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1.  Periodical assessment of genitourinary and gastrointestinal toxicity in patients who underwent prostate low-dose-rate brachytherapy 
Background
To compare the periodical incidence rates of genitourinary (GU) and gastrointestinal (GI) toxicity in patients who underwent prostate low-dose-rate brachytherapy between the monotherapy group (seed implantation alone) and the boost group (in combination with external beam radiation therapy (EBRT)).
Methods
A total of 218 patients with a median follow-up of 42.5 months were enrolled. The patients were divided into 2 groups by treatment modality, namely, the monotherapy group (155 patients) and the boost group (63 patients). The periodical incidence rates of GU and GI toxicity were separately evaluated and compared between the monotherapy group and the boost group using the National Cancer Institute - Common Terminology Criteria for Adverse Events, version 3.0. To elucidate an independent factor among clinical and postdosimetric parameters to predict grade 2 or higher GU and GI toxicity in the acute and late phases, univariate and multivariate logistic regression analyses were carried out.
Results
Of all patients, 78.0% showed acute GU toxicity, and 7.8% showed acute GI toxicity, while 63.8% showed late GU toxicity, and 21.1% showed late GI toxicity. The incidence rates of late GU and GI toxicity were significantly higher in the boost group. Multivariate analysis showed that the International Prostate Symptom Score (IPSS) before seed implantation was a significant parameter to predict acute GU toxicity, while there were no significant predictive parameters for acute GI toxicity. On the other hand, combination with EBRT was a significant predictive parameter for late GU toxicity, and rectal volume (mL) receiving 100% of the prescribed dose (R100) was a significant predictive parameter for late GI toxicity.
Conclusions
The boost group showed higher incidence rates of both GU and GI toxicity. Higher IPSS before seed implantation, combination with EBRT and a higher R100 were significant predictors for acute GU, late GU and late GI toxicity.
doi:10.1186/1748-717X-8-25
PMCID: PMC3570431  PMID: 23363647
Prostate cancer; LDR-brachytherapy; GU toxicity; GI toxicity
2.  Inhibition of COX-2 expression by topical diclofenac enhanced radiation sensitivity via enhancement of TRAIL in human prostate adenocarcinoma xenograft model 
BMC Urology  2013;13:1.
Background
COX-2 inhibitors have an antitumor potential and have been verified by many researchers. Treatment of cancer cells with external stressors such as irradiation can stimulate the over-expression of COX-2 and possibly confer radiation resistance. In this study, we tested if topical diclofenac, which inhibits both COX-1 and COX-2, administration rendered prostate tumor cells sensitize to the effects of radiation.
Methods
LNCaP-COX-2 and LNCaP-Neo cells were treated with 0 to 1000 μM diclofenac. Next, a clonogenic assay was performed in which cells were subjected to irradiation (0 to 4 Gy) with or without diclofenac. COX-2 expression and other relevant molecules were measured by real-time PCR and immunohistochemistry after irradiation and diclofenac treatment. In addition, we assessed the tumor volumes of xenograft LNCaP-COX-2 cells treated with topical diclofenac with or without radiation therapy (RT).
Results
LNCaP-COX-2 and LNCaP-Neo cell lines experienced cytotoxic effects of diclofenac in a dose related manner. Clonogenic assays demonstrated that LNCaP-COX-2 cells were significantly more resistant to RT than LNCaP-Neo cells. Furthermore, the addition of diclofenac sensitized LNCaP-COX-2 not but LNCaP-Neo cells to the cytocidal effects of radiation. In LNCaP-COX-2 cells, diclofenac enhanced radiation-induced apoptosis compared with RT alone. This phenomenon might be attributed to enhancement of RT-induced TRAIL expression as demonstrated by real-time PCR analysis. Lastly, tumor volumes of LNCaP-COX-2 cells xenograft treated with diclofenac or RT alone was >4-fold higher than in mice treated with combined diclofenac and radiation (p<0.05).
Conclusions
These in vitro and in vivo findings suggest that conventional COX inhibitor, diclofenac enhances the effect of RT on prostate cancer cells that express COX-2. Thus, diclofenac may have potential as radiosensitizer for treatment of prostate cancer.
doi:10.1186/1471-2490-13-1
PMCID: PMC3561196  PMID: 23289871
Prostate cancer; Radiation therapy; COX-2; TRAIL; Apoptosis; Topical therapy; Radiosensitizer; Diclofenac; Radioresistance
3.  Minimal percentage of dose received by 90% of the urethra (%UD90) is the most significant predictor of PSA bounce in patients who underwent low-dose-rate brachytherapy (LDR-brachytherapy) for prostate cancer 
BMC Urology  2012;12:28.
