An optimal method of hydrogel spacer insertion for stereotactic body radiation therapy of prostate cancer.

PURPOSE: This study aimed to explore an ideal method for hydrogel spacer insertion by analyzing the efficacy and safety of our originally developed apex expansion method. MATERIALS AND METHODS: Overall, 100 patients with low- and intermediate-risk localized prostate cancer treated with stereotactic body radiation therapy were included. A hydrogel spacer was inserted in 64 and 36 patients using the conventional and apex expansion methods, respectively. For dosimetry, we trisected the rectum into the upper rectum, middle rectum, and lower rectum on the sagittal section of magnetic resonance imaging. We compared the dose to each part of the rectum between the two methods using dose-volume histograms. Genitourinary and gastrointestinal toxicity assessments were conducted until 3 months of follow-up. RESULTS: The whole rectal dose in the apex expansion method group was lower than that in the conventional method group, which was significant in all dose regions (V5-V35). Similarly, in the apex expansion method group, the dose to the middle rectum was lower in the low- to high-dose region (V10-V35), and the dose to the lower rectum was lower in the middle- to high-dose region (V15-35). No Grade ≥ 3 toxicity or procedure-related complications were observed. Additionally, Grade 2 genitourinary and gastrointestinal toxicities during the treatment showed no significant differences between the two methods. CONCLUSION: The apex expansion method may be safe and effective in achieving a more efficient rectal dose reduction by expanding the anterior perirectal space in the prostatic apex area.

Vasohibin-1 expression as a biomarker of aggressive nature in ductal adenocarcinoma of the prostate: a retrospective cohort study at two centres in Japan.

OBJECTIVES: Vasohibin-1 (VASH1) is an endogenous angiogenesis regulator expressed in activated vascular endothelial cells. We previously reported that high VASH1 expression is a predictor of progression in acinar adenocarcinoma of the prostate. In this study, we evaluated the characteristics of ductal adenocarcinoma of the prostate by comparing the level of VASH1 expression between ductal and acinar adenocarcinoma specimens. DESIGN AND SETTING: A retrospective cohort study at two centres in Japan. PARTICIPANTS: Among the 1495 patients who underwent radical prostatectomy or transurethral resection for the past 15 years, a total of 14 patients diagnosed with ductal adenocarcinoma and 20 patients diagnosed with acinar adenocarcinoma with a Gleason score of 4+4 were included. INTERVENTIONS: We immunohistochemically examined the CD34 expression as the microvessel density (MVD) and activated endothelial cells as the VASH1 density (vessels per mm2). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the association of MVD and VASH1 density between ductal and acinar adenocarcinoma, and the secondary outcome was their oncological outcomes. RESULTS: Nine patients (64.3%) with ductal adenocarcinoma were diagnosed at an advanced clinical stage, and five patients (35.7%) died from cancer during a median follow-up of 56.0 months. The VASH1 densities (mean±SD) in ductal and acinar adenocarcinoma were 45.1±18.5 vs 16.1±21.0 (p<0.001), respectively, while the MVD (mean±SD) in ductal and acinar adenocarcinoma were 65.3±21.9 vs 80.8±60.7 (p=0.666), respectively. The 5-year cancer-specific survival rates for high and low VASH1 expression were 70.0% and 100.0% (p=0.006), respectively. High VASH1 expression and a diagnosis of ductal adenocarcinoma were significant predictors of cancer-specific survival. CONCLUSIONS: Ductal adenocarcinoma was more aggressive and had higher VASH1 expression than acinar adenocarcinoma, although MVD was equivalent. These results indicate that VASH1 expression may serve as a novel biomarker for the aggressive nature of ductal adenocarcinoma.

Distribution analysis of hydrogel spacer and evaluation of rectal dose reduction in Japanese prostate cancer patients undergoing stereotactic body radiation therapy.

