Extension of microglial activation is associated with epilepsy and cognitive dysfunction in Tuberous sclerosis complex: A TSPO-PET study.

BACKGROUND AND OBJECTIVES: Neuroinflammation contributes to the severity of various neurological disorders, including epilepsy. Tuberous sclerosis complex (TSC) is a condition that results in the overactivation of the mammalian target of rapamycin (mTOR) pathway, which has been linked to the activation of microglia responsible for neuroinflammation. To clarify the involvement of neuroinflammation in the neuropathophysiology of TSC, we performed a positron emission tomography (PET) study using the translocator protein (TSPO) radioligand, [11C] DPA713, and investigated microglial activation in relation to neurological manifestations, especially epilepsy and cognitive function. METHODS: This cross-sectional study included 18 patients with TSC (6 in the no-seizure group, 6 in the refractory seizure group, and 6 in the mTOR-inhibitor [mTOR-i] group). All participants underwent [11C] DPA713-PET. PET results were superimposed with a 3D T2-weighted fluid-attenuated inversion-recovery (FLAIR) and T1-weighted image (T1WI) to evaluate the location of cortical tubers. Microglial activation was assessed using the standardized uptake value ratio (SUVr) of DPA713 binding. The volume ratio of the DPA713-positive area to the intracranial volume (volume ratio of DPA713/ICV) was calculated to evaluate the extent of microglial activation. A correlation analysis was performed to examine the relationship between volume ratio of DPA713/ICV and severity of epilepsy and cognitive function. RESULTS: Most cortical tubers with hyperintensity on FLAIR and hypo- or isointensity on T1WI showed microglial activation. The extent of microglial activation was significantly greater in the refractory seizure group than in the no-seizure or mTOR-i groups (p < 0.001). The extent of microglial activation in subjects without mTOR-i treatment correlated positively with epilepsy severity (r = 0.822, P = 0.001) and negatively with cognitive function (r = -0.846, p = 0.001), but these correlations were not present in the mTOR-i group (r = 0.232, P = 0.658, r = 0.371, P = 0.469, respectively). CONCLUSION: Neuroinflammation is associated with the severity of epilepsy and cognitive dysfunction in brains with TSC. mTOR-i may suppress the extent of neuroinflammation in TSC. Investigating the spread of microglial activation using TSPO-PET in these patients may help to predict the progression of neuropathy by assessing the degree of neuroinflammation and therefore be useful for determining how aggressive the treatment should be and in assessing the effectiveness of such treatment in patients with TSC.

Semiquantitative analysis using whole-body dynamic F-18 fluoro-2-deoxy-glucose-positron emission tomography to differentiate between benign and malignant lesions.

OBJECTIVES: To investigate whether whole-body dynamic positron emission tomography (PET) is useful for differentiating benign and malignant lesions. METHODS: In this retrospective study, data from a cohort of 146 lesions from 187 patients who consecutively underwent whole-body dynamic PET scans at our hospital for suspected lesions in the lung, lymph nodes, liver, bone, esophagus, and colon were analyzed. Patients with malignant lymphomas, accumulations > 5 cm in length along the long axis of the esophagus, or lesions in the colon in which the site of accumulation moved during the imaging period were excluded. Patients were administered 3.7 MBq/kg of fluorine-18-fluorodeoxyglucose (F-18 FDG), and dynamic imaging was initiated 60 min after administration. We defined the 60-65, 65-70, 70-75, and 75-80 min time mark as the first, second, third, and fourth pass, respectively. The static image is the summed average of all the four pass images. We measured the accumulation in the mean image of the whole-body dynamic PET scan, which was arithmetically similar to the maximum standardized uptake value (SUVmax) throughout the whole-body static images obtained during 20 min of imaging (S-SUVmax). The ratio of SUVmax in the dynamic first pass(60-65 min after FDG administration) and fourth pass(75-80 min after FDG administration) was calculated as R-SUVmax. RESULTS: The S-SUVmax in the lung, lymph nodes, and bone did not differ significantly between the benign and malignant groups. However, there was a significant difference in R-SUVmax, which was > 1 in most malignant lesions indicating an increase in accumulation during routine scan time. Significant differences were observed between benign and malignant lesions of the liver in both S-SUVmax and R-SUVmax values, with the latter being > 1 in most malignant lesions. CONCLUSIONS: Whole-body dynamic PET for 20 min starting 1 h after FDG administration improved the accuracy of malignant lesion detection in the liver, lymph nodes, lung, and bone. The incremental improvement was small, and the FDG dynamics in the distribution of values between benign and malignant overlapped. Additional information from whole-body dynamic imaging can help detect malignant lesions in these sites without increasing patient burden or prolonging imaging time.

