• Evaluation of the cellular tumour rejection mechanisms in the peritumoral bladder wall after bacillus Calmette-Guerin treatment.

• N-(4-hydroxyphenyl)retinamide (4-HPR) modulates GADD45 expression in radiosensitive bladder cancer cell lines.

• [Synchronous tumor of the upper urinary tract with bladder cancer. Opportunity for nephroureterectomy and block-cystectomy]

• Intravesical epirubicin treatment following TUR in superficial bladder tumours.

• [Urinary leukocytes as a new prognostic marker of therapeutic response and of adverse effects associated with the maintenance treatment with

• Intravesical therapy for superficial cancer: need for more options.

• Phase I trial of intravesical gemcitabine in bacillus Calmette-Guerin-refractory transitional-cell carcinoma of the bladder.

• Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a

• Antisense Bcl2 oligonucleotide in cisplatin-resistant bladder cancer cell lines.

• Nurse-led cystoscopy: the next step.

• Ileal T-pouch as a urinary continent cutaneous diversion: clinical and urodynamic evaluation.

• Neo-adjuvant chemotherapy and bladder preservation in locally advanced transitional cell carcinoma of the bladder.

• Neo-adjuvant chemotherapy and bladder preservation in locally advanced transitional cell carcinoma of the bladder.

• Outcome of patients with grossly node positive bladder cancer after pelvic lymph node dissection and radical cystectomy.

• [Urinary bladder cancer]

• HER-2--a possible target for therapy of metastatic urinary bladder carcinoma.

• Feasibility trial of methotrexate-paclitaxel as a second line therapy in advanced urothelial cancer.

• Salvage therapy for platinum-refractory urothelial cancer: designing new clinical trials.

• Does smoking status influence the prognosis of bladder cancer? A systematic review.

• Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer.

• In vitro antitumor activity of bropirimine against urinary bladder tumor cells.

• Neoadjuvant chemotherapy with sequential methotrexate and 5-fluorouracil scheduling, epirubicin and cisplatin for locally advanced bladder

• Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of

• Perioperative single dose instillation of epirubicin or interferon-alpha after transurethral resection for the prophylaxis of primary superficial

• Bladder cancer.

• Arsenic trioxide as a novel anticancer agent against human transitional carcinoma--characterizing its apoptotic pathway.

• Nerve and seminal sparing radical cystectomy with orthotopic urinary diversion for select patients with superficial bladder cancer: an

• Re: Nerve and seminal sparing radical cystectomy with orthotopic urinary diversion for select patients with superficial bladder cancer: an

• [Significance of pelvic lymphadenectomy for the prognosis after radical cystectomy]

• Bladder cancer.

• Changes produced in the urothelium by traditional and newer therapeutic procedures for bladder cancer.

• Bladder adenocarcinoma: 31 reported cases.

1
UI - 11942983
AU - Cooke PW
TI - Evaluation of the cellular tumour rejection mechanisms in the peritumoral bladder wall after bacillus Calmette-Guerin treatment.
SO - BJU Int 2002 Apr;89(6):635

2
UI - 12175543
AU - Zou C; Guan Y; Zou C; Wang J; Wang LE; Liebert M; Grossman HB; Wei Q
TI - N-(4-hydroxyphenyl)retinamide (4-HPR) modulates GADD45 expression in radiosensitive bladder cancer cell lines.
SO - Cancer Lett 2002 Jun 28;180(2):131-7
AD - Department of Obstetrics and Gynecology, The University of Texas-Houston Medical School, Houston, TX 77030, USA.
We previously demonstrated that N-(4-hydroxyphenyl)retinamide (4-HPR) and gamma-irradiation, when used in combination, had a synergistic effect in inducing apoptosis in bladder cancer cells, suggesting that 4-HPR may increase radiosensitivity in bladder cancer cells. To unravel molecular correlates in this radiosensitizing effect of 4-HPR, we examined the baseline and 4-HPR-induced expression of GADD45 to elucidate possible mechanisms by which 4-HPR enhanced the effect of gamma-irradiation in three bladder cancer cell lines. To investigate the role of p53 in mediating the radiosensitizing effect of 4-HPR, we also examined mutations in exons 5-9 by using direct sequencing and the levels of p53 expression by using RT-PCR and Western blot, before and after treatment with 4-HPR in these bladder cancer cell lines. Two cell lines had low expression of GADD45, and a dose-dependent increase in GADD45 expression induced by 4-HPR was found in bladder cancer cell lines without p53 mutations in exons 5-9. A combination of gamma-irradiation and 4-HPR showed a significantly greater effect in enhancing GADD45 expression than either agent used alone. The results indicate that the combined treatment with 4-HPR and gamma-irradiation has a stronger effect on GADD45 expression than the treatment with either agent alone, which suggests that the two agents may have an additive/synergistic effect. However, a normal p53 function appears to be necessary for the dose-dependent induction of GADD45 by 4-HPR. Once our results are verified and replicated by other investigators, 4-HPR may have a potential clinical implication in effectively treating bladder cancer in combination with low-gamma-irradiation therapy.

