Kunimitsu Kanai

Gemcitabine and paclitaxel chemotherapy for advanced urothelial carcinoma in patients who have received prior cisplatin-based chemotherapy

BackgroundThe objective of this study was to evaluate the efficacy and toxicity of combination chemotherapy with gemcitabine and paclitaxel as a second-line regimen in patients with advanced urothelial carcinoma.MethodsTwenty patients with advanced urothelial carcinoma who were resistant to an M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy regimen were administered chemotherapy consisting of intravenous gemcitabine 2500 mg/m2 and paclitaxel 150 mg/m2 (GP) every 2 or 3 weeks.ResultsThe patients received a median of 7.7 cycles of treatment (range, 2–20 cycles). Six of the 20 patients (30%; 95% confidence interval [CI], 10%–50%) had a major response to treatment (a complete response [CR] in 5% and a partial response [PR] in 25%). Seven patients (35%) had stable disease (SD). The median duration of response was 4.5 months (range, 1–9 months) and the disease control rate (CR + PR + SD) was 65%. The median survival was 11.5 months (range, 2–22 months) and the 1-year survival rate was 35%. The patients tolerated this regimen well, with only grade 3–4 neutropenia being observed in 6 patients (30%), anemia in 3 (15%), and thrombocytopenia in 1 (5%). The response rate to M-VAC in the first-line chemotherapy was significantly associated with the response to GP as the second-line chemotherapy.ConclusionThe combination of gemcitabine and paclitaxel is active and well tolerated as a second-line treatment in patients with advanced urothelial carcinoma.

Vitamin E succinate induced apoptosis and enhanced chemosensitivity to paclitaxel in human bladder cancer cells in vitro and in vivo

There have been several studies on the antitumor activities of vitamin E succinate (α‐TOS) as complementary and alternative medicine. In the present study, we investigated the cytotoxic effect of α‐TOS and the enhancement of chemosensitivity to paclitaxel by α‐TOS in bladder cancer. KU‐19‐19 and 5637 bladder cancer cell lines were cultured in α‐TOS and/or paclitaxel in vitro. Cell viability, flow cytometric analysis, and nuclear factor‐kappa B (NF‐κB) activity were analyzed. For in vivo therapeutic experiments, pre‐established KU‐19‐19 tumors were treated with α‐TOS and/or paclitaxel. In KU‐19‐19 and 5637 cells, the combination treatment resulted in a significantly higher level of growth inhibition, and apoptosis was significantly induced by the combination treatment. NF‐κB was activated by paclitaxel; however, the activation of NF‐κB was inhibited by α‐TOS. Also, the combination treatment significantly inhibited tumor growth in mice. In the immunostaining of the tumors, apoptosis was induced and proliferation was inhibited by the combination treatment. Combination treatment of α‐TOS and paclitaxel showed promising anticancer effects in terms of inhibiting bladder cancer cell growth and viability in vitro and in vivo. One of the potential mechanisms by which the combination therapy has synergistic cytotoxic effects against bladder cancer may be that α‐TOS inhibits NF‐κB induced by chemotherapeutic agents. (Cancer Sci 2009;)

Prediction of PSA bounce after permanent prostate brachytherapy for localized prostate cancer.

BackgroundWe aimed to calculate the frequency and features of the development of a prostate-specific antigen (PSA) bounce after prostate brachytherapy alone, to correlate the bounce with clinical and dosimetric factors and to identify factors that predict PSA bounce.MethodsPSA bounce was evaluated in 86 patients with T1-T2 prostate cancer who underwent radioactive seed implantation using iodine-125 (I-125) without hormonal therapy or external-beam radiation therapy (EBRT) from September 2004 to December 2007. A PSA bounce was defined as a rise of at least 0.4 ng/ml greater than a previous PSA level with a subsequent decline equal to, or less than, the initial nadir.ResultsCalculated by the Kaplan-Meier method, the incidence of PSA bounce at a 2-year follow-up was 26%. Median time to the PSA bounce was 15 months. Univariate analysis demonstrated that age, dose received by 90% of the prostate gland (D90), volume of gland receiving 100% of the prescribed dose (V100), and V150 were significantly associated with the PSA bounce, while pretreatment PSA level, Gleason score, pretreatment prostate volume, clinical T stage, and V200 were not. In multivariate analysis, age 67 years or less and D90 more than 180 Gy were identified as independent factors for predicting the PSA bounce (P < 0.05).ConclusionPSA bounce is not a rare phenomenon after prostate brachytherapy. It is more common in younger patients and patients receiving higher doses of radiation.

