Preclinical evaluation of an 18F-labeled Tenascin-C aptamer for PET imaging of atherosclerotic plaque in mouse models of atherosclerosis.

Tenascin-C is an extracellular matrix glycoprotein strongly expressed in coronary atherosclerotic plaque. Aptamers are single-stranded oligonucleotides that bind to specific target molecules with high affinity. This study hypothesized that tenascin-C expression at atherosclerotic plaque in vivo could be detected by tenascin-C specific aptamers using positron emission tomography (PET). This paper reports the radiosynthesis of a fluorine-18 (18F)-labeled tenascin-C aptamer for the biodistribution and PET imaging of the tenascin-C expression in apolipoprotein E-deficient (ApoE-/-) mice. The aortas ApoE-/- mice showed significantly increased positive areas of Oil red O staining than control C57BL/6 mice, and tenascin-C expression was detected in foam cells accumulated in the subendothelial lesions of ApoE-/- mice. The ex vivo biodistribution of the 18F-labeled tenascin-C aptamer showed significantly increased uptake at the aorta of ApoE-/- mice, and ex vivo autoradiography of aorta revealed the high accumulation of the 18F-labeled tenascin-C aptamer in the atherosclerotic lesions of ApoE-/- mice, which was consistent with the location of the atherosclerotic plaques detected by Oil red O staining. PET imaging of the 18F-labeled tenascin-C aptamer revealed a significantly higher mean standardized uptake in the aorta of the ApoE-/- mice than the control C57BL/6 mice. These data highlight the potential use of tenascin-C aptamer to diagnose atherosclerotic lesions in vivo.

Does high [18F]FDG uptake always mean poor prognosis? Colon cancer with high-level microsatellite instability is associated with high [18F]FDG uptake on PET/CT.

OBJECTIVES: High-level microsatellite instability (MSI-high) is generally associated with higher F-18 fluorodeoxyglucose ([18F]FDG) uptake than stable microsatellite (MSI-stable) tumors. However, MSI-high tumors have better prognosis, which is in contrast with general understanding that high [18F]FDG uptake correlates with poor prognosis. This study evaluated metastasis incidence with MSI status and [18F]FDG uptake. METHODS: We retrospectively reviewed 108 right-side colon cancer patients who underwent preoperative [18F]FDG PET/CT and postoperative MSI evaluations using a standard polymerase chain reaction at five Bethesda guidelines panel loci. The maximum standard uptake value (SUVmax), SUVmax tumor-to-liver ratio (TLR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor were measured using SUV 2.5 cut-off threshold. Student's t-test or Mann-Whitney U test was performed for continuous variables, and χ2 test or Fisher's exact test was performed for categorical variables (p value of < 0.05 for statistical significance). Medical records were reviewed for metastasis incidence. RESULTS: Our study population had 66 MSI-stable and 42 MSI-high tumors. [18F]FDG uptake was higher in MSI-high tumors than MSI-stable tumors (TLR, median (Q1, Q3): 7.95 (6.06, 10.54) vs. 6.08 (4.09, 8.82), p = 0.021). Multivariable subgroup analysis demonstrated that higher [18F]FDG uptake was associated with higher risks of distant metastasis in MSI-stable tumors (SUVmax: p = 0.025, MTV: p = 0.008, TLG: p = 0.019) but not in MSI-high tumors. CONCLUSION: MSI-high colon cancer is associated with high [18F]FDG uptake, but unlike MSI-stable tumors, the degree of [18F]FDG uptake does not correlate with the rate of distant metastasis. CLINICAL RELEVANCE STATEMENT: MSI status should be considered during PET/CT assessment of colon cancer patients, as the degree of [18F]FDG uptake might not reflect metastatic potential in MSI-high tumors. KEY POINTS: • High-level microsatellite instability (MSI-high) tumor is a prognostic factor for distant metastasis. • MSI-high colon cancers had a tendency of demonstrating higher [18F]FDG uptake compared to MSI-stable tumors. • Although higher [18F]FDG uptake is known to represent higher risks of distant metastasis, the degree of [18F]FDG uptake in MSI-high tumors did not correlate with the rate at which distant metastasis occurred.

In vivo positron emission tomography imaging for PD-L1 expression in cancer using aptamer.

