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.

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.

Acetate-Mediated Odorant Receptor OR51E2 Activation Results in Calcitonin Secretion in Parafollicular C-Cells: A Novel Diagnostic Target of Human Medullary Thyroid Cancer.

Medullary thyroid cancer originates from parafollicular C-cells in the thyroid. Despite successful thyroidectomy, localizing remnant cancer cells in patients with elevated calcitonin and carcinoembryonic antigen levels remains a challenge. Extranasal odorant receptors are expressed in cells from non-olfactory tissues, including C-cells. This study evaluates the odorant receptor signals from parafollicular C-cells, specifically, the presence of olfactory marker protein, and further assesses the ability of the protein in localizing and treating medullary thyroid cancer. We used immunohistochemistry, immunofluorescent staining, Western blot, RNA sequencing, and real time-PCR to analyze the expression of odorant receptors in mice thyroids, thyroid cancer cell lines, and patient specimens. We used in vivo assays to analyze acetate binding, calcitonin secretion, and cAMP pathway. We also used positron emission tomography (PET) to assess C11-acetate uptake in medullary thyroid cancer patients. We investigated olfactory marker protein expression in C-cells in patients and found that it co-localizes with calcitonin in C-cells from both normal and cancer cell lines. Specifically, we found that OR51E2 and OR51E1 were expressed in thyroid cancer cell lines and human medullary thyroid cancer cells. Furthermore, we found that in the C-cells, the binding of acetate to OR51E2 activates its migration into the nucleus, subsequently resulting in calcitonin secretion via the cAMP pathway. Finally, we found that C11-acetate, a positron emission tomography radiotracer analog for acetate, binds competitively to OR51E2. We confirmed C11-acetate uptake in cancer cells and in human patients using PET. We demonstrated that acetate binds to OR51E2 in C-cells. Using C11-acetate PET, we identified recurrence sites in post-operative medullary thyroid cancer patients. Therefore, OR51E2 may be a novel diagnostic and therapeutic target for medullary thyroid cancer.

Erratum: Korean Practice Guidelines for Gastric Cancer 2022: An Evidence-based, Multidisciplinary Approach.

This corrects the article on p. 3 in vol. 23, PMID: 36750993.

Korean Practice Guidelines for Gastric Cancer 2022: An Evidence-based, Multidisciplinary Approach.

Gastric cancer is one of the most common cancers in Korea and the world. Since 2004, this is the 4th gastric cancer guideline published in Korea which is the revised version of previous evidence-based approach in 2018. Current guideline is a collaborative work of the interdisciplinary working group including experts in the field of gastric surgery, gastroenterology, endoscopy, medical oncology, abdominal radiology, pathology, nuclear medicine, radiation oncology and guideline development methodology. Total of 33 key questions were updated or proposed after a collaborative review by the working group and 40 statements were developed according to the systematic review using the MEDLINE, Embase, Cochrane Library and KoreaMed database. The level of evidence and the grading of recommendations were categorized according to the Grading of Recommendations, Assessment, Development and Evaluation proposition. Evidence level, benefit, harm, and clinical applicability was considered as the significant factors for recommendation. The working group reviewed recommendations and discussed for consensus. In the earlier part, general consideration discusses screening, diagnosis and staging of endoscopy, pathology, radiology, and nuclear medicine. Flowchart is depicted with statements which is supported by meta-analysis and references. Since clinical trial and systematic review was not suitable for postoperative oncologic and nutritional follow-up, working group agreed to conduct a nationwide survey investigating the clinical practice of all tertiary or general hospitals in Korea. The purpose of this survey was to provide baseline information on follow up. Herein we present a multidisciplinary-evidence based gastric cancer guideline.

18F-FDG PET Visualizes Systemic STING Agonist-Induced Lymphocyte Activation in Preclinical Models.

