Direct 18F-Fluorosulfurylation of Phenols and Amines Using an [18F]FSO2+ Transfer Agent Generated In Situ.

We report the direct radiofluorosulfurylation method for the synthesis of 18F-labeled fluorosulfuryl derivatives from phenols and amines using an [18F]FSO2+ transfer agent generated in situ. Nucleophilic radiofluorination is achieved even in a hydrous organic medium, obviating the need for azeotropic drying and the use of cryptands. This unprecedented, operationally simple isotopic functionalization facilitates the reliable production of potential radiotracers for positron emission tomography, rendering facile access to SuFEx radiochemistry.

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.

Molecular subtypes of oropharyngeal cancer show distinct immune microenvironment related with immune checkpoint blockade response.

BACKGROUND: Oropharyngeal cancer (OPC) exhibits diverse immunological properties; however, their implications for immunotherapy are unknown. METHODS: We analysed 37 surgically resected and nine recurrent or metastatic anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-treated OPC tumours. OPCs were classified into immune-rich (IR), mesenchymal (MS) and xenobiotic (XB) subtypes based on RNA-sequencing data. RESULTS: All IR type tumours were human papillomavirus (HPV) positive, most XB types were HPV negative, and MS types showed mixed HPV status. The IR type showed an enriched T cell exhaustion signature with PD-1+ CD8+ T cells and type I macrophages infiltrating the tumour nest on multiplex immunohistochemistry. The MS type showed an exclusion of CD8+ T cells from the tumour nest and high MS and tumour growth factor-ß signatures. The XB type showed scant CD8+ T cell infiltration and focal CD73 expression. The IR type was associated with a favourable response signature during anti-PD-1/PD-L1 therapy and showed a high APOBEC mutation signature, whereas the MS and XB types showed resistance signature upregulation. Among anti-PD-1/PD-L1-treated OPC patients, the IR type showed a favourable clinical response (3/4 patients), whereas the XB type showed early progression (3/3 patients). CONCLUSION: Our analysis classified OPCs into three subtypes with distinct immune microenvironments that are potentially related to the response to anti-PD-1/PD-L1 therapy.

Correction: Molecular subtypes of oropharyngeal cancer show distinct immune microenvironment related with immune checkpoint blockade response.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Type II Ice-Binding Proteins Isolated from an Arctic Microalga Are Similar to Adhesin-Like Proteins and Increase Freezing Tolerance in Transgenic Plants.

Microalgal ice-binding proteins (IBPs) in the polar region are poorly understood at the genome-wide level, although they are important for cold adaptation. Through the transcriptome study with the Arctic green alga Chloromonas sp. KNF0032, we identified six Chloromonas IBP genes (CmIBPs), homologous with the previously reported IBPs from Antarctic snow alga CCMP681 and Antarctic Chloromonas sp. They were organized with multiple exon/intron structures and low-temperature-responsive cis-elements in their promoters and abundantly expressed at low temperature. The biological functions of three representative CmIBPs (CmIBP1, CmIBP2 and CmIBP3) were tested using in vitro analysis and transgenic plant system. CmIBP1 had the most effective ice recrystallization inhibition (IRI) activities in both in vitro and transgenic plants, and CmIBP2 and CmIBP3 had followed. All transgenic plants grown under nonacclimated condition were freezing tolerant, and especially 35S::CmIBP1 plants were most effective. After cold acclimation, only 35S::CmIBP2 plants showed slightly increased freezing tolerance. Structurally, the CmIBPs were predicted to have ß-solenoid forms with parallel ß-sheets and repeated TXT motifs. The repeated TXT structure of CmIBPs appears similar to the AidA domain-containing adhesin-like proteins from methanogens. We have shown that the AidA domain has IRI activity as CmIBPs and phylogenetic analysis also supported that the AidA domains are monophyletic with ice-binding domain of CmIBPs, and these results suggest that CmIBPs are a type of modified adhesins.

Interregional metabolic connectivity of 2-deoxy-2[18 F]fluoro-D-glucose positron emission tomography in vagus nerve stimulation for pediatric patients with epilepsy: A retrospective cross-sectional study.

