Jaetae Lee

4-Hydroxybenzaldehyde from Gastrodia elata B1. is active in the antioxidation and GABAergic neuromodulation of the rat brain.

Ether fraction of G. elata methanol extract significantly inhibited the recovery time and severity induced by pentylenetetrazole (PTZ) treatment. Pretreatment of ether fraction of G. elata methanol extract successfully prevented diminution of brain GABA level in subconvulsive dose of PTZ-treated rats. 4-Hydroxybenzaldehyde, an analogue of p-hydroxybenzyl alcohol, showed an inhibitory effect on the GABA transaminase, and its inhibitory activity was higher than that of valproic acid, a known anticonvulsant. In the brain of PTZ-treated rats, brain lipid peroxidation was significantly increased, while it recovered to the control level after treatment with 4-hydroxybenzaldehyde. It may be concluded that antioxidation and positive modulation of GABAergic neuromodulation of 4-hydroxybenzaldehyde partially contribute to an antiepileptic and anticonvulsive activity of G. elata B1.

XPC polymorphisms and lung cancer risk

Polymorphisms in DNA repair genes may be associated with differences in the capacity to repair DNA damage and thereby influence an individuals susceptibility to smoking‐related cancer. To test this hypothesis, we investigated the potential association of 7 XPC polymorphisms (–449G→C, –371G→A, –27G→C, Val499Arg, PAT–/+, IVS11‐5C→A and Lys939Gln) and their haplotypes with lung cancer risk in a Korean population. XPC genotypes were determined in 432 lung cancer patients and 432 healthy controls frequency‐matched for age and sex. XPC haplotypes were predicted using a Bayesian algorithm in the Phase program. The combined –27CG+CC genotype was associated with a significantly increased risk for overall lung cancer compared to the –27GG genotype (adjusted OR = 1.97, 95% CI 1.22–3.17, p = 0.005). The other 6 polymorphisms were not significantly associated with overall risk of lung cancer. When lung cancer cases were categorized by tumor histology, the –371AA genotype was associated with a significantly increased risk of squamous cell carcinoma compared to the combined –371GG and GA genotype (adjusted OR = 2.08, 95% CI 1.09–4.00, p = 0.03). The PAT–/+, IVS11‐5C→A and Lys939Gln polymorphisms were associated with a significantly decreased risk of small cell carcinoma (SM) under a dominant model for the polymorphic allele (adjusted OR = 0.49, 95% CI 0.29–0.82, p = 0.006; adjusted OR = 0.60, 95% CI 0.36–1.00, p = 0.05; and adjusted OR = 0.58, 95% CI 0.35–0.97, p = 0.04, respectively). Consistent with genotyping analyses, haplotype 4 (1112222) containing the PAT+/IVS11‐5A/939Gln alleles was associated with a significantly decreased risk of SM (adjusted OR = 0.56, 95% CI 0.37–0.85, p = 0.007 and Bonferroni‐corrected p = 0.049), whereas haplotype 5 (1122111) containing the –27C allele was associated with a significantly increased risk of SM (adjusted OR = 2.88, 95% CI 1.41–5.87, p = 0.004 and Bonferroni‐corrected p = 0.028). These results suggest that XPC polymorphisms/haplotypes may contribute to genetic susceptibility for lung cancer.

Salivary Gland Function 5 Years After Radioactive Iodine Ablation in Patients with Differentiated Thyroid Cancer: Direct Comparison of Pre- and Postablation Scintigraphies and Their Relation to Xerostomia Symptoms