BACKGROUND: To report on our primary experience with the placement of a hydrogel spacer following stereotactic body radiation therapy (SBRT) in low- and intermediate-risk prostate cancer patients and assess its impact on dosimetry as well as acute toxicity. METHODS: A total of 70 patients treated with SBRT (total dose of 36.25 Gy) in 5 fractions were included. Hydrogel spacers were inserted in 53 patients along with gold fiducial markers. For dosimetry, we trisected the rectum on the sagittal image of magnetic resonance imaging and defined it as the upper rectum (UR), middle rectum (MR), and lower rectum (LR). We compared the dose to each part of the rectum with and without hydrogel spacer using dose volume histograms. Genitourinary (GU) and gastrointestinal (GI) toxicity assessments were conducted until 6 months of follow-up visits. RESULTS: The median volume of the hydrogel spacer was 12.3 mL. Overall, the hydrogel spacer could significantly reduce the rectal dose in the middle-to-high-dose region (V20-V35). The rectum doses at the UR and MR were significantly lower in the spacer group in the middle to high dose region (V20-V35); the dose at the LR was significantly lower in the spacer group in the high-dose region (V30-V35). There was no grade ≥ 3 toxicity observed, but grade 2 toxicity of GU and GI occurred in 17.1% and 1.4% of the patients, respectively. CONCLUSION: Hydrogel spacers could contribute to rectal dose reduction, especially in high dose regions, by creating a prostate-rectum distance.

PREDICTIVE FACTORS OF THE INITIAL TREATMENT FOR 207 BLUNT RENAL TRAUMA CASES BASED ON THE CLASSIFICATION FOR RENAL INJURY OF JAPANESE ASSOCIATION FOR THE SURGERY OF TRAUMA 2008's VERSION.

(Objective) We retrospectively investigated the applicability of the Japanese Association for the Surgery of Trauma (JAST) classification version 2008 for renal injuries as predictive factors of the initial treatment for 207 blunt renal injury cases. (Materials and methods) We reviewed 207 patients between 1982 and 2013 who were admitted to our institution with blunt renal trauma. Patients were classified as conservative management group, immediate transcatheter arterial embolization (TAE) group, and immediate nephrectomy group by initial treatment. We retrospectively assessed several parameters including JAST criteria version 2008 type of renal injury (type), severity of hematoma (H factor) and extravasation of urine (U factor), the shock on arrival, associated abdominal injuries, serum hemoglobin levels, and macrohematuria as predicting factors of initial treatment of blunt renal trauma. (Result) TypeIII and PV injuries, H2 factor and associated non-renal abdominal injuries were predictive factors of immediate nephrectomy (p=0.001, p=0.000, p=0.003). TypeIII and PV injuries and H2 factor were predictive factors of immediate TAE. Both of H2 and U2 factors were significant predictors of immediate nephrectomy in patients with typeIII injury. H factor was a significantly predictive factor of immediate TAE in patients with typeI/II injuries (p=0.040). The rate of immediate TAE has been increasing but the rate of partial nephrectomy except for nephrectomy has been decreasing since the year 2007 when TAE was immediately available in our hospital. (Conclusion) The type category and severity of hematoma of JAST classification version 2008 would be predictive factors of initial management of blunt renal injuries. Patients with typeIII injuries and both of H2 and U2 factors, can be adapted to immediate nephrectomy. Patients with typeI/II and H2 factors can be adapted to immediate TAE.

MUC1-C oncoprotein induces TCF7L2 transcription factor activation and promotes cyclin D1 expression in human breast cancer cells.

MUC1 is a heterodimeric glycoprotein that is overexpressed in breast cancers. The present studies demonstrate that the oncogenic MUC1 C-terminal subunit (MUC1-C) associates with the TCF7L2 transcription factor. The MUC1-C cytoplasmic domain (MUC1-CD) binds directly to the TCF7L2 C-terminal region. MUC1-C blocks the interaction between TCF7L2 and the C-terminal-binding protein (CtBP), a suppressor of TCF7L2-mediated transcription. TCF7L2 and MUC1-C form a complex on the cyclin D1 gene promoter and MUC1-C promotes TCF7L2-mediated transcription by the recruitment of ß-catenin and p300. Silencing MUC1-C in human breast cancer cells down-regulated activation of the cyclin D1 promoter and decreased cyclin D1 expression. In addition, a MUC1-C inhibitor blocked the interaction with TCF7L2 and suppressed cyclin D1 levels. These findings indicate that the MUC1-C oncoprotein contributes to TCF7L2 activation and thereby promotes cyclin D1 expression in breast cancer cells.

Inhibition of the MUC1-C oncoprotein induces multiple myeloma cell death by down-regulating TIGAR expression and depleting NADPH.

