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In cancer therapy, enhanced thymidine uptake by the salvage pathway can bypass dTMP depletion, thereby conferring resistance to thymidylate synthase inhibition. We investigated whether sequential combination therapy of capecitabine and trifluridine/tipiracil (TAS-102) could synergistically enhance antitumor efficacy in colon cancer xenograft models. We also examined 3'-deoxy-3′-[18F]fluorothymidine ([18F]FLT) PET as a means to predict therapeutic response to a sequential combination of capecitabine and trifluridine/tipiracil. [3H]FLT uptake after 5-fluorouracil treatment in vitro and [18F]FLT uptake after capecitabine (360 mg/kg/day) in athymic nude mice (Balb/c-nu) with xenografts (n = 10–12 per group) were measured using eight human colon cancer cell lines. We determined the synergistic effects of sequential combinations of 5-fluorouracil and trifluridine in vitro as well as the sequential combination of oral capecitabine (30–360 mg/kg) and trifluridine/tipiracil (trifluridine 75 or 150 mg/kg with tipiracil) in six xenograft models (n = 6–10 per group). We observed significant increases in [3H]FLT uptake in all cell lines and [18F]FLT uptake in five xenograft models after 5-fluorouracil and capecitabine treatment, respectively. Increased [18F]FLT uptake after capecitabine followed by extinction of uptake correlated strongly with tumor growth inhibition (ρ = −0.81, P = 0.02). The effects of these combinations were synergistic in vitro. A synergy for sequential capecitabine and trifluridine/tipiracil was found only in mouse xenograft models showing increased [18F]FLT uptake after capecitabine. Our results suggest that the sequential combination of capecitabine and trifluridine/tipiracil is synergistic in tumors with an activated salvage pathway after capecitabine treatment in mice, and [18F]FLT PET imaging may predict the response to capecitabine and the synergistic antitumor efficacy of a sequential combination of capecitabine and trifluridine/tipiracil. Cancer Res; 77(24); 7120–30. ©2017 AACR.

Objective To determine the clinical value of visually assessed renal tissue transit time (TTT) in 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) renography for patients undergoing pyeloplasty. Materials and Methods Medical records of 164 patients who underwent dismembered pyeloplasty were retrospectively reviewed. Baseline and postoperative renal ultrasonography and 99mTc-MAG3 renography were performed. Two urologists blinded to clinical data evaluated the renography and classified TTT as timely or delayed based on visualization of the tracer in the kidney pelvis between 2 and 10 minutes. Renal functional change after pyeloplasty was compared between patients in the timely and delayed groups. Results A total of 126 patients (median age, 9 months) were evaluated after excluding patients with bilateral ureteropelvic junction obstruction, a single functioning kidney, duplicated ureter, or 5% improvement in renal function after pyeloplasty. Conclusion Delayed TTT in 99mTc-MAG3 renography was a significant predictor of renal functional improvement after pyeloplasty in ureteropelvic junction obstruction. Because substantial improvement of renal function is anticipated, we recommend immediate pyeloplasty in patients with delayed TTT and decreased DRF.

PURPOSE Few studies have reported on predicting prognosis using myocardial perfusion single-photon emission computed tomography (SPECT) during coronary artery disease (CAD) treatment. Therefore, we aimed to assess the clinical implications of myocardial perfusion SPECT during follow-up for CAD treatment. MATERIALS AND METHODS We enrolled 1153 patients who had abnormal results at index SPECT and underwent follow-up SPECT at intervals ≥6 months. Major adverse cardiac events (MACE) were compared in overall and 346 patient pairs after propensity-score (PS) matching. RESULTS Abnormal SPECT was associated with a significantly higher risk of MACE in comparison with normal SPECT over the median of 6.3 years (32.3% vs. 19.8%; unadjusted p

We compared the effects of ezetimibe/rosuvastatin 10/5 mg versus rosuvastatin 20 mg on carotid atherosclerotic plaque inflammation measured by

4-(3S)-3-[5-(2-[We studied 30 subjects (10 with deep vein thrombosis, 10 with pulmonary embolism, and 10 with arterial thromboembolism) who had signs or symptoms of acute thromboembolism, and were confirmed to have thromboembolic foci by imaging studies. Dynamic whole-body PET/CT images were acquired for up to 140 min after injection of 250 MBq of [[[

The aim of this study was to explore the ability of 18F-fluoroestradiol (18F-FES) positron emission tomography/computed tomography (PET/CT) imaging to predict pathologic response to neoadjuvant therapy in postmenopausal women with estrogen receptor (ER)-rich breast cancer. Methods: This was a prospective, single-center study conducted as a sub-study of the neoadjuvant study of chemotherapy versus endocrine therapy in postmenopausal patients with primary breast cancer (NEOCENT) trial. Patients with ER-rich breast cancer were randomized to neoadjuvant chemotherapy (NC) or neoadjuvant endocrine therapy (NET). Baseline maximum standardized uptake values (SUVmax) of 18F-FES PET/CT were measured. The pathologic response was assessed by the Miller-Payne system as non-response (grades 1 and 2) and response (grades 3–5). Results: Twenty-six patients were enrolled, with pathological response achieved in 25 (NC: 12, and NET: 13). Two patients achieved pathological complete response (pCR) after NC, but the remaining 23 patients had residual disease after NC or NET. Eight of twelve patients responded to NC, and 4 of 13 to NET; the difference was marginally significant (P = 0.07). In the NC group, the two patients with 18F-FES-negative tumors and none of the ten patients with 18F-FES-avid tumors achieved pCR (P = 0.02). No difference in the SUVmax between responders and non-responders was observed in either group. However, five of seven NC patients with a baseline SUVmax

BACKGROUND Platelets play an important role in inflammation. Inhibitors of the P2Y12 receptor, which is involved in platelet activation, may have a direct effect on carotid atherosclerotic plaque inflammation. HYPOTHESIS We compared the effects of clopidogrel and ticagrelor therapy for carotid atherosclerotic plaque inflammation using 18 F-fluorodeoxyglucose ( 18 FDG) positron emission tomography (PET) imaging. METHODS Fifty patients with acute coronary syndrome and ≥1 18 FDG uptake in the carotid artery (target-to-background ratio [TBR] ≥1.6) were randomized to either clopidogrel or ticagrelor groups. Of these, 46 completed PET examinations at baseline and at 6 months. The primary endpoint was the percent change in TBR of the index vessel at the most diseased segment (MDS). RESULTS Baseline characteristics were similar between the 2 groups. At 6-month follow-up, low-density lipoprotein cholesterol and C-reactive protein significantly decreased in both groups (P < 0.001). The TBR of the index vessel and aorta significantly decreased in both groups (P < 0.01). The percent change in the MDS TBR of the index vessel was numerically but not significantly lower in the clopidogrel group than in the ticagrelor group (-9.5 ± 14.6% vs -13.5 ± 19.3%; P = 0.427). Likewise, the percent change in the whole-vessel TBR of the index vessel was not different between the 2 groups (P = 0.166). Similar findings were observed for changes in the MDS TBR (P = 0.412) or whole-vessel TBR of the aorta (P = 0.363). CONCLUSIONS Carotid atherosclerotic plaque inflammation significantly decreases to a similar degree following 6 months of either clopidogrel or ticagrelor treatment.

