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1.  Adjuvant Chemotherapy Correlates with Improved Survival after Radical Cystectomy in Patients with pT3b (Macroscopic Perivesical Tissue Invasion) Bladder Cancer 
Journal of Cancer  2015;6(8):750-758.
Object: To elucidate the impact of adjuvant chemotherapy (ACH) on survival in patients with urothelial carcinoma of the bladder (UCB) diagnosed with pT3 disease (perivesical tissue invasion).
Methods: We reviewed the clinical data of 424 patients who underwent radical cystectomy (RC) with bilateral pelvic lymphadenectomy for UCB in our institution between 1991 and 2012. None of the patients received neoadjuvant chemotherapy. Of all patients, 101 (23.8%) were diagnosed with pT3 disease: pT3a in 43 patients and pT3b in 58 patients. The Kaplan-Meier method with the log-rank test was used to estimate and compare overall survival (OS) and cancer-specific survival (CSS) between groups. Multivariate Cox proportional hazard models were used to identify predictors of OS and CSS.
Results: Five-year OS (48.5% vs. 45.6%) and CSS (56.1% vs. 56.2%) were similar in the pT3a and pT3b groups (p = 0.658 and 0.840, respectively). In all pT3 patients, ACH administration was an independent predictor for OS (p = 0.018), but not CSS (p = 0.623) on multivariate analyses. On multivariate analysis according to the pT3 sub-stage, ACH was significantly associated with improved OS (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.17-0.72, p = 0.004) and CSS (HR 0.33; 95% CI 0.10-0.85, p = 0.022) in only the pT3b group.
Conclusion: Our data suggest that in pT3b disease, characterized by macroscopic perivesical tissue invasion, patients may obtain an OS benefit from the administration of ACH. Thus, our findings provide evidence for establishing appropriate indications for ACH in muscle invasive UCB.
PMCID: PMC4504111  PMID: 26185537
urothelial carcinoma; radical cystectomy; perivesical tissue invasion; adjuvant chemotherapy; survival
2.  Prognostic Factors for Recurrence and Progression in Korean Non-Muscle-Invasive Bladder Cancer Patients: A Retrospective, Multi-Institutional Study 
Yonsei Medical Journal  2016;57(4):855-864.
To identify the prognostic factors related to tumor recurrence and progression in Korean patients with non-muscle-invasive bladder cancer (NMIBC).
Materials and Methods
Data were collected and analyzed for 2412 NMIBC patients from 15 centers who were initially diagnosed after transurethral resection of bladder tumor (TURBT) from January 2006 to December 2010. Using univariable and multivariable Cox proportional hazards models, the prognostic value of each variable was evaluated for the time to first recurrence and progression.
With a median follow-up duration of 37 months, 866 patients (35.9%) experienced recurrence, and 137 (5.7%) experienced progression. Patients with recurrence had a median time to the first recurrence of 10 months. Multivariable analysis conducted in all patients revealed that preoperative positive urine cytology (PUC) was independently associated with worse recurrence-free survival [RFS; hazard ratio (HR) 1.56; p<0.001], and progression-free survival (PFS; HR 1.56; p=0.037). In particular, on multivariable analysis conducted for the high-risk group (T1 tumor/high-grade Ta tumor/carcinoma in situ), preoperative PUC was an independent predictor of worse RFS (HR 1.73; p<0.001) and PFS (HR 1.96; p=0.006). On multivariable analysis in patients with T1 high-grade (T1HG) cancer (n=684), better RFS (HR 0.75; p=0.033) and PFS (HR 0.33; p<0.001) were observed in association with the administration of intravesical Bacillus Calmette-Guérin (BCG) induction therapy.
A preoperative PUC result may adversely affect RFS and PFS, particularly in high-risk NMIBC patients. Of particular note, intravesical BCG induction therapy should be administered as an adjunct to TURBT in order to improve RFS and PFS in patients with T1HG cancer.
PMCID: PMC4951460  PMID: 27189277
Urinary bladder neoplasm; recurrence; disease progression; prognosis
3.  Prevalence and management status of urologic diseases in geriatric hospitals in South Korea: A field research 
We aimed to investigate the current management status of urologic diseases in geriatric hospitals in South Korea.
Materials and Methods
Questionnaire surveys and in-depth person-to-person interviews were conducted at 13 hospitals within the Seoul and Incheon areas.
The study was carried out from July to December 2014; 75.6% of patients (1,858/2,458) and 77.5% (779/1,031) of medical personnel responded to our survey. All surveys and interviews were performed by urology specialists, fellows, residents, or nurses. The hospitals included in the study had an average of 215.2 beds (range, 110–367), 189.1 patients (range, 90–345), and 40.2 nurses (range, 10–83). The average number of physicians was 6.2 (range, 3–11), but none of these were certified urologists. Only 4 hospitals provided consultation services for urological disorders. In total, 64% of patients had urological disorders, although only 20.7% of patients were receiving medication. Most patients were being treated using urological interventions; diapers (49.7%), indwelling catheters (19.5%), clean intermittent catheters (12.2%), and external collection urinary drainage (7.9%). However, most interventions were inadequately implemented, and only 17% of the patients had been examined by a certified urologist. Urological complications were found in 20.2% of patients, and secondary complications occurred in 18.8%. Excluding redundant cases, the total prevalence of urological complications was 39.0%.
Urologic diseases are poorly managed, and no certified urologists work in geriatric hospitals. Therefore, more designated urologists are needed in geriatric hospitals.
PMCID: PMC5240285  PMID: 28097271
Health services for the aged; Patient care management; Surveys and questionnaires; Urinary incontinence; Urological diseases
4.  Recurrence rate of stress urinary incontinence in females with initial cure after transobturator tape procedure at 3-year follow-up 
To assess recurrence rates of urinary incontinence in women with initial cure after transobturator tape (TOT) procedure at 3-year follow-up.
Materials and Methods
Between June 2006 and May 2013, a total of 402 consecutive patients underwent the TOT procedure for female stress urinary incontinence (SUI) at Dongguk University Ilsan Hospital. Of the 402 patients, 223 had sufficient medical records for analysis. Therefore, they were followed-up for 3 years postoperatively. Patient characteristics, urinary symptoms, physical examination, and urodynamic parameters were evaluated. The primary end point of “cure” was defined as the absence of any complaint of urinary leakage without needing pads for usual activities.
Of the 223 patients, 196 patients (87.9%) were initially cured within 6 months postoperatively. Of the 196 patients, 70 (35.7%) had recurrent urinary incontinence at 3 years postoperatively, 51 (26.0%) had SUI, 16 (8.2%) had urgency urinary incontinence, and 3 (1.5%) had mixed urinary incontinence. In univariate analysis, preoperative urinary obstructive symptom was found to significant contributor to the recurrence of urinary incontinence at 3-year postoperatively (p=0.004).
In our study, 35.7% of the women with initial cure after TOT experienced the recurrence of urinary leakage during the 3-year follow-up. The cure rate of TOT was decreased as time went by, although the initial cure rate was high.
PMCID: PMC5240289  PMID: 28097269
Recurrence; Suburethral slings; Urinary incontinence
5.  Active duty service members who sustain a traumatic brain injury have chronically elevated peripheral concentrations of Aβ40 and lower ratios of Aβ42/40 
Brain Injury  2016;30(12):1436-1441.
Primary objective: Excessive accumulation of amyloid beta (Aβ) and tau have been observed in older individuals with chronic neurological symptoms related to a traumatic brain injury (TBI), yet little is known about the possible role of Aβ in younger active duty service members following a TBI. The purpose of the study was to determine if Aβ 40 or 42 related to sustaining a TBI or to chronic neurological symptoms in a young cohort of military personnel.
Research design: This was a cross-sectional study of active duty service members who reported sustaining a TBI and provided self-report of neurological and psychological symptoms and provided blood.
Methods and procedures: An ultrasensitive single-molecule enzyme-linked immunosorbent assay was used to compare concentrations of Aβ in active duty service members with (TBI+; n = 53) and without (TBI–; n = 18) a history of TBI. Self-report and medical history were used to measure TBI occurrence and approximate the number of total TBIs and the severity of TBIs sustained during deployment.
Main outcomes and results: This study reports that TBI is associated with higher concentrations of Aβ40 (F 1,68 = 6.948, p = 0.009) and a lower ratio of Aβ42/Aβ40 (F 1,62 = 5.671, p = 0.020). These differences remained significant after controlling for co-morbid symptoms of post-traumatic stress disorder and depression.
Conclusions: These findings suggest that alterations in Aβ relate to TBIs and may contribute to chronic neurological symptoms.
PMCID: PMC5152557  PMID: 27834544
Traumatic brain injury; military; amyloid; tauopathies
6.  BCL2 as a Subtype-Specific Prognostic Marker for Breast Cancer 
Journal of Breast Cancer  2016;19(3):252-260.
B-cell lymphoma 2 (BCL2) is an antiapoptosis protein and an important clinical breast cancer prognostic marker. As the role of BCL2 is dependent on the estrogen receptor (ER) status, this effect might differ according to molecular subtypes. The aim of this study was to evaluate the relationship between the prognostic outcomes and BCL2 expression among the molecular subtypes.
We retrieved the data of 1,356 patients who were newly diagnosed with malignant breast cancer between November 2006 and November 2011. Immunohistochemistry was used to measure ER, progesterone receptor, human epidermal growth factor receptor 2 (HER2), Ki-67, and BCL2 expression. We classified breast cancer into five molecular subtypes based on the 13th St. Gallen International Expert Consensus, including luminal A, luminal B (HER2-negative), luminal B (HER2-positive), HER2-overexpression, and triple-negative subtypes. We analyzed the clinicopathological features and assessed the correlation between BCL2 expression and clinical outcomes, such as relapse-free survival (RFS) and disease-specific survival (DSS) according to the five molecular subtypes.
A total of 605 cases of breast cancer (53.8%) showed BCL2 expression. BCL2-positive expression was associated with young age (<50 years, p=0.036), lower histological grade (p<0.001), low Ki-67 level (<14%, p<0.001), hormone receptor positivity (p<0.001), HER2 negativity (p<0.001), luminal breast cancer (p<0.001), and low recurrence rate (p=0.016). BCL2-positive expression was also associated with favorable 5-year RFS (p=0.008, 91.4%) and DSS (p=0.036, 95.6%) in all the patients. BCL2-positive expression in luminal A breast cancer resulted in significantly favorable 5-year RFS and DSS (p=0.023 and p=0.041, respectively). However, BCL2 expression was not associated with the prognosis in the other subtypes.
The prognostic role of BCL2 expression in breast cancer is subtype-specific. BCL2 expression differs according to the molecular subtype and is a good prognostic marker for only luminal A breast cancer.