BACKGROUND Chronic sialadenitis is one of the most frequent chronic complications after radioactive iodine (RAI) therapy for thyroid cancer. To evaluate the long-term effects of RAI ablation on salivary gland function, we investigated scintigraphic changes in salivary glands by direct comparison of two salivary gland scintigraphies (SGSs) taken before and at 5 years after an RAI ablation. METHODS SGS was performed just before RAI ablation (pre-SGS) and ∼5 years after RAI ablation (F/U SGS) in 213 subjects who underwent thyroidectomy for thyroid cancer. The uptake score (U score) was graded, and the ejection fraction (EF) was quantified for the parotid and submandibular glands at pre-SGS and F/U SGS. Changes in salivary gland function were graded as mild, moderate, or severe according to the differences in U score and EF between the two SGSs. Xerostomia was assessed and compared with the SGS findings. RESULTS Worsening of the U score was observed in 182 of 852 salivary glands (total: 21.3%; mild: 4.2%, moderate: 7.4%, severe: 9.7%), and 47.4% of the patients had a worsening U score for at least one of four salivary glands. A decrease in EF was observed in 173 of 852 salivary glands (total: 20.3%; mild: 5.4%, moderate: 6.8%, severe: 8.1%), and 43.7% of the patients experienced a decrease in the EF of at least one of the four salivary glands. Bilateral parotid gland dysfunction was the most commonly observed condition. Thirty-five (16.4%) patients complained of xerostomia at 5 years after RAI ablation. Scintigraphic changes in salivary gland function and xerostomia were more common in patients receiving 5.55 GBq, compared with 3.7 GBq. Xerostomia was more common in patients with submandibular gland dysfunction than those with parotid gland dysfunction (68.8% vs. 33.3%, p<0.05). The number of dysfunctional salivary glands was correlated with xerostomia (p<0.01). CONCLUSION About 20% of the salivary glands were dysfunctional on SGS 5 years after a single RAI ablation, especially in patients who received higher doses of RAI. While parotid glands are more susceptible to (131)I-related damage, xerostomia was more associated with submandibular gland dysfunction and the prevalence of dysfunctional salivary glands.

18F-FDG Uptake by Metastatic Axillary Lymph Nodes on Pretreatment PET/CT as a Prognostic Factor for Recurrence in Patients with Invasive Ductal Breast Cancer

This study assessed the maximum standardized uptake value of metastatic axillary lymph nodes in patients with invasive ductal breast cancer (IDC) to determine the pretreatment prognostic value of 18F-FDG PET/CT for disease-free survival (DFS). Methods: Sixty-five female IDC patients who had undergone pretreatment 18F-FDG PET/CT and had pathologically confirmed axillary lymph node involvement without distant metastasis were enrolled. All patients showed complete remission after first-line treatment. To obtain nodal SUVmax, a transaxial image representing the highest 18F-FDG uptake was carefully selected and a region of interest was manually drawn on the 18F-FDG–accumulating lesion. Clinicopathologic parameters such as age, TNM stage, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, and primary-tumor and nodal SUVmax on PET were analyzed for their usefulness in predicting recurrence. Combinatorial effects and interactions between variables that were significant by univariate analysis were examined using multivariate Cox proportional-hazards models. Results: Twelve of 65 patients (18.5%) experienced recurrence during follow-up (median follow-up, 36 mo; range, 21–57 mo). Nodal SUVmax was significantly higher in patients with recurrence than in those who were disease-free (recurrence group: 5.2 ± 2.3, vs. disease-free group: 1.9 ± 1.9, P < 0.0001). A receiver-operating-characteristic curve demonstrated a nodal SUVmax of 2.8 (sensitivity, 91.7%; specificity, 86.8%; area under the curve, 0.890) to be the optimal cutoff for predicting DFS. Univariate analysis revealed that T stage, N stage, estrogen receptor status, and primary-tumor and nodal SUVmax correlated significantly with DFS. Among these 5 variables, only nodal SUVmax was found to be a single determinant of DFS by multivariate analysis (hazard ratio, 31.54; 95% confidence interval, 2.66–373.39; P = 0.0065). Conclusion: Nodal SUVmax on pretreatment 18F-FDG PET/CT may be an independent prognostic factor for disease recurrence in patients with IDC.

Recurrence detection in differentiated thyroid cancer patients with elevated serum level of antithyroglobulin antibody: special emphasis on using 18F‐FDG PET/CT

Objective  A clinical challenge is presented by differentiated thyroid cancer (DTC) patients who show increased serum antithyroglobulin antibody (TgAb) level with undetectable thyroglobulin (Tg) and negative radioiodine whole body scan (I‐WBS). The aim of this study is to investigate the recurrence in DTC patients with elevated TgAb by using 18F‐FDG PET/CT (PET/CT) in addition to I‐WBS and neck ultrasonography (USG).

