Recent Update on PET/CT Radiotracers for Imaging Cerebral Glioma.

Positron emission tomography/computed tomography (PET/CT) has dramatically altered the landscape of noninvasive glioma evaluation, offering complementary insights to those gained through magnetic resonance imaging (MRI). PET/CT scans enable a multifaceted analysis of glioma biology, supporting clinical applications from grading and differential diagnosis to mapping the full extent of tumors and planning subsequent treatments and evaluations. With a broad array of specialized radiotracers, researchers and clinicians can now probe various biological characteristics of gliomas, such as glucose utilization, cellular proliferation, oxygen deficiency, amino acid trafficking, and reactive astrogliosis. This review aims to provide a recent update on the application of versatile PET/CT radiotracers in glioma research and clinical practice.

Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolism.

Acetyl-CoA synthetase 2 (ACSS2)-dependent acetate usage has generally been associated with tumorigenesis and increased malignancy in cancers under nutrient-depleted conditions. However, the nutrient usage and metabolic characteristics of the liver differ from those of other organs; therefore, the mechanism of ACSS2-mediated acetate metabolism may also differ in liver cancer. To elucidate the underlying mechanisms of ACSS2 in liver cancer and acetate metabolism, the relationships between patient acetate uptake and metabolic characteristics and between ACSS2 and tumor malignancies were comprehensively studied in vitro, in vivo and in humans. Clinically, we initially found that ACSS2 expression was decreased in liver cancer patients. Moreover, PET-CT imaging confirmed that lower-grade cancer cells take up more 11C-acetate but less 18F-fluorodeoxyglucose (18F-FDG); however, this trend was reversed in higher-grade cancer. Among liver cancer cells, those with high ACSS2 expression avidly absorbed acetate even in a glucose-sufficient environment, whereas those with low ACSS2 expression did not, thereby showing correlations with their respective ACSS2 expression. Metabolomic isotope tracing in vitro and in vivo revealed greater acetate incorporation, greater lipid anabolic metabolism, and less malignancy in high-ACSS2 tumors. Notably, ACSS2 downregulation in liver cancer cells was associated with increased tumor occurrence in vivo. In human patient cohorts, patients in the low-ACSS2 subgroup exhibited reduced anabolism, increased glycolysis/hypoxia, and poorer prognosis. We demonstrated that acetate uptake by ACSS2 in liver cancer is independent of glucose depletion and contributes to lipid anabolic metabolism and reduced malignancy, thereby leading to a better prognosis for liver cancer patients.

Combination of [18F]FDG and [18F]PSMA-1007 PET/CT predicts tumour aggressiveness at staging and biochemical failure postoperatively in patients with prostate cancer.

PURPOSE: [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) has limitations in prostate cancer (PCa) detection owing to low glycolysis in the primary tumour. Recently, prostate-specific membrane antigen (PSMA) PET/CT has been useful for biochemical failure detection and radioligand therapy (RLT) guidance. However, few studies have evaluated its use in primary prostate tumours using PSMA and [18F]FDG PET/CT. This study aimed to evaluate [18F]PSMA-1007 and [18F]FDG PET/CT for primary tumour detection and understand the association of metabolic heterogeneity with clinicopathological characteristics at staging and postoperatively. METHOD: This prospective study included 42 index tumours (27 acinar and 15 ductal-dominant) in 42 patients who underwent [18F]PSMA-1007 and [18F]FDG PET/CT and subsequent radical prostatectomy. All patients were followed for a median of 26 mo, and serum prostate-specific antigen levels were measured every 3 mo to evaluate biochemical failure. One-way analysis of variance, Tukey's multiple comparison test, and Fisher's exact test were performed. RESULTS: All 42 index tumours were detected on [18F]PSMA-1007 PET/CT, whereas only 15 were detected on [18F]FDG PET/CT (62.3% vs. 37.7%, p < 0.0001). A high SUVmax for [18F]PSMA-1007 was observed in tumours with high Gleason scores (GS 6-7 vs. GS 8-10; 12.1 vs. 20.1, p < 0.05). Tumours with [18F]FDG uptake were mostly ductal dominant (acinar-dominant 4/27; ductal-dominant; 11/15, p < 0.001), with lower [18F]PSMA-1007 uptake than tumours without [18F]FDG uptake (SUVmax 16.58 vs. 11.19, p < 0.001). There were 16.6% (7/42) of patients with pStage IV in whom the primary tumours were [18F]FDG positive. Biochemical failure was observed in 14.8% (4/27) of patients with [18F]FDG negative tumours but in 53.3% (8/15) of patients with [18F]FDG positive tumours (p = 0.013). CONCLUSIONS: [18F]PSMA-1007 PET/CT was superior to [18F]FDG PET/CT in detecting primary PCa. In contrast, tumours with [18F]FDG uptake are associated with larger size, a ductal-dominant type, and likely to undergo metastasis at staging and biochemical failure postoperatively.