OBJECTIVE: With the recognition of epilepsy as a network disease that disrupts the organizing ability of resting-state brain networks, vagus nerve stimulation (VNS) may control epileptic seizures through modulation of functional connectivity. We evaluated preoperative 2-deoxy-2[18 F]fluoro-D-glucose (FDG) positron emission tomography (PET) in VNS-implanted pediatric patients with refractory epilepsy to analyze the metabolic connectivity of patients and its prognostic role in seizure control. METHODS: Preoperative PET data of 66 VNS pediatric patients who were followed up for a minimum of 1 year after the procedure were collected for the study. Retrospective review of the patients' charts was performed, and five patients with inappropriate PET data or major health issues were excluded. We conducted an independent component analysis of FDG-PET to extract spatial metabolic components and their activities, which were used to perform cross-sectional metabolic network analysis. We divided the patients into VNS-effective and VNS-ineffective groups (VNS-effective group, ≥50% seizure reduction; VNS-ineffective group, <50% reduction) and compared metabolic connectivity differences between groups using a permutation test. RESULTS: Thirty-four (55.7%) patients showed >50% seizure reduction from baseline frequency 1 year after VNS. A significant difference in metabolic connectivity evaluated by preoperative FDG-PET was noted between groups. Relative changes in glucose metabolism were strongly connected among the areas of brainstem, cingulate gyrus, cerebellum, bilateral insula, and putamen in patients with <50% seizure control after VNS. SIGNIFICANCE: This study shows that seizure outcome of VNS may be influenced by metabolic connectivity, which can be obtained from preoperative PET imaging. This study of metabolic connectivity analysis may contribute in further understanding of the mechanism of VNS in intractable seizures.

Glutamatergic stimulation of the left dentate gyrus abolishes depressive-like behaviors in a rat learned helplessness paradigm.

BACKGROUND: Episodic experiences of stress have been identified as the leading cause of major depressive disorder (MDD). The occurrence of MDD is profoundly influenced by the individual's coping strategy, rather than the severity of the stress itself. Resting brain activity has been shown to alter in several mental disorders. However, the functional relationship between resting brain activity and coping strategies has not yet been studied. In the present study, we observed different patterns of resting brain activity in rats that had determined either positive (resilient to stress) or negative (vulnerable to stress) coping strategies, and examined whether modulation of the preset resting brain activity could influence the behavioral phenotype associated with negative coping strategy (i.e., depressive-like behaviors). METHODS: We used a learned helplessness paradigm-a well-established model of MDD-to detect coping strategies. Differences in resting state brain activity between animals with positive and negative coping strategies were assessed using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Glutamatergic stimulation was used to modulate resting brain activity. RESULTS: After exposure to repeated uncontrollable stress, seven of 23 rats exhibited positive coping strategies, while eight of 23 rats exhibited negative coping strategies. Increased resting brain activity was observed only in the left ventral dentate gyrus of the positive coping rats using FDG-PET. Furthermore, glutamatergic stimulation of the left dentate gyrus abolished depressive-like behaviors in rats with negative coping strategies. CONCLUSION: Increased resting brain activity in the left ventral dentate gyrus helps animals to select positive coping strategies in response to future stress.

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.

18F-FDG PET/CT Parameters Enhance MRI Radiomics for Predicting Human Papilloma Virus Status in Oropharyngeal Squamous Cell Carcinoma.

PURPOSE: Predicting human papillomavirus (HPV) status is critical in oropharyngeal squamous cell carcinoma (OPSCC) radiomics. In this study, we developed a model for HPV status prediction using magnetic resonance imaging (MRI) radiomics and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) parameters in patients with OPSCC. MATERIALS AND METHODS: Patients with OPSCC who underwent 18F-FDG PET/CT and contrast-enhanced MRI before treatment between January 2012 and February 2020 were enrolled. Training and test sets (3:2) were randomly selected. 18F-FDG PET/CT parameters and MRI radiomics feature were extracted. We developed three light-gradient boosting machine prediction models using the training set: Model 1, MRI radiomics features; Model 2, 18F-FDG PET/CT parameters; and Model 3, combination of MRI radiomics features and 18F-FDG PET/CT parameters. Area under the receiver operating characteristic curve (AUROC) values were used to analyze the performance of the models in predicting HPV status in the test set. RESULTS: A total of 126 patients (118 male and 8 female; mean age: 60 years) were included. Of these, 103 patients (81.7%) were HPV-positive, and 23 patients (18.3%) were HPV-negative. AUROC values in the test set were 0.762 [95% confidence interval (CI), 0.564-0.959], 0.638 (95% CI, 0.404-0.871), and 0.823 (95% CI, 0.668-0.978) for Models 1, 2, and 3, respectively. The net reclassification improvement of Model 3, compared with that of Model 1, in the test set was 0.119. CONCLUSION: When combined with an MRI radiomics model, 18F-FDG PET/CT exhibits incremental value in predicting HPV status in patients with OPSCC.