Dose-dependent frontal hypometabolism on FDG-PET in methamphetamine abusers

OBJECTIVE Although a lot of evidence from neuropsychological and neuroimaging studies supports the view that patients with substance dependence have abnormalities in the prefrontal cortex, functional deficits in the prefrontal cortex have not been fully investigated in methamphetamine (MA) dependent patients. This study was prepared to examine whether MA abusers have cerebral metabolic abnormalities and executive dysfunction. METHOD Twenty-four abstinent MA dependent patients and 21 age-matched control subjects underwent resting brain FDG-PET and completed computerized versions of the Wisconsin card sorting test (WCST). Resting brain PET images were obtained 30min after an intravenous injection of 370MBq of (18)F-FDG. Significant differences in glucose metabolism were estimated for every voxel using t-statistics on SPM2 implemented in Matlab. RESULTS Resting brain FDG-PET revealed significant hypometabolism in the left inferior frontal white matter (Talairach coordinates (x, y, z): -34, 7, 31) in MA dependent patients compared to the control subjects (corrected p=0.001, peak Z=5.37, voxel number 201). The nearest gray matter region was the left inferior frontal cortex (Brodmann area 9). There were negative correlations between the relative regional cerebral metabolism for glucose (rCMRglc) in the left inferior frontal white matter and the total cumulative dose of MA (r=-0.57, p<0.01). MA dependent patients completed significantly fewer categories (3.8+/-2.2) and made more perseveration errors (21.3+/-11.8) and total errors (43.5+/-19.5) on the WCST when compared to the control subjects (p<0.01). CONCLUSIONS These data suggest that MA dependent patients have dose-dependent frontal hypometabolism and frontal executive dysfunction.

Incidental pituitary uptake on whole-body 18F-FDG PET/CT: a multicentre study

PurposeThe purpose of this study was to determine the incidence of incidental pituitary uptake on whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and to investigate its clinical significance.MethodsThe files of 40,967 patients who underwent whole-body FDG PET/CT were retrospectively reviewed. Quantification of pituitary metabolic activity was obtained by using the maximum standardized uptake value (SUVmax). Hormone assays and pituitary MRIs were performed to assess pituitary lesions.ResultsFocally increased pituitary FDG uptake on PET/CT was found in 30 of 40,967 patients, accounting for an incidence of 0.073%. The mean SUVmax of 30 patients was 8.9 ± 6.6 (range: 3.2–32.6). Histological diagnosis was obtained in three patients and included two growth hormone-secreting adenomas and one non-functioning adenoma. Hormone assays were performed on serum samples from 11 patients, 2 of whom were shown to have hypersecretion of pituitary hormone. MRI was performed on 19 patients. Abnormal MRI findings suggesting a pituitary mass were found in 18 of 19 cases (94.7%). The mean SUVmax calculated without correction for partial volume effect for macroadenomas was significantly higher than the SUVmax for microadenomas (11.5 ± 8.4 vs 4.8 ± 1.3; p < 0.05). There were no cases diagnosed with metastasis to the pituitary gland during clinical follow-up.ConclusionIncidental pituitary FDG uptake was a very rare finding. Cases with incidental pituitary FDG uptake were diagnosed primarily with clinically non-functioning adenomas, and there were also a few functioning adenomas. Further evaluations, including hormone assays and pituitary MRI, are warranted when pituitary uptake is found on FDG PET/CT.

Prognostic implication of intratumoral metabolic heterogeneity in invasive ductal carcinoma of the breast.

BackgroundThe purpose of this study was to evaluate the prognostic implication of findings of intratumoral metabolic heterogeneity on pretreatment 18F-FDG PET/CT scans in patients with invasive ductal carcinoma (IDC) of the breast.MethodsOne hundred and twenty-three female IDC patients who underwent pretreatment 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) scans were retrospectively evaluated in this study. The heterogeneity factor (HF) defined as the derivative (dV/dT) of a volume threshold function from 40% to 80%, was computed for each primary tumor. Other metabolic PET parameters (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) were measured. The HF was compared with clinicopathologic factors and other PET parameters. Univariate and multivariate analyses for the overall survival (OS) were performed.ResultsThe HF ranged from 0.02 to 6.72 (mean, 0.35 ± 0.82) and significantly correlated with MTV (r = 0.955; p < 0.0001) and TLG (r = 0.354; p = 0.0001). The HF was significantly higher (implying more heterogeneity) in tumors with higher T and N stages. The optimal cut-off values for the OS determined using a receiver operating characteristic (ROC) curve were 0.34 for the HF, 5.6 for SUVmax, 8.55 cm3 for MTV, and 14.43 for TLG. The OS rate among the 123 patients was 86.2%. T stage (1, 2 vs. 3, 4), N stage (0, 1 vs. 2, 3), M stage (0 vs. 1), ER status (+ vs. –), SUVmax (≤ 5.6 vs. > 5.6), MTV (≤ 8.55 cm3 vs. > 8.55 cm3), TLG (≤ 14.43 vs. > 14.43), and HF (< 0.34 vs. ≥ 0.34) affected the OS on univariate analysis. After adjustment for the effects of TNM stage and ER status, the HF and MTV were significant predictors of OS. Among the PET parameters, the best prognostic factor for OS was the HF.ConclusionsIntratumoral metabolic heterogeneity correlated closely with the MTV and significantly affected the OS in IDC patients. The HF may act as a robust surrogate marker for the prediction of OS in IDC patients.