Tumor response evaluation in patients with malignant melanoma undergoing immune checkpoint inhibitor therapy and prognosis prediction using 18F-FDG PET/CT: multicenter study for comparison of EORTC, PERCIST, and imPERCIST.

OBJECTIVE: In malignant melanoma patients treated with immune checkpoint inhibitor (ICI) therapy, three different FDG-PET criteria, European Organization for Research and Treatment of Cancer (EORTC), PET Response Criteria in Solid Tumors (PERCIST), immunotherapy-modified PERCIST (imPERCIST), were compared regarding response evaluation and prognosis prediction using standardized uptake value (SUV) harmonization of results obtained with various PET/CT scanners installed at different centers. MATERIALS AND METHODS: Malignant melanoma patients (n = 27) underwent FDG-PET/CT examinations before and again 3 to 9 months after therapy initiation (nivolumab, n = 21; pembrolizumab, n = 6) with different PET scanners at five hospitals. EORTC, PERCIST, and imPERCIST criteria were used to evaluate therapeutic response, then concordance of the results was assessed using Cohen's κ coefficient. Log-rank and Cox methods were employed to determine progression-free (PFS) and overall (OS) survival. RESULTS: Complete metabolic response (CMR)/partial metabolic response (PMR)/stable metabolic disease (SMD)/progressive metabolic disease (PMD) with harmonized EORTC, PERCIST, and imPERCIST was seen in 3/5/4/15, 4/5/3/15, and 4/5/5/13 patients, respectively. Nearly perfect concordance between each pair of criteria was noted (κ = 0.939-0.972). Twenty patients showed progression and 14 died from malignant melanoma after a median 19.2 months. Responders (CMR/PMR) showed significantly longer PFS and OS than non-responders (SMD/PMD) (harmonized EORTC: p < 0.0001 and p = 0.011; harmonized PERCIST: p < 0.0001 and p = 0.0012; harmonized imPERCIST: p < 0.0001 and p = 0.0012, respectively). CONCLUSIONS: All harmonized FDG-PET criteria (EORTC, PERCIST, imPERCIST) showed accuracy for response evaluation of ICI therapy and prediction of malignant melanoma patient prognosis. Additional studies to determine their value in larger study populations will be necessary.

Advantages of FBPA PET in evaluating early response of anti-PD-1 immunotherapy in B16F10 melanoma-bearing mice: Comparison to FDG PET.

