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AVI, 161K, Maximum intensity projection of 18FFSPG in a breast cancer patient (Patient 13).

Table S1 shows RT-PCR primer sequence list. Table S2 is the summary of the in vitro and in vivo data

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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 P = 0.001) and OS (not reached vs. 14.2 months, P = 0.003).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.

CCR Translation on the Article from [18F]Fluorothymidine Positron Emission Tomography before and 7 Days after Gefitinib Treatment Predicts Response in Patients with Advanced Adenocarcinoma of the Lung

Figure S1 shows IC50 of 5-fluorouracil in cell lines. Figure S2 shows mRNA expression of ENT1, TK1, TS, TP, and DPD in human colon cancer cell lines. Table S3 shows relationship between 5-fluorouracil sensitivity (IC50) and mRNA expression of 5-fluorouracil transporter or metabolic enzymes. Figure S4 shows correlation of capecitabine sensitivity in human colon cancer xenografts (%TGI) with 5-fluorouracil sensitivity (IC50) in vitro. Figure S5 shows correlation of capecitabine sensitivity in human colon cancer xenografts (%TGI) with the maximal SUV (SUVmax) of [18F]FLT PET. Figure S6 shows capecitabine induced changes in TK1 activity of ex vivo tumor tissues on day 4 in HCT8, HT29, and HCT116 human colon cancer xenografts. Figure S7 and S8 show immunohistochemical evaluation of ENT1 and TP expression in ex vivo xenografts and correlation with %TGI by capecitabine. Figure S9 shows correlation of capecitabine sensitivity in human colon cancer xenografts (%TGI) with ex vivo mRNA expression of 5-fluorouracil transporter and metabolic enzymes.

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.

Purpose: To evaluate the usefulness of 3′-deoxy-3′-[18F]fluorothymidine (FLT)-positron emission tomography (PET) for predicting response and patient outcome of gefitinib therapy in patients with adenocarcinoma of the lung.Experimental Design: Nonsmokers with advanced or recurrent adenocarcinoma of the lung were eligible. FLT-PET images of the thorax were obtained before and 7 days after the start of gefitinib (250 mg/d) therapy, the maximum standardized uptake values (SUVmax) of primary tumors were measured, and the percent changes in SUVmax were calculated. After 6 weeks of therapy, the responses were assessed by computed tomography of the chest.Results: Among 31 patients who were enrolled, we analyzed 28 patients for whom we had complete data. Chest computed tomography revealed partial response in 14 (50%), stable disease in 4 (14%), and progressive disease in 10 (36%) after 6 weeks of treatment. Pretreatment SUVmax of the tumors did not differ between responders and nonresponders. At 7 days after the initiation of therapy, the percent changes in SUVmax were significantly different (−36.0 ± 15.4% versus 10.1 ± 19.5%; P < 0.001). Decrease of >10.9% in SUVmax was used as the criterion for predicting response. The positive and negative predictive values were both 92.9%. The time to progression was significantly longer in FLT-PET responders than nonresponders (median, 7.9 versus 1.2 months; P = 0.0041).Conclusion: FLT-PET can predict response to gefitinib 7 days after treatment in nonsmokers with advanced adenocarcinoma of the lung. The change in tumor SUVmax obtained by FLT-PET seems to be a promising predictive variable.

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AVI, 180K, Maximum intensity projection of 18FFSPG in a lung cancer patient (Patient 2).

PDF file, 358K, S1: System xC� and CD44 in glutathione biosynthesis and the cysteine-cystine redox cycle; S2: 18FFSPG distribution in normal organs and cancer; S3: Correlation between 18FFDG and 18FFSPG; S4: 18FFDG and 18FFSPG PET in a breast cancer patient; S5: Correlation analysis between the staining intensity of xC� transporter and CD44 expression.

PDF file, 72K, S1: Clinical safety laboratory parameters; S2: Tissue distribution of 18FFSPG.

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.

