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1.  Daily Collection of Self-Reporting Sleep Disturbance Data via a Smartphone App in Breast Cancer Patients Receiving Chemotherapy: A Feasibility Study 
Improvements in mobile telecommunication technologies have enabled clinicians to collect patient-reported outcome (PRO) data more frequently, but there is as yet limited evidence regarding the frequency with which PRO data can be collected via smartphone applications (apps) in breast cancer patients receiving chemotherapy.
The primary objective of this study was to determine the feasibility of an app for sleep disturbance-related data collection from breast cancer patients receiving chemotherapy. A secondary objective was to identify the variables associated with better compliance in order to identify the optimal subgroups to include in future studies of smartphone-based interventions.
Between March 2013 and July 2013, patients who planned to receive neoadjuvant chemotherapy for breast cancer at Asan Medical Center who had access to a smartphone app were enrolled just before the start of their chemotherapy and asked to self-report their sleep patterns, anxiety severity, and mood status via a smartphone app on a daily basis during the 90-day study period. Push notifications were sent to participants daily at 9 am and 7 pm. Data regarding the patients’ demographics, interval from enrollment to first self-report, baseline Beck’s Depression Inventory (BDI) score, and health-related quality of life score (as assessed using the EuroQol Five Dimensional [EQ5D-3L] questionnaire) were collected to ascertain the factors associated with compliance with the self-reporting process.
A total of 30 participants (mean age 45 years, SD 6; range 35-65 years) were analyzed in this study. In total, 2700 daily push notifications were sent to these 30 participants over the 90-day study period via their smartphones, resulting in the collection of 1215 self-reporting sleep-disturbance data items (overall compliance rate=45.0%, 1215/2700). The median value of individual patient-level reporting rates was 41.1% (range 6.7-95.6%). The longitudinal day-level compliance curve fell to 50.0% at day 34 and reached a nadir of 13.3% at day 90. The cumulative longitudinal compliance curve exhibited a steady decrease by about 50% at day 70 and continued to fall to 45% on day 90. Women without any form of employment exhibited the higher compliance rate. There was no association between any of the other patient characteristics (ie, demographics, and BDI and EQ5D-3L scores) and compliance. The mean individual patient-level reporting rate was higher for the subgroup with a 1-day lag time, defined as starting to self-report on the day immediately after enrollment, than for those with a lag of 2 or more days (51.6%, SD 24.0 and 29.6%, SD 25.3, respectively; P=.03).
The 90-day longitudinal collection of daily self-reporting sleep-disturbance data via a smartphone app was found to be feasible. Further research should focus on how to sustain compliance with this self-reporting for a longer time and select subpopulations with higher rates of compliance for mobile health care.
PMCID: PMC4051741  PMID: 24860070
mobile applications; self report; compliance; breast cancer
2.  Characteristics of BRCA1/2 Mutation-Positive Breast Cancers in Korea: A Comparison Study Based on Multicenter Data and the Korean Breast Cancer Registry 
Journal of Breast Cancer  2014;17(2):129-135.
Mutations in BRCA genes are the main cause of hereditary breast cancer in Korea. The aim of this study was to investigate the characteristics of breast cancers involving BRCA1 (BRCA1 group) and BRCA2 (BRCA2 group) mutations.
We retrospectively reviewed the medical records of patients with BRCA1 (BRCA1 group) or BRCA2 (BRCA2 group) mutation positive breast cancer from multiple centers and compared the data to that of the Korean Breast Cancer Society registry (registry group).
The patients of the BRCA1 group were diagnosed at a younger age (median age, 37 years) and had tumors of higher histological (61.3% with histological grade 3) and nuclear (37.5% with nuclear grade 3) grade than those of the registry group. In addition, the frequency of ductal carcinoma in situ in the BRCA1 group was lower (3.7%) than in the registry group, and the BRCA1 group were more likely to be triple-negative breast cancer (61.3%). Patients in the BRCA2 group were also younger at diagnosis (mean age, 41 years) and were more likely to have involvement of the axillary node than the registry group (45.5% vs. 33.5%, p=0.002). The BRCA1 and BRCA2 groups did not show a correlation between tumor size and axillary node involvement.
We report the characteristics of BRCA mutation positive breast cancer patients in the Korean population through multicenter data and nation-wide breast cancer registry study. However, BRCA-mutated breast cancers appear highly complex, and further research on their molecular basis is needed in Korea.
PMCID: PMC4090314  PMID: 25013433
BRCA1 genes; BRCA2 genes; Breast neoplasms; Korea
3.  Reliability of the Percent Density in Digital Mammography with a Semi-Automated Thresholding Method 
Journal of Breast Cancer  2014;17(2):174-179.
The reliability of the quantitative measurement of breast density with a semi-automated thresholding method (Cumulus™) has mainly been investigated with film mammograms. This study aimed to evaluate the intrarater reproducibility of percent density (PD) by Cumulus™ with digital mammograms.