Stimulator of interferon genes (STING) is a mediator of immune recognition of cytosolic DNA, which plays important roles in cancer, cytotoxic therapies, and infections with certain pathogens. Although pharmacologic STING activation stimulates potent antitumor immune responses in animal models, clinically applicable pharmacodynamic biomarkers that inform of the magnitude, duration, and location of immune activation elicited by systemic STING agonists are yet to be described. We investigated whether systemic STING activation induces metabolic alterations in immune cells that can be visualized by PET imaging. Methods: C57BL/6 mice were treated with systemic STING agonists and imaged with 18F-FDG PET after 24 h. Splenocytes were harvested 6 h after STING agonist administration and analyzed by single-cell RNA sequencing and flow cytometry. 18F-FDG uptake in total splenocytes and immunomagnetically enriched splenic B and T lymphocytes from STING agonist-treated mice was measured by γ-counting. In mice bearing prostate or pancreas cancer tumors, the effects of STING agonist treatment on 18F-FDG uptake, T-lymphocyte activation marker levels, and tumor growth were evaluated. Results: Systemic delivery of structurally distinct STING agonists in mice significantly increased 18F-FDG uptake in the spleen. The average spleen SUVmax in control mice was 1.90 (range, 1.56-2.34), compared with 4.55 (range, 3.35-6.20) in STING agonist-treated mice (P < 0.0001). Single-cell transcriptional and flow cytometry analyses of immune cells from systemic STING agonist-treated mice revealed enrichment of a glycolytic transcriptional signature in both T and B lymphocytes that correlated with the induction of immune cell activation markers. In tumor-bearing mice, STING agonist administration significantly delayed tumor growth and increased 18F-FDG uptake in secondary lymphoid organs. Conclusion: These findings reveal hitherto unknown functional links between STING signaling and immunometabolism and suggest that 18F-FDG PET may provide a widely applicable approach toward measuring the pharmacodynamic effects of systemic STING agonists at a whole-body level and guiding their clinical development.

Prognosis of resected invasive mucinous adenocarcinoma compared with the IASLC histologic grading system for invasive nonmucinous adenocarcinoma: Surgical database study in the TKIs era in Korea.

BACKGROUND: The prognosis of invasive mucinous adenocarcinoma (IMA) remains controversial and should be clarified by comparison with the International Association for the Study of Lung Cancer (IASLC) histologic grading system for invasive nonmucinous adenocarcinoma (INMA). METHODS: This study included patients with IMA who underwent curative resection. Their clinicopathological outcomes were compared with those of patients with INMA. Propensity score matching was performed to compare the prognosis of IMA with IASLC grade 2 or 3. Kaplan-Meier survival curves and log-rank tests were used to analyze recurrence-free survival (RFS) and overall survival (OS). RESULTS: The prognoses of IMA and IASLC grade 2 were similar in terms of RFS and OS. Although patients with IMA had better RFS than patients with IASLC grade 3, the OS was not significantly different. After propensity score matching, IMA demonstrated similar RFS to IASLC grade 2 but superior to IASLC grade 3; there was no difference in the OS compared with grades 2/3. Multivariate analysis revealed that tumor size (hazard ratio [HR] = 1.20, p = 0.028), lymphovascular invasion (HR = 127.5, p = 0.003), and maximum standardized uptake value (HR = 1.24, p = 0.005) were poor prognostic predictors for RFS. Patients with IMA demonstrated RFS similar to and significantly better than that of patients with IASLC grades 2 and 3, respectively. For OS, IMA prognosis was between that of IASLC grades 2 and 3. CONCLUSIONS: Since the prognosis of IMA among lung adenocarcinomas appears to be relatively worse, further clinical studies investigating IMA-specific treatment and follow-up plans are necessary to draw more inferences.

Altered Glucose Metabolism and Glucose Transporters in Systemic Organs After Bariatric Surgery.

The Roux-en-Y gastric bypass (RYGB) is highly effective in the remission of obesity and associated diabetes. The mechanisms underlying obesity and type 2 diabetes mellitus remission after RYGB remain unclear. This study aimed to evaluate the changes in continuous dynamic FDG uptake patterns after RYGB and examine the correlation between glucose metabolism and its transporters in variable endocrine organs using 18F-fluoro-2-deoxyglucose positron emission tomography images. Increased glucose metabolism in specific organs, such as the small intestine and various fat tissues, is closely associated with improved glycemic control after RYGB. In Otsuka Long-Evans Tokushima Fatty rats fed with high-fat diets, RYGB operation increases intestine glucose transporter expression and various fat tissues' glucose transporters, which are not affected by insulin. The fasting glucose decrement was significantly associated with RYGB, sustained weight loss, post-RYGB oral glucose tolerance test (OGTT) area under the curve (AUC), glucose transporter, or glycolytic enzymes in the small bowel and various fat tissues. High intestinal glucose metabolism and white adipose tissue-dependent glucose metabolism correlated with metabolic benefit after RYGB. These findings suggest that the newly developed glucose biodistribution accompanied by increased glucose transporters is a mechanism associated with the systemic effect of RYGB.

