Jae Gol Choe

A multifunctional protein EWS regulates the expression of Drosha and microRNAs

EWS (Ewing’s Sarcoma) gene encodes an RNA/DNA-binding protein that is ubiquitously expressed and involved in various cellular processes. EWS deficiency leads to impaired development and early senescence through unknown mechanisms. We found that EWS regulates the expression of Drosha and microRNAs (miRNAs). EWS deficiency resulted in increased expression of Drosha, a well-known microprocessor, and increased levels of miR-29b and miR-18b. Importantly, miR-29b and miR-18b were directly involved in the post-transcriptional regulation of collagen IV alpha 1 (Col4a1) and connective tissue growth factor (CTGF) in EWS knock-out (KO) mouse embryonic fibroblast cells. The upregulation of Drosha, miR-29b and miR-18b and the sequential downregulation of Col4a1 and CTGF contributed to the deregulation of dermal development in EWS KO mice. Otherwise, knockdown of Drosha rescued miRNA-dependent downregulation of Col4a1 and CTGF proteins. Taken together, our data indicate that EWS is involved in post-transcriptional regulation of Col4a1 and CTGF via a Drosha–miRNA-dependent pathway. This finding suggests that EWS has a novel role in dermal morphogenesis through the modulation of miRNA biogenesis.

Detection of Increased 64Cu Uptake by Human Copper Transporter 1 Gene Overexpression Using PET with 64CuCl2 in Human Breast Cancer Xenograft Model

Copper is an essential cofactor for a variety of biochemical processes including oxidative phosphorylation, cellular antioxidant activity, and elimination of free radicals. The copper transporter 1 is known to be involved in cellular uptake of copper ions. In this study, we evaluated the utility of human copper transporter 1 (hCTR1) gene as a new reporter gene for 64Cu PET imaging. Methods: Human breast cancer cells (MDA-MB-231) were infected with a lentiviral vector constitutively expressing the hCTR1 gene under super cytomegalovirus promoter, and positive clones (MDA-MB-231-hCTR1) were selected. The expression of hCTR1 gene in MDA-MB-231-hCTR1 cells was measured by reverse transcription polymerase chain reaction, Western blot, and 64Cu uptake assay. To evaluate the cytotoxic effects induced by hCTR1 expression, the dose-dependent cell survival rate after treatment with cisplatin (Cis-diaminedichloroplatinum (II) [CDDP]) was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue dye exclusion. Small-animal PET images were acquired in tumor-bearing mice from 2 to 48 h after an intravenous injection of 64Cu. Results: The hCTR1 gene expression in MDA-MB-231-hCTR1 cells was confirmed at the RNA and protein expression and the cellular 64Cu uptake level. MTT assay and trypan blue dye exclusion showed that the cell viability of MDA-MB-231-hCTR1 cells decreased more rapidly than that of MDA-MB-231 cells after treatment with CDDP for 96 or 72 h, respectively. Small-animal PET imaging revealed a higher accumulation of 64Cu in MDA-MB-231-hCTR1 tumors than in MDA-MB-231 tumors. With respect to the biodistribution data, the percentage injected dose per gram of 64Cu in the MDA-MB-231 tumors and MDA-MB-231-hCTR1 tumors at 48 h after 64Cu injection was 2.581 ± 0.254 and 5.373 ± 1.098, respectively. Conclusion: An increase in 64Cu uptake induced by the expression of hCTR1 gene was demonstrated in vivo and in vitro, suggesting the potential use of hCTR1 gene as a new imaging reporter gene for PET with 64CuCl2.

Implication of lymph node metastasis detected on 18F-FDG PET/CT for surgical planning in patients with peripheral intrahepatic cholangiocarcinoma.