11 C-Acetate PET/CT for Reactive Astrogliosis Outperforms 11 C-Methionine PET/CT in Glioma Classification and Survival Prediction.

PURPOSE: 11 C-acetate (ACE) PET/CT visualizes reactive astrogliosis in tumor microenvironment. This study compared 11 C-ACE and 11 C-methionine (MET) PET/CT for glioma classification and predicting patient survival. PATIENTS AND METHODS: In this prospective study, a total of 142 patients with cerebral gliomas underwent preoperative MRI, 11 C-MET PET/CT, and 11 C-ACE PET/CT. Tumor-to-contralateral cortex (TNR MET ) and tumor-to-choroid plexus ratios (TNR ACE ) were calculated for 11 C-MET and 11 C-ACE. The Kruskal-Wallis test and Bonferroni post hoc analysis were used to compare the differences in 11 C-TNR MET and 11 C-TNR ACE . The Cox proportional hazards regression analysis and classification and regression tree models were used to assess progression-free survival (PFS) and overall survival (OS). RESULTS: The median 11 C-TNR MET and 11 C-TNR ACE for oligodendrogliomas (ODs), IDH1 -mutant astrocytomas, IDH1 -wildtype astrocytomas, and glioblastomas were 2.75, 1.40, 2.30, and 3.70, respectively, and 1.40, 1.20, 1.77, and 2.87, respectively. The median 11 C-TNR MET was significantly different among the groups, except between ODs and IDH1 -wildtype astrocytomas, whereas the median 11 C-TNR ACE was significantly different among all groups. The classification and regression tree model identified 4 risk groups ( IDH1 -mutant with 11 C-TNR ACE ≤ 1.4, IDH1 -mutant with 11 C-TNR ACE > 1.4, IDH1 -wildtype with 11 C-TNR ACE ≤ 1.8, and IDH1 -wildtype with 11 C-TNR ACE > 1.8), with median PFS of 52.7, 44.5, 25.9, and 8.9 months, respectively. Using a 11 C-TNR ACE cutoff of 1.4 for IDH1 -mutant gliomas and a 11 C-TNR ACE cutoff of 2.0 for IDH1 -wildtype gliomas, all gliomas were divided into 4 groups with median OS of 52.7, 46.8, 27.6, and 12.0 months, respectively. Significant differences in PFS and OS were observed among the 4 groups after correcting for multiple comparisons. CONCLUSIONS: 11 C-ACE PET/CT is better for glioma classification and survival prediction than 11 C-MET PET/CT, highlighting its potential role in cerebral glioma patients.

Visualizing Cancer-Originating Acetate Uptake Through MCT1 in Reactive Astrocytes in the Glioblastoma Tumor Microenvironment.