We aimed to explore whether the imaging of antiporter system x(C)(−) of immune cells with (4S)-4-(3-(18)F-fluoropropyl)-l-glutamate ((18)F-FSPG) PET can assess inflammatory bowel disease (IBD) activity in murine models and patients (NCT03546868). Methods: (18)F-FSPG PET imaging was performed to assess IBD activity in mice with dextran sulfate sodium-induced and adoptive T-cell transfer–induced IBD and a cohort of 20 patients at a tertiary care center in South Korea. Immunohistochemical analysis of system x(C)(−) and cell surface markers was also studied. Results: Mice with experimental IBD showed increased intestinal (18)F-FSPG uptake and xCT expression in cells positive (+) for CD11c, F4/80, and CD3 in the lamina propria, increases positively associated with clinical and pathologic disease activity. (18)F-FSPG PET studies in patients, most of whom were clinically in remission or had mildly active IBD, showed that PET imaging was sufficiently accurate in diagnosing endoscopically active IBD and remission in patients and bowel segments. (18)F-FSPG PET correctly identified all 9 patients with superficial or deep ulcers. Quantitative intestinal (18)F-FSPG uptake was strongly associated with endoscopic indices of IBD activity. The number of CD68(+)xCT(+) and CD3(+)xCT(+) cells in 22 bowel segments from patients with ulcerative colitis and the number of CD68(+)xCT(+) cells in 7 bowel segments from patients with Crohn disease showed a significant positive association with endoscopic indices of IBD activity. Conclusion: The assessment of system x(C)(−) in immune cells may provide diagnostic information on the immune responses responsible for chronic active inflammation in IBD. (18)F-FSPG PET imaging of system x(C)(−) activity may noninvasively assess the IBD activity.

BACKGROUND Sodium-glucose co-transporter 2 inhibitors reduce the risk of cardiovascular events in type 2 diabetic patients with coronary artery disease (CAD); however, the underlying mechanisms remain unclear. OBJECTIVES We compared the effects of empagliflozin vs. sitagliptin therapy on myocardial perfusion reserve (MPR) using dynamic single-photon emission computed tomography (SPECT) imaging. METHODS In total, 100 patients with type 2 diabetes, CAD and an MPR

Purpose: (4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is a radiopharmaceutical for PET imaging of system xC− activity, which can be upregulated in prostate cancer. We present data on the first evaluation of patients with newly diagnosed or recurrent prostate cancer with this radiopharmaceutical. Experimental Design: Ten patients with primary and 10 patients with recurrent prostate cancer were enrolled in this prospective multicenter study. After injection of 300 MBq of 18F-FSPG, three whole-body PET/CT scans were obtained. Visual analysis was compared with step-section histopathology when available as well as other imaging studies and clinical outcomes. Metabolic parameters were measured semiquantitatively. Expression levels of xCT and CD44 were evaluated by IHC for patients with available tissue samples. Results: 18F-FSPG PET showed high tumor-to-background ratios with a relatively high tumor detection rate on a per-patient (89%) and per-lobe (87%) basis. The sensitivity was slightly higher with imaging at 105 minutes in comparison with 60 minutes. The maximum standardized uptake values (SUVmax) for cancer was significantly higher than both normal (P < 0.005) and benign pathology (P = 0.011), while there was no significant difference between normal and benign pathology (P = 0.120). In the setting of recurrence, agreement with standard imaging was demonstrated in 7 of 9 patients (78%) and 13 of 18 lesions (72%), and revealed true local recurrence in a discordant case. 18F-FSPG accumulation showed moderate correlation with CD44 expression. Conclusions: 18F-FSPG is a promising tumor imaging agent for PET that seems to have favorable biodistribution and high cancer detection rate in patients with prostate cancer. Further studies are warranted to determine the diagnostic value for both initial staging and recurrence, and how it compares with other investigational radiotracers and conventional imaging modalities.

