Prospective study of 99mTc-3PRGD2 SPECT/CT diagnosing metastatic lymph nodes in esophageal squamous cell carcinoma.

BACKGROUND: Lymph node (LN) metastasis is a significant prognostic factor for esophageal squamous cell carcinoma (ESCC), and there are no satisfactory methods for accurately predicting metastatic LNs. The present study aimed to assess the efficacy of 99mTc-3PRGD2 single-photon emission computed tomography (SPECT)/computed tomography (CT) for diagnosing metastatic LNs in ESCC. METHODS: A total of 15 enrolled patients with ESCC underwent 99mTc-3PRGD2 SPECT/CT and 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) examinations preoperatively. High-definition bone carving reconstruction technology (HD-xSPECT Bone) was applied to quantitatively assess the LN's SUVmax via SPECT/CT. The two methods were compared for diagnosing metastatic LNs with pathology as the gold standard. RESULTS: Among 15 patients, 23 metastatic lymph node stations (mLNSs) were predicted by SPECT/CT, with a mean SUVmax of 2.71 ± 1.34, of which 15 were pathologically confirmed; 32 mLNSs were predicted by PET/CT with a mean SUVmax of 4.41 ± 4.02, of which 17 were pathologically confirmed. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of SPECT/CT for diagnosing metastatic LNs were 62.50%, 91.30%, 85.34%, 65.22%, and 90.32%, respectively, and those of PET/CT were 70.83%, 83.70%, 81.03%, 53.13%, and 91.67%, respectively. There was no significant difference in sensitivity (p = 0.061) or specificity (p = 0.058) between the two methods. The AUCSPECT/CT was 0.816 and the SUVmax threshold was 2.5. CONCLUSION: 99mTc-3PRGD2 SPECT/CT might be an effective method for diagnosing metastatic LNs in ESCC, especially in combination with HD-xSPECT Bone. The diagnostic efficiency of this method was noninferior to that of 18F-FDG PET/CT. The SUVmax threshold of 2.5 showed the highest agreement with the pathology findings.

Direct attenuation correction for 99mTc-3PRGD2 chest SPECT lung cancer images using deep learning.

Introduction: The attenuation correction technique of single photon emission computed tomography (SPECT) images is essential for early diagnosis, therapeutic evaluation, and pharmacokinetic studies of lung cancer. 99mTc-3PRGD2 is a novel radiotracer for the early diagnosis and evaluation of treatment effects of lung cancer. This study preliminary discusses the deep learning method to directly correct the attenuation of 99mTc-3PRGD2 chest SPECT images. Methods: Retrospective analysis was performed on 53 patients with pathological diagnosis of lung cancer who received 99mTc-3PRGD2 chest SPECT/CT. All patients' SPECT/CT images were reconstructed with CT attenuation correction (CT-AC) and without attenuation correction (NAC). The CT-AC image was used as the reference standard (Ground Truth) to train the attenuation correction (DL-AC) SPECT image model using deep learning. A total of 48 of 53 cases were divided randomly into the training set, the remaining 5 were divided into the testing set. Using 3D Unet neural network, the mean square error loss function (MSELoss) of 0.0001 was selected. A testing set is used to evaluate the model quality, using the SPECT image quality evaluation and quantitative analysis of lung lesions tumor-to-background (T/B). Results: SPECT imaging quality metrics between DL-AC and CT-AC including mean absolute error (MAE), mean-square error (MSE), peak signal-to-noise ratio (PSNR), structural similarity (SSIM), normalized root mean square error (NRMSE), and normalized Mutual Information (NMI) of the testing set are 2.62 ± 0.45, 58.5 ± 14.85, 45.67 ± 2.80, 0.82 ± 0.02, 0.07 ± 0.04, and 1.58 ± 0.06, respectively. These results indicate PSNR > 42, SSIM > 0.8, and NRMSE < 0.11. Lung lesions T/B (maximum) of CT-AC and DL-AC groups are 4.36 ± 3.52 and 4.33 ± 3.09, respectively (p = 0.81). There are no significant differences between two attenuation correction methods. Conclusion: Our preliminary research results indicate that using the DL-AC method to directly correct 99mTc-3PRGD2 chest SPECT images is highly accurate and feasible for SPECT without configuration with CT or treatment effect evaluation using multiple SPECT/CT scans.

