Heon Yoo

Long-term outcome and growth rate of subtotally resected petroclival meningiomas: experience with 38 cases.

OBJECTIVE To evaluate the long-term outcome of a subtotally resected residual tumor and to assess its growth rate, we analyzed the records of 38 patients with residual petroclival meningioma. METHODS Clinical records and radiological findings of 38 cases of petroclival meningioma that were diagnosed and subtotally resected at Seoul National University Hospital between 1981 and 1997 were carefully reviewed. Follow-up imaging studies were reviewed, and Karnofsky performance scale scores at the last follow-up were recorded. The duration of follow-up ranged from 6 to 141 months (mean, 47.5 mo; median, 30 mo). Tumor progression and progression-free survival rates were assessed. The growth rate of a residual tumor was evaluated by measuring the equivalent diameter and the tumor volume serially; the tumor doubling time was calculated, and the predictive factors for determining the growth pattern in residual tumors and the prognosis were analyzed. RESULTS In 33 (87%) of the 38 patients, Karnofsky performance scale scores at the last follow-up were 80 or above. The median progression-free survival time among patients with subtotally resected tumors was 66 months, and the 5-year progression-free survival rate was 60%. The growth rate of residual tumors was low (volume increase, 4.94 cc/yr; diameter increase, 0.37 cm/yr). The mean tumor doubling time was 8 years. Although there were no significant predictive factors, age and extent of tumor resection seemed to influence the progression-free survival rate. Significant factors affecting the growth rate were age and occurrence of menopause. CONCLUSION Subtotal resection with or without radiation or radiosurgery should be considered as a suitable treatment option for patients with petroclival meningiomas, especially the elderly, because the growth rate of residual tumors is low.

Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas.

Gliomas are associated with high mortality because of their exceedingly invasive character. As these tumors acquire their invasiveness from low-grade tumors, it is very important to understand the detailed molecular mechanisms of invasion onset. Recent evidences suggest the significant role of microRNAs in tumor invasion. Thus, we hypothesized that deregulation of microRNAs may be important for the malignant progression of gliomas. We found that the aberrant expression of miR-21 is responsible for glioma invasion by disrupting the negative feedback circuit of Ras/MAPK signaling, which is mediated by Spry2. Upregulation of miR-21 was triggered by tumor microenvironmental factors such as hyaluronan and growth factors in glioma cells lacking functional phosphatase and tensin homolog (PTEN), but not harboring wild-type PTEN. Consistently with these in vitro results, Spry2 protein levels were significantly decreased in 79.7% of invasive WHO grade II–IV human glioma tissues, but not in non-invasive grade I and normal tissues. The Spry2 protein levels were not correlated with their mRNA levels, but inversely correlated with miR-21 levels. Taken together, these results suggest that the post-transcriptional regulation of Spry2 by miR-21 has an essential role on the malignant progression of human gliomas. Thus, Spry2 may be a novel therapeutic target for treating gliomas.

Real-time and non-invasive optical imaging of tumor-targeting glycol chitosan nanoparticles in various tumor models

Recently, various nanoparticle systems have been developed for tumor-targeted delivery of imaging agents or drugs. However, large amount of them still have insufficient tumor accumulation and this limits their further clinical applications. Moreover, the in vivo characteristics of nanoparticles have been largely unknown, because there are few proper technologies to achieve the direct and non-invasive characterization of nanoparticles in live animals. In this paper, we determined the key factors of nanoparticles for in vivo tumor-targeting using our glycol chitosan nanoparticles (CNPs) which have proved their tumor-targeting ability in many previous papers. For this study, CNPs were labeled with near-infrared fluorescence (NIRF) dye, Cy5.5 for in vivo analysis by non-invasive optical imaging techniques. With these Cy5.5-CNPs, the factors such as in vitro/in vivo stability, deformability, and rapid uptake into target tumor cells and their effects on in vivo tumor-targeting were evaluated in various tumor-bearing mice models. In flank tumor models, Cy5.5-CNPs were selectively localized in tumor tissue than other organs, and the real-time intravascular tracking of CNPs proved the enhanced permeation and retention (EPR) effect of nanoparticles in tumor vasculature. Importantly, tumor-targeting CNPs showed an excellent tumor-specificity in brain tumors, liver tumors, and metastasis tumor models, indicating their great potential in both cancer imaging and therapy.