Background
To clarify the significant clinicopathological and postdosimetric parameters to predict PSA bounce in patients who underwent low-dose-rate brachytherapy (LDR-brachytherapy) for prostate cancer.
Methods
We studied 200 consecutive patients who received LDR-brachytherapy between July 2004 and November 2008. Of them, 137 patients did not receive neoadjuvant or adjuvant androgen deprivation therapy. One hundred and forty-two patients were treated with LDR-brachytherapy alone, and 58 were treated with LDR-brachytherapy in combination with external beam radiation therapy. The cut-off value of PSA bounce was 0.1 ng/mL. The incidence, time, height, and duration of PSA bounce were investigated. Clinicopathological and postdosimetric parameters were evaluated to elucidate independent factors to predict PSA bounce in hormone-naïve patients who underwent LDR-brachytherapy alone.
Results
Fifty patients (25%) showed PSA bounce and 10 patients (5%) showed PSA failure. The median time, height, and duration of PSA bounce were 17 months, 0.29 ng/mL, and 7.0 months, respectively. In 103 hormone-naïve patients treated with LDR-brachytherapy alone, and univariate Cox proportional regression hazard model indicated that age and minimal percentage of the dose received by 30% and 90% of the urethra were independent predictors of PSA bounce. With a multivariate Cox proportional regression hazard model, minimal percentage of the dose received by 90% of the urethra was the most significant parameter of PSA bounce.
Conclusions
Minimal percentage of the dose received by 90% of the urethra was the most significant predictor of PSA bounce in hormone-naïve patients treated with LDR-brachytherapy alone.
doi:10.1186/1471-2490-12-28
PMCID: PMC3487947  PMID: 22974428
Prostate cancer; Brachytherapy; PSA bounce; Post-dosimetry; UD90 (%)
4.  Calculated Tumor Volume Is an Independent Predictor of Biochemical Recurrence in Patients Who Underwent Retropubic Radical Prostatectomy 
Advances in Urology  2012;2012:204215.
Purpose. The purpose of this study is to investigate whether the clinicopathological biopsy findings can predict the oncological outcome in patients who undergo radical prostatectomy. Materials and Methods. Between January 1997 and March 2006, 255 patients with clinically localized adenocarcinoma of the prostate (clinical T1-3N0M0) who had undergone retropubic radical prostatectomy were enrolled in this study. None of the patients received neoadjuvant or adjuvant therapy. Clinicopathological parameters were assessed to determine a predictive parameter of biochemical recurrence. Results. Of the total 255 patients, 77 showed biochemical recurrence during the follow-up period. The estimated 5-year overall survival, 5-year cause-specific survival, and 5-year biochemical recurrence-free survival rates were 97.7%, 99.5%, and 67.3%, respectively. Multivariate analysis using the Cox proportional hazards model showed that calculated cancer volume was an independent predictor among the preoperative clinicopathological parameters (P < 0.05). SVI and PSM were independent predictors among the postoperative parameters (SVI; P < 0.001, PSM; P = 0.049). Among the significant preoperative and postoperative parameters, calculated cancer volume remained an independent predictive parameter in multivariate analysis (P < 0.01). Conclusions. Tumor volume, as calculated by preoperative parameters, is an independent predictor of biochemical recurrence in patients who had undergone radical prostatectomy.
doi:10.1155/2012/204215
PMCID: PMC3359669  PMID: 22654901
5.  5-fluorouracil enhances the antitumor effect of sorafenib and sunitinib in a xenograft model of human renal cell carcinoma 
Oncology Letters  2012;3(6):1195-1202.