Sarcoidosis Mimicking Primary Lung Cancer on 99mTc-3PRGD2 Scintigraphy in a PTC Patient.

Sarcoidosis is a multi-system disease of unknown etiology that typically occurs in middle-aged adults, often presenting as the formation of granulomas in various organs, including the lungs. Non-typical pulmonary sarcoidosis is rare, and it isnecessary to distinguish its imaging features from lung cancer and tuberculosis. They may appear as an irregular mass with multiple nodules on thoracic computed tomography (CT). In this case, primary lung cancer was suspected in a 57-year-old papillary thyroid carcinoma patient, as the pulmonary lesions were non-radioiodine avid and progressed shortly afterward. The asymmetrical focal uptake that was demonstrated in integrin receptor imaging (99mTc-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2)) warranted flexible-bronchoscope biopsy. Meanwhile, no evidence of malignancy was found, and pathological manifestations led to the subsequent six months of anti-tuberculosis treatment. Combined with the fact that standard anti-tuberculosis showed no improvement, and the patient's condition was stabilized by corticosteroid treatment alone, a final diagnosis of sarcoidosis was made by an MDT (multidisciplinary consultation). Reported herein is the first case of a hyper vascularization condition within the non-typical asymmetrical sarcoidosis lesions, which should help to establish that the uptake of 3PRDG2 in sarcoidosis can avoid imaging pitfalls.

Evaluation of integrin αvß3-targeted imaging for predicting disease progression in patients with high-risk differentiated thyroid cancer (using 99mTc-3PRGD2).

BACKGROUND: High-risk differentiated thyroid cancer (DTC) needs effective early prediction tools to improving clinical management and prognosis. This cohort study aimed to investigate the prognostic impact of 99mTc-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2) SPECT/CT in high-risk DTC patients after initial radioactive iodine (RAI) therapy. METHODS: Thirty-three patients with high-risk DTC were prospectively recruited; all patients underwent total thyroidectomy and received 99mTc-3PRGD2 SPECT/CT before RAI ablation. Follow-up was done with serological and imaging studies. The correlation between 99mTc-3PRGD2 avidity and remission rate for initial RAI therapy was evaluated using logistic regression analysis. The prognostic value of 99mTc-3PRGD2 SPECT/CT was evaluated by Kaplan-Meier curve and Cox regression analysis. RESULTS: 99mTc-3PRGD2 avidity was significantly correlated with the efficacy of initial RAI ablation and an effective predictor for non-remission in high-risk DTC (OR = 9.36; 95% CI = 1.10-79.83; P = 0.041). 99mTc-3PRGD2 avidity was associated with poor prognosis in patients with high-risk DTC and an independent prognostic factor for shorter progression-free survival (PFS) (HR = 9.47; 95% CI = 1.08-83.20; P = 0.043). Survival analysis, which was performed between DTC patients with concordant (131I positive/99mTc-3PRGD2 positive) and discordant (131I negative/99mTc-3PRGD2 positive) lesions, indicated that patients with concordant lesions had significantly better PFS than those with discordant lesions (P = 0.022). Moreover, compared with repeated RAI, additional surgery or targeted therapy with multikinase inhibitors could lead to a higher rate of remission in 99mTc-3PRGD2-positive patients with progressive disease. CONCLUSIONS: 99mTc-3PRGD2 SPECT/CT is a useful modality in predicting progression of the disease after initial RAI and guiding further treatment in high-risk DTC patients.

Evaluation of 99m Tc-3PRGD2 SPECT imaging on angiogenesis in animal models of lung cancer.

