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1.  Low-Dose Whole Brain Radiotherapy with Tumor Bed Boost after Methotrexate-Based Chemotherapy for Primary Central Nervous System Lymphoma 
The purpose of this study is to evaluate the outcome of low-dose whole brain radiotherapy (WBRT) with tumor bed boost after methotrexate-based chemotherapy in the management of primary central nervous system lymphoma (PCNSL).
Materials and Methods
We retrospectively analyzed 64 patients with pathologically proven PCNSL between 2000 and 2011. Methotrexate-based chemotherapy with a median of five cycles was followed by radiotherapy to the whole brain and to the initial tumor bed. The median dose to the whole brain and to the tumor bed was 27 Gy (range, 18 to 36 Gy) and 50.4 Gy (range, 45 to 54 Gy), respectively.
With a median follow-up period of 27 months, 55 patients (85.9%) achieved complete response (CR). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 52.6% and 39.3%, respectively. In univariate analysis, factors associated with OS were age, performance status, involvement of deep structure, and CR to sequential chemoradiotherapy (CRT). These variables remained as significant factors for OS in multivariate analysis. CR to sequential CRT was the only positive factor associated with PFS (p=0.009). Neurologic toxicity was more common in elderly patients older than 60 years (p=0.025).
Low-dose WBRT with tumor bed boost after methotrexate-based chemotherapy might be an effective method for management of PCNSL.
PMCID: PMC4132445  PMID: 25038761
Radiotherapy; Methotrexate; Central nervous system; Lymphoma
2.  Sequence-Dependent Radiosensitization of Histone Deacetylase Inhibitors Trichostatin A and SK-7041 
This preclinical study is to determine whether the capacity of histone deacetylase (HDAC) inhibitors to enhance radiation response depends on temporal sequences of HDAC inhibition and irradiation.
Materials and Methods
The effects of HDAC inhibitors trichostatin A (TSA) and SK-7041 on radiosensitivity in human lung cancer cells were examined using a clonogenic assay, exposing cells to HDAC inhibitors in various sequences of HDAC inhibition and radiation. We performed Western blot of acetylated histone H3 and flow cytometry to analyze cell cycle phase distribution.
TSA and SK-7041 augmented radiation cell lethality in an exposure time-dependent manner when delivered before irradiation. The impact of TSA and SK-7041 on radiosensitivity rapidly diminished when HDAC inhibition was delayed after irradiation. Radiation induced the acetylation of histone H3 in cells exposed to TSA, while irradiation alone had no effect on the expression of acetylated histone H3 in TSA-naïve cells. Preirradiation exposure to TSA abrogated radiation-induced G2/M-phase arrest. When delivered after irradiation, TSA had no effect on the peak of radiation-induced G2/M-phase arrest.
TSA and SK-7041 enhances radiosensitivity only when delivered before irradiation. Unless proven otherwise, it seems prudent to apply scheduling including preirradiation HDAC inhibition so that maximal radiosensitization is obtained.
PMCID: PMC3893331  PMID: 24454006
Histone deacetylase inhibitors; Radiation-sensitizing agents; Preclinical drug evaluation
3.  Role of radiotherapy in local control of non-AIDS associated Kaposi's sarcoma patients in Korea: a single institution experience 
Radiation Oncology Journal  2012;30(4):153-157.
There has been no definite consensus on standard treatment, either local or systemic, for the Kaposi's sarcoma (KS). Radiotherapy (RT) can be a good local therapeutic choice especially in non-AIDS associated KS (NAKS) for its indolent behavior.
Materials and Methods
Medical records of 17 KS patients treated with RT at the Seoul National University Hospital from February 1998 to January 2012 were retrospectively reviewed. One human immunodeficiency virus (HIV)+ patient with 3 lesions was excluded. The total number of the lesion was 23 among the 16 patients. The median follow-up period was 27.9 months. Correlation between response and variables was analyzed using the logistic regression model. Median age of the patients was 75 years. All the 23 lesions were located at the extremities. Fourteen (61%) of those had pain or local swelling as the initial presentation. Ten patients had possible causes of immunodeficiency and were regarded as iatrogenic, and other 6 were classic KS. Median dose of RT was 36 Gy.
No KS-related death was observed. Excluding 2 with short-term follow-up only, complete response and partial response were obtained in 2 (9%) and 19 (73%) lesions, respectively. Of those, 3 lesions underwent local progression. Six had out-of-field recurrence after RT. Symptom improvement was achieved in 13 (93%) of 14 patients. Grade 2 skin toxicities were found in 9 lesions but all got improvement after treatment. When divided into responsive and progressive group, free from progression was not related to any of the possible variables.
RT is effective in local control of NAKS resulting great response rate.
