Abstract
Purpose
Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) is a useful imaging modality that visualizes glucose utilization. Diffuse colonic FDG uptake is frequently observed in patients being treated for diabetes mellitus (DM), especially with metformin. The aim of this study was to evaluate whether patients without increased colonic FDG uptake after taking oral hypoglycemic agents (OHA) are associated with insufficient glycemic control.
Methods
A total of 279 subjects who underwent FDG PET/CT scans for health examinations and had been diagnosed with DM and taken an OHA before the day of the FDG PET/CT were included. Colonic FDG uptake in the study subjects was visually assessed, and the maximal and mean standard uptake value (SUV) was measured. Fasting blood glucose and glycated hemoglobin A1c (HbA1c) levels at both baseline and follow-up visits as well as DM management were compared according to the colonic FDG uptake.
Results
The mean age of study subjects was 48.8 years old, and 251 of subjects were male. Positive colonic FDG uptake was observed in 200 (71.7%) subjects. Fasting blood glucose and Hb1Ac levels on the day of FDG PET/CT were higher in subjects without positive colonic FDG uptake than those with positive colonic FDG uptake (p ≤ 0.001). But there was no significant difference between the two groups at follow-up visits.
Conclusions
Patients with DM who did not show increased colonic FDG uptake after taking OHA were associated with higher fasting blood glucose and HbA1c levels on the day of FDG PET/CT.
Keywords: 18F-FDG, Diabetes mellitus, Oral hypoglycemic agent, Glycated hemoglobin A1c
Introduction
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with hyperglycemia. Diabetes mellitus (DM) affects about 1 in 11 adults worldwide, and T2DM comprises 90% of these [1]. Management of T2DM is aimed to achieve an appropriate glycemic target and avoid comorbidities [2]. Various oral hypoglycemic agents (OHAs) use different mechanisms for pharmacologic management of T2DM [3]. Metformin is the first-line OHA and is recommended to be continued in patients with T2DM unless it is contraindicated [4]. The liver has been traditionally known as the main target organ for metformin. Additionally, the intestines are also related to the hypoglycemic action of metformin [5].
Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) is a useful imaging modality to evaluate various diseases including malignancy throughout the whole body. FDG is a glucose analog that facilitates visualization of both pathologic and physiologic glucose utilization. Biodistribution of FDG in patients with T2DM is different from that of others, and diffuse colonic FDG uptake is frequently observed in patients diagnosed with and treated for T2DM [6, 7]. Metformin is especially well associated with diffuse colonic FDG uptake in many previous studies [8, 9]. Bahler et al. evaluated whether increased colonic FDG uptake is correlated with energy expenditure in healthy subjects after taking metformin, but no significant association arose between them [8]. By contrast, Koffert et al. showed that in patients with newly diagnosed T2DM, colonic FDG uptake increased three fold after metformin medication and was associated with improved glycemic control [10].
We thus hypothesized that patients who do not show increased colonic FDG uptake after taking OHA are associated with insufficient control of blood glucose level and consequent treatment failure resulting in a subsequent switch to insulin.
Materials and Methods
Study Subjects
Study subjects were selected from 281 adults who underwent FDG PET/CT scans for health examinations at Kangbuk Samsung Hospital Total Healthcare Screening Center in Seoul, South Korea, from January 2012 to December 2012 and who also had been diagnosed with DM and had taken OHA before the day of the FDG PET/CT. Of these, 103 (36.7%) subjects underwent colonoscopy on the same day of the FDG PET/CT. Two of these subjects had colitis in their colonoscopic findings and were excluded. Consequently, a total of 279 subjects were included in this study (Fig. 1).
Fig. 1.
Scheme of patient enrollment
This retrospective observational study was approved by our institutional review board, and the requirement for written consent from study subjects was waived.
