrasts. For example, liver uptake was only 0.39 ± 0.07% ID/g and the tumor to liver ratio was 5.69 at 1 h p.i. Furthermore, coinjection of cyclo(RGDyK) with 18F-FP–3-4A significantly inhibited tumor uptake (0.41 ± 0.12 vs 1.02 ± 0.19% ID/g at 2.5 h) in U87MG xenograft models, demonstrating specific accumulation of the probe in the tumor. In summary, the divalent probe 18F-FP–3-4A is characterized by rapid and high tumor uptake and excellent tumor-to-normal tissue ratios. 18F-FP–3-4A is a highly promising knottin based PET probe for translating into clinical imaging of tumor angiogenesis.

177Lu-labeled RGD-BBN heterodimeric peptide for targeting prostate carcinoma.

IntroductionRadiolabeled Arg-Gly-Asp (RGD) and bombesin (BBN) heterodimers have been investigated for dual targeting of tumor integrin &agr;v&bgr;3 receptors and gastrin-releasing peptide receptors. The goal of this study was to evaluate the potential use of a 177Lu-labeled RGD-BBN heterodimer for targeted prostate cancer therapy. Materials and methodsA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated RGD-BBN peptide (DO3A-RGD-BBN) was radiolabeled with 177Lu and purified by high-performance liquid chromatography. The in-vivo biodistribution study of 177Lu-DO3A-RGD-BBN was carried out in mice bearing human prostate cancer PC3 xenografts. The receptor-targeting specificity of the radiolabeled peptide was assayed by injecting the tracer with the unlabeled RGD-BBN peptide. Radiation absorbed doses in adult male patients, based on biodistribution data from mice, were also calculated. ResultsDO3A-RGD-BBN peptides were successfully labeled with 177Lu, and high radiochemical purity (>95%) could be achieved after high-performance liquid chromatography purification. In human PC3 xenograft-bearing mice, the tumor accumulation of 177Lu-DO3A-RGD-BBN was 5.88±1.12, 2.77±0.30, 2.04±0.19, and 1.18±0.19%ID/g at 0.5, 2, 24, and 48 h, respectively. With rapid clearance from normal tissues, the radiolabeled probe displayed high tumor-to-blood and tumor-to-muscle ratios. On calculating the radiation absorbed doses for 177Lu-DO3A-RGD-BBN, we found that the prostate tumor and the pancreas were the organs receiving the highest radiation absorbed doses. ConclusionDual integrin &agr;v&bgr;3 and GPRP-targeted agent 177Lu-DO3A-RGD-BBN shows excellent prostate cancer-targeting ability, and it is worthy of further evaluation for prostate cancer-targeted therapy.

Pilot Study of 64Cu(I) for PET Imaging of Melanoma

At present, 64Cu(II) labeled tracers including 64CuCl2 have been widely applied in the research of molecular imaging and therapy. Human copper transporter 1 (hCTR1) is the major high affinity copper influx transporter in mammalian cells, and specially responsible for the transportation of Cu(I) not Cu(II). Thus, we investigated the feasible application of 64Cu(I) for PET imaging. 64Cu(II) was reduced to 64Cu(I) with the existence of sodium L-ascorbate, DL-Dithiothreitol or cysteine. Cell uptake and efflux assay was investigated using B16F10 and A375 cell lines, respectively. Small animal PET and biodistribution studies were performed in both B16F10 and A375 tumor-bearing mice. Compared with 64Cu(II), 64Cu(I) exhibited higher cellular uptake by melanoma, which testified CTR1 specially influx of Cu(I). However, due to oxidation reaction in vivo, no significant difference between 64Cu(I) and 64Cu(II) was observed through PET images and biodistribution. Additionally, radiation absorbed doses for major tissues of human were calculated based on the mouse biodistribution. Radiodosimetry calculations for 64/67Cu(I) and 64/67Cu(II) were similar, which suggested that although melanoma were with high radiation absorbed doses, high radioactivity accumulation by liver and kidney should be noticed for the further application. Thus, 64Cu(I) should be further studied to evaluate it as a PET imaging radiotracer.

Neovascularization of hepatocellular carcinoma in a nude mouse orthotopic liver cancer model: a morphological study using X-ray in-line phase-contrast imaging

BackgroundThis study aimed to determine whether synchrotron radiation (SR)-based X-ray in-line phase-contrast imaging (IL-PCI) can be used to investigate the morphological characteristics of tumor neovascularization in a liver xenograft animal model.MethodsA human hepatocellular carcinoma HCCLM3 xenograft model was established in nude mice. Xenografts were sampled each week for 4xa0weeks and fixed to analyze tissue characteristics and neovascularization using SR-based X-ray in-line phase contrast computed tomography (IL-XPCT) without any contrast agent.ResultsThe effect of the energy level and object–to-detector distance on phase-contrast difference was in good agreement with the theory of IL-PCI. Boundaries between the tumor and adjacent normal tissues at week 1 were clearly observed in two-dimensional phase contrast projection imaging. A quantitative contrast difference was observed from weeks 1 to 4. Moreover, 3D image reconstruction of hepatocellular carcinoma (HCC) samples showed blood vessels inside the tumor were abnormal. The smallest blood vessels measured approximately 20xa0μm in diameter. The tumor vascular density initially increased and then decreased gradually over time. The maximum tumor vascular density was 4.29% at week 2.ConclusionIL-XPCTxa0successfully acquired images of neovascularization in HCC xenografts in nude mice.