Purpose: PET with L-4-borono-2-[18F] fluoro-phenylalanine (FBPA) was reported to be useful to differentiate malignant tumors and inflammation. Although immunotherapy with immune checkpoint inhibitors (ICIs) has been applied to cancer treatment recently, FDG PET may not be suitable to determine the effect of ICIs because of false-positive findings caused by treatment-related inflammation. In this study, we aimed to demonstrate that FBPA PET allowed detection of the early response of anti-PD-1 immunotherapy in tumor-bearing mice, comparing the results with those of FDG PET. Materials and methods: Mice with B16F10 melanoma tumor xenografts were prepared. Anti-mouse PD-1 antibody or PBS was administered twice intraperitoneally to the tumor-bearing mice on Day 0 (3 days after inoculation) and Day 5 (treatment or control group ). PET/CT imaging was performed twice for each mouse on Day 0 before the anti-PD-1 antibody/PBS administration and on Day 7 using a micro-PET/CT scanner. FBPA and FDG PET/CT studies were conducted separately. SUVmax and the tumor to liver ratio (T/L ratio) were used as parameters exhibiting tumor activity. Tumor uptake volume (TUV) and metabolic tumor volume (MTV) were also calculated for FBPA and FDG, respectively. Changes between pre- and posttreatment SUVmax or T/L ratio were observed using the formula as follows: [(posttreatment parameter values/pretreatment values - 1) × 100] (%). Results: Tumors in TrG were smaller than those in CoG on Day 7. SUVmax and T/L ratio represented no differences between TrG and CoG in FBPA and FDG PET before treatment. FBPA PET on Day 7 demonstrated that SUVmax, T/L ratio, and TUV in TrG were statistically smaller than those in CoG. %T/L ratio and %SUVmax exhibited the same trend in FBPA PET. However, FDG PET on Day 7 revealed no differences in all parameters between TrG and CoG. T/L ratio and %SUVmax in TrG represented larger values than those in CoG without statistical significances. Conclusion: This study demonstrated that FBPA PET allowed detection of the early response of anti-PD-1 immunotherapy in B16F10 melanoma-bearing mice. FDG PET did not detect the response. Further studies are required to determine whether FBPA PET is useful in evaluating the treatment effect of ICIs in humans.

Effects of New Bayesian Penalized Likelihood Reconstruction Algorithm on Visualization and Quantification of Upper Abdominal Malignant Tumors in Clinical FDG PET/CT Examinations.

PURPOSE: This study evaluated the effects of new Bayesian penalized likelihood (BPL) reconstruction algorithm on visualization and quantification of upper abdominal malignant tumors in clinical FDG PET/CT examinations, comparing the results to those obtained by an ordered subset expectation maximization (OSEM) reconstruction algorithm. Metabolic tumor volume (MTV) and texture features (TFs), as well as SUV-related metrics, were evaluated to clarify the BPL effects on quantification. MATERIALS AND METHODS: A total of 153 upper abdominal lesions (82 liver metastatic and 71 pancreatic cancers) were included in this study. FDG PET/CT images were acquired with a GE Discovery 710 scanner equipped with a time-of-flight system. Images were reconstructed using OSEM and BPL (beta 700) algorithms. In 58 lesions <1.5 cm in greatest diameter (small-lesion group), visual image quality of each lesion was evaluated using a four-point scale. SUVmax was obtained for quantitative metrics. Visual scores and SUVmax were compared between OSEM and BPL images. In 95 lesions >2.0 cm in greatest diameter (larger-lesion group), SUVmax, SUVpeak, MTV, and six TFs were compared between OSEM and BPL images. In addition to the size-based analyses, an increase of SUVmax with BPL was evaluated according to the original SUVmax in OSEM images. RESULTS: In the small-lesion group, both visual score and SUVmax were significantly higher in the BPL than OSEM images. The increase in visual score was observed in 20 (34%) of all 58 lesions. In the larger-lesion group, no statistical difference was observed in SUVmax, SUVpeak, or MTV between OSEM and BPL images. BPL increased high gray-level zone emphasis and decreased low gray-level zone emphasis among six TFs compared to OSEM with statistical significance. No statistical differences were observed in other TFs. SUVmax-based analysis demonstrated that BPL increased and decreased SUVmax in lesions with low (<5) and high (>10) SUVmax in original OSEM images, respectively. CONCLUSION: This study demonstrated that BPL improved conspicuity of small or low-count upper abdominal malignant lesions in clinical FDG PET/CT examinations. Only two TFs represented significant differences between OSEM and BPL images of all quantitative metrics in larger lesions.

High detection rate in [18F]PSMA-1007 PET: interim results focusing on biochemical recurrence in prostate cancer patients.