Background/aim Somatic mutations were investigated in 21 patients with postmenopausal estrogen receptor (ER)-positive and human epidermal growth factor receptor-2 (HER-2)-positive (ER+HER2+) breast cancer (BC) treated with neoadjuvant letrozole and lapatinib, to identify their distinct molecular landscape. Patients and methods We used tissue samples of 21 patients from phase II Neo ALL-IN cohort, and somatic alterations were examined using targeted exome sequencing performed in Foundation Medicine, Inc. (FMI). Results TP53 (61.9%) and PIK3CA (57.1%) were the two most frequently mutated genes that were inter-correlated (p=0.026). They were associated with unfavorable clinical outcomes, particularly when accompanying PIK3CA mutations at exon 9 in helical domains. Meanwhile, MLL2 alteration was negatively associated with mutations of TP53 or PIK3CA, and it tended to be present in patients with low KI-67 levels and no initial nodal involvement. Moreover, patients with MLL2 mutations numerically showed more favorable overall response rates (ORR) (80% vs. 56.2%) and better 5-year event-free survival (EFS) rates (100% vs. 87.5%) compared to the wild-type. Conclusion Mutations in TP53 and PIK3CA hotspot at exon 9 may be potential negative predictors of ER+HER2+ BC treated with neoadjuvant letrozole and lapatinib, while MLL2 inactivating mutation might confer therapeutic benefit in these patients.

We compared the effects of ezetimibe/rosuvastatin 10/5 mg versus rosuvastatin 20 mg on carotid atherosclerotic plaque inflammation measured by 18FDG PET/CT. Fifty patients with acute coronary syndrome (ACS) were randomly assigned to the ezetimibe/rosuvastatin 10/5 mg and rosuvastatin 20 mg groups. The primary outcome was the percent change in the target-to-background ratio (TBR) of the index vessel in the most diseased segment (MDS), as assessed by 18FDG PET/CT at baseline and at 6 months. Forty-eight patients completed follow-up PET/CT. MDS TBR was − 6.2 ± 13.9% for patients in the ezetimibe/rosuvastatin group and − 10.8 ± 17.7% for those in the rosuvastatin group (difference, 4.6 percentage points; upper limitation of one-sided confidence interval = 13.8; p = 0.60 for noninferiority). In conclusion, combination therapy with ezetimibe 10 mg and rosuvastatin 5 mg compared with rosuvastatin 20 mg did not meet the criterion for non-inferiority for primary outcome, and the present study was not conclusive on whether the former was non-inferior to the latter.

Accurate determination of the hormone receptor status in patients with breast cancer is necessary to provide better palliative treatment because of the frequent discordant status of hormone receptors between primary breast cancer and metastatic lesions. In particular, the invasive nature and small number of cells recovered from the cerebrospinal fluid collected through lumbar puncture limit the detailed immunocytochemistry investigation of leptomeningeal metastasis. Moreover, none of the conventional imaging modalities provide any information on the hormone receptor status of leptomeningeal metastasis in patients with breast cancer. Herein, we report estrogen receptor–positive leptomeningeal metastasis clearly demonstrated by 16α-[(18)F]-fluoro-17β-estradiol ([(18)F]-FES) positron emission tomography/computed tomography (PET/CT) in a patient with metastatic breast cancer.

We examined whether

Tyrosine kinase inhibitor-induced hypothyroidism is associated with favorable survival in patients with various cancers. We aimed to investigate the incidence of regorafenib-induced hypothyroidism and assess its prognostic value in patients with metastatic or unresectable colorectal cancer (CRC) receiving regorafenib. This study included 68 patients treated at Asan Medical Center (Seoul, Republic of Korea) between 2014 and 2016 with metastatic or unresectable CRC refractory to standard therapies. Regorafenib (160 mg/day on days 1–21 followed by a 7-day break) was administered. The median patient age was 58 (range 26–72) years; 61.8% of patients were male. Among the 68 patients, 50 (73.5%) showed hypothyroidism; 39 (57.4%) had subclinical and 11 (16.2%) had symptomatic hypothyroidism. Overall, the objective response rate (ORR) and disease control rate (DCR) were 7.4% and 70.6%, respectively; both were significantly higher in patients with symptomatic or subclinical hypothyroidism than in euthyroid patients (ORR 27.3% vs. 5.1% vs. 0.0%, P = 0.001; DCR 100% vs. 76.9% vs. 38.9%, P = 0.001). Median progression-free survival (PFS) and overall survival (OS) were longer in patients with symptomatic hypothyroidism than in those with subclinical hypothyroidism (median PFS 9.1 vs. 3.8 months, P = 0.018; median OS: 19.2 vs. 9.4 months, P = 0.012) or with euthyroid status (median PFS 9.1 vs. 1.8 months, P