FDG PET/CT Imaging
After fasting at least 8 h, all subjects were checked for their blood glucose level which was indicated less than 200 mg/dL at the time of FDG injection. PET/CT images were acquired on a Discovery 600 (GE Healthcare, Milwaukee, WI, USA) without intravenous or oral contrast at 60 min after injection of 3.7 MBq/kg of FDG. Whole-body CT was performed with a continuous spiral technique with a 16-slice helical CT (120 kVp; 40–120 mA; section thickness, 3.75 mm). After CT, an emission PET was obtained from the skull base to the thigh. Scanning was performed at 2 min per bed in 3-D mode. The acquisition time per bed was extended up to 4 min according to body weight and body mass index (BMI) in obese subjects because the maximum dose of FDG was restricted to 296 MBq. PET images were reconstructed using an ordered-subset expectation maximization algorithm (16 subsets, 2 iterations) with attenuation-corrected images.
Image Analyses
FDG PET/CT images were reviewed by two nuclear medicine physicians blinded to clinical information on a dedicated workstation (AW; GE Healthcare). They worked separately, and when there were discrepancies, they reviewed the images and reached almost perfect agreement.
Colonic FDG uptake of each subject was visually assessed. FDG uptakes of each colon segment (ascending, transverse, descending, and sigmoid colon, as well as the rectum) were graded from 0 to 2, comparing with the hepatic activity (0 = no uptake, 1 = activity less than that of hepatic activity, 2 = activity greater than that of hepatic activity). This score was defined as the bowel uptake score (BUS) [11]. Colon segment was determined as positive if its BUS was 2. Subjects displaying one or more positive segment for colonic FDG uptake were considered positive [7]. We considered the pattern of positive colonic FDG uptake to be diffuse when all segments of the colon of a subject were positive; otherwise, it was segmental [6].
The maximal and mean standard uptake value (SUV) was measured for each segment with BUS 1 or 2 by manually tracing the each segment of the colons and placing a spherical volume-of-interest (VOI). The mean SUV (SUVmean) of each segment was measured with a margin threshold of 60% of maximal SUV (SUVmax) [14]. We had set the VOI confined to the boundary of the colon, referring to CT images of PET/CT. The presence of focal hypermetabolic lesion, which may represent pathology in the colon, was also assessed.
There were 33 subjects whose 80 segments of the colon were affected by a partial image data loss arising from a problem in electronic data processing. Some of PET images of them were missed, but maximal intensity projection (MIP) and captured fusion images were intact. It was possible to reach agreement on grading the affected 80 segments into positive (correspond to BUS 2) or negative (correspond to BUS 0, 1). But the affected 80 segments of 33 subjects were not assigned BUS nor measured for SUV, hence excluded in further analysis using BUS or SUV.
Clinical Data Collection
Clinical data including demographic characteristics, medical history, and medication was collected from standardized self-administered questionnaires on the day of the FDG PET/CT. Subjects were requested to inform whether they had been diagnosed with DM by physicians and to choose their DM treatment modality on those questionnaires. We also collected BMI, fasting blood glucose level, glycated hemoglobin A1c (HbA1c), and colonoscopic findings from a health screening process of the study subjects. Follow-up clinical data was collected if the subjects visited the healthcare screening center again before December 2018. Additionally, laboratory parameters including total cholesterol, triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), blood urea nitrogen (BUN), creatinine, and C reactive protein (CRP) levels on the day of FDG PET/CT were also collected.
Statistical Analyses
Subjects were divided into two groups according to their colonic FDG uptake. The clinical characteristics of groups were compared by Student’s t test or Pearson’s chi-squared test. Paired t test for comparison of initial and follow-up fasting blood glucose level and HbA1c in subjects who had a follow-up visit was also performed. Correlations between the SUVmax, SUVmean, and BUS of each colon segment and fasting blood glucose level or HbA1c were analyzed by the Pearson correlation test or Spearman correlation test. Statistical analyses were performed using SPSS version 24.0 for Windows (Chicago, IL, USA), R (version 3.6.1), and p values < 0.05 were considered significant.
Results
Characteristics of Study Subjects
The mean age of the study subjects was 48.8 (range 38–79) years, and 251 of 279 (89.9%) subjects were male (Table 1). Three (1.1%) subjects had taken insulin injection for DM control in addition to OHA. The mean fasting blood glucose level was 130.3 ± 26.1 mg/dL, and the mean HbA1c was 6.9% ± 1.0%. The mean BMI of the study subjects was 25.8 kg/m2.
Table 1.
