Zhaohui Zhu

Glucagon-Like Peptide-1 Receptor PET/CT with 68Ga-NOTA-Exendin-4 for Detecting Localized Insulinoma: A Prospective Cohort Study

Preoperative localization of insulinoma is a clinical dilemma. We aimed to investigate whether glucagon-like peptide-1 receptor (GLP-1R) PET/CT with 68Ga-NOTA-MAL-cys40-exendin-4 (68Ga-NOTA-exendin-4) is efficient in detecting insulinoma. Methods: In our prospective cohort study, patients with endogenous hyperinsulinemic hypoglycemia were enrolled. CT, MRI, endoscopic ultrasound, and 99mTc-hydrazinonicotinamide-TOC SPECT/CT were done according to standard protocols. GLP-1R PET/CT was performed 30–60 min after the injection of 68Ga-NOTA-exendin-4. The gold standard for diagnosis was the histopathologic results after surgery. Results: Of 52 recruited patients, 43 patients with histopathologically proven insulinomas were included for the imaging studies. Nine patients did not undergo surgical intervention. 68Ga-NOTA-exendin-4 PET/CT correctly detected insulinomas in 42 of 43 patients with high tumor uptake (mean SUVavg ± SD, 10.2 ± 4.9; mean SUVmax ± SD, 23.6 ± 11.7), resulting in sensitivity of 97.7%. In contrast, 99mTc-hydrazinonicotinamide-TOC SPECT/CT showed a low sensitivity of 19.5% (8/41) in this group of patients; however, it successfully localized the tumor that was false-negative with GLP-1R PET/CT. The sensitivities of CT, MR, and endoscopic ultrasonography were 74.4% (32/43), 56.0% (14/25), and 84.0% (21/25), respectively. Conclusion: 68Ga-NOTA-exendin-4 PET/CT is a highly sensitive imaging technique for the localization of insulinoma.

Evaluation of synovial angiogenesis in patients with rheumatoid arthritis using ⁶⁸Ga-PRGD2 PET/CT: a prospective proof-of-concept cohort study.

Background The study aimed to evaluate the use of positron emission tomography/computed tomography (PET/CT) with 68Ga-PRGD2 as the tracer for imaging of synovial angiogenesis in patients with rheumatoid arthritis (RA). Methods Twenty untreated active patients with RA underwent 68Ga-PRGD2 PET/CT and 18F-FDG PET/CT before treatment; two patients with osteoarthritis served as controls. Among the 20 patients with RA, 12 repeated the evaluations after 3-month treatment. The image findings were correlated with core variables of disease activity, including the clinical disease activity index (cDAI). Results Our findings demonstrated that 68Ga-PRGD2 specifically accumulated in the synovia with active inflammation rich in neovasculature with high-level αvβ3-integrin expression, but not in the 18F-FDG-avid inflammatory lymph nodes. In patients with intense 18F-FDG uptake in muscles caused by arthritic pain, we observed that 68Ga-PRGD2 PET/CT was better able to evaluate disease severity than 18F-FDG PET/CT. Both 68Ga-PRGD2 accumulation and 18F-FDG uptake changed in response to therapeutic intervention, whereas the changes of 68Ga-PRGD2, not 18F-FDG, significantly correlated with clinical measures of changes in the form of cDAI. Conclusions This is the first integrin imaging study conducted in patients with RA that preliminarily indicates the effectiveness of the novel method for evaluating synovial angiogenesis. Clinical trial registration This study has been registered online at NIH ClinicalTrial.gov (NCT01940926).

Longitudinal PET Imaging of Muscular Inflammation Using 18F-DPA-714 and 18F-Alfatide II and Differentiation with Tumors

Aim: 18F-DPA-714 is a PET tracer that recognizes macrophage translocator protein (TSPO), and 18F-Alfatide II (18F-AlF-NOTA-E[PEG4-c(RGDfk)]2) is specific for integrin αvβ3. This study aims to apply these two tracers for longitudinal PET imaging of muscular inflammation, and evaluate the value of 18F-DPA-714 in differentiating inflammation from tumor. Methods: RAW264.7 mouse macrophage cells were used for cell uptake analysis of 18F-DPA-714. A mouse hind limb muscular inflammation model was established by intramuscular injection of turpentine oil. For the inflammation model, PET imaging was performed at different days using 18F-DPA-714 and 18F-Alfatide II. The specificity of the imaging probes was tested by co- or pre-injection of PK11195 or unlabeled RGD (Arg-Gly-Asp) peptide. PET imaging using 18F-DPA-714 was performed in A549, HT29, U87MG, INS-1, and 4T1 xenograft models. Immunofluorescence staining was performed to evaluate infiltrated macrophages and angiogenesis in inflammation and/or tumors. Results: Uptake of 18F-DPA-714 in RAW264.7 cells was 45.5% at 1 h after incubation, and could be blocked by PK11195. PET imaging showed increased 18F-DPA-714 and 18F-Alfatide II uptake at inflammatory muscles. Peak uptake of 18F-DPA-714 was seen on day 6 (4.02 ± 0.64 %ID/g), and peak uptake of 18F-Alfatide II was shown on day 12 (1.87 ± 0.35 %ID/g) at 1 h p.i.. Tracer uptakes could be inhibited by PK11195 for 18F-DPA-714 or cold RGD for 18F-Alfatide II. Moreover, macrophage depletion with liposomal clodronate also reduced the local accumulation of both tracers. A549, HT29, U87MG, INS-1, and 4T1 tumor uptakes of 18F-DPA-714 (0.46 ± 0.28, 0.91 ± 0.08, 1.69 ± 0.67, 1.13 ± 0.33, 1.22 ± 0.55 %ID/g at 1 h p.i., respectively) were significantly lower than inflammation uptake (All P < 0.05). Conclusion: PET imaging using 18F-DPA-714 as a TSPO targeting tracer could evaluate the dynamics of macrophage activation and infiltration in different stages of inflammatory diseases. The concomitant longitudinal PET imaging with both 18F-DPA-714 and 18F-Alfatide II matched the causal relationship between macrophage infiltration and angiogenesis. Moreover, we found 18F-DPA-714 uptake in several types of tumors is significantly lower than that in inflammatory muscles, suggesting 18F-DPA-714 PET has the potential for better differentiation of tumor and non-tumor inflammation.

Clinical translation of a dual integrin αvβ3 and GRPR targeting PET radiotracer 68Ga-NOTA-BBN-RGD

This study aimed to document the first-in-human application of a 68Ga-labeled heterodimeric peptide BBN-RGD (bombesin-RGD) that targets both integrin αvβ3 and gastrin-releasing peptide receptor (GRPR). We evaluated the safety and assessed the clinical diagnostic value of 68Ga-BBN-RGD PET/CT in prostate cancer patients in comparison with 68Ga-BBN. Methods: Five healthy volunteers (4 men and 1 woman; age range, 28–53 y) were enrolled to validate the safety of 68Ga-BBN-RGD. Dosimetry was calculated using the OLINDA/EXM software. Thirteen patients with prostate cancer (4 newly diagnosed and 9 posttherapy) were enrolled. All the patients underwent PET/CT scans 15–30 min after intravenous injection of 1.85 MBq (0.05 mCi) per kilogram of body weight of 68Ga-BBN-RGD and also accepted 68Ga-BBN PET/CT within 2 wk for comparison. Results: With a mean injected dose of 107.3 ± 14.8 MBq per patient, no side effect was found during the whole procedure and 2 wk follow-up, demonstrating the safety of 68Ga-BBN-RGD. A patient would be exposed to a radiation dose of 2.90 mSv with an injected dose of 129.5 MBq (3.5 mCi), which is much lower than the dose limit set by the Food and Drug Administration. In 13 patients with prostate cancer diagnosed by biopsy, 68Ga-BBN-RGD PET/CT detected 3 of 4 primary tumors, 14 metastatic lymph nodes, and 20 bone lesions with an SUVmax of 4.46 ± 0.50, 6.26 ± 2.95, and 4.84 ± 1.57, respectively. Only 2 of 4 primary tumors, 5 lymph nodes, and 12 bone lesions were positive on 68Ga-BBN PET/CT, with the SUVmax of 2.98 ± 1.24, 4.17 ± 1.89, and 3.61 ± 1.85, respectively. Conclusion: This study indicates the safety and efficiency of a new type of dual integrin αvβ3– and GRPR-targeting PET radiotracer in prostate cancer diagnosis and staging.