Sorafenib and sunitinib are multi-kinase inhibitors with antitumor activity in patients with advanced renal cell carcinoma (RCC). Several studies have evaluated the effect of sorafenib/sunitinib in combination with chemotherapeutic agents in different types of tumor. However, few studies have addressed the activity of fluorinated pyrimidine in combination with sorafenib/sunitinib. In this study, we examined the potential of combination therapy with 5FU and sorafenib/sunitinib in human RCC cell lines. Three human RCC cell lines, ACHN, Caki-1 and Caki-2, were used to assess sensitivity to 5-fluorouracil (5FU), sorafenib and sunitinib alone or in combination using an in vitro cell survival assay. Caki-2 cells demonstrated significantly higher resistance to 5FU and sorafenib as compared to ACHN and Caki-1. Additive antitumor effects of the combination therapy were observed in the in vitro study. There was a tendency for a positive correlation between the sensitivity to sunitinib and platelet-derived growth factor β (PDGFR-β) expression levels, which were examined by reverse transcription polymerase chain reaction. Caki-1 xenograft models were prepared by inoculating cells subcutaneously into nude mice, which were divided randomly into six groups: control, 5FU (8 mg/kg/day, intraperitoneally), sorafenib (15 mg/kg/day, orally), sunitinib (20 mg/kg/day, orally), and 5FU with sorafenib or sunitinib. The treatments were administered on 5 days each week, and tumor growth was monitored for 42 days following inoculation of cells. Synergistic antitumor effects of the combination therapy were observed in an in vivo study. The resected tumors were evaluated using the Ki-67 labeling index and microvessel density. Both the Ki-67 labeling index and microvessel density were decreased in tumors treated with the combination therapy compared to those treated with sorafenib/sunitinib alone. These findings suggest that the combination therapy of 5FU with sorafenib/sunitinib may be an effective therapeutic modality for advanced RCC patients.
doi:10.3892/ol.2012.662
PMCID: PMC3392575  PMID: 22783417
renal cell carcinoma; 5-fluorouracil; sorafenib; sunitinib; angiogenesis
6.  ROS generation via NOX4 and its utility in the cytological diagnosis of urothelial carcinoma of the urinary bladder 
BMC Urology  2011;11:22.
Background
Reactive oxygen species (ROS) production via NADPH oxidase (NOX) contributes to various types of cancer progression. In the present research, we examined the pathobiological role of NADPH oxidase (NOX)4-mediated generation of reactive oxygen species (ROS) in urothelial carcinoma (UC) of the urinary bladder, and demonstrated the utility of ROS labeling in urine cytology.
Methods
NOX4 gene was silenced in vivo and in vitro by NOX4 siRNA transfection with or without atlocollagen. Cell cycle and measurement of ROS were analyzed by flowcytometry. Orthotopic implantation animal model was used in vivo experiment. NOX4 expression in urothelial carcinoma cells was observed by immunohistochemical analysis using surgical specimens of human bladder cancer. Urine cytology was performed after treatment with ROS detection reagents in addition to Papanicolaou staining.
Results
NOX4 was overexpressed in several UC cell lines and the NOX inhibitor, diphenylene iodonium reduced intracellular ROS and induced p16-dependent cell cycle arrest at the G1 phase. Moreover, silencing of NOX4 by siRNA significantly reduced cancer cell growth in vivo as assessed in an orthotopic mouse model. Immunohistochemistry demonstrated high expression of NOX4 in low grade/non-invasive and high grade/invasive UC including precancerous lesions such as dysplasia but not in normal urothelium. Then, we assessed the usefulness of cytological analysis of ROS producing cells in urine (ROS-C). Urine samples obtained from UC cases and normal controls were treated with fluorescent reagents labeling the hydrogen peroxide/superoxide anion and cytological atypia of ROS positive cells were analyzed. As a result, the sensitivity for detection of low grade, non-invasive UC was greatly increased (35% in conventional cytology (C-C) vs. 75% in ROS-C), and the specificity was 95%. Through ROS-C, we observed robust improvement in the accuracy of follow-up urine cytology for cases with previously diagnosed UC, especially in those with low grade/non-invasive cancer recurrence (0% in C-C vs. 64% in ROS-C).
Conclusions
This is the first report demonstrating that ROS generation through NOX4 contributes to an early step of urothelial carcinogenesis and cancer cell survival. In addition, cytology using ROS labeling could be a useful diagnostic tool in human bladder cancer.
doi:10.1186/1471-2490-11-22
PMCID: PMC3215170  PMID: 22032647
7.  Cyclooxygenase 2-dependent and independent activation of Akt through casein kinase 2α contributes to human bladder cancer cell survival 
BMC Urology  2011;11:8.
