Beschreibung: The usefulness of 18 F-FDG PET in gastric cancer recurrence is limited by low sensitivity. Given that detectability by PET is dependent on the tumor’s metabolic characteristics, we tested whether the performance of PET for gastric cancer recurrence is enhanced in patients with 18 F-FDG–avid primary tumors. Methods: Three hundred sixty-eight patients with advanced gastric cancer underwent 18 F-FDG PET/CT for initial staging and for recurrence surveillance after curative surgery. On initial PET/CT, primary tumors were 18 F-FDG–avid if they displayed focal uptake with an SUV max 4 or more. Follow-up 18 F-FDG PET/CT was evaluated for recurrent disease. Results: On initial PET/CT, the primary tumor was 18 F-FDG–avid in 236 of 368 (64.1%) and nonavid in 132 patients (35.9%). During follow-up for 18.9 ± 13.3 mo, 72 patients (19.6%) had recurrence. Of the 63 PET scans with recurrence, 42 (66.7%) and 21 (33.3%) were scans of patients with 18 F-FDG–avid and nonavid primary tumors, respectively. PET sensitivity was higher in scans of patients with 18 F-FDG–avid than nonavid tumors for all recurrences (81.0% vs. 52.4%; P = 0.018) and nonanastomosis site recurrences (82.1% vs. 47.4%; P = 0.006). The sensitivity for detecting peritoneal recurrence was also higher for the avid tumor group. PET specificity was similarly high (97.1% and 97.5%) for both groups. Adding cell type and Lauren classification to tumor 18 F-FDG avidity further enhanced PET sensitivity. Conclusion: Surveillance 18 F-FDG PET/CT after resection of gastric cancer has significantly higher sensitivity in patients with 18 F-FDG–avid primary tumors and may have greater value in this group.

Beschreibung: The utility of 18 F-FDG PET/CT in patients with nasal-type natural killer (NK)/T-cell lymphoma has not been established. Therefore, we evaluated the role of 18 F-FDG PET/CT for determining cancer staging by comparing its results to those of conventional staging methods (CSMs) (physical examination, CT with intravenous contrast, biopsies from primary sites, and bone marrow examinations) in patients with nasal-type NK/T-cell lymphoma. Methods: In this study, 52 consecutive patients (34 men, 18 women; mean age, 49.4 y) with newly diagnosed nasal-type NK/T-cell lymphoma were studied. Anatomic regions ( n = 1,300; 16 nodal and 9 extranodal regions per patient) were assessed with an 18 F-FDG PET/CT scan and with CSMs, and each anatomic region was classified as positive or negative for malignancy. Biopsy and clinical follow-up, including additional imaging studies, were used as the gold standard for diagnosis. Results: Of the 59 nodal and 71 extranodal anatomic regions that were truly positive for malignancy, 18 F-FDG PET/CT detected 58 nodal and 69 extranodal. CSMs, however, detected only 44 of the nodal and 61 of the extranodal anatomic regions that were positive for malignancy (nodal comparison of PET/CT vs. CSMs, P 〈 0.001; extranodal comparison of PET/CT vs. CSMs, P = 0.008). PET/CT scans exhibited a significantly better sensitivity (97.7% vs. 80.7%, P 〈 0.001) than CSMs for the detection of malignant lesions. PET/CT findings altered the original staging category for 12 patients (21.2%) and affected treatment planning in 23 cases (44.2%). Conclusion: Our study demonstrated that 18 F-FDG PET/CT scanning is a valuable modality for staging and treatment planning in patients with nasal-type NK/T-cell lymphoma.

Beschreibung: 11 C-LY2795050 is a novel -selective antagonist PET tracer. The in vitro binding affinities ( K i ) of LY2795050 at the -opioid (KOR) and μ-opioid (MOR) receptors are 0.72 and 25.8 nM, respectively. Thus, the in vitro KOR/MOR binding selectivity is about 36:1. Our goal in this study was to determine the in vivo selectivity of this new KOR antagonist tracer in the monkey. Methods: To estimate the ED 50 value (dose of a compound [or drug] that gives 50% occupancy of the target receptor) of LY2795050 at the MOR and KOR sites, 2 series of blocking experiments were performed in 3 rhesus monkeys using 11 C-LY2795050 and 11 C-carfentanil with coinjections of various doses of unlabeled LY2795050. Kinetic modeling was applied to calculate regional binding potential ( BP ND ), and 1- and 2-site binding curves were fitted to these data to measure 11 C-LY2795050 binding selectivity. Results: The LY2795050 ED 50 at MOR was 119 μg/kg based on a 1-site model for 11 C-carfentanil. The 1-site binding model was also deemed sufficient to describe the specific binding of 11 C-LY2795050 at KOR. The ED 50 at KOR estimated from the 1-site model was 15.6 μg/kg. Thus, the ED 50 ratio for MOR:KOR was 7.6. Conclusion: The in vivo selectivity of 11 C-LY2795050 for KOR over MOR is 7.6. 11 C-LY2795050 has 4.7-fold-lower selectivity at KOR over MOR in vivo as compared with in vitro. Nevertheless, on the basis of our finding in vivo, 88% of the PET-observed specific binding of 11 C-LY2795050 under baseline conditions will be due to binding of the tracer at the KOR site in a region with similar prevalence of KOR and MOR. 11 C-LY2795050 is sufficiently selective for KOR over MOR in vivo to be considered an appropriate probe for studying the KOR with PET.