We evaluated the prognostic value of pretreatment 18F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET/CT) in patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A hepatocellular carcinoma (HCC) who had received curative treatment or transarterial chemoembolization (TACE). Between 2009 and 2010, 317 patients diagnosed with HCC at seven hospitals were enrolled. Among these, 195 patients underwent curative treatments including resection, liver transplantation, and radiofrequency ablation. TACE was performed in 122 patients. The tumor-to-normal liver standardized uptake value ratio (TLR) of the primary tumor was measured using pretreatment FDG PET/CT. The prognostic significance of TLR and other clinical variables was assessed using Cox regression models. Differences in the overall survival (OS) associated with TLR or other significant clinical factors were examined using the Kaplan-Meier method. Over a median follow-up period of 46 months, 77 patients died from cancer. In the curative cohort, higher TLR (≥2) was significantly associated with death (hazard ratio [HR] = 2.68; 95 % CI, 1.16–6.15; P = 0.020) in multivariable analysis. Patients with a higher TLR had significantly worse OS than patients with a lower TLR (5-year overall survival, 61 % vs. 79.4 %; P = 0.006). In the TACE cohort, the Model for End-Stage Liver Disease (MELD) score (≥8) was a significant independent prognostic factor for OS (HR = 3.34; 95 % CI, 1.49–7.48; P = 0.003), whereas TLR was not associated with OS. The Kaplan-Meier curves showed significantly poorer OS in patients with higher MELD scores (≥8) than in those with lower MELD scores (5-year survival rate, 33.1 % vs. 79.6 %; P

509 Objectives Left atrial fibrosis is a prominent feature in patients with atrial fibrillation (AF) and the degree of fibrosis as measured by delayed enhancement magnetic resonance imaging (MRI) has prognostic and therapeutic implications. However, MRI imaging of the thin-walled left atrium can be technically challenging and is prone to artifacts. FDG-PET has the potential to assess left atrial fibrosis as the absence of metabolism. In this study, we evaluated the feasibility of assessing left atrial fibrosis using FDG-PET and compare the degree of fibrosis in clinically-referred patients in sinus rhythm and AF. Methods 28 patients in sinus rhythm and 31 with paroxysmal AF were randomly selected from patients undergoing FDG-PET myocardial viability assessment from 2013 to 2015. Gated rest Rb-82 and F-18 FDG-PET imaging with CT attenuation correction were performed. Images were manually segmented to isolate the left atrium. Volumetric assessment was performed over all vertical long axis, horizontal long axis, and short axis images to visually score extent of FDG uptake on a semi-quantitative basis. The extent of FDG uptake defects was defined as small or normal ( 50%). Results Images for the classification of FDG uptake defects are shown in Figure 1. In patients in sinus rhythm, 8 (28.6%) patients were classified as having small or normal FDG uptake defects, 3 (10.7%) with medium, 6 (21.4%) with large, and 11 (39.4%) with extensive. In patients with paroxysmal AF, 5 (16.1%) had small or normal FDG uptake defects, 6 (19.4%) had medium, 3 (9.7%) had large, and 17 (54.8%) had extensive defects. Overall, patients with paroxysmal AF had more FDG uptake defects than those in sinus rhythm. (P Conclusions FDG-PET appears capable of assessing left atrial myopathy in patients with and without AF. Patients with AF have a higher burden of left atrial fibrosis compared to those in sinus rhythm. Further research is required to determine if FDG-PET can be used to identify those at risk for developing AF or predict therapeutic response to ablation.

Background The renin‐angiotensin system plays an important role in promoting atherosclerotic plaque inflammation, which may be inhibited by angiotension‐II receptor blockers. Hypothesis We investigated the effects of fimasartan and amlodipine therapy on carotid atherosclerotic plaque inflammation using 18F‐fluorodeoxyglucose (18FDG) positron emission tomography (PET) imaging. Methods Fifty patients with acute coronary syndrome (ACS) and at least one lesion with 18FDG uptake in the carotid artery (target‐to‐background ratio [TBR] ≥ 1.6) were randomly assigned to receive either fimasartan (60 mg once a day) or amlodipine (5 mg once a day). 18FDG PET examinations were performed in all patients at baseline and 6 months. The primary endpoint was the percent change in the index vessel TBR for the most diseased segment (MDS TBR). Results The two groups had similar baseline characteristics. At the 6‐month follow‐up, index vessel and aorta MDS TBR significantly decreased in both groups. However, the percent change in index vessel MDS TBR was similar between the two groups (−9.33 ± 14.2% vs −7.73 ± 19.1%, respectively, P = 0.9). No significant difference was found for the percent change in the whole vessel TBR for the index vessel between the two groups, with similar findings for changes in MDS TBR or whole vessel TBR for the aorta. Total cholesterol, low‐density lipoprotein cholesterol levels, and blood pressure improved to a similar degree in both groups. Conclusions Fimasartan and amlodipine reduce carotid atherosclerotic plaque inflammation similarly in patients with ACS, offering the same level of effectiveness.

The purpose of this study was to evaluate the value of 3'-deoxy-3'-Sixty-eight patients with mCRC refractory to standard cytotoxic chemotherapy were enrolled and received Regorafenib (160 mg/day on days 1-21, following a 7-day break). Standard anatomical response was evaluated every 8 weeks. Both scans were performed before and on day 21 of Regorafenib.Of the 61 patients included in per-protocol analysis, complete response was not observed, but partial response was observed in 8.2% (n = 5), stable disease in 67.2% (n = 41), and progressive disease in 24.6% (n = 15). The objective response rate was 8.2% and disease control rate 75.4%. Five responders (8.2%) and 13 non-responders (21.3%) met the CT andSurvival outcome was significantly associated with PERCIST using

PURPOSE: This study aimed to determine the diagnostic value of the relative filtration fraction (RFF) assessed by dynamic (99m)Tc-diethylenetriaminepentaacetic acid ((99m)Tc-DTPA) renal scintigraphy after angiotensin-converting enzyme (ACE) inhibition for renovascular hypertension (RVHT) diagnosis. METHODS: (99m)Tc-DTPA captopril renal scintigraphy performed in adolescents or adults (≥ 10 years) with suspected RVHT was retrospectively reviewed. The RFF of the affected kidney was qualitatively assessed as the relative glomerular filtration rate during the 2 to 3-min period compared with the relative perfusion during the first 60 s (qualitative RFF) and scored from 1 (definitely same) to 5 (definitely decreased). The quantitative RFF of the affected kidney was obtained by dividing the percentage of glomerular filtration rate by the percentage of renal perfusion. RESULTS: Overall, 173 patients (high probability, n = 15; and low probability, n = 158) were included based on conventional captopril renal scintigraphic criteria. An abnormal qualitative RFF was observed in 12 patients with high probability, and the diagnostic sensitivity was 80.0% (95% CI, 51.9–95.7). The RFF was normal in 152 patients with low probability, and the diagnostic specificity was 96.2% (95% CI, 91.9–98.6). The RFF was lower in patients with high probability than in those with low probability (0.79 ± 0.15 vs. 1.02 ± 0.11, P

There is a lack of evidence regarding the efficacy of ischemia-guided coronary artery bypass grafting. We compared the incidence of graft failure between grafts bypassing ischemia-inducing and nonischemia-inducing stenoses. Between 1997 and 2011, 2,304 patients for whom baseline coronary angiography and myocardial perfusion imaging were available were identified from a single-center coronary artery bypass grafting registry. According to baseline myocardial perfusion imaging, each graft was assigned to either graft bypassing ischemia-inducing or nonischemia-inducing stenoses (ischemia-related grafts, n = 4,904; ischemia-unrelated grafts, n = 2,709). Graft failure was defined as total occlusion on coronary computed tomography angiography, performed at the discretion of the treating physician. The incidence of graft failure was compared on a per-graft basis. At 5 years, the incidence of graft failure was significantly higher in the ischemia-unrelated grafts (4.2% vs 2.9% in ischemia-related grafts; p = 0.003). Ischemia-related graft was an independent determinant of graft patency (adjusted hazard ratio 0.61; 95% confidence interval 0.44 to 0.84; p = 0.002). Increased risk of graft failure associated with ischemia-unrelated graft was observed only in the internal thoracic artery (3.3% vs 2.0%, p = 0.021) and arterial grafts (6.5% vs 4.3%, p = 0.020), but not in the venous grafts (2.7% vs 2.7%; p = 0.99). In terms of major adverse cardiac and cerebrovascular events, 5-year incidences were comparable between the patients with and without ischemia-unrelated grafts (219, 19.3% vs 160, 18.0%; p = 0.61). In conclusion, ischemia-unrelated grafts became dysfunctional more frequently than ischemia-related grafts, and were not preventive of adverse events.