OBJECTIVE: 18F-labeled prostate-specific membrane antigen (PSMA) ligand, [18F]PSMA-1007, has the benefit of a higher synthetic yield and minimal excretion in the urine. High detection efficacy was reported in biochemical recurrence (BCR) of prostate cancer after radical prostatectomy. Thus, we evaluated the preliminary diagnostic utility of [18F]PSMA-1007 PET in patients with prostate cancer, focusing on the BCR which is not detected on conventional imaging. METHODS: We enrolled a total of 28 patients (age 51-79 years) with BCR of prostate cancer. BCR was defined as a continuous increase in PSA after radical prostatectomy or radiation therapy without any apparent recurrent lesions on conventional diagnostic imaging (CT and bone scintigraphy). PSMA-PET scanning was performed approximately 60 min after intravenous injection of [18F]PSMA-1007 (259 ± 37 MBq). PSMA-PET images were evaluated for lesion detection as well as its relation to PSA values and location. RESULTS: Abnormal uptake, which was suspected to be recurrence or metastasis, was detected in 92.9% (26/28) of patients with BCR. The SUVmax was 8.4 ± 6.4 in local recurrence, 11.5 ± 11.8 in pelvic lymph nodes (LN), and 4.1 ± 1.6 in bone metastasis. The detection rates were 66.7% in the PSA group-1 (0.1-0.5 ng/mL), 85.7% in the PSA group-2 (0.5-1.0 ng/mL), and 100% in the PSA group-3 (above 1.0 ng/mL). Among the PET-positive BCR patients (n = 26), local recurrence was detected in 57.7% (15/26), pelvic LN in 42.3% (11/26), and bone metastasis in 15.4% (4/26). In 53% (8/15) of BCR patients who were suspected of local recurrence, focal uptake was detected adjacent to the bladder on [18F]PSMA-1007 PET. This suggested the significant advantage of having minimal physiological urine excretion. CONCLUSIONS: [18F]PSMA-1007 PET showed a high detection rate in recurrent and metastatic lesions. In patients with BCR, its high detection led to suitable treatment strategies, such as salvage radiation therapy or surgical removal of recurrent lymph nodes. TRIAL REGISTRATION: (UMIN Clinical Trials Registry) UMIN000037697.

Duodenal Adenocarcinoma Mimicking Metastasis of Prostate Cancer on 18F-Prostate-Specific Membrane Antigen-1007 PET/CT.

A 76-year-old man with dyspnea (initial prostate-specific antigen [PSA]: 216 ng/mL) underwent F-FDG PET/CT, with uptake in the prostate, lymph nodes, fifth thoracic vertebra (T5), and cricoid cartilage. A biopsy revealed prostate adenocarcinoma (Gleason score 4 + 5, cT4 N1 M1). On initiation of combined androgen blockade therapy, PSA value decreased. However, 4 years later, in a castration-resistant state (PSA 2.14 ng/mL), CT and bone scintigraphy revealed a duodenal tumor and T5 metastasis. F-prostate-specific membrane antigen-1007 PET/CT showed uptake in the already known T5 metastasis (SUVmax, 33.55) and even in the duodenal tumor (16.55). The latter was histologically diagnosed as duodenal adenocarcinoma.

Automated [18F]PSMA-1007 production by a single use cassette-type synthesizer for clinical examination.