This study included 1,496 craniocaudal digital mammograms from the unaffected breast of breast cancer patients. One rater reviewed each mammogram and estimated the PD using the Cumulus™ method. All images were reassessed by the same rater 1 month later without reference to the previously assigned values. The repeatability of the PD was evaluated by an intraclass correlation coefficient (ICC). All patients were grouped based on their body mass index (BMI), age, family history of breast cancer, breastfeeding history and breast area (calculated with Cumulus™), and subgroup analysis for the ICC of each group was performed. All patients were categorized by their Breast Imaging Reporting and Data System (BI-RADS) density pattern, and the mean and standard deviation of the PD by each BI-RADS categories were compared.
The ICC for the PD was 0.94, indicating excellent repeatability. The discrepancy between the paired PD values ranged from 0 to 23.93, with an average of 3.90 (standard deviation=3.39). The subgroup ICCs for the PD ranged from 0.88 to 0.96, indicating excellent reliability in all subgroups regardless of patient variables. The ICCs of the PD for the high-risk (BI-RADS 3 and 4) and low-risk (BI-RADS 1 and 2) groups were 0.90 and 0.88, respectively.
This study suggests that PD calculated with digital mammograms has an acceptable reliability regardless of patient age, BMI, family history of breast cancer, breastfeeding history, breast size, and BI-RADS density pattern.
PMCID: PMC4090321  PMID: 25013440
Breast; Mammography; Observer variation
4.  Effect Modification of Hormonal Therapy by p53 Status in Invasive Breast Cancer 
Journal of Breast Cancer  2013;16(4):386-394.
We aimed to confirm the prognostic and predictive value of p53 expression, particularly in invasive breast cancer patients, according to immunohistochemical hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status.
Immunohistochemical data for p53, estrogen receptor, progesterone receptor, and HER2 expression from a total of 15,598 patients were retrospectively retrieved from the web-based database of the Korean Breast Cancer Society. Overall survival (OS) and breast cancer-specific survival (BCSS) were calculated and compared using the Kaplan-Meier method and log-rank test, respectively. Multivariate analyses were performed using a stratified Cox proportional hazard regression model. A model evaluating interactions between p53 expression and both hormonal therapy and chemotherapy was used to determine the treatment benefit from both modalities.
The prognostic value of p53 for OS and BCSS was most significant in the HR+/HER2- subgroup, with hazard ratios of 1.44 (95% confidence interval [CI], 1.08-1.93) and 1.47 (95% CI, 1.09-1.99), respectively. The p53 overexpression hazard ratios were of borderline significance for the HR+/HER2+ subgroup and were not significant for the HR-/HER2+ and HR-/HER2- subgroups. The model with interaction terms revealed that hormonal therapy significantly interacts with p53 status (p=0.002 and p=0.007 for OS and BCSS, respectively), suggesting an insignificant prognostic value for p53 status (p=0.268 and p=0.296 for OS and BCSS, respectively). An interaction between chemotherapy and p53 status was not found in this model.
p53 overexpression has independent prognostic value, particularly in cases of HR+/HER2- invasive breast cancer, which may be due to effect modification of hormonal therapy dependent on p53 status.
PMCID: PMC3893340  PMID: 24454460
Breast neoplasms; Drug resistance; Tumor suppressor protein p53
5.  Extracellular matrix protein 1 regulates cell proliferation and trastuzumab resistance through activation of epidermal growth factor signaling 
Extracellular matrix protein 1 (ECM1) is a secreted glycoprotein with putative functions in cell proliferation, angiogenesis and differentiation. Expression of ECM1 in several types of carcinoma suggests that it may promote tumor development. In this study, we investigated the role of ECM1 in oncogenic cell signaling in breast cancer, and potential mechanisms for its effects.
In order to find out the functional role of ECM1, we used the recombinant human ECM1 and viral transduction systems which stably regulated the expression level of ECM1. We examined the effect of ECM1 on cell proliferation and cell signaling in vitro and in vivo. Moreover, tissues and sera of patients with breast cancer were used to confirm the effect of ECM1.
ECM1 protein was increased in trastuzumab-resistant (TR) cells, in association with trastuzumab resistance and cell proliferation. Through physical interaction with epidermal growth factor receptor (EGFR), ECM1 potentiated the phosphorylation of EGFR and extracellular signal-regulated kinase upon EGF treatment. Moreover, ECM1-induced galectin-3 cleavage through upregulation of matrix metalloproteinase 9 not only improved mucin 1 expression, but also increased EGFR and human epidermal growth factor receptor 3 protein stability as a secondary signaling.
ECM1 has important roles in both cancer development and trastuzumab resistance in breast cancer through activation of EGFR signaling.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0479-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4308848  PMID: 25499743
6.  A multi-institutional study of the prevalence of BRCA1 and BRCA2 large genomic rearrangements in familial breast cancer patients 
BMC Cancer  2014;14(1):645.
Large genomic rearrangements (LGRs) in the BRCA1/2 genes are frequently observed in breast cancer patients who are negative for BRCA1/2 small mutations. Here, we examined 221 familial breast cancer patients from 37 hospitals to estimate the contribution of LGRs, in a nationwide context, to the development of breast cancer.
Direct sequencing or mutation scanning followed by direct sequencing was performed to screen small mutations. BRCA1/2 small mutation-negative patients were screened for the presence of LGRs using a multiple ligation-dependent probe amplification (MLPA) assay.