Quality control and quality assurance (QC/QA) have been two of the most important issues in modern nuclear medicine (NM) imaging for both clinical practices and academic research. Whereas quantitative QC analysis software is common to modern positron emission tomography (PET) scanners, the QC of gamma cameras and/or single-photon-emission computed tomography (SPECT) scanners has not been sufficiently addressed. Although a thorough standard operating process (SOP) for mechanical and software maintenance may help the QC/QA of a gamma camera and SPECT-computed tomography (CT), no previous study has addressed a unified platform or process to decipher or analyze SPECT phantom images acquired from various scanners thus far. In addition, a few approaches have established cross-platform software to enable the technologists and physicists to assess the variety of SPECT scanners from different manufacturers. To resolve these issues, we have developed Interactive Data Language (IDL)-based in-house software for crossplatform (in terms of not only operating systems (OS) but also manufacturers) analyses of the QC data on an ACR SPECT phantom, which is essential for assessing and assuring the tomographical image quality of SPECT. We applied our devised software to our routine quarterly QC of ACR SPECT phantom images acquired from a number of platforms (OS/manufacturers). Based on our experience, we suggest that our devised software can offer a unified platform that allows images acquired from various types of scanners to be analyzed with great precision and accuracy.

Purpose Neo-ALL-In (NCT 01275859) is a single center, prospective study aimed to evaluate the recruitment feasibility, efficacy and safety profiles as well as biologic features of neoadjuvant letrozole plus lapatinib in postmenopausal women with ER and HER2 positive breast cancer. Methods Postmenopausal women with stage IIA to IIIB ER and HER-2 positive breast cancer were eligible. Patients received combination therapy of letrozole 2.5 mg orally daily plus lapatinib 1,500 mg orally daily for 18-21 weeks before surgery. Clinical responses were assessed by clinical palpation, ultrasonography (US), mammography and/or MRI. Tissue and/or blood samples were collected for analysis of biomarkers at three time points (baseline, day 15, and before surgery). Baseline Fluorine-18 Fluorodeoxyglucose (18F-FDG) and Fluorine-18 Fluoroestradiol (18F-FES) PET-CT imagings were obtained. Results Among twenty-four patients enrolled, 22 patients underwent surgery while 1 patient is currently on neoadjuvant therapy and the other patient is waiting for surgery. Among 22 patients completed surgery, 16 patients (72.7%) completed planned neoadjuvant letrozole and lapatinib, whereas 3 patients (13.6%) prematurely terminated the treatment and proceeded to surgery due to minimal clinical response or progression. Except grade 3 liver toxicities revealed in 3 patients (13.6%), which resulted in sequential dose reduction and discontinuation, adverse events were mainly grades 1 to 2 (Skin, 83.3%; GI, 77.3%), and these were generally tolerable with excellent compliance. Overall clinical response rates including complete and partial response was 72.7% (n=16), and pathologic complete response in breast (pCR; ypT0-is) was 4.5% (n=1). Clinical and pathologic responses of 22 patients by assessment modalitiesTotal (N=22, %)Clinical palpationUSMammographyMRpathologic response in breast (ypT0-is)pathologic response in breast and lymph nodes (ypT0-is N0)Overall responseCR1 (4.5)0 (0.0)0 (0.0)1 (4.5)1 (4.5)0 (0.0)1 (4.5)PR17 (77.3)12 (54.5)9 (40.9)9 (40.9)11 (50.0)15 (68.215 (68.2)No change3 (13.6)9 (40.9)13 (59.1)5 (22.7)9 (40.9)7 (31.8)4 (18.2)PD1(4.5)1 (4.5)0 (0.0)1 (4.5)1 (4.5)0 (0.0)2 (9.1)Not available/evaluable0 (0.0)0 (0.0)0 (0.0)6 (27.3)0 (0.0)0 (0.0)0 (0.0)CR, complete response; PR, partial response; PD, progressive disease; US, ultrasonography In analyses of biomarkers thus far, 81.8% of patients showed stationary expression of HER-2, 54.5% of patients showed decrease in Ki-67 expression, and 27.3% of patients showed increase in ER expression from baseline to surgery by immunothistochemistry (IHC) staining. Decreased expression of ER after surgery by IHC staining was significantly correlated with poor clinical response (p=0.004). However, no significant differences in baseline SUVmax in FDG-PET were found between responders and non-responders (8.8 VS 10.7, p=0.53). Conclusion This chemo-free combination neoadjuvant therapy was feasible, with comparable efficacy outcomes and manageable toxicities profiles. Updated data on 18F-FES PET-CT and biomarkers will be provided. Citation Format: Ji Hyun Park, Myoung Joo Kang, Jin-Hee Ahn, Jeong Eun Kim, Kyung Hae Jung, Gyung-Yub Gong, Hee Jin Lee, Byung-Ho Son, Sei-Hyun Ahn, Hak-Hee Kim, Hee Jung Shin, Dae-Hyuk Moon, Sung-Bae Kim. Neoadjuvant letrozole and lapatinib is feasible in Asian postmenopausal women with estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER-2) positive breast cancer [Neo-All-In]: First efficacy and safety report [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-14-02.

TAS-102 is an orally administered anticancer agent composed of α,α,α-trifluorothymidine (FTD) and thymidine phosphorylase inhibitor (TPI). This study assessed 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) uptake after TAS-102 administration.The human colorectal carcinoma cell lines HCT116, HT29, HCT8 and SW620 were exposed to FTD for 2 h, further incubated for 0, 2 and 24 h, and assayed for [(3)H]FLT uptake, nucleoside transport, thymidine kinase 1 (TK1) expression and TK1 activity. Static and 2-h dynamic [(18)F]FLT positron emission tomography (PET) was performed in mice bearing HT29 or SW620 tumours orally administered with vehicle or TAS-102.FTD decreased the viability of all cell lines, whereas increased [(3)H]FLT uptake (P 0.05). Increased nucleoside transport and/or TK1 expression were observed 24 h after FTD, but not in 0-2 h. Static [(18)F]FLT PET in mice bearing HT29 tumours showed accumulation of [(18)F]FLT in tumours 1 h (day 1) after TAS-102. Two-hour dynamic PET in mice bearing SW620 tumours showed increased influx constant and volume of distribution of phosphorylated [(18)F]FLT on days 1 and 8 (P 0.05) after TAS-102 with decreased dephosphorylation on day 1 (P 0.001). Ex vivo studies showed that SW620 tumours after TAS-102 had higher TK1 expression than those with vehicle on days 8 and 15.TAS-102 administration induces an increase in [(18)F]FLT uptake. Mechanisms may involve decreased dephosphorylation of [(18)F]FLT phosphate early after TAS-102 administration. Increased TK1 expression and/or nucleoside transporter may be related to increased [(18)F]FLT uptake at a later time. [(18)F]FLT PET has a potential to assess the pharmacodynamics of TAS-102 in cancer patients.

