Jeung Il Kim

Inactivation of O6-methylguanine-DNA methyltransferase in soft tissue sarcomas: association with K-ras mutations

The DNA-repair protein O(6)-methylguanine-DNA methyltransferase removes alkyl adducts from the O(6)-position of guanine. The adducts can mispair with T during DNA replication, resulting in a G-to-A mutation. Epigenetic inactivation of O(6)-methylguanine-DNA methyltransferase has been found in human neoplasia and is considered one of the implicated factors in chemoresistance. Sixty-two patients with soft tissue sarcomas were analyzed with regard to the status of O(6)-methylguanine-DNA methyltransferase protein expression status using immunohistochemistry and promoter hypermethylation of the MGMT gene using methylation-specific PCR. G-to-A transitions in codons 12 and 13 of the K-ras oncogene were investigated using PCR and direct automated sequencing analysis. A loss of O(6)-methylguanine-DNA methyltransferase expression was noted in 20 (32.3%) cases of 62 total soft tissue sarcomas. The MGMT promoter hypermethylation rate was 33.9% (21/62 cases). Of the 54 sarcomas evaluated, K-ras mutations were found in only 2 (3.7%) cases. Loss of O(6)-methylguanine-DNA methyltransferase expression and MGMT promoter hypermethylation showed a significant association with high American Joint Committee on Cancer stage, high French Federation of Cancer Centers grade, and aggressive behavior. On multivariate analysis, these were not an independently significant prognostic factors. However, when the group receiving chemotherapy was analyzed (n = 27), loss of O(6)-methylguanine-DNA methyltransferase expression was correlated with worse survival on multivariate analysis (P = .024). MGMT promoter hypermethylation status had a strong correlation with loss of O(6)-methylguanine-DNA methyltransferase expression (P = .000). Our results suggest that MGMT promoter hypermethylation and loss of O(6)-methylguanine-DNA methyltransferase expression tend to be associated with poor prognosis and that the loss of O(6)-methylguanine-DNA methyltransferase protein expression frequently occurs via MGMT promoter hypermethylation. However, MGMT promoter hypermethylation was not significantly associated with point mutations of K-ras at codons 12 and 13 in sarcomas.

Gene expression in mixed type liposarcoma

Aims: Mixed type liposarcomas are rare. Here, we analysed the characteristics of an unusual case of mixed type liposarcoma, which consisted of a well‐differentiated liposarcoma (WDL) and a pleomorphic liposarcoma (PL), with a special emphasis on molecular alterations. Methods: Microscopic and immunohistochemical approaches were used to investigate this case of mixed type liposarcoma, and to identify molecular alterations in this tumour, gene expression was examined in PL, WDL, and normal adipose tissue (NA) samples using a 17 000 cDNA microarray. Results: The tumour mass, 9×5×5 cm, was located in the left upper arm of a 76‐year‐old man. Grossly, the proximal portion of the tumour was composed of a yellowish fatty lesion, whereas the distal portion of the tumour was whitish and necrotic in nature. Histologically, the tumour was composed of two distinct components. The proximal component of the tumour was a WDL and the distal component was a PL. Immunohistochemically, S100 protein immunoreactivity highlighted lipoblasts in both tumour portions. The Ki‐67 proliferation index was <1% in the WDL and 20% in the PL. MDM2 was positive in the WDL, but negative in the PL. p53 was negative in both areas. Numerous differentially expressed genes were found, which included genes coding for signal transduction, transcription, cell cycle, enzyme, structural protein, immune system and others. Conclusions: Our data demonstrate that multiple genes are differentially expressed in mixed type liposarcoma and suggest that these genes are associated with the differences in the morphological characteristics and pathogenesis of mixed type liposarcoma.

Expression of hypoxic markers and their prognostic significance in soft tissue sarcoma

Tumor hypoxia is significant in promoting tumor progression and resistance to therapy, and hypoxia-inducible factor 1α (HIF-1α) is essential in the adaptive response of cells to hypoxia. The aim of the present study was to investigate the expression of hypoxic markers and evaluate their prognostic significance in soft tissue sarcoma (STS). A retrospective analysis of 55 patients with STS from Pusan National University Hospital (Busan, Korea) between 1998 and 2007 was conducted, using immunohistochemistry to analyze the expression of HIF-1α, carbonic anhydrase 9 (CA9), glucose transporter-1 (GLUT1) and vascular endothelial growth factor (VEGF). The association between the overexpression of these markers and clinicopathological characteristics, including the overall survival (OS) and progression-free survival (PFS) in cases of STS, were investigated. Overexpression of HIF-1α, CA9, GLUT1 and VEGF was shown in 54.5, 32.7, 52.7 and 25.5% of tumors, respectively, and all exhibited a significant association with high French Federation of Cancer Centers (FNCLCC) grade and high American Joint Committee on Cancer (AJCC) stage. Overexpression of HIF-1α and CA9 was associated with a shorter OS and a shorter PFS. On multivariate analysis, AJCC stage and HIF-1α overexpression had independent prognostic significance. In the group receiving chemotherapy (n=27), HIF-1α overexpression was independently associated with a decreased OS. These results indicate that overexpression of HIF-1α and CA9 is associated with poor prognosis, and that HIF-1α overexpression is an independent unfavorable prognostic factor in STS.