Background Using 18F-fluorodeoxyglucose (18FDG) positron emission tomography-computed tomography (PET/CT) imaging, we examined the effects of ezetimibe/simvastatin 10/10 mg versus rosuvastatin 10 mg on carotid atherosclerotic plaque inflammation. Whether the combination therapy of ezetimibe with low-dose statin is as effective as potent statin monotherapy in attenuating carotid atherosclerotic plaque inflammation remains unclear. Methods In this 2-by-2 factorial trial, 50 patients with 18FDG uptake (target-to-background ratio [TBR] ≥1.6) in the carotid artery and acute coronary syndrome were randomized to receive either simvastatin/ezetimibe 10/10 mg or rosuvastatin 10 mg. 18FDG PET/CT examinations were performed at baseline and at 6 months. The percent change in the TBR of the index vessel at the most diseased segment (MDS) was the primary endpoint. Results Baseline characteristics of the two groups were largely similar. At 6-month follow-up, the MDS TBR of the index vessel and aorta significantly decreased in ezetimibe/simvastatin group and tended to decrease in rosuvastatin group. However, the percent change in the MDS TBR of the index vessel was similar between the 2 groups (− 10.22 ± 17.49% vs. -5.84 ± 15.78%, respectively, p = 0.357), as was the percent change in the whole vessel TBR of the index vessel. Likewise, the changes in the MDS TBR or whole vessel TBR of the aorta were similar in both groups. Total cholesterol and low-density lipoprotein cholesterol levels improved to a similar degree in both groups. Conclusion Treatment with ezetimibe/simvastatin versus rosuvastatin resulted in a similar improvement of carotid atherosclerotic plaque inflammation, suggesting their equivalent anti-inflammatory effects. Trial registration The trial is registered at ClinicalTrials.gov: NCT02378064, 3-4-2015. /IRB No. 2015–0194.

This study aimed to determine the diagnostic value of the relative filtration fraction (RFF) assessed by dynamic 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) renal scintigraphy after angiotensin-converting enzyme (ACE) inhibition for renovascular hypertension (RVHT) diagnosis. 99mTc-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. 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

Purpose 4-(3S)-3-[5-(2-[18F]-fluoroethoxy)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]-piperidin-3-yl}carbonyl)amino]propanoic acid ([18F]GP1) is a radiotracer developed for targeted imaging of activated platelet glycoprotein IIb/IIIa receptors with positron emission tomography/computed tomography (PET/CT) in acute thromboembolism. We evaluated here radiation dosimetry of [18F]GP1 in humans. Procedures 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 [18F]GP1. Radiation absorbed dose and effective dose were calculated using the OLINDA/EXM software. Results [18F]GP1 PET images showed high initial uptake of the tracer in the heart, spleen, kidney, and liver. [18F]GP1 activity was cleared by hepatobiliary and urinary excretion. The organ receiving the highest radiation absorbed dose (mGy/MBq) was the urinary bladder (0.0884 ± 0.0458), followed by upper large intestine (0.0498 ± 0.0189), small intestine (0.0454 ± 0.0166), and kidneys (0.0350 ± 0.0231). The effective dose (mSv/MBq) was 0.0212 ± 0.0027 (ICRP 103). ED was not significantly different between the three disease groups (p = 0.94). A 45-minute voiding reduced the urinary bladder wall radiation dose to 0.0495 ± 0.0140 mGy/MBq, and effective dose (ICRP 103) to 0.0186 ± 0.0030. Conclusions [18F]GP1 has favorable radiation dosimetry profile for clinical PET/CT imaging. The ED is comparable to commonly used 18F PET tracers.

Summary Background A biopsy of first recurrence or metastatic disease is recommended to re-evaluate oestrogen receptor status in patients with breast cancer and to select appropriate treatment. However, retesting for oestrogen receptor status with rebiopsy is not always feasible, depending on lesion location and the risk associated with biopsy, and in these cases clinicians continue to treat patients according to the oestrogen receptor status of the primary tumour. Consequently suboptimal therapy might be offered to these patients. We assessed the diagnostic accuracy and safety of 16α-[18F]fluoro-17β-oestradiol (18F-FES) PET-CT to assess oestrogen receptor status in patients with recurrent or metastatic breast cancer. Methods We did a prospective cohort study at the Asan Medical Center, Seoul, South Korea. Eligible patients had breast cancer, with first recurrence or metastatic disease at presentation, were 19 years or older, and had an Eastern Cooperative Oncology Group performance status of 0–2. The primary objective was to show the agreement between qualitative 18F-FES PET-CT interpretation and the results of oestrogen receptor expression by immunohistochemical assay, a non-reference standard test. Whole-body 18F-FES PET-CT imaging was done after intravenous injection of 111–222 MBq of 18F-FES, with dosing primarily determined by radiation dosimetry analysis. 18F-FES uptake above background intensity was interpreted as positive. Efficacy was assessed in all patients with histologically confirmed recurrent or metastatic breast cancer who received 18F-FES and had PET-CT images available (intention-to-diagnose analysis), and safety was assessed in all patients who received 18F-FES. This study is registered with ClinicalTrials.gov, number NCT01986569. Findings Between Nov 27, 2013, and Nov 10, 2016, 93 patients were enrolled. Of the 85 patients included in the efficacy analysis, 47 (55%) were oestrogen receptor-positive and 38 (45%) were oestrogen receptor-negative. Positive status percent agreement between the 18F-FES PET-CT results and oestrogen receptor status by immunohistochemical assay was 76·6% (95% CI 62·0–87·7) and the negative status percent agreement was 100·0% (90·8–100·0). Patients who were oestrogen receptor-positive and had a positive 18F-FES PET-CT result had a significantly higher progesterone receptor expression than those who were oestrogen receptor-positive and had a negative 18F-FES PET-CT result (23 [68%] of 34 patients vs 0 of 11 patients; p Interpretation The high negative percent agreement between 18F-FES PET-CT and oestrogen receptor status by immunohistochemical assay in this cohort suggests that positive 18F-FES uptake by recurrent or metastatic oestrogen receptor-positive breast cancer lesions could be an alternative to oestrogen receptor assays in this setting. Staging assessment should include 18F-FES PET-CT when retesting oestrogen receptor status is not feasible. Funding Asan Institute for Life Sciences, Ministry of Health and Welfare, South Korea.

Background We aimed to compare the myocardial ischemic burden assessed using semi-quantitative and quantitative analysis of computed tomography-myocardial perfusion imaging (CT-MPI) with that of single-photon emission computed tomography (SPECT). Methods From 2011 to 2013, 97 patients who underwent CT-MPI and SPECT were evaluated. The extent and severity of perfusion defects were assessed on a 5-point scale using a standard 16-segment model, and were expressed as summed stress score (SSS) and summed difference score (SDS). Receiver operating characteristic (ROC) curves for quantitative parameters were generated for the diagnosis of abnormal perfusion defect (SSS ≥ 4) and presence of ischemia (SDS ≥ 2) on SPECT. Results On CT-MPI, 298 (19.2%) of the 1552 segments showed perfusion abnormalities during stress, whereas perfusion abnormalities were shown in 179 (11.5%) segments on SPECT-MPI. On a per-person basis, there was good agreement, with intraclass correlation coefficients of 0.78 for SSS and 0.72 for SDS. A significant reduction of attenuation in stress and myocardial perfusion reserve index, along with an increase in % defect volume of CT-MPI, were demonstrated as the degree of perfusion defect or ischemia on SPECT increased. On the ROC curves, % defect volume on CT-MPI demonstrated the highest area under the curve: 0.91 for abnormal perfusion defect and 0.89 (all p Conclusions Semi-quantitative analysis of CT-MPI showed good accordance with SPECT. A quantitative approach for CT-MPI, especially % defect volume, may provide additional value in the identification of myocardial perfusion abnormalities. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01696006 .