The MUC1-C oncoprotein is aberrantly expressed in most multiple myeloma cells. However, the functional significance of MUC1-C expression in multiple myeloma is not known. The present studies demonstrate that treatment of multiple myeloma cells with a MUC1-C inhibitor is associated with increases in reactive oxygen species (ROS), oxidation of mitochondrial cardiolipin, and loss of the mitochondrial transmembrane potential. The MUC1-C inhibitor-induced increases in ROS were also associated with down-regulation of the p53-inducible regulator of glycolysis and apoptosis (TIGAR). In concert with the decrease in TIGAR expression, which regulates the pentose phosphate pathway, treatment with the MUC1-C inhibitor reduced production of NADPH, and in turn glutathione (GSH) levels. TIGAR protects against oxidative stress-induced apoptosis. The suppression of TIGAR and NADPH levels thus contributed to ROS-mediated late apoptosis/necrosis of multiple myeloma cells. These findings indicate that multiple myeloma cells are dependent on MUC1-C and TIGAR for maintenance of redox balance and that targeting MUC1-C activates a cascade involving TIGAR suppression that contributes to multiple myeloma cell death.

MUC1-C oncoprotein regulates glycolysis and pyruvate kinase M2 activity in cancer cells.

Aerobic glycolysis in cancer cells is regulated by multiple effectors that include Akt and pyruvate kinase M2 (PKM2). Mucin 1 (MUC1) is a heterodimeric glycoprotein that is aberrantly overexpressed by human breast and other carcinomas. Here we show that transformation of rat fibroblasts by the oncogenic MUC1-C subunit is associated with Akt-mediated increases in glucose uptake and lactate production, consistent with the stimulation of glycolysis. The results also demonstrate that the MUC1-C cytoplasmic domain binds directly to PKM2 at the B- and C-domains. Interaction between the MUC1-C cytoplasmic domain Cys-3 and the PKM2 C-domain Cys-474 was found to stimulate PKM2 activity. Conversely, epidermal growth factor receptor (EGFR)-mediated phosphorylation of the MUC1-C cytoplasmic domain on Tyr-46 conferred binding to PKM2 Lys-433 and inhibited PKM2 activity. In human breast cancer cells, silencing MUC1-C was associated with decreases in glucose uptake and lactate production, confirming involvement of MUC1-C in the regulation of glycolysis. In addition, EGFR-mediated phosphorylation of MUC1-C in breast cancer cells was associated with decreases in PKM2 activity. These findings indicate that the MUC1-C subunit regulates glycolysis and that this response is conferred in part by PKM2. Thus, the overexpression of MUC1-C oncoprotein in diverse human carcinomas could be of importance to the Warburg effect of aerobic glycolysis.

Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells.

Non-small cell lung cancer (NSCLC) cells are often associated with constitutive activation of the phosphoinositide 3-kinase (PI3K) → Akt → mTOR pathway. The mucin 1 (MUC1) heterodimeric glycoprotein is aberrantly overexpressed in NSCLC cells and induces gene signatures that are associated with poor survival of NSCLC patients. The present results show that the MUC1 C-terminal subunit (MUC1-C) cytoplasmic domain associates with PI3K p85 in NSCLC cells. We show that inhibition of MUC1-C with cell-penetrating peptides blocks this interaction with PI3K p85 and suppresses constitutive phosphorylation of Akt and its downstream effector, mTOR. In concert with these results, treatment of NSCLC cells with the MUC1-C peptide inhibitor GO-203 was associated with downregulation of PI3K → Akt signaling and inhibition of growth. GO-203 treatment was also associated with increases in reactive oxygen species (ROS) and induction of necrosis by a ROS-dependent mechanism. Moreover, GO-203 treatment of H1975 (EGFR L858R/T790M) and A549 (K-Ras G12S) xenografts growing in nude mice resulted in tumor regressions. These findings indicate that NSCLC cells are dependent on MUC1-C both for activation of the PI3K → Akt pathway and for survival.

MUC1-C oncoprotein promotes STAT3 activation in an autoinductive regulatory loop.