The programmed death-1 (PD-1) receptor is an immunosuppressive receptor expressed on activated T-cells that elicits an inhibitory signal upon the engagement of its ligand, which is the programmed death ligand 1 (PD-L1). Recent studies have shown that PD-1/PD-L1 blockade can enhance endogenous antitumor immunity. Thus, the PD-1/PD-L1 axis may be a potential therapeutic target for cancer immunotherapy. Aptamers are oligonucleotides with high specificity and affinity for target molecules and promising candidates for molecular imaging and targeted therapy. 68Ga is an attractive radionuclide that serves as a low-cost alternative to cyclotron-produced positron emission tomography (PET) radionuclides. In this study, we developed a 68Ga-labeled PD-L1 aptamer and investigated its target specificity and utility for in vivo PET scanning. In the first part of our study, we evaluated the binding affinity of three PD-L1 aptamers in PD-L1-positive (H1975 and B16F10) and negative (A549 and HT-29) tumor cells by flow cytometry and confocal microscopy. Optical imaging studies of PD-L1 aptamers were performed in H1975 tumor-bearing mice, and the aptamer with the highest binding affinity to PD-L1 positive tumors was selected. PD-L1 aptamers were radiolabeled with 68Ga. PET was performed for in vivo imaging of the 68Ga-NOTA-PD-L1 aptamer in H1975 tumor-bearing mice (PD-L1-positive cells) and A549 tumor-bearing mice (PD-L1-negative cells). Flow cytometry and confocal microscopy showed that PD-L1 aptamers had strong binding to PD-L1-positive H1975 and B16F10 cells. In contrast, PD-L1-negative A549 and HT-29 cells showed low binding to PD-L1 aptamers. Optical imaging studies of H1975 tumor-bearing mice showed the highest uptake of the 2198-06-07 PD-L1 aptamer. PET of 68Ga-NOTA-PD-L1 aptamers demonstrated increased uptake into PD-L1-positive H1975 tumors compared with PD-L1-negative A549 tumors. We confirmed that 68Ga-NOTA-PD-L1 aptamers facilitated the visualization of PD-L1 expression by in vivo PET scanning. These data suggest that 68Ga-NOTA-PD-L1 aptamers could potentially act as tracers for imaging for PD-L1-positive cancers.

Usefulness and potential pitfalls of pre-operative PET-CT in patients with endometrial cancer undergoing one- and two-step sentinel lymph node mapping: Do negative findings on PET-CT negativity really indicate node negativity?

OBJECTIVE: We investigated the utility of Positron emission tomography-Computed tomography (PET-CT) in the setting of two different sentinel lymph node (SLN) mapping techniques; the conventional cervical injection method (one-step) and the two-step method, which involves fundal injection followed by cervical injection. METHODS: Patients with endometrial cancer undergoing FDG PET-CT followed by laparoscopic or robotic surgical staging with SLN mapping at the Yonsei Cancer Center between July 2014 and April 2021 were stratified into the PET-positive group (with suspected or likely lymph nodes metastasis) and PET-negative group. A chart review was performed for the number of harvested SLNs, patterns of SLN metastases, and recurrence. RESULTS: Among 466 patients undergoing one-step (n = 276) and two-step (n = 190) SLN mapping, LN metastasis was identified in 21 of 434 PET-negative and 18 of 32 PET-positive patients. The sensitivity and specificity of PET-CT for diagnosing lymph node metastasis were 46.2% and 96.7%, respectively. Among PET-positive patients with LN metastasis, anatomical distribution was concordant in 14/18 patients (77.8%). Among PET-negative patients, four (2.3%) had metastatic para-aortic SLNs, including three (1.7%) with isolated para-aortic metastases; metastatic para-aortic SLNs were exclusively found in the two-step group. Among PET-positive patients, para-aortic SLN metastasis was identified in 35.7% of two-step and 16.7% of one-step group. Among the 21 PET false-negative patients, recurrence was seen in four patients (19%) after a median follow-up of 34 months (range: 7-70 months). CONCLUSIONS: PET-CT served as a useful guide to clinicians with high anatomical concordance rate in patients with LN metastasis. However, despite high specificity, sensitivity was limited. SLN metastasis pattern, especially at the para-aortic level, indicates that the two-step SLN technique might be useful in PET-negative and PET-positive patients.

Fabrication and evaluation of bilateral Helmholtz radiofrequency coil for thermo-stable breast image with reduced artifacts.