BACKGROUND: Reactive astrogliosis is a hallmark of various brain pathologies, including neurodegenerative diseases and glioblastomas. However, the specific intermediate metabolites contributing to reactive astrogliosis remain unknown. This study investigated how glioblastomas induce reactive astrogliosis in the neighboring microenvironment and explores 11C-acetate PET as an imaging technique for detecting reactive astrogliosis. METHODS: Through in vitro, mouse models, and human tissue experiments, we examined the association between elevated 11C-acetate uptake and reactive astrogliosis in gliomas. We explored acetate from glioblastoma cells, which triggers reactive astrogliosis in neighboring astrocytes by upregulating MAO-B and MCT1 expression. We evaluated the presence of cancer stem cells in the reactive astrogliosis region of glioblastomas and assessed the correlation between the volume of 11C-acetate uptake beyond MRI and prognosis. RESULTS: Elevated 11C-acetate uptake is associated with reactive astrogliosis and astrocytic MCT1 in the periphery of glioblastomas in human tissues and mouse models. Glioblastoma cells exhibit increased acetate production as a result of glucose metabolism, with subsequent secretion of acetate. Acetate derived from glioblastoma cells induces reactive astrogliosis in neighboring astrocytes by increasing the expression of MAO-B and MCT1. We found cancer stem cells within the reactive astrogliosis at the tumor periphery. Consequently, a larger volume of 11C-acetate uptake beyond contrast-enhanced MRI was associated with worse prognosis. CONCLUSION: Our results highlight the role of acetate derived from glioblastoma cells in inducing reactive astrogliosis and underscore the potential value of 11C-acetate PET as an imaging technique for detecting reactive astrogliosis, offering important implications for the diagnosis and treatment of glioblastomas.

Astrocytic scar restricting glioblastoma via glutamate-MAO-B activity in glioblastoma-microglia assembloid.

BACKGROUND: Glial scar formation is a reactive glial response confining injured regions in a central nervous system. However, it remains challenging to identify key factors formulating glial scar in response to glioblastoma (GBM) due to complex glia-GBM crosstalk. METHODS: Here, we constructed an astrocytic scar enclosing GBM in a human assembloid and a mouse xenograft model. GBM spheroids were preformed and then co-cultured with microglia and astrocytes in 3D Matrigel. For the xenograft model, U87-MG cells were subcutaneously injected to the Balb/C nude female mice. RESULTS: Additional glutamate was released from GBM-microglia assembloid by 3.2-folds compared to GBM alone. The glutamate upregulated astrocytic monoamine oxidase-B (MAO-B) activity and chondroitin sulfate proteoglycans (CSPGs) deposition, forming the astrocytic scar and restricting GBM growth. Attenuating scar formation by the glutamate-MAO-B inhibition increased drug penetration into GBM assembloid, while reducing GBM confinement. CONCLUSIONS: Taken together, our study suggests that astrocytic scar could be a critical modulator in GBM therapeutics.

Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG.

Reactive astrogliosis is a hallmark of Alzheimer's disease (AD). However, a clinically validated neuroimaging probe to visualize the reactive astrogliosis is yet to be discovered. Here, we show that PET imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. To investigate the alterations of acetate and glucose metabolism in the diseased brains and their impact on the AD pathology, we adopted multifaceted approaches including microPET imaging, autoradiography, immunohistochemistry, metabolomics, and electrophysiology. Two AD rodent models, APP/PS1 and 5xFAD transgenic mice, one adenovirus-induced rat model of reactive astrogliosis, and post-mortem human brain tissues were used in this study. We further curated a proof-of-concept human study that included 11C-acetate and 18F-FDG PET imaging analyses along with neuropsychological assessments from 11 AD patients and 10 healthy control subjects. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. The elevated acetate uptake is associated with reactive astrogliosis and boosts the aberrant astrocytic GABA synthesis when amyloid-ß is present. The excessive astrocytic GABA subsequently suppresses neuronal activity, which could lead to glucose uptake through decreased glucose transporter-3 in the diseased brains. We further demonstrate that 11C-acetate uptake was significantly increased in the entorhinal cortex, hippocampus and temporo-parietal neocortex of the AD patients compared to the healthy controls, while 18F-FDG uptake was significantly reduced in the same regions. Additionally, we discover a strong correlation between the patients' cognitive function and the PET signals of both 11C-acetate and 18F-FDG. We demonstrate the potential value of PET imaging with 11C-acetate and 18F-FDG by visualizing reactive astrogliosis and the associated neuronal glucose hypometablosim for AD patients. Our findings further suggest that the acetate-boosted reactive astrocyte-neuron interaction could contribute to the cognitive decline in AD.

Preclinical Evaluation of a Companion Diagnostic Radiopharmaceutical, [18F]PSMA-1007, in a Subcutaneous Prostate Cancer Xenograft Mouse Model.