Impact of MRI-based postimplant dosimetric assessment in prostate brachytherapy using contrast-enhanced T1-weighted images.

PURPOSE To compare contrast-enhanced T1-weighted (CE-T1WI) magnetic resonance imaging (MRI) with computed tomography (CT) for postimplant dosimetry and seed recognition in prostate brachytherapy. METHODS AND MATERIALS A total of 245 patients who received (125)I prostate brachytherapy with or without external beam radiotherapy were enrolled. For postimplant analysis, CT and MRI scans were obtained at 1 month after seed implantation. For MRI-based dosimetry, T2-weighted images were fused with the CE-T1WI; the prostate was delineated on the T2-weighted images, and the seed detection was performed manually on the CE-T1WI. In CT-based dosimetry, the seed detection was essentially performed automatically. The dosimetric results obtained by MRI-based and CT-based dosimetry were compared. RESULTS The mean prostate D(90) (the minimum dose received by 90% of the prostate volume) estimated by MRI-based and CT-based dosimetry were 113% and 115%, respectively, with no significant difference. The mean prostate V(100) (the percent volume of the postimplant prostate receiving 100% of the prescribed dose) estimated by MRI-based and CT-based dosimetry were 95.2% and 95.8%, respectively, again with no significant difference. The mean prostate V(150) (the percent volume of the postimplant prostate receiving 150% of the prescribed dose) estimated by MRI-based and CT-based dosimetry were 52.8% and 57.0%, respectively (p<0.01). In all of the 35 patients (14%) in whom the MRI-based V(150) were at least 10% lower than the CT-based results, the seed detection by CT-based dosimetry was overestimated in highly seed-clustered areas or in the areas close to calcifications because of reconstruction artifacts in CT images. CONCLUSIONS MRI-based dosimetry using CE-T1WI appears to be acceptable. Our results suggest that MRI-based dosimetry is a practical method for estimation of the higher dose distribution, especially if seeds are clustered together or when they are close to calcifications.

Potent Cytotoxic Effect of a Novel Nuclear Factor-κB 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.

Efficacy of tension-free vaginal tape compared with transobturator tape in the treatment of stress urinary incontinence in women: analysis of learning curve, perioperative changes of voiding function

BackgroundIn this study, by comparing TVT surgery and TOT surgery for stress urinary incontinence in women, the characteristics and learning curves of both operative methods were studied.MethodsA total of 83 women with stress urinary incontinence treated with tension-free vaginal tape (TVT) (n = 38) or transobturator tape (TOT) (n = 45) at Saiseikai Central Hospital between April 2004 and September 2009 were included. We compare the outcomes and learning curves between TVT surgery and TOT surgery. In statistical analysis, Students t test, Fishers exact test, and Mann-Whitneys U test were used.ResultsThe surgical durations were 37.4 ± 15.7 minutes with TVT surgery and 31.0 ± 8.3 minutes with TOT surgery. A longer period of time was required for TVT surgery (p = 0.025). The residual urine at post-operative day 1 was higher in TVT surgery (25.9 ± 44.2 ml) than in TOT surgery (10.6 ± 19.2 ml) (p = 0.0452). The surgical duration of TVT surgery was shortened after the operator had performed 15 operations (p = 0.019).ConclusionsIn comparison of TVT surgery and TOT surgery, the surgical duration of TVT surgery was longer and the residual urine of TVT surgery was higher at post-operative day 1. Surgical experience could shorten the duration of TVT surgery.