Beschreibung: The -opioid receptors (KORs) are implicated in several neuropsychiatric diseases and addictive disorders. PET with radioligands provides a means to image the KOR in vivo and investigate its function in health and disease. The purpose of this study was to develop the selective KOR antagonist 11 C-LY2459989 as a PET radioligand and characterize its imaging performance in nonhuman primates. Methods: LY2459989 was synthesized and assayed for in vitro binding to opioid receptors. Ex vivo studies in rodents were conducted to assess its potential as a tracer candidate. 11 C-LY2459989 was synthesized by reaction of its iodophenyl precursor with 11 C-cyanide, followed by partial hydrolysis of the resulting 11 C-cyanophenyl intermediate. Imaging experiments with 11 C-LY2459989 were performed in rhesus monkeys with arterial input function measurement. Imaging data were analyzed with kinetic models to derive in vivo binding parameters. Results: LY2459989 is a full antagonist with high binding affinity and selectivity for KOR (0.18, 7.68, and 91.3 nM, respectively, for , μ, and receptors). Ex vivo studies in rats indicated LY2459989 as an appropriate tracer candidate with high specific binding signals and confirmed its KOR binding selectivity in vivo. 11 C-LY2459989 was synthesized in high radiochemical purity and good specific activity. In rhesus monkeys, 11 C-LY2459989 displayed a fast rate of peripheral metabolism. Similarly, 11 C-LY2459989 displayed fast uptake kinetics in the brain and an uptake pattern consistent with the distribution of KOR in primates. Pretreatment with naloxone (1 mg/kg, intravenously) resulted in a uniform distribution of radioactivity in the brain. Further, specific binding of 11 C-LY2459989 was dose-dependently reduced by the selective KOR antagonist LY2456302 and the unlabeled LY2459989. Regional binding potential values derived from the multilinear analysis-1 (MA1) method, as a measure of in vivo specific binding signal, were 2.18, 1.39, 1.08, 1.04, 1.03, 0.59, 0.51, and 0.50, respectively, for the globus pallidus, cingulate cortex, insula, caudate, putamen, frontal cortex, temporal cortex, and thalamus. Conclusion: The novel PET radioligand 11 C-LY2459989 displayed favorable pharmacokinetic properties, a specific and KOR-selective binding profile, and high specific binding signals in vivo, thus making it a promising PET imaging agent for KOR.

Beschreibung: This was a study to compare the diagnostic efficacies of endoscopic ultrasonography (EUS), CT, PET/MR imaging, and PET/CT for the preoperative local and regional staging of esophageal cancer, with postoperative pathologic stage used as the reference standard. Methods: During 1 y, 19 patients with resectable esophageal cancer were enrolled and underwent preoperative EUS, CT, PET/CT, and PET/MR imaging. A chest radiologist and nuclear medicine physician retrospectively reviewed the images and assigned tumor and lymph node stages according to the seventh version of the TNM system and the American Joint Committee on Cancer staging system. Four patients who were treated nonsurgically were excluded from data analysis. The efficacies of EUS, CT, PET/CT, and PET/MR imaging were compared. Results: Primary tumors were correctly staged in 13 (86.7%), 10 (66.7%), and 5 (33.3%) patients at EUS, PET/MR imaging, and CT, respectively ( P value ranging from 0.021 to 0.375). The accuracy of determining T1 lesions was 86.7%, 80.0%, and 46.7% for EUS, PET/MR imaging, and CT, respectively. For distinguishing T3 lesions, the accuracy was 93.3% for EUS and 86.7% for both PET/MR imaging and CT. For lymph node staging, the accuracy was 83.3%, 75.0%, 66.7%, and 50.0% for PET/MR imaging, EUS, PET/CT, and CT, respectively. In addition, area-under-the-curve values were 0.800, 0.700, 0.629, and 0.543 for PET/MR imaging, EUS, PET/CT, and CT, respectively. Conclusion: PET/MR imaging demonstrated acceptable accuracy for T staging compared with EUS and, although not statistically significant, even higher accuracy than EUS and PET/CT for prediction of N staging. With adjustments in protocols, PET/MR imaging may provide an important role in preoperative esophageal cancer staging in the future.