BACKGROUND: The main purpose of the study was to evaluate the activity and selectivity of 99m Tc-3PRGD2 SPECT/CT and 18 F-FDG PET-CT in order to detect the neovascularization of A549 cell subcutaneously transplanted tumors, and clarify the relationship among tumor vasculature, hypoxia and cell proliferation in the tumor microenvironment. METHODS: We established a subcutaneous tumor model, and used 99m Tc-3PRGD2 SPECT/CT and 18 F-FDG PET-CT when the average tumor size reached 0.3-0.5 cm3 . The mice were anesthetized and sacrificed and the tumors were completely removed for frozen section analysis. We subsequently evaluated the status of neovascularization, hypoxia, as well as cell proliferation via immunofluorescence staining (IF) by detecting CD31, pimonidazole and EdU, respectively. RESULTS: There was a significant positive correlation (r = 0.88, p < 0.05) between the microvascular density (41.20 ± 18.60) and tumor to nontumor ratio (T/M), which was based on the value of 99m Tc-3PRGD2 (4.20 ± 1.33); meanwhile, no significance (r = -0.16, p > 0.05) was found between the T/M and hypoxic area (116.71 ± 9.36). Neovascular proliferation was particularly vigorous in the parenchymal region of the tumor, while the cells around the cavity were generally hypoxic. 99m TC-3PRGD2 SPECT/CT was more specific than 18 F-FDG PET-CT in detecting malignant tumors. CONCLUSION: Both 99m TC-3PRGD2 and 18 F-FDG PET-CT can be used for the detection of malignant tumors, but the specificity and accuracy of 99m TC-3PRGD2 are better. The subcutaneous tumors showed a heterogeneous microenvironment as a result of neovascularization, a high proliferation rate of cancer cells as well as subsequent hypoxia, while most of the hypoxic areas appeared around the cavities of the vessels.

Advances in Clinical Oncology Research on 99mTc-3PRGD2 SPECT Imaging.

The integrin alpha(α)v beta(ß)3 receptor is ubiquitous in malignant tumors and has a certain level of specificity for tumors. Technetium-99m hydrazinonicotinamide-dimeric cyclic arginyl-glycyl-aspartic acid peptide with three polyethylene glycol spacers (99mTc-3PRGD2) can bind specifically to the integrin αvß3 receptor with high selectivity and strong affinity. Thus, it can specifically mark tumors and regions with angiogenesis for tumor detection and be used in single-photon emission computed tomography (SPECT) imaging. This modality has good application value for diagnosing and treating tumor lesions, such as those in the lung, breast, esophagus, head, and neck. This review provides an overview of the current clinical research progress of 99mTc-3PRGD2 SPECT imaging for tumor lesions, including for the diagnosis and differential diagnosis of tumors in different body parts, evaluation of related metastases, and evaluation of efficacy. In addition, the future clinical application prospects and possibilities of 99mTc-3PRGD2 SPECT imaging are further discussed.

Effect of teach-back health education combined with structured psychological nursing on adverse emotion and patient cooperation during 99mTc-3PRGD2.SPECT/CT.

BACKGROUND: 99mTc-3PRGD2.SPECT/CT is a commonly used examination method in nuclear medicine. However, patients receiving 99mTc-3PRGD2.SPECT/CT have insufficient knowledge of this method and worry about the examination results. AIM: To investigate the effect of teach-back health education combined with structured psychological nursing on adverse emotion and cooperation in patients undergoing 99mTc-3PRGD2.SPECT/CT examination. METHODS: Ninety patients undergoing 99mTc-3PRGD2.SPECT/CT examinations were divided into a study group and a control group using a simple random number table, and 45 cases were allocated to each group. Routine nursing was provided to the control group, and teach-back health education combined with structured psychological nursing was provided to the study group on the basis of the control group. Heart rate, diastolic blood pressure, systolic blood pressure, self-rating depression scale (SDS), and self-rating anxiety scale (SAS) were assessed before and after the intervention, and examination cooperation and intervention satisfaction were assessed in the two groups before, during, and after the examination. RESULTS: Before the examination, heart rate, diastolic blood pressure, and systolic blood pressure in the study group were not significantly different from the values of the control group (P > 0.05). The results of the study group before and after the examination were lower than those in the control group (P < 0.05). Before the intervention, SDS and SAS scores in the study group were not significantly different from those in the control group (P > 0.05). After the intervention, SDS and SAS scores in the study group were lower than those in the control group (P < 0.05). The degree of cooperation was higher in the study group than in the control group (P < 0.05). The satisfaction rate with the intervention was higher in the study group than in the control group (P < 0.05). CONCLUSION: Teach-back health education combined with structured psychological nursing can help maintain the stability of blood pressure and heart rate, relieve negative emotions, and improve the satisfaction and cooperation of patients undergoing 99mTc-3PRGD2.SPECT/CT examinations.