Background Inflammation plays an important role in the development of ischemic stroke. We hypothesized that inflammation of carotid atherosclerosis, as measured by 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), associates with the early recurrent ischemic lesions (ERILs). Methods This prospective study included patients with symptomatic carotid atherosclerosis. ERILs were defined as newly developed ischemic lesions in the territory of symptomatic internal carotid artery stenosis, as detected by follow-up diffusion-weighted imaging (DWI). The patients with and without ERILs were compared in terms of risk factors, inflammatory markers, and FDG uptake on PET. Results Of the 21 patients, 8 had ERILs (38.1%). Compared to the patients without ERILs, those with ERILs had higher FDG uptake (maximum standardized uptake value, 3.07 ± 0.79 vs. 2.17 ± 0.68, p = 0.013) and were more likely to have irregular carotid plaques (100% vs. 38.5%, p = 0.007). Inflammatory markers were not different between the two groups, and also did not correlate with FDG uptake. Conclusions Increased carotid plaque inflammation, as measured by FDG uptake on PET, may be a useful marker for identifying patients with symptomatic carotid atherosclerosis who are at risk of recurrence.

We explored system x C − transporter activity and the detection of inflammatory or infectious lesions using (4S)-4-(3-18F-fluoropropyl)-l-glutamate (18F-FSPG) PET. Methods: In 10 patients with various inflammatory or infectious diseases, as many as 5 of the largest lesions were selected as reference lesions. 18F-FSPG images were assessed visually and quantitatively. Expression levels of xCT, CD44, and surface markers of inflammatory cells were evaluated by immunohistochemistry. Results:18F-FSPG PET detected all reference lesions. 18F-FSPG uptake in sarcoidosis was significantly higher than that in nonsarcoidosis. The lesion–to–blood-pool SUV ratio for 18F-FSPG was comparable to that for 18F-FDG in sarcoidosis. In nonsarcoidosis, however, it was significantly lower. In 5 patients with available tissue samples, the SUVmax for 18F-FSPG and CD163 were negatively correlated (ρ = –0.872, P = 0.054). Conclusion:18F-FSPG PET may detect inflammatory lesions when activated macrophages or monocytes are present, such as in sarcoidosis.

BACKGROUND: Platelets play an important role in inflammation. Inhibitors of the P2Y(12) receptor, which is involved in platelet activation, may have a direct effect on carotid atherosclerotic plaque inflammation. HYPOTHESIS: We compared the effects of clopidogrel and ticagrelor therapy for carotid atherosclerotic plaque inflammation using (18)F‐fluorodeoxyglucose ((18)FDG) positron emission tomography (PET) imaging. METHODS: Fifty patients with acute coronary syndrome and ≥1 (18)FDG uptake in the carotid artery (target‐to‐background ratio [TBR] ≥1.6) were randomized to either clopidogrel or ticagrelor groups. Of these, 46 completed PET examinations at baseline and at 6 months. The primary endpoint was the percent change in TBR of the index vessel at the most diseased segment (MDS). RESULTS: Baseline characteristics were similar between the 2 groups. At 6‐month follow‐up, low‐density lipoprotein cholesterol and C‐reactive protein significantly decreased in both groups (P < 0.001). The TBR of the index vessel and aorta significantly decreased in both groups (P < 0.01). The percent change in the MDS TBR of the index vessel was numerically but not significantly lower in the clopidogrel group than in the ticagrelor group (−9.5 ± 14.6% vs −13.5 ± 19.3%; P = 0.427). Likewise, the percent change in the whole‐vessel TBR of the index vessel was not different between the 2 groups (P = 0.166). Similar findings were observed for changes in the MDS TBR (P = 0.412) or whole‐vessel TBR of the aorta (P = 0.363). CONCLUSIONS: Carotid atherosclerotic plaque inflammation significantly decreases to a similar degree following 6 months of either clopidogrel or ticagrelor treatment.

Neo-ALL-IN (NCT 01275859) is a single-center, phase II study aimed to evaluate the efficacy and safety profiles of neoadjuvant letrozole plus lapatinib, as well as potential biomarkers, in postmenopausal women with ER- and HER2-positive (ER+HER2+) breast cancer. Postmenopausal ER+HER2+ breast cancer of stages II–III was eligible. Daily 2.5 mg letrozole plus 1500 mg lapatinib were administered for 18–21 weeks before surgery. Clinical responses were assessed by palpation with caliper, breast ultrasonography, mammogram, and/or MRI. Biologic samples were collected for biomarker analyses at three time points (baseline, day 14, and before surgery). Baseline fluorine-18 fluorodeoxyglucose and fluorine-18 fluoroestradiol PET-CT scans were performed. Among 24 patients enrolled, 17 (70.8 %) completed planned neoadjuvant treatment, whereas 7 prematurely terminated the treatment and proceeded to surgery because of toxicity or progression; 2 patients showed definite progression, and 2 showed clinical regrowth by palpation regardless of minimal response. All patients eventually underwent breast cancer surgery. Toxicities were generally mild mostly within grades 1–2 except prolonged or recurrent grade 3 liver toxicities in 3 patients (13.6 %) regardless of sequential dose reduction, which finally led to discontinuation of treatment. The overall clinical response rates were 62.5 % (n = 15) including 1 CR in breast. However, no pathologic CR (ypT0–is N0) was achieved. SUVmax lower than 5.5 in baseline FES PET-CT (p = 0.007), baseline TILs over 20 % (p = 0.026), and decreased IHC ER Allred score after neoadjuvant treatment (p = 0.021) were significantly associated with adverse clinical response. When this chemo-free, combination neoadjuvant therapy with letrozole and lapatinib is given for Asian postmenopausal ER+HER2+ breast cancer, TILs, change of ER expression following neoadjuvant treatment, and SUVmax in baseline FES-PET are to be considered potential biomarkers in these patients.

Purpose: (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (BAY 94-9392, alias [18F]FSPG) is a new tracer to image xC− transporter activity with positron emission tomography (PET). We aimed to explore the tumor detection rate of [18F]FSPG in patients relative to 2-[18F]fluoro-2-deoxyglucose ([18F]FDG). The correlation of [18F]FSPG uptake with immunohistochemical expression of xC− transporter and CD44, which stabilizes the xCT subunit of system xC−, was also analyzed. Experimental Design: Patients with non–small cell lung cancer (NSCLC, n = 10) or breast cancer (n = 5) who had a positive [18F]FDG uptake were included in this exploratory study. PET images were acquired following injection of approximately 300 MBq [18F]FSPG. Immunohistochemistry was done using xCT- and CD44-specific antibody. Results: [18F]FSPG PET showed high uptake in the kidney and pancreas with rapid blood clearance. [18F]FSPG identified all 10 NSCLC and three of the five breast cancer lesions that were confirmed by pathology. [18F]FSPG detected 59 of 67 (88%) [18F]FDG lesions in NSCLC, and 30 of 73 (41%) in breast cancer. Seven lesions were additionally detected only on [18F]FSPG in NSCLC. The tumor-to-blood pool standardized uptake value (SUV) ratio was not significantly different from that of [18F]FDG in NSCLC; however, in breast cancer, it was significantly lower (P < 0.05). The maximum SUV of [18F]FSPG correlated significantly with the intensity of immunohistochemical staining of xC− transporter and CD44 (P < 0.01). Conclusions: [18F]FSPG seems to be a promising tracer with a relatively high cancer detection rate in patients with NSCLC. [18F]FSPG PET may assess xC− transporter activity in patients with cancer. Clin Cancer Res; 18(19); 5427–37. ©2012 AACR.