Beschreibung: Patients with breast cancer have a relatively high prevalence of diffuse thyroid uptake of 18 F-FDG related to thyroid autoimmunity. It is postulated that the presence of thyroid autoimmunity has prognostic implications for breast cancer. The aim of this study was to evaluate the prognostic value of incidental diffuse thyroid uptake in breast cancer patients. Methods: This was a retrospective observational cohort study in a tertiary referral hospital. We evaluated a total of 564 patients who had undergone surgery for primary breast cancer between January 2006 and December 2009. Patients were divided into 2 groups according to their diffuse thyroid uptake. The main outcome measure was disease-free survival. Results: Of the 564 patients, 108 (19.1%) showed diffuse thyroid uptake. The median follow-up period was 36.0 mo (range, 1.0–77.0 mo). Both thyroperoxidase and thyroglobulin antibody titers were higher in patients with thyroid uptake than in those without ( P 〈 0.001 for both). Of the 108 patients with thyroid uptake, 5 had a recurrence of breast cancer during the follow-up, whereas 85 without uptake had a recurrence (log-rank statics, 12.28; P 〈 0.001). The association between diffuse thyroid uptake and tumor recurrence was not significant in multivariate analysis of patients with early-stage breast cancer (hazard ratio, 0.26; 95% confidence interval, 0.06–1.10; P = 0.067). However, the association between diffuse thyroid uptake and breast cancer recurrence was statistically significant in multivariate analysis with adjustment for several prognostic variables (hazard ratio, 0.19; 95% confidence interval, 0.57–0.62; P = 0.006). Conclusion: Incidental diffuse thyroid uptake related to autoimmune thyroiditis was an independently favorable prognostic factor in advanced breast cancer. These findings support evidence that thyroid autoimmunity has a beneficial effect on the outcomes of breast cancer patients.

Beschreibung: Although the role of IL-7 and IL-7R has been implicated in the pathogenesis of rheumatoid arthritis (RA), the majority of the studies have focused on the effect of IL-7/IL-7R in T cell development and function. Our novel data, however, document that patients with RA and greater disease activity have higher levels of IL-7, IL-7R, and TNF-α in RA monocytes, suggesting a feedback regulation between IL-7/IL-7R and TNF-α cascades in myeloid cells that is linked to chronic disease progression. Investigations into the involved mechanism showed that IL-7 is a novel and potent chemoattractant that attracts IL-7R + monocytes through activation of the PI3K/AKT1 and ERK pathways at similar concentrations of IL-7 detected in RA synovial fluid. To determine whether ligation of IL-7 to IL-7R is a potential target for RA treatment and to identify their mechanism of action, collagen-induced arthritis (CIA) was therapeutically treated with anti–IL-7 Ab or IgG control. Anti–IL-7 Ab treatment significantly reduces CIA monocyte recruitment and osteoclast differentiation as well as potent joint monocyte chemoattractants and bone erosion markers, suggesting that both direct and indirect pathways might contribute to the observed effect. We also demonstrate that reduction in joint MIP-2 levels is responsible for suppressed vascularization detected in mice treated with anti–IL-7 Ab compared with the control group. To our knowledge, we show for the first time that expression of IL-7/IL-7R in myeloid cells is strongly correlated with RA disease activity and that ligation of IL-7 to IL-7R contributes to monocyte homing, differentiation of osteoclasts, and vascularization in the CIA effector phase.