Characteristics of the study subjects
| Total (n = 279) | Colonic FDG uptake | p value | |||
|---|---|---|---|---|---|
| Positive (n = 200) | Negative (n = 79) | ||||
| Age | Mean ± SD (year) | 48.8 ± 7.4 | 48.4 ± 7.0 | 49.5 ± 8.2 | 0.264a |
| Gender | Male (%) | 251 (89.9) | 180 (90.0) | 71 (89.9) | 0.975b |
| BMI | Mean ± SD (kg/m2) | 25.8 ± 3.3 | 25.8 ± 3.4 | 25.6 ± 3.2 | 0.583a |
| DM treatment | OHA only (%) | 267 (95.7) | 193 (96.5) | 74 (93.7) | 0.330c |
| OHA + insulin (%) | 3 (1.1) | 2 (1.0) | 1 (1.3) | 1.000c | |
| Fasting blood glucose | Mean ± SD (mg/dL) | 130.3 ± 26.1 | 126.9 ± 23.9 | 138.7 ± 29.4 | 0.001a |
| HbA1c | Mean ± SD (%) | 6.9 ± 1.0 | 6.8 ± 0.9 | 7.3 ± 1.2 | < 0.001a |
| HbA1c > 7.0 | Number (%) | 96 (34.4) | 61 (30.5) | 35 (44.3) | 0.029b |
| BUN | Mean ± SD (mg/dL) | 14.0 ± 3.8 | 14.1 ± 4.0 | 13.5 ± 3.2 | 0.223a |
| Creatinine | Mean ± SD (mg/dL) | 0.95 ± 0.17 | 0.96 ± 0.17 | 0.94 ± 0.16 | 0.556a |
| Total cholesterol | Mean ± SD (mg/dL) | 176.6 ± 33.1 | 172.8 ± 33.0 | 186.3 ± 31.6 | 0.002a |
| TG | Mean ± SD (mg/dL) | 154.4 ± 94.8 | 149.2 ± 96.5 | 167.8 ± 89.5 | 0.141a |
| HDL | Mean ± SD (mg/dL) | 48.8 ± 11.3 | 48.3 ± 11.0 | 50.2 ± 12.0 | 0.200a |
| LDL | Mean ± SD (mg/dL) | 106.5 ± 30.3 | 103.9 ± 30.6 | 113.2 ± 28.7 | 0.022a |
| CRP | Mean ± SD (mg/dL) | 0.13 ± 0.42 | 0.13 ± 0.44 | 0.14 ± 0.35 | 0.885a |
| Follow-up visit | (%) | 207 (74.2) | 153 (76.5) | 54 (68.4) | 0.161b |
| Interval | Mean ± SD (m) | 58.7 ± 17.7 | 59.9 ± 17.3 | 55.2 ± 18.5 | 0.099a |
| DM treatment | OHA only (%) | 187 (90.3) | 139 (90.8) | 48 (88.9) | 0.675b |
| OHA + insulin (%) | 7 (3.4) | 6 (4.0) | 1 (1.9) | 0.679c | |
| Life style modification without OHA (%) | 1 (0.5) | 1 (0.7) | 0 | 1.000c | |
| Fasting blood glucose | Mean ± SD (mg/dL) | 137.5 ± 34.7 | 133.7 ± 33.1 | 148.1 ± 37.1 | 0.009a |
| HbA1c | Mean ± SD (%) | 7.1 ± 1.1 | 7.0 ± 1.1 | 7.3 ± 0.8 | 0.124a |
| HbA1c > 7.0 | Number (%) | 84 (40.6) | 53 (34.6) | 31 (57.4) | 0.003b |
OHA oral hypoglycemic agent, HbA1c hemoglobin A1c, BUN blood urea nitrogen, TG triglyceride, HDL high density lipoprotein, LDL low density lipoprotein, CRP C reactive protein
at test
bPearson chi square test
cFisher’s exact test
Of the 279 total subjects, 207 (74.2%) subjects had a follow-up visit at a mean interval of 58.7 months. Seven (3.4%) subjects informed that they had taken insulin injection for DM control in addition to OHA, and one subject was on lifestyle modification without OHA at a follow-up visit. The mean fasting blood glucose level was 137.5 ± 34.7 mg/dL, and the mean HbA1c was 7.1% ± 1.1% at a follow-up visit. The mean BMI of the study subjects was 25.7 kg/m2. Fasting blood glucose level was higher in follow-up visit than initial (137.5 mg/dL vs. 131.1 mg/dL, p = 0.004) by paired t test. But the difference between initial and follow-up HbA1c did not reach statistical significance (6.9% vs. 7.1%, p = 0.055).