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.

Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity.

Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here, we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with downregulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll-like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a potentially novel metabolic immune checkpoint.

Profile of vascular markers and CT enhancement of hyaline vascular type Castleman's disease.

Blood vessels in lymph nodes (LNs) are unique in comprising both capillaries and high endothelial venules (HEVs). Hyaline vascular type Castleman's disease accompanies robust angiogenesis, but it is unclear how the capillaries and HEVs respond. We retrospectively examined surgical specimens of hyaline vascular type unicentric Castleman's disease patients (n = 24) and control LNs (n = 9). We performed immunohistochemistry of CD 31 for capillaries and MECA-79 for HEVs and calculated their microvascular density. We measured CT enhancement as the ratio of Hounsfield Units (HUs) of the target lesion against muscle compared with microvascular density. The microvascular density of Castleman's disease specimen were (CD 31+) 169.7 ± 77.6, (MECA-79+) 203.5 ± 96.7, and the microvascular density of control LNs were (CD 31+) 80.7 ± 20.1, (MECA-79+) 67.4 ± 23.7, respectively. The microvascular density of both CD 31+ (P < 0.001) and MECA-79+ (P < 0.001) was higher in Castleman's disease. A positive correlation existed between CT HU ratio and microvascular density for both markers (CD 31: r = 0.517, P = 0.002; MECA-79: r = 0.521, P = 0.002). Intra-nodal angiogenesis of Castleman's disease involves robust proliferation of not only CD 31+ capillaries, but also MECA-79+ HVEs, which each correlated with degree of CT enhancement.

Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells.

We determine that type I interferon (IFN) response biomarkers are enriched in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors; however, actionable vulnerabilities associated with IFN signaling have not been systematically defined. Integration of a phosphoproteomic analysis and a chemical genomics synergy screen reveals that IFN activates the replication stress response kinase ataxia telangiectasia and Rad3-related protein (ATR) in PDAC cells and sensitizes them to ATR inhibitors. IFN triggers cell-cycle arrest in S-phase, which is accompanied by nucleotide pool insufficiency and nucleoside efflux. In combination with IFN, ATR inhibitors induce lethal DNA damage and downregulate nucleotide biosynthesis. ATR inhibition limits the growth of PDAC tumors in which IFN signaling is driven by stimulator of interferon genes (STING). These results identify a cross talk between IFN, DNA replication stress response networks, and nucleotide metabolism while providing the rationale for targeted therapeutic interventions that leverage IFN signaling in tumors.

Predicting treatment outcomes using 18F-FDG PET biomarkers in patients with non-small-cell lung cancer receiving chemoimmunotherapy.

BACKGROUND: Predictive markers for treatment response and survival outcome have not been identified in patients with advanced non-small-cell lung cancer (NSCLC) receiving chemoimmunotherapy. We aimed to evaluate whether imaging biomarkers of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and routinely assessed clinico-laboratory values were associated with clinical outcomes in patients with advanced NSCLC receiving pembrolizumab plus platinum-doublet chemotherapy as a first-line treatment. METHODS: We retrospectively enrolled 52 patients with advanced NSCLC who underwent baseline 18F-FDG PET/CT before treatment initiation. PET/CT parameters and clinico-laboratory variables, constituting the prognostic immunotherapy scoring system, were collected. Optimal cut-off values for PET/CT parameters were determined using the maximized log-rank test for progression-free survival (PFS). A multivariate prediction model was developed based on Cox models for PFS, and a scoring system was established based on hazard ratios of the predictive factors. RESULTS: During the median follow-up period of 16.7 months (95% confidence interval: 15.7-17.7 months), 43 (82.7%) and 31 (59.6%) patients experienced disease progression and death, respectively. Objective response was observed in 23 (44.2%) patients. In the multivariate analysis, maximum standardized uptake value, metabolic tumour volume2.5, total lesion glycolysis2.5, and bone marrow-to-liver uptake ratio from the PET/CT variables and neutrophil-to-lymphocyte ratio (NLR) from the clinico-laboratory variables were independently associated with PFS. The scoring system based on these independent predictive variables significantly predicted the treatment response, PFS, and overall survival. CONCLUSION: PET/CT variables and NLR were useful biomarkers for predicting outcomes of patients with NSCLC receiving pembrolizumab and chemotherapy as a first-line treatment, suggesting their potential as effective markers for combined PD-1 blockade and chemotherapy.