Several radiolabeled prostate-specific membrane antigen (PSMA)-targeted agents have been developed for detecting prostate cancer, using positron emission tomography imaging and targeted radionuclide therapy. Among them, [18F]PSMA-1007 has several advantages, including a comparatively long half-life, delayed renal excretion, and compatible structure with α-/ß-particle emitter-labeled therapeutics. This study aimed to characterize the preclinical pharmacokinetics and internal radiation dosimetry of [18F]PSMA-1007, as well as its repeatability and specificity for target binding using prostate tumor-bearing mice. In PSMA-positive tumor-bearing mice, the kidney showed the greatest accumulation of [18F]PSMA-1007. The distribution in the tumor attained its peak concentration of 2.8%ID/g at 112 min after intravenous injection. The absorbed doses in the tumor and salivary glands were 0.079 ± 0.010 Gy/MBq and 0.036 ± 0.006 Gy/MBq, respectively. The variance of the net influx (Ki) of [18F]PSMA-1007 to the tumor was minimal between scans performed in the same animals (within-subject coefficient of variation = 7.57%). [18F]PSMA-1007 uptake in the tumor was specifically decreased by 32% in Ki after treatment with a PSMA inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). In the present study, we investigated the in vivo preclinical characteristics of [18F]PSMA-1007. Our data from [18F]PSMA-1007 PET/computed tomography (CT) studies in a subcutaneous prostate cancer xenograft mouse model supports clinical therapeutic strategies that use paired therapeutic radiopharmaceuticals (such as [177Lu]Lu-PSMA-617), especially strategies with a quantitative radiation dose estimate for target lesions while minimizing radiation-induced toxicity to off-target tissues.

Update on Preoperative Parathyroid Localization in Primary Hyperparathyroidism.

Parathyroidectomy is the treatment of choice for primary hyperparathyroidism when the clinical criteria are met. Although bilateral neck exploration is traditionally the standard method for surgery, minimally invasive parathyroidectomy (MIP), or focused parathyroidectomy, has been widely accepted with comparable curative outcomes. For successful MIP, accurate preoperative localization of parathyroid lesions is essential. However, no consensus exists on the optimal approach for localization. Currently, ultrasonography and technetium-99m-sestamibi-single photon emission computed tomography/computed tomography are widely accepted in most cases. However, exact localization cannot always be achieved, especially in cases with multiglandular disease, ectopic glands, recurrent disease, and normocalcemic primary hyperparathyroidism. Therefore, new modalities for preoperative localization have been developed and evaluated. Positron emission tomography/computed tomography and parathyroid venous sampling have demonstrated improvements in sensitivity and accuracy. Both anatomical and functional information can be obtained by combining these methods. As each approach has its advantages and disadvantages, the localization study should be deliberately chosen based on each patient's clinical profile, costs, radiation exposure, and the availability of experienced experts. In this review, we summarize various methods for the localization of hyperfunctioning parathyroid tissues in primary hyperparathyroidism.

Regional lymph node metastasis detected on preoperative CT and/or FDG-PET may predict early recurrence of pancreatic adenocarcinoma after curative resection.

The objective of this study was to evaluate the role of regional lymph node (LN) metastasis detected on preoperative CT and/or 18F-fluoro-2-deoxyglucose-positron emission tomography (FDG-PET) scans in the prediction of early tumor recurrence after curative surgical resection of pancreatic ductal adenocarcinoma (PDAC). This retrospective study included 137 patients who underwent upfront surgery with R0 resection of PDAC between 2013 and 2016. Regional LN metastasis was identified using two criteria: positive findings for regional LN metastasis on either preoperative CT or FDG-PET scans (LNOR), or on both preoperative CT and FDG-PET scans (LNAND). A total of 55 patients had early tumor recurrence within 12 months after curative resection. Univariable and multivariable Cox proportional hazard regression analysis showed that preoperative carbohydrate antigen 19-9 (CA19-9) levels, preoperative locally advanced status, and regional LN metastasis (both LNOR and LNAND criteria) were significant risk factors for early recurrence. Positive LNOR and LNAND showed significantly poorer recurrence-free survival compared to negative regional LN metastasis groups (p = 0.048 and p = 0.020, respectively). Compared with the LNAND criteria, the LNOR criteria provided higher sensitivity (22.4% vs. 15.5%, p = 0.046) and a higher negative predictive value (61.9% vs. 59.8%, p = 0.046). The LNOR definition provided more sensitive and accurate performance in diagnosing preoperative regional LN metastasis.