68Ga-NOTA-PRGD2 PET/CT for Integrin Imaging in Patients with Lung Cancer

This study was designed to assess the diagnostic value of 68Ga-NOTA-PRGD2 (NOTA-PRGD2 is NOTA-PEG4-E[c(RGDfK)]2) PET/CT in lung cancer. Methods: Ninety-one patients (48 men and 43 women; age, 22–82 y) with suspected lung lesions on CT were enrolled with informed consent. Immediately after intravenous injection of 117.7 ± 37.7 MBq of 68Ga-NOTA-PRGD2, 15 patients underwent dynamic whole-body PET/CT scans for 1–2 h, and the remaining 76 patients underwent whole-body PET/CT scans at 30 ± 10 min after bolus injection. Each patient also underwent standard 18F-FDG PET/CT for comparison. Results: No side effect was found after 68Ga-NOTA-PRGD2 injection. 68Ga-NOTA-PRGD2 was rapidly cleared from the blood pool and primarily excreted through the urinary system. The standardized uptake values of proven malignancies were significantly higher than those of the benign ones. With an average standardized uptake value of greater than 1.3 being considered malignant, the sensitivity, specificity, and accuracy of 68Ga-NOTA-PRGD2 PET/CT in diagnosing lung cancer were 83.8% (57/68), 91.3% (21/23), and 85.7% (78/91), respectively. The diagnostic value of 68Ga-NOTA-PRGD2 for lung cancer is comparable to that of 18F-FDG PET/CT. However, 68Ga-NOTA-PRGD2 PET/CT is more specific than 18F-FDG PET/CT in assessing lymph node metastasis, with positive and negative predictive values of 90.0% (27/30) and 93.8% (121/129), respectively, whereas those of 18F-FDG PET/CT were 30.2% (29/96) and 90.5% (57/63), respectively. Conclusion: This study indicates the efficacy of 68Ga-NOTA-PRGD2 PET/CT in lung cancer diagnosis. 68Ga-NOTA-PRGD2 PET/CT shows significant advantage over 18F-FDG PET/CT in judging metastatic lymph nodes with higher specificity.

Intense FDG activity in the brown adipose tissue in omental and mesenteric regions in a patient with malignant pheochromocytoma.

A 39-year-old man who had a history of surgical excision of left adrenal pheochromocytoma 3 years ago underwent an FDG PET/CT scan to evaluate possible metastatic/recurrent disease. In addition to multiple FDG-avid lesions typical of hypermetabolic malignant disease and the FDG uptake in regions rich in brown adipose tissue, there was also intense FDG activity in the omental and mesenteric regions, which are not common locations of elevated FDG activity. On the repeat FDG PET/CT scan 3 days later after the patient was prepared with propranolol, the omental and mesenteric FDG activity was diminished.

Clinical Translation of an Albumin-Binding PET Radiotracer 68Ga-NEB

Suitably labeled Evans blue dye has been successfully applied to evaluate cardiac function, vascular permeability, and lymphatic imaging in preclinical settings. This study documented the first-in-human application of 68Ga-1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA)-NEB. Methods: The NOTA-conjugated truncated form of Evans blue, NEB, was labeled with 68Ga and tested in BALB/C mice for dynamic PET and ex vivo biodistribution studies. Three healthy volunteers (2 men and 1 woman) underwent 90-min whole-body dynamic PET. The absorbed doses for major organs and whole body were calculated using OLINDA/EXM software. Eleven patients with focal hepatic lesions diagnosed by enhanced CT or MR imaging were subjected to whole-body PET/CT acquisitions at 30 min after intravenous injection of 111–148 MBq (3–4 mCi) of 68Ga-NEB. Results: NEB dye was labeled with 68Ga (half-time, 68 min) with high yield and purity. After intravenous injection, 68Ga-NEB formed a complex with serum albumin, thus most of the radioactivity was retained in blood circulation. The tracer was demonstrated to be safe in both healthy volunteers and recruited patients without side effects or allergies. Among the 11 patients, hemangiomas showed much higher 68Ga-NEB signal intensity than the surrounding normal hepatic tissues, whereas no apparent difference between lesions and hepatic tissues was identified on 18F-FDG PET. All other focal hepatic lesions including hepatocellular carcinoma, hepatic cysts, and neuroendocrine tumor liver metastases showed negative 68Ga-NEB contrast to hepatic tissues. Conclusion: As a blood-pool imaging agent, 68Ga-NEB is safe to use in the clinic, and our preliminary studies demonstrate the value of differentiating hepatic hemangioma from other benign or malignant focal hepatic lesions. Easy labeling with different positron emitters of various half-lives, excellent pharmacokinetics, and imaging quality warrant further clinical applications of NEB-based PET tracers.