3
UI - 11852517
AU - Navas Pastor J; Garcia Ligero J; Garcia Garcia F; Tomas Ros M; Rico
TI - Galiano JL; Sempere Gutierrez A; Gil Franco J; Fontana Compiano LO [Synchronous tumor of the upper urinary tract with bladder cancer. Opportunity for nephroureterectomy and block-cystectomy]
SO - Arch Esp Urol 2001 Dec;54(10):1095-102
AD - Servicio de Urologia, Hospital General Universitario, Murcia, Espana.
OBJECTIVE: One of the basic characteristics of urothelial carcinoma is its tendency to synchronous or metachronous multifocality. Thus the need to explore the entire urinary tract of patients with urothelial neoformations. The aim of this article is to study the tumors of the upper urinary tract that appear synchronously with infiltrating carcinoma of the bladder. The clinicopathological characteristics and the morbidity and mortality of en bloc surgery of both tumors are analyzed. METHODS: A retrospective study was carried out on 170 radical cystectomies for infiltrating bladder tumor performed in our department over a 13-year period. Patient history, clinicopathological characteristics, complementary tests, type of surgery performed, postoperative complications and follow-up were analyzed. RESULTS: Tumor of the upper urinary tract appeared in 14 (1 bilateral) of these patients and were synchronous in 10 cases. All patients were male; mean age 63 years. Three were localized in the pelvis, 2 in the proximal ureter and 6 in the distal third. Diagnosis was made by IVP in 6 patients and by US and antegrade pyelography in the other 4 patients. Nephroureterectomy and radical cystectomy were performed en bloc in 8 cases; 6 had a Bricker procedure and 2 ileal substitution. Salvage radical cystectomy + distal ureterectomy were performed in the other two patients. Two patients submitted to en bloc surgery had postoperative complications; one presented prolonged ileua and the other required surgery for retroperitoneal hemorrhage. The two patients submitted to palliative surgery died of and sepsis during the postoperative period. At 33 months' mean follow-up, 3 patients have shown tumor progression. CONCLUSIONS: There is a high proportion of synchronous tumor of the upper urinary tract in our series of patients with infiltrating carcinoma of the bladder undergoing radical cystectomy, therefore we consider it necessary to explore the entire urinary system. Surgical removal of both tumors en bloc does not increase the morbidity and mortality.

4
UI - 11852530
AU - Imamoglu MA; Bakirtas H; Yigitbasi O; Ersoy H; Sertcelik AN
TI - Intravesical epirubicin treatment following TUR in superficial bladder tumours.
SO - Arch Esp Urol 2001 Dec;54(10):1147-53
AD - S.S.K. Ankara Hospital 1, Urology Clinic, Ankara, Turkey. mai2603@superonline.com
OBJECTIVE: To evaluate the effectiveness and tolerability of intravesical epirubicin treatment to prevent recurrence and progression of superficial bladder tumor after TUR. METHODS: 44 patients with superficial bladder tumor, 28 primary and 16 recurrent cases were given 50 mg intravesical epirubicin once a week for 8 weeks after TUR. Recurrent cases had not been treated by any intravesical agent before. Follow-up was done by cystoscopy, urine cytology and random biopsies. RESULTS: Local recurrence after treatment was found in 14.28% and 18.75%, and recurrence in another area was found in 21.42% and 31.25% of the primary and recurrent tumor groups respectively. Total recurrence in both groups was 40.91%. No systemic toxicity was observed and local side effects were treated symptomatically. CONCLUSION: Intravesical epirubicin after TUR for superficial bladder tumors especially for the primary ones, is a reliable method that provides effective prophylaxis with tolerable side effects.