Objectives Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma. ICC can be divided into 2 types according to their location: peripheral and hilar types. Intense 18F-FDG uptake on PET was reported in peripheral ICC. However, the usefulness of PET/CT in detecting tumors and predicting prognosis in peripheral ICC has not been fully evaluated. In this study, we evaluated the clinical role of 18F-FDG PET/CT to predict the recurrence after the curative resection in patients with surgically indicated peripheral ICC. Methods Eighteen patients with ICC underwent preoperative CT and 18F-FDG PET/CT scans. SUVmax of tumor, tumor to normal liver SUV ratio (TNR), lymph node status evaluated by 18F-FDG PET/CT, tumor and lymph node size measured by CT, vascular invasion confirmed by pathology, and satellite nodules found on CT were compared between 1-year recurrence group and recurrence-free group by chi-square test. Results Of total 23 measurable lymph nodes, 4 nodes were positive and other 19 nodes were negative or equivocal on CT. Among those 23 nodes, 9 nodes were positive and other 14 nodes were negative on 18F-FDG PET/CT. The sensitivity and specificity of CT were 20.0% and 86.4%, and those of 18F-FDG PET/CT were 80.0% and 92.3%. In the comparison between 1-year recurrent and nonrecurrent groups, lymph node metastasis detected on 18F-FDG PET/CT had statistically positive correlation with the 1-year recurrence after surgical resection (P = 0.02). Other factors showed no statistically significant difference between the groups. Conclusion We found that lymph node metastasis detected on 18F-FDG PET/CT correlated positively with 1-year recurrence after surgical resection in patients with peripheral ICC.

Double-Blind Placebo-Controlled Study of Cisapride in Patients with Nonspecific Esophageal Motility Disorder Accompanied by Delayed Esophageal Transit

BACKGROUND Nonspecific esophageal motility disorder (NEMD) represents a difficult therapeutic challenge because of the heterogeneous nature of the esophageal motor functions. We studied the effects of cisapride on the esophageal symptoms and esophageal motor function in a group of patients with NEMD showing delayed esophageal transit. METHODS Seventy eligible patients were entered into a 4-week, double-blind randomized comparison of 10 mg of cisapride or placebo, four times daily. Symptom assessment, esophageal manometry after wet swallows, and esophageal scintigraphy after intake of a liquid and solid bolus were performed in each patient before and after treatment. RESULTS After 4 weeks of treatment cisapride significantly increased the prevalence of esophageal peristaltic contractions (percentage of total contractions, P < 0.05 versus base line and placebo) and significantly improved esophageal emptying of the solid bolus (P < 0.05 versus placebo) but not of the liquid bolus. Placebo did not have any significant effects versus base line on these variables. Both placebo and cisapride improved the distal esophageal amplitude versus base line (no significant intergroup differences). Symptom scores were significantly reduced after 4 weeks of treatment versus base line in both groups (no significant intergroup differences except for heartburn and regurgitation, P < 0.05). On global evaluation of treatment, significantly more patients in the cisapride group were rated as markedly or moderately improved, when compared with placebo. CONCLUSIONS The results of the present study showed that cisapride is effective and well tolerated in patients with NEMD accompanied by delayed esophageal transit. Symptomatic improvement may possibly be related to its beneficial action on the esophageal body by increasing the number of peristaltic contractions and esophageal emptying of solids.

Diagnostic Value of CT Density in Patients With Diffusely Increased FDG Uptake in the Thyroid Gland on PET/CT Images

OBJECTIVE The purpose of this article is to determine the diagnostic significance of thyroid density as determined by CT in patients with a diffuse hypermetabolic thyroid on PET/CT images. SUBJECTS AND METHODS One hundred twelve patients were enrolled in this study, and all underwent PET/CT and a thyroid function test between August 2007 and December 2008. The 56 study patients enrolled had visible (18)F-FDG uptake in the thyroid, whereas the 56 control subjects had no visible FDG uptake. Maximum standardized uptake values (SUV(max)), Hounsfield units, thyroid-stimulating hormone levels, free thyroxine levels, and visual assessments of thyroid CT densities (grades 0-2) were evaluated. Analyses were performed to identify variables that differed between patients and control subjects and to examine relationships between Hounsfield unit and SUV(max) values, free thyroxine level, or thyroid-stimulating hormone level. RESULTS Mean Hounsfield unit and SUV(max) values were significantly different between the two groups (p < 0.001), and SUV(max) values were found to be significantly different between grades. Free thyroxine and thyroid-stimulating hormone levels were also significantly different between thyroid density grades 0 and 2 (p < 0.001). A strongly negative relationship was found between Hounsfield units and SUV(max) values (r = 0.75), whereas Hounsfield units were found to be weakly correlated with free thyroxine level (r = 0.36) and thyroid-stimulating hormone level (r = -0.33). CONCLUSION CT density is closely related to FDG uptake, and low CT density coupled with high FDG uptake suggests a change in thyroid tissue composition and is probably helpful for assessing the disease process and thyroid function of patients whose thyroid show diffuse FDG uptake on FDG PET/CT.