Combination of MEK inhibitor and 5-FU had showed limited efficacy in clinical trials. We previously reported that acquired resistance to 5-FU was related with continued activation of salvage pathway. Here we investigated whether combination of 5-FU and a MEK inhibitor had treatment sequence-dependent synergistic effects in KRAS or BRAF mutant colon cancer models. Treatment with 5-FU followed by selumetinib (FS) induced highest cell death and synergy compared with reverse (SF) and concomitant (cFS) treatment in six cell lines. SF or cFS combination induced synergy in 1 or 2 cell lines, respectively, in which the synergy was less than that by FS combination. FS enhanced apoptosis and decreased anchorage-independent growth. Induction of thymidine kinase 1, a rate-limiting enzyme in salvage pathway, by 5-FU was abrogated by subsequent treatment with selumetinib, and ERK reactivation after selumetinib was prohibited by pretreatment with 5-FU. FS altered mRNA expression in groups of genes distinct from SF. Administration of 5-FU (10 or 30 mg/kg/day) for 7 days, followed by selumetinib (10 or 25 mg/kg/day) for another 7 days, in colo205 and HCT8 xenograft models significantly decreased tumor growth compared with a single agent. However, co-administration in the reverse sequence did not show the difference in tumor size compared with the treatment of single agent. Decreased expression of Ki67 was observed in tumors from mice treated with FS. Our results suggest that sequential administration of 5-FU plus selumetinib would be a promising strategy for patients having KRAS or BRAF mutant colon cancers.

It remains uncertain whether statin/ezetimibe combination therapy serves as a useful and equivalent alternative to statin monotherapy for reducing atherosclerotic plaque inflammation. The aim of the present study was to compare the effects of statin/ezetimibe combination therapy and statin monotherapy on carotid atherosclerotic plaque inflammation using 18F-fluorodeoxyglucose (18FDG) positron emission tomography (PET)/computed tomography (CT) imaging. Data were pooled from 2 clinical trials that used serial 18FDG PET/CT examination to investigate the effects of cholesterol-lowering therapy on carotid atherosclerotic plaque inflammation. The primary outcome was the percent change in the target-to-background ratio (TBR) of the index vessel in the most diseased segment (MDS) at 6-month follow-up. Baseline characteristics were largely similar between the 2 groups. At the 6-month follow-up, the MDS TBR of the index vessel significantly decreased in both groups. The percent change in the MDS TBR of the index vessel (primary outcome) did not differ significantly between the 2 groups (-8.41 ± 15.9% vs -8.08 ± 17.0%, respectively, P = .936). Likewise, the percent change in the whole vessel TBR of the index vessel did not differ significantly between the 2 groups. There were significant decreases in total and LDL cholesterol levels in both groups at follow-up (P

System xc− contributes to glutathione (GSH) synthesis and protects cells against ferroptosis by importing cystine and exchanging it with glutamate. Transforming growth factor β1 (TGF-β1) induces redox imbalance; however, its role in system xc− regulation remains poorly understood. The present study was the first to show that TGF-β1 repressed the protein and mRNA levels of xCT, a catalytic subunit of system xc−, in PLC/PRF/5, Huh7, Huh6, and HepG2 cells with an early TGF-β1 gene signature but not in SNU387, SNU449, SNU475, and SK-Hep1 cells with a late TGF-β1 gene signature. TGF-β1 treatment for 24 h reduced xCT expression in a dose-dependent manner but this TGF-β1-induced repression was blunted by pretreatment with a TGF-β1 receptor inhibitor. TGF-β1-mediated xCT repression was prevented by Smad3, but not Smad2 or Smad4, knockdown, whereas it was enhanced by Smad3 overexpression. TGF-β1 decreased GSH levels in control cells but not xCT-overexpressed cells. Furthermore, TGF-β1 increased reactive oxygen species (ROS) levels in PLC/PRF/5 cells and enhanced tert-butyl hydroperoxide-induced ROS levels in Huh7 cells; these changes were reversed by xCT overexpression. TGF-β1 treatment ultimately induced the ferrostatin-1- and deferoxamine-dependent lipid peroxidation after 2 days and 8 days in PLC/PRF/5 and Huh7 cells but not in SNU475 and SK-Hep1 cells. Pre-treatment of TGF-β1 for 2 days enhanced the reduction of cell viability induced by RSL3, a GSH peroxidase 4 (GPX4) inhibitor, in PLC/PRF/5 and Huh7 cells. In conclusion, TGF-β1 represses xCT expression via Smad3 activation and enhances lipid peroxidation in hepatocellular carcinoma cells with an early TGF-β1 signature, which would benefit from the targeting of GPX4.

