June-Key Chung

Cross-modal plasticity and cochlear implants.

Hearing in profoundly deaf people can be helped by inserting an implant into the inner ear to stimulate the cochlear nerve. This also boosts the low metabolic activity of the auditory cortex, the region of the brain normally used for hearing. Other sensory modalities, such as sign language, can also activate the auditory cortex, a phenomenon known as cross-modal plasticity. Here we show that when metabolism in the auditory cortex of prelingually deaf children (whose hearing was lost before they learned to talk) has been restored by cross-modal plasticity, the auditory cortex can no longer respond to signals from a cochlear implant installed afterwards. Neural substrates in the auditory cortex might therefore be routed permanently to other cognitive processes in prelingually deaf patients.

Molecular-genetic imaging based on reporter gene expression.

Molecular imaging includes proteomic, metabolic, cellular biologic process, and genetic imaging. In a narrow sense, molecular imaging means genetic imaging and can be called molecular-genetic imaging. Imaging reporter genes play a leading role in molecular-genetic imaging. There are 3 major methods of molecular-genetic imaging, based on optical, MRI, and nuclear medicine modalities. For each of these modalities, various reporter genes and probes have been developed, and these have resulted in successful transitions from bench to bedside applications. Each of these imaging modalities has its unique advantages and disadvantages. Fluorescent and bioluminescent optical imaging modalities are simple, less expensive, more convenient, and more user friendly than other imaging modalities. Another advantage, especially of bioluminescence imaging, is its ability to detect low levels of gene expression. MRI has the advantage of high spatial resolution, whereas nuclear medicine methods are highly sensitive and allow data from small-animal imaging studies to be translated to clinical practice. Moreover, multimodality imaging reporter genes will allow us to choose the imaging technologies that are most appropriate for the biologic problem at hand and facilitate the clinical application of reporter gene technologies. Reporter genes can be used to visualize the levels of expression of particular exogenous and endogenous genes and several intracellular biologic phenomena, including specific signal transduction pathways, nuclear receptor activities, and protein–protein interactions. This technique provides a straightforward means of monitoring tumor mass and can visualize the in vivo distributions of target cells, such as immune cells and stem cells. Molecular imaging has gradually evolved into an important tool for drug discovery and development, and transgenic mice with an imaging reporter gene can be useful during drug and stem cell therapy development. Moreover, instrumentation improvements, the identification of novel targets and genes, and imaging probe developments suggest that molecular-genetic imaging is likely to play an increasingly important role in the diagnosis and therapy of cancer.

Preparation of a Promising Angiogenesis PET Imaging Agent: 68Ga-Labeled c(RGDyK)–Isothiocyanatobenzyl-1,4,7-Triazacyclononane-1,4,7-Triacetic Acid and Feasibility Studies in Mice

Arg-Gly-Asp (RGD) derivatives have been labeled with various radioisotopes for the imaging of angiogenesis in ischemic tissue, in which αvβ3 integrin plays an important role. In this study, cyclic Arg-Gly-Asp-d-Tyr-Lys [c(RGDyK)] was conjugated with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bz-NOTA) and then labeled with 68Ga. The labeled RGD so produced was subjected to an in vitro binding assay and in vivo biodistribution and PET studies. Methods: A mixture of SCN-Bz-NOTA (660 nmol) and c(RGDyK) (600 nmol) in 0.1 M sodium carbonate buffer (pH 9.5) was allowed to react for 20 h at room temperature in the dark for thiourea bond formation. The conjugate obtained was purified by semipreparative high-performance liquid chromatography (HPLC). The purified c(RGDyK)–SCN-Bz-NOTA (NOTA-RGD) was then labeled with 68Ga from a 68Ge/68Ga generator and purified by semipreparative HPLC. A competitive binding assay for c(RGDyK) and NOTA-RGD was performed with 125I-c(RGDyK) as a radioligand and αvβ3 integrin–coated plates as a solid phase. 68Ga-NOTA-RGD (0.222 MBq/100 μL) was injected, through a tail vein, into mice with hind limb ischemia and into mice bearing human colon cancer SNU-C4 xenografts. Biodistribution and imaging studies were performed at 1 and 2 h after injection. Results: The labeling of NOTA-RGD with 68Ga was straightforward. The Ki values of c(RGDyK) and NOTA-RGD were 1.3 and 1.9 nM, respectively. In the biodistribution study, the mean ± SD uptake of 68Ga-NOTA-RGD by ischemic muscles was 1.6 ± 0.2 percentage injected dose per gram (%ID/g); this uptake was significantly blocked by cold c(RGDyK) to 0.6 ± 0.3 %ID/g (P < 0.01). Tumor uptake was 5.1 ± 1.0 %ID/g, and the tumor-to-blood ratio was 10.3 ± 4.8. Small-animal PET revealed rapid excretion through the urine and high levels of tumor and kidney uptake. Conclusion: Stable 68Ga-NOTA-RGD was obtained in a straightforward manner at a high yield and showed a high affinity for αvβ3 integrin, specific uptake by angiogenic muscles, a high level of uptake by tumors, and rapid renal excretion. 68Ga-NOTA-RGD was found to be a promising radioligand for the imaging of angiogenesis.

Determination of the prognostic value of [18F]fluorodeoxyglucose uptake by using positron emission tomography in patients with non-small cell lung cancer

The aim of this study was to determine whether quantitative information obtained from [18F]fluorodeoxyglucose positron emission tomography (18F-FDG PET) has a prognostic significance for patients with non-small cell lung cancer (NSCLC). We investigated 18F-FDG PET imaging of 73 patients with NSCLC. The maximum standardized uptake value (SUVmax) was significantly different between the histopathological types of tumour (squamous cell carcinoma (n = 37, 12.4±5.1), adenocarcinoma (n = 30, 8.2±5.8), bronchioloalveolar carcinoma (n = 4, 2.6±1.7), P<0.01). In the univariate analysis of all patients, staging (P = 0.0001), tumour cell type (P = 0.013), and a SUVmax greater than 7 (P = 0.0011) was correlated with survival. However, a multivariate analysis identified staging and SUVmax greater than 7 were affected survival adversely. The mortality rate of patients with group I disease (stage I to stage IIIA) was 5.8 times lower than that of patients with group II disease (stage IIIB to stage IV). Patients with a high SUVmax (⩾7) had a 6.3 times higher mortality than those with a low SUVmax (<7). By multivariate analysis of patients with squamous cell carcinoma, only grouping affected survival (P = 0.008, relative risk = 4.3). In the case of adenocarcinoma, the SUVmax (>10) correlated exclusively with poorer survival (P = 0.031, relative risk = 11.152). 18F-FDG uptake correlated with survival in NSCLC. Especially in adenocarcinomas, the SUVmax was complementary to other known prognostic factors.

11C-methionine PET as a prognostic marker in patients with glioma: comparison with 18F-FDG PET

PurposeThe purpose of this study was to compare the prognostic value of 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in glioma patients.MethodsThe study population comprised 47 patients with gliomas (19 glioblastoma, 28 others). Pretreatment magnetic resonance imaging, MET PET and FDG PET were performed within a time interval of 2 weeks in all patients. The uptake ratio and standard uptake values were calculated. Univariate and multivariate analyses were done to determine significant prognostic factors. Ki-67 index was measured by immunohistochemical staining, and compared with FDG and MET uptake in glioma.ResultsAmong the several clinicopathological prognostic factors, tumour pathology (glioblastoma or not), age (≥60 or <60 years), Karnofsky performance status (KPS) (≥70 or <70) and MET PET (higher uptake or not compared with normal cortex) were found to be significant predictors by univariate analysis. In multivariate analysis, tumour pathology, KPS and MET PET were identified as significant independent predictors. The Ki-67 proliferation index was significantly correlated with MET uptake (r=0.64), but not with FDG uptake.ConclusionCompared with FDG PET in glioma, MET PET was an independent significant prognostic factor and MET uptake was correlated with cellular proliferation. MET PET may be a useful biological prognostic marker in glioma patients.

Prediction of Tumor Recurrence by 18F-FDG PET in Liver Transplantation for Hepatocellular Carcinoma

Although several prognostic factors are used to predict recurrence and to select adequate candidates for liver transplantation for hepatocellular carcinoma (HCC), these prognostic factors have some clinical limitations. The purpose of this study was to evaluate 18F-FDG PET as a prognostic factor and to optimize its ability to predict tumor recurrence in liver transplantation for HCC. Methods: The study included a total of 59 HCC patients (45 men and 15 women; mean age ± SD, 56 ± 8 y) who underwent 18F-FDG PET and subsequent orthotopic liver transplantation. All patients were followed up for more than 1 y (mean, 29 ± 17 mo), and recurrence of tumor was monitored. Three PET parameters—maximal standardized uptake value (SUVmax), ratio of tumor SUVmax to normal-liver SUVmax (TSUVmax/LSUVmax), and ratio of tumor SUVmax to normal-liver mean SUV (TSUVmax/LSUVmean)—were tested as prognostic factors and compared with conventional prognostic factors. Results: Among the 3 parameters tested, TSUVmax/LSUVmax was the most significant in the prediction of tumor recurrence, with a cutoff value of 1.15. In a multivariate analysis of various prognostic factors including TSUVmax/LSUVmax, serum α-fetoprotein, T stage, size of tumor, and vascular invasion of tumor, TSUVmax/LSUVmax was the most significant, and only vascular invasion of tumor had additional significance. According to TSUVmax/LSUVmax, the 1-y recurrence-free survival rate above the cutoff was markedly different from the rate below the cutoff (97% vs. 57%, P < 0.001). Conclusion: In this study, 18F-FDG PET was an independent and significant predictor of tumor recurrence. In liver transplantation for HCC, 18F-FDG PET can provide effective information on the prognosis for tumor recurrence and the selection of adequate candidates for liver transplantation.

Tumor Targeting and Imaging Using Cyclic RGD‐PEGylated Gold Nanoparticle Probes with Directly Conjugated Iodine‐125

Radioactive iodine-labeled, cyclic RGD-PEGylated gold nanoparticle (AuNP) probes are designed and synthesized for targeting cancer cells and imaging tumor sites. These iodine-125-labeled cRGD-PEG-AuNP probes are stable in various conditions including a range of pHs and high salt and temperature conditions. These probes can target selectively and be taken up by tumor cells via integrin αvβ3-receptor-mediated endocytosis with no cytotoxicity. The probes show a significant increase in the avidity of αvβ3 integrin compared to the corresponding free cRGD peptides. In-vivo SPECT/CT imaging results show that the iodine-125-labeled cRGD-PEG-AuNP probes can target the tumor site as soon as 10 min after injection, and also that cyclic RGD peptides are needed for efficient and long-term in-vivo monitoring. The results suggest that the probes circulate through the whole body, including renal filtration, and are excretable. These promising results show that radioactive-iodine-labeled gold nanoprobes have potential for highly specific and sensitive tumor imaging or for use as angiogenesis-targeted SPECT/CT imaging probes.

Establishment and characterization of human gastric carcinoma cell lines

We report 8 newly established gastric‐carcinoma cell lines (SNU‐216, 484, 520, 601, 620, 638, 668, 719) from Korean patients. Morphologic study was carried out using light and electron microscopes. CEA, αFP, and CA 19‐9 and TPA in supernatant and in cell lysate were measured by radioimmunoassay. p53 and c‐Ki‐ras gene mutations were screened and confirmed by sequencing. The cell lines, derived from tumors with moderate differentiation, grew as a diffuse monolayer, and those from tumors with poor differentiation and minimal desmoplasia grew exclusively as non‐adherent. Out of the 8 gastric‐cancer cell lines, 5 had detectable levels of CEA both in supernatant and in cell lysate; there was no expression or secretion of αFP in these cells; 4 cell lines showed high levels of CA 19‐9 in cell pellets. All cell lines except SNU‐484 had high concentrations of TPA both in cell lysate and in supernatants. p53 mutation was found in 6 cell lines (75%): 2 (SNU‐216 and SNU‐668) had mutations in exon 6, and other 3 in exon 8. The c‐Ki‐ras mutation was found in 2 cell lines (25%), SNU‐601 and SNU‐668. The former showed GGT‐to‐GAT transition mutation at codon 12, while the latter showed CAA‐to‐AAA transversion mutation at codon 61. DNA profiles using restriction endonuclease Hinfl and polymorphic DNA probes ChdTC‐15 and ChdTC‐114 showed different unique patterns; which suggests that these cell lines are unique and not cross‐contaminated. We believe that the newly characterized gastric‐cancer cell lines presented in this paper will provide a useful in vitro model for studies related to human gastric cancer. Int. J. Cancer, 70:0–0, 1997.