Using a combined strategy to detect the presence of small mutations and LGRs, we identified BRCA1/2 small mutations in 78 (35.3%) out of 221 familial breast cancer patients and BRCA1 LGRs in 3 (2.1%) out of 143 BRCA1/2 small mutation-negative patients: the deletion of exons 11–13, the deletion of exons 13–15, and whole gene deletion of exons 1-24. The novel deletion of exons 11–13 is thought to result from a non-homologous recombination event mediated by a microhomology sequence comprised of 3 or 4 base pairs: c.3416_4357 + 1863delins187 (NG_005905.2: g.33369_44944delins187).
In this study, we showed that LGRs were found in 3.7% (3/81) of the patients who had mutations in BRCA1 or BRCA2, and 7.5% (3/40) of patients with mutations in BRCA1. This suggests that the contribution of LGRs to familial breast cancer in this population might be comparable to that in other ethnic populations. Given these findings, an MLPA to screen for mutations in the BRCA1 gene is recommended as an initial screening test in highly selective settings.
PMCID: PMC4164743  PMID: 25176351
Breast cancer; Hereditary cancer; Large genomic rearrangement; BRCA1; BRCA2
7.  A Review of Breast Cancer Survivorship Issues from Survivors' Perspectives 
Journal of Breast Cancer  2014;17(3):189-199.
Despite the fact that more breast cancer survivors are currently enjoying longer lifespans, there remains limited knowledge about the factors and issues that are of greatest significance for these survivors, particularly from their perspectives. This review was based on the concept that the topics addressed should focus on the perspectives of current survivors and should be extended to future modalities, which physicians will be able to use to gain a better understanding of the hidden needs of these patients. We intended to choose and review dimensions other than the pathology and the disease process that could have been overlooked during treatment. The eight topics upon which we focused included: delay of treatment and survival outcome; sexual well-being; concerns about childbearing; tailored follow-up; presence of a family history of breast cancer; diet and physical activity for survivors and their families; qualitative approach toward understanding of breast cancer survivorship, and; mobile health care for breast cancer survivors. Through this review, we aimed to examine the present clinical basis of the central issues noted from the survivors' perspectives and suggest a direction for future survivorship-related research.
PMCID: PMC4197348  PMID: 25320616
Breast neoplasms; Quality of life; Survivors
8.  The Associations between Immunity-Related Genes and Breast Cancer Prognosis in Korean Women 
PLoS ONE  2014;9(7):e103593.
We investigated the role of common genetic variation in immune-related genes on breast cancer disease-free survival (DFS) in Korean women. 107 breast cancer patients of the Seoul Breast Cancer Study (SEBCS) were selected for this study. A total of 2,432 tag single nucleotide polymorphisms (SNPs) in 283 immune-related genes were genotyped with the GoldenGate Oligonucleotide pool assay (OPA). A multivariate Cox-proportional hazard model and polygenic risk score model were used to estimate the effects of SNPs on breast cancer prognosis. Harrell’s C index was calculated to estimate the predictive accuracy of polygenic risk score model. Subsequently, an extended gene set enrichment analysis (GSEA-SNP) was conducted to approximate the biological pathway. In addition, to confirm our results with current evidence, previous studies were systematically reviewed. Sixty-two SNPs were statistically significant at p-value less than 0.05. The most significant SNPs were rs1952438 in SOCS4 gene (hazard ratio (HR) = 11.99, 95% CI = 3.62–39.72, P = 4.84E-05), rs2289278 in TSLP gene (HR = 4.25, 95% CI = 2.10–8.62, P = 5.99E-05) and rs2074724 in HGF gene (HR = 4.63, 95% CI = 2.18–9.87, P = 7.04E-05). In the polygenic risk score model, the HR of women in the 3rd tertile was 6.78 (95% CI = 1.48–31.06) compared to patients in the 1st tertile of polygenic risk score. Harrell’s C index was 0.813 with total patients and 0.924 in 4-fold cross validation. In the pathway analysis, 18 pathways were significantly associated with breast cancer prognosis (P<0.1). The IL-6R, IL-8, IL-10RB, IL-12A, and IL-12B was associated with the prognosis of cancer in data of both our study and a previous study. Therefore, our results suggest that genetic polymorphisms in immune-related genes have relevance to breast cancer prognosis among Korean women.
PMCID: PMC4116221  PMID: 25075970
9.  New Breast Cancer Risk Variant Discovered at 10q25 in East Asian Women 
Recently, 41 new genetic susceptibility loci for breast cancer risk were identified in a genome-wide association study conducted in European descendants. Most of these risk variants have not been directly replicated in Asian populations.
We evaluated nine of those non-replication loci in East Asians in order to identify new risk variants for breast cancer in these regions. First, we analyzed single nucleotide polymorphisms (SNPs) in these regions using data from two GWAS conducted among Chinese and Korean women, including 5,083 cases and 4,376 controls (Stage 1). In each region we selected a SNP showing the strongest association with breast cancer risk for replication in an independent set of 7,294 cases and 9,404 controls of East Asian descents (Stage 2). Logistic regression models were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) as a measure of the association of breast cancer risk and genetic variants.
