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1.  Targeting Plasminogen Activator Inhibitor-1 Inhibits Angiogenesis and Tumor Growth in a Human Cancer Xenograft Model 
Molecular cancer therapeutics  2013;12(12):2697-2708.
Cancers of the urinary bladder result in aggressive and highly angiogenic tumors for which standard treatments have only limited success. Patients with advanced disease have a 5-year survival rate of less than 20%, and no new anticancer agent has been successfully introduced into the clinic armamentarium for the treatment of bladder cancer in more than 20 years. Investigations have identified plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, as being highly expressed in several malignancies, including bladder cancer, in which high expression is associated with a poor prognosis. In this study, we evaluated PAI-1 as a potential therapeutic target for bladder cancer. PAI-1 expression was manipulated in a panel of cell lines and functional inhibition was achieved using the small molecule tiplaxtinin. Reduction or inhibition of PAI-1 resulted in the reduction of cellular proliferation, cell adhesion, and colony formation, and the induction of apoptosis and anoikis in vitro. Treatment of T24 xenografts with tiplaxtinin resulted in inhibition of angiogenesis and induction of apoptosis, leading to a significant reduction in tumor growth. Similar results were obtained through evaluation of the human cervical cancer HeLa cell line, showing that PAI-1–mediated effects are not restricted to tumor cells of bladder origin. Collectively, these data show that targeting PAI-1 may be beneficial and support the notion that novel drugs such as tiplaxtinin could be investigated as anticancer agents.
doi:10.1158/1535-7163.MCT-13-0500
PMCID: PMC4317369  PMID: 24072883
2.  Use of alpha-1 adrenoceptor antagonists in patients who underwent low-dose-rate brachytherapy for prostate cancer - a randomized controlled trial of silodosin versus naftopidil - 
Background
To evaluate the effect of two different alpha-1 adrenoceptor antagonists on lower urinary tract symptoms in patients who underwent LDR-brachytherapy.
Methods
A total of 141 patients who had been clinically diagnosed with localized prostate cancer and underwent LDR-brachytherapy were enrolled. Patients were randomized and allocated to two groups (silodosin 8 mg vs. naftopidil 75 mg). The primary endpoint was a change in the international prostate symptom score (IPSS) at 3 months after seed implantation. Secondary endpoints included the recovery rate of IPSS at 12 months after seed implantation, the change in IPSS and overactive bladder symptom score, uroflowmetric parameters, and frequency volume chart (FVC). To determine independent variables that can predict IPSS recovery, logistic regression analysis was carried out.
Results
The mean change in the IPSS at 3 months after seed implantation in both groups was ⊿10.6 (naftopidil) and ⊿10.4 (silodosin), respectively. There was not a significant difference between the two groups (p=0.728). An increase in urinary frequency and a decrease in total urinated volume and mean voided volume were observed in FVC for 12 months after seed implantation. Multivariate analysis revealed that the urethral dose (UD30) was an independent predictive parameter of IPSS recovery. Patients with UD30 < 200Gy showed a higher recovery rate of IPSS at 12 months after seed implantation.
Conclusion
There was no significant difference of serial change in IPSS between silodosin and naftopidil during the first year after seed implantation. A lower dose on the urethra was an independent predictor of IPSS recovery at 12 months after seed implantation.
doi:10.1186/s13014-014-0302-7
PMCID: PMC4300048  PMID: 25544509
Prostate cancer; LDR-brachytherapy; Alpha-1 adrenoceptor antagonist; Urinary morbidity; Randomized controlled study
3.  Validation and clinicopathologic associations of a urine-based bladder cancer biomarker signature 
Diagnostic Pathology  2014;9(1):200.
Background
To validate the expression of a urine-based bladder cancer associated diagnostic signature comprised of 10 targets; ANG, CA9, MMP9, MMP10, SERPINA1, APOE, SDC1, VEGFA, SERPINE1 and IL8 in bladder tumor tissues.
Methods
Immunohistochemical analyses were performed on tumor specimens from 213 bladder cancer patients (transitional cell carcinoma only) and 74 controls. Staining patterns were digitally captured and quantitated (Aperio, Vista, CA), and expression was correlated with tumor stage, tumor grade and outcome measures.
