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Purpose: Image quality of positron emission tomography (PET) is limited by various physical degradation factors. Our study aims to perform PET image denoising by utilizing prior information from the same patient. The proposed method is based on unsupervised deep learning, where no training pairs are needed., Methods: In this method, the prior high-quality image from the patient was employed as the network input and the noisy PET image itself was treated as the training label. Constrained by the network structure and the prior image input, the network was trained to learn the intrinsic structure information from the noisy image and output a restored PET image. To validate the performance of the proposed method, a computer simulation study based on the BrainWeb phantom was first performed. A 68 Ga-PRGD2 PET/CT dataset containing 10 patients and a 18 F-FDG PET/MR dataset containing 30 patients were later on used for clinical data evaluation. The Gaussian, non-local mean (NLM) using CT/MR image as priors, BM4D, and Deep Decoder methods were included as reference methods. The contrast-to-noise ratio (CNR) improvements were used to rank different methods based on Wilcoxon signed-rank test., Results: For the simulation study, contrast recovery coefficient (CRC) vs. standard deviation (STD) curves showed that the proposed method achieved the best performance regarding the bias-variance tradeoff. For the clinical PET/CT dataset, the proposed method achieved the highest CNR improvement ratio (53.35% ± 21.78%), compared with the Gaussian (12.64% ± 6.15%, P = 0.002), NLM guided by CT (24.35% ± 16.30%, P = 0.002), BM4D (38.31% ± 20.26%, P = 0.002), and Deep Decoder (41.67% ± 22.28%, P = 0.002) methods. For the clinical PET/MR dataset, the CNR improvement ratio of the proposed method achieved 46.80% ± 25.23%, higher than the Gaussian (18.16% ± 10.02%, P < 0.0001), NLM guided by MR (25.36% ± 19.48%, P < 0.0001), BM4D (37.02% ± 21.38%, P < 0.0001), and Deep Decoder (30.03% ± 20.64%, P < 0.0001) methods. Restored images for all the datasets demonstrate that the proposed method can effectively smooth out the noise while recovering image details., Conclusion: The proposed unsupervised deep learning framework provides excellent image restoration effects, outperforming the Gaussian, NLM methods, BM4D, and Deep Decoder methods.

Purpose : Despite the use of fluorescence-guided surgery (FGS), maximum safe resection of glioblastoma multiforme (GBM) remains a major challenge. It has restricted surgeons between preoperative diagnosis and intraoperative treatment. Currently, an integrated approach combining preoperative assessment with intraoperative guidance would be a significant step in this direction. Experimental design : We developed a novel 68 Ga-IRDye800CW-BBN PET/near-infrared fluorescence (NIRF) dual-modality imaging probe targeting gastrin-releasing peptide receptor (GRPR) in GBM. The preclinical in vivo tumor imaging and FGS were first evaluated using an orthotopic U87MG glioma xenograft model. Subsequently, the first-in-human prospective cohort study (NCT 02910804) of GBM patients were conducted with preoperative PET assessment and intraoperative FGS. Results : The orthotopic tumors in mice could be precisely resected using the near-infrared intraoperative system. Translational cohort research in 14 GBM patients demonstrated an excellent correlation between preoperative positive PET uptake and intraoperative NIRF signal. The tumor fluorescence signals were significantly higher than those from adjacent brain tissue in vivo and ex vivo (p < 0.0001). Compared with pathology, the sensitivity and specificity of fluorescence using 42 loci of fluorescence-guided sampling were 93.9% (95% CI 79.8%-99.3%) and 100% (95% CI 66.4%-100%), respectively. The tracer was safe and the extent of resection was satisfactory without newly developed neurologic deficits. Progression-free survival (PFS) at 6 months was 80% and two newly diagnosed patients achieved long PFS. Conclusions: This initial study has demonstrated that the novel dual-modality imaging technique is feasible for integrated pre- and intraoperative targeted imaging via the same molecular receptor and improved intraoperative GBM visualization and maximum safe resection., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