Combined adjuvant effects of ambient vapor-phase organic components and particulate matter potently promote allergic sensitization and Th2-skewing cytokine and chemokine milieux in mice: The importance of mechanistic multi-pollutant research.

Although exposure to ambient particulate matter (PM) is linked to asthma, the health effects of co-existing vapor-phase organic pollutants (vapor) and their combined effects with PM on this disease are poorly understood. We used a murine asthma model to test the hypothesis that exposure to vapor would enhance allergic sensitization and this effect would be further strengthened by co-existing PM. We found that vapor and PM each individually exerted adjuvant effects on OVA sensitization. Co-exposure to vapor and PM during sensitization further enhanced allergic lung inflammation and OVA-specific antibody production which was accompanied by pulmonary cytokine/chemokine milieu that favored T-helper 2 immunity (i.e. increased IL-4, downregulation of Il12a and Ifng, and upregulation of Ccl11 and Ccl8). TNFα, IL-6, Ccl12, Cxcl1 and detoxification/antioxidant enzyme responses in the lung were pollutant-dependent. Inhibition of lipopolysaccharide-induced IL-12 secretion from primary antigen-presenting dendritic cells correlated positively with vapor's oxidant potential. In conclusion, concurrent exposure to vapor and PM led to significantly exaggerated adjuvant effects on allergic lung inflammation which were more potent than that of each pollutant type alone. These findings suggest that the effects of multi-component air pollution on asthma may be significantly underestimated if research only focuses on a single air pollutant (e.g., PM).

STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging.

Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT). Accordingly, IFN treatment up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.

Splenic uptake on FDG PET/CT correlates with Kikuchi-Fujimoto disease severity.

Kikuchi-Fujimoto disease (KFD) is usually self-limiting, but prolonged systemic symptoms often result in frequent hospital visits, long admission durations, or missed workdays. We investigated the role of fluorine-18 fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in assessing KFD severity. We reviewed the records of 31 adult patients with pathologically confirmed KFD who underwent 18F-FDG PET/CT between November 2007 and April 2018 at a tertiary-care referral hospital. Disease severity was assessed using criteria based on clinical manifestations of advanced KFD. Systemic activated lymph nodes and severity of splenic activation were determined using semi-quantitative and volumetric PET/CT parameters. The median of the mean splenic standardized uptake value (SUVmean) was higher in patients with severe KFD than those with mild KFD (2.38 ± 1.18 vs. 1.79 ± 0.99, p = 0.058). Patients with severe KFD had more systemically activated volume and glycolytic activity than those with mild KFD (total lesion glycolysis: 473.5 ± 504.4 vs. 201.6 ± 363.5, p = 0.024). Multivariate logistic regression showed that myalgia (odds ratio [OR] 0.035; 95% confidence interval [CI] 0.001-0.792; p = 0.035), total lymph node SUVmax (cutoff 9.27; OR 24.734; 95% CI 1.323-462.407; p = 0.032), and spleen SUVmean (cutoff 1.79; OR 37.770; 95% CI 1.769-806.583; p = 0.020) were significantly associated with severe KFD. 18F-FDG PET/CT could be useful in assessing KFD severity.

Prognostic value of metabolic tumor volume and total lesion glycolysis on preoperative 18F-FDG PET/CT in patients with localized primary gastrointestinal stromal tumors.