PMCID: PMC3546282  PMID: 23346533
Kaposi sarcoma; Radiotherapy; Local control
4.  Nonrigid Registration of 2-D and 3-D Dynamic Cell Nuclei Images for Improved Classification of Subcellular Particle Motion 
The observed motion of subcellular particles in fluorescence microscopy image sequences of live cells is generally a superposition of the motion and deformation of the cell and the motion of the particles. Decoupling the two types of movements to enable accurate classification of the particle motion requires the application of registration algorithms. We have developed an intensity-based approach for nonrigid registration of multi-channel microscopy image sequences of cell nuclei. First, based on 3-D synthetic images we demonstrate that cell nucleus deformations change the observed motion types of particles and that our approach allows to recover the original motion. Second, we have successfully applied our approach to register 2-D and 3-D real microscopy image sequences. A quantitative experimental comparison with previous approaches for nonrigid registration of cell microscopy has also been performed.
PMCID: PMC3282047  PMID: 20840894
Biomedical image processing; image sequence analysis; microscopy; registration
5.  The Role of Radiotherapy in the Treatment of Newly Diagnosed Supratentorial Low-grade Oligodendrogliomas: Comparative Analysis with Immediate Radiotherapy versus Surgery Alone 
The purpose of this study was to evaluate the role of immediate postoperative radiotherapy (RT) in adult patients with a low-grade oligodendroglioma (LODG).
Materials and Methods
A total of 74 patients, older than 15 years, were treated in our institution between April 1990 and March 2006 for newly diagnosed LODGs. After surgery, 43 patients were treated with immediate RT with a total dose of 54~55.8 Gy with 1.8 Gy fractions (RT group) and 31 patients were followed with no adjuvant RT (OP group). All patients were closely observed until tumor progression or death with frequent work-ups including neurological examinations and MRI. Primary endpoints were overall survival and progression-free survival. The median follow-up duration of survivors was 6.2 years in the RT group and 5.8 years in the OP group.
Median progression-free survival was 13.2 years in the RT group and 4.6 years in the OP group; multivariate analysis confirmed improved outcome with the use of immediate RT (hazard ratio, 0.22; 95% confidence interval-CI, 0.09~0.55; p<0.001). Median overall survival was 14.9 years in the RT group and 9.8 years in the OP group; the use of adjuvant RT was also associated with a trend toward better overall survival after immediate RT based on multivariate analysis (hazard ratio, 0.3; 95% CI, 0.08~1.17; p=0.082). No severe RT related complications were observed.
Immediate RT following surgery appears to be an effective treatment modality for supratentorial LODGs. However, the potential benefit of adjuvant RT for overall survival needs to be tested prospectively in the future.
PMCID: PMC2757663  PMID: 19809562
Brain neoplasms; Oligodendroglioma; Radiotherapy
6.  A Histone Deacetylase Inhibitor, Trichostatin A, Enhances Radiosensitivity by Abrogating G2/M Arrest in Human Carcinoma Cells 
Histone deacetylase inhibitors (HDIs) are emerging as potentially useful components in anticancer therapy. In this study, we tried to confirm the radiosensitizing effect of trichostatin A (TSA) on a panel of human carcinoma cell lines and elucidate its mechanism of interaction.
Materials and Methods
A549, HeLa and Caski cells were exposed to TSA for 18 hr prior to irradiation, and the cell survival then measured using a clonogenic assay. Western blot and flow cytometric analyses, for histone acetylation, and cell cycle and apoptosis, respectively, were also performed.
TSA increased the acetylation of histone H3. The pretreatment of TSA consistently radiosensitized all three cell lines. The SF2 (surviving fraction at 2 Gy) of TSA-treated cells was significantly lower than that of mock treated cells. The SER (sensitizer enhancement ratio) increased in all 3 cell lines, in concentration dependent manners. The TSA treated cells showed abrogation of radiation-induced G2/M arrest, in a concentration dependent manner.
The pretreatment of TSA enhanced the radiosensitivity of a panel of human carcinoma cells, which was attributed, in part, to the abrogation of radiation-induced G2/M arrest.
PMCID: PMC2785402  PMID: 19956491
Trichostatin A; Histone deacetylase inhibitor; Radiosensitization; G2/M arrest
7.  Outcome and Prognostic Factors of Childhood Diffuse Brainstem Glioma 
The outcome and prognostic factors of brainstem glioma were evaluated following radiotherapy methods.
Materials and Methods
Between 1986 and 2001, 45 childhood patients with diffuse brainstem glioma were treated. There were 26 boys and 19 girls, with a median age of 7 years (range 3~18). The histopathological diagnoses were confirmed in 13 patients, which revealed a low-grade glioma in four patients, and high-grade glioma in the other nine. Before 1993, radiation therapy using a regime of 1.8 to 2.0 Gy once a day was performed in 16 cases; thereafter, a regimes of 1.1 or 1.5 Gy twice a day was given in 15 and 14 cases, respectively. Nine patients were treated with adjuvant chemotherapy. The response to the treatment was evaluated by the MRI findings 4 weeks after radiotherapy.