Trafficking Macrophage Migration Using Reporter Gene Imaging with Human Sodium Iodide Symporter in Animal Models of Inflammation

The aim of this study was to investigate the feasibility of nuclear molecular imaging using the human sodium iodide symporter (hNIS) as a reporter gene to monitor macrophage migration toward the inflammatory foci. Methods: A stable macrophage cell line coexpressing hNIS and green fluorescent protein (GFP) genes (RAW264.7/hNIS-GFP and RNIS cell) was established from an immortalized macrophage cell line (RAW264.7 cells). 125I uptake was determined (for hNIS protein functional activity), and flow cytometry analysis (to examine GFP gene expression), a cell proliferation assay, a cytokine assay, and a phagocytic activity assay were performed. 99mTc-pertechnetate images were acquired at 1 d after subcutaneous inoculation of RNIS cells in nude mice. Chemical inflammation was induced for in vivo imaging in the thigh of nude mice by turpentine oil injection. Small-animal PET with 18F-FDG and 124I was performed with an intravenous administration of RAW264.7 or RNIS cells in inflammation-induced animals. Results: The expression of hNIS and GFP genes was confirmed in RNIS cells by flow cytometry and immunofluorescent staining. 125I uptake was about 67 times higher in RNIS cells than in RAW264.7 cells. No significant difference was observed in cell proliferation, cytokine production, and phagocytic activity between RAW264.7 and RNIS cells. 99mTc-pertechnetate imaging revealed increased tracer uptake at the inoculation site. PET with 124I demonstrated a donut-shaped uptake, correlating with uptake shown by the 18F-FDG PET images, at the inflammation site of mice administered RNIS cells. 124I uptake (percentage injected dose per gram) was about 2.12 times higher at the inflammation site in the RNIS mice than in RAW264.7 mice. By immunohistochemistry, the migration of macrophages was further confirmed by positive staining for GFP and hNIS at the inflammation site of RNIS mice. Conclusion: These data support the feasibility of hNIS reporter gene imaging to monitor the macrophage migration toward an inflammatory lesion. Macrophages expressing hNIS may provide a new strategy to investigate the cellular behavior seen with inflammatory response in a preclinical model.

Detection of apoptosis in a rat model of focal cerebral ischemia using a homing peptide selected from in vivo phage display

Focal cerebral ischemia, known as stroke, is caused by a sudden interruption in the blood supply to the brain. We attempted to identify peptides that can home to ischemic stroke tissue and detect the apoptosis of cells. A phage library displaying random peptides was screened for homing peptides to ischemic stroke tissue in a rat transient middle cerebral artery (MCA) occlusion model. After three rounds of in vivo screening, a phage clone displaying the most frequently occurring CLEVSRKNC sequence was selected. The CLEVSRKNC-phage preferentially homed to ischemic stroke tissue after intravenous administration into the MCA occlusion rats. The fluorescein-labeled synthetic CLEVSRKNC peptide, but not a scrambled control peptide, homed to ischemic stroke tissue with a lack of homing to non-ischemic brain tissue. The CLEVSRKNC peptide co-localized with a portion of neuronal cells, rather than with astrocytes, undergoing apoptosis at the penumbra region of stroke lesions. In autoradiographic studies, the uptake of the (131)I-labeled CLEVSRKNC peptide into an ischemic lesion increased at the first day and peaked at the third day after the injury. These results demonstrate that the CLEVSRKNC peptide can home to ischemic stroke tissue, while detecting apoptotic neuronal cells, and suggest it has applications as a targeting moiety for molecular imaging and selective drug delivery to stroke tissue.