PURPOSE: The positron emission tomography (PET)-magnetic resonance (MR) system is a newly emerging technique that yields hybrid images with high-resolution anatomical and metabolic information. With PET-MR imaging, a definitive diagnosis of breast abnormalities will be possible with high spatial accuracy and images will be acquired for the optimal fusion of anatomic locations. Therefore, we propose a PET-compatible two-channel breast MR coil with minimal disturbance to image acquisition which can be used for simultaneous PET-MR imaging in patients with breast cancer. MATERIALS AND METHODS: For coil design and construction, the conductor loops of the Helmholtz coil were tuned, matched, and subdivided with nonmagnetic components. Element values were optimized with an electromagnetic field simulation. Images were acquired on a GE 600 PET-computed tomography (CT) and GE 3.0 T MR system. For this study, we used the T1-weighted image (volunteer; repetition time (TR), 694 ms; echo time (TE), 9.6 ms) and T2-weighted image (phantom; TR, 8742 ms; TE, 104 ms) with the fast spin-echo sequence. RESULTS: The results of measuring image factors with the proposed radiofrequency (RF) coil and standard conventional RF coil were as follows: signal-to-noise ratio (breast; 207.7 vs. 175.2), percent image uniformity (phantom; 89.22%-91.27% vs. 94.63%-94.77%), and Hounsfield units (phantom; -4.51 vs. 2.38). CONCLUSIONS: Our study focused on the feasibility of proposed two-channel Helmholtz loops (by minimizing metallic components and soldering) for PET-MR imaging and found the comparable image quality to the standard conventional coil. We believe our work will help significantly to improve image quality with the development of a less metallic breast MR coil.

Serum glucose excretion after Roux-en-Y gastric bypass: a potential target for diabetes treatment.

OBJECTIVE: The mechanisms underlying type 2 diabetes resolution after Roux-en-Y gastric bypass (RYGB) are unclear. We suspected that glucose excretion may occur in the small bowel based on observations in humans. The aim of this study was to evaluate the mechanisms underlying serum glucose excretion in the small intestine and its contribution to glucose homeostasis after bariatric surgery. DESIGN: 2-Deoxy-2-[18F]-fluoro-D-glucose (FDG) was measured in RYGB-operated or sham-operated obese diabetic rats. Altered glucose metabolism was targeted and RNA sequencing was performed in areas of high or low FDG uptake in the ileum or common limb. Intestinal glucose metabolism and excretion were confirmed using 14C-glucose and FDG. Increased glucose metabolism was evaluated in IEC-18 cells and mouse intestinal organoids. Obese or ob/ob mice were treated with amphiregulin (AREG) to correlate intestinal glycolysis changes with changes in serum glucose homeostasis. RESULTS: The AREG/EGFR/mTOR/AKT/GLUT1 signal transduction pathway was activated in areas of increased glycolysis and intestinal glucose excretion in RYGB-operated rats. Intraluminal GLUT1 inhibitor administration offset improved glucose homeostasis in RYGB-operated rats. AREG-induced signal transduction pathway was confirmed using IEC-18 cells and mouse organoids, resulting in a greater capacity for glucose uptake via GLUT1 overexpression and sequestration in apical and basolateral membranes. Systemic and local AREG administration increased GLUT1 expression and small intestinal membrane translocation and prevented hyperglycaemic exacerbation. CONCLUSION: Bariatric surgery or AREG administration induces apical and basolateral membrane GLUT1 expression in the small intestinal enterocytes, resulting in increased serum glucose excretion in the gut lumen. Our findings suggest a novel, potentially targetable glucose homeostatic mechanism in the small intestine.

Is Chest Computed Tomography Always Necessary Following Nephrectomy for Renal Cell Carcinoma? A Pilot Study in Single Tertiary Institution.

PURPOSE: We evaluated patterns of thoracic recurrence from renal cell carcinoma (RCC) following nephrectomy as a pilot study. METHODS: Data of consecutive 39 patients who had recurrent RCC in the abdomen or thorax following curative nephrectomy were evaluated. Recurrence sites were analyzed with abdomen and chest computed tomography (CT), or positron emission tomography/CT. All patients had no metastasis before initial nephrectomy. Recurrence was classified into 3 types according to the site of initially detected recurrence: (a) abdomen-only type, (b) abdomen and thorax type, and (c) thorax-only type. Vertebral level of recurrence site in the thorax-only level was investigated. University of California Los Angeles-Integrated Staging System was utilized for risk stratification (eg, low, intermediate, and high-risk). RESULTS: Rate of intermediate or high risk was 89.7% (37/39). Rate of thoracic recurrence, regardless of concurrent abdominal recurrence, was 71.8% (28/39). Rate of thorax-only type was 53.8% (21/39). In thorax-only type, median vertebral level of recurrence site was T10 (range, T3-T12), and no patient with low risk had metastasis above the T10 level alone. In intermediate or high risk, 89.2% (33/37) had at least a recurrent lesion at the level of T7 or lower. CONCLUSIONS: In low-risk patients, upper thoracic recurrence alone may be very rare after curative surgery. In majority of intermediate- or high-risk patients, initial recurrence may occur in the abdomen or lower thorax, which indicates abdomen CT covering T7 level may be an effective tool for postoperative follow-up in RCC.