This study was designed to evaluate the ability of PET/MRI, using 18 F-FDG and 68 Ga-DOTATATE as tracers, to detect hormone-producing pituitary microadenoma when diagnosis is difficult using MRI alone. Methods: We recruited 37 patients with elevated hormone levels, including 19 with undiagnosable primary pituitary adenoma and 18 with suspected recurrent pituitary adenoma. 18 F-FDG PET/MRI and 68 Ga-DOTATATE PET/MRI were performed within 1 wk of each other in all patients. Within 2 wk afterward, 27 of the 37 patients underwent transsphenoidal adenomectomy, 3 underwent sella region radiotherapy, 1 underwent somatostatin therapy, and 6 had only clinical follow-up. The image characteristics and uptake levels were correlated with the surgical findings and pathologic results. Receiver-operating-characteristic curves were analyzed to determine the optimal cutoff to differentiate adenoma from normal pituitary tissue. The area under the receiver-operating-characteristic curve was calculated to compare diagnostic performance. Results: The PET/MR images were of diagnostic quality and without obvious image artifacts. The high contrast of the PET images provided complementary information to the fine anatomic display of the MR images. Increased 18 F-FDG uptake was clearly observed in all patients. MRI enhanced using a 0.05 mmol/kg dose of gadopentetate dimeglumine showed suggestive findings in only 47% of the patients with primary adenoma and 39% of those with recurrent adenoma; when a 0.1 mmol/kg dose was used, the respective percentages were 37% and 50%. The 18 F-FDG SUV max of the 16 primary adenomas that underwent transsphenoidal adenomectomy (6.8 ± 3.7) was significantly higher than that of normal pituitary tissue (3.2 ± 1.1, P < 0.01). The adenomas showed moderate 68 Ga-DOTATATE uptake (SUV max , 3.8 ± 2.6), but the 68 Ga-DOTATATE uptake was generally lower than that of normal pituitary tissue (SUV max , 6.2 ± 3.2, P < 0.05). In the 11 suspected recurrent pituitary adenomas that underwent transsphenoidal adenomectomy, the 18 F-FDG SUV max was 6.1 ± 3.5, significantly higher than that of normal pituitary tissue (2.5 ± 1.1, P < 0.01), and the 68 Ga-DOTATATE SUV max was 3.0 ± 1.1, significantly lower than that of normal pituitary tissue (5.5 ± 1.7, P < 0.01). The 18 F-FDG/ 68 Ga-DOTATATE SUV max ratio of the adenomas (2.3 ± 1.5) was significantly higher than that of normal pituitary tissue (0.6 ± 0.3, P < 0.05). When the 18 F-FDG SUV max alone and the 18 F-FDG/ 68 Ga-DOTATATE SUV max ratio were used as criteria to discriminate between adenoma and pituitary tissue, the best analysis came from the ratio, and that from 18 F-FDG SUV max alone was slightly less, with optimal diagnostic cutoffs of 1.04 and 3.88, respectively. Conclusion: PET/MRI provides an ideal tool for the detection of hormone-producing pituitary microadenoma. Dual-tracer 18 F-FDG and 68 Ga-DOTATATE PET/MRI was useful for distinguishing pituitary microadenoma from normal pituitary tissue., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Potentials of 68Ga-NEB as a PET tracer in the evaluation of a variety of lymphatic drainage disorders were analyzed., Methods: 68Ga-NEB was injected subcutaneously, and the PET/CT images were acquired in 13 patients with different suspected lymphatic drainage abnormality. The 68Ga-NEB PET/CT findings were compared with Tc-SC lymphoscintigraphy., Results: 68Ga-NEB activity could be clearly observed in the lymphatic route on the PET/CT images from all the patients. In 5 (38.5%) of 13 patients tested, 68Ga-NEB PET/CT provided more information than the Tc-SC lymphoscintigraphy., Conclusions: 68Ga-NEB PET/CT can be used as an alternative of Tc-SC lymphoscintigraphy in the evaluation of lymphatic disorders, which enables fast results and might be more accurate than the conventional Tc-SC lymphoscintigraphy.