PMCID: PMC5053309  PMID: 27721874
B-cell lymphoma 2 protein; Breast neoplasms; Prognosis; Tumor biomarkers
7.  Perioperative Blood Transfusion as a Significant Predictor of Biochemical Recurrence and Survival after Radical Prostatectomy in Patients with Prostate Cancer 
PLoS ONE  2016;11(5):e0154918.
There have been conflicting reports regarding the association of perioperative blood transfusion (PBT) with oncologic outcomes including recurrence rates and survival outcomes in prostate cancer. We aimed to evaluate whether perioperative blood transfusion (PBT) affects biochemical recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS) following radical prostatectomy (RP) for patients with prostate cancer.
Materials and Methods
A total of 2,713 patients who underwent RP for clinically localized prostate cancer between 1993 and 2014 were retrospectively analyzed. We performed a comparative analysis based on receipt of transfusion (PBT group vs. no-PBT group) and transfusion type (autologous PBT vs. allogeneic PBT). Univariate and multivariate Cox-proportional hazard regression analysis were performed to evaluate variables associated with BRFS, CSS, and OS. The Kaplan-Meier method was used to calculate survival estimates for BRFS, CSS, and OS, and log-rank test was used to conduct comparisons between the groups.
The number of patients who received PBT was 440 (16.5%). Among these patients, 350 (79.5%) received allogeneic transfusion and the other 90 (20.5%) received autologous transfusion. In a multivariate analysis, allogeneic PBT was found to be statistically significant predictors of BRFS, CSS, and OS; conversely, autologous PBT was not. The Kaplan-Meier survival analysis showed significantly decreased 5-year BRFS (79.2% vs. 70.1%, log-rank, p = 0.001), CSS (98.5% vs. 96.7%, log-rank, p = 0.012), and OS (95.5% vs. 90.6%, log-rank, p < 0.001) in the allogeneic PBT group compared to the no-allogeneic PBT group. In the autologous PBT group, however, none of these were statistically significant compared to the no-autologous PBT group.
We found that allogeneic PBT was significantly associated with decreased BRFS, CSS, and OS. This provides further support for the immunomodulation hypothesis for allogeneic PBT.
PMCID: PMC4861293  PMID: 27159369
8.  Conditional Survival and Associated Prognostic Factors in Patients with Upper Tract Urothelial Carcinoma after Radical Nephroureterectomy: A Retrospective Study at a Single Institution 
The purpose of this study is to evaluate the changes of conditional survival (CS) probabilities and to identify the prognostic parameters that significantly affect CS over time post-surgery in upper tract urothelial carcinoma (UTUC) patients.
Materials and Methods
A total of 330 patients were examined in the final analysis. Primary end point was conditional cancer-specific survival (CSS), overall survival (OS), and intravesical recurrence-free survival (IVRFS) after surgery. The Kaplan-Meier method was used for calculation of CS. Cox regression hazard ratio model was used to determine the predictors of CS.
UTUC patients who had already survived 5 years after radical nephroureterectomy had a more favorable CS probability in all given survivorships compared to those with shorter survival times. Patients with unfavorable pathologic features showed a higher increment of 5-year conditional CSS and OS compared to their counterparts. For 5-year conditional CSS, several factors, including high-grade tumor, lymphovascular invasion, and tumor location showed significant association with risk elevation over time. Only age remained as a predictor of 5-year conditional OS with increased risk in all given survivorships. For 5-year IVRFS, no variables remained as significant predictive factors over time after surgery.
Our study provides valuable information for practical survival estimation and relevant prognostic factors for patients with UTUC after surgery.
PMCID: PMC4843715  PMID: 26511817
Survival; Conditional variables; Transitional cell carcinoma; Urinary tract; Urologic surgical procedures
9.  Development of an Analysis Pipeline Characterizing Multiple Hypervariable Regions of 16S rRNA Using Mock Samples 
PLoS ONE  2016;11(2):e0148047.
There is much speculation on which hypervariable region provides the highest bacterial specificity in 16S rRNA sequencing. The optimum solution to prevent bias and to obtain a comprehensive view of complex bacterial communities would be to sequence the entire 16S rRNA gene; however, this is not possible with second generation standard library design and short-read next-generation sequencing technology.
This paper examines a new process using seven hypervariable or V regions of the 16S rRNA (six amplicons: V2, V3, V4, V6-7, V8, and V9) processed simultaneously on the Ion Torrent Personal Genome Machine (Life Technologies, Grand Island, NY). Four mock samples were amplified using the 16S Ion Metagenomics Kit™ (Life Technologies) and their sequencing data is subjected to a novel analytical pipeline.
Results are presented at family and genus level. The Kullback-Leibler divergence (DKL), a measure of the departure of the computed from the nominal bacterial distribution in the mock samples, was used to infer which region performed best at the family and genus levels. Three different hypervariable regions, V2, V4, and V6-7, produced the lowest divergence compared to the known mock sample. The V9 region gave the highest (worst) average DKL while the V4 gave the lowest (best) average DKL. In addition to having a high DKL, the V9 region in both the forward and reverse directions performed the worst finding only 17% and 53% of the known family level and 12% and 47% of the genus level bacteria, while results from the forward and reverse V4 region identified all 17 family level bacteria.
The results of our analysis have shown that our sequencing methods using 6 hypervariable regions of the 16S rRNA and subsequent analysis is valid. This method also allowed for the assessment of how well each of the variable regions might perform simultaneously. Our findings will provide the basis for future work intended to assess microbial abundance at different time points throughout a clinical protocol.
PMCID: PMC4734828  PMID: 26829716
10.  Systemic Inflammatory Response Based on Neutrophil-to-Lymphocyte Ratio as a Prognostic Marker in Bladder Cancer 
Disease Markers  2016;2016:8345286.
A growing body of evidence suggests that systemic inflammatory response (SIR) in the tumor microenvironment is closely related to poor oncologic outcomes in cancer patients. Over the past decade, several SIR-related hematological factors have been extensively investigated in an effort to risk-stratify cancer patients to improve treatment selection and to predict posttreatment survival outcomes in various types of cancers. In particular, one readily available marker of SIR is neutrophil-to-lymphocyte ratio (NLR), which can easily be measured on the basis of absolute neutrophils and absolute lymphocytes in a differential white blood cell count performed in the clinical setting. Many investigators have vigorously assessed NLR as a potential prognostic biomarker predicting pathological and survival outcomes in patients with urothelial carcinoma (UC) of the bladder. In this paper, we aim to present the prognostic role of NLR in patients with UC of the bladder through a thorough review of the literature.
PMCID: PMC4736380  PMID: 26880857
11.  Knowledge and Practice Behaviors Regarding Urinary Incontinence Among Korean Healthcare Providers in Long-term Care Hospitals 
The purpose of this study was to assess the current management status of patients with urological issues and to examine the level of knowledge and practice behaviors regarding urinary incontinence (UI) among Korean healthcare providers in long-term care hospitals.
This study used a cross-sectional descriptive design with a written questionnaire to assess knowledge and practice behaviors of 756 healthcare providers in 11 long-term care hospitals in Korean metropolitan areas.
A total 42.6% of participants reported that more than 50% of patients had urologic issues, and that 68.1% of patients were regularly sent to urologists; no participants reported an on-site urologist in their facility. Participants identified collaboration with other hospitals and regular consultations by urologists as important factors in improving urologic care. Although the overall UI knowledge score was upper intermediate, a knowledge deficit was found for risk factors of UI. The knowledge level of physicians was significantly higher than that of other healthcare providers. Practice behaviors of nurses seemed to be better than those of other healthcare providers.
Systematic collaboration between healthcare providers and urologic specialists, enhancing staff competence, and patient-tailored intervention should be recommended to improve quality of care for patients with urologic issues in long-term care hospitals.
PMCID: PMC4703933  PMID: 26739180
Urinary Incontinence; Knowledge; Professional Practice; Health Personnel; Long-Term Care
12.  Adjuvant chemotherapy for locally advanced upper tract urothelial carcinoma: updated results of the Seoul National university hospital experience 
The objective of this study was to update the long-term outcome in the treatment of locally advanced upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU) regarding the role of adjuvant chemotherapy.
Materials and methods:
Clinical data from 138 patients who underwent RNU for locally advanced UTUC (pT3/4 or pN+) were analyzed.
The adjuvant chemotherapy group comprised 66 patients, and other 72 patients did not receive adjuvant chemotherapy. Cisplatin-based chemotherapy was the most common regimen, depending on the patient's eligibility and renal function. The median follow-up period was 48.7 months (interquartile range: 29.2-96.9 months). The 3-and 5-year disease-specific survival (DSS) rates were 76.0% and 69.9% for the non-adjuvant chemotherapy group versus 74.6% and 54.5% for the adjuvant chemotherapy group (p=0.301, log-rank test). Overall survival (OS) rates for the same time period were 70.1% and 62.9% for the non-adjuvant chemotherapy group versus 73.8% and 53.2% for the adjuvant chemotherapy group (p=0.931, log-rank test). On multivariate analysis, adjuvant chemotherapy could not predict DSS and OS after surgery. When patients who received cisplatin-based adjuvant chemotherapy (n=59) were compared to those who did not receive adjuvant chemotherapy, similar results were found.
There does not appear to be a significant DSS or OS benefit associated with adjuvant chemotherapy. Prospective randomized clinical trials are necessary to verify the effect of adjuvant chemotherapy on locally advanced UTUC.
PMCID: PMC4756931  PMID: 26742963
Urinary Tract; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Survival
13.  The clinical application of the sliding loop technique for renorrhaphy during robot-assisted laparoscopic partial nephrectomy: Surgical technique and outcomes 
Korean Journal of Urology  2015;56(11):762-768.
To report the initial clinical outcomes of the newly devised sliding loop technique (SLT) used for renorrhaphy in patients who underwent robot-assisted laparoscopic partial nephrectomy (RALPN) for small renal mass.
Materials and Methods
We reviewed the surgical videos and medical charts of 31 patients who had undergone RALPN with the SLT renorrhaphy performed by two surgeons (CWJ and CK) between January 2014 and October 2014. SLT renorrhaphy was performed after tumor excision and renal parenchymal defect repair. Assessed outcomes included renorrhaphy time (RT), warm ischemic time, perioperative complications, and perioperative renal function change. RT was defined as interval from the end of bed suture to the renal artery declamping.
In all patients, sliding loop renorrhaphy was successfully conducted without conversions to radical nephrectomy or open approaches. Mean renorrhaphy and warm ischemic time were 9.0 and 22.6 minutes, respectively. After completing renorrhaphy, there were no adverse events such as dehiscence of approximated renal parenchyma, renal parenchymal tearing, or significant bleeding. Furthermore, no postoperative complications or significant renal function decline were observed as of the last follow-up for all patients. The limitations of this study include the small volume case series, the retrospective nature of the study, and the heterogeneity of surgeons.
From our initial clinical experience, SLT may be an efficient and safe renorrhaphy method in real clinical practice. Further large scale, prospective, long-term follow-up, and direct comparative studies with other techniques are required to confirm the clinical applicability of SLT.
PMCID: PMC4643172  PMID: 26568794
Nephrectomy; Renorrhphy; Small renal mass; Technique
14.  Highly efficient organic light emitting diodes formed by solution processed red emitters with evaporated blue common layer structure 
Scientific Reports  2015;5:15903.
We prepared highly-efficient solution-processed red phosphorescent organic light emitting diodes (PHOLEDs) with a blue common layer structure that can reasonably confine the triplet excitons inside of the red emission layer (EML) with the assistance of a bipolar exciton blocking layer. The red PHOLEDs containing EML with a 7 : 3 ratio of 11-(4,6-diphenyl-[1,3,5]triazin-2-yl)-12-phenyl-11,12-dihydro-11,12-diaza-indeno[2,1-a]fluorene (n-type host, NH) : 4-(3-(triphenylen-2-yl)phenyl)dibenzo[b,d]thiophene (p-type host, PH) doped with 5% Iridium(III) bis(2-(3,5-dimethylphenyl)quinolinato-N,C2’)tetramethylheptadionate (Red Dopant, RD) produced the highest current and power efficiencies at 23.4 cd/A and 13.6 lm/W, with a 19% external quantum efficiency at 1000 cd/m2. To the best of our knowledge, such efficiency was the best among those that have been obtained from solution-processed small molecular red PHOLEDs. In addition, the host molecules utilized in this study have no flexible spacers, such as an alkyl chain, which normally deteriorate the stability of the device.
PMCID: PMC4626861  PMID: 26514274
15.  A Representational Similarity Analysis of the Dynamics of Object Processing Using Single-Trial EEG Classification 
PLoS ONE  2015;10(8):e0135697.
The recognition of object categories is effortlessly accomplished in everyday life, yet its neural underpinnings remain not fully understood. In this electroencephalography (EEG) study, we used single-trial classification to perform a Representational Similarity Analysis (RSA) of categorical representation of objects in human visual cortex. Brain responses were recorded while participants viewed a set of 72 photographs of objects with a planned category structure. The Representational Dissimilarity Matrix (RDM) used for RSA was derived from confusions of a linear classifier operating on single EEG trials. In contrast to past studies, which used pairwise correlation or classification to derive the RDM, we used confusion matrices from multi-class classifications, which provided novel self-similarity measures that were used to derive the overall size of the representational space. We additionally performed classifications on subsets of the brain response in order to identify spatial and temporal EEG components that best discriminated object categories and exemplars. Results from category-level classifications revealed that brain responses to images of human faces formed the most distinct category, while responses to images from the two inanimate categories formed a single category cluster. Exemplar-level classifications produced a broadly similar category structure, as well as sub-clusters corresponding to natural language categories. Spatiotemporal components of the brain response that differentiated exemplars within a category were found to differ from those implicated in differentiating between categories. Our results show that a classification approach can be successfully applied to single-trial scalp-recorded EEG to recover fine-grained object category structure, as well as to identify interpretable spatiotemporal components underlying object processing. Finally, object category can be decoded from purely temporal information recorded at single electrodes.
PMCID: PMC4546653  PMID: 26295970
16.  Trends in the Use of Chemotherapy before and after Radical Cystectomy in Patients with Muscle-invasive Bladder Cancer in Korea 
Journal of Korean Medical Science  2015;30(8):1150-1156.
We investigated trends in perioperative chemotherapy use, and determined factors associated with neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (AC) use in Korean patients with muscle-invasive bladder cancer (MIBC). We recruited 1,324 patients who had MIBC without nodal invasion or metastases and had undergone radical cystectomies (RC) between 2003 and 2013. The study's cut-off time for AC was three months after surgery, and the study's timespan was divided into three periods based on NAC use, namely, 2003-2005, 2006-2009, and 2010-2013. Complete remission was defined as histologically confirmed T0N0M0 after RC. NAC and AC were administered to 7.3% and 18.1% of the patients, respectively. The median time interval between completing NAC and undergoing RC was 32 days and the mean number of cycles was 3.2. The median time interval between RC and AC was 43 days and the mean number of cycles was 4.1. Gemcitabine and cisplatin were most frequently used in combination for NAC (49.0%) and AC (74.9%). NAC use increased significantly from 4.6% between 2003 and 2005 to 8.4% between 2010 and 2013 (P < 0.05), but AC use did not increase. Only 1.9% of patients received NAC and AC. Complete remission after NAC was achieved in 12 patients (12.5%). Multivariable modeling revealed that an advanced age, the earliest time period analyzed, and clinical tumor stage ≤ cT2 bladder cancer were negatively associated with NAC use (P < 0.05). While NAC use has slowly increased over time, it remains an underutilized therapeutic approach in Korean clinical practice.
PMCID: PMC4520947  PMID: 26240494
Urinary Bladder Neoplasms; Neoadjuvant Therapy; Adjuvant; Chemotherapy; Cystectomy
17.  Predictors of Neurocognitive Syndromes in Combat Veterans 
Cureus  null;7(7):e293.
Traumatic brain injury, depression and posttraumatic stress disorder (PTSD) are neurocognitive syndromes often associated with impairment of physical and mental health, as well as functional status. These syndromes are also frequent in military service members (SMs) after combat, although their presentation is often delayed until months after their return. The objective of this prospective cohort study was the identification of independent predictors of neurocognitive syndromes upon return from deployment could facilitate early intervention to prevent disability. We completed a comprehensive baseline assessment, followed by serial evaluations at three, six, and 12 months, to assess for new-onset PTSD, depression, or postconcussive syndrome (PCS) in order to identify baseline factors most strongly associated with subsequent neurocognitive syndromes. On serial follow-up, seven participants developed at least one neurocognitive syndrome: five with PTSD, one with depression and PTSD, and one with PCS. On univariate analysis, 60 items were associated with syndrome development at p < 0.15. Decision trees and ensemble tree multivariate models yielded four common independent predictors of PTSD: right superior longitudinal fasciculus tract volume on MRI; resting state connectivity between the right amygdala and left superior temporal gyrus (BA41/42) on functional MRI; and single nucleotide polymorphisms in the genes coding for myelin basic protein as well as brain-derived neurotrophic factor. Our findings require follow-up studies with greater sample size and suggest that neuroimaging and molecular biomarkers may help distinguish those at high risk for post-deployment neurocognitive syndromes.
PMCID: PMC4524772  PMID: 26251769
traumatic brain injury; depression; posttraumatic stress disorder; combat military veterans; neuroimaging; biomarkers
18.  Lymph node density as a prognostic variable in node-positive bladder cancer: a meta-analysis 
BMC Cancer  2015;15:447.
Although lymph node (LN) status and the LN burden determine the outcome of bladder cancer patients treated with cystectomy, compelling arguments have been made for the incorporation of LN density into the current staging system. Here, we investigate the relationship between LN density and clinical outcome in patients with LN-positive disease, following radical cystectomy for bladder cancer.
PubMed, SCOPUS, the Institute for Scientific Information Web of Science, and the Cochrane Library were searched to identify relevant published literature.
Fourteen studies were included in the meta-analysis, with a total number of 3311 patients. Of these 14 publications, 6 studies, (533 patients), 10 studies (2966 patients), and 5 studies (1108 patients) investigated the prognostic association of LN density with disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS), respectively. The pooled hazard ratio (HR) for DFS was 1.45 (95 % confidence interval [CI], 1.10–1.91) without heterogeneity (I2 = 0 %, p = 0.52). Higher LN density was significantly associated with poor DSS (pooled HR, 1.53; 95 % CI, 1.23–1.89). However, significant heterogeneity was found between studies (I2 = 66 %, p = 0.002). The pooled HR for OS was statistically significant (pooled HR, 1.45; 95 % CI, 1.11–1.90) without heterogeneity (I2 = 42 %, p = 0.14). The results of the Begg and Egger tests suggested that publication bias was not evident in this meta-analysis.
The data from this meta-analysis indicate that LN density is an independent predictor of clinical outcome in LN-positive patients. LN density may be useful in future staging systems, thus allowing better prognostic classification of LN-positive bladder cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1448-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4450458  PMID: 26027955
Bladder cancer; Meta-analysis; Lymph node density; Prognosis; Radical cystectomy
19.  Histological variant as the significant predictor of survival in patients with lymph node positive urothelial carcinoma of the bladder 
Scientific Reports  2015;5:9626.
The aim of this study was to evaluate the impact of histological variants of urothelial carcinoma (UC) on survival outcomes in patients with lymph node (LN) positive UC of the bladder. We reviewed and analyzed the clinical data from 424 patients who underwent radical cystectomy (RC) with pelvic lymph node dissection (PLND) for UC of the bladder and who did not receive neoadjuvant chemotherapy in our institution between 1991 and 2012. In total, 92 patients (21.7%) had histologically confirmed LN positive disease. In the LN negative group (332 patients), histological variants of UC were not a significant predictor in univariate analysis. However, in the LN positive group, histological variants of UC were a significant independent prognostic factor of overall survival (hazard ratio (HR) 3.54; 95% confidence interval (CI) 1.77–7.08, p < 0.001) and cancer specific survival (HR 3.66; 95% CI 1.69–7.90, p = 0.001) in both uni-variate and multivariate Cox regression analyses. The presence of histological variants of UC may indicate a worse prognosis in LN positive patients after RC with PLND for UC of the bladder and more aggressive adjuvant therapy may be required for the improvement of postoperative survival.
PMCID: PMC4427059  PMID: 25959144
20.  The prognostic impact of perioperative blood transfusion on survival in patients with bladder urothelial carcinoma treated with radical cystectomy 
Korean Journal of Urology  2015;56(4):295-304.
The aim of our study was to assess the influence of perioperative blood transfusion (PBT) on survival outcomes following radical cystectomy (RC) and pelvic lymph node dissection (PLND).
Materials and Methods
We reviewed and analyzed the clinical data of 432 patients who underwent RC for bladder cancer from 1991 to 2012. PBT was defined as the transfusion of allogeneic red blood cells during RC or postoperative hospitalization.
Of all patients, 315 patients (72.9%) received PBT. On multivariate logistic regression analysis, female gender (p=0.015), a lower preoperative hemoglobin level (p=0.003), estimated blood loss>800 mL (p<0.001), and performance of neoadjuvant chemotherapy (p<0.001) were independent risk factors related to requiring perioperative transfusions. The receipt of PBT was associated with increased overall mortality (hazard ratio, 1.91; 95% confidence interval, 1.25-2.94; p=0.003) on univariate analysis, but its association was not confirmed by multivariate analysis (p=0.058). In transfused patients, a transfusion of >4 packed red blood cell units was an independent predictor of overall survival (p=0.007), but not in cancer specific survival.
Our study was not conclusive to detect a clear association between PBT and survival after RC. However, the efforts should be made to continue limiting the overuse of transfusion especially in patients who are expected to have a high probability of PBT, such as females and those with a low preoperative hemoglobin level and history of neoadjuvant chemotherapy.
PMCID: PMC4392029  PMID: 25874043
Blood transfusion; Cystectomy; Survival; Urinary bladder neoplasms
21.  Disease-Free Survival at 2 and 3 Years is a Significant Early Surrogate Marker Predicting the 5-Year Overall Survival in Patients Treated with Radical Cystectomy for Urothelial Carcinoma of the Bladder: External Evaluation and Validation in a Cohort of Korean Patients 
Frontiers in Oncology  2015;5:246.
We aimed to externally validate the association of 2- and 3-year disease-free survival (DFS) with 5-year overall survival (OS) in patients treated with radical cystectomy (RC) for urothelial carcinoma (UC) of the bladder.
Materials and Methods
We reviewed the clinical data of 422 patients who underwent RC for UC of the bladder in our institution between 1991 and 2012. Survival curves were plotted with the Kaplan–Meier method. The Kappa statistic and Kendall tau-b test were used to assess the agreements between 2- and 3-year DFS and 5-year OS.
In the entire study population, 2- and 3-year DFS and 5-year OS rates were 76.4, 71.5, and 67.4%, respectively. All Kappa and Kendall’s tau-b test values for agreements between 2- and 3-year DFS and 5-year OS were more than 0.40, indicating moderate agreement for all patients and in each patient subgroup selected according to specific variables (all p-values <0.05). Kaplan–Meier analysis for DFS and Cox-proportional hazard models for landmark analysis at each time point indicated that most recurrences occurred within 3 years after surgery. The 5-year OS rates of patients who were recurrence-free at each time point gradually increased to more than 95% in an extended recurrence-free interval of 12–36 months.
Our external validation results support the existing finding that 2- and 3-year DFS can be a valid early surrogate end point to predict 5-year OS after RC in patients with UC of the bladder.
PMCID: PMC4625059  PMID: 26579498
urothelial carcinoma; radical cystectomy; surrogate; disease-specific survival; overall survival
22.  MicroRNA-22 and promoter motif polymorphisms at the Chga locus in genetic hypertension: functional and therapeutic implications for gene expression and the pathogenesis of hypertension 
Human Molecular Genetics  2013;22(18):3624-3640.
Hypertension is a common hereditary syndrome with unclear pathogenesis. Chromogranin A (Chga), which catalyzes formation and cargo storage of regulated secretory granules in neuroendocrine cells, contributes to blood pressure homeostasis centrally and peripherally. Elevated Chga occurs in spontaneously hypertensive rat (SHR) adrenal glands and plasma, but central expression is unexplored. In this report, we measured SHR and Wistar–Kyoto rat (control) Chga expression in central and peripheral nervous systems, and found Chga protein to be decreased in the SHR brainstem, yet increased in the adrenal and the plasma. By re-sequencing, we systematically identified five promoter, two coding and one 3′-untranslated region (3′-UTR) polymorphism at the SHR (versus WKY or BN) Chga locus. Using HXB/BXH recombinant inbred (RI) strain linkage and correlations, we demonstrated genetic determination of Chga expression in SHR, including a cis-quantitative trait loci (QTLs) (i.e. at the Chga locus), and such expression influenced biochemical determinants of blood pressure, including a cascade of catecholamine biosynthetic enzymes, catecholamines themselves and steroids. Luciferase reporter assays demonstrated that the 3′-UTR polymorphism (which disrupts a microRNA miR-22 motif) and promoter polymorphisms altered gene expression consistent with the decline in SHR central Chga expression. Coding region polymorphisms did not account for changes in Chga expression or function. Thus, we hypothesized that the 3′-UTR and promoter mutations lead to dysregulation (diminution) of Chga in brainstem cardiovascular control nuclei, ultimately contributing to the pathogenesis of hypertension in SHR. Accordingly, we demonstrated that in vivo administration of miR-22 antagomir to SHR causes substantial (∼18 mmHg) reductions in blood pressure, opening a novel therapeutic avenue for hypertension.
PMCID: PMC3749858  PMID: 23674521
23.  Multifactorial, Site-Specific Recurrence Models after Radical Cystectomy for Urothelial Carcinoma: External Validation in a Cohort of Korean Patients 
PLoS ONE  2014;9(6):e100491.
The aim of this study was to evaluate the accuracy of site-specific recurrence models after radical cystectomy in the Korean population.
Materials and Methods
We conducted a review of an electronic medical record of 572 patients who underwent radical cystectomy for urothelial carcinoma of the bladder. Primary end point was the site-specific recurrence after radical cystectomy.
The median follow-up in the validation cohort was 42.3 months (interquartile range: 23.0–89.3 months). During the follow-up period, there were 165 patients (28.8%), 85 (14.9%), 31 (5.4%), and 78 (13.6%) who recurred in abdomen/pelvis, thoracic region, upper urinary tract, and bone, respectively. The c-indices of abdomen/pelvis, thoracic region, upper urinary tract, and bone models 3 years after radical cystectomy were 0.69 (95% confidence interval [CI], 0.65–0.73), 0.69 (95% CI, 0.64–0.75), 0.61 (95% CI, 0.52–0.69), and 0.65 (95% CI, 0.59–0.71), respectively. Kaplan-Meier curves demonstrated that models discriminated well and log-rank test were all highly significant (all p<0.001), except upper urinary tract model (p = 0.366). Decision curve analysis revealed that the use of prediction models for abdomen/pelvis, thoracic region, and bone recurrence was associated with net benefit gains relative to the treat-all strategy, but not the model for upper urinary tract recurrence.
Abdomen/pelvis, thoracic region, and bone models demonstrate moderate discrimination, adequate calibration, and meaningful net benefit gains, whereas upper urinary tract model does not seem applicable to patients from Asia because it has suboptimal accuracy.
PMCID: PMC4061079  PMID: 24937260
24.  Quantitative Trait Loci Affecting Atherosclerosis at the Aortic Root Identified in an Intercross between DBA2J and 129S6 Apolipoprotein E-Null Mice 
PLoS ONE  2014;9(2):e88274.
Apolipoprotein E-null mice on a DBA/2J genetic background (DBA-apoE) are highly susceptible to atherosclerosis in the aortic root area compared with those on a 129S6 background (129-apoE). To explore atherosclerosis-responsible genetic regions, we performed a quantitative trait locus (QTL) analysis using 172 male and 137 female F2 derived from an intercross between DBA-apoE and 129-apoE mice. A genome-wide scan identified two significant QTL for the size of lesions at the root: one is Ath44 on Chromosome (Chr) 1 at 158 Mb, and the other Ath45 on Chr 2 at 162 Mb. Ath44 co-localizes with but appears to be independent of a previously reported QTL, Ath1, while Ath45 is a novel QTL. DBA alleles of both Ath44 and Ath45 confer atherosclerosis-susceptibility. In addition, a QTL on Chr 14 at 73 Mb was found significant only in males, and 129 allele conferring susceptibility. Further analysis detected female-specific interactions between a second QTL on Chr 1 at 73 Mb and a QTL on Chr 3 at 21 Mb, and between Chr 7 at 84 Mb and Chr 12 at 77 Mb. These loci for the root atherosclerosis were independent of QTLs for plasma total cholesterol and QTLs for triglycerides, but a QTL for HDL (Chr 1 at 126 Mb) overlapped with the Ath44. Notably, haplotype analysis among 129S6, DBA/2J and C57BL/6 genomes and their gene expression data narrowed the candidate regions for Ath44 and Ath45 to less than 5 Mb intervals where multiple genome wide associations with cardiovascular phenotypes have also been reported in humans. SNPs in or near Fmo3, Sele and Selp for Ath44, and Lbp and Pkig for Ath45 were suggested for further investigation as potential candidates underlying the atherosclerosis susceptibility.
PMCID: PMC3930552  PMID: 24586312
25.  Heredity and cardiometabolic risk: naturally occurring polymorphisms in the human neuropeptide Y2 receptor promoter disrupt multiple transcriptional response motifs 
Journal of hypertension  2013;31(1):123-133.
The neuropeptide Y2 G-protein-coupled receptor (NPY2R) relays signals from PYY or neuropeptide Y toward satiety and control of body mass. Targeted ablation of the NPY2R locus in mice yields obesity, and studies of NPY2R promoter genetic variation in more than 10 000 human participants indicate its involvement in control of obesity and BMI. Here we searched for genetic variation across the human NPY2R locus and probed its functional effects, especially in the proximal promoter.
Methods and results
Twin pair studies indicated substantial heritability for multiple cardiometabolic traits, including BMI, SBP, DBP, and PYY, an endogenous agonist at NPY2R. Systematic polymorphism discovery by resequencing across NPY2R uncovered 21 genetic variants, 10 of which were common [minor allele frequency (MAF) >5%], creating one to two linkage disequilibrium blocks in multiple biogeographic ancestries. In vivo, NPY2R haplotypes were associated with both BMI (P =3.75E–04) and PYY (P =4.01E–06). Computational approaches revealed that proximal promoter variants G-1606A, C-599T, and A-224G disrupt predicted IRF1 (A>G), FOXI1 (T>C), and SNAI1 (A>G) response elements. In neuroendocrine cells transfected with NPY2R promoter/luciferase reporter plasmids, all three variants and their resulting haplotypes influenced transcription (G-1606A, P <2.97E–06; C-599T, P <1.17E–06; A-224G, P <2.04E–06), and transcription was differentially augmented or impaired by coexpression of either the cognate full-length transcription factors or their specific siRNAs at each site. Endogenous expression of transcripts for NPY2R, IRF1, and SNAI1 was documented in neuroendocrine cells, and the NPY2R mRNA was differentially expressed in two neuroendocrine tissues (adrenal gland, brainstem) of a rodent model of hypertension and the metabolic syndrome, the spontaneously hypertensive rat.
We conclude that common genetic variation in the proximal NPY2R promoter influences transcription factor binding so as to alter gene expression in neuroendocrine cells, and consequently cardiometabolic traits in humans. These results unveil a novel control point, whereby cis-acting genetic variation contributes to control of complex cardiometabolic traits, and point to new transcriptional strategies for intervention into neuropeptide actions and their cardiometabolic consequences.
PMCID: PMC3615981  PMID: 23149563
autonomic; genetics; hypertension; nervous system; obesity

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