Impact of an adjuvant chemotherapeutic regimen on the clinical outcome in high risk patients with upper tract urothelial carcinoma: a Japanese multi-institution experience.

PURPOSE: Current guidelines do not yet provide any recommendations for adjuvant chemotherapy in patients with upper tract urothelial carcinoma managed with radical nephroureterectomy. We evaluated whether an adjuvant chemotherapeutic regimen would affect the clinical outcome in patients with high risk upper tract urothelial carcinoma. MATERIALS AND METHODS: We identified 873 patients who had undergone radical nephrouretectomy for localized upper tract urothelial carcinoma at 14 Japanese institutions between 1993 and 2011. We assessed whether the type of regimen, such as methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and cisplatin, in an adjuvant setting, could affect the subsequent clinical outcome of patients with upper tract urothelial carcinoma. RESULTS: On multivariate analysis pathological T stage, tumor grade, lymphovascular invasion and lymph node involvement were prognostic factors for recurrence-free survival and cancer specific survival. We defined 229 patients with 3 or more of these factors as the high risk group. In an analysis according to adjuvant regimen, Kaplan-Meier curves showed that the 1 and 2-year recurrence-free survival rates in the methotrexate, vinblastine, doxorubicin and cisplatin treated group were 71.4% and 47.9%, which were significantly higher than in the gemcitabine and cisplatin treated group (48.2% and not reached, p=0.022) or those not treated with adjuvant chemotherapy (53.4% and 39.6%, p=0.039). Similar results were observed in terms of cancer specific survival. CONCLUSIONS: Our study showed that pT3-4, tumor grade 3, positive lymphovascular invasion and lymph node involvement were independent risk factors for disease mortality in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. In the high risk group methotrexate, vinblastine, doxorubicin and cisplatin adjuvant chemotherapy contributed to improve subsequent mortality compared to gemcitabine and cisplatin or no adjuvant chemotherapy.

Combination of hemoglobin, alkaline phosphatase, and age predicts optimal docetaxel regimen for patients with castration-resistant prostate cancer.

BACKGROUND: We aimed to find the prognostic factors predicting overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) who had docetaxel (DTX) chemotherapy, and to construct a model predicting the optimum number of cycles of DTX. METHODS: A total of 279 CRPC patients who received DTX (≥50 mg/m(2)) every 3-4 weeks were studied retrospectively. Prognostic factors predicting treatment cycles as well as OS were analyzed, and a risk table for predicting treatment cycles was constructed. RESULTS: The longer treatment group (>10 cycles) had a significantly longer OS than the standard treatment group (p < 0.0001). Multivariate analysis demonstrated that a decrease of ≥50 % in prostate-specific antigen (PSA), serum markers at the start of DTX therapy [PSA, alkaline phosphatase (ALP), and C-reactive protein (CRP)], and the number of DTX courses were independent predictors of OS. The risk table employing the combination of three factors [ALP (cut-off 189 IU/L), hemoglobin (11.3 g/dL), and age (65 years) at the start of DTX therapy], and scoring based on the hazard ratio of each risk factor (ALP 4, hemoglobin 2, age 3) could effectively predict the probability of the length of DTX therapy, with lower score (0-6) predicting >10 cycles, and higher score (7-9) predicting ≤5 cycles (p < 0.0001). No significant difference was found regarding grade 3/4 adverse events between the two groups. CONCLUSION: A model using three factors prior to chemotherapy may be beneficial for deciding the duration of DTX therapy in patients with CRPC.

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.

BACKGROUND: In 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. METHODS: A 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, Student's t test, Fisher's exact test, and Mann-Whitney's U test were used. RESULTS: The 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). CONCLUSIONS: In 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.

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 (alpha-TOS) as complementary and alternative medicine. In the present study, we investigated the cytotoxic effect of alpha-TOS and the enhancement of chemosensitivity to paclitaxel by alpha-TOS in bladder cancer. KU-19-19 and 5637 bladder cancer cell lines were cultured in alpha-TOS and/or paclitaxel in vitro. Cell viability, flow cytometric analysis, and nuclear factor-kappa B (NF-kappaB) activity were analyzed. For in vivo therapeutic experiments, pre-established KU-19-19 tumors were treated with alpha-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-kappaB was activated by paclitaxel; however, the activation of NF-kappaB was inhibited by alpha-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 alpha-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 alpha-TOS inhibits NF-kappaB induced by chemotherapeutic agents.

[Assessments of quality of life in women with urinary incontinence using: King's Health Questionnaire and International Consultation on Incontinence Questionnaire-Short Form].

The differences in quality of life (QOL) impairment due to urinary incontinence between elderly and younger women were evaluated using King's Health Questionnaire (KHQ) and International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF). The subjects were 313 women who consulted the Women's Urinary Incontinence Clinic of Saiseikai Central Hospital between March, 2005 and January, 2008. They were divided into those below or above the cut-off age of 55, 60 or 65 years. The difference in QOL impairment was greatest when the cut-off age was 60 years. Similar comparisons were made by dividing the subjects into those aged 65-74 years and those aged 75 years and above, but no significant difference was noted in the score of any KHQ domain or ICIQ-SF between the two groups. The stress urinary incontinence occurred in younger women and caused the severest impairment. The response rate to KHQ in this study was low especially in the elderly, but that to ICIQ-SF was as high in the elderly as in younger age group. Social activities and lifestyle change around age 60 were considered to be associated with the change of QOL impairment in women with urinary incontinence. The stress urinary incontinence caused the severest impairment. KHQ was often difficult for the elderly to complete, but, ICIQ-SF seemed to be easy.