After radiotherapy, the neurological deficit improved in 42 of the 45 patients (93%). The MRI responses were as follows; partial response 22/39 (56%), minimal to no response in 16/39 (41%) and tumor progression in 1/39 (3%). The median time to disease progression was 7 months, and the median survival was 12 months; the overall survival rate at 1 year was 41%. There was no significant prognostic factor for overall survival. The progression-free survival was influenced by the tumor histology (low grade vs. high grade, p=0.05) in those patients whose pathology was confirmed.
The radiation therapy fractionation schedule did not influence the survival. Low grade histology was a possible favorable prognostic factor of progression-free survival in pediatric brainstem glioma patients.
PMCID: PMC2785398  PMID: 19956489
Brainstem glioma; Radiotherapy
8.  Prognosis Prediction of Measurable Enhancing Lesion after Completion of Standard Concomitant Chemoradiotherapy and Adjuvant Temozolomide in Glioblastoma Patients: Application of Dynamic Susceptibility Contrast Perfusion and Diffusion-Weighted Imaging 
PLoS ONE  2014;9(11):e113587.
To assess the prognosis predictability of a measurable enhancing lesion using histogram parameters produced by the normalized cerebral blood volume (nCBV) and normalized apparent diffusion coefficient (nADC) after completion of standard concomitant chemoradiotherapy (CCRT) and adjuvant temozolomide (TMZ) medication in glioblastoma multiforme (GBM) patients.
Materials and Methods
This study was approved by the institutional review board (IRB), and the requirement for informed consent was waived. A total of 59 patients with newly diagnosed GBM who received standard CCRT with TMZ and adjuvant TMZ for six cycles underwent perfusion-weighted and diffusion-weighted imaging. Twenty-seven patients had a measurable enhancing lesion and 32 patients lacked a measurable enhancing lesion based on the Response Assessment in Neuro-Oncology (RANO) criteria in the follow-up MRI, which was performed within 3 months after adjuvant TMZ therapy was completed. We measured the nCBV and nADC histogram parameters based on the measurable enhancing lesion. The progression free survival (PFS) was analyzed by the Kaplan-Meier method with the use of the log-rank test.
The median PFS of patients lacking measurable enhancing lesion was longer than for those with measurable enhancing lesions (17.6 vs 3.3 months, P<.0001). There was a significant, positive correlation between the 99th percentile nCBV value of a measurable enhancing lesion and the PFS (P = .044, R2 = .152). In addition, the median PFS was longer in patients with a 99th percentile nCBV value ≧4.5 than it was in those with a value <4.5 (4.4 vs 3.1 months, P = .036).
We found that the nCBV value can be used for the prognosis prediction of a measurable enhancing lesion after the completion of standard treatment for GBM, wherein a high 99th percentile nCBV value (≧4.5) suggests a better PFS for GBM patients.
PMCID: PMC4242641  PMID: 25419975
9.  Dosimetric comparison of 4 MeV and 6 MeV electron beams for total skin irradiation 
In this study, dosimetric aspects of TSEI consisting of a 4 MeV beam with no spoiler were investigated in comparison to a nominal 6 MeV beam with spoiler, and the potential for clinical applications was evaluated.
The TSEI technique is based on the Stanford technique, which utilizes a beam configuration of six-dual fields. MOSFETs were used to measure the optimal gantry angle, profile uniformity, and absolute dose at the calibration point. The depth dose curve of the central axis was measured in the treatment plane using EBT2 film. Photon contamination was measured as the dose at 5 cm depth in a solid water phantom relative to the maximum dose using a parallel plate ion chamber. A MOSFET dosimeter placed on the surface of a humanoid phantom, and EBT2 films inserted into a humanoid phantom were used to verify the TSEI commissioning.
Dosimetric aspects of the 4 MeV TSEI beam, such as profile uniformity (±10%) and relative photon contamination (<0.001%), were comparable to those of a 6 MeV TSEI beam. The relative depth dose of the 4 MeV electrons was 81.4% at the surface and 100% at 0.4 cm. For the 6 MeV electrons, the relative depth dose was 93.4% at the surface and 100% from 0.2 cm to 0.4 cm. The calculated B-factor of the 4 MeV TSEI beam was 1.55, and 1.53 for the 6 MeV TSEI. 80% of the prescribed dose was obtained at 0.22 cm depth for the 4 MeV TSEI beam and 0.53 cm for the 6 MeV TSEI beam in the humanoid phantom measurement.
The suggested 4 MeV beam for TSEI could be applied to shallow depth skin diseases and to electron boost as second treatment course.
PMCID: PMC4261910  PMID: 25194217
Total skin electron irradiation (TSEI); Electron energy; Stanford Technique; Mycosis fungoides
10.  A practical scoring system to determine whether to proceed with surgical resection in recurrent glioblastoma 
Neuro-Oncology  2013;15(8):1096-1101.
To determine the benefit of surgical management in recurrent glioblastoma, we analyzed a series of patients with recurrent glioblastoma who had undergone surgery, and we devised a new scale to predict their survival.
Clinical data from 55 consecutive patients with recurrent glioblastoma were evaluated after surgical management. Kaplan–Meier survival analysis and Cox proportional hazards regression modeling were used to identify prognostic variables for the development of a predictive scale. After the multivariate analysis, performance status (P = .078) and ependymal involvement (P = .025) were selected for inclusion in the new prognostic scale. The devised scale was validated with a separate set of 96 patients from 3 different institutes.
A 3-tier scale (scoring range, 0–2 points) composed of additive scores for the Karnofsky performance status (KPS) (0 for KPS ≥ 70 and 1 for KPS < 70) and ependymal involvement (0 for no enhancement and 1 for enhancement of the ventricle wall in the magnetic resonance imaging) significantly distinguished groups with good (0 points; median survival, 18.0 months), intermediate (1 point; median survival, 10.0 months), and poor prognoses (2 points; median survival, 4.0 months). The new scale was successfully applied to the validation cohort of patients showing distinct prognosis among the groups (median survivals of 11.0, 9.0, and 4.0 months for the 0-, 1-, and 2-point groups, respectively).
We developed a practical scale to facilitate deciding whether to proceed with surgical management in patients with recurrent glioblastoma. This scale was useful for the diagnosis of prognostic groups and can be used to develop guidelines for patient treatment.
PMCID: PMC3714158  PMID: 23800677
ependymal involvement; performance status; recurrent glioblastoma; scoring system; surgery
11.  Impact of Multimodality Approach for Patients with Leptomeningeal Metastases from Solid Tumors 
Journal of Korean Medical Science  2014;29(8):1094-1101.
The purpose of this study was to evaluate treatment patterns, outcome and prognosticators for patients with leptomeningeal metastases from solid tumor. Medical records of 80 patients from January 1, 2004 to May 31, 2011 were retrospectively reviewed. Most frequent site of origin was the lung (59%) followed by the breast (25%). Most patients were treated with intrathecal chemotherapy (90%) and/or whole brain radiotherapy (67.5%). Systemic therapy was offered to 27 patients (33.8%). Percentage of patients treated with single, dual, and triple modality were 32.5%, 43.8%, and 23.8%, respectively. Median survival was 2.7 months and 1 yr survival rate was 11.3%. Multivariate analysis showed that negative cerebrospinal fluid cytology, fewer chemotherapy regimen prior to leptomeningeal metastases, whole brain radiotherapy, systemic therapy, and combined modality treatment (median survival; single 1.4 vs. dual 2.8 vs. triple 8.3 months, P<0.001) had statistical significance on survival. Subgroup analysis of non-small cell lung cancer (NSCLC) patients showed that targeted therapy had significant independent impact on survival (median survival; 10.5 vs. 3.0 months, P=0.008). Unlike previous reports, survival of patients with NSCLC primary was comparable to breast primary. Furthermore, combined modality treatment for all patients and additionally targeted therapy for NSCLC patients should be considered in the treatment of leptomeningeal metastases from solid tumor.
Graphical Abstract
PMCID: PMC4129201  PMID: 25120319
Leptomeningeal Metastases; Prognostic Factor; Solid Tumor
12.  Adjuvant single-fraction radiotherapy is safe and effective for intractable keloids 
Journal of Radiation Research  2014;55(5):912-916.
The aim of this study was to assess the feasibility and efficacy of high-dose, single-fraction electron beam radiotherapy for therapy-resistant keloids. Before 2010, intractable keloids were treated at our institution with post-operative irradiation of 6–15 Gy in 3–5 fractionations. For convenience and cost effectiveness, we have changed our treatment protocol to high-dose single-fraction radiotherapy. A total of 12 patients with 16 keloid lesions were treated from January 2010 to January 2013 in our department. A 10-Gy dose of electron irradiation was given within 72 h of the surgical excision. The mean follow-up period was 20 months. Treatments were well tolerated, and there was no recurrence in any of the patients. Severe adverse effects were not observed. Surgical excision of the keloid, followed by immediate, single-fraction, high-dose radiotherapy, is both safe and effective in preventing recurrence of therapy-resistant keloids.
PMCID: PMC4202283  PMID: 24801475
keloid; radiation; electron beam; single fraction
13.  Expression level of hTERT is regulated by somatic mutation and common single nucleotide polymorphism at promoter region in glioblastoma 
Oncotarget  2014;5(10):3399-3407.
We investigated the role of somatic mutations and a common single nucleotide polymorphism (SNP) in the hTERT promoter region on hTERT expression and clinical outcomes. The hTERT promoter region was sequenced from 48 glioblastomas. hTERT expression was analyzed by quantitative real time-PCR. The association between hTERT promoter genetic changes and other genomic events and clinical variables common in gliomas were examined. C228T and C250T somatic mutations were found in 60.4% of glioblastomas, and a common SNP (T349C) was found in 66.6%. Somatic mutations and the SNP likely have opposing effects on hTERT expression. hTERT expression was significantly higher in the C228T or C250T mutated tumors. Tumors with the T349C genotype showed lower hTERT expression when C228T or C250T mutations were present. However, no significant survival differences were observed among the groups with or without hTERT promoter mutations and SNP. There was a significant association between genetic changes in the hTERT promoter and patient age as well as MGMT promoter methylation and EGFR amplification. hTERT expression is modulated by somatic mutations in the hTERT promoter as well as a common polymorphism. However, hTERT related genomic changes have limited value as an independent prognostic factor for clinical outcomes in glioblastomas.
PMCID: PMC4102818  PMID: 24930669
Glioblastoma; hTERT; promoter mutation; hTERT expression; single nucleotide polymorphism; rs2853669
14.  Thioredoxin 1 as a serum marker for breast cancer and its use in combination with CEA or CA15-3 for improving the sensitivity of breast cancer diagnoses 
BMC Research Notes  2014;7:7.
The human cytosolic thioredoxin (Trx) contains a redox-active dithiol moiety in its conserved active-site sequence. Activation by a wide variety of stimuli leads to secretion of this cytoplasmic protein. Function of Trx1 has been implicated in regulating cell proliferation, differentiation, and apoptosis. The aim of this study was to assess the clinical significance of serum Trx1 level in patients with breast carcinoma.
To clarify whether serum levels of Trx1 could be a serum marker for breast carcinoma, we measured the serum levels of Trx1 in patients with various carcinomas (breast, lung, colorectal, and kidney cancers) using an ELISA, and investigated its associations with the tumour grading from I to III. At the cut-off point 33.1725 ng/ml on the receiver operating characteristic curve (ROC) Trx1 could well discriminate breast carcinoma from normal controls with a sensitivity of 89.8%, specificity 78.0%, and area under the ROC (AUC) 0.901 ± 0.0252. The serum level was well correlated with the progress of the breast carcinoma. We also investigated the diagnostic capacity of CEA and CA15-3 for the early detection of metastatic breast cancer comparing that of Trx1. In contrast to the serum CEA and CA15-3 tumour markers, the serum Trx1 levels of the early cancer (grade I) patients were significantly higher than those of normal control subjects, showing a high diagnostic sensitivity and selectivity (89.4% sensitivity, and 72.0% specificity). The serum levels of Trx1 in various patients with lung, colorectal, and kidney carcinomas indicate that the level of Trx1 is significantly higher than those of other cancer patients. Combinational analysis of CEA or CA15-3 with Trx1 for the detection of breast cancer suggest that the diagnostic capacity of CEA or CA15-3 alone for the early detection of breast cancer, especially regarding sensitivity, is significantly improved by its combination with Trx1.
Taken together, we conclude that serum Trx1 is useful for the early diagnosis of breast cancer or the early prediction prognosis of breast cancer, and therefore has a valuable use as a diagnostic marker and companion marker to CEA and CA15-3 for breast cancer.
PMCID: PMC3891982  PMID: 24393391
Breast cancer; Diagnosis; Thioredoxin 1; Companion marker; Carcinoembryonic antigen (CEA); Cancer antigen 15–3 (CA15-3); Reactive oxygen species
16.  True Progression versus Pseudoprogression in the Treatment of Glioblastomas: A Comparison Study of Normalized Cerebral Blood Volume and Apparent Diffusion Coefficient by Histogram Analysis 
Korean Journal of Radiology  2013;14(4):662-672.
The purpose of this study was to differentiate true progression from pseudoprogression of glioblastomas treated with concurrent chemoradiotherapy (CCRT) with temozolomide (TMZ) by using histogram analysis of apparent diffusion coefficient (ADC) and normalized cerebral blood volume (nCBV) maps.
Materials and Methods
Twenty patients with histopathologically proven glioblastoma who had received CCRT with TMZ underwent perfusion-weighted imaging and diffusion-weighted imaging (b = 0, 1000 sec/mm2). The corresponding nCBV and ADC maps for the newly visible, entirely enhancing lesions were calculated after the completion of CCRT with TMZ. Two observers independently measured the histogram parameters of the nCBV and ADC maps. The histogram parameters between the true progression group (n = 10) and the pseudoprogression group (n = 10) were compared by use of an unpaired Student's t test and subsequent multivariable stepwise logistic regression analysis to determine the best predictors for the differential diagnosis between the two groups. Receiver operating characteristic analysis was employed to determine the best cutoff values for the histogram parameters that proved to be significant predictors for differentiating true progression from pseudoprogression. Intraclass correlation coefficient was used to determine the level of inter-observer reliability for the histogram parameters.
The 5th percentile value (C5) of the cumulative ADC histograms was a significant predictor for the differential diagnosis between true progression and pseudoprogression (p = 0.044 for observer 1; p = 0.011 for observer 2). Optimal cutoff values of 892 × 10-6 mm2/sec for observer 1 and 907 × 10-6 mm2/sec for observer 2 could help differentiate between the two groups with a sensitivity of 90% and 80%, respectively, a specificity of 90% and 80%, respectively, and an area under the curve of 0.880 and 0.840, respectively. There was no other significant differentiating parameter on the nCBV histograms. Inter-observer reliability was excellent or good for all histogram parameters (intraclass correlation coefficient range: 0.70-0.99).
The C5 of the cumulative ADC histogram can be a promising parameter for the differentiation of true progression from pseudoprogression of newly visible, entirely enhancing lesions after CCRT with TMZ for glioblastomas.
PMCID: PMC3725362  PMID: 23901325
Apparent diffusion coefficient; Cerebral blood volume; Glioblastoma multiforme; Histogram analysis; Pseudoprogression
17.  The Changes in MGMT Promoter Methylation Status in Initial and Recurrent Glioblastomas12 
Translational Oncology  2012;5(5):393-397.
To evaluate the mechanism of the development of therapeutic resistance after temozolomide treatment, we focused on changes in O6-methylguanine DNA methyltransferase (MGMT) and mismatch repair (MMR) between initial and recurrent glioblastomas. Tissue samples obtained from 24 paired histologically confirmed initial and recurrent adult glioblastoma patients who were initially treated with temozolomide were used for MGMT and MMR gene promoter methylation status and protein expression analysis using methylation-specific multiplex ligation probe amplification (MS-MLPA), methylation-specific polymerase chain reaction (MSP), and immunohistochemical staining. There was a significant decrease in the methylation ratio of the MGMT promoter determined by MS-MLPA, which was not detectable with MSP, and MGMT protein expression changes were not remarkable. However, there was no epigenetic variability in MMR genes, and a relatively homogeneous expression of MMR proteins was observed in initial and recurrent tumors. We conclude that the development of reduced methylation in the MGMT promoter is one of the mechanisms for acquiring therapeutic resistance after temozolomide treatment in glioblastomas.
PMCID: PMC3468928  PMID: 23066447
19.  DNMT (DNA methyltransferase) inhibitors radiosensitize human cancer cells by suppressing DNA repair activity 
Histone modifications and DNA methylation are two major factors in epigenetic phenomenon. Unlike the histone deacetylase inhibitors, which are known to exert radiosensitizing effects, there have only been a few studies thus far concerning the role of DNA methyltransferase (DNMT) inhibitors as radiosensitizers. The principal objective of this study was to evaluate the effects of DNMT inhibitors on the radiosensitivity of human cancer cell lines, and to elucidate the mechanisms relevant to that process.
A549 (lung cancer) and U373MG (glioblastoma) cells were exposed to radiation with or without six DNMT inhibitors (5-azacytidine, 5-aza-2'-deoxycytidine, zebularine, hydralazine, epigallocatechin gallate, and psammaplin A) for 18 hours prior to radiation, after which cell survival was evaluated via clonogenic assays. Cell cycle and apoptosis were analyzed via flow cytometry. Expressions of DNMT1, 3A/3B, and cleaved caspase-3 were detected via Western blotting. Expression of γH2AX, a marker of radiation-induced DNA double-strand break, was examined by immunocytochemistry.
Pretreatment with psammaplin A, 5-aza-2'-deoxycytidine, and zebularine radiosensitized both A549 and U373MG cells. Pretreatment with psammaplin A increased the sub-G1 fraction of A549 cells, as compared to cells exposed to radiation alone. Prolongation of γH2AX expression was observed in the cells treated with DNMT inhibitors prior to radiation as compared with those treated by radiation alone.
Psammaplin A, 5-aza-2'-deoxycytidine, and zebularine induce radiosensitivity in both A549 and U373MG cell lines, and suggest that this effect might be associated with the inhibition of DNA repair.
PMCID: PMC3375186  PMID: 22429326
Cancer; Epigenetics; DNA methylation; DNA methyltransferase inhibitor; Radiosensitization
20.  Cerebrospinal fluid M staging for medulloblastoma: Reappraisal of Chang's M staging based on the CSF flow 
Neuro-Oncology  2010;13(3):334-344.