Signal transducer and activator of transcription 3 (STAT3) is activated in human breast cancer and other malignancies. Mucin 1 (MUC1) is a heterodimeric cell surface glycoprotein that is overexpressed in human carcinomas and, like STAT3, promotes cell survival and induces transformation. We found that in breast cancer cells, the MUC1 carboxyl-terminal receptor subunit (MUC1-C) associates with the gp130-Janus-activated kinase 1 (JAK1)-STAT3 complex. The MUC1-C cytoplasmic domain interacted directly with JAK1 and STAT3, and MUC1-C was necessary for JAK1-mediated STAT3 activation. In turn, MUC1-C and activated STAT3 occupied the promoter of MUC1, and MUC1-C contributed to STAT3-mediated activation of MUC1 transcription. The MUC1-C inhibitor GO-201 blocked the MUC1-C interaction with STAT3, thereby decreasing MUC1-C and STAT3 occupancy on the MUC1 and STAT3 promoters and activation of STAT3 target genes, including MUC1 itself. These findings indicate that MUC1-C promotes STAT3 activation and that MUC1-C and STAT3 function in an autoinductive loop that may play a role in cancer cell survival.

Terminal differentiation of chronic myelogenous leukemia cells is induced by targeting of the MUC1-C oncoprotein.

Chronic myelogenous leukemia (CML) is caused by expression of the Bcr-Abl fusion protein in hematopoietic stem cells. The MUC1-C oncoprotein is expressed in CML blasts and stabilizes Bcr-Abl. The present studies demonstrate that treatment of KU812 and K562 CML cells with GO-201, a cell-penetrating peptide inhibitor of MUC1-C oligomerization, downregulates Bcr-Abl expression and inhibits cell growth. In concert with decreases in Bcr-Abl levels, KU812 and K562 cells responded to GO-201 with induction of a differentiated myeloid phenotype as evidenced by increased expression of CD11b, CD11c and CD14. The results also show that the GO-201-treated cells undergo a late apoptotic/necrotic response, consistent with induction of terminal differentiation. Primary CML blasts expressing MUC1 similarly responded to GO-201 with induction of a more differentiated phenotype and late apoptosis/necrosis. In addition, treatment of KU812 xenografts in nude mice was associated with upregulation of CD11 and tumor regression. These findings indicate that CML blasts respond to targeting of the MUC1-C oncoprotein with induction of terminal differentiation.

Survival of human multiple myeloma cells is dependent on MUC1 C-terminal transmembrane subunit oncoprotein function.

The MUC1 C-terminal transmembrane subunit (MUC1-C) oncoprotein is a direct activator of the canonical nuclear factor-kappaB (NF-kappaB) RelA/p65 pathway and is aberrantly expressed in human multiple myeloma cells. However, it is not known whether multiple myeloma cells are sensitive to the disruption of MUC1-C function for survival. The present studies demonstrate that peptide inhibitors of MUC1-C oligomerization block growth of human multiple myeloma cells in vitro. Inhibition of MUC1-C function also blocked the interaction between MUC1-C and NF-kappaB p65 and activation of the NF-kappaB pathway. In addition, inhibition of MUC1-C in multiple myeloma cells was associated with activation of the intrinsic apoptotic pathway and induction of late apoptosis/necrosis. Primary multiple myeloma cells, but not normal B-cells, were also sensitive to MUC1-C inhibition. Significantly, treatment of established U266 multiple myeloma xenografts growing in nude mice with a lead candidate MUC1-C inhibitor resulted in complete tumor regression and lack of recurrence. These findings indicate that multiple myeloma cells are dependent on intact MUC1-C function for constitutive activation of the canonical NF-kappaB pathway and for their growth and survival.

Potent cytotoxic effect of a novel nuclear factor-kappaB inhibitor dehydroxymethylepoxyquinomicin on human bladder cancer cells producing various cytokines.