Scintigraphic Imaging of Neovascularization With 99mTc-3PRGD2 for Evaluating Early Response to Endostar Involved Therapies on Pancreatic Cancer Xenografts In Vivo.

Background: Molecular imaging targeting angiogenesis can specifically monitor the early therapeutic effect of antiangiogenesis therapy. We explore the predictive values of an integrin αvß3-targeted tracer, 99mTc-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2), for monitoring the efficacy of Endostar antiangiogenic therapy and chemotherapy in animal models. Methods: The pancreatic cancer xenograft mice were randomly divided into four groups, with seven animals in each group and treated in different groups with 10 mg/kg/day of Endostar, 10 mg/kg/day of gemcitabine, 10 mg/kg/day of Endostar +10 mg/kg/day of gemcitabine at the same time, and the control group with 0.9% saline (0.1 ml/day). 99mTc-3PRGD2 scintigraphic imaging was carried out to monitor therapeutic effects. Microvessel density (MVD) was measured using immunohistochemical staining of the tumor tissues. The region of interest (ROI) of tumor (T) and contralateral corresponding site (NT) was delineated, and the ratio of radioactivity (T/NT) was calculated. Two-way repeated-measure analysis of variance (ANOVA) was used to assess differences between treatment groups. Results: Tumor growth was significantly lower in treatment groups than that in the control group (p < 0.05), and the differences were noted on day 28 posttreatment. The differences of 99mTc-3PRGD2 uptakes were observed between the control group and Endostar group (p = 0.033) and the combined treatment group (p < 0.01) on day 7 posttreatment and on day 14 posttreatment between the control group and gemcitabine group (p < 0.01). The accumulation of 99mTc-3PRGD2 was significantly correlated with MVD (r = 0.998, p = 0.002). Conclusion: With 99mTc-3PRGD2 scintigraphic imaging, the tumor response to antiangiogenic therapy, chemotherapy, and the combined treatment can be observed at an early stage of the treatments, much earlier than the tumor volume change. It provides new opportunities for developing individualized therapies and dose optimization.

99mTc-3PRGD2 SPECT Predicts the Outcome of Endostar and Cisplatin Therapy in Xenograft Animals.

AIMS: Our study was designed to investigate the usefulness of 99mTc-3PRGD2 single-photon emission computed tomography (SPECT) for noninvasively monitoring the response of integrin αvß3 expression to antiangiogenic treatment with endostar and cisplatin in xenograft animals. METHODS: 99mTc-3PRGD2 SPECT imaging was performed at days 0, 7, 14, and 21. Tumors were harvested at all imaging time points for Western blotting and histopathological analysis. RESULT: In 99mTc-3PRGD2 SPECT imaging, the radioactivity accumulation of NaCl group rised gradually in the first half and dispersed on day 21 due to the necrosis of the tumor. While the radioactivity accumulation of treated groups gradually decreased throughout the course. The downtrend of tumor to nontumor ratio in endostar-treated group was more remarkable than cisplatin-treated group. The expression of intergrin αvß3 of treated groups was lower than NaCl group from day 14. The expression of intergrin αvß3 of endostar-treated group was significantly lower than cisplatin-treated group from baseline onward. CONCLUSION: It's demonstrated that the 99mTc-3PRGD2 could noninvasively visualize and semiquantify tumor angiogenesis in the xenograft model and monitor the response to the antiangiogenic therapy of endostar and cisplatin effectively. It also can predict the outcome of endostar and cisplatin therapy in xenograft animals.