Background To compare the diagnostic sensitivity of [18F]fluoroestradiol ([18F]FES) and [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) for breast cancer recurrence in patients with estrogen receptor (ER)-positive primary breast cancer. Methods Our database of consecutive patients enrolled in a previous prospective cohort study to assess [18F]FES PET/CT was reviewed to identify eligible patients who had ER-positive primary breast cancer with suspected first recurrence at presentation and who underwent [18F]FDG PET/CT. The sensitivity of qualitative [18F]FES and [18F]FDG PET/CT interpretations was assessed, comparing them with histological diagnoses. Results Of the 46 enrolled patients, 45 were confirmed as having recurrent breast cancer, while one was diagnosed with chronic granulomatous inflammation. Forty (89%) patients were ER-positive, four (9%) were ER-negative, and one (2%) patient did not undergo an ER assay. The sensitivity of [18F]FES PET/CT was 71.1% (32/45, 95% CI, 55.7–83.6), while that of [18F]FDG PET/CT was 80.0% (36/45, 95% CI, 65.4–90.4) with a threshold of positive interpretation, and 93.3% (42/45, 95% CI, 81.7–98.6) when a threshold of equivocal was used. There was no significant difference in sensitivity between [18F]FES and [18F]FDG PET/CT (P = 0.48) with a threshold of positive [18F]FDG uptake, but the sensitivity of [18F]FDG was significantly higher than [18F]FES (P = 0.013) with a threshold of equivocal [18F]FDG uptake. One patient with a benign lesion showed negative [18F]FES but positive [18F]FDG uptake. Conclusions The restaging of patients who had ER-positive primary breast cancer and present with recurrent disease may include [18F]FES PET/CT as an initial test when standard imaging studies are equivocal or suspicious.

Background To compare the diagnostic accuracy of 18F-fluoroestradiol (18F-FES) and 18F-fluorodoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for breast cancer recurrence in patients with estrogen receptor (ER)-positive primary breast cancer.Methods Our database of consecutive patients enrolled in a previous prospective cohort study to assess 18F-FES PET/CT was reviewed to identify eligible patients who had ER-positive primary breast cancer with suspected first recurrence at presentation and who underwent 18F-FDG PET/CT. The diagnostic accuracy of qualitative 18F-FES and 18F-FDG PET/CT interpretations was assessed, comparing them with histological diagnoses.Results Of the 46 enrolled patients, 45 were confirmed as having recurrent breast cancer, while one was diagnosed with chronic granulomatous inflammation. Forty (89%) patients were ER-positive, four (9%) were ER-negative, and one (2%) patient did not undergo an ER assay. The sensitivity of 18F-FES PET/CT was 71.1% (32/45, 95% CI: 55.7–83.6), while that of 18F-FDG PET/CT was 80.0% (36/45, 95% CI: 65.4–90.4) when malignant interpretation was defined as positive, and 93.3% (42/45, 95% CI: 81.7–98.6) when an equivocal or malignant interpretation was considered positive. There was no significant difference in sensitivity between 18F-FES and 18F-FDG PET/CT (P=0.48) when malignant 18F-FDG interpretation was considered positive, but the sensitivity of 18F-FDG was significantly higher than 18F-FES (P=0.013) when equivocal or malignant interpretation was considered positive. One patient with a benign lesion showed negative 18F-FES but malignant 18F-FDG uptake.Conclusions The restaging of patients who had ER-positive primary breast cancer and present with recurrent disease may include 18F-FES PET/CT.

