Biomedical subjects

Hiroshi Kanetake

Publications and source records attributed to Hiroshi Kanetake.

At least 19 recordsLinked to original sources

PubMed2003

The role of c-Fes in vascular endothelial growth factor-A-mediated signaling by endothelial cells.

c-Fes plays pivotal roles in angiogenic cellular responses of endothelial cells. Here we examined the role of c-Fes in vascular endothelial growth factor-A (VEGF-A)-mediated signaling pathways in endothelial cells. We introduced either wild-type or kinase-inactive c-Fes in porcine aortic endothelial (PAE) cell lines, which endogenously express VEGF receptor (VEGFR)-1, and PAE cells ectopically expressing VEGFR-2 (denoted KDR/PAE cells) and generated stable cell lines. VEGF-A induced autophosphorylation of c-Fes only in KDR/PAE cells, suggesting that VEGFR-2 was required for its activation. Expression of kinase-inactive c-Fes failed to demonstrate dominant negative effect on VEGF-A-induced chemotaxis and capillary morphogenesis. Phosphoinositide 3-kinase (PI3-kinase) was activated in KDR/PAE cells and c-Fes contributed to this process in a kinase activity-dependent manner. However, VEGFR-2, insulin receptor substrate-1, and c-Src were also involved in VEGF-A-induced activation of PI3-kinase, resulting in the compensation in cells expressing kinase-inactive c-Fes. Interestingly, overexpression of wild-type c-Fes in PAE cells induced VEGF-A-independent capillary morphogenesis. Considered collectively, VEGF-A activated PI3-kinase partly through c-Fes and increase in c-Fes kinase activity enhanced capillary morphogenesis by yet unknown signaling pathways.

Animals↗

PubMed2003

Overexpression of hepatocyte growth factor receptor in renal carcinoma cells indirectly stimulates tumor growth in vivo.

We examined the role of increased expression of HGFR kinase in in vivo growth of renal carcinoma. Human renal carcinoma cell line, ACHN cells, was transfected with plasmid encoding wild-type HGFR gene to generate cell lines with increased HGFR protein. ACHN cells with elevated HGFR expression, denoted clones 8 and 10, respectively, showed higher basal kinase activities of HGFR and PI3-kinase than those of empty-vector (mock)-transfected cells. Clone 8 and 10 cells grew similar to mock cells in culture. In mice, tumors of these clones grew more rapidly than those of mock cells. Microvessel density of clone 8 or 10 tumors was higher than that of mock tumors. Clone 8 and 10 cells secreted vascular endothelial growth factor-A (VEGF-A) more than mock cells and the secretion was PI3-kinase inhibitor, LY294002-sensitive. Anti-VEGF-A neutralizing antibody significantly inhibited tumor growth of clones 8 and 10 in mice. These results indicate for the first time that overexpression of HGFR tyrosine kinase in renal carcinoma cells participates in rapid tumor growth in vivo.

Animals↗

PubMed2003

Serum insulin-like growth factor binding protein-3/prostate-specific antigen ratio is a useful predictive marker in patients with advanced prostate cancer.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) play an important role in regulation of prostate cancer cell growth. We studied the prognostic significance of serum IGF-1 and IGFBP-3 levels, and IGF-1/prostate-specific antigen (PSA) and IGFBP-3/PSA ratios in patients with prostate cancer. METHODS: Serum levels of IGF-1, IGFBP-3, and PSA were determined in 112 patients diagnosed with prostate cancer. Serum samples from 32 patients with histologically confined benign prostatatic hyperplasia (BPH) served as control. RESULTS: Serum IGF-1 levels were significantly higher in advanced prostate cancer (n = 84) than in BPH patients (P < 0.01). IGFBP-3 levels were significantly lower in patients with advanced prostate cancer than in localized tumor (n = 28) or BPH (P < 0.05, each). Univariate analysis showed that serum PSA, IGF-1/PSA ratio, IGFBP-3/PSA ratio, T, N and M classifications correlated significantly with relapse-free survival of advanced prostate cancer patients treated with hormonal therapy. Multivariate analysis identified IGFBP-3/PSA ratio as the only significant variable for relapse-free survival (odds ratio 5.81, 95% CI 1.57-21.51). IGFBP-3/PSA ratio was also an independent predictor of cause-specific survival (stepwise analysis, odds ratio 4.86, P < 0.01). CONCLUSIONS: Our results suggested that IGFBP-3/PSA ratio might be a useful prognostic marker of advanced prostate cancer.

Aged↗

PubMed2003

The novel imprinted carboxypeptidase A4 gene ( CPA4) in the 7q32 imprinting domain.

By a search for novel human imprinted genes in the vicinity of the imprinted gene MEST, at chromosome 7q32, we identified the carboxypeptidase A4 gene ( CPA4) in a gene cluster of the carboxypeptidase family, 200 kb centromeric to MEST. Because CPA4 was originally identified as a protein induced in a prostate cancer cell line (PC-3) by histone deacetylase inhibitors, and was located at the putative prostate cancer-aggressiveness locus at 7q32, we investigated its imprinting status in fetal tissues and in adult benign hypertrophic prostate (BPH). RT-PCR using four intragenic polymorphisms as markers showed that CPA4 was expressed preferentially from the maternal allele in the fetal heart, lung, liver, intestine, kidney, adrenal gland, and spleen, but not in the fetal brain. It was also preferentially expressed in the BPH. These findings support that CPA4 is imprinted and may become a strong candidate gene for prostate cancer-aggressiveness. As a Silver-Russell syndrome (SRS) locus has been proposed to be located to a region near MEST and to be involved in imprinting, CPA4 would have been a candidate gene for SRS. However, analysis of ten SRS patients revealed no mutations in CPA4.

Adrenal Glands↗

PubMed2003

Sonic hedgehog induces capillary morphogenesis by endothelial cells through phosphoinositide 3-kinase.

Sonic hedgehog (Shh) acts as a morphogen in many cell types. Recent studies have shown that hedgehog signaling is involved in vascular development as well as postnatal angiogenesis. However, the direct action of Shh on cultured endothelial cells has not been clearly shown. To address this issue, we examined the effect of Shh on morphological changes by murine brain capillary endothelial cells (IBE cells) and human umbilical endothelial cells (HUVECs). Shh induced capillary morphogenesis by these cells. The effect was inhibited by cyclopamine or pertussis toxin. Shh-induced capillary morphogenesis was also blocked by LY294002, a phosphoinositide 3-kinase (PI3-kinase) inhibitor. Shh rapidly increased PI3-kinase activity in IBE cells and HUVECs; this activity was inhibited by cyclopamine. Nuclear localization of Gli1 was increased in Shh-treated IBE cells, which was not affected by LY294002. Actinomycin D and cycloheximide inhibited Shh-induced capillary morphogenesis. In IBE cells expressing kinase-inactive c-Fes, Shh failed to stimulate PI3-kinase activity and capillary morphogenesis. Considered collectively, Shh induced capillary morphogenesis of endothelial cells through both rapid activation of c-Fes/PI3-kinase pathways and transcriptionally regulated pathways.

Animals↗

PubMed2003

Correlation study showing no concordance between EPAS-1/HIF-2alpha mRNA and protein expression in transitional cellcancer of the bladder.

OBJECTIVES: Endothelial Per-ARNT-Sim (PAS) domain protein-1 (EPAS-1)/hypoxia-inducible factor (HIF)-2alpha is a recently identified, endothelial-specific, hypoxia-induced transcription factor and is reputed to have an important role in tumor angiogenesis and tumor progression. Only a few studies have reported on the clinical correlation with grade, stage, necrosis, and microvessel density in transitional cell carcinoma of the bladder. In vitro studies have reported no concordance of EPAS-1/HIF-2alpha mRNA and protein expression. We sought to elucidate these two issues. METHODS: Surgical specimens from 110 patients with transitional cell carcinoma comprised the study, including 51 from radical cystectomy and 59 from transurethral resection of bladder tumor. Immunohistochemistry and in situ hybridization were performed with antibodies against EPAS-1/HIF-2alpha, CD31, and a human EPAS-1/HIF-2alpha cDNA subclone probe. RESULTS: EPAS-1/HIF-2alpha protein expression was found almost exclusively in high-grade and high-stage tumors (P <0.0001). EPAS-1/HIF-2alpha mRNA expression was detectable only in high-grade (grade 3) and high-stage (pT3a or greater) cases with positive EPAS-1/HIF-2alpha protein expression (P = 0.0017). The presence of necrosis correlated with EPAS-1/HIF-2alpha expression, tumor grade, and tumor stage (P <0.0001). Microvessel density was much lower in invasive, larger tumor nodules in EPAS-1/HIF-2alpha-positive cases than in the negative cases (P <0.0001). CONCLUSIONS: EPAS-1/HIF-2alpha protein and mRNA levels correlate with higher grade and advanced bladder transitional cell carcinoma. In lower stage cases, no concordance was found between transcription and translation of EPAS-1/HIF-2alpha gene expression. Because EPAS-1/HIF-2alpha mRNA is only detectable in highly invasive cancer cases, it may serve as a therapeutic target (eg, by an antisense mRNA approach) for bladder cancer.

Adult↗

PubMed2003

EPO-producing gastric carcinoma in a hemodialysis patient.

A case of erythrocytosis caused by gastric cancer that produced erythropoietin is described. To the authors' knowledge, no case of erythropoietin-producing gastric cancer has been reported until now. A 73-year-old man with a 4-year history of maintenance hemodialysis for diabetic nephropathy required phlebotomy. Serum erythropoietin level was 181 mU/mL (181 IU/L). Gastroscopy results showed rough mucosa with hemorrhaging caused by gastric cancer. The patient underwent distal gastrectomy, and serum erythropoietin level decreased to 27.1 mU/mL (27.1 IU/L) by postoperative day 8. Existence of erythropoietin in the tumor tissue was confirmed immunohistochemically. The presence of severe acquired cystic disease of the kidney, renal cell carcinoma, and other malignant tumors should be investigated in hemodialysis patients displaying erythrocytosis.

Adenocarcinoma↗

PubMed2003

Spontaneous rupture of an aneurysmal intrarenal arteriovenous fistula.

We present a 65-year-old woman who was found to have a spontaneous rupture of an aneurysmal intrarenal arteriovenous fistula. To our knowledge, the present case is only the 3rd reported in the literature. The preferred method of treatment of ruptures of arteriovenous fistulae is embolization. However, the process of choosing among embolization, surgery, or a combination of both procedures must be individualized for each patient based on vital signs and symptoms.

Aged↗

PubMed2003

Zone-dependent expression of estrogen receptors alpha and beta in human benign prostatic hyperplasia.

Estrogen, which acts through estrogen receptors (ERs) alpha and beta, has been implicated in the pathogenesis of benign and malignant human prostatic tumors, i.e. benign prostatic hyperplasia and prostate cancer, thought to originate from different zones of the prostate [the transition zone (TZ) and peripheral zone (PZ), respectively]. Here, we examined the cellular distribution of ERalpha and ERbeta in human normal and hyperplastic prostate tissues, using in situ hybridization and immunohistochemistry. ERalpha expression was restricted to stromal cells of PZ. In contrast, ERbeta was expressed in the stromal cells of PZ as well as TZ. ERbeta-positive epithelial cells were evenly distributed in PZ and TZ of the prostate. Our results suggest that estrogen may play a crucial role in the pathogenesis of benign prostatic hyperplasia through ERbeta.

Aged↗

PubMed2003

[First line therapy in the treatment of metastatic prostate cancer].

Hormonal therapy has been the main treatment for advanced prostate cancer for the past six decades. Maximum androgen blockade (MAB), combination therapy with castration and antiandrogens, has been compared with castration monotherapy since the late 1980s. However, the results of the different trials have been conflicting. Recently published meta-analyses have revealed that MAB with non-steroidal antiandrogens is slightly superior to monotherapy (surgical or medical castration) in the treatment of advanced prostate cancer, and that MAB has more adverse effects. The question of whether the modest survival advantage of MAB balances with the increase in adverse effects should be investigated. Some studies indicated that the survival of metastatic prostate cancer patients treated with immediate therapy was similar to that of men in whom treatment was delayed. Hormonal therapy has side effects and is costly, and delayed treatment may be beneficial to elderly men with silent metastasis. Intermittent hormonal therapy is a controversial approach to management of advanced prostate cancer, although laboratory data suggest that intermittent androgen deprivation may prolong the duration of androgen dependence. Intermittent hormonal therapy for patients with metastatic prostate cancer needs to be assessed in a randomized trial to determine the effect on overall survival and quality of life. Our results in a randomized clinical trial of chemo-endocrine therapy versus endocrine therapy alone suggested that the addition of chemotherapy (cisplatin plus pirarubicin) to initial endocrine therapy might be beneficial to patients with advanced prostate cancer, especially an aggressive form of prostate cancer. However, chemo-endocrine therapy should be considered an experimental approach at present.

Androgen Antagonists↗

PubMed2003

[Clinical study of sarcomatoid renal cell carcinoma].

Patients with sarcomatoid renal cell carcinoma are rare and have poor survival. We evaluated 14 patients who had renal cell carcinoma with a sarcomatoid component between 1982 and 2000. There were 9 men and 5 women with a median age of 59.5 years (range 32 to 77). Seven patients had a tumor on the right side and 7 on the left side. Thirteen patients had some symptoms and 11 had metastases at the initial visit. Most of them were stage T4 and high nuclear grade cancer and showed elevated acute phase reactants. There were 7 patients followed by interferon therapy, and the cause-specific 5-year survival rate was less than 10%. We confirmed that renal cell carcinoma with a sarcomatoid component often showed local invasion, distant metastasis and poor prognosis.

Adult↗

PubMed2003

Expression of thrombospondin-derived 4N1K peptide-containing proteins in renal cell carcinoma tissues is associated with a decrease in tumor growth and angiogenesis.

PURPOSE: We have reported that the 4N1K peptide (KRFYVVMWKK) from thrombospondin (TSP) 1 has antiangiogenic activities. The goal of this study was to examine whether the expression of 4N1K-containing proteins correlates with reduced growth of human renal cell carcinoma (RCC). EXPERIMENTAL DESIGN: We examined the expression of 4N1K-containing proteins and TSP1, microvessel density, proliferation index, and apoptotic index in 119 surgically excised RCC tissues by immunohistochemical techniques. The correlation between the above variables and clinicopathological features was analyzed statistically. RESULTS: The antibody raised against the 4N1K peptide recognized protein fragments of matrix metalloproteinase 3-digested TSP1 and positively stained the sections of renal cancer tissues. These reactions disappeared when the antibody was preincubated with immobilized 4N1K peptide, suggesting that the reactions were 4N1K peptide specific. Although TSP1 expression did not correlate with various clinicopathological features and tumor size, all 4N1K-positive tumors were locally confined and of significantly smaller size (median, 3.3 cm; range, 2.0-4.4 cm) than 4N1K-negative tumors (median, 5.2 cm; range, 2.8-8.8 cm; P < 0.001). 4N1K-positive tumors exhibited significantly lower microvessel density and higher apoptotic index of tumor cells than 4N1K-negative tumors (P < 0.001 and P = 0.042, respectively). CONCLUSIONS: Our data suggest that expression of 4N1K-containing proteins in tumor tissues is associated with reduced angiogenesis and tumor growth; thus, it would be a potentially predictive marker for progression of RCC.

Adult↗

PubMed2003

Expression of cyclooxygenase-2 in renal cell carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, expression of matrix metalloproteinase-2, and survival.

PURPOSE: Cyclooxygenase (COX)-2 plays an important role in tumor cell proliferation, resistance to apoptosis, angiogenesis, and invasion in various malignant tumors. However, the relationships between COX-2 expression and these biological processes, clinicopathological features, and survival rate in patients with renal cell carcinoma are not clear. EXPERIMENTAL DESIGN: Tumor sections surgically removed from 131 patients were examined for COX-2 expression by immunohistochemistry. We also examined Ki-67 labeling index, apoptotic index, microvessel density, and matrix metalloproteinase (MMP)-2 expression, and correlated COX-2 expression with various clinicopathological features and survival. RESULTS: Of 131 sections, 70 (53.4%) were positive for COX-2 expression. COX-2 expression was associated significantly with various clinicopathological features, and correlated with the Ki-67 labeling index, microvessel density, and MMP-2 expression (P < 0.01), but not with the apoptotic index (P = 0.054). COX-2 expression was also identified as an independent risk factor for large tumor size (>7 cm) in multivariate logistic regression model. COX proportional hazards analysis showed that distant metastasis and high T stage were independent prognostic factors [odds ratio (OR), 9.41; 95% confidence interval (CI), 2.16-41.11; P < 0.01 and OR, 5.19; 95% CI, 1.02-26.54; P = 0.048, respectively), whereas COX-2 expression was not (OR, 1.46; 95% CI, 0.24-9.00; P = 0.68). CONCLUSION: COX-2 expression in patients with renal cell carcinoma is associated with several clinicopathological factors, and appeared to play an important role in tumor cell proliferation and MMP-2 expression, but is not a significant prognostic factor.

Adult↗

PubMed2002

Stromal cell-derived factor-1alpha induces tube-like structure formation of endothelial cells through phosphoinositide 3-kinase.

Stromal cell-derived factor-1alpha (SDF-1alpha) is a CXC chemokine, which induces tube formation of endothelial cells. Although SDF-1alpha transduces signals via CXC receptor 4 (CXCR4), resulting in activating a panel of downstream signaling molecules, such as phosphoinositide 3-kinase (PI3-kinase), little is known about the SDF-1alpha-mediated signaling pathways leading to tube formation. Here we examined the signal transduction pathway involved in SDF-1alpha-mediated tube formation by primary human umbilical endothelial cells and murine brain capillary endothelial cell line (IBE (immortalized murine brain capillary endothelial) cells). SDF-1alpha stimulated tube formation by IBE cells, which was blocked by LY294002 and pertussis toxin, suggesting that PI3-kinase and G(i) protein were involved in this process. SDF-1 also stimulated tube formation of human umbilical endothelial cells, and the response was LY294002-sensitive. SDF-1alpha activated PI3-kinase in IBE cells. In stable IBE cell lines expressing either the mutant p85 subunit of PI3-kinase (denoted Deltap85-8 cells), which lacks association with the p110 subunit, or kinase-inactive c-Fes (denoted KEFes 5-15 cells), SDF-1alpha failed to activate PI3-kinase and to stimulate tube formation. SDF-1alpha-induced tube formation was inhibited by an antibody against murine vascular endothelial cadherin. The antibody as well as LY294002 attenuated SDF-1alpha-mediated compact cell-cell contact, which proceeded to tube formation. Taken together, SDF-1alpha induces compact cell-cell contact through PI3-kinase, resulting in tube formation of endothelial cells.

Animals↗

PubMed2002

Negative regulation of urokinase-type plasminogen activator production through FGF-2-mediated activation of phosphoinositide 3-kinase.

Activation of phosphoinositide 3-kinase (PI3-kinase) is involved in many cellular responses. FGF-2 is one of the potent inducers of urokinase-type plasminogen activator (uPA) production in endothelial cells. However, little is known about the molecular mechanisms underlying FGF-2-mediated uPA production. Here we examined the signal transduction pathways involved in the regulation of uPA production by FGF-2-treatment. FGF-2 potently upregulated uPA production in murine brain capillary endothelial cells (IBE cells), as well as porcine aortic endothelial (PAE) cells and L6 myoblasts ectopically expressing FGFR1. PI3-kinase inhibitors, wortmannin and LY294002, both enhanced FGF-2-dependent uPA production by these cells. Stable expression of activated mutant p110alpha catalytic subunit of PI3-kinase into IBE cells decreased FGF-2-mediated uPA production, suggesting that PI3-kinase exhibited the negative regulatory effect on uPA production. No increase in FGF-2-induced PI3-kinase activity was observed in proteins immunoprecipitated by anti-phosphotyrosine antibody. Although stable expression of deleted mutant p85alpha regulatory subunit, which lacks association with p110 catalytic subunit, in IBE cells showed no dominant negative effect, transient expression of dominant negative Ras inhibited FGF-2-mediated PI3-kinase activation. These results suggest that only activated Ras contributed the FGF-2-mediated PI3-kinase activation. In cells stably expressing mutant p85alpha subunit, FGF-2 efficiently induced uPA production. Taken together, activation of PI3-kinase by FGF-2 is Ras-dependent and results in down-regulation of uPA production.

Animals↗

PubMed2002

Effects of vitamin D(3)-binding protein-derived macrophage activating factor (GcMAF) on angiogenesis.

BACKGROUND: The vitamin D(3)-binding protein (Gc protein)-derived macrophage activating factor (GcMAF) activates tumoricidal macrophages against a variety of cancers indiscriminately. We investigated whether GcMAF also acts as an antiangiogenic factor on endothelial cells. METHODS: The effects of GcMAF on angiogenic growth factor-induced cell proliferation, chemotaxis, and tube formation were examined in vitro by using cultured endothelial cells (murine IBE cells, porcine PAE cells, and human umbilical vein endothelial cells [HUVECs]) and in vivo by using a mouse cornea micropocket assay. Blocking monoclonal antibodies to CD36, a receptor for the antiangiogenic factor thrombospondin-1, which is also a possible receptor for GcMAF, were used to investigate the mechanism of GcMAF action. RESULTS: GcMAF inhibited the endothelial cell proliferation, chemotaxis, and tube formation that were all stimulated by fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor-A, or angiopoietin 2. FGF-2-induced neovascularization in murine cornea was also inhibited by GcMAF. Monoclonal antibodies against murine and human CD36 receptor blocked the antiangiogenic action of GcMAF on the angiogenic factor stimulation of endothelial cell chemotaxis. CONCLUSIONS: In addition to its ability to activate tumoricidal macrophages, GcMAF has direct antiangiogenic effects on endothelial cells independent of tissue origin. The antiangiogenic effects of GcMAF may be mediated through the CD36 receptor.

Angiogenesis Inhibitors↗

PubMed2002

Donor-specific blood transfusion prolongs cardiac allograft survival in rats by low nitric oxide production and elevated serum levels of prostaglandin E(2).

Donor-specific blood transfusion (DST) improves allograft survival, although the exact mechanism(s) is not completely understood. The purpose of this study was to determine the role of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in DST-protective effects, using a rat cardiac transplantation model. Lewis rats (RT-1(1)) were transfused with fully allogeneic ACI rats (RT-l(a)) blood (DST group) or Lewis syngeneic blood (ST) through the portal vein 7 days prior to allogeneic cardiac transplantation. Posttransplantation, aminoguanidine (AG)-treated rat received continuous intravenous infusion of AG, an inhibitor of inducible nitric oxide synthase (iNOS). The survival times of grafted hearts were 5.7+/-0.5, 6.8+/-0.8 and 9.2+/-1.2 days in ST, ST/AG, and DST groups (n=6 for each group), respectively. Inhibition of iNOS in ST/AG group prolonged allograft survival, but it was shorter than that in DST rats. Serum nitrite/nitrate levels on postgrafting day 5 were significantly higher in ST than in ST/AG and DST groups, but were similar in ST/AG and DST groups. These results were confirmed by immunohistochemical staining with anti-iNOS antibody. Serum PGE(2) concentrations in DST rats were significantly higher than in ST and ST/AG groups. Our results suggest that DST prolongs graft survival by enhanced production of PGE(2) with a resultant suppression of immune activation. In addition, DST-induced prolongation of graft survival may be partially mediated by NO suppression.

Animals↗

PubMed2002

Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of a randomized trial with epirubicin comparing short-term versus long-term maintenance treatment.

PURPOSE: Intravesical instillation of epirubicin (EPI) is one of the most effective adjuvant therapies for non-muscle-invasive bladder cancer after transurethral resection. We evaluated the optimal duration of EPI instillation in a multi-institution prospective randomized clinical study. METHODS: Between June 1995 and May 1998, a total of 125 patients with superficial bladder cancer (transitional cell carcinoma grade 1 or 2) were enrolled in this study, and 102 patients were fully evaluated for recurrence. Two protocols for intravesical therapy (arm A - 30 mg EPI/30 ml saline 19 times over 1 year; arm B - 30 mg EPI/30 ml 12 times over 5 months) were established. Instillations were given every week for 4 weeks and then every 2 weeks for 4 months in arm B. After 5 months of treatment, maintenance was performed with seven further instillations (one every month for 7 months) in arm A. The analyzed background factors were the therapeutic method, gender, history (primary or recurrent tumor), stage (T classification), grade, number of tumors, and tumor size. RESULTS: There were no significant differences in the analyzed background factors between the two arms, and there were no serious side effects in the study. In an intent-to-treat analysis, the overall 3-year recurrence-free survival rates were 48.5% in arm A and 55.1% in arm B. The difference between the two groups was not significant. CONCLUSIONS: This analysis indicated that extended prophylactic maintenance instillation of EPI was not significantly effective in reducing bladder cancer recurrence.

Administration, Intravesical↗