Reduced local recurrence of a single brain metastasis through microscopic total resection

OBJECT The goal of this study was to evaluate the therapeutic impact of the resection of metastatic brain tumor cells infiltrating adjacent brain parenchyma. METHODS Between July 2001 and February 2007, 94 patients (67 males and 27 females, with a mean age of 55.0 +/-12.0 years) underwent resection of a single brain metastasis, followed by systemic chemotherapy with or without radiotherapy. In 43 patients with tumors located in noneloquent areas, the authors performed microscopic total resections (MTRs) that included tumor cells infiltrating adjacent brain parenchyma, and they pathologically confirmed during surgery that the resection margins were free of tumor cells (MTR group). In 51 patients with lesions in eloquent locations, gross-total resections (GTRs) were performed without the removal of neighboring brain parenchyma (GTR group). The 2 groups were then compared for local recurrence and survival. RESULTS The MTR group had better local control of the tumor than did the GTR group; 10 (23.3%) of 43 patients in the MTR group and 22 (43.1%) of 51 patients in the GTR group had a local recurrence (p = 0.04). The median time to tumor progression in the MTR group could not be calculated using the Kaplan-Meier method, whereas it was 11.4 months in the GTR group. The 1- and 2-year respective local recurrence rates were 29.1 and 29.1% in the MTR group and 58.6 and 63.2% in the GTR group (p = 0.01). Multivariate analysis showed that the MTR procedure was associated with a decreased risk of local recurrence (p = 0.003). A Cox regression analysis revealed that the hazard ratio for a local recurrence in the MTR group versus the GTR group was 3.14 (95% CI 1.47-6.72, p = 0.003). There was no significant difference in the local recurrence rate between the MTR group without radiotherapy (10 [30.3%] of 33) and the GTR group with postoperative radiotherapy (5 [26.3%] of 19). CONCLUSIONS The results in this study suggest that MTRs including tumor cells infiltrating adjacent brain parenchyma for a single brain metastasis provide better local tumor control.

Silencing of MicroRNA-21 Confers Radio-Sensitivity through Inhibition of the PI3K/AKT Pathway and Enhancing Autophagy in Malignant Glioma Cell Lines

Radiation is a core part of therapy for malignant glioma and is often provided following debulking surgery. However, resistance to radiation occurs in most patients, and the underlying molecular mechanisms of radio-resistance are not fully understood. Here, we demonstrated that microRNA 21 (miR-21), a well-known onco-microRNA in malignant glioma, is one of the major players in radio-resistance. Radio-resistance in different malignant glioma cell lines measured by cytotoxic cell survival assay was closely associated with miR-21 expression level. Blocking miR-21 with anti-miR-21 resulted in radio-sensitization of U373 and U87 cells, whereas overexpression of miR-21 lead to a decrease in radio-sensitivity of LN18 and LN428 cells. Anti-miR-21 sustained γ-H2AX DNA foci formation, which is an indicator of double-strand DNA damage, up to 24 hours and suppressed phospho-Akt (ser473) expression after exposure to γ-irradiation. In a cell cycle analysis, a significant increase in the G2/M phase transition by anti-miR-21 was observed at 48 hours after irradiation. Interestingly, our results showed that anti-miR-21 increased factors associated with autophagosome formation and autophagy activity, which was measured by acid vesicular organelles, LC3 protein expression, and the percentage of GFP-LC3 positive cells. Furthermore, augmented autophagy by anti-miR-21 resulted in an increase in the apoptotic population after irradiation. Our results show that miR-21 is a pivotal molecule for circumventing radiation-induced cell death in malignant glioma cells through the regulation of autophagy and provide a novel phenomenon for the acquisition of radio-resistance.

Single-Dose Versus Fractionated Stereotactic Radiotherapy for Brain Metastases

PURPOSE To evaluate the efficacy of stereotactic radiotherapy in patients with brain metastases by comparing two different treatment regimens, single-dose radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT). METHODS AND MATERIALS Between November 2003 and December 2008, 98 patients with brain metastases were included. Fifty-eight patients were treated with SRS, and forty were treated with FSRT. Fractionated stereotactic radiotherapy was used for large lesions or lesions located near critical structures. The median doses were 20 Gy for the SRS group and 36 Gy in 6 fractions for the FSRT group. RESULTS With a median follow-up period of 7 months, the median survival was 7 months for all patients, with a median of 6 months for the SRS group and 8 months for the FSRT group (p = 0.89). Local progression-free survival (LPFS) rates at 6 months and 1 year were 81% and 71%, respectively, for the SRS group and 97% and 69%, respectively, for the FSRT group (p = 0.31). Despite the fact that FSRT was used for large lesions and lesions in adverse locations, LPFS was not inferior to SRS. Toxicity was more frequently observed in the SRS group than in the FSRT group (17% vs. 5%, p = 0.05). CONCLUSIONS Because patients treated with FSRT exhibited similar survival times and LPFS rates with a lower risk of toxicity in comparison to those treated with SRS, despite the fact that FSRT was used for large lesions and lesions in adverse locations, we find that FSRT can particularly be beneficial for patients with large lesions or lesions located near critical structures. Further investigation is warranted to determine the optimal dose/fractionation.