Advantages of 99mTc-3PRGD2 SPECT over CT in the preoperative assessment of lymph node metastasis in patients with esophageal cancer.

BACKGROUND: Our study was designed to compare the diagnostic efficacies of integrated 99mTc-HYNIC-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2) single-photon emission computed tomography (SPECT) images and computed tomography (CT) images in lymph node metastasis in the patients with esophageal cancer. METHODS: From September 2015 and May 2018, 32 patients with histologically proven primary esophageal carcinoma underwent both 99mTc-3PRGD2 SPECT and CT scans followed by esophagectomy with lymph node dissection. The results of reviewing 99mTc-3PRGD2 SPECT and CT images for the lymph node metastasis were compared in relation with pathologic findings. RESULTS: During surgery, a total of 168 lymph nodes were dissected in 32 patients, of which 42 node groups in 18 patients were malignant on histologic examination. Preoperative nodal staging was compared with postoperative histopathological staging, The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 99mTc-3PRGD2 SPECT for lymph nodes were 80.95%, 86.51%, 85.12%, 66.67%, and 93.16% on per-node basis, respectively; compared with 59.52%, 73.02%, 69.64%, 42.37%, and 84.40% for CT (p = 0.034, 0.008, 0.005, 0.011, and 0.038, respectively). 70.59% (12/17) false-negative interpretations and 50% (17/34) false-positive interpretations on CT were corrected by 99mTc-3PRGD2 SPECT. 37.5% false-negative interpretations on 99mTc-3PRGD2 SPECT were corrected by CT. 11.90% (5/42) positive lymph nodes and 13.49% (17/126) negative nodes at pathology were incorrectly diagnosed both by 99mTc-3PRGD2 SPECT and CT. The accuracy of 99mTc-3PRGD2 SPECT (87.50%, 28/32) was significantly higher than that of CT (62.50, 20/32; p = 0.022) on per-patient basis. 99mTc-3PRGD2 SPECT showed significantly higher sensitivity and accuracy in the neck and upper thoracic regions than CT. For nodal staging, 99mTc-3PRGD2 SPECT was correct in 78.12% (25/32) of the patients, whereas CT was correct in 53.12% (17/32), p = 0.037. CONCLUSION: 99mTc-3PRGD2 SPECT is more accurate than CT for preoperative assessment of lymph node metastasis in esophageal cancer and may be helpful in determining the therapeutic plan.

[99mTc]3PRGD2 for integrin receptor imaging of esophageal cancer: a comparative study with [18F]FDG PET/CT.

OBJECTIVES: This study was designed to investigate the efficacy of 99mtechnetium-three polyethylene glycol spacers-arginine-glycine-aspartic acid ([99mTc]3PRGD2) in the evaluation of patients with esophageal cancer. METHODS: Twenty-nine patients with a suspected esophageal lesion and for whom definite pathological diagnosis was finally obtained were recruited. Whole-body planar scanning and chest single-photon-emission computed tomography/computed tomography (SPECT/CT) were performed at 30 and 40 min, respectively, after intravenous injection of 11.1 MBq/kg of [99mTc]3PRGD2. 2-Deoxy-2-[18F] fluoro-D-glucose ([18F]FDG) positron-emission tomography/computed tomography (PET/CT) was performed in 1 week. The tumor-to-background ratio (T/B) and the maximum standard uptake value (SUVmax) were calculated for semi-quantitative and quantitative analyses. Integrin αvß3 was analyzed through immunohistochemistry. RESULTS: The T/B, SUVmax and expression of integrin αvß3 in malignant lesions were higher than those in benign lesions (t = 3.691, P = 0.001; t = 8.271, P = 0.000; t = 3.632, P = 0.001, respectively). There was a significant correlation between T/B and SUVmax in esophageal lesions (r = 0.660, P = 0.000). The expression of integrin αvß3 was correlated with [99mTc]3PRGD2 uptake (r = 0.782, P = 0.000). In visual analysis, the sensitivity and accuracy of the whole-body planar RGD scan were lower than those of the chest SPECT/CT RGD scan and the [18F]FDG PET/CT scan (x2 = 6.769, P = 0.022). The sensitivity, specificity and accuracy of the chest SPECT/CT RGD scan were similar to those of the [18F] FDG PET/CT scan. In semi-quantitative analysis, the sensitivity, specificity and accuracy of chest SPECT/CT RGD from the receiver operating characteristic (ROC) analysis were 87%, 100% and 94%, respectively [cutoff = 3.1 of T/B, area under the curve (AUC) = 0.957]. Thirteen patients (30 lymph nodes) and 16 patients (105 lymph nodes) were suspected to have lymph node metastases based on the RGD and FDG scans, respectively. CONCLUSION: This prospective study demonstrated that [99mTc]3PRGD2 imaging is valuable for the diagnosis and staging of esophageal cancer. It may be less sensitive than [18F]FDG imaging for detecting metastatic lesions in small lymph nodes. The T/B value was correlated with the expression of integrin αvß3. NIH CLINICALTRIALS.GOV: NCT 02744729.