Development and Testing of a Machine Learning Model Using 18F-Fluorodeoxyglucose PET/CT-Derived Metabolic Parameters to Classify Human Papillomavirus Status in Oropharyngeal Squamous Carcinoma.

OBJECTIVE: To develop and test a machine learning model for classifying human papillomavirus (HPV) status of patients with oropharyngeal squamous cell carcinoma (OPSCC) using 18F-fluorodeoxyglucose (18F-FDG) PET-derived parameters in derived parameters and an appropriate combination of machine learning methods in patients with OPSCC. MATERIALS AND METHODS: This retrospective study enrolled 126 patients (118 male; mean age, 60 years) with newly diagnosed, pathologically confirmed OPSCC, that underwent 18F-FDG PET-computed tomography (CT) between January 2012 and February 2020. Patients were randomly assigned to training and internal validation sets in a 7:3 ratio. An external test set of 19 patients (16 male; mean age, 65.3 years) was recruited sequentially from two other tertiary hospitals. Model 1 used only PET parameters, Model 2 used only clinical features, and Model 3 used both PET and clinical parameters. Multiple feature transforms, feature selection, oversampling, and training models are all investigated. The external test set was used to test the three models that performed best in the internal validation set. The values for area under the receiver operating characteristic curve (AUC) were compared between models. RESULTS: In the external test set, ExtraTrees-based Model 3, which uses two PET-derived parameters and three clinical features, with a combination of MinMaxScaler, mutual information selection, and adaptive synthetic sampling approach, showed the best performance (AUC = 0.78; 95% confidence interval, 0.46-1). Model 3 outperformed Model 1 using PET parameters alone (AUC = 0.48, p = 0.047) and Model 2 using clinical parameters alone (AUC = 0.52, p = 0.142) in predicting HPV status. CONCLUSION: Using oversampling and mutual information selection, an ExtraTree-based HPV status classifier was developed by combining metabolic parameters derived from 18F-FDG PET/CT and clinical parameters in OPSCC, which exhibited higher performance than the models using either PET or clinical parameters alone.

Prognosis Associated with Glycolytic Activity in Regional Lymph Nodes of Patients with Previously Untreated Metastatic Breast Cancer: A Preliminary Study.

Better mechanisms of predicting prognoses in patients with metastatic breast cancer will improve the identification of patients for whom curative treatments may be the most effective. In this study, the prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was assessed in patients with metastatic breast cancer. A retrospective analysis of women who underwent 18F-FDG PET/CT for staging of newly diagnosed metastatic breast cancer was conducted. In each patient, the maximum standardized uptake value (SUV) and total lesion glycolysis (TLG) of primary tumors and regional lymph nodes were measured and analyzed for association with survival using the Cox proportional hazards regression model. From 346 consecutive patients, 32 with metastatic invasive ductal carcinoma of the breast were included in the study. The median duration of follow-up was 22.5 months. Disease progression occurred in 26 patients, and 11 patients died. When multivariate analyses with a stepwise forward regression were applied, only the maximum SUV and TLG of regional lymph nodes showed a significant correlation with progression-free survival and overall survival, respectively. This study demonstrates that increased 18F-FDG uptake in regional lymph nodes is a strong independent predictor of survival in women with metastatic invasive ductal carcinoma of the breast.

Metabolic network is related to surgical outcome in temporal lobe epilepsy with hippocampal sclerosis: A brain FDG-PET study.