The mean of total cholesterol, TG, HDL, and LDL level was 176.6 ± 33.1 mg/dL, 154.4 ± 94.8 mg/dL, 48.8 ± 11.3 mg/dL, and 106.5 ± 30.3 mg/dL, respectively. And the mean CRP level was 0.13 ± 0.42 mg/dL.
Colonic FDG Uptake Characteristics
A total of 200 (71.7%) subjects had positive colonic FDG uptake on their FDG PET/CT. A diffuse pattern was observed in 44 (22%) of these. None of the study subjects had a focal hypermetabolic lesion on the colon. The ascending colon was positive in 95 (47.5%) subjects; the transverse colon was positive in 63 (31.5%) subjects; the descending colon was positive in 95 (47.5%), and the sigmoid colon and rectum were positive in 181 (90.5%) subjects.
BUS assignment was done in 1036 (92.8%) of a total 1116 segments of the colon. BUS of the ascending colon was 0 in 5 subjects, 1 in 164 subjects, and 2 in 87 subjects, respectively. BUS of the transverse colon was 0 in 14 subjects, 1 in 185 subjects, and 2 in 59 subjects, respectively. BUS of the descending colon was 0 in 13 subjects, 1 in 155 subjects, and 2 in 90 subjects. And BUS of the sigmoid colon and rectum was 0 in 1 subject, 1 in 90 subjects, and 2 in 173 subjects, respectively.
The mean SUVmax of the ascending, transverse, and descending colon as well as the sigmoid colon and rectum was 3.1 ± 1.9, 2.8 ± 1.9, 3.2 ± 2.3, and 4.9 ± 2.4, respectively. And the mean SUVmean of the ascending, transverse, descending colon, and sigmoid colon and rectum was 2.0 ± 1.1, 1.7 ± 1.0, 1.8 ± 1.0, and 2.6 ± 1.1, respectively.
Comparison of Positive and Negative Colonic FDG Uptake Groups
There was no significant difference in age, gender, or BMI between positive and negative colonic FDG uptake groups. The mean fasting blood glucose levels of the negative colonic FDG uptake group were higher than that of the positive group at the day of FDG PET/CT (138.7 vs. 126.9 mg/dL, p = 0.001). The mean of HbA1c of the negative colonic FDG uptake group was also higher than that of the positive group on the day of FDG PET/CT (7.3% vs. 6.8%, p < 0.001). There was no significant difference in the proportion of subjects who had taken insulin injection on the day of FDG PET/CT between the two groups (1.0% vs. 1.3%, p = 1.000). There were more subjects with HbA1c more than 7.0% in negative colonic FDG uptake group than in positive group (44.3% vs. 30.5%, p = 0.029). The total cholesterol and LDL level were higher in negative group than positive group (186.3 mg/dL vs.172.8 mg/dL; 113.2 mg/dL vs. 103.9 mg/dL). But there was no significant difference in TG, HDL, CRP, BUN, and creatinine levels between positive and negative groups.
Follow-up visits were attended by 153 (76.5%) of the positive group and 54 (68.4%) of the negative group. Among these, 6 (3.9%) of positive group and 1 (1.9%) of negative group informed that they had taken insulin injection in addition to OHA at the follow-up visit. No statistically significant difference arose between the proportions of subjects with or without insulin injection. Similarly, mean fasting glucose levels and mean HbA1c in both of these groups at follow-up appointments showed no significant difference. However, more subjects had an HbA1c level of > 7.0% in the negative colonic FDG uptake group than in positive group (57.4% vs. 34.6%, p = 0.003). Representative subjects of positive and negative colonic FDG uptake groups are presented in Fig. 2.
Fig. 2.