Two SNPs were replicated in Stage 2 at P < 0.05: rs1419026 at 6q14 (per allele OR = 1.07, 95% CI: 1.03-1.12, P = 3.0×10−4) and rs941827 at 10q25 (OR = 0.92, 95% CI: 0.89-0.96, P = 5.3×10−5). The association with rs941827 remained highly statistically significant after adjusting for the risk variant identified initially in women of European ancestry (OR = 0.88, 95% CI: 0.82-0.97, P = 5.3×10−5).
We identified a new breast cancer risk variant at 10q25 in East Asian women.
Results from this study improve the understanding of the genetic basis for breast cancer.
PMCID: PMC3720126  PMID: 23677579
breast cancer; genetic susceptibility; GWAS replication; single nucleotide polymorphism
10.  Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls 
Human Molecular Genetics  2013;22(12):2539-2550.
In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ∼10% of excess familial risk of breast cancer in Asian populations.
PMCID: PMC3658167  PMID: 23535825
11.  Survival Outcomes of Different Treatment Methods for the Ipsilateral Breast of Occult Breast Cancer Patients with Axillary Lymph Node Metastasis: A Single Center Experience 
Journal of Breast Cancer  2013;16(4):410-416.
This study compared the survival outcomes of different treatment methods for the ipsilateral breast of occult breast cancer (OBC) patients with axillary lymph node metastasis.
A retrospective study was conducted in which forty OBC patients with axillary lymph node metastasis were identified out of 15,029 patients who had been diagnosed with a primary breast cancer at between 1992 and 2010. The patients were categorized into three treatment groups based on ipsilateral breast management: breast-conserving surgery (BCS) (n=17), mastectomy (n=12), and nonsurgical intervention with or without radiation therapy (No surgery with or without radiation therapy [No Op±RT]) (n=11). All patients underwent axillary lymph node dissection. Cases were evaluated based on treatment and potential prognostic factors with respect to overall survival (OS) and disease-free survival (DFS).
During the follow-up period (median follow-up of 71.5 months), the overall OS and DFS were 76.9% and 74.9%, respectively. The 5-year treatment-specific OS was 72.0% for the BCS group, 74.0% for the mastectomy group, and 87.5% for the No Op±RT group (log-rank p=0.49). The 5-year DFS was 70.6% for the BCS group, 66.7% for the mastectomy group, and 90.9% for the No Op±RT group (log-rank p=0.36). Recurrence rates for the BCS and No Op±RT groups were 5.9% and 18.2%, respectively. Histologic grade and lymph node status were inversely correlated with DFS (log-rank p=0.04 and p<0.01, respectively).
There was no difference in survival outcomes between the three treatment methods for the ipsilateral breast (mastectomy, BCS, and No Op±RT) of OBC patients with axillary lymph node metastasis. A large-scale multicenter study is needed to validate the results from this small retrospective study.
PMCID: PMC3893343  PMID: 24454463
Mastectomy; Occult breast cancer; Radiation therapy; Segmental mastectomy; Survival
12.  The Efficacy and Perioperative Complications Associated with Lumbar Spinal Fusion Surgery, Focusing on Geriatric Patients in the Republic of Korea 
The purpose of this study was to examine the efficacy and perioperative complications associated with lumbar spinal fusion surgery, focusing on geriatric patients in the Republic of Korea.
We retrospectively investigated 485 patients with degenerative spinal diseases who had lumbar spinal fusion surgeries between March 2006 and December 2010 at our institution. Age, sex, comorbidity, American Society of Anesthesiologists (ASA) class, fusion segments, perioperative complications, and outcomes were analyzed in this study. Risk factors for complications and their association with age were analyzed.
In this study, 81 patients presented complications (16.7%). The rate of perioperative complications was significantly higher in patients 70 years or older than in other age groups (univariate analysis, p=0.015; multivariate analysis, p=0.024). The perioperative complications were not significantly associated with the other factors tested (sex, comorbidity, ASA class, and fusion segments). Post-operative outcomes of lumbar spinal fusion surgeries for the patients were determined on the basis of MacNab's criteria (average follow up period : 19.7 months), and 412 patients (85.0%) were classified as having "excellent" or "good" results.
Increasing age was an important risk factor for perioperative complications in patients undergoing lumbar spinal fusion surgery, whereas other factors were not significant. However, patients' satisfaction or return to daily activities when compared with younger patients did not show much difference. We recommend good clinical judgment as well as careful selection of geriatric patients for lumbar spinal fusion surgery.
PMCID: PMC3841275  PMID: 24294456
Complications; Elderly patients; Lumbar spinal fusion surgery
13.  Treatment results of breast cancer patients with locoregional recurrence after mastectomy 
Radiation Oncology Journal  2013;31(3):138-146.
To analyze the results of locoregional and systemic therapy in the breast cancer patients with locoregional recurrence (LRR) after mastectomy.
Materials and Methods
Seventy-one patients who received radiotherapy for isolated LRR after mastectomy between January 1999 and December 2009 were retrospectively reviewed. Among the 71 patients, 59 (83.1%) underwent wide excision and radiotherapy and 12 (16.9%) received radiotherapy alone. Adjuvant hormonal therapy was given to 45 patients (63.4%). Oncologic outcomes including locoregional recurrence-free survival, disease-free survival (DFS), and overall survival (OS) and prognostic factors were analyzed.