Extracellular Citrate Treatment Induces HIF1α Degradation and Inhibits the Growth of Low-Glycolytic Hepatocellular Carcinoma under Hypoxia.

HCC is well known for low glycolysis in the tumors, whereas hypoxia induces glycolytic phenotype and tumor progression. This study was conducted to evaluate the expression of SLCs in human HCCs and investigated whether extracellular nutrient administration related to SLCs in low-glycolytic HCC can prevent hypoxic tumor progression. SLCs expression was screened according to the level of glycolysis in HCCs. Then, whether extracellular nutrient treatment can affect hypoxic tumor progression, as well as the mechanisms, were evaluated in an in vitro cell line and an in vivo animal model. Low-glycolytic HCCs showed high SLC13A5/NaCT and SLC16A1/MCT1 but low SLC2A1/GLUT1 and HIF1α/HIF1α expression. Especially, high SLC13A5 expression was significantly associated with good overall survival in the Cancer Genome Atlas (TCGA) database. In HepG2 cells with the highest NaCT expression, extracellular citrate treatment upon hypoxia induced HIF1α degradation, which led to reduced glycolysis and cellular proliferation. Finally, in HepG2-animal models, the citrate-treated group showed smaller tumor with less hypoxic areas than the vehicle-treated group. In patients with HCC, SLC13A5/NaCT is an important SLC, which is associated with low glycolysis and good prognosis. Extracellular citrate treatment induced the failure of metabolic adaptation to hypoxia and tumor growth inhibition, which can be a potential therapeutic strategy in HCCs.

11 C-Acetate PET/CT Detects Reactive Astrogliosis Helping Glioma Classification.

PURPOSE: 11 C-acetate ( 11 C-ACE) uptake on PET/CT was recently discovered to represent reactive astrocytes in the tumor microenvironment. This study aimed at evaluating the role of 11 C-ACE PET/CT as an imaging biomarker of reactive astrogliosis in characterizing different types of gliomas. METHODS: In this prospective study, a total of 182 patients underwent 11 C-ACE PET/CT before surgery. The ratio of SUV max of a glioma to the SUV mean of the contralateral choroid plexus ( 11 C-ACE TCR) on PET/CT was calculated. 11 C-ACE TCRs were compared with the World Health Organization grades and isocitrate dehydrogenase 1 ( IDH1 ) mutation status. Grade 2 was considered low-grade tumor, and grades 3 and 4 were considered high-grade tumors. RESULTS: The median 11 C-ACE TCR was significantly higher in IDH1 wild-type (wt) tumors (n = 91) than in IDH1 -mutant (mt) tumors (n = 91) (2.38 vs 1.30, P < 0.001). Of the 91 IDH1 -mt tumors, there were no differences in the median 11 C-ACE TCRs between oligodendrogliomas (ODs) and astrocytic tumors (1.40 vs 1.20, P > 0.05). In grading low- versus high-grade gliomas, the receiver operating characteristic curve analyses showed a higher area under the curve (0.951) in IDH1 -wt tumors than in IDH1 -mt tumors (0.783, P = 0.002). Grade 2 ODs were well differentiated from high-grade gliomas. The 11 C-ACE TCR of grade 3 ODs was significantly lower than that of IDH1 -wt glioblastomas. CONCLUSIONS: High 11 C-ACE uptake is associated with high-grade IDH1 -wt tumors, thus facilitating differentiation from high-grade IDH1-mt and low-grade gliomas. In particular, low 11 C-ACE uptake in ODs is advantageous in overcoming the limitation of radiolabeled amino acid tracers.

Total Lesion Glycolysis on 18F-FDG PET/CT Is a Better Prognostic Factor Than Tumor Dose on 90Y PET/CT in Patients With Hepatocellular Carcinoma Treated With 90Y Transarterial Radioembolization.