Results
We revealed a positive association of 9 of the 10 proteins (excluding VEGF) in bladder cancer. Relative to control cases, a reduction in SDC1 and overexpression of MMP9, MMP10, SERPINE1, IL8, APOE, SERPINA1, ANG were associated with high stage bladder cancer. Reduced VEGF and increased SERPINA1 were associated with high-grade bladder cancer. Disease-specific survival was significantly reduced in tumors with high expression of SERPINE1 and/or IL8.
Conclusions
These findings confirm that the proteins in a urine-based diagnostic signature are aberrantly expressed in bladder tumor tissues, and support the potential additional utility of selected biomarkers for the clinicopathological evaluation of excised tissue or biopsy material.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_200
doi:10.1186/s13000-014-0200-1
PMCID: PMC4245773  PMID: 25387487
Bladder cancer; Diagnosis; Grade; Signature; Stage
4.  Proposed salvage treatment strategy for biochemical failure after radical prostatectomy in patients with prostate cancer: a retrospective study 
Background
Treatment options for patients with recurrent disease after radical prostatectomy include salvage radiotherapy of the prostatic bed and/or androgen deprivation therapy. To establish an effective treatment strategy for recurrent disease after radical prostatectomy, we retrospectively analyzed the outcome of salvage radiation monotherapy in such cases.
Methods
Data from 61 men who had undergone salvage radiation monotherapy for biochemical recurrent disease after radical prostatectomy were retrospectively reviewed. In all patients, salvage radiotherapy consisted of iraradiation to the prostatic bed (70 Gy) using three-dimensional conformal radiotherapy techniques. Treatment outcome was analyzed to identify predictive factors of salvage radiotherapy.
Results
The biochemical recurrence-free survival after salvage radiation monotherapy at 2 and 5 years was 55% and 38%, respectively. Cox proportional regression models revealed that the independent predictive factors for biochemical recurrence were Gleason Score ≥ 8, negative surgical margin, and PSA velocity ≥ 0.38 ng/mL/year. Negative surgical margin and PSA velocity ≥ 0.8 ng/mL/year were significantly associated with poor response in the serum PSA levels after salvage radiotherapy.
Conclusions
Based on our findings, we propose a treatment strategy for biochemical recurrent disease after radical prostatectomy. Patients with Gleason score ≤ 7, positive surgical margin, and PSA velocity < 0.38 ng/mL/year are categorized the most favorable group, so that eradication by salvage radiation monotherapy could be expected. Other patients could be divided to two groups depending on surgical margin status and PSA velocity: 1) patients who might require combination of SRT and short-term androgen deprivation therapy and 2) patients who should be treated by androgen deprivation monotherapy.
doi:10.1186/1748-717X-9-208
PMCID: PMC4283125  PMID: 25331298
Prostate cancer; Biochemical failure; Salvage radiotherapy; Prostate-specific antigen; PSA doubling time; PSA velocity
5.  Photodynamic diagnosis of shed prostate cancer cells in voided urine treated with 5-aminolevulinic acid 
BMC Urology  2014;14:59.
Background
Past attempts at detecting prostate cancer (PCa) cells in voided urine by traditional cytology have been impeded by undesirably low sensitivities but high specificities. To improve the sensitivities, we evaluate the feasibility and clinical utility of photodynamic diagnosis (PDD) of prostate cancer by using 5-aminolevulinic acid (5-ALA) to examine shed prostate cancer cells in voided urine samples.
Methods
One hundred thirty-eight patients with an abnormal digital rectal exam (DRE) and/or abnormal prostate-specific antigen (PSA) levels were recruited between April 2009 and December 2010. Voided urine specimens were collected before prostate biopsy. Urine specimens were treated with 5-ALA and imaged by fluorescence microscopy and reported as protoporphyrin IX (PPIX) positive (presence of cells demonstrating simultaneous PPIX fluorescence) or PPIX negative (lack of cells demonstrating fluorescence).
Results
Of the 138 patients, PCa was detected on needle biopsy in 81 patients (58.7%); of these 81 patients with PCa, 60 were PPIX-positive (sensitivity: 74.1%). Although 57 patients did not harbor PCa by conventional diagnostic procedures, 17 of these at-risk patients were found to be PPIX-positive (specificity: 70.2%). PPIX–PDD was more sensitive compared with DRE and transrectal ultrasound and more specific compared with PSA and PSA density. The incidence of PPIX–PDD positivity did not increase with increasing total PSA levels, tumor stage or Gleason score.