Purpose: The noninvasive imaging of bacterial infections is critical in order to reduce mortality and morbidity caused by these diseases. The recently reported (18)F-FDS ((18)F-2-fluorodeoxy sorbitol) as a PET (positron emission tomography) tracer can be used to image Enterobacteriaceae-specific infections and provides a potential alternative to this problem compared with other probes for imaging infections. In this study, automatic synthesis, validation of (18)F-FDS and a first-in-human study were performed and discussed., Methods: A multifunctional synthesis module was employed for the radiosynthesis of (18)F-FDG ((18)F-2-fluorodeoxy glucose) and (18)F-FDS starting from (18)F ion using two-pot three-step fully automated reactions. The behavior of (18)F-FDS as an in vivo imaging probe for infections was evaluated in an Escherichia coli mouse infection model. The first detailed pharmacokinetic and biodistribution parameters were obtained from healthy human volunteers., Results: The uptake of (18)F-FDS in an E. coli mouse-myositis infection model was easily differentiated from other organs and normal muscle. Intensive lesion uptake declined after antibiotic treatment. In the pilot human study, no adverse effects due to (18)F-FDS were observed up to 24 h post-injection. The radiotracer was rapidly cleared from the circulation and excreted mainly through the urinary system., Conclusion: We conclude that (18)F-FDS PET holds great potential for appropriate and effective for the imaging of bacterial infections in vivo. These preliminary results indicate that further clinical studies are warranted., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Unlabelled: This work was designed to study the safety, biodistribution, and radiation dosimetry of a gastrin-releasing peptide receptor (GRPR)-targeting, (68)Ga-labeled bombesin (BBN) peptide derivative PET tracer, NOTA-Aca-BBN(7-14) (denoted as (68)Ga-BBN) in healthy volunteers and to assess the level of receptor expression in glioma patients., Methods: Four healthy volunteers (2 male and 2 female) underwent whole-body PET/CT at multiple time points after a bolus injection of (68)Ga-BBN (111 ± 148 MBq). Regions of interest were drawn manually over major organs, and time-activity curves were obtained. Dosimetry was calculated using the OLINDA/EXM software. Twelve patients with glioma diagnosed by contrast-enhanced MRI underwent PET/CT at 30-45 min after (68)Ga-BBN injection. Within 1 wk afterward, the tumor was surgically removed and immunohistochemical staining of tumor samples against GRPR was performed and correlated with the PET/CT results., Results: (68)Ga-BBN was well tolerated in all healthy volunteers, with no adverse symptoms being noticed or reported. (68)Ga-BBN cleared rapidly from the circulation and was excreted mainly through the kidneys and urinary tract. The total effective dose equivalent and effective dose were 0.0335 ± 0.0079 and 0.0276 ± 0.0066 mSv/MBq, respectively. In glioma patients, all MRI-identified lesions showed high signal intensity on (68)Ga-BBN PET/CT. SUVmax and SUVmean were 2.08 ± 0.58 and 1.32 ± 0.37, respectively. With normal brain tissue as background, tumor-to-background ratios were 24.0 ± 8.85 and 13.4 ± 4.54 based on SUVmax and SUVmean, respectively. The immunohistochemical staining confirmed a positive correlation between SUV and GRPR expression level (r(2) = 0.71, P < 0.001)., Conclusion: (68)Ga-BBN is a PET tracer with favorable pharmacokinetics and a favorable dosimetry profile. It has the potential to evaluate GRPR expression in glioma patients and guide GRPR-targeted therapy of glioma., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: This study was designed to assess the diagnostic value of (68)Ga-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 (68)Ga-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 (18)F-FDG PET/CT for comparison., Results: No side effect was found after (68)Ga-NOTA-PRGD2 injection. (68)Ga-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 (68)Ga-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 (68)Ga-NOTA-PRGD2 for lung cancer is comparable to that of (18)F-FDG PET/CT. However, (68)Ga-NOTA-PRGD2 PET/CT is more specific than (18)F-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 (18)F-FDG PET/CT were 30.2% (29/96) and 90.5% (57/63), respectively., Conclusion: This study indicates the efficacy of (68)Ga-NOTA-PRGD2 PET/CT in lung cancer diagnosis. (68)Ga-NOTA-PRGD2 PET/CT shows significant advantage over (18)F-FDG PET/CT in judging metastatic lymph nodes with higher specificity., Competing Interests: No other potential conflict of interest relevant to this article was reported., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: 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., Competing Interests: No other potential conflict of interest relevant to this article was reported., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein elevation, and skin changes) syndrome is a rare paraneoplastic syndrome caused by an underlying plasma cell disorder. The patients usually present with multisystemic involvement. Thus, we performed a study to investigate the role of (18)F-FDG PET/CT in characterizing POEMS syndrome., Methods: Ninety-one untreated patients with proven or suspected POEMS syndrome were recruited to undergo (18)F-FDG PET/CT. Features of bone lesions, lymphadenopathy, hepatomegaly or splenomegaly, bone marrow, and serous cavity effusion were examined, and 15 patients were followed up with PET/CT scans 3 mo after therapy., Results: Of the 90 patients diagnosed with POEMS syndrome, there were 140 (18)F-FDG-avid bone lesions. These lesions were frequently found in the pelvis, and most showed mixed characteristics. Four patients showed enlarged and (18)F-FDG-avid lymph nodes. Sixty-five patients had hepatomegaly or splenomegaly. Some of them had hypermetabolic spleen and bone marrow. Forty-six patients had serous cavity effusion. Five male patients had gynecomastia. Three months after therapy, (18)F-FDG-avid bone lesions showed decreased metabolism., Conclusion: (18)F-FDG PET/CT is a useful tool for the evaluation of patients with suspected POEMS syndrome. (18)F-FDG PET/CT may contribute to the diagnosis, evaluation, and follow-up of patients with POEMS syndrome by providing systematic findings of bone lesions, lymphadenopathy, liver or spleen involvement, serous cavity effusion, and the metabolic status of the lesions., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

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 (68)Ga DOTATATE PET/CT in this clinical setting., Methods: Images of (68)Ga 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: (68)Ga 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 (68)Ga 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 (68)Ga 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 (68)Ga DOTATATE PET/CT imaging had a sensitivity of 100% (32/32) and a specificity of 90.9% (10/11). The overall accuracy of (68)Ga DOTATATE PET/CT scan in the detection of tumors responsible for osteomalacia is 97.7% (42/43)., Conclusions: (68)Ga DOTATATE PET/CT scan is an accurate imaging modality in the detection of tumors causing TIO.