Tumor seeding is a strong negative prognostic factor for patients with medulloblastoma. Because Chang's M staging is based primarily on CT and myelographic findings and might be contradictory to the direction of normal cerebrospinal fluid (CSF) flow, seeding patterns and appropriate staging of medulloblastoma need to be revisited in patients diagnosed in the MRI era. We retrospectively reviewed the clinical and radiological data of 86 patients with a diagnosis of medulloblastoma who were treated in the MRI era. The presence of seeding in each subarachnoid space compartment and the patterns of seeding were analyzed in correlation with patient survival data. Thirty-four patients had gross seeding on perioperative MRI. Thirty-two patients had seeding in the spinal compartment. Sixteen and 12 patients had seeding in the infratentorial and supratentorial compartments, respectively. There was an apparent hierarchy of seeding (ie, from seeding in the spinal compartment up to the supratentorial compartment). Patients with seeding in the spinal compartment had longer progression-free survival (P = .038) and a tendency toward better overall survival (P = .053) compared with patients with seeding in intracranial compartments. We modified Chang's M staging based on the CSF flow and termed this approach “CSF M staging.” CSF M staging for medulloblastoma, in which intracranial seeding occupies a higher rank than spinal seeding, was a better predictor of patient prognosis. This modified staging method may be applied to metastatic staging of brain tumors located in the fourth ventricle.
PMCID: PMC3064600  PMID: 21134897
cerebrospinal fluid, medulloblastoma; prognosis; seeding; staging
21.  Efficacy of High-dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with Relapsed Medulloblastoma: A Report on The Korean Society for Pediatric Neuro-Oncology (KSPNO)-S-053 Study 
Journal of Korean Medical Science  2010;25(8):1160-1166.
The efficacy and toxicity of high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) were investigated for improving the outcomes of patients with relapsed medulloblastoma. A total of 15 patients with relapsed medulloblastoma were enrolled in the KSPNO-S-053 study from May 2005 to May 2007. All patients received approximately 4 cycles of salvage chemotherapy after relapse. Thirteen underwent HDCT/ASCT; CTE and CM regimen were employed for the first HDCT (HDCT1) and second HDCT (HDCT2), respectively, and 7 underwent HDCT2. One transplant related mortality (TRM) due to veno-occlusive disease (VOD) occurred during HDCT1 but HDCT2 was tolerable with no further TRM. The 3-yr overall survival probability and event-free survival rates ±95% confidence intervals (CI) were 33.3±12.2% and 26.7% ±11.4%, respectively. When analysis was confined to only patients who had a complete response (CR) or partial response (PR) prior to HDCT, the probability of 3-yr overall survival rates ±95% CI was 40.0±15.5%. No patients with stable disease (SD) or progressive disease (PD) survived. Survival rates from protocol KSPNO-S-053 are encouraging and show that tumor status prior to HDCT/ASCT is an important factor to consider for improving survival rates of patients with relapsed medulloblastoma.
PMCID: PMC2908784  PMID: 20676326
Recurrence; Medulloblastoma; Transplantation, Autologous; Tandem; Hematopoietic Stem Cell Transplantation
22.  Recursive partitioning analysis of prognostic factors in WHO grade III glioma patients treated with radiotherapy or radiotherapy plus chemotherapy 
BMC Cancer  2009;9:450.
We evaluated the hierarchical risk groups for the estimated survival of WHO grade III glioma patients using recursive partitioning analysis (RPA). To our knowledge, this is the first study to address the results of RPA specifically for WHO grade III gliomas.
A total of 133 patients with anaplastic astrocytoma (AA, n = 56), anaplastic oligodendroglioma (AO, n = 67), or anaplastic oligoastrocytoma (AOA, n = 10) were included in the study. These patients were treated with either radiotherapy alone or radiotherapy followed by PCV chemotherapy after surgery. Five prognostic factors, including histological subsets, age, performance status, extent of resection, and treatment modality were incorporated into the RPA. The final nodes of RPA were grouped according to their survival times, and the Kaplan-Meier graphs are presented as the final set of prognostic groups.
Four risk groups were defined based on the clinical prognostic factors excluding age, and split variables were all incorporated into the RPA. Survival analysis showed significant differences in mean survival between the different groups: 163.4 months (95% CI: 144.9-182.0), 109.5 months (86.7-132.4), 66.6 months (50.8-82.4), and 27.7 months (16.3-39.0), respectively, from the lowest to the highest risk group (p = 0.00).
The present study shows that RPA grouping with clinical prognostic factors can successfully predict the survival of patients with WHO grade III glioma.