Conclusions
To our knowledge, this is the first successful demonstration of PPIX in urine sediments treated with 5-ALA used to detect PCa in a noninvasive yet highly sensitive manner. However, further studies are warranted to determine the role of PPIX–PPD for PCa detection.
doi:10.1186/1471-2490-14-59
PMCID: PMC4130698  PMID: 25086448
5-aminolevulinic acid; Prostate cancer; Photodynamic diagnosis; Urine cytology
6.  Intravesical ALT-803 and BCG Treatment Reduces Tumor Burden in a Carcinogen Induced Bladder Cancer Rat Model; a Role for Cytokine Production and NK Cell Expansion 
PLoS ONE  2014;9(6):e96705.
Intravesical Bacillus Calmette-Guérin (BCG) has been shown to induce a specific immunologic response (i.e., activation of IL-2 and effector T-cells), while preclinical studies using ALT-803 (mutated IL-15 analogue combined with IL-15Rα-Fc fusion) have shown promising results by prolonging the agent's half-life and stimulating CD8+ T-cells. Based on these results, we hypothesized that the intravesical administration of ALT-803 along with BCG will generate an immunologic response leading to significant bladder tumor burden reduction. Using a well-established carcinogen induced rat non-muscle invasive bladder cancer (NMIBC) model, we studied the effects of intravesical ALT-803 with and without BCG. Rat tissues were evaluated to document treatment response. Intravesical ALT-803 was safe and well tolerated alone and in combination with BCG. As a single treatment agent, ALT-803 reduced tumor burden by 35% compared to control whereas BCG alone only reduced tumor burden by 15%. However, the combination of ALT-803 plus BCG reduced tumor burden by 46% compared to control. Immune monitoring suggested that the antitumor response was linked to the production and secretion of IL-1α, IL-1β and RANTES, which in turn, induced the proliferation and activation of NK cells. Lastly, tumoral responses of the combinational treatment were associated with 76% reduction in angiogenesis, which is significantly higher than when assessed with either agent alone. The enhanced therapeutic index seen with this duplet provides justification for the development of this regimen for future clinical trials.
doi:10.1371/journal.pone.0096705
PMCID: PMC4045574  PMID: 24896845
7.  Matrix metalloproteinase-10 promotes tumor progression through regulation of angiogenic and apoptotic pathways in cervical tumors 
BMC Cancer  2014;14:310.
Background
Cancer invasion and metastasis develops through a series of steps that involve the loss of cell to cell and cell to matrix adhesion, degradation of extracellular matrix and induction of angiogenesis. Different protease systems (e.g., matrix metalloproteinases, MMPs) are involved in these steps. MMP-10, one of the lesser studied MMPs, is limited to epithelial cells and can facilitate tumor cell invasion by targeting collagen, elastin and laminin. Enhanced MMP-10 expression has been linked to poor clinical prognosis in some cancers, however, mechanisms underlying a role for MMP-10 in tumorigenesis and progression remain largely unknown. Here, we report that MMP-10 expression is positively correlated with the invasiveness of human cervical and bladder cancers.
Methods
Using commercial tissue microarray (TMA) of cervical and bladder tissues, MMP-10 immunohistochemical staining was performed. Furthermore using a panel of human cells (HeLa and UROtsa), in vitro and in vivo experiments were performed in which MMP-10 was overexpressed or silenced and we noted phenotypic and genotypic changes.
Results
Experimentally, we showed that MMP-10 can regulate tumor cell migration and invasion, and endothelial cell tube formation, and that MMP-10 effects are associated with a resistance to apoptosis. Further investigation revealed that increasing MMP-10 expression stimulates the expression of HIF-1α and MMP-2 (pro-angiogenic factors) and PAI-1 and CXCR2 (pro-metastatic factors), and accordingly, targeting MMP-10 with siRNA in vivo resulted in diminution of xenograft tumor growth with a concomitant reduction of angiogenesis and a stimulation of apoptosis.
Conclusion
Taken together, our findings show that MMP-10 can play a significant role in tumor growth and progression, and that MMP-10 perturbation may represent a rational strategy for cancer treatment.
doi:10.1186/1471-2407-14-310
PMCID: PMC4022983  PMID: 24885595
Angiogenesis; Apoptosis; Cancer; Invasion; MMP-10
8.  Nadir PSA level and time to nadir PSA are prognostic factors in patients with metastatic prostate cancer 
BMC Urology  2014;14:33.
Background
Primary androgen deprivation therapy (PADT) is the most effective systemic therapy for patients with metastatic prostate cancer. Nevertheless, once PSA progression develops, the prognosis is serious and mortal. We sought to identify factors that predicted the prognosis in a series of patients with metastatic prostate cancer.
Methods
Two-hundred eighty-six metastatic prostate cancer patients who received PADT from 1998 to 2005 in Nara Uro-Oncology Research Group were enrolled. The log-rank test and Cox’s proportional hazards model were used to determine the predictive factors for prognosis; rate of castration-resistant prostate cancer (CRPC) and overall survival.
Results
The median age, follow-up period and PSA level at diagnosis were 73 years, 47 months and 174 ng/mL, respectively. The 5-year overall survival rate was 63.0%. The multivariable analysis showed that Gleason score (Hazard ratio [HR]:1.362; 95% confidence interval [C.I.], 1.023-1.813), nadir PSA (HR:6.332; 95% C.I., 4.006-9.861) and time from PADT to nadir (HR:4.408; 95% C.I., 3.099-6.271) were independent prognostic factors of the incidence of CRPC. The independent parameters in the multivariate analysis that predicted overall survival were nadir PSA (HR:5.221; 95% C.I., 2.757-9.889) and time from PADT to nadir (HR:4.008; 95% C.I., 2.137-7.517).
Conclusions
Nadir PSA and time from PADT to nadir were factors that affect both CRPC and overall survival in a cohort of patients with metastatic prostate cancer. Lower nadir PSA level and longer time from PADT to nadir were good for survival and progression.
doi:10.1186/1471-2490-14-33
PMCID: PMC4018264  PMID: 24773608
Prostate cancer; Metastasis; Risk factors
9.  Simultaneous multi-analyte urinary protein assay for bladder cancer detection 
BMC Biotechnology  2014;14:24.
Background
The ability to accurately measure multiple proteins simultaneously in a single assay has the potential to markedly improve the efficiency of a myriad of clinical assays. Here, we tested the performance of a new, multiplex protein array platform to quantitate three bladder cancer-associated proteins in urine samples. The following analytes, interleukin 8 (IL8), matrix metallopeptidase 9 (MMP9), and vascular endothelial growth factor A (VEGFA) were monitored using Q-plex, a customized multiplex ELISA system from Quansys Biosciences, and individual target commercial ELISA kits. The performance of the two approaches was compared by evaluating the diagnostic accuracy of the biomarker assays in samples from a cohort of 73 subjects of known bladder cancer status.
Results
The combination biomarker panel analyses revealed an AUROC value of 0.9476 for the Q-plex assay, and 0.9119 for the combination of the single-target ELISA assays. The Q-plex assay achieved an overall diagnostic sensitivity of 0.93 and specificity of 0.81, and the individual target ELISA assays achieved an overall sensitivity of 0.77 and specificity of 0.91.
Conclusion
Based on these encouraging preliminary data, we believe that the Q-Plex technology is a viable platform that can be exploited as an efficient, highly accurate tool to quantitate multiplex panels of diagnostic proteins in biologic specimens.
doi:10.1186/1472-6750-14-24
PMCID: PMC4230247  PMID: 24684904
Biomarkers; Bladder cancer; Q-plex; Protein; Urine
10.  Clinical implications in the shift of syndecan-1 expression from the cell membrane to the cytoplasm in bladder cancer 
BMC Cancer  2014;14:86.
Background
To determine the diagnostic and prognostic capability of urinary and tumoral syndecan-1 (SDC-1) levels in patients with cancer of the urinary bladder.
Methods
SDC-1 levels were quantitated by enzyme-linked immunosorbent assay (ELISA) in 308 subjects (102 cancer subjects and 206 non-cancer subjects) to assess its diagnostic capabilities in voided urine. The performance of SDC-1 was evaluated using the area under the curve of a receiver operating characteristic curve. In addition, immunohistochemical (IHC) staining assessed SDC-1 protein expression in 193 bladder specimens (185 cancer subjects and 8 non-cancer subjects). Outcomes were correlated to SDC-1 levels.
Results
Mean urinary levels of SDC-1 did not differ between the cancer subjects and the non-cancer subjects, however, the mean urinary levels of SDC-1 were reduced in high-grade compared to low-grade disease (p < 0.0001), and in muscle invasive bladder cancer (MIBC) compared to non-muscle invasive bladder cancer (NMIBC) (p = 0.005). Correspondingly, preliminary data note a shift from a membranous cellular localization of SDC-1 in normal tissue, low-grade tumors and NMIBC, to a distinctly cytoplasmic localization in high-grade tumors and MIBC was observed in tissue specimens.
Conclusion
Alone urinary SDC-1 may not be a diagnostic biomarker for bladder cancer, but its urinary levels and cellular localization were associated with the differentiation status of patients with bladder tumors. Further studies are warranted to define the potential role for SDC-1 in bladder cancer progression.
doi:10.1186/1471-2407-14-86
PMCID: PMC3930286  PMID: 24524203
Syndecan; Bladder; Cancer biomarker; Specificity
11.  Urinary BTA: Indicator of Bladder Cancer or of Hematuria 
World journal of urology  2012;30(6):869-873.
Background
In this study, we investigated the influence of hematuria on the performance of the BTA tests in a clinical cohort and in an experimental model.
Materials and Methods
Analysis of urine samples from a cohort of 126 subjects (64 with BCa and 62 controls) were analyzed by ELISA for hemoglobin and BTA. The experimental model involved the spiking of urine with blood from the same subject, and hemoglobin, red blood cell count, and BTA levels (BTA stat© and BTA-TRAK©). BTA-TRAK© analyses were also performed on serum samples obtained from 40 subjects (20 with confirmed with BCa).
Results
In the 126-subject cohort, correlation between hemoglobin and BTA was 0.732. Of the 64 BCa samples, 72% had a positive BTA assay, but 47% of controls were also positive. The sensitivity and specificity of BTA to detect BCa was 72% and 53%, respectively. Hematuria, measured by urinary hemoglobin, was a better indicator of BCa with 75% sensitivity and 90% specificity. Spiking of BTA-negative urine samples with as little as 1μl/10ml was enough to produce positive a BTA test. High levels of BTA were found equally in the serum of subjects with, or without BCa (mean BTA levels 355,159 U/ml vs. 332,329 U/ml, respectively).
Conclusions
Rather than detecting a bladder tumor antigen, urinary BTA assays may be measuring serum cFH introduced by bleeding, a common presenting factor in BCa subjects. The presence of hematuria in subjects without malignant disease can result in false-positive BTA assays.
doi:10.1007/s00345-012-0935-9
PMCID: PMC3537326  PMID: 22932760
complement factor H; hematuria; BTA; bladder cancer; diagnosis
12.  Pilot study comparing the two hemostatic agents in patients undergoing partial nephrectomy 
BMC Research Notes  2013;6:399.
Background
Recently studies have demonstrated improved outcomes in patients undergoing nephron-sparing surgery (NSS) for low stage renal tumors, thus NSS is widely accepted as the treatment option for these patients. With NSS, there is a risk of renal hemorrhage and thus haemostatic agents may be routinely applied to the cut surface of the kidney. Herein we compare two commercially available haemostatic agents applied intra-operatively to the cut surface of the kidney. Post-operative outcomes (oncologic and non-oncologic) are reported.
Methods
The medical records of 23 patients with suspicious renal mass documented on axial imaging and who underwent open NSS via a mini-subcostal incision were extensively reviewed. One of two haemostatic agents (Floseal®, n = 11; Arista®, n = 12) was intra-operatively applied to the cut surface of the kidney. Chi-square and T- student test was used to compare outcomes between the cohort of 11 patients who had Floseal® and the 12 patients who had Arista®.
Results
Median pre-operative size of renal mass was 4.3 cm (range 1.5-7.0 cm). Final pathology revealed 3 oncocytomas and 20 renal cell carcinoma (17 clear cell, 1 chromophobe and 2 papillary), pT1a = 14 and pT1b = 6. Mean intra-operative blood loss and hospital stay between the Floseal®vs. Arista® cohorts did not significantly differ (227 mL vs. 250 mL, p = 0.68 and 4.4 days vs. 4.5 days, p = 0.76, respectively). Intra-operative and post-operative complications were not different between the two cohorts. No recurrences have been documented with a mean follow-up of 18 months.
Conclusion
Along with meticulous surgical technique, the use of either haemostatic agent (Floseal® or Arista®) was not associated with high rate of intra-operative or post-operative haemorrhage. Thus either haemostatic agent may be successfully used during NSS.
doi:10.1186/1756-0500-6-399
PMCID: PMC3850670  PMID: 24090237
Haemostatic agent; Nephrectomy; Nephron-sparing; Partial; Renal mass
13.  Investigation of CCL18 and A1AT as potential urinary biomarkers for bladder cancer detection 
BMC Urology  2013;13:42.
Background
In this study, we further investigated the association of two biomarkers, CCL18 and A1AT, with bladder cancer (BCa) and evaluated the influence of potentially confounding factors in an experimental model.
Methods
In a cohort of 308 subjects (102 with BCa), urinary concentrations of CCL18 and A1AT were assessed by enzyme-linked immunosorbent assay (ELISA). In an experimental model, benign or cancerous cells, in addition to blood, were added to urines from healthy controls and analyzed by ELISA. Lastly, immunohistochemical staining for CCL18 and A1AT in human bladder tumors was performed.
Results
Median urinary protein concentrations of CCL18 (52.84 pg/ml vs. 11.13 pg/ml, p < 0.0001) and A1AT (606.4 ng/ml vs. 120.0 ng/ml, p < 0.0001) were significantly elevated in BCa subjects compared to controls. Furthermore, the addition of whole blood to pooled normal urine resulted in a significant increase in both CCL18 and A1AT. IHC staining of bladder tumors revealed CCL18 immunoreactivity in inflammatory cells only, and there was no significant increase in these immunoreactive cells within benign and cancerous tissue and no association with BCa grade nor stage was noted. A1AT immunoreactivity was observed in the cytoplasm of epithelia cells and intensity of immunostaining increased with tumor grade, but not tumor stage.
Conclusions
Further development of A1AT as a diagnostic biomarker for BCa is warranted.
doi:10.1186/1471-2490-13-42
PMCID: PMC3846766  PMID: 24011266
Biomarkers; Bladder cancer; Specificity; Urine
14.  Erythropoietin is a JAK2 and ERK1/2 effector that can promote renal tumor cell proliferation under hypoxic conditions 
Background
Erythropoietin (EPO) provides an alternative to transfusion for increasing red blood cell mass and treating anemia in cancer patients. However, recent studies have reported increased adverse events and/or reduced survival in patients receiving both EPO and chemotherapy, potentially related to EPO-induced cancer progression. Additional preclinical studies that elucidate the possible mechanism underlying EPO cellular growth stimulation are needed.
Methods
Using commercial tissue microarray (TMA) of a variety of cancers and benign tissues, EPO and EPO receptor immunohistochemical staining was performed. Furthermore using a panel of human renal cells (Caki-1, 786-O, 769-P, RPTEC), in vitro and in vivo experiments were performed with the addition of EPO in normoxic and hypoxic states to note phenotypic and genotypic changes.
Results
EPO expression score was significantly elevated in lung cancer and lymphoma (compared to benign tissues), while EPOR expression score was significantly elevated in lymphoma, thyroid, uterine, lung and prostate cancers (compared to benign tissues). EPO and EPOR expression scores in RCC and benign renal tissue were not significantly different. Experimentally, we show that exposure of human renal cells to recombinant EPO (rhEPO) induces cellular proliferation, which we report for the first time, is further enhanced in a hypoxic state. Mechanistic investigations revealed that EPO stimulates the expression of cyclin D1 while inhibiting the expression of p21cip1 and p27kip1 through the phosphorylation of JAK2 and ERK1/2, leading to a more rapid progression through the cell cycle. We also demonstrate an increase in the growth of renal cell carcinoma xenograft tumors when systemic rhEPO is administered.
Conclusions
In summary, we elucidated a previously unidentified mechanism by which EPO administration regulates progression through the cell cycle, and show that EPO effects are significantly enhanced under hypoxic conditions.
doi:10.1186/1756-8722-6-65
PMCID: PMC3844377  PMID: 24004818
Cancer; ERK1/2; Erythropoietin; Hypoxia; JAK2; Renal
15.  Chemokine (C-X-C) ligand 1 (CXCL1) protein expression is increased in aggressive bladder cancers 
BMC Cancer  2013;13:322.
Background
Chemokines, including chemokine (C-X-C motif) ligand 1 (CXCL1), may regulate tumor epithelial-stromal interactions that facilitate tumor growth and invasion. Studies have linked CXCL1 expression to gastric, colon and skin cancers, but limited studies to date have described CXCL1 protein expression in human bladder cancer (BCa).
Methods
CXCL1 protein expression was examined in 152 bladder tissue specimens (142 BCa) by immunohistochemical staining. The expression of CXCL1 was scored by assigning a combined score based on the proportion of cells staining and intensity of staining. CXCL1 expression patterns were correlated with clinicopathological features and follow-up data.
Results
CXCL1 protein expression was present in cancerous tissues, but was entirely absent in benign tissue. CXCL1 combined immunostaining score was significantly higher in high-grade tumors relative to low-grade tumors (p = 0.012). Similarly, CXCL1 combined immunostaining score was higher in high stage tumors (T2-T4) than in low stage tumors (Ta-T1) (p < 0.0001). An increase in the combined immunostaining score of CXCL1 was also associated with reduced disease-specific survival.
Conclusion
To date, this is the largest study describing increased CXCL1 protein expression in more aggressive phenotypes in human BCa. Further studies are warranted to define the role CXCL1 plays in bladder carcinogenesis and progression.
doi:10.1186/1471-2407-13-322
PMCID: PMC3708804  PMID: 23815949
Bladder Cancer; Chemokine Ligand 1 (CXCL1); Tumor Grade; Tumor Stage
16.  Radiosensitization in prostate cancer: mechanisms and targets 
BMC Urology  2013;13:4.
Prostate cancer is the second most commonly diagnosed cancer in American men over the age of 45 years and is the third most common cause of cancer related deaths in American men. In 2012 it is estimated that 241,740 men will be diagnosed with prostate cancer and 28,170 men will succumb to prostate cancer. Currently, radiation therapy is one of the most common definitive treatment options for localized prostate cancer. However, significant number of patients undergoing radiation therapy will develop locally persistent/recurrent tumours. The varying response rates to radiation may be due to 1) tumor microenvironment, 2) tumor stage/grade, 3) modality used to deliver radiation, and 4) dose of radiation. Higher doses of radiation has not always proved to be effective and have been associated with increased morbidity. Compounds designed to enhance the killing effects of radiation, radiosensitizers, have been extensively investigated over the past decade. The development of radiosensitizing agents could improve survival, improve quality of life and reduce costs, thus benefiting both patients and healthcare systems. Herin, we shall review the role and mechanisms of various agents that can sensitize tumours, specifically prostate cancer.
doi:10.1186/1471-2490-13-4
PMCID: PMC3583813  PMID: 23351141
Cancer; Prostate; Radiation; Radiosensitizer
17.  Focal cryosurgical ablation of the prostate: a single institute’s perspective 
BMC Urology  2013;13:2.
Background
With the stage migration of prostate cancer witnessed in the late 1990’s and early 2000’s along with the persistent morbidities associated with prostatectomy and radiation therapy, the concept of focal prostate cancer treatment remains quite attractive. Herein we evaluate the tolerability and non-oncologic outcomes of a highly select cohort of men that underwent focal cryoablation of the prostate for the treatment of localized prostate cancer.
Methods
Pre-operatively, erectile function was assessed by SHIM questionnaire while voiding symptoms were assessed by AUA symptom score. Twenty-six highly select patients (23 low-risk prostate cancer and 3 intermediate-risk prostate cancer) with documented minimal disease on saturation prostate biopsy underwent focal cryoablation of the prostate (24 hemi-ablation and 2 subtotal ablation). Subsequently, serum PSAs were obtained every 3 months for 2 years and then every 6 months thereafter. PSA failure was defined as an increase of 0.50 ng/ml over nadir. Mean follow-up was 19.1 months. Subjective assessment of erectile function and voiding was assessed post-operatively at each visit.
Results
Based on our PSA failure definition, 11.5% (3 patients) of the cohort experienced biochemical failure. In two of the three patients, localized disease was detected on subsequent transrectal ultrasound guided biopsy. These two patients went on to have favorable PSA nadirs after undergoing conventional definitive therapy (one patient had external beam radiation and one patient had whole gland cryoablation). Within the study cohort, 27% (7 patients) reported new post-operative erectile dysfunction requiring therapy while no patients reported new post-operative urinary incontinence or worsening of voiding symptoms.