BACKGROUND AND PURPOSE: The aim of this study was to investigate differences in metabolic networks based on preoperative fluorodeoxyglucose (FDG)-positron emission tomography (PET) in temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) between patients with complete seizure-free (SF) and those with noncomplete seizure-free (non-SF) after anterior temporal lobectomy. METHODS: This study was retrospectively performed at a tertiary hospital. We recruited pathologically confirmed 75 TLE patients with HS who underwent preoperative FDG-PET. All patients underwent a standard anterior temporal lobectomy. The surgical outcome was evaluated at least 12 months after surgery, and we divided the subjects into patients with SF (International League Against Epilepsy [ILAE] class I) and those with non-SF (ILAE class II-VI). We evaluated the metabolic network using graph theoretical analysis based on FDG-PET. We investigated the differences in network measures between the two groups. RESULTS: Of the 75 TLE patients with HS, 32 patients (42.6%) had SF, whereas 43 patients (57.3%) had non-SF. There were significant differences in global metabolic networks according to surgical outcomes. The patients with SF had a lower assortative coefficient than those with non-SF (-0.020 vs. -0.009, p = .044). We also found widespread regional differences in local metabolic networks according to surgical outcomes. CONCLUSION: Our study demonstrates significant differences in preoperative metabolic networks based on FDG-PET in TLE patients with HS according to surgical outcomes. This work introduces a metabolic network based on FDG-PET and can be used as a potential tool for predicting surgical outcome in TLE patients with HS.

Tumor Glucose Metabolism and Its Heterogeneity on F-18 FDG PET/CT Provide Better Prognostication in Nonmetastatic Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma.

BACKGROUND: We aimed to evaluate the prognostic role of metabolic parameters on baseline F-18 fluorodeoxyglucose (FDG) PET/CT in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). METHODS: We retrospectively reviewed patients who were diagnosed with nonmetastatic HPV-related OPSCC using the 8th TNM staging system from 2010 to 2015 and underwent baseline F-18 FDG PET/CT. Tumor SUVmax to liver SUVmean ratio (SUVmax-TLR), metabolic tumor volume (MTV), tumor total lesion glycolysis to liver SUVmean ratio (TLG-TLR), and coefficient of variation (CV) of the primary tumor were measured. Patients were primarily treated with surgery or radiotherapy. Endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Ninety consecutive patients (male, 72; female, 18) were enrolled. They were followed up for a median of 77.4 months (interquartile range, 48.4-106.4). Sixteen patients progressed, and 13 died. Multivariate analysis revealed that patients with advanced age, overall stage, and higher SUVmax-TLR or CV had poorer PFS and OS. CONCLUSION: Higher SUVmax-TLR and CV of the primary tumor on baseline F-18 FDG PET/CT were associated with poorer PFS and OS in patients with nonmetastatic HPV-related OPSCC. Further study is warranted to address the possible implications of F-18 FDG PET/CT on treatment de-intensification in these patients.

Malignant Transformation of an Epidermoid Cyst in an Intrapancreatic Accessory Spleen: A Case Report.

A 33-year-old man was evaluated because of an incidentally found cyst in the pancreatic tail, which was first seen 6 years ago. The cyst was a unilocular cystic mass, 13.0 cm in diameter, and had increased in size in last 2 months. On F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), the cystic wall showed increased FDG uptake. The patient underwent distal pancreatectomy with suspicion of mucinous cystic neoplasm of the pancreas. The mass turned out to be a squamous carcinoma arising from an epidermoid cyst in an intrapancreatic accessory spleen (ECIPAS). FDG PET/CT may assist recognition of a potential malignant lesion arising from an ECIPAS.

Prognostic Value of Bone Marrow F-18 FDG Uptake in Patients with Advanced-Stage Diffuse Large B-Cell Lymphoma.

PURPOSE: We assessed prognostic implication of bone marrow uptake on baseline F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in patients with advanced-stage diffuse large B-cell lymphoma (DLBCL). METHODS: We retrospectively reviewed 140 patients with stage III and IV DLBCL, who underwent baseline F-18 FDG PET/CT at diagnosis. Bone marrow uptake on F-18 FDG PET/CT (BM FDG) was compared with findings on bone marrow biopsy (BMB), and patients were grouped based on these results: BMB-positive and BM FDG-positive (group 1), BMB-positive and BM FDG-negative (group 2), BMB-negative and BM FDG-positive (group 3), and BMB-negative and BM FDG-negative (group 4). The prognostic value of clinicopathologic factors and BM FDG for predicting progression-free survival (PFS) and overall survival (OS) was assessed using a Cox proportional hazards model. Differences in PFS and OS were examined by the Kaplan-Meier method. RESULTS: BMB was the only significant indicator in predicting PFS, and age, IPI score higher than 3, and BM FDG significantly predicted OS. Group 1 showed inferior PFS than group 2 (median PFS, 7.4 vs. 13.9 months; p = 0.04). In contrast, there was no significant difference either in PFS or OS between group 2 and group 3. CONCLUSION: We showed that BM FDG-positive predicted a poorer survival in patients with advanced stage DBLCL. We also found that BMB-negative and BM FDG-positive patients had similar PFS or OS to BMB-positive and BM FDG-negative patients. Further study in a larger population is needed to clarify clinical significance of BM FDG in these patients.

Prognostic values of mid-radiotherapy 18F-FDG PET/CT in patients with esophageal cancer.

BACKGROUND: To identify whether early metabolic responses as determined using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) during radiotherapy (RT) predict outcomes in patients with esophageal cancer. METHODS: Twenty-one patients with esophageal cancer who received pre-treatment 18F-FDG PET/CT (PET1) and inter-fractional 18F-FDG PET/CT (PET2) after 11 fractions of RT (median 23.1 Gy, 2.1 Gy per fraction) were retrospectively reviewed. The region of interest for each calculation was delineated using "PET Edge". We calculated PET parameters including maximum and mean standardized uptake values (SUVmax and SUVmean, respectively), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The relative changes (%) were calculated using the logarithmically transformed parameter values for the PET1 and PET2 scans. Multivariate analysis of locoregional recurrence and distant failures were performed using Cox regression analysis. After identifying statistically significant PET parameters for discriminating responders from non-responders, receiver operating characteristics curve analyses were used to assess the potentials of the studied PET parameters. RESULTS: After a median follow-up of 13 months, the 1-year overall and progression-free survival rates were 79.0% and 34.4%, respectively. Four patients developed locoregional recurrences (LRRs) and 8 had distant metastases (DMs). The 1-year overall LRR-free rate was 76.9% while the DM-free rate was 60.6%. The relative changes in MTV (ΔMTV) were significantly associated with LRR (p = 0.03). Conversely, the relative changes in SUVmean (ΔSUVmean) were associated with the risk of DM (p = 0.02). An ΔMTV threshold of 1.14 yielded a sensitivity of 60%, specificity of 94%, and an accuracy of 86% for predicting an LRR. Additionally, a ΔSUVmean threshold of a 35% decrease yielded a sensitivity of 67%, specificity of 83%, and accuracy of 76% for the prediction DM. TRIAL REGISTRATION: Retrospectively registered. CONCLUSIONS: Changes in tumor metabolism during RT could be used to predict treatment responses, recurrences, and prognoses in patients with esophageal cancer.

The Prognostic Value of 18F-FDG Uptake in the Supraclavicular Lymph Node (N3c) on PET/CT in Patients With Locally Advanced Breast Cancer With Clinical N3c.