Background and Objectives 18F-fluorodeoxyglucose (18F-FDG) uptake may identify poorly differentiated tumors with a high proliferation rate that are more responsive to neoadjuvant chemotherapy. Methods We retrospectively evaluated 273 patients (mean age, 44.2 years; range 23–78 years) newly diagnosed with stage II or III invasive ductal breast cancer between 2006 and 2010. All patients were treated with neoadjuvant chemotherapy followed by surgery. The ability of parameters to predict pathological complete response (pCR), was assessed by multivariate analysis. Results Of the 273 breast cancer patients, 30 (11.0%) achieved pCR. Univariate analysis revealed that higher histologic grade (P 0.05 for each comparison). Multivariate analysis showed that negative ER (odds ratio [OR] = 9.98; 95% confidence interval [CI], 2.88–34.52, P

F]fluoride is used. To prevent this problem, an exactamount of base must be added to the reactor without appli-cation of an anion exchange cartridge.Direct base addition without an anion exchange cartridgemay control the exact amount of base added, but this methodhas some problems with controlling the

ObjectivesThe aim of this study was to evaluate the impact of ischemia-guided (IG) revascularization.BackgroundThe importance of IG revascularization has not been well-determined.MethodsThe outcomes of IG revascularization, in which revascularization was performed in the matched coronary artery with the perfusion abnormality on myocardial perfusion image (MPI), were retrospectively compared with those of non-IG revascularization in a registry of 5,340 patients with multivessel coronary disease comprising 2,587 percutaneous coronary interventions (PCIs) with drug-eluting stents and 2,753 coronary artery bypass graft (CABG) surgeries after adjustment with inverse-probability-of-treatment weighting.ResultsThe MPI was performed in 42.3% of patients, and IG revascularization was performed in 17.3%, including 12.4% in PCI and 21.8% in CABG patients (p < 0.001). The incidence of major adverse cardiac and cerebrovascular events (MACCE) including death, myocardial infarction, stroke, or repeat revascularization was significantly lower in the IG than in the non-IG group (16.2% vs. 20.7%; adjusted hazard ratio [aHR]: 0.73; 95% confidence interval [CI]: 0.60 to 0.88; p = 0.001), primarily driven by the lower repeat revascularization rate (9.9% vs. 22.8%; aHR: 0.66; 95% CI: 0.49 to 0.90; p = 0.009). Subgroup analysis showed that IG reduced the risk of MACCE in PCI (17.4% vs. 22.8%; aHR: 0.59; 95% CI: 0.43 to 0.81; p = 0.001) but not in CABG (16.0% vs. 18.5%; aHR: 0.87; 95% CI: 0.67 to 1.14; p = 0.31) patients.ConclusionsIschemia-guided revascularization with MPI, particularly in PCI-treated patients, seems to decrease the risk of repeat revascularization and MACCE for patients with multivessel disease.

Parkinson disease (PD), progressive supranuclear palsy (PSP), and multiple-system atrophy (MSA) are known to affect dopaminergic neurons of the brain stem and striatum with different preferential involvement. Here we investigated differences in striatal subregional dopamine transporter loss in PD, PSP, and MSA and assessed the diagnostic value of (18)F-fluorinated-N-3-fluoropropyl-2-β-carboxymethoxy-3-β-(4-iodophenyl)nortropane ((18)F-FP-CIT) PET in differentiating PSP and MSA from PD.Forty-nine patients with PD, 19 patients with PSP, 24 patients with MSA, and 21 healthy people (healthy controls) were examined with (18)F-FP-CIT PET. The PET images were spatially normalized and analyzed with 12 striatal subregional volume-of-interest (VOI) templates (bilateral ventral striatum [VS], anterior caudate [AC], posterior caudate, anterior putamen, posterior putamen [PP], and ventral putamen [VP]) and 1 occipital VOI template. The nondisplaceable binding potential (BP(ND)) and intersubregional ratio (ISR; defined as the ratio of the BP(ND) of one striatal subregion to that of another striatal subregion) of subregional VOIs were calculated.The BP(ND) of all VOIs in the PD, MSA, and PSP groups were significantly lower than those in the healthy controls (P0.05). The BP(ND) of AC and the AC/VS ISR in the PSP group were significantly lower than those in the PD group. The BP(ND) of VP was significantly lower, but the PP/VP ISR was significantly higher in the MSA group than in the PD group. At the cutoff value for the AC/VS ISR (0.7), the sensitivity and specificity for differentiating PSP from PD were 94% and 92%, respectively. At the cutoff value for the PP/VP ISR (0.65), the sensitivity and specificity for differentiating MSA from PD were 90% and 45%, respectively. The diagnostic accuracy of visual analysis was similar to that of quantitative analysis for differentiating PSP from PD but was significantly higher for differentiating MSA from PD.Compared with PD, PSP and MSA showed more prominent and earlier dopamine transporter loss in the AC and VP, respectively. These findings could be useful for suggesting PSP or MSA in parkinsonian cases without characteristic atypical features.

Some patients have elevated stimulated thyroglobulin (sTg) concentrations after reoperation for locoregionally recurrent/persistent papillary thyroid cancer (PTC). Little is known, however, about the efficacy of adjuvant radioactive iodine (RAI) therapy in these patients.The objective of the study was to evaluate the efficacy of adjuvant RAI therapy in patients with elevated sTg after reoperation for locally recurrent/persistent PTC.This was a retrospective observational cohort study in a tertiary referral hospital.We evaluated 45 consecutive patients with sTg greater than 2 ng/ml after reoperation for locoregionally recurrent PTC, all of whom had previously undergone initial total thyroidectomy followed by high-dose RAI remnant ablation. Of these 45 patients, 23 received adjuvant RAI therapy (adjuvant group) and 22 did not (control group).Main outcome measures included changes in sTg concentration after reoperation and disease-free survival.Over time, there were no significant differences in mean sTg concentration in the adjuvant (P = 0.35) and control (P = 0.74) groups. Only 15% of patients in the adjuvant group and 33% in the control group showed a greater than 50% decrease in sTg level from baseline. There were no between-group differences in changes (P = 0.83) or percent decrease (P = 0.97) in sTg concentration and no difference in clinical recurrence-free survival (P = 0.20).In patients who still have elevated sTg after reoperation for locally recurrent/persistent PTC, adjuvant RAI therapy compared with no additional RAI therapy resulted in no significant differences in the subsequent sTg changes or the recurrence-free survival.

Purpose: To investigate whether 18F-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) may be a potential tool to select a subgroup of patients who might be spared maintenance treatment, if the metabolic response after first-line chemotherapy could predict time-to-progression (TTP). Experimental Design: A total of 43 patients who underwent baseline FDG-PET scan and did not show disease progression (DP) after 4 cycles of first-line chemotherapy were enrolled and underwent second FDG-PET 3 weeks after completion of the first-line chemotherapy. The primary endpoint was to compare percent decrease in maximum standard uptake value (SUVmax) between early (TTP after second PET examination Results: Percent decreases in SUVmax in late DP subgroup were greater than those in early DP subgroup (mean reduction, 54.7% ± 27.2% vs. 27.8% ± 46.8%, P = 0.021). Receiver operating characteristic curves identified a 50.0% decrease in SUVmax as the optimal threshold to distinguish these subgroups. Using this value as the cutoff resulted in a positive predictive value of 82.6% and negative predictive value of 60.0% in predicting TTP ≥8 weeks. Patients with SUVmax decrease Conclusions: Fractional decrease in SUVmax of the main lesion after completion of 4 cycles of chemotherapy may discriminate patients with TTP ≥8 weeks and predict TTP and OS in patients with advanced NSCLC. Clin Cancer Res; 17(15); 5093–100. ©2011 AACR.