Prognostic significance of supradiaphragmatic lymph node metastasis detected by 18F-FDG PET/CT in advanced epithelial ovarian cancer.

BACKGROUND: Supradiaphragmatic lymph node metastases (SdLNM) are frequently identified using 18F-FDG positron emission tomography/computed tomography (PET/CT) in advanced epithelial ovarian cancers (AEOC). This study aimed to determine the prognostic significance of SdLNM detected by PET/CT in patients with AEOC. METHODS: Medical records of patients diagnosed with AEOC were retrospectively registered from January 2009 to July 2015. Patients were categorized according to PET/CT stage: PET/CT stage III, PET/CT stage IV with SdLNM, and PET/CT stage IV with other metastases. Clinicopathologic characteristics, recurrence patterns, survival outcomes were compared according to PET/CT stage. Anatomical distribution of SdLNM and effect of thoracic debulking surgery were estimated. RESULTS: A total of 295 patients were identified, including 176 patients who underwent primary debulking surgeries (PDS). Progression-free (P = 0.671) and overall (P = 0.525) survival did not differ significantly between patients with PET/CT IV with SdLNM and PET/CT IV with other metastases; however, patients with PET/CT IV with SdLNM had significantly poorer progression-free (P < 0.001) and overall (P = 0.016) survival than those with PET/CT stage III. Recurrence patterns were similar in all groups; intraperitoneal metastasis was the most common (78.8%) and thoracic recurrence alone accounted for less than 10%. Debulking of SdLNM lesions did not improve progression-free survival (P = 0.425) or overall survival (P = 0.465) of patients with AEOC. CONCLUSIONS: SdLNM detected using preoperative PET/CT are a negative prognostic factor in AEOC. Resection of suspicious SdLNM may not have effect to survival of patients with AEOC.

The diagnostic ability of 18F-FDG PET/CT for mediastinal lymph node staging using 18F-FDG uptake and volumetric CT histogram analysis in non-small cell lung cancer.

OBJECTIVES: To evaluate the clinical implications of lymph node (LN) density on 18F-FDG PET/CT for mediastinal LN characterization in non-small cell lung cancer (NSCLC). METHODS: One hundred and fifty-two patients with 271 mediastinal LNs who underwent PET/CT and endobronchial ultrasound-guided transbronchial needle aspiration for staging were enrolled. Maximum standardized uptake value (SUVmax), short axis diameter, LN-to-primary cancer ratio of SUVmax, and median Hounsfield unit (HU) based on CT histogram were correlated to histopathology. RESULTS: Of 271 nodes, 162 (59.8 %) were malignant. SUVmax, short axis diameter, and LPR of malignant LNs were higher than those of benign nodes. Among malignant LNs, 71.0 % had median HU between 25 and 45, while 78.9 % of benign LNs had values <25 HU or >45 HU. Using a cutoff value of 4.0, SUVmax showed the highest diagnostic ability for detecting malignant LNs with a specificity of 94.5 %, but showing a sensitivity of 70.4 %. Using additional density criteria (median HU 25-45) in LNs with 2.0< SUVmax ≤4.0, the sensitivity increased to 88.3 % with the specificity of 82.6 %. CONCLUSIONS: LN density is useful for the characterization of LNs with mild 18F-FDG uptake. The risk of mediastinal LN metastasis in NSCLC patients could be further stratified using both 18F-FDG uptake and LN density. KEY POINTS: • SUVmax showed the highest diagnostic ability for detecting malignant LNs. • LN density was useful in characterization of LNs with mild FDG uptake. • SUVmax and LN density together could stratify the risk of LN metastasis.

Is there an additive value of 18 F-FDG PET-CT to CT/MRI for detecting nodal metastasis in oropharyngeal squamous cell carcinoma patients with palpably negative neck?