Integrin αVß3-targeted SPECT/CT for the assessment of Bevacizumab therapy in orthotopic lung cancer xenografts.

The present study aimed to determine the utility of 99mTc-3PRGD2 single photon emission computed tomography (SPECT)/computed tomography (CT) for the non-invasive monitoring of the response of integrin αvß3 expression to anti-angiogenic treatment with bevacizumab. Bevacizumab or vehicle therapy was performed in athymic nu/nu mice bearing A549 lung tumors (moderately high integrin αvß3 expression) or PC-3 prostate tumors (low integrin αvß3 expression) at a dose of 1 mg twice a week. The average tumor volume was 180±90 mm3 the day prior to baseline SPECT/CT. Longitudinal 99mTc-3PRGD2 SPECT/CT imaging was performed at baseline (-1 day) and at days 5 and 15. Tumors were harvested at all imaging time points for histopathological analysis with hematoxylin and eosin (H&E) and immunohistochemistry staining. Results revealed a significant difference in tumor volume between vehicle- and bevacizumab-treated groups at 5 and 15 days following the start of treatment in the A549 lung model (P<0.05). At 5 days after the start of therapy, the percent injected dose per gram of tissue (%ID/g) and tumor-to-muscle ratio for bevacizumab-treated A549 declined persistently (P<0.05). However, for the vehicle-treated A549 model, the %ID and %ID/g value increased 5 days after the start of treatment (P<0.05). For the PC-3 model, slow-growing tumors and low tumor uptake was observed throughout the study. Alterations in tumor vasculature were confirmed by histopathological H&E analysis and immunohistochemistry. In conclusion, longitudinal imaging using 99mTc-3PRGD2 SPECT/CT may be a useful tool for monitoring the anti-angiogenic effect of bevacizumab therapy.

Comparison of [99mTc]3PRGD2 Imaging and [18F]FDG PET/CT in Breast Cancer and Expression of Integrin αvß3 in Breast Cancer Vascular Endothelial Cells.