Objectives This study sought to evaluate the ability of minimal luminal area (MLA) measured by intravascular ultrasound (IVUS) to assess the functional significance of coronary artery disease. Background The use of IVUS to determine the functional significance of coronary artery lesions remains a matter for debate. Methods From our prospective IVUS imaging database, between July 2009 and April 2010, 170 coronary lesions in 150 patients who underwent stress myocardial single-photon emission computed tomography (SPECT) performed within 1 month of IVUS evaluation were identified and analyzed. MLA and other parameters were measured by IVUS and compared with the results of myocardial SPECT. Results Overall, 45 lesions had positive SPECT, and 125 lesions had negative SPECT. The MLA of lesions with positive SPECT was smaller than the MLA of those with negative SPECT (1.7 ± 0.5 mm 2 vs. 2.3 ± 1.1 mm 2 , p 2 , 95% confidence interval [CI]: 1.75 to 5.5, p 2 with an 86.7% sensitivity, a 50.4% specificity, a 38.6% positive predictive value, and a 91.3% negative predictive value versus lesions with a positive SPECT (area under the curve: 0.690, 95% CI: 0.615 to 0.759, p Conclusions The best cutoff value of MLA measured by IVUS to predict myocardial ischemia was 2.1 mm 2 . The IVUS-measured MLA appeared to play a limited role in detecting functionally significant lesions assessed by myocardial SPECT.

We describe new [(18)F]Fluoropropylcarbomethoxyiodophenyl-nor-tropane ([(18)F]FP-CIT) automatic preparation method by (1) using 2-methyl-2-butanol as [(18)F]fluorination solvent, (2) base amount control to minimize side reaction and (3) salt elution method to elute trapped [(18)F]fluoride. We developed manual synthesis procedures for automatic synthesis application. In this manual synthesis, we trapped [(18)F]F(-) on ion exchange cartridge and eluted with 0.2 M potassium methanesulfonate solution. We have [(18)F]fluorination at 100°C with 2-methyl-2-butanol as protic solvent for [(18)F]fluorination. After high-performance liquid chromatography analysis, we have 69.3±3.2% of [(18)F]F(-) incorporation ratio on the manual synthesis and applied these conditions to automatic preparation with GE TracerLab FX module. After setting-up of automatic synthesis and quality control procedures for clinical procedures, we have routine production of [(18)F]FP-CIT with 86.9±9.5 GBq/2.5 ml of [(18)F]F(-) as initial radioactivity and have 192 productions for 1.5 year. We have 42.5±10.9% of decay corrected radiochemical yields and they were satisfied all quality control procedures and stability to 6 h. New [(18)F]FP-CIT automatic preparation method showed high and reliable radiochemical yield and we could have enough >35 patient doses of [(18)F]FP-CIT from one production.

Background/aims Early tumor detection is crucial for the prevention of colon cancer. Near-infrared fluorescence (NIRF) imaging using a target-activatable probe may permit earlier disease detection. Matrix metalloproteinases (MMPs) participate in tumorigenesis and tumor growth. The aim of this study was to determine whether NIRF imaging using an MMP-activatable probe can detect colon tumors at early stages. Methods WE UTILIZED TWO MURINE COLON CANCER MODELS: a sporadic colon cancer model induced by azoxymethane (AOM), and a colitis-associated cancer model induced by a combination of AOM and dextran sodium sulfate (DSS). Colonic lesions were analyzed by histologic examination, Western blotting, immunohistochemical staining, and NIRF imaging using an MMP-activatable probe. Results Multiple variable-sized tumors developed in both models and progressed from adenomas to adenocarcinomas over time. At the early stage of the AOM/DSS model, diffuse inflammation was observed within the tumors. MMP expression increased progressively through normal, inflammation, adenoma, and adenocarcionoma stages. NIRF signal intensities were strongly correlated with each tumor stage from adenoma to adenocarcinoma. NIRF imaging also distinguished tumors from inflamed mucosa. Conclusions NIRF imaging using a protease-activatable probe may be a useful tool for early tumor detection. This approach could translate to improve the endoscopic detection of colon tumors, especially in patients with inflammatory bowel disease.

Histone deacetylase inhibitors (HDACIs), such as PXD101 and suberoylanilide hydroxamic acid, inhibit proliferation and stimulate apoptosis of tumor cells. The enhanced effectiveness of chemotherapy or radiotherapy when combined with HDACIs has been observed in several cancers. In this study, we investigated the antitumor effect of PXD101 combined with irinotecan in colon cancer.HCT116 and HT29 colon cancer cells for cell viability assay were treated with PXD101 and/or SN-38, the active form of irinotecan. Antitumor effects of HCT116 and HT29 xenografts treated with these combinations were evaluated. [(18)F]FLT-PET was used to detect early responses to PXD101 and irinotecan in colon cancer.PXD101 and SN38 possessed dose-dependent antiproliferative activity against HCT116 and HT29 cells and exerted a synergistic effect when used in combination. In xenografted mice, PXD101 in combination with irinotecan dramatically inhibited tumor growth without causing additive toxicity. Apoptotic effects on xenograft tumors were greater with combined treatment than with irinotecan alone. [(18)F]FLT-PET imaging revealed a 64% decrease in [(18)F]FLT uptake in tumors of HCT116 xenograft-bearing mice treated with a combination of PXD101 and irinotecan, indicating a decrease in thymidine kinase 1 (TK1) activity. These results were supported by Western blot analyses showing a decrease in tumor thymidine kinase 1 protein levels, suggesting that [(18)F]FLT-PET can be used to non-invasively detect early responses to these agents.These data show that PXD101 increases the cytotoxic activity of irinotecan in in vitro and in vivo colon cancer models and suggest these agent combinations should be explored in the treatment of colon cancer.

Imaging the pharmacodynamics of anti-cancer drugs may allow early assessment of anti-cancer effects. Increases in 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) uptake early after thymidylate synthase inhibition (TS) inhibition, the so-called flare response, is considered to be largely due to an increase in binding sites for type-1 equilibrative nucleoside transporter. We investigated the induction of thymidine kinase 1 (TK1) after 5-fluorouracil (5-FU) treatment as one of mechanisms for [(18)F]FLT flare. Exposure of nine cancer cell lines to 5-FU for 24h induced a 2.5- to 3.5-fold increase in [(18)F]FLT uptake, significantly higher than the 1.5-fold increase observed 2h after treatment. The increase of [(18)F]FLT uptake 24h after 5-FU exposure accompanied TK1 induction in most cell lines. In representative cell lines (A431 and HT29), 5-FU time-dependently increased [(18)F]FLT uptake, kinase activity and the levels of protein and mRNA for TK1, sequential cyclin E and A induction, and G(1)-S phase transition. Cycloheximide treatment and knockdown of TK1 completely inhibited 5-FU-induced [(18)F]FLT flare. On the other hand, HCT8 cells showed a biphasic [(18)F]FLT flare with lacked TK1 induction in response to the dosage of 5-FU. Cycloheximide did not inhibit 5-FU-induced [(18)F]FLT flare in this cells. In vivo dynamic [(18)F]FLT-PET and ex vivo analysis in HT29 tumor-bearing mice showed significantly increased [(18)F]FLT flux and TK1 activity of tumor tissue 24h after 5-FU administration (P

Vol. 29, No. 9 1767In conclusion, functionalized benzoxazole derivatives basedon the structural features of PIB and FDDNP showed ex-cellent binding affinities to aggregated Aβ42 fibrils. Thesecompounds could be considered as ligands for molecularimaging agents to monitor Aβ42 fibrils in AD brain due totheir high binding affinity.