β-Emitters can produce Cerenkov radiation that is detectable by Cerenkov luminescence imaging (CLI), allowing the combination of PET and CLI with one radiotracer for both tumor diagnosis and visual guidance during surgery. Recently, the clinical feasibility of CLI with the established therapeutic reagent Na(131)I and the PET tracer (18)F-FDG was demonstrated. (68)Ga possesses a higher Cerenkov light output than (18)F and (131)I, which would result in higher sensitivity for CLI and improve the outcome of CLI in clinical applications. However, the research on (68)Ga-based tumor-specific tracers for CLI is limited. In this study, we examined the use of (68)Ga-radiolabeled DOTA-3PRGD2 ((68)Ga-3PRGD2) for dual PET and CLI of orthotopic U87MG human glioblastoma. For this purpose, the Cerenkov efficiencies of (68)Ga and (18)F were measured with the IVIS Spectrum system (PerkinElmer, USA). The CLI signal intensity of (68)Ga was 15 times stronger than that of (18)F. PET and CLI of (68)Ga-3PRGD2 were performed in U87MG human glioblastoma xenografts. Both PET and CLI revealed a remarkable accumulation of (68)Ga-3PRGD2 in the U87MG human glioblastoma xenografts at 1 h p.i. with an extremely low background in the brain when compared with (18)F-FDG. Furthermore, (68)Ga-3PRGD2 was used for dual PET and CLI of orthotopic human glioblastoma. The orthotopic human glioblastoma was clearly visualized by both imaging modalities. In addition, the biodistribution of (68)Ga-3PRGD2 was assessed in normal mice to estimate the radiation dosimetry. The whole-body effective dose is 20.1 ± 3.3 μSv/MBq, which is equal to 3.7 mSv per whole-body PET scan with a 5 mCi injection dose. Thus, (68)Ga-3PRGD2 involves less radiation exposure in patients when compared with (18)F-FDG (7.0 mSv). The use of (68)Ga-3PRGD2 in dual PET and CLI shows great promise for tumor diagnosis and image-guided surgery.

A 48-year-old man with progressive respiratory symptoms was suspected of having relapsing polychondritis (RPC). A 99mTc-MDP bone scintigraphy showed only mild activity in the bilateral costal cartilage. In contrast, 18F-fluoride PET/CT revealed intense radioactivity accumulation in the tracheal cartilages. Biopsy results from tracheal cartilage were consistent with a diagnosis of RPC. The patient received therapy toward RPC, and his symptoms was gradually alleviated.

Competing Interests: None.

Pituitary carcinoma is a rare disease with a challenge in both diagnosis and treatment. A 50-year-old female patient who underwent transsphenoidal resection of a pituitary tumor experienced progressive headache. For the evaluation, Ga DOTATATE PET/CT was used and compared with F-FDG PET/CT and enhanced MRI. Multiple lesions were detected by Ga DOTATATE PET/CT at the cerebral cortex, cerebellum, and cerebellopontine angle with a higher contrast than F-FDG PET/CT and enhanced MRI. With a biopsy, the patient was diagnosed as metastatic pituitary carcinoma. Moreover, it thus presents potential therapeutic implications on molecular-targeted therapy using somatostatin analogs and peptide receptor radionuclide therapy targeting the somatostatin receptors.

Integrin αvβ3 is overexpressed in both neovasculature and glioma cells. We aimed to evaluate (68)gallium-BNOTA-PRGD2 ((68)Ga-PRGD2) as a new reagent for noninvasive integrin αvβ3 imaging in glioma patients. With informed consent, 12 patients with suspicious brain glioma, as diagnosed by enhanced magnetic resonance imaging (MRI) scanning, were enrolled to undergo (68)Ga-PRGD2 PET/CT and (18)F-FDG PET/CT scans before surgery. The preoperative images were compared and correlated with the pathologically determined WHO grade. Next, the expression of integrin αvβ3, CD34, and Ki-67 were determined by immunohistochemical staining of the resected brain tumor tissue. Our findings demonstrated that (68)Ga-PRGD2 specifically accumulated in the brain tumors that were rich of integrin αvβ3 and other neovasculature markers, but not in the brain parenchyma other than the choroid plexus. Therefore, (68)Ga-PRGD2 PET/CT was able to evaluate the glioma demarcation more specifically than (18)F-FDG PET/CT. The maximum standardized uptake values (SUVmax) of (68)Ga-PRGD2, rather than those of (18)F-FDG, were significantly correlated with the glioma grading. The maximum tumor-to-brain ratios (TBRmax) of both tracers were significantly correlated with glioma grading, whereas (68)Ga-PRGD2 seemed to be more superior to (18)F-FDG in differentiating high-grade glioma (HGG) from low-grade glioma (LGG). Moreover, (68)Ga-PRGD2 PET/CT showed different accumulation patterns for HGG of WHO grades III and IV. This is the first noninvasive integrin imaging study, to the best of our knowledge, conducted in preoperative patients with different grades of glioma, and it preliminarily indicated the effectiveness of this novel method for evaluating glioma grading and demarcation.