[A case of double cancer involving the urachus and the bladder].

A 49-year-old male was referred to our hospital with the chief complaint of gross hematuria. We performed cystoscopy, and found a solid tumor at the dome of the bladder. Sagittal magnetic resonance imaging revealed an extravesical tumor at the position of the urachus. Transurethral resection of bladder tumor was performed. A solid tumor at the dome and two papillary tumors at the right lateral region of the bladder were observed. A pathological examination revealed adenocarcinoma from the solid tumor and urothelial carcinoma from the papillary tumors. Under a diagnosis of double cancer, adenocarcinoma of the urachus and urothelial carcinoma of bladder, we performed a total cystectomy, neobladder and total resection of the urachus.

[A case of intravesical foreign body with a vesical rupture invading the peritoneal cavity: a case report].

A 63-year-old male presented with an intravesical foreign body. We could not remove it by a transurethral operation. We performed open surgery, and found the urinary bladder to be perforated by a foreign body which invaded the peritoneal cavity. To our knowledge, there were 10 similar cases in Japan.

[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.

Determining the optimum way to maintain quality of life for very elderly patients with advanced bladder cancer and poor performance status: A case report.

Locally advanced bladder cancer causes unpleasant symptoms such as irritative voiding symptoms, lower abdominal pain, gross hematuria and urinary retention, and lowers the quality of life. Treatment decisions in elderly patients may be difficult, as elderly patients are physically and psychologically different from younger patients. An 89-year-old male was referred to hospital for the treatment of an invasive bladder tumor with right hydronephrosis from tumor obstruction. The patient was elderly and did not have a good performance status; therefore curative radical cystectomy or chemotherapy was not indicated. Left retroperitoneoscopic ureterocutaneostomy was performed to alleviate gross hematuria and voiding difficulty. Intensity-modulated radiotherapy was administered 9 days after the surgery to control bleeding in the bladder tumor. After completing 8 days of radiotherapy, the patient was discharged from hospital. The patient exhibited no signs of either postrenal failure or gross hematuria for 7 months prior to mortality. Retroperitoneoscopic ureterocutaneostomy for very elderly patients with advanced bladder cancer with a poor performance status may be an important procedure for alleviating symptoms and improving quality of life.

The impact of HIF1α on the Per2 circadian rhythm in renal cancer cell lines.

In mammals, the circadian rhythm central generator consists of interactions among clock genes, including Per1/2/3, Cry1/2, Bmal1, and Clock. Circadian rhythm disruption may lead to increased risk of cancer in humans, and deregulation of clock genes has been implicated in many types of cancers. Among these genes, Per2 is reported to have tumor suppressor properties, but little is known about the correlation between Per2 and HIF, which is the main target of renal cell carcinoma (RCC) therapy. In this study, the rhythmic expression of the Per2 gene was not detectable in renal cancer cell lines, with the exception of Caki-2 cells. In Caki-2 cells, HIF1α increased the amplitude of Per2 oscillation by directly binding to the HIF-binding site located on the Per2 promoter. These results indicate that HIF1α may enhance the amplitude of the Per2 circadian rhythm.

The predictive value of C-reactive protein for prognosis in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy: a multi-institutional study.

BACKGROUND: Few studies have discussed the prognostic impact of serum C-reactive protein (CRP) level in upper tract urothelial carcinoma (UTUC). OBJECTIVE: To investigate whether the perioperative level of CRP provides additional prognostic information following radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS: A total of 564 patients with UTUC from a retrospective multi-institutional cohort were included. The median follow-up was 32 mo. INTERVENTION: All patients underwent RNU without neoadjuvant chemotherapy, while 106 patients (18.8%) received adjuvant chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between perioperative CRP level and outcome were assessed using multivariate analysis. A serum CRP level >0.50mg/dl was defined as elevated. RESULTS AND LIMITATIONS: Preoperative CRP (pre-CRP) level was elevated in 136 patients (24.1%). Multivariate analysis showed that pre-CRP elevation was an independent predictor of subsequent disease recurrence (hazard ratio [HR]: 1.47 for CRP 0.51-2.00; HR: 1.89 for CRP >2.00). Five-year recurrence-free survival rates were 69.2% in patients with pre-CRP levels ≤ 0.50 mg/dl, 54.3% in patients with pre-CRP levels between 0.51 and 2.00 mg/dl, and 35.4% in patients with pre-CRP levels >2.00 mg/dl (p<0.001). Similar results were found in cancer-specific mortality, showing that pre-CRP elevation was an independent predictor of worse outcome (HR: 1.74 for CRP 0.51-2.00; HR: 2.31 for CRP >2.00). In a subgroup analysis of the elevated pre-CRP group, postoperative normalisation of CRP level was an independent predictor of better outcome. This study is limited by its retrospective nature as well as its heterogeneous group of patients and variable follow-up protocols resulting from the multi-institution design. CONCLUSIONS: Serum CRP may become a possible biomarker in UTUC, suggesting that patients with an elevated pre-CRP level could be predicted to have subsequent disease recurrence and cancer-specific mortality, while postoperative normalisation of CRP level was an independent predictor for prognosis.

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.