Background Cervical node metastasis is one of the most significant prognostic factors in patients with oropharyngeal squamous cell carcinoma (SCC). There is little information regarding the comparison of histopathologic analysis following neck dissection with imaging results in oropharyngeal SCC. Purpose To investigate the clinical utility of PET-CT compared with computed tomography (CT) or magnetic resonance imaging (MRI) for detecting nodal metastasis in oropharyngeal SCC patients with palpably negative neck and to investigate whether pretreatment imaging modalities support the rationale for elective neck treatment. Material and Methods A total of 49 oropharyngeal SCC patients with palpably negative neck (42 men, 7 women; average age, 59.1 years) underwent primary tumor resection and neck dissection as a primary treatment. All patients were preoperatively evaluated with PET-CT and CT/MRI, and the diagnostic accuracy of each imaging modality was assessed by comparison with histopathologic results of the surgical specimen. Results Twenty-five (51.0%) of our 49 patients had neck metastases. On a level-by-level analysis, the sensitivity of PET-CT, CT/MRI, and a combination of PET-CT and CT/MRI was 54.6%, 54.6%, and 60.6%, respectively, at all neck levels. The area under the ROC showed that the diagnostic performance of the combined interpretation was not significantly different from that of CT/MRI alone (0.780 vs. 0.750, respectively; P = 0.158) and PET-CT alone (0.780 vs. 0.765, respectively; P = 0.501). Conclusion Addition of PET-CT to CT/MRI did not provide better diagnostic accuracy for detecting nodal metastasis in preoperative evaluation of oropharyngeal SCC patients with palpably negative neck, suggesting that current imaging studies might not replace elective neck dissection.

Clinical usefulness of [18F]FDG PET-CT and CT/MRI for detecting nodal metastasis in patients with hypopharyngeal squamous cell carcinoma.

BACKGROUND AND PURPOSE: The aim of this study was to investigate whether pretreatment imaging modalities, including [18F]fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) and CT/magnetic resonance imaging (MRI) are helpful for the selection of patient groups requiring contralateral neck dissection in patients with hypopharyngeal squamous cell carcinoma (SCC). METHODS: A total of 72 consecutive patients with histologically proven hypopharyngeal SCC who underwent both PET-CT and CT/MRI preoperatively were recruited. To assess the diagnostic accuracy of each imaging modality, the neck was divided into levels based on the imaging-based nodal classification, and the histopathologic results of the surgical specimen were used as a standard reference. RESULTS: Fifty-one (70.8%) of the 72 patients had neck metastasis, and 12 (26.7%) had contralateral metastatic nodes. The sensitivities of PET-CT and CT/MRI for detecting nodal metastasis in the contralateral neck were significantly lower than those in the ipsilateral neck (60.0 and 53.3 vs. 89.1 and 84.8%, respectively; p < 0.001). Among the patients who underwent bilateral neck dissection (n = 45), three (13.0%) of the 23 patients with a palpably negative neck on the ipsilateral side showed occult contralateral lymph node metastasis, while none of the 11 patients without ipsilateral metastatic nodes on imaging studies had contralateral neck metastasis. CONCLUSIONS: With accurate assessment of ipsilateral neck metastasis in hypopharyngeal SCC patients, PET-CT and CT/MRI may be helpful in identifying patients at high risk of contralateral neck metastasis. Elective contralateral neck treatment is not necessary in hypopharyngeal SCC patients who do not show evidence of ipsilateral neck metastasis on preoperative imaging studies.

Glycyrrhizin, inhibitor of high mobility group box-1, attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling in rats.

BACKGROUND: High mobility group box-1 (HMGB1), a proinflammatory cytokine, plays a pivotal role in tissue remodeling and angiogenesis, both of which are crucial for the pathogenesis of pulmonary arterial hypertension. In this study, we explored the relationship between HMGB1 and pulmonary hypertension and whether glycyrrhizin, an inhibitor of HMGB1, attenuates disease progression in an animal model of pulmonary hypertension induced by monocrotaline sodium (MCT). METHODS: After inducing pulmonary hypertension through a single subcutaneous injection of MCT (60 mg/kg) to Sprague-Dawley rats, we administered daily intraperitoneal injections of either glycyrrhizin (GLY, 50 mg/kg), an inhibitor of HMGB1, or saline (control) for either 4 or 6 weeks. RESULTS: Expression levels of HMGB1 in serum increased from the second week after MCT injection and remained elevated throughout the experiment periods. Lung tissue levels of HMGB1 assessed by immunohistochemical staining at 4 weeks after MCT injection also increased. Chronic inhibition of HMGB1 by GLY treatment reduced the MCT-induced increase in right ventricular (RV) systolic pressure, RV hypertrophy (ratio of RV to [left ventricle + septum]), and pulmonary inflammation. MCT-induced muscularization of the pulmonary artery was also attenuated in the GLY-treated group. As assessed 6 weeks after MCT injection, the GLY-treated group exhibited increased survival (90% [18 of 20]) when compared with the control group (60% [12 of 20]; p =0.0027). CONCLUSIONS: Glycyrrhizin, an inhibitor of HMGB1, attenuates pulmonary hypertension progression and pulmonary vascular remodeling in the MCT-induced pulmonary hypertension rat model. Further studies are needed to confirm the potential of HMGB1 as a novel therapeutic target for pulmonary hypertension.