Beschreibung: Kappa-opioid receptors (KOR) are believed to be involved in the pathophysiology of depression, anxiety disorders, drug abuse, and alcoholism. To date, only 1 tracer, the KOR agonist 11 C-GR103545, has been reported to be able to image KOR in primates. The goal of the present study was to synthesize the selective KOR antagonist 11 C-LY2795050 and evaluate its potential as a PET tracer to image KOR in vivo. Methods: The in vitro binding affinity of LY2795050 was measured in radioligand competition binding assays. Ex vivo experiments were conducted using microdosing of the unlabeled ligand in Sprague–Dawley rats and in wild-type and KOR knockout mice, to assess the ligand’s potential as a tracer candidate. Imaging experiments with 11 C-LY2795050 in monkeys were performed on the Focus-220 scanner with arterial blood input function measurement. Binding parameters were determined with kinetic modeling analysis. Results: LY2795050 displays full antagonist activity and high binding affinity and selectivity for KOR. Microdosing studies in rodents and ex vivo analysis of tissue concentrations with liquid chromatography–tandem mass spectrometry identified LY2795050 as an appropriate tracer candidate able to provide specific binding signals in vivo. 11 C-LY2795050 was prepared in an average yield of 12% and greater than 99% radiochemical purity. In rhesus monkeys, 11 C-LY2795050 displayed a moderate rate of peripheral metabolism, with approximately 40% of parent compound remaining at 30 min after injection. In the brain, 11 C-LY2795050 displayed fast uptake kinetics (regional activity peak times of 〈20 min) and an uptake pattern consistent with the distribution of KOR in primates. Pretreatment with naloxone (1 mg/kg, intravenously) resulted in a uniform distribution of radioactivity. Further, specific binding of 11 C-LY2795050 was reduced by the selective KOR antagonist LY2456302 in a dose-dependent manner. Conclusion: 11 C-LY2795050 displayed favorable pharmacokinetic properties and binding profiles in vivo and therefore is a suitable ligand for imaging the KOR in primates. This newly developed KOR antagonist tracer has since been advanced to PET imaging of KOR in humans and constitutes the first successful KOR antagonist radiotracer.

Beschreibung: Our aim was to examine the impact of TLR5 ligation in rheumatoid arthritis (RA) and experimental arthritis pathology. Studies were conducted to investigate the role of TLR5 ligation on RA and mouse myeloid cell chemotaxis or osteoclast formation, and in addition, to uncover the significance of TNF-α function in TLR5-mediated pathogenesis. Next, the in vivo mechanism of action was determined in collagen-induced arthritis (CIA) and local joint TLR5 ligation models. Last, to evaluate the importance of TLR5 function in RA, we used anti-TLR5 Ab therapy in CIA mice. We show that TLR5 agonist, flagellin, can promote monocyte infiltration and osteoclast maturation directly through myeloid TLR5 ligation and indirectly via TNF-α production from RA and mouse cells. These two identified TLR5 functions are potentiated by TNF-α, because inhibition of both pathways can more strongly impair RA synovial fluid–driven monocyte migration and osteoclast differentiation compared with each factor alone. In preclinical studies, flagellin postonset treatment in CIA and local TLR5 ligation in vivo provoke homing and osteoclastic development of myeloid cells, which are associated with the TNF-α cascade. Conversely, CIA joint inflammation and bone erosion are alleviated when TLR5 function is blocked. We found that TLR5 and TNF-α pathways are interconnected, because TNF-α is produced by TLR5 ligation in RA myeloid cells, and anti–TNF-α therapy can markedly suppress TLR5 expression in RA monocytes. Our novel findings demonstrate that a direct and an indirect mechanism are involved in TLR5-driven RA inflammation and bone destruction.

Beschreibung: We conducted a comprehensive systematic review of the literature on volumetric parameters and a meta-analysis of the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with head and neck cancer (HNC). Methods: A systematic search of MEDLINE and EMBASE was performed using the key words PET, head and neck, and volume. Inclusion criteria were 18 F-FDG PET used as an initial imaging tool; studies limited to HNC; patients who had not undergone surgery, chemotherapy, or radiotherapy before PET scans; and studies reporting survival data. Event-free survival and overall survival were considered markers of outcome. The impact of MTV or TLG on survival was measured by the effect size hazard ratio (HR). Data from each study were analyzed using Review Manager. Results: Thirteen studies comprising 1,180 patients were included in this study. The combined HR for adverse events was 3.06 (2.33–4.01, P 〈 0.00001) with MTV and 3.10 (2.27–4.24, P 〈 0.00001) with TLG, meaning that tumors with high volumetric parameters were associated with progression or recurrence. Regarding overall survival, the pooled HR was 3.51 (2.62–4.72, P 〈 0.00001) with MTV and 3.14 (2.24–4.40, P 〈 0.00001) with TLG. There was no evidence of significant statistical heterogeneity at an I 2 of 0%. Conclusion: MTV and TLG are prognostic predictors of outcome in patients with HNC. Despite clinically heterogeneous HNC and the various methods adopted between studies, we can confirm that patients with a high MTV or TLG have a higher risk of adverse events or death.