Maximum intensity projection (MIP) FDG PET images of representative subjects of the positive and negative colonic FDG uptake groups. a A 49-year-old male who has diagnosed DM and had taken OHA showed diffusely increased colonic FDG uptake in all segments. His fasting blood glucose level was 118 mg/dL, and HbA1c was 6.3% at the day of FDG PET/CT. He was under OHA medication, and at a follow-up appointment after 5 years, his fasting blood glucose level was 114 mg/dL, and HbA1c was 6.2%. b A 57-year-old female who was diagnosed with DM and had taken OHA did not show increased colonic FDG uptake. Her fasting blood glucose level was 151 mg/dL, and HbA1c was 7.2% at the day of FDG PET/CT. She was under insulin with OHA medication, and after 6 years, her fasting blood glucose level was 193 mg/dL, and HbA1c was 7.3%
Correlation Analysis of Patterns, BUS, and SUV of Colonic FDG Uptake to HbA1c
No significant difference was found in HbA1c levels between subjects with diffuse patterns of colonic FDG uptake and subjects with segmental patterns on the day of FDG PET/CT (Table 2).
Table 2.
Subgroup analysis of positive colonic FDG uptake group by uptake pattern
| Diffuse (n = 44) | Segmental (n = 156) | p value | ||
|---|---|---|---|---|
| Fasting blood glucose at the day of PET/CT | Mean ± SD (mg/dL) | 129.6 ± 29.5 | 126.2 ± 22.1 | 0.401a |
| HbA1c at the day of PET/CT | Mean ± SD (%) | 7.1 ± 1.3 | 6.7 ± 0.7 | 0.008a |
| Follow-up visit | (%) | 37 (84.1) | 116 (74.4) | 0.179b |
| Fasting blood glucose at follow-up visit | Mean ± SD (mg/dL) | 134.4 ± 37.4 | 133.5 ± 31.8 | 0.897a |
| HbA1c at follow-up visit | Mean ± SD (%) | 7.1 ± 1.4 | 7.0 ± 1.1 | 0.511a |
at test
bPearson chi square test
Neither SUVmax of colonic FDG uptake per segment nor per subject showed a significant correlation to HbA1c (Table 3). SUVmean or BUS of the ascending colon, transverse colon, sigmoid colon, and rectum did not show a significant correlation to HbA1c, either. But SUVmean of the sigmoid colon and rectum negatively correlated with HbA1c on the day of FDG PET/CT (Pearson’s r = − 0.152, p = 0.017). It was also true for BUS of the sigmoid colon and rectum (Spearman’s rho = −0.191, p = 0.003).
Table 3.
Correlation analysis of SUVmax, SUVmean, and bowel uptake score of colonic FDG uptake and HbA1c
| HbA1c at the day of FDG PET/CT | ||||
|---|---|---|---|---|
| Mean ± SD | Correlation coefficient | p value | ||
| SUVmax per subject | 5.0 ± 2.5 | − 0.084a | 0.189 | |
| SUVmax per segment | ||||
| Ascending colon | 3.1 ± 1.9 | 0.035a | 0.588 | |
| Transverse colon | 2.8 ± 1.9 | 0.060a | 0.358 | |
| Descending colon | 3.2 ± 2.3 | 0.029a | 0.655 | |
| Sigmoid colon and rectum | 4.8 ± 2.4 | − 0.114a | 0.075 | |
| SUVmean per segment | ||||
| Ascending colon | 2.0 ± 1.1 | 0.045a | 0.491 | |
| Transverse colon | 1.7 ± 1.0 | 0.087a | 0.186 | |
| Descending colon | 1.8 ± 1.0 | 0.036a | 0.580 | |
| Sigmoid colon and rectum | 2.6 ± 1.1 | − 0.152a | 0.017 | |
| Bowel uptake score per segment | ||||
| Ascending colon | 1.32 ± 0.51 | − 0.039b | 0.546 | |
| Transverse colon | 1.17 ± 0.51 | 0.000b | 0.998 | |
| Descending colon | 1.30 ± 0.56 | − 0.005b | 0.942 | |
| Sigmoid colon and rectum | 1.64 ± 0.49 | − 0.191b | 0.003 | |
aPearson’s r
bSpearman’s rho
Discussion
We investigated the differences in glycemic control status and consequent DM treatment switch between two groups according to normal or increased colonic FDG uptake. The negative colonic FDG uptake group was associated with higher fasting blood glucose and HbA1c levels than those of the positive colonic FDG uptake group on the day of FDG PET/CT. The proportion of subjects with HbA1c reaching > 7.0% in the negative colonic FDG uptake group was higher than that of positive colonic FDG uptake group both on the day of FDG PET/CT and at follow-up visit. But the proportions of subjects who had insulin injection in addition to OHA at follow-up visit were not significantly different between these groups.