Correlation between Semi-Quantitative (18)F-FDG PET/CT Parameters and Ki-67 Expression in Small Cell Lung Cancer.

PurposeThe aim of this study was to evaluate the relationship between semiquantitative parameters on 18F-FDG PET/CT including maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and the expression level of Ki-67 in small-cell lung cancer (SCLC).MethodsNinety-four consecutive patients with SCLC were enrolled in this study. They underwent 18F-FDG PET/CT for initial evaluation of SCLC, and we measured SUVmax, avgSUVmean, MTVsum, and TLGtotal on 18F-FDG PET/CT images. The protein expression of Ki-67 was examined by immunohistochemical staining.ResultsSignificant correlations were found between the MTVsum and Ki-67 labeling index (r = 0.254, p = 0.014) and the TLGtotal and Ki-67 labeling index (r = 0.239, p = 0.020). No correlation was found between the SUVmax and Ki-67 labeling index (r = 0.116, p = 0.264) and the avgSUVmean and Ki-67 labeling index (r = 0.031, p = 0.770). Dividing the Ki-67 expression level into three categories, it was suggested that increasing Ki-67 expression level caused a stepwise increase in the MTVsum and TLGtotal. (p = 0.028 and 0.039, respectively), but not the SUVmax and avgSUVmean (p = 0.526 and 0.729, respectively).ConclusionIn conclusion, the volume-based parameters of 18F-FDG PET/CT correlate with immunohistochemical staining of Ki-67 in SCLC. Measurement of the MTVsum and TLGtotal by 18F-FDG PET/CT might be a simple, noninvasive, and useful method to determine the proliferative potential of cancer cells.

Predictive Role of Functional Visceral Fat Activity Assessed by Preoperative F-18 FDG PET/CT for Regional Lymph Node or Distant Metastasis in Patients with Colorectal Cancer

Objectives To investigate the role of functional visceral fat activity assessed by preoperative F-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in colorectal cancer (CRC) for predicting regional lymph node (LN) or distant metastasis. Method We evaluated 131 patients with newly diagnosed CRC. They all underwent pre-operative 18F-FDG PET/CT and surgery. Functional fat activity was measured by maximum standardized uptake value (SUVmax) using 18F-FDG PET/CT. Functional visceral fat activity was measured by SUVmax of visceral fat/SUVmax of subcutaneous fat (V/S) ratio. Mann-Whitney U test, χ2 test, Fisher’s exact test, receiver-operating characteristic (ROC) analysis, Spearrman’s correlation coefficient, and uni- and multivariate logistic regression statistical analyses were done. Results Patients with higher V/S ratio displayed a significantly higher rate of regional LN (p = 0.004) and distant metastasis (p<0.001). In addition, V/S ratio was the only factor that was significantly associated with distant metastasis. An optimal cut-off V/S ratio of 1.88 was proposed for predicting distant metastasis with a sensitivity of 84.6% and specificity of 78.8% (area under the curve: 0.86; p<0.0001) Conclusion Functional visceral fat activity is significantly associated with distant metastasis in CRC patients. Furthermore, V/S ratio can be useful as a complementary factor in predicting distant metastasis.

Early prediction of pathological complete response in luminal B type neoadjuvant chemotherapy-treated breast cancer patients: comparison between interim 18F-FDG PET/CT and MRI.