In this study, we synthesized (99m)Tc(CO)(3)-2'-aminomethylpyridyl-2'-deoxyuridine ((99m)Tc(CO)(3)-AMPDU) and (99m)Tc(CO)(3)-aminoethylpyridyl-2'-deoxyuridine ((99m)Tc(CO)(3)-AEPDU) as potential agents for imaging the expression of the non-invasive herpes simplex virus type-1 thymidine kinase. AMPDU and AEPDU were synthesized from uridine in five chemical steps and then labeled with [(99m)Tc(CO)(3)(H(2)O)(3)](+) (370MBq/0.5 mL) at 100 degrees C for 10 min. Under optimal conditions (0.5 and 1.0mg for AMPDU and AEPDU and heating for 10 min), the labeling efficiency was 95.3+/-2.8% for AMPDU and 94.2+/-5.1% for AEPDU. To validate the chemical structure of (99m)Tc(CO)(3)-labeled compounds, we also synthesized ReBr(CO)(3)-AMPDU and ReBr(CO)(3)-AEPDU by reacting [Et(4)N][ReBr(3)(CO)(3)] and AMPDU or AEPDU in methanol at 25 degrees C for 6h. (99m)Tc(CO)(3)-AMPDU and (99m)Tc(CO)(3)-AEPDU had the same retention time on HPLC analysis as ReBr(CO)(3)-AMPDU and ReBr(CO)(3)-AEPDU. (99m)Tc(CO)(3)-AMPDU and (99m)Tc(CO)(3)-AEPDU had high radiochemical stabilities of 98.1+/-1.5% and 98.0+/-1.7% for 6h, respectively.

Purpose To present the preliminary results of β irradiation with use of liquid rhenium 188 ( 188 Re)-filled balloon dilation in the treatment of refractory benign airway strictures. Materials and Methods Ten sessions of β irradiation by using liquid 188 Re-filled balloon dilation were prospectively performed in nine patients with refractory bronchial strictures between 2003 and 2006. Indications for treatment were dyspnea caused by repeat stricture or no response to previous treatment (ie, balloon dilation and/or temporary stent placement or laser therapy) in seven patients and dyspnea caused by exuberant granulation tissue formation at the distal end of the placed stent in two. To assess the treatment efficacy, the authors calculated and compared the mean intervals of interventional treatments before and after dilation with 188 Re and mercaptoacetyltriglycine (MAG 3 )–filled balloons. Results Liquid 188 Re-filled balloon dilation was successfully performed in all nine patients, with no procedure-related complications. Immediately after the procedure, all patients showed resolution of their dyspnea. Five patients remained asymptomatic at 5–25-month follow-up. Four patients experienced dyspnea caused by recurrent stricture 1–10 months after dilation. The mean intervals between interventional treatments increased significantly from 3.1 months ± 2.1 before 188 Re-MAG 3 –filled balloon dilation to 10.8 months ± 8.8 after 188 Re-MAG 3 –filled balloon dilation in all nine patients (Wilcoxon signed rank test, P = .025). Conclusions β irradiation with liquid 188 Re-filled balloon dilation can be safely used for refractory benign airway strictures. A large study with longer follow-up is needed to draw a definite conclusion.

This paper describes a novel series of stilbenylbenzoxazole (SBO) and stilbenylbenzothiazole (SBT) derivatives for beta-amyloid specific binding probes. These 24 compounds were synthesized and evaluated by competitive binding assay against beta-amyloid 1-42 (Abeta42) aggregates using [(125)I]TZDM. All the derivatives displayed higher binding affinities with K(i) value in the subnanomolar range (0.10-0.74 nM) than Pittsburgh Compound-B (PIB) (0.77 nM). Among these derivatives, SBT-2, 5-fluoroethoxy-2-{4-[2-(4-methylaminophenyl)vinyl]phenyl}benzothiazole, showed lowest K(i) value (0.10 nM). In conclusion, the preliminary results suggest that these compounds are implying a possibility as a probe for detection of Abeta fibrils in Alzheimer's disease (AD) patients.

The enhanced permeability and retention (EPR) effect is used extensively for the passive targeting of many macromolecular drugs for tumors. Indeed, the EPR concept has been a gold standard in polymeric anticancer drug delivery systems. This study investigated the tumoral distribution of self-assembled nanoparticles based on the EPR effect using fluorescein and radio-labeled nanoparticles. Self-assembled nanoparticles were prepared from amphiphilic chitosan derivatives, and their tissue distribution was examined in tumor-bearing mice. The size of the nanoparticles was controlled to be 330 nm, which is a size suited for opening between thedefective endothelial cells in tumors. The long-circulating polymer nanoparticles were allowed to gradually accumulate in the tumors for 11 days. The amount of nanoparticles accumulated in the tumors was remarkably augmented from 3.4%ID/g tissue at 1 day to 25.9%ID/g tissue at 11 days after i.v. administration. The self-assembled nanoparticles were sustained at a high level throughout the 14 day experimental period, indicating their long systemic retention in the blood circulation. The γ-images provided clear evidence of selective tumor localization of the131 I-labeled nanoparticles. Confocal microscopy revealed the fluorescein-labeled nanoparticles to be preferentially localized in the perivascular regions, suggesting their extravasation to the tumors through the hyperpermeable angiogenic tumor vasculature. This highly selective tumoral accumulation of nanoparticles was attributed to the leakiness of the blood vessels in the tumors and their long residence time in the blood circulation.

We have developed three methods for removing organic impurities as well as a solid-phase extraction (SPE) method for removing metallic and ionic impurities from recovered [18O]H2O. Preliminary experiments with [16O]H2O were used to determine the optimal purification conditions. These showed that UV irradiation rapidly (

We have developed a fully automatic method for the synthesis of 16 α -[ 18 F]fluoroestradiol ([ 18 F]FES) using a disposable cassette system and conventional [ 18 F]FDG module. [ 18 F]FES was synthesized using a GE TracerLab MX module and a modified module control program. Following [ 18 F]fluorination, we hydrolyzed the product three times with a mixture of 2 N HCl and CH 3 CN. After HPLC purification, the decay corrected radiochemical yield of [ 18 F]FES was 45.3±2.8%, which was stable to 98.2±0.2% at 6 h after synthesis. This new automated synthesis method provides high and reproducible yields with the advantage of a disposable cassette system.

The objective of this study was to evaluate the usefulness of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting malignancy in thyroid nodules cytologically diagnosed as follicular neoplasm.A total of 46 patients with thyroid nodules larger than 1 cm in diameter cytologically diagnosed as follicular neoplasm at Asan Medical Center (Seoul, Korea) were included. FDG-PET images were taken in all patients before surgical resection, and the maximum standardized uptake value (SUVmax) of each nodule was measured.FDG-PET showed hypermetabolic activity of all nodules compared with normal thyroid tissue. Thirty-six patients underwent surgery, whereas 10 refused immediate operation. Fifteen patients had cancer: 11 with follicular and two each with Hürthle cell and follicular variants of papillary cancer. Twenty-one patients had benign nodules: 11 follicular adenomas, eight adenomatous hyperplasias, and two Hürthle cell adenomas. SUVmax did not differ significantly between malignant and benign nodules (3.6 +/- 3.5 vs. 3.4 +/- 3.2; P = 0.83) or among subtypes of benign nodules (P = 0.23). However, SUVmax differed significantly among subtypes of malignant nodules (P = 0.02).On FDG-PET, the glucose metabolic activities of benign thyroid follicular nodules were as high as those of malignant nodules. These findings suggest that FDG-PET has limited value for selecting candidates for surgery among patients cytologically diagnosed as follicular neoplasm.