PMCID: PMC2806410  PMID: 20017960
23.  Overexpression of peroxiredoxin I and thioredoxin1 in human breast carcinoma 
Peroxiredoxins (Prxs) are a novel group of peroxidases containing high antioxidant efficiency. The mammalian Prx family has six distinct members (Prx I-VI) in various subcellular locations, including peroxisomes and mitochondria, places where oxidative stress is most evident. The function of Prx I in particular has been implicated in regulating cell proliferation, differentiation, and apoptosis. Since thioredoxin1 (Trx1) as an electron donor is functionally associated with Prx I, we investigated levels of expression of both Prx I and Trx1.
We investigated levels of expression of both Prx I and Trx1 in breast cancer by real-time polymerase chain reaction (RT-PCR) and Western blot.
Levels of messenger RNA (mRNA) for both Prx I and Trx1 in normal human breast tissue were very low compared to other major human tissues, whereas their levels in breast cancer exceeded that in other solid cancers (colon, kidney, liver, lung, ovary, prostate, and thyroid). Among members of the Prx family (Prx I-VI) and Trx family (Trx1, Trx2), Prx I and Trx1 were preferentially induced in breast cancer. Moreover, the expression of each was associated with progress of breast cancer and correlated with each other. Western blot analysis of different and paired breast tissues revealed consistent and preferential expression of Prx I and Trx1 protein in breast cancer tissue.
Prx I and Trx1 are overexpressed in human breast carcinoma and the expression levels are associated with tumor grade. The striking induction of Prx I and Trx1 in breast cancer may enable their use as breast cancer markers.
PMCID: PMC2711968  PMID: 19566940
24.  Clinical Results of Chemotherapy based Treatment in Retinoblastoma Patients: A Single Center Experience 
Retinoblastoma is the most common intraocular malignancy in children. Since the 1990s, chemotherapy was indicated for intraocluar disease to reduce the frequency of enucleation and spare the complications associated with external beam radiation. In this study, we analyzed treatment results of retinoblastoma in our institute.
Materials and Methods
Datas from children diagnosed with retinoblastoma and treated at Seoul National University Children's Hospital between 1986 and 2008 were analyzed retrospectively. We utilized cyclophosphamide, vincristine, adriamycin, and methotrexate (CVAM) for OPD-based adjuvant chemotherapy. From 1990, primary chemotherapy was administered to patients with intraocular disease for eyeball-saving and patients received a combination of etoposide, vincristine, cisplatin (or ifosfamide) as a moderately intensive regimen, or a combination of cisplatin, doxorubicin, etoposide, and cycophosphamide (CDEC) as a highly intensive regimen.
One hundred eighteen children were analyzed. There were 68 unilateral and 50 bilateral diseases. The median age at diagnosis was 1 year and Reese-Ellsworth stage V was the most common stage at the time of diagnosis. All patients were treated by chemotherapy-based multimodality methods, and primary chemotherapy was administered to 80 patients. The 10-year overall and event-free survival rate of all patients were 93.9% and 91.6%, respectively. Two patients who died were in the CDEC regimen group, but there was no significant statistical difference in survival rates by chemotherapy regimens. Fifty-six of 114 eyeballs were saved after primary chemotherapy-based treatment, and the eyeball-saving rate was 49.1%. Six patients relapsed after enucleation and 2 patients were treated successfully after autologous PBSCT. Osteosarcoma occurred in 2 patients as a secondary malignancy, and facial asymmetry after radiotherapy was the most common long-term sequelae.
In this study, the overall and event-free survival rates of retinoblastoma were satisfactory and eye-saving was possible with primary chemotherapy. Development of new chemotherapeutic regimens and a team approach are necessary to improve the eyeball-saving rate.
PMCID: PMC2697477  PMID: 19688125
Retinoblastoma; Chemotherapy; Radiotherapy; Enucleation; Survival rate; Eyeball-saving
25.  Initial Response to Treatment was Highly Associated with the Prognosis of Childhood Rhabdomyosarcoma: A Retrospective Analysis of a Single Center Experience in Korea 
Following the introduction of a multimodal approach to diagnosis and treatment, the prognosis of rhabdomyosarcoma (RMS) has markedly improved over the last three decades. However, there are few data on treatment outcomes in Korean patients.
Materials and Methods
We performed a retrospective analysis of 77 patients with RMS diagnosed and treated at Seoul National University Children's Hospital between 1986 and 2005.
The overall 5-year survival and event-free survival rates for all patients were 77% and 59%, respectively. The Intergroup Rhabdomyosarcoma Study clinical grouping and initial response to treatment (20-week response) were important prognostic factors.
The outcome of childhood RMS was closely associated with the initial staging and the initial response to treatment. Modulating therapies according to initial responses and risk factors is critical, and new treatment strategies for high-risk patients are needed.
PMCID: PMC2697467  PMID: 19688116
Rhabdomyosarcoma; Prognosis; Korea; Child

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