Studies evaluating the nature of ischemic burden of chronic total occlusion (CTO) vessels are still lacking.A total of 165 patients with single vessel CTO2.5 mm in an epicardial coronary artery who underwent single photon emission computed tomography (SPECT) were enrolled in the study. Ischemic burden was calculated with the use of semi-quantitative SPECT analysis, and was defined as the summed difference score (SDS) divided by the maximal limit of the score (=SDS/68).The mean age of the participants was 59.5 years and the CTO of the left anterior descending coronary artery (LAD), left circumplex coronary artery (LCX), and right coronary artery (RCA) accounted for 93 (56.4%), 18 (10.9%), and 54 (32.7%) patients, respectively. The median ischemic burden of the total population was 8.8%, and it was highest in the LAD CTO (10.3%) compared with the LCX (5.9%) and RCA CTO (5.9%, p0.001). High-ischemic burden (ischemic burden10%) was observed in 66 patients (40.0%), and in 47 patients (50.5%) of the LAD CTO. Ischemic burden was different according to the CTO location only in LAD CTO. The statistically significant predictors for high-ischemic burden were hypertension, baseline ejection fraction45%, LAD CTO, proximal CTO location, and de novo CTO. Japanese-CTO score and Rentrop scale collateral grade were not associated with high-ischemic burden.Only 40% of patients with single vessel CTO had ischemic burden10%. For CTO vessels, measurement of ischemic burden using SPECT prior to revascularization may be helpful in identifying beneficial subjects.

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

18F-GP1 is a derivative of elarofiban with a high affinity to activated platelet glycoprotein IIb/IIIa (GPIIb/IIIa) and favorable in vivo characteristics for thrombus imaging in preclinical models. We aimed to explore the detection rate of thromboembolic foci with 18F-GP1 positron emission tomography/computed tomography (PET/CT) in patients with acute venous thromboembolism (VTE), and to evaluate the safety, biodistribution, pharmacokinetics, and metabolism of 18F-GP1. Methods: We studied patients who had signs or symptoms of acute deep vein thrombosis (DVT) of the leg or acute pulmonary embolism (PE) within 14 days prior to 18F-GP1 PET/CT, and had thromboembolic foci confirmed by conventional imaging (n = 10 for DVT and n = 10 for PE). Dynamic whole-body PET/CT images were acquired for up to 140 minutes after injection of 250 MBq of 18F-GP1. Results:18F-GP1 PET/CT was well tolerated without any drug-related adverse events, and showed high initial uptake in spleen, kidney, and blood pool, followed by rapid clearance. The overall image quality was excellent and allowed interpretation in all patients. 18F-GP1 PET/CT identified thromboembolic foci in all 20 patients with either DVT or PE. Vessel-level analysis revealed that 18F-GP1 PET/CT detected 89% (68/76) of vessels with DVT, and 60% (146/245) for PE. Importantly, 18F-GP1 PET/CT showed increased uptake in 32 vessels that were not detected by conventional imaging, of which 25 were located in distal veins of the lower extremity in 12 patients. A positive correlation was found between 18F-GP1 uptake and P-selectin-positive circulating platelets (r = 0.656, P = 0.002). Conclusion:18F-GP1 is a promising PET tracer for imaging acute VTE in patients. 18F-GP1 PET/CT may identify thrombi in distal veins of the leg, where conventional imaging has limitations.

We evaluated the feasibility of dynamic stress 201Tl/rest 99mTc-tetrofosmin SPECT imaging using a cardiac camera equipped with cadmium-zinc-telluride detectors for the quantification of myocardial perfusion reserve (MPR). Subjects with stable known or suspected coronary artery disease (CAD) who had undergone or were scheduled to undergo fractional flow reserve (FFR) measurement were prospectively enrolled. Dynamic stress 201Tl/rest 99mTc-tetrofosmin SPECT imaging was performed using a dedicated multiple pinhole SPECT camera with cadmium-zinc-telluride detectors. MPR was derived using Corridor4DM software. A total of 34 subjects were enrolled (25 men and 9 women; mean age 60.4 years). FFR was measured in 65 coronary arteries with intermediate lesions. The average global MPR was 2.58 ± 1.03. Global MPR was associated with the extent of CAD (P = 0.028) and global summed stress score (r = −0.60, P