BACKGROUND: [18F]PSMA-1007, a positron emission tomography (PET) tracer, specifically targets prostate-specific membrane antigen (PSMA), which is highly expressed in prostate cancer. PSMA-PET is effective especially for regional detection of biochemical recurrence, which significantly affects patient management. Herein, we established and optimized a one-step radiolabeling protocol to separate and purify [18F]PSMA-1007 with a CFN-MPS200 synthesizer for clinical application. RESULTS: A dedicated single use cassette and synthesis program for [18F]PSMA-1007 was generated using a single-step method for direct precursor radiolabeling. In the cassette, three tube types (fluoro-elastomer, PharMed® BPT, silicone) and two different precursor salts (trifluoroacetic acid or acetic acid) were compared for optimization. Furthermore, three-lot tests were performed under optimized conditions for quality confirmation. Activity yields and mean radiochemical purity of [18F]PSMA-1007 were > 5000 MBq and 95%, respectively, at the end of synthesis, and the decay-corrected mean radiochemical yield from all three cassettes was approximately 40% using a trifluoroacetic acid salt precursor. Fluoro-elastomer tubings significantly increased the amount of non-radioactive PSMA-1007 (8.5 ± 3.1 µg/mL) compared to those with other tubings (0.3 µg/mL). This reduced the molar activity of [18F]PSMA-1007 synthesized in the cassette assembled by fluoro-elastomer tubings (46 GBq/µmol) compared to that with PharMed® BPT and silicone tubings (1184 and 1411 GBq/µmol, respectively). Residual tetrabutylammonium, acetonitrile, and dimethyl sulfoxide levels were <  2.6 µg/mL, < 8 ppm, and <  11 ppm, respectively, and ethanol content was 8.0-8.1% in all three cassettes and two different salts. Higher activity yields, radiochemical purities, and decay-corrected radiochemical yields were obtained using an acetic acid salt precursor rather than a trifluoroacetic acid salt precursor (7906 ± 1216 MBq, 97% ± 0%, and 56% ± 4%). In the three-lot tests under conditions optimized with silicone cassettes and acetic acid salt precursor, all quality items passed the specifications required for human use. CONCLUSIONS: We successfully automated the production of [18F]PSMA-1007 for clinical use and optimized synthesis procedures with a CFN-MPS200 synthesizer using a silicone cassette and acetic acid salt precursor. Cassette availability will facilitate a wide spread use of [18F]PSMA-1007-PET, leading to an effective prostate cancer management.

Impact of 18F-PSMA-1007 Uptake in Prostate Cancer Using Different Peptide Concentrations: Preclinical PET/CT Study on Mice.

PET radioligands with low molar activity (MA) may underestimate the quantity of the target of interest because of competitive binding of the target with unlabeled ligand. The aim of this study was to evaluate the change in the whole-body distribution of 18F-PSMA-1007 targeting prostate-specific membrane antigen (PSMA) when solutions with different peptide concentrations are used. Methods: Mouse xenograft models of LNCaP (PSMA-positive prostate cancer) (n = 18) were prepared and divided into 3 groups according to the peptide concentration injected: a high-MA group (1,013 ± 146 GBq/µmol; n = 6), a medium-MA group (100.7 ± 23.1 GBq/µmol; n = 6), and a low-MA group (10.80 ± 2.84 GBq/µmol; n = 6). Static PET scans were performed 1 h after injection (scan duration, 10 min). SUVmean in tumor and normal organs was compared by the multiple-comparison test. Immunohistochemical staining and Western blot analysis were performed to confirm expression of PSMA in tumor, salivary gland, and kidney. Results: The low-MA group (SUVmean, 1.12 ± 0.30) showed significantly lower uptake of 18F-PSMA-1007 in tumor than did the high-MA group (1.97 ± 0.77) and the medium-MA group (1.81 ± 0.57). On the other hand, in salivary gland, both the low-MA group (SUVmean, 0.24 ± 0.04) and the medium-MA group (0.57 ± 0.08) showed significantly lower uptake than the high MA group (1.27 ± 0.28). The tumor-to-salivary gland SUVmean ratio was 1.73 ± 0.55 in the high-MA group, 3.16 ± 0.86 in the medium-MA group, and 4.78 ± 1.29 in the low-MA group. The immunohistochemical staining and Western blot analysis revealed significant overexpression of PSMA in tumor and low expression in salivary gland and kidney. Conclusion: A decrease in the MA level of the injected 18F-PSMA-1007 solution resulted in decreased uptake in tumor and, to a greater degree, in normal salivary gland. Thus, there is a possibility of minimizing the adverse effects in salivary gland by setting an appropriate MA level in PSMA-targeting therapy.