PURPOSE: This study aimed to evaluate the prognostic value of metabolic parameters on 18F-FDG PET/CT and tumor dose (TD) on posttreatment 90Y PET/CT in patients with hepatocellular carcinoma (HCC) who underwent 90Y transarterial radioembolization (TARE). PATIENTS AND METHODS: Forty-seven HCC patients treated with 90Y TARE were retrospectively enrolled between January 2013 and October 2018. 18F-FDG PET/CT was performed before treatment. Maximum tumor SUV-to-mean normal liver SUV ratio (TLR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured for each patient. Voxel dosimetry was performed on 90Y PET/CT images to measure TD. The prognostic significance of metabolic parameters on 18F-FDG PET/CT, TD on 90Y PET/CT, and clinical factors for overall survival (OS) was evaluated. In addition, TD on 90Y PET/CT was analyzed in relation to the administered dose of 90Y-labeled microspheres and metabolic parameters on 18F-FDG PET/CT. RESULTS: The median patient age was 57 years, and 37 patients (78.7%) were men. During the follow-up period, 25 patients (53.2%) died. In univariable analysis, Barcelona Clinic Liver Cancer stage C, Child-Pugh score, TD on 90Y PET/CT, TLR, MTV, and TLG were significant prognostic factors affecting OS (P < 0.05). In multivariable analysis, Barcelona Clinic Liver Cancer stage C and high TLG on 18F-FDG PET/CT were independent prognostic factors for OS (P < 0.05). The 1-year OS rates were 72.9% in patients with low TLG and 33.3% in patients with high TLG (P < 0.05). We also found that TD on 90Y PET/CT was not correlated with the administered dose of 90Y-labeled microspheres, but negatively correlated with TLG on pretreatment 18F-FDG PET/CT (P < 0.05). CONCLUSIONS: TLG, a parameter incorporating both the degree of 18F-FDG uptake and amount of metabolically active tumor volume on pretreatment 18F-FDG PET/CT, is a better prognostic factor than TD on 90Y PET/CT for predicting OS in HCC patients treated with 90Y TARE.

Impact of Exogenous Treatment with Histidine on Hepatocellular Carcinoma Cells.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib, a multi-kinase inhibitor, is the first-line therapy for advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity and the development of resistance. Although various amino acids have been shown to contribute to cancer initiation and progression, little is known about the effects of histidine, a dietary essential amino acid that is partially taken up via histidine/large neutral amino acid transporter (LAT1), on cancer cells. In this study, we evaluated the effects of histidine on HCC cells and sensitivity to sorafenib. Remarkably, we found that exogenous histidine treatment induced a reduction in the expression of tumor markers related to glycolysis (GLUT1 and HK2), inflammation (STAT3), angiogenesis (VEGFB and VEGFC), and stem cells (CD133). In addition, LAT1 expression was downregulated in HCC tumor regions with high expression of GLUT1, CD133, and pSTAT3, which are known to induce sorafenib resistance. Finally, we demonstrated that combined treatment with sorafenib and histidine could be a novel therapeutic strategy to enhance the sensitivity to sorafenib, thereby improving long-term survival in HCC.