Antiangiogenic therapy is an effective strategy to inhibit tumor growth. Endostar, as an approved antiangiogenesis agent, inhibits the newborn vascular endothelial cells, causing the decrease of integrin αvβ3 expression. Radiolabeled 3PRGD2, a novel PEGlayted RGD dimer probe (PEG4-E[PEG4-c(RGDfK)]2) showed highly specific targeting capability to integrin αvβ3, which could be used for monitoring the efficacy of Endostar antiangiogenic therapy. In this study, (68)Ga-3PRGD2 PET imaging was performed in Endostar treated/untreated Lewis Lung Carcinoma (LLC) mice on days 3, 7, 14, and 21 post-treatment for monitoring the tumor response to Endostar treatment, with the (18)F-FDG imaging as control. As a result, (68)Ga-3PRGD2 PET reflected the tumor response to Endostar antiangiogenic therapy much earlier (day 3 post-treatment vs day 14 post-treatment) and more accurately than that of (18)F-FDG metabolic imaging, which provides new opportunities to develop individualized therapeutic approaches, establish optimized dosages and dose intervals for effective treatment that improve the survival rate of patients.

Objective: To evaluate the clinical diagnostic contribution of (18)F-FDG PET/CT in giant cell arteritis with initial presentation as fever of unknown origin (FUO) ., Methods: Eight cases with initial presentation as FUO diagnosed with the contribution of PET/CT were retrospectively studied in Peking Union Medical College Hospital. The radiologic manifestations of PET/CT were analyzed., Results: Eight patients (4 men and 4 women) with average (63 ± 7) years (range from 55-75 years) were included in our study based on the criteria.Non-specific clinical symptoms were common in these patients, including fatigue, night sweat and weight loss. They all suffered from anemia of chronic disease.Not surprisingly, the inflammatory parameters were elevated significantly in all patients. The medical history, physical examination and routine lab and radiologic examinations couldn't reveal the causes of fever. PET/CT was performed in all of them, which demonstrated intense (18)F-FDG uptake in the area of aorta and its major branches with maximal standard uptake value (SUVmax) 2.1- 4.6 (3.6 ± 0.9).Immunosuppressive agents were effective to control the inflammation activity. The SUV decreased significantly after treatment in the follow-up PET/CT., Conclusions: PET/CT has demonstrated high yield of diagnostic contribution in giant cell arteritis with initial presentation as fever of unknown origin. As to elderly FUO patients presenting with prominent inflammatory reaction, PET/CT may provide potential value to differentiate diagnosis from maligancies.

Purpose: IgG4-related disease (IgG4-RD) is an increasingly recognized clinicopathological disorder with immune-mediated inflammatory lesions mimicking malignancies. A cohort study was prospectively designed to investigate the value of (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in characterizing IgG4-RD., Methods: Thirty-five patients diagnosed with IgG4-RD according to the consensus criteria were enrolled with informed consent. All patients underwent baseline (18)F-FDG PET/CT evaluation. Among them, 29 patients underwent a second (18)F-FDG PET/CT scan after 2 to 4 weeks of steroid-based therapy., Results: All 35 patients were found with (18)F-FDG-avid hypermetabolic lesion(s); 97.1% (34/35) of these patients showed multi-organ involvement. Among the 35 patients, 71.4% (25/35) patients were found with more organ involvement on (18)F-FDG PET/CT than conventional evaluations including physical examination, ultrasonography, and computed tomography (CT). (18)F-FDG PET/CT demonstrated specific image characteristics and pattern of IgG4-RD, including diffusely elevated (18)F-FDG uptake in the pancreas and salivary glands, patchy lesions in the retroperitoneal region and vascular wall, and multi-organ involvement that cannot be interpreted as metastasis. Comprehensive understanding of all involvement aided the biopsy-site selection in seven patients and the recanalization of ureteral obstruction in five patients. After 2 to 4 weeks of steroid-based therapy at 40 mg to 50 mg prednisone per day, 72.4% (21/29) of the patients showed complete remission, whereas the others exhibited > 81.8% decrease in (18)F-FDG uptake., Conclusion: F-FDG PET/CT is a useful tool for assessing organ involvement, monitoring therapeutic response, and guiding interventional treatment of IgG4-RD. The image pattern is suggested to be updated into the consensus diagnostic criteria for IgG4-RD.