Validation of the Korean version of the Quebec Back Pain Disability Scale.

Study Design: Prospective study. Objective: To evaluate the reliability and validity of the adapted Korean version of the Quebec Back Pain Disability Scale (QDS). Summary of Background Data: The Korean version of the QDS has not been validated. Methods: Translation/retranslation of the English version of QDS was conducted, and all steps of the cross-cultural adaptation process were performed. The Korean version of the Visual Analog Scale (VAS) measure of pain, QDS and the previously validated Oswestry Disability Index (ODI) and Short Form-36 (SF-36) were mailed to 100 consecutive patients with chronic low back pain of at least 3 months duration. Eighty patients responded to the first mailing of questionnaires and 59 of the first time responder returned their second survey. The average age of the 59 patients (39 female, 20 male) was 48.0 years. Reliability assessment was determined by estimating &kgr; statistics of agreement for each item, the intraclass correlation coefficient (ICC) and the Cronbach &agr;. Concurrent and construct validity was evaluated by comparing the responses of QDS with the results of VAS and responses of ODI and SF-36 by using the Pearson correlation coefficient. Results: The constructed Bland Altman plot showed a good reliability. All items had a &kgr; statistics of agreement >0.6. The QDS showed excellent test/retest reliability as evidenced by the high ICC for both assessments (ICC=0.9094; P<0.001). Internal consistency was found to be very good at both assessments with the Cronbach &agr; (0.9172 and 0.9319 at first and second assessments, respectively). The QDS was correlated with the VAS (r=0.647; P<0.001 and r=0.609; P<0.001 at first and second assessments, respectively) and with the ODI (r=0.718; P<0.001 and r=0.690; P<0.001, respectively). The Korean version of the QDS showed a good significant correlation with functional scales of SF-36. Conclusions: The adapted Korean version of the QDS was successfully translated and showed acceptable measurement properties, and as such, is considered suitable for outcome assessments in the Korean-speaking patients with low back pain.

Cilostazol induces cellular senescence and confers resistance to etoposide-induced apoptosis in articular chondrocytes.

We recently reported that cilostazol protects chondrocytes against stress-induced apoptosis and prevents cartilage destruction in an osteoarthritis (OA) model. In the present study, we elucidate the mechanism underlying the protective effect induced by cilostazol against stress-induced apoptosis in chondrocytes. Cilostazol significantly reduced the expression of type II collagen and stimulated the accumulation of β-catenin in primary rat articular chondrocytes. Moreover, cilostazol-induced chondrocytes showed induction of senescent phenotypes, such as changes in cell morphology, decrease in cell proliferation and increase in specific senescence-associated β-galactosidase (SA-β-gal) staining. Moreover, dedifferentiated chondrocytes obtained by serial subculture showed cellular senescence that increased with passage number. In addition, the percentage of terminal dUTP nick end-labeling (TUNEL)-positive cells was higher when chondrocytes were treated with cilostazol and the apoptosis inducer etoposide than when the cells were treated with etoposide alone. Our findings suggest that cilostazol induces dedifferentiation and senescence in rat articular chondrocytes and renders them resistant to etoposide-induced apoptosis.

Validation of the Korean Version of the Neck Pain and Disability Scale

Study Design A prospective study. Purpose To evaluate the reliability and validity of the adapted Korean version of the Neck Pain and Disability Scale (NPDS). Overview of Literature The validity of Korean version of NPDS has not been completely demonstrated yet. Methods Translation/retranslation of the English version of NPDS was conducted, and all steps of the cross-cultural adaptation process were performed. The Korean version of the visual analog scale (VAS) measure of pain, NPDS and the previously validated Short Form-36 (SF-36) were mailed to 91 patients, who had been surgically treated for degenerative cervical disease. Eighty-one patients responded to the first mailing of questionnaires and 69 of the first time responder returned their second survey. Factor analysis and reliability assessment by kappa statistics of agreement for each item, the intraclass correlation coefficient and Cronbachs α were conducted. Concurrent and construct validity were also evaluated by comparing the responses of NPDS with the results of VAS and responses of SF-36. Results Factor analysis extracted 3 factors. All items had a kappa statistics of agreement greater than 0.6. The NPDS showed excellent test/re-test reliability. Internal consistency of Cronbachs α was found to be very good. The NPDS was correlated with the VAS. The Korean version of NPDS showed good significant correlation with SF-36 total score and with single SF-36 domains scores. Conclusions The adapted Korean version of the NPDS was successfully translated and is considered suitable for outcome assessments in the Korean-speaking patients with neck pain.