Hepatic paragonimiasis revealed by FDG PET/CT.

A 72-year-old asymptomatic man with a hepatic lesion incidentally detected by ultrasonography in routine examination undertook fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography for further evaluation. The images revealed increased FDG activity in the lesion, which was suggestive of malignancy. However, the pathologic examination demonstrated that the lesion was a granuloma caused by Paragonimus westermani, a lung fluke. Although increased FDG activity in the lung due to P. westermani infection is expected and reported previously, such lesion identified in the liver by FDG positron emission tomography/computed tomography is unusual.

68Ga DOTATATE PET/CT is an Accurate Imaging Modality in the Detection of Culprit Tumors Causing Osteomalacia.

Objectives Tumor-induced osteomalacia (TIO) is generally caused by small benign mesenchymal tumors producing fibroblast growth factor-23 (FGF-23). The only curative therapy of the disease is resection of the causative tumors. However, these tumors are extremely difficult to detect using conventional imaging modalities. This research was undertaken to evaluate efficacy of 68Ga DOTATATE PET/CT in this clinical setting. Methods Images of 68Ga DOTATATE PET/CT and clinical charts from 54 patients with clinically suspected TIO were retrospectively reviewed. The image findings were compared with the results of histopathological examinations and clinical follow-ups. Results 68Ga DOTATATE PET/CT scans were positive in 44 patients, among which, 33 had surgery to remove the lesions. Postsurgical pathological examination confirmed causative tumors in 32 patients whose symptoms diminished promptly, and the serum phosphate levels became normal, which confirmed the diagnoses of TIO. Eleven patients with positive 68Ga DOTATATE PET/CT did not have surgery. These 11 patients continued to have symptoms and hypophosphatemia but were not included in the final analysis because of lack of evidence to confirm or exclude TIO. Ten patients had negative 68Ga DOTATATE PET/CT scans. All of these10 patients responded to conservative therapy and had normal serum phosphate levels in the follow-up, which excluded TIO. Therefore, the 68Ga DOTATATE PET/CT imaging had a sensitivity of 100% (32/32) and a specificity of 90.9% (10/11). The overall accuracy of 68Ga DOTATATE PET/CT scan in the detection of tumors responsible for osteomalacia is 97.7% (42/43). Conclusions 68Ga DOTATATE PET/CT scan is an accurate imaging modality in the detection of tumors causing TIO.

68Ga-NOTA-exendin-4 PET/CT in detection of occult insulinoma and evaluation of physiological uptake

A 52-year-old man who had hypoglycaemia for 8 years was found to have endogenous hyperinsulinism indicating an insulinoma. Abdominal MRI, CT perfusion, endoscopic ultrasonography, and Tc-HYNIC-TOC SPECT/CT were negative. Thus, the patient was referred for Ga-NOTA-exendin-4 PET/CT with the approval of the Institutional Review Board of our hospital. As well as the intense physiological distribution in the kidneys and bladder due to urinary excretion, moderately elevated uptake is apparent in the proximal duodenum (a–c long arrows, SUVmax 5.2) and pancreas (SUVmax 2.9) at 1 h after injection of Ga-NOTAexendin-4. Because visualization of the pancreas tail was significantly influenced by the intense radioactivity in the left kidney, the patient was reimaged at 2 h after injection. A lesion with intense uptake (SUVmax 20.7) was clearly seen in the pancreas tail (d, e short arrows). Interestingly, radioactivity in the proximal duodenum significantly decreased (d, e long arrows, SUVmax 2.3) while the appearance of the normal pancreas remained unchanged. The patient recovered from hypoglycemia after surgical removal of the pancreas tail insulinoma (WHO grade 1). Intraoperative ultrasonography excluded a duodenal tumor. Glucagon-like peptide-1 receptor (GLP-1R) is highly overexpressed in insulinoma [1, 2]. SPECT/CT imaging of GLP-1R using In-labelled or Tc-labelled exendin-4 has been shown to be highly accurate in the detection of insulinoma [2–4]. However, PET/CT imaging of GLP-1R has rarely been reported [5]. We present the first successful use of Ga-NOTA-exendin-4 PET/ CT for the identification of an occult insulinoma that could not be detected by other standard imaging methods. Ga-NOTAexendin-4 also shows great potential for evaluation of pancreatic physiology due to its uptake, presumably, by islet cells. Yaping Luo and Miao Yu contributed equally to the article.