Unlabelled: Previous in vitro studies demonstrated that treating tumors expressing both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 with trastuzumab resulted in increased EGFR homodimerization and subsequent rapid downregulation of EGFR. We investigated whether molecular imaging using near-infrared fluorescence (NIRF) imaging and PET probes could sensitively detect trastuzumab-induced EGFR downregulation in vivo., Methods: The F(ab')2 antibody fragment PaniF(ab')2 was generated by digesting the anti-EGFR monoclonal antibody panitumumab. PaniF(ab')2 was labeled with either a NIRF dye or (68)Ga, and optical imaging and small-animal PET imaging of Dye-PaniF(ab')2 and (68)Ga-PaniF(ab')2, respectively, were performed in HT-29 tumor-bearing nude mice treated with trastuzumab or untreated control., Results: Longitudinal NIRF imaging studies revealed significantly reduced tumor uptake of Dye-PaniF(ab')2 on days 5 and 7 in trastuzumab-treated HT-29 tumors, compared with control. Western blotting confirmed the downregulation of EGFR after treatment with trastuzumab. Small-animal PET on day 5 after trastuzumab treatment also demonstrated decreased (68)Ga-PaniF(ab')2 uptake in trastuzumab-treated HT-29 tumors. The tumor uptake value of (68)Ga-PaniF(ab')2 obtained from PET imaging had an excellent linear correlation with the uptake value measured using biodistribution., Conclusion: The downregulation of EGFR induced by trastuzumab treatment could be detected noninvasively using optical and PET imaging. This molecular imaging strategy could provide a dynamic readout of changes in the tumor signaling and may facilitate the noninvasive monitoring of the early tumor response to drug treatment., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: Ischemic vascular diseases, including myocardial infarction (MI) and stroke, have been found to be associated with elevated expression of αvβ3-integrin, which provides a promising target for semi-quantitative monitoring of the disease. For the first time, we employed (68)Ga-S-2-(isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid-PEG3-E[c(RGDyK)]2 ((68)Ga-PRGD2) to evaluate the αvβ3-integrin-related repair in post-MI and post-stroke patients via positron emission tomography/computed tomography (PET/CT)., Methods: With Institutional Review Board approval, 23 MI patients (3 days-2 years post-MI) and 16 stroke patients (3 days-13 years post-stroke) were recruited. After giving informed consent, each patient underwent a cardiac or brain PET/CT scan 30 min after the intravenous injection of (68)Ga-PRGD2 in a dose of approximately 1.85 MBq (0.05 mCi) per kilogram body weight. Two stroke patients underwent repeat scans three months after the event., Results: Patchy (68)Ga-PRGD2 uptake occurred in or around the ischemic regions in 20/23 MI patients and punctate multifocal uptake occurred in 8/16 stroke patients. The peak standardized uptake values (pSUVs) in MI were 1.94 ± 0.48 (mean ± SD; range, 0.62-2.69), significantly higher than those in stroke (mean ± SD, 0.46 ± 0.29; range, 0.15-0.93; P < 0.001). Higher (68)Ga-PRGD2 uptake was observed in the patients 1-3 weeks after the initial onset of the MI/stroke event. The uptake levels were significantly correlated with the diameter of the diseases (r = 0.748, P = 0.001 for MI and r = 0.835, P = 0.003 for stroke). Smaller or older lesions displayed no uptake., Conclusions: (68)Ga-PRGD2 uptake was observed around the ischemic region in both MI and stroke patients, which was correlated with the disease phase and severity. The different image patterns and uptake levels in MI and stroke patients warrant further investigations.

Aim: (18)F-DPA-714 is a PET tracer that recognizes macrophage translocator protein (TSPO), and (18)F-Alfatide II ((18)F-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 (18)F-DPA-714 in differentiating inflammation from tumor., Methods: RAW264.7 mouse macrophage cells were used for cell uptake analysis of (18)F-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 (18)F-DPA-714 and (18)F-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 (18)F-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 (18)F-DPA-714 in RAW264.7 cells was 45.5% at 1 h after incubation, and could be blocked by PK11195. PET imaging showed increased (18)F-DPA-714 and (18)F-Alfatide II uptake at inflammatory muscles. Peak uptake of (18)F-DPA-714 was seen on day 6 (4.02 ± 0.64 %ID/g), and peak uptake of (18)F-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 (18)F-DPA-714 or cold RGD for (18)F-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 (18)F-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 (18)F-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 (18)F-DPA-714 and (18)F-Alfatide II matched the causal relationship between macrophage infiltration and angiogenesis. Moreover, we found (18)F-DPA-714 uptake in several types of tumors is significantly lower than that in inflammatory muscles, suggesting (18)F-DPA-714 PET has the potential for better differentiation of tumor and non-tumor inflammation.