5
UI - 11859659
AU - Saint F; Irani J; Salomon L; Legrand P; Abbou CC; Chopin D
TI - [Urinary leukocytes as a new prognostic marker of therapeutic response and of adverse effects associated with the maintenance treatment with endovesical BCG, for the prophylaxis of superficial bladder tumors]
SO - Prog Urol 2001 Dec;11(6):1242-50
AD - Service d'Urologie, Hopital Henri Mondor, 51, avenue du Marechal de Lattre de Tassigny, 94010 Creteil. Saintf@wanadoo.fr
The use of Bacillus Calmette-Guerin (BCG) vaccine as immunotherapy for superficial bladder cancer constitutes a major progress, although it remains limited by the development of adverse effects and problems related to safety. No individual tool is currently available in clinical practice to predict the efficacy or adverse effects of BCG therapy. These problems are accentuated in the case of maintenance therapy according to the protocol of D.L. Lamm. OBJECTIVES: To define whether the urinary leukocyte count observed after intravesical BCG instillation could be associated with adverse effects and efficacy of treatment. MATERIAL AND METHODS: A cohort of 72 consecutive patients (518 instillations) was studied prospectively. We defined four classes of adverse effects associated with BCG, according to their type, severity and duration. In combination with this classification, we performed systematic optical urinary leukocyte count on the third day after each instillation (KOVA-Slide 10). RESULTS: A high urinary leukocyte count (cut-off value: 165,000/ml) was correlated with absence of recurrence (p = 0.009). The adverse effect classification also demonstrated that urinary leukocyte count was related to the severity and duration of adverse effects (p < 0.0001). Median values observed for class I, II and III adverse effects were 40,000 leukocytes/ml, 150,000 leukocytes/ml and 350,000 leukocytes/ml, respectively. No class IV adverse effects were observed. The risk of developing class III adverse effects was increased when the urinary leukocyte count was greater than 86,000 leukocytes per ml. CONCLUSION: These results suggest a probable relationship between efficacy and safety of BCG, during maintenance therapy. Randomized prospective studies are necessary to evaluate urinary leukocyte count as a tool for adaptation and optimization of BCG therapy.

6
UI - 12149286
AU - Crawford ED
TI - Intravesical therapy for superficial cancer: need for more options.
SO - J Clin Oncol 2002 Aug 1;20(15):3185-6

7
UI - 12149290
AU - Dalbagni G; Russo P; Sheinfeld J; Mazumdar M; Tong W; Rabbani F; Donat
TI - MS; Herr HW; Sogani P; dePalma D; Bajorin D Phase I trial of intravesical gemcitabine in bacillus Calmette-Guerin-refractory transitional-cell carcinoma of the bladder.
SO - J Clin Oncol 2002 Aug 1;20(15):3193-8
AD - Department of Urology, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. dalbagng@mskcc.org
PURPOSE: The aim of this phase I study was to determine the safety and toxicity profile of gemcitabine administered as an intravesical agent in patients with transitional-cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Patients with superficial bladder cancer refractory to intravesical bacillus Calmette-Guerin (BCG) therapy and refusing a cystectomy were considered eligible for the trial. Gemcitabine was given in the bladder for 1 hour twice weekly in 100 mL sodium chloride for a total of six treatments. After a 1-week break, a second course of six treatments over 3 weeks was given, followed by response assessment. Four dose levels were explored: 500 mg, 1,000 mg, 1,500 mg, and 2,000 mg. RESULTS: Eighteen patients completed therapy: three at 500 mg, six at 1,000 mg, three at 1,500 mg, and six at 2,000 mg. No grade 3 or 4 toxicity was observed at 500 mg. At 1,000 mg, three patients developed hematuria and one had a skin reaction resembling grade 3 hand-foot syndrome. Three patients at 1,500 mg had no grade 3 or 4 toxicity. Of six patients at 2,000 mg, one had grade 3 thrombocytopenia and neutropenia without infection. Seven patients had a complete response (negative cytology and posttreatment biopsy), and four patients had a mixed response (negative bladder biopsy but positive cytology). CONCLUSION: Gemcitabine has substantial activity as an intravesical agent in BCG-refractory TCC and warrants further investigation. Therapy given twice weekly was associated with minimal bladder irritation and tolerable myelosuppression. The recommended phase II dose for twice-weekly therapy is 2,000 mg.

8
UI - 12074794
AU - Brausi M; Collette L; Kurth K; van der Meijden AP; Oosterlinck W; Witjes
TI - JA; Newling D; Bouffioux C; Sylvester RJ; EORTC Genito-Urinary Tract Cancer Collaborative Group Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies.
SO - Eur Urol 2002 May;41(5):523-31
AD - Institute Sant'Agostino, Estense, Modena, Italy.
OBJECTIVES: To assess the variability between institutions in the recurrence rate at the first follow-up cystoscopy (RR-FFC) after transurethral resection (TUR) in patients with stage Ta T1 bladder cancer.METHODS: A total of 2410 patients from seven EORTC phase III trials conducted between 1979 and 1989 were included. Patients with single and with multiple tumors were analyzed separately according to whether or not they received adjuvant intravesical treatment.RESULTS: The RR-FFC varied greatly between institutions. For patients with a single tumor, it ranged from 3.4% to 20.6% for patients not receiving any intravesical adjuvant treatment and from 0% to 15.4% in those receiving it. In patients with multiple tumors who had adjuvant treatment, it varied between 7.4% and 45.8%. There was a slight decrease over time in the recurrence rate for patients with single tumors, particularly in those receiving adjuvant intravesical treatment.CONCLUSIONS: For both patients with single and with multiple tumors, the percentage of patients with a recurrence in the bladder at the first follow-up cystoscopy after TUR varies substantially between institutions and cannot be explained by the factors that were assessed. It is suggested that the quality of the TUR performed by the individual surgeons may be responsible.