Primary chemotherapy for newly diagnosed nonsmall cell lung cancer patients with synchronous brain metastases compared with whole-brain radiotherapy administered first : result of a randomized pilot study.

This randomized pilot trial investigated whether primary chemotherapy was feasible in terms of efficacy, survival, toxicity profile, and quality of life compared with whole‐brain radiotherapy (WBRT) given first in chemotherapy‐naive patients nonsmall cell lung cancer (NSCLC) with synchronous brain metastasis when neurologic symptoms or signs are absent or controlled by supportive care.

Epidemiology of primary brain and central nervous system tumors in Korea.

OBJECTIVE The aim of this report is to provide accurate nationwide epidemiologic data on primary central nervous system (CNS) tumors in Korea. Despite its importance, there are no accurate statistics on primary CNS tumors in Korea. We analyzed primary CNS tumors diagnosed in 2005 from the nationwide registry. METHODS Data on primary CNS tumors diagnosed in 2005 were collected from the Korean Central Cancer Registry and the Korean Brain Tumor Society. Crude and age-standardized rates were calculated in terms of gender, age, and histological type. Tumors of uncertain histology were investigated individually at the corresponding hospitals and had their diagnoses confirmed. RESULTS A total of 5,692 patients diagnosed with primary CNS tumors in 2005 were included in this study. CNS tumors occurred in females more often than in males (female to male, 1.43 : 1). The most common tumor was meningioma (31.2%). Glioblastoma accounted for 30.7% of all gliomas, and 19.3% of all malignant primary CNS tumors. In children under 19 years of age, both germ cell tumor and embryonal/primitive/medulloblastoma were the most common tumors. CONCLUSION This article is the first nationwide primary CNS tumor epidemiology report in Korea. Data from this study should provide valuable information regarding the understanding of primary CNS tumors epidemiology in Korea.

Roles of Long Non-Coding RNAs on Tumorigenesis and Glioma Development

More than 98% of eukaryotic transcriptomes are composed of non-coding RNAs with no functional protein-coding capacity. Those transcripts also include tens of thousands of long non-coding RNAs (lncRNAs) which are emerging as key elements of cellular homeostasis, essentially tumorigenesis steps. However, we are only beginning to understand the nature and extent of the involvement of lncRNAs on tumorigeneis. Here, we highlight recent progresses that have identified a myriad of molecular functions on tumorigenesis for several lncRNAs including metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), prostate cancer associated non-coding RNA 1 (PRNCR1), prostate cancer gene expression marker 1 (PCGEM1), H19, and homeobox transcript antisense intergenic RNA (HOTAIR), and several new lncRNAs for glioma development. Potential therapeutic approaches for the lncRNAs in various human diseases are also discussed.

Association between the location of transposed ovary and ovarian function in patients with uterine cervical cancer treated with (postoperative or primary) pelvic radiotherapy

OBJECTIVE To evaluate the effectiveness of ovarian transposition procedures in preserving ovarian function in relation to the location of the transposed ovaries in patients who underwent surgery with or without pelvic radiotherapy. DESIGN Retrospective. SETTING Uterine cancer center. PATIENT(S) A total of 53 patients with cervical cancer who underwent ovarian transposition between November 2002 and November 2010. INTERVENTION(S) Ovarian transposition to the paracolic gutters with or without radical hysterectomy and lymph node dissection. MAIN OUTCOME MEASURE(S) Preservation of ovarian function, which was assessed by patients symptoms and serum FSH level. RESULT(S) Lateral ovarian transposition was performed in 53 patients. Based on receiver operator characteristic curve analysis, optimum cutoff value of location more than 1.5 cm above the iliac crest was significantly associated with preservation of ovarian function after treatment (area under receiver operator characteristic curve: 0.757, 95% confidence interval [CI]: 0.572-0.943). In univariate analysis, higher location of transposed ovary more than 1.5 cm from the iliac crest was the only independent factor for intact ovarian function (odds ratio 9.91, 95% CI: 1.75-56.3). Multivariate analysis confirmed that the location of transposed ovary (odds ratio 11.72, 95% CI 1.64-83.39) was the most important factor for intact ovarian function. CONCLUSION(S) Location of transposed ovary higher than 1.5 cm above the iliac crest is recommended to avoid ovarian failure after lateral ovarian transposition after primary or adjuvant pelvic radiotherapy in cervical cancer.