Diagnostic Utility of Somatostatin Receptor 2A Immunohistochemistry for Tumor-induced Osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disorder caused by excessive fibroblast growth factor 23 (FGF23) secretion. FGF23 immunohistochemistry (IHC) is proposed as a useful adjunctive marker to confirm TIO diagnosis. However, it often stains focally, limiting its diagnostic utility. OBJECTIVE: This work aimed to compare the diagnostic performance between somatostatin receptor 2A (SSTR2A) and FGF23 IHC for TIO. METHODS: We retrospectively reviewed TIO-diagnosed patients in Severance Hospital between July 2006 and May 2020. Histologic evaluation was performed using histoscore (H score) (expression area proportion score [0-2] × intensity score [1-3], [total, 0-6]). FGF23 and SSTR2A IHC were performed using unstained slides from 18 localized TIO patients and 9 and 15 non-TIO controls with bone and soft-tissue tumors, respectively. SSTR2A positivity was defined as cytoplasmic, membranous, or Golgi staining in more than 1% of tumor cells, and negativity as nonspecific nuclear staining. FGF23 positivity was defined as cytoplasmic expression in more than 1% of the tumor area and negativity as nonspecific nuclear staining. RESULTS: Suspicious lesions were successfully detected in 14 of 15 patients who underwent 68Ga-DOTATOC scans. Diffuse cytoplasmic SSTR2A expression was identified in all TIO patients and focal weak nuclear staining in 12 of 15 controls. FGF23 cytoplasmic expression was identified in 11 of 18 TIO patients and diffuse nuclear staining in 9 of 9 controls. The H score was higher in SSTR2A than in FGF23 IHC (median [interquartile range]: 6 [6-6] vs 1 [0-2], P < .001). CONCLUSION: SSTR2A IHC with H-score quantification might be a more sensitive, adjunctive diagnostic tool than FGF23 IHC for TIO diagnosis.

Metabolic tumour volume on 18F-FDG PET/CT predicts extended pathological T stages in patients with renal cell carcinoma at staging.

We evaluated the predictive value of 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/CT (PET/CT) for extended pathological T (pT) stages (≥ pT3a) in Renal cell carcinoma (RCC) patients at staging. Thirty-eight RCC patients who underwent 18F-FDG PET/CT at staging, followed by radical nephrectomy between September 2016 and September 2018, were included in this prospective study. Patients were classified into two groups (limited pT stage: stage T1/2, n = 17; extended pT stage: T3/4, n = 21). Univariate and multivariate logistic regression analyses were performed to identify clinicopathological and metabolic variables to predict extended pT stages. 18F-FDG metabolic parameters were compared in relation to International Society of Urological Pathology (ISUP) grade and lymphovascular invasion (LVI). In univariate analysis, maximum standardised uptake value, metabolic tumour volume (MTV), and ISUP grade were significant. In multivariate analysis, MTV was the only significant factor of extended pT stages. With a cut-off MTV of 21.2, an area under the curve was 0.944, which was higher than 0.824 for clinical T stages (p = 0.037). In addition, high MTV, but not tumour size, was significantly correlated with aggressive pathologic features (ISUP grade and LVI). High glycolytic tumour volume on 18F-FDG PET/CT in RCC patients at staging is predictive of extended pT stages which could aid decision-making regarding the best type of surgery.

Glycolysis on F-18 FDG PET/CT Is Superior to Amino Acid Metabolism on C-11 Methionine PET/CT in Identifying Advanced Renal Cell Carcinoma at Staging.

We evaluated the value of F-18 fluorodeoxyglucose (FDG) and C-11 methionine positron emission tomography/computed tomography (PET/CT) to predict high-Fuhrman grade and advanced-stage tumours in patients with renal cell carcinoma (RCC). Forty patients with RCC underwent F-18 FDG and C-11 methionine PET/CT between September 2016 and September 2018. They were classified into limited (stages I and II, n = 15) or advanced stages (stages III and IV, n = 25) according to pathological staging. Logistic regressions were used to predict the advanced stage using various parameters, including maximum standardised uptake value (SUVmax) and metabolic tumour volume (MTV). Receiver operating characteristic analyses were performed to predict high-grade tumours (Fuhrman 3 and 4). On univariate analysis, tumour size, SUVmax and MTV of F-18 FDG and C-11 methionine, and Fuhrman grades were significant predictors for the advanced stage. On multivariate analysis, F-18 FDG MTV > 21.3 cm3 was the most significant predictor (p < 0.001). The area under the curve for predicting high-grade tumours was 0.830 for F-18 FDG (p < 0.001) and 0.726 for C-11 methionine PET/CT (p = 0.014). In conclusion, glycolysis on F-18 FDG PET/CT and amino acid metabolism on C-11 methionine PET/CT were variable but increased in high-grade RCCs. Increased MTV on F-18 FDG PET/CT is a powerful predictor of advanced-stage tumours.

Prone position [18F]FDG PET/CT to reduce respiratory motion artefacts in the evaluation of lung nodules.