PurposeThe aim of this study is to justify the effectiveness of interim PET/computed tomography (CT) for predicting pathological complete response (pCR) in luminal B type breast cancer patients and to compare the diagnostic performance of interim PET/CT and MRI. Materials and methodsTwenty-one patients with neoadjuvant chemotherapy (NAC)-treated luminal B type breast cancer were included. All patients underwent PET/CT and MRI at baseline and interim (mid-point). Breast surgery was performed after completion of NAC. Maximum standardized uptake values (SUVmax) of breast malignant lesions in each PET/CT scan were acquired in each patient. The metabolic response was calculated as follows: &Dgr;SUV (%)=(baseline SUVmax−interim SUVmax)/baseline SUVmax×100 (%). In MRI, the relative size change was calculated as follows: Size change (%)=longest diameter interim MRI−longest diameter baseline MRI/longest diameter baseline MRI×100 (%). pCR was concluded through the final pathologic specimen after breast surgery. The receiver-operating characteristic analysis was used as a statistical method. ResultsOf 21 patients, seven achieved a pCR after surgery. In PET/CT, an optimal cut-off &Dgr;SUV (%) of 69.0% was proposed with a sensitivity of 85.7% and a specificity of 100% (P<0.0001). In MRI, an optimal cut-off size change (%) was 38.2% with a sensitivity of 64.3% and a specificity of 71.4% (P=0.29). The area under the curve was 0.92 and 0.65, respectively. PET/CT presented better predictability of the pCR than MRI (P=0.04). ConclusionIn luminal B type NAC-treated breast cancer patients, it is possible to use PET/CT as an early surrogate marker for predicting pCR and it is significantly more predictable for pCR than MRI.

Feasibility of PET Template-Based Analysis on F-18 FP-CIT PET in Patients with De Novo Parkinson’s Disease

PurposeThe aim of this study was to evaluate the feasibility of FP-CIT PET template-based quantitative analysis on F-18 FP-CIT PET in patients with de novo Parkinson’s disease (PD), compared with MR-based and manual methods. We also assessed the correlation of quantitative parameters of those methods with clinical severity of the disease.MethodsForty patients with de novo PD underwent both MRI and F-18 FP-CIT PET. Images were spatially normalized to a standardized PET template. Mean counts of 4 ROIs: putamen, caudate, occipital cortex and cerebellum, were obtained using the quantification program, Korean Statistical Probabilistic Anatomical Map (KSPAM). Putamen-to-caudate ratio (PCR), asymmetry index (ASI), specific-to-nonspecific ratios with two different references: to occipital cortex (SOR) and cerebellum (SCR) were compared. Parameters were also calculated from manually drawn ROI method and MR-coregistrated method.ResultsAll quantitative parameters showed significant correlations across the three different methods, especially between the PET-based and manual methods. Among them, PET-based SOR and SCR values showed an excellent correlation and concordance with those of manual method. In relationship with clinical severity, only ASI achieved significantly inverse correlations with H&Y stage and UPDRS motor score. There was no significant difference between the quantitative parameters of both occipital cortex and cerebellum in all three methods, which implied that quantitation using PET-based method could be reproducible regardless of the reference region.ConclusionsQuantitative parameters using FP-CIT PET template-based method correlated well with those using laborious manual method with excellent concordance. Moreover, PET-based quantitation was less influenced by the reference region than MR-based method. It suggests that PET-based method can provide objective and quantitative parameters quickly and easily as a feasible analysis in place of conventional method.

Usefulness of Bremsstrahlung Images after Intra-arterial Y-90 Resin Microphere Radioembolization for Hepatic Tumors

PurposeY-90 resin microsphere radioembolization is used to treat inoperable hepatic tumors. After injection of Y-90 resin microsphere, the only method to visualize the distribution of Y-90 is the scintigraphic imaging of bremsstrahlung radiation. The purpose of this study was to evaluate the characteristics and usefulness of bremsstrahlung imaging in Y-90 resin microsphere treatment.MethodsTwenty patients (22 administrations) underwent intra-arterial Y-90 resin microsphere treatment. For pre-treatment planning, images of Tc-99m albumin macroaggregate (MAA) arterial injection and hepatic contrast angiography were obtained. Post-treatment bremsstrahlung images were taken and compared with pre-treatment images. The extrahepatic activity was evaluated on bremsstrahlung images. To correlate the size and vascularity of the tumors with tumor visualization on bremsstrahlung images, the individual tumors were grouped according to visualization on each image and compared with one another by size and tumor-to-normal ratio.ResultsAll post-therapeutic bremsstrahlung images showed similar contours of the liver with pre-treatment angiography. No extrahepatic activity was seen in all cases. The visualized tumors on bremsstrahlung images were significantly larger than the non-visualized tumors. Tumor-to-normal ratios of the visualized tumors on bremsstrahlung images were significantly higher than those of the non-visualized tumors.ConclusionsBremsstrahlung images after intra-arterial Y-90 resin microsphere treatment are useful in evaluating the intrahepatic distribution of radioisotope and detecting possible extrahepatic activity.