Background: Integrated positron emission tomography and computed tomography (PET/CT) is increasingly used for the preoperative nodal staging of non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the accuracy of PET/CT in comparison with CT in detection of nodal metastasis and preoperative nodal staging in patients with NSCLC, and to analyze the causes of the PET/CT false-negative and false-positive results., Methods: Consecutive patients with pathologically proven NSCLC who underwent staging using PET/CT from July 2008 to February 2012 were evaluated retrospectively. Nodal staging was pathologically confirmed on tissue specimens obtained at thoracotomy. The accuracy of PET/CT and CT in the assessment of intrathoracic nodal involvement was determined using histological results as the reference standard. Logistic regression was used to define the causes of the false-negative and false-positive results., Results: A total of 528 lymph node stations were evaluated in 101 patients. Lymph nodes were positive for malignancy in 43 out of 101 patients (42.6%), and 101 out of 528 nodal stations (19.2%). PET/CT was significantly more accurate for nodal staging than CT. The sensitivity, specificity, positive and negative predictive values, and accuracy of PET/CT for detecting nodal metastasis were 51.5%, 95.8%, 74.3%, 89.3%, and 87.3% and the corresponding data by CT were 45.5%, 87.1%, 45.5%, 87.1%, and 79.2%, respectively. PET/CT confers significantly higher specificity, positive predictive value, and accuracy than CT in detecting nodal metastasis. False-negative results by PET/CT are significantly associated with smaller lymph node size, whereas false-positive results are related to a combination of inflammatory disorders and larger lymph node size., Conclusion: PET/CT confers significantly higher accuracy than CT in nodal staging, and is more specific and accurate than CT in detecting nodal metastasis but has a low sensitivity and high false-negative rate.

We compare F-FDG PET/CT and 99mTc 3PRGD2 SPECT/CT scans in a case of histologically proved pituitary metastases. The ratio of tumor to cerebellum (T/C) of 99mTc 3PRGD2 SPECT is much higher than that for 18F-FDG PET. We then conduct the same scans for a pituitary adenoma patient for better comparison. The T/C of 18F-FDG is not able to differentiate pituitary metastases from pituitary adenoma. However, The T/C of 99mTc 3PRGD2 observed in pituitary metastases was higher than that in pituitary adenoma.

Cancer is becoming the largest threat to human health. Apart from classical anti-cancer therapies such as surgery, chemotherapies, and radiotherapy, many new therapies are being developed or translated into clinical use. These therapies include various neoadjuvant chemotherapies, minimally invasive treatments, and molecular-targeted therapies. However, none of these methods benefit all patients because treatment should be personalized according to the response of each patient. A futile therapy makes a patient miss the optimum time for treatment and increases the medical burden to the society. Thus, a great challenge is encountered in monitoring such therapies. Classical methods based on anatomical changes such as computed tomography (CT) and magnetic resonance imaging (MRI) have well-known limitations in early response evaluation. Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) as tracer is a promising method especially when integrated with CT or MRI in one system. This article reviews the current status of monitoring anti-cancer therapies, including the evolution of evaluation criteria from the World Health Organization to the Response Evaluation Criteria in Solid Tumor and the PET Response Criteria in Solid Tumor. The advantages of 18F-FDG PET/CT for response evaluation are analyzed in various malignant tumors, and the pertinent weaknesses are discussed. Finally, several future directions in monitoring anti-cancer therapies are prospected.

The rising interest in using functional cells for diagnosis and treatment has created an urgent need for in vivo cell-tracking techniques. Certain advanced techniques, such as those involving reporter genes or nanoparticles, are still awaiting confirmation of their safety and feasibility in human patients. Tracking cells by labeling them with (18)F-fluorodeoxyglucose, a tracer clinically used in positron emission tomography (PET), may be one way to rapidly translate some of these principles from bench to bedside. The preliminary results are exciting, although further development, optimization, and validation are required. Here, several applications of the technique are surveyed: finding inflammatory foci, targeting cancer immunotherapies, tracking transplanted islet cells, and monitoring cardiac stem cells. Advantages, limitations, and prospects of the technique are discussed. These early experiences only highlight the existing need to improve cell-labeling techniques using PET tracers. This method may finally lead to the development of effective and convenient methods for clinical cell-tracking techniques involving PET/computed tomography., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Brown adipose tissue (BAT) is emerging as a potential target for treating human obesity. It has been indicated that BAT is rich in innervations of sympathetic nerve control. Using (18)F-FDG microPET imaging, this study aims at evaluating how factors related to sympathetic activation/inhibition changed BAT metabolism of mice. BAT (18)F-FDG uptake were semiquantitatively evaluated in different groups of mice under temperature (cold or warm stimulus) or pharmacological interventions (norepinephrine, epinephrine, isoprenaline, or propranolol) and were compared with the corresponding controls. It was found that BAT activation can be stimulated by cold exposure (P = 1.96 × 10(-4)), norepinephrine (P = .002), or both (P = 2.19 × 10(-6)) within an hour before (18)F-FDG injection and can also be alleviated by warming up (P = .001) or propranolol lavage (P = .027). This preliminary study indicated that BAT function could be evaluated by (18)F-FDG PET imaging through short-term interventions, which paved the way for further investigation of the relationship between human obesity and BAT dysfunction.