Although [18F] fluoropropylcarbomethoxyiodophenylnortropane (FP-CIT) is a promising radiopharmaceutical for dopamine transporter imaging, it has not been used for clinical studies because of low radiochemical yield. The purpose of our study was to develop a new radiochemistry method using a protic solvent system to obtain a high radiochemical yield of [18F]FP-CIT in single-step manual and automatic preparation procedures. [18F]F(-) was trapped on a QMA Sep-Pak cartridge or PS-HCO(3) cartridge and eluted with Cs2CO(3)/K222 buffer or TBAHCO3 respectively, or 8 microl of TBAOH was added directly to [18F]F(-)/H(2)(18)O solution in a reactor without using a cartridge. After drying, 18F] fluorination was performed with 2-6 mg of mesylate precursor, 100 microl of CH(3)CN and 500 microl of t-BuOH at 50-120 degrees C for 5-30 min, followed by high-performance liquid chromatography (HPLC) purification to obtain the final product. For comparison, the same procedure was performed with a tosylate precursor. Manual synthesis gave a decay-corrected radiochemical yield of 52.2+/-4.5%, and optimal synthesis conditions were as follows: TBAOH addition, 4 mg of precursor, 100 degrees C and 20 min of [18F] fluorination (n=3). We obtained low radiochemical yields of [18F]FP-CIT with carbonate elution systems such as Cs2CO(3) or TBAHCO3. We also developed an automatic synthesis method based on manual synthesis results. In automatic production, we obtained a decay-corrected radiochemical yield of 35.8+/-5.2% after HPLC purification, and we did not have any synthesis failures (n=14). Here, we describe our new method for the synthesis of [18F]FP-CIT using a protic solvent system. This method gave a high radiochemical yield with high reproducibility and might enable [18F]FP-CIT to be used clinically and commercially.

The development of more selective delivery systems for cancer diagnosis and chemotherapy is one of the most important goals of current anticancer research. The purpose of this study is to evaluate various self-assembled nanoparticles as candidates to shuttle radionuclide and/or drugs into tumors and to investigate the mechanisms underlying the tumor targeting with self-assembled nanoparticles. By combining different hydrophobic moieties and hydrophilic polymer backbones, various self-assembled nanoparticles were prepared, and their in vivo distributions in tumor-bearing mice were studied by radionuclide imaging. One type of nanoparticles (fluorescein isothiocyanate-conjugated glycol chitosan (FGC) nanoparticles) exhibited highly selective tumoral localization. Scintigraphic images obtained 1 day after the intravenous injection of FGC nanoparticles clearly delineated the tumor against adjacent tissues. The mechanisms underlying the tumor targeting with self-assembled nanoparticles were investigated in terms of the physicochemical properties of nanoparticles and tumor microenvironments. FGC nanoparticles were preferentially localized in perivascular regions, implying their extravasation to tumors through the hyperpermeable tumor vasculature. The magnitude and pattern of tumoral distribution of self-assembled nanoparticles were influenced by several key factors —(i) in vivo colloidal stability: nanoparticles should maintain their intact nanostructures in vivo for a long period of time, (ii) particle size, (iii) intracellular uptake of nanoparticle: fast cellular uptake greatly facilitates the tumor targeting, (iv) tumor angiogenesis: pathological angiogenesis permits access of nanoparticles to tumors. We believe that this work can provide insight for the engineering of nanoparticles and be extended to cancer therapy and diagnosis, so as to deliver multiple therapeutic agents and imaging probes at high local concentrations.

Little data are available to compare the clinical implications of coronary angiography (CAG) or myocardial perfusion imaging (MPI) as an initial evaluation for stable coronary artery disease (CAD).From national health insurance claims data in South Korea, patients aged 18 y or older without a known history of CAD, who underwent CAG or MPI for the diagnosis of stable CAD between 2009 and 2013, were enrolled. Patients were divided into CAG (n = 117,134) and MPI (n = 19,932) groups. The primary endpoint, defined as a composite of all-cause death and myocardial infarction, was compared by a propensity score analysis between the 2 groups.There was a significant increase (39%) in the annual rate of CAG from 23,985 in 2009-2010 to 33,373 in 2012-2013. However, a substantial reduction (41%) in the annual MPI rate was also noted from 6,389 in 2009-2010 to 3,790 in 2012-2013. During the follow-up period (median, 2.4 y; interquartile range, 1.5-3.5), coronary revascularization was more frequently performed in the CAG group (adjusted hazard ratio [aHR] of CAG, 24.15; 95% confidence interval [CI], 19.66-29.68; P0.001). However, the incidence of the primary endpoint was significantly higher in the CAG group (aHR, 1.26; 95% CI, 1.17-1.36; P0.001). The individual endpoints of death (aHR, 1.16; 95% CI, 1.06-1.25; P = 0.001) and myocardial infarction (aHR, 1.95; 95% CI, 1.60-2.36; P0.001) were also higher in the CAG group.As an initial diagnostic test in patients with stable CAD, MPI is associated with a better clinical outcomes than CAG.

Purpose Hypoxia is an important factor influencing tumor progression and treatment efficacy. The aim of this study was to investigate the repeatability of hypoxia PET imaging with [18F]HX4 in patients with head and neck and lung cancer. Methods Nine patients with lung cancer and ten with head and neck cancer were included in the analysis (NCT01075399). Two sequential pretreatment [18F]HX4 PET/CT scans were acquired within 1 week. The maximal and mean standardized uptake values (SUVmax and SUVmean) were defined and the tumor-to-background ratios (TBR) were calculated. In addition, hypoxic volumes were determined as the volume of the tumor with a TBR >1.2 (HV1.2). Bland Altman analysis of the uptake parameters was performed and coefficients of repeatability were calculated. To evaluate the spatial repeatability of the uptake, the PET/CT images were registered and a voxel-wise comparison of the uptake was performed, providing a correlation coefficient. Results All parameters of [18F]HX4 uptake were significantly correlated between scans: SUVmax (r = 0.958, p

This study aimed to assess the prognostic value of (18)F-FDG uptake in hepatocellular carcinoma (HCC) patients who had transarterial chemoembolization (TACE) or concurrent intraarterial chemotherapy with external-beam radiotherapy (CCRT) and to compare the prognosis between patients treated with TACE and those with CCRT according to (18)F-FDG uptake.Two hundred fourteen intermediate-to-advanced-stage HCC patients without extrahepatic metastasis who underwent staging (18)F-FDG PET/CT before TACE (153 patients) or CCRT (61 patients) were recruited from 7 hospitals. Progression-free survival (PFS) and overall survival (OS) were compared using an optimal cutoff value for tumor-to-normal liver uptake ratio (TLR). Further, PFS and OS were compared according to treatment modalities (TACE vs. CCRT) using the same TLR cutoff value.On multivariate analysis, age and TLR were independent prognostic factors for PFS (P0.050). For OS, Child-Pugh classification and TLR were independent prognostic factors (P0.050). When the TLR was greater than 2.0, patients treated with CCRT showed significantly better PFS and OS than those treated with TACE after adjusting for tumor size and number (P= 0.014, for all). In contrast, there was no significant difference in PFS and OS between patients treated with TACE or CCRT when the TLR was 2.0 or less.(18)F-FDG uptake was an independent prognostic factor for PFS and OS in HCC patients treated with TACE or CCRT. Especially, in HCCs with high (18)F-FDG uptake, patients treated with CCRT showed better survival than those treated with TACE. (18)F-FDG PET/CT may help determine the treatment modality for intermediate-to-advanced-stage HCCs.