Median follow-up time was 49.2 months. Of the 71 patients, 5 (7%) experienced second isolated LRR, and 40 (56%) underwent distant metastasis (DM). The median DFS was 35.6 months, and the 3- and 5-year DFS were 49.1% and 28.6%, respectively. The median OS was 86.7 months, and the 5-year OS was 62.3%. Patients who received hormone therapy together showed better 5-year DFS and OS than the patients treated with locoregional therapy only (31.6% vs. 22.1%, p = 0.036; 66.5% vs. 55.2%, p = 0.022). In multivariate analysis, higher N stage at recurrence was a significant prognostic factor for DFS and OS. Disease free interval (≤30 months vs. >30 months) from mastectomy to LRR was also significant for OS. The patients who received hormone therapy showed superior DFS and showed trend to better OS.
DM was a major pattern of failure after the treatment of LRR after mastectomy. The role of systemic treatment for LRR after mastectomy should be investigated at prospective trials.
PMCID: PMC3797273  PMID: 24137559
Breast cancer; Locoregional recurrence; Mastectomy
14.  Giant Cystic Cerebral Cavernous Malformation with Multiple Calcification - Case Report 
Cerebral cavernous malformation with giant cysts is rare and literature descriptions of its clinical features are few. In this case study, the authors describe the clinical symptoms, radiological findings, and pathological diagnosis of cerebral cavernous malformations with giant cysts, reviewing the relevant literature to clearly differentiate this from other disease entities. The authors present a case of a 19-year-old male with a giant cystic cavernous malformation, who was referred to the division of neurosurgery due to right sided motor weakness (grade II/II). Imaging revealed a large homogenous cystic mass, 7.2×4.6×6 cm in size, in the left fronto-parietal lobe and basal ganglia. The mass had an intra-cystic lesion, abutting the basal portion of the mass. The initial diagnosis considered this mass a glioma or infection. A left frontal craniotomy was performed, followed by a transcortical approach to resect the mass. Total removal was accomplished without post-operative complications. An open biopsy and a histopathological exam diagnosed the mass as a giant cystic cavernous malformation. Imaging appearances of giant cavernous malformations may vary. The clinical features, radiological features, and management of giant cavernous malformations are described based on pertinent literature review.
PMCID: PMC3804668  PMID: 24167810
Cavernous malformation; Giant cyst
15.  Wnt5a Is Associated with Cigarette Smoke-Related Lung Carcinogenesis via Protein Kinase C 
PLoS ONE  2013;8(1):e53012.
Wnt5a is overexpressed during the progression of human non-small cell lung cancer. However, the roles of Wnt5a during smoking-related lung carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related lung cancer using human bronchial epithelial (HBE) cells (NHBE, BEAS-2B, 1799, 1198 and 1170I) at different malignant stages established by exposure to cigarette smoke condensate (CSC). Abnormal up-regulation of Wnt5a mRNA and proteins was detected in CSC-exposed transformed 1198 and tumorigenic 1170I cells as compared with other non-CSC exposed HBE cells. Tumor tissues obtained from smokers showed higher Wnt5a expressions than matched normal tissues. In non-CSC exposed 1799 cells, treatment of recombinant Wnt5a caused the activations of PKC and Akt, and the blockage of Wnt5a and PKC significantly decreased the viabilities of CSC-transformed 1198 cells expressing high levels of Wnt5a. This reduced cell survival rate was associated with increased apoptosis via the down-regulation of Bcl2 and the induction of cleaved poly ADP-ribose polymerase. Moreover, CSC-treated 1799 cells showed induction of Wnt5a expression and enhanced colony-forming capacity. The CSC-induced colony forming efficiency was suppressed by the co-incubation with a PKC inhibitor. In conclusion, these results suggest that cigarette smoke induces Wnt5a-coupled PKC activity during lung carcinogenesis, which causes Akt activity and anti-apoptosis in lung cancer. Therefore, current study provides novel clues for the crucial role of Wnt5a in the smoking-related lung carcinogenesis.
PMCID: PMC3549912  PMID: 23349696
16.  Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium 
Human Molecular Genetics  2011;20(24):4991-4999.
Although approximately 20 common genetic susceptibility loci have been identified for breast cancer risk through genome-wide association studies (GWASs), genetic risk variants reported to date explain only a small fraction of heritability for this common cancer. We conducted a four-stage GWAS including 17 153 cases and 16 943 controls among East-Asian women to search for new genetic risk factors for breast cancer. After analyzing 684 457 SNPs in 2062 cases and 2066 controls (Stage I), we selected for replication among 5969 Chinese women (4146 cases and 1823 controls) the top 49 SNPs that had neither been reported previously nor were in strong linkage disequilibrium with reported SNPs (Stage II). Three SNPs were further evaluated in up to 13 152 Chinese and Japanese women (6436 cases and 6716 controls) (Stage III). Finally, two SNPs were evaluated in 10 847 Korean women (4509 cases and 6338 controls) (Stage IV). SNP rs10822013 on chromosome 10q21.2, located in the zinc finger protein 365 (ZNF365) gene, showed a consistent association with breast cancer risk in all four stages with a combined per-risk allele odds ratio of 1.10 (95% CI: 1.07–1.14) (P-value for trend = 5.87 × 10−9). In vitro electrophoretic mobility shift assays demonstrated the potential functional significance of rs10822013. Our results strongly implicate rs10822013 at 10q21.2 as a genetic risk variant for breast cancer among East-Asian women.
PMCID: PMC3221542  PMID: 21908515
17.  Comparison of Posterior Fixation Alone and Supplementation with Posterolateral Fusion in Thoracolumbar Burst Fractures 
We compared the radiological and clinical outcomes between patients who underwent posterior fixation alone and supplemented with fusion following the onset of thoracolumbar burst fractures. In addition, we also evaluated the necessity of posterolateral fusion for patients treated with posterior pedicle screw fixation.
From January 2007 to December 2009, 46 consecutive patients with thoracolumbar burst fracture were included in this study. On the basis of posterolateral fusion, we divided our patients into the non-fusion group and the fusion group. The radiological assessment was performed according to the Cobb's method, and results were obtained at immediately, 3, 6, 12 months after surgery. The clinical outcomes were evaluated using the modified Mcnab criteria at the final follow-up.
The demographic data and the mean follow-up period were similar between the two groups. Patients of both groups achieved satisfactory clinical outcomes. The mean loss of kyphosis correction showed that patients of both groups experienced loss of correction with no respect to whether they underwent the posterolateral fusion. There was no significant difference in the degree of loss of correction at any time points of the follow-up between the two groups. In addition, we also compared the effect of fixed levels (i.e., short versus long segment) on loss of correction between the two groups and there was no significant difference. There were no major complications postoperatively and during follow-up period.
We suggest that posterolateral fusion may be unnecessary for patients with thoracolumbar burst fractures who underwent posterior pedicle screw fixation.
PMCID: PMC3488643  PMID: 23133723
Thoracolumbar burst fracture; Posterior pedicle screw fixation; Posterolateral fusion; Loss of kyphosis correction
18.  The Role of Hyperthyroidism as the Predisposing Factor for Superior Sagittal Sinus Thrombosis 
Superior sagittal sinus thrombosis (SSST) is an uncommon cause of stroke, whose symptoms and clinical course are highly variable. It is frequently associated with a variety of hypercoagulable states. Coagulation abnormalities are commonly seen in patients with hyperthyroidism. To the best of our knowledge, there are few reports on the association between hyperthyroidism and cerebral venous thrombosis. We report on a 31-year-old male patient with a six-year history of hyperthyroidism who developed seizure and mental deterioration. Findings on brain computed tomography (CT) showed multiple hemorrhages in the subcortical area of both middle frontal gyrus and cerebral digital subtraction angiography (DSA) showed irregular intra-luminal filling defects of the superior sagittal sinus. These findings were consistent with hemorrhagic transformation of SSST. Findings on clinical laboratory tests were consistent with hyperthyroidism. In addition, our patient also showed high activity of factors IX and XI. The patient received treatment with oral anticoagulant and prophylthiouracil. His symptoms showed complete improvement. A follow-up cerebral angiography four weeks after treatment showed a recanalization of the SSS. In conclusion, findings of our case indicate that hypercoagulability may contribute to development of SSST in a patient with hyperthyroidism.
PMCID: PMC3491224  PMID: 23210057
Cerebral venous thrombosis; Superior sagittal sinus; Hyperthyroidism; Hypercoagulability
19.  Survey of the Application of the Korean Clinical Practice Recommendations on Breast Cancer Treatment: The Utility of the Korean Breast Cancer Society Guidelines 
Journal of Breast Cancer  2012;15(2):239-243.
This survey was performed to analyze the usability of the third edition of the Korean breast cancer clinical practice guidelines (KBCCPG) in clinical practice. We made a questionnaire composed of 18 general and 82 specific questions regarding benign breast disease (B; 1 question); non-invasive disease (N; 12 questions); early-stage disease (E; 26 questions); advanced disease (A; 24 questions); and metastatic (M) breast cancer-related problems (19 questions). A total of 100 questionnaires, with a link to an online survey, were delivered via e-mail to over 700 members of the Korean Breast Cancer Society (KBCS), and associated academy members, over 20 days between 26th February and 16th May 2010. Out of 270 respondents who read the e-mail, 96 answered the questionnaire. Participants included 87 surgical oncologists, 5 radiation oncologists, 2 oncoplastic surgeons, 1 pathologist, and 1 medical oncologist. The third KBCCPG were perceived as differing from the second guidelines in terms of the level of clinical evidence required before choosing a recommendation. For the progress of the KBCCPG, the guideline committee should try to reinforce all courses of guideline development with several elements including data from clinical trials of Korean breast cancer patients, securing a multidisciplinary approach, developing consistent and reasonable processes for each step of the revision of the guidelines, induction of liberal scientific and ethical discussion about all issues with all KBCS members. The cost-effectiveness of healthcare and the logical development of the KBCCPG would also be ensured. Timely updates of the clinical guidelines for breast cancer treatment are essential to facilitate optimal decision-making in daily practice, and to ensure adequate patient feedback.
PMCID: PMC3395749  PMID: 22807943
Breast neoplasms; Guideline; Korea; Surveys
20.  A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study 
Although approximately 25 common genetic susceptibility loci have been identified to be independently associated with breast cancer risk through genome-wide association studies (GWAS), the genetic risk variants reported to date only explain a small fraction of the heritability of breast cancer. Furthermore, GWAS-identified loci were primarily identified in women of European descent.
To evaluate previously identified loci in Korean women and to identify additional novel breast cancer susceptibility variants, we conducted a three-stage GWAS that included 6,322 cases and 5,897 controls.
In the validation study using Stage I of the 2,273 cases and 2,052 controls, seven GWAS-identified loci [5q11.2/MAP3K1 (rs889312 and rs16886165), 5p15.2/ROPN1L (rs1092913), 5q12/MRPS30 (rs7716600), 6q25.1/ESR1 (rs2046210 and rs3734802), 8q24.21 (rs1562430), 10q26.13/FGFR2 (rs10736303), and 16q12.1/TOX3 (rs4784227 and rs3803662)] were significantly associated with breast cancer risk in Korean women (Ptrend < 0.05). To identify additional genetic risk variants, we selected the most promising 17 SNPs in Stage I and replicated these SNPs in 2,052 cases and 2,169 controls (Stage II). Four SNPs were further evaluated in 1,997 cases and 1,676 controls (Stage III). SNP rs13393577 at chromosome 2q34, located in the Epidermal Growth Factor Receptor 4 (ERBB4) gene, showed a consistent association with breast cancer risk with combined odds ratios (95% CI) of 1.53 (1.37-1.70) (combined P for trend = 8.8 × 10-14).
This study shows that seven breast cancer susceptibility loci, which were previously identified in European and/or Chinese populations, could be directly replicated in Korean women. Furthermore, this study provides strong evidence implicating rs13393577 at 2q34 as a new risk variant for breast cancer.
PMCID: PMC3446390  PMID: 22452962
21.  Comparative profiling of plasma proteome from breast cancer patients reveals thrombospondin-1 and BRWD3 as serological biomarkers 
Breast cancer is the most common cancer in women worldwide. It is necessary to identify biomarkers for early detection, to make accurate prognoses, and to monitor for any recurrence of the cancer. In order to identify potential breast cancer biomarkers, we analyzed the plasma samples of women diagnosed with breast cancer and age-matched normal healthy women by mTRAQ-based stable isotope-labeling mass spectrometry. We identified and quantified 204 proteins including thrombospondin-1 (THBS1) and bromodomain and WD repeat-containing protein 3 (BRWD3) which were increased by more than 5-fold in breast cancer plasma. The plasma levels of the two proteins were evaluated by Western blot assay to confirm for their diagnostic value as serum markers. A 1.8-fold increase in BRWD3 was observed while comparing the plasma levels of breast cancer patients (n = 54) with age-matched normal healthy controls (n = 30), and the area under the receiver operating characteristic curve (AUC) was 0.917. THBS1 was detected in pooled breast cancer plasma at the ratio similar to mTRAQ ratio (> 5-fold). The AUC value for THBS1 was 0.875. The increase of THBS1 was more prominent in estrogen receptor negative and progesterone receptor negative patients than receptor-positive patients. Our results are evidence of the diagnostic value of THBS1 in detecting breast cancer. Based on our findings, we suggest a proteomic method for protein identification and quantification lead to effective biomarker discovery.
PMCID: PMC3277896  PMID: 22024541
biological markers; breast neoplasms; BRWD3 protein, human; mass spectrometry; proteomics; thrombospondin 1
22.  Comparative Study of Posterior Lumbar Interbody Fusion via Unilateral and Bilateral Approaches in Patients with Unilateral Leg Symptoms 
We investigated the clinical and radiological advantages of unilateral laminectomy in posterior lumbar interbody fusion (PLIF) procedure comparing with bilateral laminectomy, under the same procedural condition including bilateral instrumentation and insertion of two cages, in patients with degenerative lumbar disease with unilateral leg symptoms.
We retrospectively reviewed 124 consecutive cases of PLIF via unilateral or bilateral approach between January 2006 and April 2010. In 80 cases (bilateral group), two cages were inserted via bilateral laminectomy, and in 44 cases (unilateral group), via unilateral laminectomy. The average follow-up duration was 29.5 months. The clinical outcomes were evaluated with the Visual Analogue Scale (VAS) and the Oswestry disability index (ODI). The fusion rates and disc space heights were determined by dynamic standing radiographs and/or computed tomography. Operative times, intra-operative and post-operative blood losses and hospitalization periods were also evaluated.
In clinical evaluation, the VAS and ODI scores showed excellent outcomes in both groups. There were no significant differences in term of fusion rate, but the perioperative blood loss and the operative time of the unilateral group were lower than that of the bilateral group.
Unilateral laminectomy can minimize the operative time and perioperative blood loss in PLIF procedure. However, the different preoperative disc height between two groups is a limitation of this study. Despite this limitation, solid fusion and satisfactory symptomatic improvement could be achieved uniquely by our surgical method. This surgical method can be an alternative surgical technique in patients with unilateral leg pain.