The role of metabolic tumor volume and total lesion glycolysis on ¹8F-FDG PET/CT in the prognosis of epithelial ovarian cancer.

PURPOSE: This study assessed the prognostic value of pre-operative 2-[(18)F] fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) volumetric parameters, including metabolic tumor volume (MTV) and total lesion glycolysis (TLG), in patients with epithelial ovarian cancer. METHODS: A total of 175 patients with epithelial ovarian cancer who underwent (18) F-FDG PET/CT and subsequent cytoreductive surgery were retrospectively enrolled. Maximum standardized uptake value (SUVmax) on (18)F-FDG PET/CT was measured for all patients. Because nine patients showed low tumor-to-background uptake ratios, MTV and TLG were measured in 166 patients. Univariate and multivariate analyses were performed to evaluate the prognostic significance of SUVmax, MTV, TLG, and clinicopathological factors for disease progression-free survival. RESULTS: Disease progressed in 78 (44.6 %) of the 175 patients, and the 2-year disease progression-free survival rate was 57.5 %. Univariate analysis showed that tumor stage, histopathological type, presence of regional lymph node metastasis, residual tumor after cytoreductive surgery, pre-operative serum carbohydrate antigen 125 (CA125) level, SUVmax, MTV, and TLG were significant prognostic factors (p < 0.05). Among these variables, tumor stage (p = 0.0006) and TLG (p = 0.008) independently correlated with disease progression-free survival on multivariate analysis. The disease progression rate was only 2.3 % in stage I-II patients with low TLG (≤100.0), compared to 80.0 % in stage III-IV patients with high TLG (>100.0). CONCLUSION: Along with tumor stage, TLG is an independent prognostic factor for disease progression after cytoreductive surgery in patients with epithelial ovarian cancer. By combining tumor stage and TLG, one can further stratify the risk of disease progression for patients undergoing cytoreductive surgery.

Grading of cerebral glioma with multiparametric MR imaging and 18F-FDG-PET: concordance and accuracy.

OBJECTIVES: To retrospectively evaluate concordance rates and predictive values in concordant cases among multiparametric MR techniques and FDG-PET to grade cerebral gliomas. METHODS: Multiparametric MR imaging and FDG-PET were performed in 60 consecutive patients with cerebral gliomas (12 low-grade and 48 high-grade gliomas). As the dichotomic variables, conventional MRI, minimum apparent diffusion coefficient in diffusion-weighted imaging, maximum relative cerebral blood volume ratio in perfusion-weighted imaging, choline/creatine ratio and (lipid and lactate)/creatine ratio in MR spectroscopy, and maximum standardised uptake value ratio in FDG-PET in low- and high-grade gliomas were compared. Their concordance rates and positive/negative predictive values (PPV/NPV) in concordant cases were obtained for the various combinations of multiparametric MR techniques and FDG-PET. RESULTS: There were significant differences between low- and high-grade gliomas in all techniques. Combinations of two, three, four, and five out of the five techniques showed concordance rates of 77.0 ± 4.8%, 65.5 ± 4.0%, 58.3 ± 2.6% and 53.3%, PPV in high-grade concordant cases of 97.3 ± 1.7%, 99.1 ± 1.4%, 100.0 ± 0% and 100.0% and NPV in low-grade concordant cases of 70.2 ± 7.5%, 78.0 ± 6.0%, 80.3 ± 3.4% and 80.0%, respectively. CONCLUSION: Multiparametric MR techniques and FDG-PET have a concordant tendency in a two-tiered classification for the grading of cerebral glioma. If at least two examinations concordantly indicated high-grade gliomas, the PPV was about 95%. KEY POINTS: • Modern imaging techniques can help predict the aggressiveness of cerebral gliomas. • Multiparametric MRI and FDG-PET have a concordant tendency to grade cerebral gliomas. • Their high-grade concordant cases revealed at least 95 % positive predictive values. • Their low-grade concordant cases revealed about 70­80% negative predictive values.

In Vivo Evaluation of 68Ga-Labeled NOTA-EGFRvIII Aptamer in EGFRvIII-Positive Glioblastoma Xenografted Model.