PURPOSE: This study aimed to investigate the value of 99mtechnetium-three polyethylene glycol spacers-arginine-glycine-aspartic acid ([99mTc]3PRGD2) imaging in diagnosis and staging of breast cancer compared with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) imaging, and to explore the expression of integrin αvß3 in tumor vascular endothelial cells. PROCEDURES: Forty-two women with suspected breast cancer underwent both [99mTc]3PRGD2 imaging and [18F]FDG imaging. Visual analysis was used to assess primary breast lesion, axillary lymph node, and distant metastasis. The tumor-blood (T/B) ratios from [99mTc]3PRGD2 imaging and the maximum standardized uptake value (SUVmax) from [18F]FDG imaging were analyzed for breast lesions. Integrin αvß3 was analyzed through immunohistochemistry. RESULTS: Forty-five breast lesions were found (malignant, n = 38; benign, n = 7). The sensitivity, specificity, and accuracy of [99mTc]3PRGD2 and [18F]FDG imaging in visual analysis for the breast lesion were 97.4, 87.5, and 95.6 % and 97.4, 71.4, and 93.3 %, respectively (P > 0.05). For semi-quantitative analysis, no significant difference of the area under the curves (AUC) was found in the imaging using the two radiopharmaceuticals (0.880 and 0.955; Z = 0.88, P > 0.05). The sensitivity, specificity, and accuracy for axillary lymph node metastasis with [99mTc]3PRGD2 and [18F]FDG were 78.05, 99.36, and 94.92 % and 85.37, 98.72, and 95.64 %, respectively (P > 0.05). Nine patients with distant metastases were all detected with the two radiopharmaceuticals. The expression of integrin αvß3 was correlated with [99mTc]3PRGD2 uptake (r = 0.582, P = 0.001), which were significantly higher in the HER2-positive and stage III-IV patients (P < 0.05). CONCLUSIONS: The prospective study demonstrated that [99mTc]3PRGD2 imaging seems to be valuable for diagnosis of breast cancer and its staging. It may be less sensitive for detecting small lymph node metastatic lesions when compared with [18F]FDG imaging. Integrin αvß3 in tumor microvessels was associated with the breast cancer subtype and its staging.

Early detection of rheumatoid arthritis in rats and humans with 99mTc-3PRGD2 scintigraphy: imaging synovial neoangiogenesis.

OBJECTIVES: To validate 99mTc-labeled arginylglycylaspartic acid (99mTc-3PRGD2) scintigraphy as a means to image synovial neoangiogenesis in joints afflicted by rheumatoid arthritis and to investigate its potential in the early detection and management of rheumatoid arthritis. METHODS: Rheumatoid arthritis and osteoarthritis were generated in Sprague Dawley rats by type II collagen immunization and papain injection, respectively. Rats were imaged with 99mTc-3PRGD2 and 99mTc- methyl diphosphonate (99mTc MDP). X-ray images were also obtained and assessed by a radiologist. Immunohistochemistry of αvß3 and CD31confirmed the onset of synovial neoangiogenesis. The effect of bevacizumab on rheumatoid arthritis was followed with 99mTc-3PRGD2 scintigraphy. A patient with rheumatoid arthritis and a healthy volunteer were scanned with 99mTc-3PRGD2. RESULTS: Two weeks after immunization, a significant increase in 99mTc-3PRGD2 was observed in the joints of the rheumatoid arthritis model though uptake in osteoarthritis model and untreated controls was low. 99mTc-MDP whole body scans failed to distinguish early rheumatoid arthritis joints from healthy controls. The expression of αvß3 and CD31was significantly higher in the joints of rheumatoid arthritis rats compared to normal controls. In serial 99mTc-3PRGD2 scintigraphy studies, 99mTc-3PRGD2 uptake increased in parallel with disease progression. Bevacizumab anti-angiogenetic therapy both improved the symptoms of the rheumatoid arthritis rats and significantly decreased 99mTc-3PRGD2 uptake. Significantly higher 99mTc-3PRGD2 accumulation was also observed in rheumatoid arthritis joints in the patient. CONCLUSIONS: Our findings indicate that 99mTc-3PRGD2 scintigraphy could detect early rheumatoid arthritis by imaging the associated synovial neoangiogenesis, and may be useful in disease management.

Evaluation of 99mTc-3PRGD2 integrin receptor imaging in hepatocellular carcinoma tumour-bearing mice: comparison with 18F-FDG metabolic imaging.