BACKGROUND: This study aimed to evaluate the prognostic value of pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with localized primary gastrointestinal stromal tumors (GISTs) and to compare the predictive values of 18F-FDG PET/CT parameters with those of clinicopathological prognostic factors. METHODS: Sixty-two localized GIST patients who underwent staging with 18F-FDG PET/CT from January 2007 to December 2013 before surgery were retrospectively enrolled. A volume of interest with a standardized uptake value (SUV) threshold of 2.5 was used to determine the metabolic tumor volume (MTV) and total lesion glycolysis (TLG). These metabolic indices, along with the maximum SUV (SUVmax), were analyzed to evaluate recurrence-free survival (RFS). Other significant clinical and pathologic indices were also retrospectively reviewed for RFS analysis. RESULTS: Patients were followed up for a median of 42.0 months (range, 5.6-111.5). During the follow-up period, 13 patients (21.0%) experienced disease recurrence. In univariate analysis, tumor size (> 5 cm), mitotic count (> 5/high-power field), modified National Institutes of Health (NIH) consensus criteria, adjuvant imatinib treatment, SUVmax (≥ 7.04), MTV (≥ 50.76 cm3), and TLG (≥ 228.79 g) were significant prognostic factors affecting RFS (p < 0.05). In multivariate analysis, only MTV (hazard ratio, 17.69; 95% confidence interval [CI], 2.03-154.17, p = 0.009) and TLG (hazard ratio, 20.48; 95% CI, 2.19-191.16, p = 0.008) were independent prognostic factors for RFS. The 5-year RFS rates were 96.4% and 96.6% in patients with a low MTV and TLG and 27.3% and 23.6% in patients with a high MTV and TLG, respectively (p < 0.001). CONCLUSION: MTV and TLG are independent prognostic factors for predicting recurrence in patients with localized primary GIST. Patients with a high MTV or TLG are at risk for poor prognosis and should be closely observed for disease recurrence.

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.

Different roles of surveillance positron emission tomography according to the histologic subtype of non-Hodgkin's lymphoma.

BACKGROUND/AIMS: Although the use of surveillance 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is discouraged in patients with diffuse large B-cell lymphoma, its usefulness in different subtypes has not been thoroughly investigated. METHODS: We retrospectively evaluated 157 patients who showed positive results on surveillance FDG-PET/CT every 6 months following complete response for up to 5 years. All of the patients also underwent biopsies. RESULTS: Seventy-eight (49.6%) of 157 patients had true positive results; the remaining 79 (50.3%), including eight (5.1%) with secondary malignancies, were confirmed to yield false positive results. Among the 78 patients with true positive results, the disease in seven (8.9%) had transformed to a different subtype. The positive predictive value (PPV) of FDG-PET/CT for aggressive B-cell non-Hodgkin's lymphoma (NHL) was lower than that for indolent B-cell or aggressive T-cell NHL (p = 0.003 and p = 0.018, respectively), especially in patients with a low/low-intermediate international prognostic index (IPI) upon a positive PET/CT finding. On the other hand, indolent B-cell and aggressive T-cell NHL patients showed PPVs of > 60%, including those with low/low-intermediate secondary IPIs. CONCLUSION: The role of FDG-PET/CT surveillance is limited, and differs according to the lymphoma subtype. FDG-PET/CT may be useful in detecting early relapse in patients with aggressive T-cell NHL, including those with low/low-intermediate risk secondary IPI; as already known, FDG-PET/CT has no role in aggressive B-cell NHL. Repeat biopsy should be performed to discriminate relapse or transformation from false positive findings in patients with positive surveillance FDG-PET/CT results.

CYP2D6 genotype may moderate measures of brain structure in methamphetamine users.

Chronic methamphetamine use is linked to abnormalities in brain structure, which may reflect neurotoxicity related to metabolism of the drug. As the cytochrome P450 2D6 (CYP2D6) enzyme is central to the metabolism of methamphetamine, genotypic variation in its activity may moderate effects of methamphetamine on brain structure and function. This study explored the relationship between CYP2D6 genotype and measures of brain structure and cognition in methamphetamine users. Based on the function of genetic variants, a CYP2D6 activity score was determined in 82 methamphetamine-dependent (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria) and 79 healthy-control participants who completed tests of cognitive function (i.e., attention, memory, and executive function); most were also evaluated with structural magnetic resonance imaging (MRI) (66 methamphetamine-dependent and 52 controls). The relationship between CYP2D6 activity score and whole brain cortical thickness differed by group (interaction p = 0.024), as increasing CYP2D6 activity was associated with thinner cortical thickness in the methamphetamine users (ß = -0.254; p = 0.035), but not in control subjects (ß = 0.095; p = 0.52). Interactions between CYP2D6 activity and group were nonsignificant for hippocampal volume (ps > 0.05), but both hippocampi showed trends similar to those observed for cortical thickness (negative relationships in methamphetamine users [ps < 0.05], and no relationships in controls [ps > 0.50]). Methamphetamine users had lower cognitive scores than control subjects (p = 0.007), but there was no interaction between CYP2D6 activity score and group on cognition (p > 0.05). Results suggest that CYP2D6 genotypes linked to higher enzymatic activity may confer risk for methamphetamine-induced deficits in brain structure. The behavioral consequences of these effects are unclear and warrant additional investigation.