Conclusion
These preliminary results add to the expanding body of literature that the minimally invasive focal cryosurgical ablation of the prostate is a safe procedure with few side effects. The true extent of cancer control remains in question, but in highly select patients, favorable PSA kinetics have been demonstrated. If confirmed by further studies with long-term follow-up, this treatment approach could have a profound effect on prostate cancer management.
doi:10.1186/1471-2490-13-2
PMCID: PMC3585847  PMID: 23311921
Prostate cancer; Therapy; Focal; Cryoablation
18.  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
19.  Influencing factors on the NMP-22 urine assay: an experimental model 
BMC Urology  2012;12:23.
Background
The commercial NMP-22 urine assays for bladder cancer (BCa) detect nuclear mitotic apparatus protein 1 (NUMA1) using monoclonal antibodies. It remains unclear whether these assays are monitoring a tumor antigen or some other phenomenon associated with the disease state. In this study, we investigated the influence of urinary cellular and protein concentration, and hematuria on the performance of the NMP-22 tests in an experimental model.
Methods
Pooled urine from healthy subjects were spiked with varying concentrations of benign (UROtsa) cells, cancer cells (RT4, T24, KU-7 and UM-UC-14), whole blood or serum, prior to analysis with both NMP22® Bladder Cancer ELISA test and the NMP22® BladderChek® point-of-care test.
Results
Urines from control subjects were negative for NMP-22. The addition of whole blood at 50ul/10 ml, but not serum, resulted in a false-positive result. Furthermore, the addition of a high concentration of benign urothelial cells (106) or the cell lysate from these cells (306 μg protein) resulted in a false-positive result. High concentrations of pooled-cancer cells (106) or cell lysate (30.6 μg and above) resulted in a positive NMP-22 assay. Concordance between the NMP-22 ELISA assay and the NMP-22 point of care assay was >90%.
Conclusions
Rather than detecting a specific tumor antigen, urinary NMP-22 assays may be measuring the cellularity or amount of cell turnover that may be introduced into the urine by a variety of conditions, including surface shedding from bladder tumors. The absence of significant urinary cellularity in some cases due to lesion characteristics or the timing of sampling may result in false-negative NMP-2 assays.
doi:10.1186/1471-2490-12-23
PMCID: PMC3480828  PMID: 22928931
Bladder cancer; Urine; NMP-22
20.  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
21.  Clinical significance of subepithelial growth patterns in non-muscle invasive bladder cancer 
BMC Urology  2011;11:17.
Background
We evaluated the clinical significance and prognostic value of histopathological features of bladder cancer, such as subepithelial growth patterns and tumor growth pattern at the invasion front.
Methods
In total, 130 patients newly diagnosed with non-muscle invasive bladder cancer and underwent transurethral resection between 1998 and 2009 were enrolled. Subepithelial growth patterns consisting of endophytic growth pattern (EGP) and von Brunn's nest involvement (VBNI) were investigated using hematoxylin and eosin-stained slides, and their frequency of occurrence, prognostic value, and correlation with other clinicopathological features was evaluated.
Results
EGP and VBNI were found in 40 (30.8%) and 5 (3.9%) of the 130 cases, respectively. Of the 26 pT1 tumors, the growth pattern at the invasion front was trabecular in 17 (65.4%) and infiltrative in 9 (34.6%). Although 8 (47.1%) of 17 trabecular tumors coexisted with EGP, no cases with infiltrative tumors had EGP (p = 0.023). VBNI correlated with high tumor grades (p = 0.006) and lymphovascular involvement (p = 0.026). The multivariate Cox proportional hazards analysis revealed that tumor diameter less than 3 cm (p = 0.04) and intravesical bacillus Calmette-Guérin therapy (p = 0.004) were independent favorable prognostic factors for recurrence-free survival, whereas tumor stage was an independent poor prognostic factor for disease progression (p = 0.006).
Conclusions
Subepithelial growth patterns were not a significant prognostic factor in this study. Additionally, no tumors with an infiltrative growth pattern coexisted with EGP, suggesting that determining the presence of EGP might be helpful for managing non-muscle invasive bladder cancers.
doi:10.1186/1471-2490-11-17
PMCID: PMC3167754  PMID: 21816111
bladder cancer; endophytic growth pattern; prognostic factor; infiltrative pattern

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