OBJECTIVE: Our study was designed to explore the utility of 99mTc-HYNIC-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2) for the detection of hepatocellular carcinoma (HCC) and specifically to compare the diagnostic performance of 99mTc-3PRGD2 integrin receptor imaging and 2-18-fluoro-2-deoxy-D-glucose (18F-FDG) metabolic imaging in a nude mouse model. METHODS: 99mTc-3PRGD2 was synthesized using a HYNIC-3PRGD2 lyophilized kit with 99mTcO4 labelling. The nude mouse animal model was established by subcutaneously injecting 5 × 107/ml HepG2 cells into the shoulder flank of each mouse. Biodistribution studies were performed at 0.5, 1, 2 and 4 h after intravenous administration of 0.37 MBq of 99mTc-3PRGD2. Immunohistochemistry was performed to evaluate the expression level of integrin αvß3 in the HCC tissues. Dynamic imaging was performed using list-mode after the administration of 55.5 MBq of 99mTc-3PRGD2, to reconstruct the multiphase images and acquire the best initial scan time. At 8, 12, 16, 20 and 24 days after inoculation with HepG2 cells, 55.5 MBq of 99mTc-3PRGD2 and 37 MBq of 18F-FDG were injected successively into the nude mouse model, subsequently, simultaneous SPECT/PET imaging was performed to calculate the tumour volume and tumour uptake of 99mTc-3PRGD2 and 18F-FDG. RESULTS: The biodistribution study first validated that the tumour uptake of 99mTc-3PRGD2 at the different time points was higher than that of all the other organs tested in the experiment, except for the kidney. Integrin αvß3 expressed highly in early stage HCC and declined for further necrosis of the tumour tissue. Subcutaneous tumours were visualized clearly with excellent contrast under 99mTc-3PRGD2 SPECT/CT imaging, and the multiphase imaging comparison showed the tumours were prominent at 0.5 h, suggesting that the best initial scan time is 0.5 h post-injection. The comparison of the imaging results of the two methods showed that 99mTc-3PRGD2 integrin receptor imaging was more sensitive than 18F-FDG metabolic imaging for the detection of early stage HCC, meanwhile the tumour uptake of 99mTc-3PRGD2 was consistently higher than that of 18F-FDG. However, as tumour necrosis further increased in HCC tissues, the uptake of 18F-FDG was higher than that of 99mTc-3PRGD2. CONCLUSION: Our study demonstrated that 99mTc-3PRGD2 is a valuable tumour molecular probe for the detection of early stage HCC compared with 18F-FDG, meriting further investigation of 99mTc-3PRGD2 as a novel SPECT tracer for tumour imaging.

(99m)Tc-3PRGD2 SPECT/CT Imaging for Monitoring Early Response of EGFR-TKIs Therapy in Patients with Advanced-Stage Lung Adenocarcinoma.

OBJECTIVE: This study was aimed to assess the efficacy of (99m)Tc-3PRGD2 imaging for evaluating both early treatment response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and prognosis in advanced-stage lung adenocarcinoma. MATERIAL AND METHODS: Eighteen patients with lung adenocarcinoma were enrolled for EGFR-TKIs therapy. (99m)Tc-3PRGD2 SPECT/CT and planar imaging were performed pre- and post-therapy. The tumor to nontumor (T/NT) ratio and percentage change in T/NT ratio were assessed for the treatment response. Receiver operator characteristic (ROC) analysis was utilized to analyze the power of identifying responders based on the changes in T/NT ratios. RESULTS: After treatment, 10 patients had partial response (PR), and 6 patients stable disease (SD), while 2 patients progressive disease (PD). The mean changes in T/NT ratios on SPECT/CT and planar images in PR group were 35.8% and 15.0% and in SD group were 8.9% and 0.7%, while in PD group were 76.1% and 18.7%, respectively. For ROC analysis, using a cutoff value of 23.8% decrease in T/NT ratio on SPECT/CT images, the sensitivity and specificity in identifying responders were 80.0% and 87.5%, respectively. The median progression-free survival (PFS) for patients with responders and nonresponders (on (99m)Tc-3PRGD2 SPECT/CT) was 18 months (95% CI 5.8-30.2 months) and 7 months (95% CI 5.2-8.8 months), respectively (p = 0.006). CONCLUSION: (99m)Tc-3PRGD2 imaging can evaluate the early response to EGFR-targeted therapy and predict the PFS of lung adenocarcinoma patients.