Association between estrogen receptor gene polymorphism and back pain intensity in female patients with degenerative lumbar spondylolisthesis.

Study Design: Prospective study. Objective: To examine the possible association of estrogen receptor &agr; (ER&agr;) polymorphisms and pain intensity in symptomatic female degenerative spondylolisthesis (DS) patients. Summary of Background Data: DS has been associated with a significant sex effect. Thus, several studies about the association between the ER gene and osteoarthritis have been reported. However, whether estrogen is associated with pain sensitivity is inconsistent in the existing literatures from both human and animal studies. Methods: The PvuII and XbaI polymorphisms, bone mineral density at the lumbar spine (LSBMD) and at the femoral neck (FNBMD), pain intensity at the leg and lower back, and radiologic and anthropometric findings were analyzed in 192 patients with DS. Results: There was a significant association between XbaI polymorphism and the visual analog scale score of back pain. The back pain visual analog scale in patients with a GG genotype was significantly higher than in patients with the AG (P<0.05) or the AA (P<0.05) genotypes. In addition, the presence of the CG haplotype was found to be associated with back pain intensity in the haplotype analysis of the PvuII and the XbaI polymorphisms of ER&agr;. Conclusions: These results suggest that the ER&agr; gene polymorphism using XbaI restriction enzyme influences the perception of back pain in patients with DS.

Baker's Cyst with Intramuscular Extension into Vastus Medialis Muscle

Bakers cysts are one of the most common cystic lesions around the knee joint and mainly caused by fluid distension of the gastrocnemius-semimembranous bursa that is situated along the medial side of the popliteal fossa. Typically, a Bakers cyst extends along the intermuscular planes around the knee joint and may enlarge any direction. However, it is mostly located in the inferomedial or superficial layers of the knee joint and less commonly extends laterally or proximally. Expansion of the cyst tends to respect the intermuscular planes, and Bakers cysts along the intramuscular route have been rarely reported. Thus, we report a case of Bakers cyst with intramuscular extension into the vastus medialis muscle.

Analysis of sagittal balance of ankylosing spondylitis using spinopelvic parameters.

Study Design: Prospective study. Objective: To analyze sagittal spinopelvic parameters in ankylosing spondylitis (AS) patients. Summary of Background Data: There are little data on the relationship between the sagittal spinopelvic parameters and AS. Methods: The study and control groups comprised 90 AS patients and 40 controls. Participants were classified into 3 groups: normal (n=40), sagittal balance (n=58), and sagittal imbalance (n=32) groups. All underwent lateral radiograph of the whole spine including hip joints. The radiographic parameters were sacral slope, pelvic tilting, pelvic incidence, overhang of S1, thoracic kyphosis, lumbar lordosis, and C7 plumbline. Statistical analysis was performed to identify significant differences between the 2 groups. Correlations between radiological parameters and symptoms were sought. Results: AS patients and controls were found to be significantly different in terms of sagittal balance, sacral slope, pelvic tilt, pelvic incidence, S1 overhang, and lumbar lordosis. However, no significant difference was observed between these 2 groups for thoracic kyphosis (P>0.05). Of the 90 AS patients, 32 patients (5 women and 27 men) were assigned to the sagittal imbalance group and 58 (12 women and 46 men) to the sagittal balance group. There was a significant difference in all sagittal parameters and visual analogue scale (VAS) score between these 2 groups. Correlation analysis revealed significant relationships between sagittal parameters in AS. However, there was no association between sacral slope and S1 overhang, and between pelvic incidence and VAS score. Stepwise logistic regression analysis revealed that pelvic tilt contributed significantly to sagittal balance. Conclusions: AS patients and normal controls were found to be significantly different in terms of sagittal spinopelvic parameters. Significant relationships were found between sagittal spinopelvic parameters in AS patients. Pelvic tilt was a significant parameter in determination of sagittal balance in AS patient. Furthermore, VAS scores were significantly related to sagittal spinal parameters which were closely related with pelvic orientation in AS patients.

Effects of growth factors and kinase inhibitors on the properties of human adipose-stromal cells in different culture conditions

The best‐fit environments for the proliferation and differentiation of human adipose tissue‐derived stromal cells (hADSCs) may require specific media and stimuli. The characteristics of hADSCs cultured in different media might be different. We evaluated the effects of growth factors on the proliferation and differentiation of hADSCs and compared the effects of these growth factors on hADSCs cultured in different serum‐contained media. The effects of kinase inhibitors on the proliferation of hADSCs were also examined.