Background
Survival rate for patients presenting muscle invasive bladder cancer is very low, and useful therapeutic target has not been identified yet. In the present study, new COX2 downstream signals involved in urothelial carcinoma cell survival were investigated in vitro and in vivo.
Methods
COX2 gene was silenced by siRNA transfection. Orthotopic implantation animal model and transurethral instillation of siRNA with atelocollagen was constructed to examine the effects of COX2 knockdown in vivo. Cell cycle was examined by flowcytoketry. Surgical specimens derived from patients with urinary bladder cancer (all were initially diagnosed cases) were used for immunohistochemical analysis of the indicated protein expression in urothelial carcinoma cells.
Results
Treatment with the COX2 inhibitor or knockdown of COX2 reduced expression of casein kinase (CK) 2 α, a phophorylated Akt and urokinase type plasminogen activator (uPA), resulting in p27 induction, cell cycle arrest at G1 phase and cell growth suppression in human urothelial carcinoma cell lines expressing COX2. Silencing of CK2α exhibited the similar effects. Even in UMUC3 cells lacking the COX2 gene, COX2 inhibition also inhibited cell growth through down-regulation of the CK2α-Akt/uPA axis. The mouse orthotropic bladder cancer model demonstrated that the COX2 inhibitor, meloxicam significantly reduced CK2α, phosphorylated Akt and uPA expression, whereas induced p27 by which growth and invasiveness of bladder cancer cells were strongly inhibited. Immunohistochemically, high expression of COX2, CK2α and phosphorylated form of Akt was found in high-grade, invasive carcinomas as well as carcinoma in situ, but not in low-grade and noninvasive phenotypes.
Conclusions
COX2-dependent and independent activation of CK2α-Akt/uPA signal is mainly involved in urothelial carcinoma cell survival, moreover, not only COX2 but also CK2α could be direct targets of COX2 inhibitors.
doi:10.1186/1471-2490-11-8
PMCID: PMC3111585  PMID: 21592330
cyclooxygenase 2; urothelial carcinoma; casein kinase 2α; Akt
8.  Utility of serial urinary cytology in the initial evaluation of the patient with microscopic hematuria 
BMC Urology  2009;9:12.
Background
We determine the utility of serial urinary cytologies in patients presenting with microscopic hematuria who were evaluated with upper and lower urinary tract studies to rule out a malignancy.
Methods
Two hundred and thirty-seven patients with the diagnosis of microscopic hematuria were evaluated at an inner-city tertiary care hospital. Of these 239 patients, 182 patients had 405 cytologies obtained as part of their evaluation for hematuria. In addition, all patients had their lower urinary tract and upper tract thoroughly evaluated.
Results
Two hundred and seventy four cytology samples were read as normal, 104 (26%) as atypia, 7 (2%) as suspicious/malignant, and 20 (5%) as unsatisfactory. Seventeen patients (9.3%) had biopsy confirmed bladder cancer. Of these 17 patients, 2 had normal cytology, 11 had atypia, and 5 had suspicious/malignant. No patient had a positive cytology and a negative biopsy. Overall the number of hematuric patients harboring bladder cancer was small (7%). Cytology #1 detected 4 cases of cancer, cytology #2 detected an additional case and cytology #3 did not detect any additional cancers.
Conclusion
Because of this low prevalence of bladder cancer in patients presenting with microscopic hematuria and the low sensitivity of detecting bladder cancers, the utility of urinary cytology in the initial evaluation of patients with hematuria may be minimal. The exact role of urinary cytology in the evaluation of hematuria is unknown.
doi:10.1186/1471-2490-9-12
PMCID: PMC2751768  PMID: 19744317
9.  Phase II trial of isoflavone in prostate-specific antigen recurrent prostate cancer after previous local therapy 
BMC Cancer  2008;8:132.
Background-
Data exist that demonstrate isoflavones' potent antiproliferative effects on prostate cancer cells. We evaluated the efficacy of isoflavone in patients with PSA recurrent prostate cancer after prior therapy. We postulated that isoflavone therapy would slow the rate of rise of serum PSA.
Methods-
Twenty patients with rising PSA after prior local therapy were enrolled in this open-labeled, Phase II, nonrandomized trial (Trial registration # NCT00596895). Patients were treated with soy milk containing 47 mg of isoflavonoid per 8 oz serving three times per day for 12 months. Serum PSA, testosterone, lipids, isoflavone levels (genistein, daidzein, and equol), and quality of life (QOL) were measured at various time points from 0 to 12 months. PSA outcome was evaluated.