PURPOSE: We investigated the prognostic value of F-FDG uptake in the supraclavicular lymph node (SCLN) on PET/CT in breast cancer patients with clinical ipsilateral SCLN metastasis (cN3c). METHODS: Fifty-five female patients with initial F-FDG PET/CT were treated with curative intent. For semiquantitative analysis, the SUVmax of the primary tumor, axillary lymph node, and SCLN were normalized by the SUVmean of the liver (defined as SUVR-tumor, SUVR-axillary lymph node, and SUVR-SCLN, respectively). Cox proportional hazards models were used to predict disease-free survival (DFS) and overall survival (OS). Differences in DFS and OS were assessed by Kaplan-Meier analysis. RESULTS: Twenty-three patients (41.8%) experienced recurrence, and 13 (23.6%) died during follow-up (median, 70.0 months; range, 6-128 months). In multivariate analysis, SUVR-tumor greater than 3.26 (hazards ratio, 7.26; 95% confidence interval, 1.58-33.31; P = 0.01) and SUVR-SCLN greater than 1.05 (hazards ratio, 8.47; 95% confidence interval, 1.09-65.87; P = 0.04) were prognostic for OS. No clinicopathologic or PET/CT parameters were prognostic for DFS. The patients were divided into 3 groups: group 1 (n = 11, SUVR-tumor ≤3.26 and SUVR-SCLN ≤1.05); group 2 (n = 27, SUVR-tumor >3.26 or SUVR-SCLN >1.05); and group 3 (n = 17, SUVR-tumor >3.26 and SUVR-SCLN >1.05). The 5-year OS rates were 100% in group 1, 85.2% in group 2, and 51.0% in group 3. Group 3 showed worse prognosis than group 1 (P < 0.01) and group 2 (P < 0.01). CONCLUSIONS: In addition to SUVR-tumor, SUVR-SCLN seemed to play an important role in selecting patients with the worst prognosis.

Lymph Node With the Highest FDG Uptake Predicts Distant Metastasis-Free Survival in Patients With Locally Advanced Nasopharyngeal Carcinoma.

PURPOSE: Distant failure is a major concern in patients with nasopharyngeal carcinoma. We evaluated whether the metabolic features on F-FDG PET/CT can predict distant metastasis-free survival (DMFS) in patients with locally advanced nasopharyngeal carcinoma. METHODS: We retrospectively reviewed 51 patients stage III, IVA, and IVB nasopharyngeal carcinoma who underwent F-FDG PET/CT at staging. The SUVmax for the primary site and the lymph nodes with the highest uptake as well as at the farthest station were divided by the SUVmean of the background liver (TLR, NLR-H, and NLR-F, respectively). The prognostic value of clinicopathologic factors and SUV parameters for predicting DMFS were assessed using a Cox proportional hazards model. Differences in DMFS were examined by the Kaplan-Meier method. RESULTS: In the median follow-up period of 50.4 ± 39.3 months (median ± interquartile range; range, 3.8-130.9), distant metastasis developed in 11 patients (21.6%). In univariate analyses, N stage (N3b) (P = 0.003) and NLR-H >5.70 (P = 0.02) were significant prognostic factors for DMFS, and remained significant in multivariate analysis, whereas TLR (P = 0.18) and NLR-F (P = 0.76) did not. The Kaplan-Meier curves showed significantly poorer DMFS in patients with NLR-H >5.70 than in those with lower NLR-H (≤5.70) (1-year DMFS rate, 84.2% vs 93.5%; P = 0.01). CONCLUSIONS: In addition to anatomical N stage, higher NLR-H on pretreatment F-FDG PET/CT is an independent prognostic factor for worse DMFS in patients with locally advanced nasopharyngeal carcinoma.

Changes in brain metabolic connectivity underlie autistic-like social deficits in a rat model of autism spectrum disorder.

The neurobiological basis of social dysfunction and the high male prevalence in autism spectrum disorder (ASD) remain poorly understood. Although network alterations presumably underlie the development of autistic-like behaviors, a clear pattern of connectivity differences specific to ASD has not yet emerged. Because the heterogeneous nature of ASD hinders investigations in human subjects, we explored brain connectivity in an etiologically homogenous rat model of ASD induced by exposure to valproic acid (VPA) in utero. We performed partial correlation analysis of cross-sectional resting-state 18F-fluorodeoxyglucose positron emission tomography scans from VPA-exposed and control rats to estimate metabolic connectivity and conducted canonical correlation analysis of metabolic activity and behavior scores. VPA-treated rats exhibited impairments in social behaviors, and this difference was more pronounced in male than female rats. Similarly, current analyses revealed sex-specific changes in network connectivity and identified distinct alterations in the distributed metabolic activity patterns associated with autistic-like social deficits. Specifically, diminished activity in the salience network and enhanced activity in a cortico-cerebellar circuit correlated with the severity of social behavioral deficits. Such metabolic connectivity features may represent neurobiological substrates of autistic-like behavior, particularly in males, and may serve as a pathognomonic sign in the VPA rat model of ASD.