OBJECTIVES: To explore the potential therapeutic effects of the nuclear factor-kappaB (NF-kappaB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ). KU-19-19 cells, originally derived from a patient with invasive bladder cancer who exhibited marked leukocytosis, produce multiple cytokines. This model of clinically advanced bladder cancer, in which NF-kappaB is constitutively activated, was used in this study. METHODS: Expression of p65 protein in fractionated KU-19-19 cells was determined by Western blotting analysis. DNA-binding activity of NF-kappaB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis by DHMEQ were analyzed, and cytokines in the supernatant of KU-19-19 cells cultured with or without DHMEQ were measured by enzyme-linked immunosorbent assay (ELISA). Athymic nude mice bearing KU-19-19 subcutaneous tumors were subjected to intraperitoneal administration of 2 mg/kg/d DHMEQ for 3 weeks. Tumor growth was monitored and microvessel density, vascular endothelial growth factor expression, and the apoptotic index of tumors were evaluated by tissue immunohistochemistry. RESULTS: NF-kappaB was constitutively activated in KU-19-19 cells. DHMEQ reversibly inhibited the DNA-binding activity of NF-kappaB by blocking its nuclear translocation. Both cell viability and production of cytokines were significantly and dose-dependently suppressed by DHMEQ, and significant apoptosis was also induced. In in vivo studies, the mean tumor volume in mice treated with DHMEQ was significantly smaller than in controls. Immunohistochemical analysis of tumors revealed marked reduction in microvessel density, vascular endothelial growth factor expression, and induction of apoptosis. CONCLUSIONS: Blockade of NF-kappaB function by DHMEQ may be a useful new molecular targeting treatment for highly aggressive bladder cancer.

[Primary small cell carcinoma of the ureter: a case report].

An 84-year-old female was referred to our hospital to be examined for left hydronephrosis. Abdominal pelvic computed tomography and ureteroscopy showed an obstructing mass in the left ureter. A biopsy of the mass revealed the presence of small cell carcinoma. A left nephroureterectomy were thus performed.

Tumour length of the largest focus predicts prostate-specific antigen-based recurrence after radical prostatectomy in clinically localized prostate cancer.

OBJECTIVE: To investigate the possible significance of tumour dimensional variables, including maximum tumour diameter (MTD), maximum tumour area (MTA) and total tumour volume (TTV), with standard prognostic factors for predicting prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). PATIENTS AND METHODS: Serial whole sections of the prostate from 164 patients who had RP for localized prostate cancer were investigated. Cox proportional hazards regression models were used for univariate and multivariate analyses to test the relationships between biochemical failure and clinicopathological factors, including tumour dimensional variables. The results were analysed retrospectively to develop a prognostic factor-based model for risk stratification. RESULTS: In the univariate Cox proportional hazard model, pathological T stage, Gleason score, perineural invasion, microvascular invasion, positive surgical margins, MTD, MTA and TTV were significantly associated with biochemical failure. In the multivariate Cox proportional hazard model using a stepwise inclusion of these factors, Gleason score, positive surgical margins and MTD were independent indices in association with biochemical failure. Using the three statistically significant variables, the relative risk of biochemical failure could be calculated. CONCLUSION: These results imply that MTD is possibly one of the most important prognostic factors for predicting biochemical recurrence after RP. As calculating the MTD on the section a rapid, simple and objective method, it can be used instead of the TTV calculation. The prognostic factor- based risk stratification might help clinicians to predict biochemical failure after RP.

Angiotensin II type 1 receptor antagonist enhances cis-dichlorodiammineplatinum-induced cytotoxicity in mouse xenograft model of bladder cancer.

OBJECTIVES: To examine whether candesartan enhances the cytotoxicity of cis-dichlorodiammineplatinum (CDDP) in mice with bladder cancer as a method to enhance the therapeutic effects of CDDP. CDDP is an antitumor agent conventionally used against bladder cancer; however, its therapeutic efficacy appears to not be fully satisfactory. Recent studies have shown the antitumor activity of the angiotensin II type 1 receptor antagonist candesartan. METHODS: A xenograft model was prepared in nude mice using human bladder cancer cells (KU-19-19). Candesartan (1 mg/kg/d) was administered daily by oral gavage from the day of implantation plus 28 days, and CDDP (1 mg/kg/d) was administered intraperitoneally from days 5 to 9. The microvessel density, vascular endothelial growth factor expression, and apoptosis were investigated immunohistochemically. RESULTS: Candesartan, CDDP, and candesartan-CDDP suppressed tumor growth to 41.9%, 33.8%, and 13.2%, respectively, of the tumor volume in the control group, showing that combined treatment significantly inhibited tumor growth compared with each single agent alone. The microvessel density was significantly decreased in the candesartan and candesartan-CDDP groups compared with the control group. Vascular endothelial growth factor expression was significantly decreased in the candesartan, CDDP, and candesartan-CDDP groups compared with the control group. The apoptotic index was significantly increased in the CDDP and candesartan-CDDP groups compared with the control and candesartan groups. CONCLUSIONS: It is quite likely that candesartan and CDDP suppressed tumor growth by inhibiting angiogenesis and inducing apoptosis, respectively. Furthermore, combined treatment with candesartan enhanced CDDP-induced cytotoxicity by further suppressing angiogenesis. These results suggest that candesartan could be a candidate for innovational therapy of bladder cancer.