Results-
Within the mixed regression model, it was estimated that PSA had increased 56% per year before study entry and only increased 20% per year for the 12-month study period (p = 0.05). Specifically, the slope of PSA after study entry was significantly lower than that before study entry in 6 patients and the slope of PSA after study entry was significantly higher than before study entry in 2 patients. For the remaining 12 patients, the change in slope was statistically insignificant. Nearly two thirds of the patients were noted to have significant levels of free equol in their serum while on therapy.
Conclusion-
Dietary intervention with isoflavone supplementation may have biologic activity in men with biochemical recurrent prostate cancer as shown by a decline in the slope of PSA. This study may lend support to the literature that nutritional supplements have biologic activity in prostate cancer and therefore, further studies with these agents in randomized clinical trials should be encouraged.
doi:10.1186/1471-2407-8-132
PMCID: PMC2394534  PMID: 18471323
10.  Outcomes of men who present with elevated serum PSA (>20 ng/mL) to an inner-city hospital. 
INTRODUCTION: We report the incidence, clinicopathologic features, and outcomes of men who presented to an inner-city hospital with serum PSA >20 ng/ml. MATERIALS AND METHODS: Five-hundred-sixty men underwent a transrectal ultrasound needle-guided biopsy of the prostate for elevated PSA >4 ng/ml with or without an abnormal digital rectal examination. RESULTS: Of the 560 men, 65 (12%) were found to have a serum PSA >20 ng/ml, and 57 (10%) were diagnosed with prostate cancer. In the group of 57 men with cancer, the positive predictive value of PSA alone was 72% for PSA levels of 20-29.99 ng/ml and 100% for PSA >30 ng/ml. Of the 57 men, 18 underwent definitive therapy, 24 underwent androgen deprivation, 8 refused treatment or were lost to follow-up, and 7 were treated on protocol. An additional seven men with cancer refused therapy or were lost to follow-up, thus giving a total of 15 (26%) men who were noncompliant to medical advice. CONCLUSIONS: Serum PSA >30 ng/ml is an almost certain predictor of the presence of prostate cancer. Aggressive prostate cancer education and screening programs are needed in our inner cities in order to detect prostate cancer at an earlier, treatable stage.
PMCID: PMC2574301  PMID: 17722667
11.  Prostate cancer screening and detection in inner-city and underserved men. 
CONTEXT: In the era of serum prostate-specific antigen (PSA) screening, the incidence of prostate cancer has increased dramatically. Simultaneously however, stage migration has occurred, and treatment outcomes have improved. Inner-city men have lower screening rates and, thus, may be diagnosed with more advanced disease that it less likely to be successfully treated. OBJECTIVE: To assess the detection rate of prostate cancer and tumor stage at presentation in inner-city men. DESIGN, SETTING, AND PATIENTS: A retrospective cohort of 368 men underwent transrectal ultrasound needle-guided biopsy at an inner-city hospital from January 2003 to May 2005. Clinical and pathologic data were collected and analyzed. MAIN OUTCOME MEASURES: Clinic and hospital records were reviewed for several key outcomes, including prostate cancer incidence, tumor stage and tumor grade. RESULTS: The median age of the cohort was 67 +/- 9.1 years (range, 23-93 years). Prostate cancer was diagnosed in 44% of subjects (161/368). The median PSA level at the time of diagnosis was significantly higher in African-American men than in Caucasian men (9.82 vs. 5.97 ng/mL, P=0.008). Abnormally high serum PSA levels (>20 ng/mL) were present in disproportionately more African-American men than Caucasian men with prostate cancer (32.9% vs. 19.7% P=0.011). African-American men in this inner-city cohort also had a higher incidence of advanced disease or distant metastasis (T3/T4, N1, or M1) than did Caucasians (16.1% vs. 3.8%; P=0.045). CONCLUSIONS: Compared with inner-city Caucasian men, disproportionately more inner-city, African-American men present with advanced prostate cancer. This observation warrants prostate cancer education and consideration of early detection programs in underserved inner-city communities.
PMCID: PMC2569232  PMID: 16623063

Results 1-11 (11)