The proportion of subjects who showed increased colonic FDG uptake greater than that of hepatic activity after taking OHA was 71.7% in this study, and this corresponds with previous studies. In the study of Gontier et al. [7], 52.7% of all subjects treated with OHA showed an increased colonic FDG uptake greater than that of hepatic activity, and the proportion was 78% when it comes to subjects with metformin. Ozguven et al. reported that 75% of subjects with OHA showed positive colonic FDG uptake, and 75% of these were the diffuse pattern [6].
Subjects without increased colonic FDG uptake after taking OHA showed higher fasting blood glucose levels than subjects with increased colonic FDG uptake after taking OHA in the present study. This result is similar to that of Koffert et al., which showed that enhanced colonic glucose uptake correlated with the reduction of fasting plasma glucose [10]. Meanwhile, our study also revealed a significant difference in HbA1c levels according to the presence of increased colonic FDG uptake. HbA1c is a major indicator for glycemic management and is recommended to be lower than 7% in many non-pregnant adults [2]. There was a weak negative correlation between SUVmean or BUS of the sigmoid colon and rectum and HbA1c. However, we could not find significant correlation between colonic SUVmax per subject or segment and HbA1c. Meanwhile, colonic FDG uptake patterns, which represented the extent of the positive colonic segments in each subject, were not associated with HbA1c.
The exact mechanism underlying increased colonic FDG uptake in subjects taking OHA remains unclear. Koffert et al. reported that enhanced intestinal FDG uptake was localized in the mucosal enterocyte in a rodent model, and they suggested the result was indicative of improved mucosal cell function [10]. Meanwhile, metformin is associated with microbiome alteration [12]. Emerging data support the association of colonic FDG uptake to microbiome [13, 14]. Microbiome could be a major component that explains the colonic FDG uptake after taking OHA.
There were several limitations in the current study. First, not all study subjects underwent colonoscopy on the same day as the FDG PET/CT to exclude possible pathologic causes of increased colonic FDG uptake. It is known that inflammation in the colon is a possible cause of colonic FDG uptake [15]. We therefore cannot exclude the possibility that some of the 178 subjects without colonoscopy had colitis on the day of FDG PET/CT. Second, species and doses of OHA for each subject were not specified in this retrospective study. Metformin is known to be associated with higher colonic FDG uptake than other OHAs [7]. Different DM medications may be a confounding factor, although most of the subjects were expected to have taken metformin according to the guidelines [4]. Third, the pharmacologic management of DM patients is influenced by various factors including complications, not only by glycemic effect of OHA. We considered the addition of insulin injection to be a meaningful change for DM management in this study, but a change or combination of OHAs without insulin may also occur in subjects with DM. Further study with more specific clinical information is needed to clarify the association with colonic FDG uptake and consequent DM management.
Conclusions
Our study demonstrated that patients with DM who did not show increased colonic FDG uptake after taking OHA were associated with higher fasting blood glucose and HbA1c levels on the day of FDG PET/CT. More subjects displayed HbA1c of > 7.0% at follow-up visit in the group with negative colonic FDG uptake. Colonic FDG uptake may reflect hypoglycemic effect of OHA.
Compliance with Ethical Standards
Conflict of Interest
Hyung Seok Chang, Soo Jeong Kim, and Young Hwan Kim declare that they have no conflict of interest.
Ethical Approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
For this type of study, formal consent is not required.
Research Grant and Funds
There is no source of funding.
Informed Consent
The institutional review board of our institute approved this retrospective study, and the requirement to obtain informed consent was waived.
Footnotes
Publisher’s Note
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Contributor Information
Hyung Seok Chang, Email: hs712.chang@samsung.com.
Soo Jeong Kim, Email: sj12345.kim@samsung.com.
Young Hwan Kim, Email: yh27.kim@samsung.com.
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