9
UI - 12081782
AU - Hong JH; Lee E; Hong J; Shin YJ; Ahn H
TI - Antisense Bcl2 oligonucleotide in cisplatin-resistant bladder cancer cell lines.
SO - BJU Int 2002 Jul;90(1):113-7
AD - Department of Urology, University of Ulsan College of Medicine, Korea.
OBJECTIVE: To determine the change of expression of Bcl2 in cisplatin-resistant bladder cancer cell lines and the reversibility of chemoresistance to cisplatin with antisense oligonucleotide against Bcl2, as higher expression of Bcl2 is associated with drug resistance in many different cancer cell lines. MATERIALS AND METHODS: In the cisplatin-resistant bladder tumour cell lines T24R1 and T24R2, the expression of Bcl2 was determined by reverse transcription-polymerase chain reaction and Western blot assay, and antisense oligonucleotide targeting of the Bcl2 coding sequence was administered with lipofectin. RESULTS: The expression of Bcl2 mRNA and protein was greater in T24R1 and T24R2 cells than in the parent T24 cells. Short-term exposure to cisplatin up-regulated Bcl2 mRNA and protein expression in parent T24 cells. Treatment with antisense oligonucleotide down-regulated Bcl2 protein expression and significantly enhanced the cytotoxicity of cisplatin. CONCLUSIONS: Up-regulation of Bcl2 protein expression might be one of the mechanisms of cisplatin resistance in bladder cancer cells, and antisense Bcl2 oligonucleotide may be helpful in chemotherapy for bladder cancer by reversing cisplatin resistance.

10
UI - 12081768
AU - Taylor JM; Pearce I; O'Flynn KJ
TI - Nurse-led cystoscopy: the next step.
SO - BJU Int 2002 Jul;90(1):45-6
AD - Department of Urology, Hope Hospital, Salford, Manchester, UK. floppyoliver@yahoo.com
OBJECTIVES: To determine and compare the accuracy of flexible cystoscopy and subsequent management by a specialist urology registrar (SpR) and a specialist urology nurse (SUN). PATIENTS AND METHODS: Flexible cystoscopy was undertaken on 50 patients by both endoscopists each unaware of the results of the other's examination. The findings and management plans were independently declared and then compared. Any cystoscopic discrepancies were assessed by one consultant with the patients under a general anaesthetic. RESULTS: Tumours were found in 20% of patients; there was a consensus of the endoscopic findings and subsequent management plan between the SpR and the SUN in 94% of the patients. Any missed tumours (all surveillance) were minute and clinically insignificant. The chance-corrected proportional agreement (kappa value) between the SUN and final diagnosis and management was 0.94. CONCLUSION: A properly trained SUN can undertake both diagnostic and surveillance flexible cystoscopy, and decide upon further management to the same degree as can a urology SpR.

11
UI - 12081769
AU - Marino G; Laudi M
TI - Ileal T-pouch as a urinary continent cutaneous diversion: clinical and urodynamic evaluation.
SO - BJU Int 2002 Jul;90(1):47-50
AD - Department of Urology, Mauriziano Hospital, Turin, Italy. gae007@libero.it
OBJECTIVE: To report the functional results of continent cutaneous urinary diversion with ileum, using the serous-lined extramural valve and Mitrofanoff procedure for the continence mechanism. PATIENTS AND years) underwent radical cystectomy for invasive bladder cancer involving the bladder neck, urethra or prostate; they then had an ileal continent cutaneous T pouch constructed. The mean (range) follow-up was 12 (4-20) months. The first five patients had reconstructions using the original orthotopic T-pouch configuration, but in subsequent patients the technique was simplified, reducing the ileal segments. The ureteric-intestinal anastomosis was made using a split-cuff nipple technique. RESULTS: All patients were continent day and night, and there were no late complications. All cutaneous continent T pouches had a good capacity and low pressure, with no urinary reflux. No catheterization difficulties were reported and the evacuation intervals were approximately 4 h. CONCLUSIONS: This ileal cutaneous continent diversion is a versatile technique; the T-valve can be used successfully as a continent mechanism, ensuring continence day and night. The simplified technique maintains a reservoir of good capacity and compliance, thus preserving approximately 13 cm of ileal tract. The ureteric intestinal anastomosis by the split-cuff nipple technique is suitable in undilated and peristaltic ureters.

12
UI - 10631452
AU - