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Terry Lichtor, Roberta P. Glick, Tae Sung Kim, Roger Hand and Edward P. Cohen

✓ A novel approach toward the treatment of glioma was developed in a murine model. The genes for both interleukin-2 (IL-2) and interferon-γ (IFN-γ) were first transfected into a mouse fibroblast cell line that expresses defined major histocompatibility complex (MHC) determinants (H—2k). The double cytokine—secreting cells were then cotransplanted intracerebrally with the Gl261 murine glioma cell line into syngeneic C57BL/6 mice (H—2b) whose cells differed at the MHC from the cellular immunogen. The results indicate that the survival of mice with glioma injected with the cytokine-secreting allogeneic cells was significantly prolonged, relative to the survival of mice receiving equivalent numbers of glioma cells alone. Using a standard 51Cr-release assay, the specific release of isotope from labeled Gl261 cells coincubated with spleen cells from mice injected intracerebrally with the glioma cells and the cytokine-secreting fibroblasts was significantly higher than the release of isotope from glioma cells coincubated with spleen cells from nonimmunized mice. The cellular antiglioma response was mediated by natural killer/lymphokine-activated killer and Lyt-2.2+ (CD8+) cells. The increased survival of mice with glioma and the specific immunocytotoxic responses after immunization with fibroblasts modified to secrete both IL-2 and IFN-γ indicate the potential of an immunotherapeutic approach to gliomas with cytokine-secreting cells.

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Sung Bae Park, Tae-Ahn Jahng, Chi Heon Kim and Chun Kee Chung

Object

The aim of this study was to describe a novel technique for laminoplasty in which translaminar screws are used in the thoracic and lumbar spine.

Methods

The authors first performed a morphometric study in 20 control individuals using 3D reconstructed CT scans and spine simulation software to measure the lengths and diameters of the spaces available for translaminar screw placement from the T-1 to S-1.

Based on the results of the morphometric study, the authors then attempted translaminar screw fixation in 5 patients (April 2007–July 2007) after en bloc laminectomy in the thoracic and lumbar regions. All patients had intradural lesions: 3 schwannomas, 1 cavernoma, and 1 arachnoid cyst.

Results

The morphometric study in control individuals revealed that the safe trajectories for simulated screws measured 25–30 mm in length and 8–11 mm in diameter in the thoracic region (T1–12) and 26–34 mm in length and 6–7 mm in diameter in the lumbosacral region (L1–S1). This morphometric and simulation study showed that translaminar screw placement would be possible in practice.

Five patients underwent en bloc laminoplasty and translaminar screw fixation in which the screws measured 2.7 mm in diameter and 24 or 26 mm in length. Sixteen attempts at translaminar fixation were made in 8 vertebrae. Fourteen translaminar screws were successfully placed at the thoracic and lumbar levels. Two microplates had to be used because the laminae were too thin and narrow after further laminectomy with undercutting. There were no complications associated with the translaminar screws.

The mean follow-up period was 14.5 months. There was no screw breakage or displacement. Solid osseous fusion was documented in 2 patients who underwent CT scanning 15 months postoperatively.

Conclusions

The authors found that the laminoplasty and translaminar screw technique is feasible in the thoracic and lumbar regions, but further studies are needed to analyze the biomechanical effects and long-term outcomes in a large number of patients.

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Hae Yu Kim, Yun Jung Hur, Heung-Dong Kim, Kang Min Park, Sung Eun Kim and Tae Gyu Hwang

OBJECTIVE

Thalamic stimulation can provoke electroencephalography (EEG) synchronization or desynchronization, which can help to reduce the occurrence of seizures in intractable epilepsy, though the underlying mechanism is not fully understood. Therefore, the authors investigated changes in EEG electrical activity to better understand the seizure-reducing effects of deep brain stimulation (DBS) in patients with intractable epilepsy.

METHODS

Electrical activation patterns in the epileptogenic brains of 3 patients were analyzed using classical low-resolution electromagnetic tomography analysis recursively applied (CLARA). Electrical activity recorded during thalamic stimulation was compared with that recorded during the preoperative and postoperative off-stimulation states in patients who underwent anterior thalamic nucleus DBS for intractable epilepsy.

RESULTS

Interictal EEG was fully synchronized to the β frequency in the postoperative on-stimulation period. The CLARA showed that electrical activity during preoperative and postoperative off-stimulation states was localized in cortical and subcortical areas, including the insular, middle frontal, mesial temporal, and precentral areas. No electrical activity was localized in deep nucleus structures. However, with CLARA, electrical activity in the postoperative on-stimulation period was localized in the anterior cingulate area, basal ganglia, and midbrain.

CONCLUSIONS

Anterior thalamic stimulation could spread electrical current to the underlying neuronal networks that connect with the thalamus, which functions as a cortical pacemaker. Consequently, the thalamus could modify electrical activity within these neuronal networks and influence cortical EEG activity by inducing neuronal synchronization between the thalamus and cortical structures.

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Sung-Min Kim, T. Jesse Lim, Josemaria Paterno, Tae-Jin Hwang, Kun-Woo Lee, Raju S. V. Balabhadra and Daniel H. Kim

Object. The authors compared the biomechanical stability of two anterior fixation procedures—anterior C1–2 Harms plate/screw (AHPS) fixation and the anterior C1–2 transarticular screw (ATS) fixation; and two posterior fixation procedures—the posterior C-1 lateral mass combined with C-2 pedicle screw/rod (PLM/APSR) fixation and the posterior C1–2 transarticular screw (PTS) fixation after destabilization.

Methods. Sixteen human cervical spine specimens (Oc—C3) were tested in three-dimensional flexion—extension, axial rotation, and lateral bending motions after destabilization by using an atlantoaxial C1–2 instability model. In each loading mode, moments were applied to a maximum of 1.5 Nm, and the range of motion (ROM), neutral zone (NZ), and elastic zone (EZ) were determined and values compared using the intact spine, the destabilized spine, and the postfixation spine.

The AHPS method produced inferior biomechanical results in flexion—extension and lateral bending modes compared with the intact spine. The lateral bending NZ and ROM for this method differed significantly from the other three fixation techniques (p < 0.05), although statistically significant differences were not obtained for all other values of ROM and NZ for the other three procedures. The remaining three methods restored biomechanical stability and improved it over that of the intact spine.

Conclusions. The PLM/APSR fixation method was found to have the highest biomechanical stiffness followed by PTS, ATS, and AHPS fixation. The PLM/APSR fixation and AATS methods can be considered good procedures for stabilizing the atlantoaxial joints, although specific fixation methods are determined by the proper clinical and radiological characteristics in each patient.

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Jae Taek Hong, Tae Hyung Kim, Il Sup Kim, Seung Ho Yang, Jae Hoon Sung, Byung Chul Son and Sang Won Lee

Object

The aim of this study was to analyze the exact location of the internal carotid artery (ICA) relative to the C-1 lateral mass and describe the effect of age on the tortuosity of the ICA.

Methods

The authors analyzed 641 patients who had undergone CT angiography to evaluate the location of the ICA in relation to the C-1 lateral mass. Each patient was assigned to 1 of 3 age groups (< 41 years, 41–60 years, and > 60 years of age). The degree of lateral positioning of the ICA was classified into 4 groups: Group 1 (lateral to the C-1 lateral mass), Group 2 (lateral half of the lateral mass), Group 3 (medial half of the lateral mass), or Group 4 (medial to the lateral mass). The anteroposterior relationship of the ICA was classified into Group A (posterior to the anterior tubercle) or Group B (anterior to the anterior tubercle). Distances from the ICA to the midline, anterior tubercle, and anterior cortex of the lateral mass were measured. Distances between the lateral margin of the lateral mass and the longus capitis muscle were also evaluated.

Results

The prevalence of the ICA located in front of the lateral mass (Groups 2 and 3) was 47.4% overall. The position of the ICA changes with age due to vessel tortuosity. Only 18.3% of patients in the youngest age group (< 41 years of age) had an ICA in front of the lateral mass (Group 2 or 3 area). However, this percentage increased in the older 2 groups (43.5% in the 41–60 year old group, and 57% in the > 60-year-old age group). The mean distance from the midline to the ICA was 22.6 mm, and the mean distance from the ICA to the C-1 anterior tubercle and the ventral cortex of the lateral mass was 4.7 and 4.5 mm, respectively. Moreover, the ICA is more prone to injury during bicortical C-1 screw placement when the longus capitis muscle is hypotrophic and does not cover the entire ventral surface of the lateral mass.

Conclusions

Elderly patients have a higher incidence of a medially located ICA that may contribute to the risk of injury to the ICA during bicortical C-1 screw or C1–2 transarticular screw placement. Although the small number of reported cases of ICA injury does not allow for determination of a direct relationship with specific anatomical characteristics, the presence of unfavorable anatomy does warrant serious consideration during evaluation for C-1 screw placement in elderly patients.

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Eun-Hee Kim, Mi-Sun Yum, Young-Shin Ra, Jun Bum Park, Jae Sung Ahn, Gu-Hwan Kim, Hyun Woo Goo, Tae-Sung Ko and Han-Wook Yoo

OBJECT

Moyamoya disease (MMD) is an idiopathic cerebrovascular occlusive disorder prevalent in East Asia. In the pathogenesis of MMD, the important role of genetic factors is being elucidated, and RNF213 has recently been identified as a susceptibility gene for MMD. The aim of this retrospective study was to investigate the RNF213 genotype in patients with MMD and to determine their genotype-phenotype associations.

METHODS

The study involved 165 Korean MMD patients from 155 unrelated families who were diagnosed with MMD at a single center from 1995 to 2013. Their demographic, radiological, and clinical findings were evaluated. Direct sequencing of the major RNF213 single nucleotide polymorphisms was performed. The association of the common RNF213 variant with MMD risk was evaluated using historical controls for comparison. Correlations between RNF213 genotype and phenotype were statistically analyzed.

RESULTS

The c.14429G>A (p.R4810K) variant was identified in 125 (75.8%) of 165 MMD patients. Most patients (112) were heterozygous, and 13 patients had 2 copies of the c.14429G>A variant. A novel heterozygous variant, c.12086A>G (p.Q4029R), was found in 1 additional patient. The minor allele frequency of the c.14429G>A variant was significantly higher in the MMD group (138 [41.8%] of 330 patients) than in the control group (8 [1.36%] of 588 subjects; p < 0.001). The c.14429G>A (p.R4810K) variant significantly increased the risk of MMD in Korean patients, with an OR of 52.11 (p < 0.001) compared with controls. Moreover, c.14429G>A (p.R4810K) genotypes occurred more frequently in patients with a family history of MMD. The homozygous variant was highly associated with early-onset MMD (age at onset < 5 years), cerebral infarction at diagnosis, and cognitive impairment in long-term outcome.

CONCLUSIONS

The findings indicate that the c.14429G>A (p.R4810K) allele of RNF213 is strongly associated with Korean patients with MMD. The homozygous c.14429G>A (p.R4810K) variant is particularly related to early-onset MMD, severe symptomatic manifestations at diagnosis, and poor prognosis. This genotypic variant may be a useful biomarker for early-onset MMD or unstable MMD with cerebral infarction, which requires early diagnosis and revascularization treatment.

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Chang-Hyun Lee, Tae-Ahn Jahng, Seung-Jae Hyun, Chi Heon Kim, Sung-Bae Park, Ki-Jeong Kim, Chun Kee Chung, Hyun-Jib Kim and Soo-Eon Lee

OBJECTIVE

The Dynesys, a pedicle-based dynamic stabilization (PDS) system, was introduced to overcome the drawbacks of fusion procedures. Nevertheless, the theoretical advantages of PDS over fusion have not been clearly confirmed. The aim of this study was to compare clinical and radiological outcomes of patients who underwent PDS using the Dynesys system with those who underwent posterior lumbar interbody fusion (PLIF).

METHODS

The authors searched PubMed, Embase, Web of Science, and the Cochrane Database. Studies that reported outcomes of patients who underwent PDS or PLIF for the treatment of degenerative lumbar spinal disease were included. The primary efficacy end points were perioperative outcomes. The secondary efficacy end points were changes in the Oswestry Disability Index (ODI) and back and leg pain visual analog scale (VAS) scores and in range of motion (ROM) at the treated and adjacent segments. A meta-analysis was performed to calculate weighted mean differences (WMDs), 95% confidence intervals, Q statistics, and I2 values. Forest plots were constructed for each analysis group.

RESULTS

Of the 274 retrieved articles, 7 (which involved 506 participants [Dynesys, 250; PLIF, 256]) met the inclusion criteria. The Dynesys group showed a competitive advantage in mean surgery duration (20.73 minutes, 95% CI 8.76–32.70 minutes), blood loss (81.87 ml, 95% CI 45.11–118.63 ml), and length of hospital stay (1.32 days, 95% CI 0.23–2.41 days). Both the Dynesys and PLIF groups experienced improved ODI and VAS scores after 2 years of follow-up. Regarding the ODI and VAS scores, no statistically significant difference was noted according to surgical procedure (ODI: WMD 0.12, 95% CI −3.48 to 3.72; back pain VAS score: WMD −0.15; 95% CI −0.56 to 0.26; leg pain VAS score: WMD −0.07; 95% CI −0.47 to 0.32). The mean ROM at the adjacent segment increased in both groups, and there was no substantial difference between them (WMD 1.13; 95% CI −0.33 to 2.59). Although the United States is the biggest market for Dynesys, no eligible study from the United States was found, and 4 of 8 enrolled studies were performed in China. The results must be interpreted with caution because of publication bias. During Dynesys implantation, surgeons have to decide the length of the spacer and cord pretension. These values are debatable and can vary according to the surgeon's experience and the patient's condition. Differences between the surgical procedures were not considered in this study.

CONCLUSIONS

Fusion still remains the method of choice for advanced degeneration and gross instability. However, spinal degenerative disease with or without Grade I spondylolisthesis, particularly in patients who require a quicker recovery, will likely constitute the main indication for PDS using the Dynesys system.

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Tae Hoon Roh, Seok-Gu Kang, Ju Hyung Moon, Kyoung Su Sung, Hun Ho Park, Se Hoon Kim, Eui Hyun Kim, Chang-Ki Hong, Chang-Ok Suh and Jong Hee Chang

OBJECTIVE

Following resection of glioblastoma (GBM), microscopic remnants of the GBM tumor remaining in nearby tissue cause tumor recurrence more often than for other types of tumors, even after gross-total resection (GTR). Although surgical oncologists traditionally resect some of the surrounding normal tissue, whether further removal of nearby tissue may improve survival in GBM patients is unknown. In this single-center retrospective study, the authors assessed whether lobectomy confers a survival benefit over GTR without lobectomy when treating GBMs in the noneloquent area.

METHODS

The authors selected 40 patients who had undergone GTR of a histopathologically diagnosed isocitrate dehydrogenase (IDH)–wild type GBM in the right frontal or temporal lobe and divided the patients into 2 groups according to whether GTR of the tumor involved lobectomy, defined as a supratotal resection (SupTR group, n = 20) or did not (GTR group, n = 20). Progression-free survival (PFS), overall survival (OS), and Karnofsky Performance Status (KPS) scores were compared between groups (p ≤ 0.05 for statistically significant differences).

RESULTS

The median postoperative PFS times for each group were as follows: GTR group, 11.5 months (95% CI 8.8–14.2) and SupTR group, 30.7 months (95% CI 4.3–57.1; p = 0.007). The median postoperative OS times for each group were as follows: GTR group, 18.7 months (95% CI 14.3–23.1) and SupTR group, 44.1 months (95% CI 25.1–63.1; p = 0.040). The mean postoperative KPS scores (GTR, 76.5; SupTR, 77.5; p = 0.904) were not significantly different. In multivariate analysis, survival for the SupTR group was significantly longer than that for the GTR group in terms of both PFS (HR 0.230; 95% CI 0.090–0.583; p = 0.002) and OS (HR 0.247; 95% CI 0.086–0.704; p = 0.009).

CONCLUSIONS

In cases of completely resectable, noneloquent-area GBMs, SupTR provides superior PFS and OS without negatively impacting patient performance.