OBJECTIVES: 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron-emission tomography/computed tomography (PET/CT) is widely used to evaluate lung nodules, although respiratory motion artefacts may occur. We investigated the value of prone position PET/CT (pPET/CT) in lung nodule evaluation compared with standard supine position PET/CT (sPET/CT). METHODS: We retrospectively reviewed 28 consecutive patients (20 men; age, 65.6 ± 12.1 years) with a lung nodule (size, 16.8 ± 5.5 mm) located below the sub-carinal level who underwent [18F]FDG PET/CT in a standard supine position and additional prone position. The maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV), difference of diaphragm position between PET and CT (DDP), Dice's similarity coefficient (DSC) and occurrence of mis-registration were analysed. The [18F]FDG uptake of 20 biopsy-confirmed (15 malignant) nodules was evaluated visually. RESULTS: pPET/CT yielded a significantly higher SUVmax, lower MTV and shorter DDP than with sPET/CT (p = 0.043, 0.007 and 0.021, respectively). Mis-registration occurred in 53.6% of cases in sPET/CT and in 28.6% of cases in pPET/CT (p = 0.092). Among the 15 patients with mis-registration in sPET/CT, 10 patients (66.7%) did not show mis-registration in pPET/CT. DSC was higher in pPET/CT than in sPET/CT in 18 out of 28 patients (64.3%). In visual analysis, malignant nodules exhibited a higher [18F]FDG uptake positivity than benign nodules in pPET/CT (93.3% vs. 40.0%, p = 0.032) but not in sPET/CT (80.0% vs. 40.0%, p = 0.131). CONCLUSIONS: pPET/CT reduces respiratory motion artefact and enables more-precise measurements of PET parameters. KEY POINTS: • In prone position PET/CT, the decrease in the blurring effect caused by reduced respiratory motion resulted in a higher SUVmax and lower MTV in lung nodules than that with supine position PET/CT. • Prone position PET/CT was useful to interpret correctly malignant lung nodules as being positive in individual cases that had a negative result in supine position PET/CT.

Segmentation of white matter hyperintensities on 18F-FDG PET/CT images with a generative adversarial network.

PURPOSE: White matter hyperintensities (WMH) are typically segmented using MRI because WMH are hardly visible on 18F-FDG PET/CT. This retrospective study was conducted to segment WMH and estimate their volumes from 18F-FDG PET with a generative adversarial network (WhyperGAN). METHODS: We selected patients whose interval between MRI and FDG PET/CT scans was within 3 months, from January 2017 to December 2018, and classified them into mild, moderate, and severe groups by following the semiquantitative rating method of Fazekas. For each group, 50 patients were selected, and of them, we randomly selected 35 patients for training and 15 for testing. WMH were automatically segmented from FLAIR MRI with manual adjustment. Patches of WMH were extracted from 18F-FDG PET and segmented MRI. WhyperGAN was compared with H-DenseUnet, a deep learning method widely used for segmentation tasks, for segmentation performance based on the dice similarity coefficient (DSC), recall, and average volume differences (AVD). For volume estimation, the predicted WMH volumes from PET were compared with ground truth volumes. RESULTS: The DSC values were associated with WMH volumes on MRI. For volumes >60 mL, the DSC values were 0.751 for WhyperGAN and 0.564 for H-DenseUnet. For volumes ≤60 mL, the DSC values rapidly decreased as the volume decreased (0.362 for WhyperGAN vs. 0.237 for H-DenseUnet). For recall, WhyperGAN achieved the highest value in the severe group (0.579 for WhyperGAN vs. 0.509 for H-DenseUnet). For AVD, WhyperGAN achieved the lowest score in the severe group (0.494 for WhyperGAN vs. 0.941 for H-DenseUnet). For the WMH volume estimation, WhyperGAN performed better than H-DenseUnet and yielded excellent correlation coefficients (r = 0.998, 0.983, and 0.908 in the severe, moderate, and mild group). CONCLUSIONS: Although limited by visual analysis, the WhyperGAN based can be used to automatically segment and estimate volumes of WMH from 18F-FDG PET/CT. This would increase the usefulness of 18F-FDG PET/CT for the evaluation of WMH in patients with cognitive impairment.

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.