EGFRvIII is expressed only in tumor cells and strongly in glioblastoma and is considered a promising target in cancer diagnosis and therapy. Aptamers are synthetic single-stranded oligonucleotides that bind to biochemical target molecules with high binding affinity and specificity. This study examined the potential of the 68Ga-NOTA-EGFRvIII aptamer as a nuclear imaging probe for visualizing EGFRvIII-expressing glioblastoma by positron emission tomography (PET). EGFRvIII aptamer was selected using the SELEX technology, and flow cytometry and fluorescence microscopy verified the high binding affinity to EGFRvIII positive U87MG vIII 4.12 glioma cells but not to EGFRvIII negative U87MG cells. The EGFRvIII aptamer was conjugated with a chelator (1,4,7-triazanonane-1,4,7-triyl)triacetic acid (NOTA) for 68Ga-labeling. The 68Ga-NOTA-EGFRvIII aptamer was prepared using the preconcentration-based labeling method with a high radiolabeling yield at room temperature. Ex vivo biodistribution analyses confirmed the significantly higher tumor uptake of the 68Ga-NOTA-EGFRvIII aptamer in EGFRvIII-expressing xenograft tumors than that in EGFRvIII negative tumors, confirming the specific tumor uptake of the 68Ga-NOTA-EGFRvIII aptamer in vivo. PET imaging studies revealed a high retention rate of the 68Ga-NOTA-EGFRvIII aptamer in U87MG vIII 4.12 tumors but only low uptake levels in U87-MG tumors, suggesting that the 68Ga-NOTA-EGFRvIII aptamer may be used as a PET imaging agent for EGFRvIII-expressing glioblastoma.

Correlation between remnant thyroid gland I-131 uptake and serum thyroglobulin levels: can we rely on I-131 whole body scans?

BACKGROUND: I-131 treatment (RAI) decision relies heavily on serum thyroglobulin (Tg) levels, as higher Tg levels are assumed to be correlated with higher I-131 uptake. Tg elevation, negative iodine scintigraphy (TENIS) definition is becoming more clinically relevant as alternative treatment methods are available. This study examined the correlation between Tg levels with I-131 uptake in remnant thyroid gland to evaluate the reliability of serum Tg levels in predicting I-131 uptake. METHODS: From March 2012 to July 2019, 281 papillary thyroid cancer patients treated with 150 mCi RAI were retrospectively enrolled. Early (2nd day) and Delayed (7th day) post-RAI whole-body scan (WBS) neck counts were correlated with clinical and pathologic findings. Patients with normal neck ultrasound and undetectable level of serum Tg (< 0.2 ng/mL) and thyroglobulin antibody (TgAb) (< 10 IU/mL) were defined as ablation success within 2 years after I-131 ablation. RESULTS: Thyroid gland weight, tumor size and thyroiditis were independent factors of preoperative serum Tg levels. Serum off-Tg levels correlated with Early and Delayed WBS neck counts, and thyroiditis pathology contributed to lower neck counts in both Early and Delayed WBSs. In multivariable analysis, Delayed WBS neck count, serum off-Tg and off-TgAb were significant factors for predicting ablation success. CONCLUSION: I-131 uptake and retention in remnant thyroid gland correlates with serum off-Tg levels, thyroiditis, and ablation success in thyroid cancer patients receiving high-dose I-131 therapy. Semi-quantitative I-131 analysis with Early and Delayed WBSs provides additional information in evaluating ablation success, with the potential application for metastasis treatment response evaluation.

Detection of the inflammatory process in a Behçet's disease-like mouse model using 18F-fluorodeoxyglucose positron emission tomography.

OBJECTIVES: The major role of herpes simplex virus (HSV) type 1 infection in Behçet's disease (BD) immunopathogenesis has been demonstrated and inoculating the earlobes of ICR mice with HSV produced a BD-like mouse model. (18)Ffluorodeoxyglucose positron emission tomography (FDG PET) is widely used for diagnosing numerous human diseases other than malignancies. The aim of our study was to evaluate the inflammatory activities of BD-like symptoms in a HSV type 1-induced BD-like mouse model by small-animal FDG PET. METHODS: Five HSV-infected ICR mice with BD-like lesions, two asymptomatic HSV-infected mice, and two untreated mice were scanned with microPET, and autopsy specimens were histopathologically assessed to evaluate for infiltration by mixed inflammatory cells. RESULTS: The histopathological evaluation of the inflammatory process in knee and elbow joints significantly correlated with the quantitative assessment of FDG accumulation in the same joints in BD-like ICR mice, HSV-infected asymptomatic mice, and untreated control mice. Small-animal FDG PET clearly detected asymptomatic joint inflammatory processes in both BD-like mice and HSV-infected asymptomatic mice. In addition, genital ulcers and skin ulcers with associated perilesional lymphadenopathies in BD-like models were detected by microPET. However, biodistributed PET-positive images from the stasis of secreted FDG into the bowel lumen could not be distinguished from the inflammatory bowel lesions of BD when compared to FDG uptake in control mice. CONCLUSIONS: Our data indicate that FDG PET can non-invasively and quantitatively detect the inflammatory process in an HSV-induced BD-like mouse model.