Brachytherapy with permanent seed implantation.

Permanent interstitial brachytherapy with iodine-125 (I-125) or palladium 103 (Pd-103) seeds is a common treatment option in the United States, and numerous articles on outcomes after long-term follow up have been published. With the treatment's apparent high efficacy and low morbidity, permanent seed implantation has become the most frequently employed procedure for localized prostate cancer and has replaced radical prostatectomy. Even taking into account the good features of the treatment, the performance of permanent seed implantation in Japan had not been allowed because of the country's strict laws on radiation safety. However, after a long period of discussion between Japanese medical associations and the government, permanent interstitial brachytherapy with I-125 was finally approved in Japan in July 2003. The guidelines for this treatment include several restrictions that should be followed by each institution that is to perform the treatment. Over 70 institutes around the country had started the treatment before the end of June 2007. With high expectations for this new radiation therapy, which may be effective, and less invasive than previous treatments and with a low incidence of treatment morbidity, brachytherapy for prostate cancer will become more common in Japan. For the purpose of improving the quality of seed implantation, which may lead to better clinical outcomes and radiation safety, medical conferences and technical training courses have been carried out regularly, and multi-institutional clinical studies have also been carried out countrywide.

Comparison of intraoperative ultrasound with postimplant computed tomography--dosimetric values at Day 1 and Day 30 after prostate brachytherapy.

PURPOSE: To compare the results of intraoperative dosimetry with those of postimplant computed tomography (CT)-based dosimetry after (125)I prostate brachytherapy. METHODS AND MATERIALS: We treated 412 prostate cancer patients with (125)I prostate brachytherapy, with or without external beam radiotherapy at our institution. Neoadjuvant hormone therapy was administered to 331 patients (80.3%). Implantation was performed using an intraoperative interactive technique. Postimplant dosimetry was performed on Day 1 and Day 30 using CT imaging. The dosimetric results for the prostate, urethra, and rectum were compared among intraoperative ultrasound, and CT scans of Day 1 and Day 30. RESULTS: The mean intraoperative minimal dose received by 90% of the prostate volume (D(90)) was 118.8% of the prescribed dose vs. 106.4% for Day 1 (p < 0.01) and 119.2% for Day 30 (p = 0.25). There were no significant correlations between the intraoperative D(90) and the postimplant D(90) values (intraclass correlation coefficients=0.42 and 0.33 for Day 1 and Day 30, respectively). Prostatic edema at Day 1 had the largest effect on the Day 1 D(90) (p < 0.01). The factor significantly affecting the Day 30 D(90) was neoadjuvant hormone therapy (p < 0.01). The mean Day 30 D(90) for the hormone-treated patients was 117.9%, compared with 124.6% for those who remained hormone naïve. The intraoperative and postimplant dosimetric values differed significantly for the urethra and rectum. CONCLUSIONS: Our results demonstrate that there are no significant differences between the D(90) assessments obtained intraoperatively and at Day 30 postoperatively. Furthermore, there are no definite correlations between intra- and postimplantation dosimetric values. Other D(90) values differed significantly between the intraoperative and postimplant dosimetry. This study suggests that dosimetry has negligible clinical utility for informing patients, at discharge, of whether or not their implants are adequate.

Effect of angiotensin II type 1 receptor antagonist on tumor growth and angiogenesis in a xenograft model of human bladder cancer.