Dosimetric effects of prone and supine positions on post-implant assessments for prostate brachytherapy

PURPOSE Post-implant dosimetric assessment is essential for optimal care of patients receiving prostate brachytherapy. In most institutions, post-implant computed tomography (CT) is performed in the supine position. This study aimed to assess variability in dosimetric parameters with postural changes during acquisition of post-implant CT scans. MATERIAL AND METHODS In total, 85 consecutive patients were enrolled in this study. Fifty-three patients underwent seed implantation alone, and the remaining 32 received a combination of seed implantation and external beam radiotherapy. For post-implant analyses, CT scans were obtained in two patient positions, supine and prone. To evaluate differences in dosimetric parameters associated with postural change, the dosimetric data obtained in the supine position were defined as the standard. RESULTS The median prostate volume was 22.4 ml in the supine and 22.5 ml in the prone position (p = 0.51). The median prostate D90 was 120.1% in the supine and 120.3% in the prone position, not significantly different. The mean prostate V100 was 97.1% in the supine and 97.0% in the prone position, again not significantly different. Median rectal V100 in supine and prone positions were 0.42 ml and 0.33 ml, respectively (p < 0.01). Rectal D2cc was also significantly decreased in the prone as compared with the supine position (median, 59.1% vs. 63.6%; p < 0.01). A larger post-implant prostate volume was associated with decreased rectal doses in the prone position. CONCLUSIONS Though there were no significant differences among prostate D90 assessments according to postural changes, our results suggest that post-implant rectal doses decreased in the prone position.

History of Non–Muscle-Invasive Bladder Cancer May Have a Worse Prognostic Impact in cT2-4aN0M0 Bladder Cancer Patients Treated With Radical Cystectomy

Micro‐Abstract We performed a retrospective study comparing clinical outcomes between patients with initially diagnosed muscle‐invasive bladder cancer (MIBC) without a history of non‐MIBC (NMIBC) and those with MIBC that progressed from NMIBC. A history of NMIBC was independently associated with cancer death in cT2‐T4a MIBC patients treated with radical cystectomy and without lymph node involvement. MIBC that progresses from NMIBC may not respond to neoadjuvant chemotherapy. Purpose To investigate whether a history of non–muscle‐invasive bladder cancer (NMIBC) plays a prognostic role in patients with muscle‐invasive bladder cancer (MIBC) treated with radical cystectomy in the era when neoadjuvant chemotherapy was established as standard therapy for MIBC. Patients and Methods A total of 282 patients who were diagnosed with cT2‐T4aN0M0 bladder cancer treated with open radical cystectomy at our institutions were included. Initially diagnosed MIBC without a history of NMIBC was defined as primary MIBC group (n = 231), and MIBC that progressed from NMIBC was defined as progressive MIBC (n = 51). Results The rate of cT3/4a tumors was significantly higher in the primary MIBC group than in the progressive MIBC group (P = .004). Five‐year recurrence‐free survival and cancer‐specific survival (CSS) rates for the primary MIBC group versus progressive MIBC group were 68.2% versus 55.9% (P = .039) and 76.1% versus 61.6% (P = .005), respectively. Progressive MIBC (hazard ratio, 2.170; P = .008) was independently associated with cancer death. In the primary MIBC group, the 5‐year CSS rate in patients treated with neoadjuvant chemotherapy was 85.4%, which was significantly higher than that in patients without (71.5%, P = .023). In the progressive MIBC group, no significant differences were observed in CSS between patients treated with and without neoadjuvant chemotherapy. Conclusion MIBC that progressed from NMIBC had a significantly worse clinical outcome than MIBC without a history of NMIBC and may not respond as well to neoadjuvant chemotherapy. These results are informative, even for NMIBC patients treated with conservative intravesical therapy.