Modulation of FDG Uptake by Cell Cycle Synchronization Using a T-Type Calcium Channel Inhibitor.

BACKGROUND: We investigated whether cell cycle synchronization induced by the T-type calcium channel inhibitor mibefradil could increase tumoral 2-[18F] fluoro-2-deoxy-d-glucose (FDG) uptake in vitro and in vivo. METHODS: Human prostate cancer cells (PC-3) were treated with 10 µM mibefradil for 24, 48, and 72 h to induce G1 arrest. Cell cycle distribution was analyzed at 0, 4, 8, 12, 15, 18, and 24 h after mibefradil withdrawal. Cellular uptake was measured after incubating cells with [3H] Deoxy-d-Glucose (DDG) for 1 h at the same time points used in the cell cycle analysis. The correlation between [3H] DDG uptake and each cell cycle phase was evaluated in the early (0-12 h) and late phases (15-24 h) of synchronization. In vivo FDG PET imaging was performed in PC-3-bearing mice at baseline, 24 h, and 48 h after mibefradil treatment. RESULTS: The G0/G1 fraction of PC-3 cells was significantly increased from 33.1% ± 0.2% to 60.9% ± 0.8% after 24 h mibefradil treatment, whereas the S and G2/M fractions were decreased from 36.3% ± 1.4% to 23.2% ± 1.1% and from 29.7% ± 1.3% to 14.9% ± 0.9%, respectively, which were similar to the results by serum starvation. Mibefradil treatment for 24, 48, and 72 h increased the number of cells in S phase at 18-24 h after withdrawal; however, only the 72 h treatment increased [3H] DDG uptake (145.8 ± 5.8% of control at 24 h after withdrawal). [3H] DDG uptake was positively correlated with the size of the S phase fraction and negatively correlated with the size of the G0/G1 fraction in the late phase of synchronization. DDG uptake was significantly increased by mibefradil-induced cell cycle synchronization and correlated with the sizes of cell cycle fractions. In vivo FDG PET imaging also demonstrated a significant increase in tumor uptake after mibefradil treatment. Quantified tumor FDG uptake (%ID/g) increased from 4.13 ± 2.10 to 4.7 ± 2.16 at 24 h, and 5.95 ± 2.57 at 48 h (p < 0.05). CONCLUSION: Cell cycle synchronization could be used to increase the diagnostic sensitivity of clinical FDG positron emission tomography.

Enhancement of in vivo targeting properties of ErbB2 aptamer by chemical modification.

Aptamers have great potential for diagnostics and therapeutics due to high specificity to target molecules. However, studies have shown that aptamers are rapidly distributed and excreted from blood circulation due to nuclease degradation. To overcome this issue and to improve in vivo pharmacokinetic properties, inverted deoxythymidine (idT) incorporation at the end of aptamer has been developed. The goal of this study was to evaluate the biological characterization of 3'-idT modified ErbB2 aptamer and compare with that of unmodified aptamer via nuclear imaging. ErbB2-idT aptamer was labeled with radioisotope F-18 by base-pair hybridization using complementary oligonucleotide platform. The hyErbB2-idT aptamer demonstrated specific binding to targets in a ErbB2 expressing SK-BR-3 and KPL4 cells in vitro. Ex vivo biodistribution and in vivo imaging was studied in KPL4 xenograft bearing Balb/c nu/nu mice. 18F-hyErbB2-idT aptamer had significantly higher retention in the tumor (1.36 ± 0.17%ID/g) than unmodified 18F-hyErbB2 (0.98 ± 0.19%ID/g) or scrambled aptamer (0.79 ± 0.26% ID/g) at 1 h post-injection. 18F-hyErbB2-idT aptamer exhibited relatively slow blood clearance and delayed excretion by the renal and hepatobiliary system than 18F-hyErbB2 aptamer. In vivo PET imaging study showed that 18F-hyErbB2-idT aptamer had more stronger PET signals on KPL4 tumor than 18F-hyErbB2 aptamer. The results of this study demonstrate that attachment of idT at 3'-end of aptamer have a substantial influence on biological stability and extended blood circulation led to enhanced tumor uptake of aptamer.