PMCID: PMC3243841  PMID: 22200020
Posterior lumbar interbody fusion; Iatrogenic root injury; Unilateral approach; Unilateral leg symptoms
23.  Conductive cable fibers with insulating surface prepared by co-axial electrospinning of multi-walled nanotubes and cellulose 
Biomacromolecules  2010;11(9):2440-2445.
A core-sheath of multi-walled carbon nanotube (MWNT)-cellulose fibers of diameters from several hundreds nm to several µm were prepared by co-axial electrospinning from a non-valatile, non-flammable ionic liquid (IL) solvent, 1-methyl-3-methylimidazolium acetate ([EMIM][Ac]). MWNTs were dispersed in IL to form a gel solution. This gel core solution was electrospun surrounded by a sheath solution of cellulose disolved in the same IL. Electrospun fibers were collected in a coagulation bath containing ethanol-water to completely remove the IL and dried to form a core-sheath MWNT-cellulose fibers having a cable structure with a conductive core and insulating sheath. Enzymatic treatment of a portion of a mat of these fibers with cellulase selectively removed the cellulose sheath exposing the MWNT core for connection to an electrode. These MWNT-cellulose fiber mats demonstrated excellent conductivity due to a conductive pathway of bundleled MWNTs. Fiber mat conductivity increased with increasing ratio of MWNT in the fibers with a maximum conductivity of 10.7 S/m obtained at 45 wt% MWNT loading.
PMCID: PMC2939169  PMID: 20690644
24.  Vitamin D Deficiency is Correlated with Poor Outcomes in Patients with Luminal-type Breast Cancer 
Annals of Surgical Oncology  2010;18(7):1830-1836.
Vitamin D deficiency may be an indicator of poor prognosis in patients with breast cancer before surgery. We investigated the association between serum vitamin D concentration and breast cancer prognosis according to intrinsic cancer subtypes.
From June to December 2006, serum 25-OHD was measured in 310 Korean women with breast cancer who were treated at the Asan Medical Center, Korea. Clinicopathologic data were examined to determine the prognostic effects of serum 25-OHD. Expression of estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (Her2) were measured using tissue microarrays. Patients were classified with luminal A, luminal B, Her2-enriched, or basal-like subtypes of breast cancer.
Mean patient age was 48.7 years, and mean serum 25-OHD concentration was 31.4 ± 16.1 ng/ml. The 25-OHD levels were deficient (< 20 ng/ml) in 75 patients (24.2%), insufficient (20–29 ng/ml) in 95 (30.6%), and sufficient (30–150 ng/ml) in 140 (45.2%). Women with deficient 25-OHD levels were at increased risk of recurrence compared with those with sufficient vitamin D levels (P = 0.002). The 25-OHD concentration was inversely associated with prognosis of patients with cancer of the luminal A (P = 0.012) and luminal B subtypes (P = 0.023), but not with the prognosis of patients with Her2/neu-enriched (P = 0.245) or triple-negative (P = 0.879) cancer subtypes. This association remained valid after adjustment for age, tumor size, nodal status, and estrogen receptor status (hazards ratio = 3.97; 95% confidence interval = 1.77–9.61).
Vitamin D deficiency may be associated with poor outcomes in patients with luminal-type breast cancer.
PMCID: PMC3115047  PMID: 21573699
25.  Comparison of Fusion with Cage Alone and Plate Instrumentation in Two-Level Cervical Degenerative Disease 
This study assessed the efficacy of anterior cervical discectomy and fusion (ACDF) with cage alone compared with ACDF with plate instrumentation for radiologic and clinical outcomes in two-level cervical degenerative disease.
Patients with cervical degenerative disc disease from September 2004 to December 2009 were assessed retrospectively. A total of 42 patients received all ACDF at two-level cervical lesion. Twenty-two patients who underwent ACDF with cage alone were compared with 20 patients who underwent ACDF with plate fixation in consideration of radiologic and clinical outcomes. Clinical outcomes were assessed using Robinson's criteria and posterior neck pain, arm pain described by a 10 point-visual analog scale. Fusion rate, subsidence, kyphotic angle, instrument failure and the degenerative changes in adjacent segments were examined during each follow-up examination.
VAS was checked during each follow-up and Robinson's criteria were compared in both groups. Both groups showed no significant difference. Fusion rates were 90.9% (20/22) in ACDF with the cage alone group, 95% (19/20) in ACDF with the plate fixation group (p = 0.966). Subsidence rates of ACDF with cage alone were 31.81% (7/22) and ACDF with plate fixation were 30% (6/20) (p = 0.928). Local and regional kyphotic angle difference showed no significant difference. At the final follow-up, adjacent level disease developed in 4.54% (1/22) of ACDF with cage alone and 10% (2/20) of ACDF with plate fixation (p = 0.654).
In two-level ACDF, ACDF with cage alone would be comparable with ACDF with plate fixation with regard to clinical outcome and radiologic result with no significant difference. We suggest that the routine use of plate and screw in 2-level surgery may not be beneficial.
PMCID: PMC2982913  PMID: 21113362
ACDF with cage alone; ACDF with plate fixation; Fusion rate; Subsidence; Adjacent level degeneration

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