Unlabelled: This study evaluated the efficacy of human mesenchymal stem cells (hMSCs) in the treatment of intracerebral hematoma (ICH) using a primate model and serial 18F-FDG PET scans., Methods: Twenty-four Macaca fascicularis monkeys (male, 4.2±0.2 kg) were enrolled. The ICH models were established using a stereo-guided injection of 1.5 mL of autologous arterial blood between the right cortex and basal ganglia. One week (early treatment group, n=8) or 4 wk (late treatment group, n=8) after an ICH was established, (1-5)×10(6) hMSCs were transplanted near the hematoma using a stereotactic method. Control monkeys received saline only, either 1 or 4 wk (n=4 for each subgroup) after ICH establishment. The efficacy of treatment was evaluated by serial 18F-FDG PET scans (n=19) and neurologic deficit scoring weekly or biweekly. Pathologic analysis was performed 8 wk after hMSC transplantation., Results: One week after hMSC injection, higher 18F-FDG accumulated at the ipsilateral basal ganglia in both early and late hMSC-treated groups, indicating an early response to the treatment. When recovery reached a plateau, 18F-FDG uptake in the adjacent cortex was significantly higher in the early treatment group (P<0.05). The neurologic deficit scoring was significantly lower in the hMSC-treated groups, which also indicated better recovery. Pathologic analysis revealed higher vessel density surrounding the remains of hematoma in the hMSC-treated groups., Conclusion: This preliminary study indicates that transplantation of hMSCs may improve the recovery from ICH in a primate model, and early treatment may lead to better results.

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.

Unlabelled: This study was designed to investigate the feasibility and effectiveness of a modified protocol for (18)F-FDG PET that was proposed to improve the identification of primary gastric malignancies., Methods: In the modified protocol, patients were asked to drink 300-500 mL of cow milk to distend the stomach immediately before PET scans instead of fasting all along. For investigation of the influence of ingested milk on (18)F-FDG distributions, 43 nondiabetic patients without documented gastric diseases underwent both empty- and distended-stomach PET scans (79 and 72 scans, respectively) in their serial follow-up studies. For the evaluation of proven gastric malignancies, 24 patients who underwent distended-stomach PET scans were compared with 17 patients who underwent conventional empty-stomach examinations., Results: Ingestion of milk nearly 1 h after (18)F-FDG injection had no significant influence on distributions to the heart (P = 0.16), mediastinum (P = 0.50), and liver (P = 0.49), whereas the percentages of intense and moderate uptake in the stomach changed from 38.0% and 59.5% to 0% and 11.1%, respectively. With the normal gastric wall distended, malignant lesions were observed with higher contrast and clearer outlines, and some of them were detected at a small size (1.2 cm) at an early stage and with mild uptake., Conclusion: Gastric distention with milk just before (18)F-FDG PET is a simple and effective method for improving the evaluation of primary gastric malignancies.

Gastric carcinoma is the second leading cause of cancer-related death worldwide. Detection and surgical resection of gastric cancer in the early stage provides the only hope for improved survival in patients with gastric cancer. Positron emission tomography (PET) with F-18 2-deoxy-2-fluoro-D-glucose (FDG) has been shown to be essential in the evaluation of a variety of malignancies. However, conventional FDG PET has limited value for detecting a primary tumor of the stomach, mostly because of the relatively high levels of physiological uptake by the contracted stomach. We report 3 cases of primary gastric carcinomas detected successfully by FDG PET after the ingestion of food. The PET images of the stomach after ingesting food were compared with the routine fasting-state whole-body PET images for each patient. When the stomach was distended by food, the malignant lesions were more discernible. These cases indicate that gastric distension by ingesting food may be a simple method that can help to detect a primary gastric malignancy by FDG PET.

Background: Positron emission tomography/computed tomography (PET/CT) has been recognized for diagnosing and staging lung cancer, but the prognostic value of standardized uptake value (SUV) on 18F‐FDG PET/CT imaging in patients with advanced non‐small cell lung cancer (NSCLC) remains controversial. Methods: We performed a retrospective analysis of patients with advanced NSCLC who had undergone 18F‐FDG PET/CT before systemic treatment between June 2012 and June 2016. The relationship between the maximum SUV (SUVmax) of the pulmonary lesion and lesion size was evaluated via Spearman's correlation analysis. We collected patients' clinical and pathological data. Univariate and multivariate analyses were performed to analyze the factors influencing survival. Results: We included 157 patients with advanced NSCLC. Among these, 135 died, 13 survived, and nine were lost to follow‐up (median follow‐up period, 69 months). SUVmax was correlated with lesion size and was significantly greater for tumors ≥3 cm than for tumors <3 cm (10.2 ± 5.4 vs. 5.6 ± 3.3, t = −6.709, p = 0.000). Univariate analysis showed that survival was associated with gender, tumor size, epidermal growth factor receptor gene mutation or anaplastic lymphoma kinase rearrangement, SUVmax of the primary lung lesion, and treatment lines. Multivariate analysis showed a significant correlation between SUVmax of the primary lung lesion and survival. The mortality risk of patients with SUVmax ≤6 was 35% lower than that of patients with SUVmax >6 (HR = 0.651, 95% confidence interval, 0.436–0.972; Wald value, 4.400; p = 0.036). Conclusions: The SUVmax of the primary lung lesion on PET/CT is significantly correlated with survival in treatment‐naive patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]