Regional cerebral blood flow in children with attention deficit hyperactivity disorder: Comparison before and after methylphenidate treatment

Differences in brain activity of children with attention deficit hyperactivity disorder (ADHD) have been compared to normal healthy controls, suggesting neural correlates of cognitive/behavioral symptoms. Symptoms are improved with methylphenidate treatment but limited sources can be cited to show how brain activity in ADHD is altered after pharmacologic treatment. We investigated how long‐term oral medication of methylphenidate affects the resting regional cerebral blood flow (rCBF) in ADHD children, using single photon emission computerized tomography (SPECT). rCBF was decreased in the orbitofrontal cortex and middle temporal gyrus in the right hemisphere whereas it was increased in the dorsomedial prefrontal and somatosensory area bilaterally in drug‐naïve ADHD children compared to control child subjects. After treatment with methylphenidate, the extent of hyperperfusion in the somatosensory area was reduced and significant reduction of rCBF was found in the right striatum for the first time. Methylphenidate treatment also resulted in rCBF increase in superior prefrontal and reduction in ventral higher visual areas bilaterally. The results indicated that improving ADHD symptom after methylphenidate is associated with normalization of abnormally reduced orbitofrontal activity and abnormally increased somatosensory cortical activity. These changes were accompanied with reduced striatum activity lower than that of normal controls. These changes might be associated with improving ADHD to control attention and motor response to irrelevant environmental stimuli after methylphenidate treatment. Hum. Brain Mapp 24:157–164, 2005.

Changes in the Clinicopathological Characteristics and Outcomes of Thyroid Cancer in Korea over the Past Four Decades

BACKGROUND Thyroid cancer has increased globally, with a prominent increase in small, papillary thyroid cancers (PTC). The Korean population has a high iodine intake, high prevalence of BRAF V600E mutations, and family histories of thyroid cancer. We examined the clinicopathological characteristics and outcomes of thyroid cancers in Korean patients over four decades. METHODS The medical records of 4500 thyroid cancer patients, between 1962 and 2009 at a single center, including 3147 PTC patients, were reviewed. RESULTS The mean age of the patients was 46.8±13.2 years; women accounted for 82.9% of the patients, and the median follow-up duration was 4.8 years (mean 7.0±5.8 years, range 1-43 years). The number of patients visiting the clinic increased from 411 during 1962-1990 to 2900 during 2000-2009. Age at diagnosis increased from 39.6±12.9 to 48.6±12.4 years. The male to female ratio increased from 1:6 to 1:4.5. The proportion of small (<1 cm) tumors increased from 6.1% to 43.1%, and the proportion of cancers with lymph node (LN) involvement or extrathyroidal extension (ETE) decreased from 76.4% to 44.4% and from 65.5% to 54.8% respectively. Although there were decreases in the proportion of LN involvement and ETE, these decreasing rates were not proportional to the expected rates based on the decreased proportion of large tumors. The overall recurrence and mortality rates were 13.3% and 1.4%. The five-year recurrence rate significantly decreased (from 11% to 5.9%), and the five-year mortality also improved (from 1.5% to 0.2%). CONCLUSIONS The incidence of thyroid cancer has rapidly increased, with a decrease in tumors of large size, LN involvement, and ETE, although the decreasing rates of LN involvement and ETE were not as prominent as decreasing rates of large size tumors. The mortality and recurrence rates have also decreased. Future long-term follow-up of patients diagnosed in the most recent decade is needed to confirm the prognostic characteristics of Korean PTC patients.