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Kyung Hwan Kim, Doo-Sik Kong, Kyung Rae Cho, Min Ho Lee, Jung-Won Choi, Ho Jun Seol, Sung Tae Kim, Do-Hyun Nam and Jung-Il Lee

OBJECTIVE

Fractionated Gamma Knife radiosurgery (GKS) represents a feasible option for patients with large brain metastases (BM). However, the dose-fractionation scheme balanced between local control and radiation-induced toxicity remains unclear. Therefore, the authors conducted a dose-escalation study using fractionated GKS as the primary treatment for large (> 3 cm) BM.

METHODS

The exclusion criteria were more than 3 lesions, evidence of leptomeningeal disease, metastatic melanoma, poor general condition, and previously treated lesions. Patients were randomized to receive 24, 27, or 30 Gy in 3 fractions (8, 9, or 10 Gy per fraction, respectively). The primary endpoint was the development of radiation necrosis assessed by a neuroradiologist blinded to the study. The secondary endpoints included the local progression-free survival (PFS) rate, change in tumor volume, development of distant intracranial progression, and overall survival.

RESULTS

Between September 2016 and April 2018, 60 patients were eligible for the study, with 46 patients (15, 17, and 14 patients in the 8-, 9-, and 10-Gy groups, respectively) available for analysis. The median follow-up duration was 9.6 months (range 2.5–25.1 months). The 6-month estimated cumulative incidence of radiation necrosis was 0% in the 8-Gy group, 13% (95% confidence interval [CI] 0%–29%) in the 9-Gy group, and 37% (95% CI 1%–58%) in the 10-Gy group. Being in the 10-Gy group was a significant risk factor for the development of radiation necrosis (p = 0.047; hazard ratio [HR] 7.2, 95% CI 1.1–51.4). The 12-month local PFS rates were 65%, 80%, and 75% in the 8-, 9-, and 10-Gy groups, respectively. Being in the 8-Gy group was a risk factor for local treatment failure (p = 0.037; HR 2.5, 95% CI 1.1–29.6). The mean volume change from baseline was a 47.5% decrease in this cohort. Distant intracranial progression and overall survival did not differ among the 3 groups.

CONCLUSIONS

In this dose-escalation study, 27 Gy in 3 fractions appeared to be a relevant regimen of fractionated GKS for large BM because 30 Gy in 3 fractions resulted in unacceptable toxicities and 24 Gy in 3 fractions was associated with local treatment failure.

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Jin-Young Hwang, Seong-Won Min, Young-Tae Jeon, Jung-Won Hwang, Sang-Heon Park, Jin-Hee Kim and Sung-Hee Han

OBJECT

Spinal cord ischemia remains a serious complication of thoracoabdominal aortic aneurysm surgery. Coenzyme Q10, a potent antioxidant, has been reported to exert a neuroprotective effect. In the present study, we evaluated the effect of coenzyme Q10 pretreatment on spinal cord ischemia-reperfusion injury.

METHODS

Male Sprague-Dawley rats were treated with either 300 mg/kg coenzyme Q10 (CoQ10 group, n = 12) or saline (control and sham groups, n = 12 for each group) for 5 days before ischemia. Spinal cord ischemia was induced in the control and CoQ10 groups. Neurological function was assessed using the Basso-Beattie-Bresnahan (BBB) motor rating scale until 7 days after reperfusion, and then the spinal cord was harvested for histopathological examinations and an evaluation of malondialdehyde level.

RESULTS

On post-reperfusion Day 1, the CoQ10 group showed higher BBB scores compared with those in the control group, although the difference was not significant. However, on Day 2, the CoQ10 group showed a significantly higher BBB score than the control group (14.0 [10.3–15.0] vs 8.0 [5.0–9.8], median [IQR], respectively; p = 0.021), and this trend was maintained until Day 7 (17.5 [16.0–18.0] vs 9.0 [6.5–12.8], respectively; p < 0.001). Compared with the control group, the CoQ10 group had more normal motor neurons (p = 0.003), fewer apoptotic changes (p = 0.003) and a lower level of tissue malondialdehyde (p = 0.024).

CONCLUSIONS

Pretreatment with 300 mg/kg coenzyme Q10 resulted in significantly improved neurological function and preservation of more normal motor neurons.