Several authors have investigated the antitumor activity of angiotensin II type 1 receptor (AT1R) antagonists, which are widely used as antihypertensive drugs. In this study, we evaluated the efficacy of the AT1R antagonist candesartan against bladder cancer. For the study in vitro, human bladder cancer cells (KU-19-19) were cultured with and without angiotensin II (A II) and candesartan, and cell viability and vascular endothelial growth factor (VEGF) secretion were analyzed. Also for the study in vivo, a tumor xenograft model was prepared in nude mice using KU-19-19 cells. Mice were administered candesartan daily by oral gavage, and paclitaxel via intravenous infusion. Microvessel density, VEGF expression, and apoptosis were investigated. Candesartan did not induce direct toxicity in KU-19-19 cells, but VEGF was significantly lower in candesartan-treated cells than in the A II-treated control cells. In mice, candesartan, paclitaxel and candesartan-paclitaxel significantly suppressed tumor growth to 46.0%, 35.8% and 17.3%, respectively, of the tumor volume in the control group, showing that combined treatment significantly inhibited tumor growth compared to the candesartan group. Microvessel density and VEGF were significantly decreased in the candesartan and candesartan-paclitaxel groups compared to the control group. The apoptotic index was significantly increased in the paclitaxel and candesartan-paclitaxel groups compared to the control and candesartan groups. In our experimental model, candesartan prevented bladder cancer growth by inhibiting angiogenesis. Furthermore, combined treatment with candesartan and paclitaxel enhanced paclitaxel-induced cytotoxicity. These results suggest that the AT1R antagonist candesartan may be a candidate for innovative therapy for bladder cancer.

Rectal morbidity following I-125 prostate brachytherapy in relation to dosimetry.

BACKGROUND: To investigate rectal morbidity after I-125 prostate brachytherapy and to analyze predictive factors of rectal morbidity. METHODS: A group of 227 consecutive patients with localized prostate cancer were treated with I-125 prostate brachytherapy with or without external beam radiotherapy (EBRT) between September 2003 and January 2005. Rectal morbidity (diarrhea, bleeding and pain) was evaluated using the Radiation Therapy Oncology Group (RTOG) criteria. Dosimetry was based on computerized tomography (CT) scan 1 month post-implant. The clinical, treatment-related and dosimetric factors were evaluated for the risk of grade 2 rectal morbidity. Rectal dosimetric factors included the rectal volume that received >100% and 150% of the prescribed dose, and the maximal rectal dose which was defined as the sum of the minimal dose received by 1% of the rectum volume and the prescribed dose of EBRT. RESULTS: Grade 2 rectal bleeding occurred in 10 (4.4%): for nine patients within the first year and for one patient between the first and second year. Grade 2 diarrhea occurred in one patient (0.4%) within the first year. No patient reported grade 2 pain. In the univariate analysis with grade 2 rectal bleeding, there were significant correlations with number of seeds, supplemental EBRT, and all of the rectal dosimetric parameters. On subsequent multivariate analysis, the only significant factor was the maximal rectal dose (P < 0.001). Rectal dose > 160 Gy was correlated to grade 2 rectal morbidity. All the patients with rectal dose > 160 Gy received EBRT. CONCLUSIONS: Manifestations of rectal morbidity are acceptable events after I-125 prostate brachytherapy. Rectal dose-volume histogram for the brachytherapy is a predictive method for assessing the risk of developing grade 2 rectal bleeding. Delivery of the rectal dose should not exceed 160 Gy in order to avoid rectal complications.

[Influence of androgen deprivation therapy on prostate volume in patients with prostate cancer undergoing prostate brachytherapy with permanent seed implantation].

OBJECTIVE: Enlarged prostate often causes pubic arch interference during needle insertion on transperineal interstitial permanent prostate brachytherapy. Pre-treatment hormonal therapy is necessary for downsizing the prostate gland in such cases. The degree of prostate downsizing with anti-androgen treatment before iodine 125 permanent seed implant brachytherapy and its relation to clinical as well as pathological parameters were assessed. METHODS: From September 2003 to March 2005, 110 patients underwent permanent seed implantation and 86 patients of all received antiandrogen depriviation prior to the treatment at our institute. Prostate volume was measured using transrectal ultrasound at the time of cancer diagnosis and before the seed implant. Correlations between prostate downsizing and clinical as well as pathological parameters were evaluated. RESULTS: Mean percent volume of the prostate after the size reduction with average of 6.0 months antiandrogen monotherapy, 7.7 months LHRH agoniost and 8.2 months maximum androgen blockage (MAB) was 83%, 63%, and 60%, respectively. Mann-Whitney U test revealed that the degree of prostate downsizing is significantly correlated with the prostate volume in patients with prostate cancer utilizing LHRH agonists. CONCLUSIONS: Antiandrogen monotherapy can be an alternative for prostate downsizing before interstitial brachytherapy. Utilizing LHRH agonists or MAB is recommended for cases with larger gland volume.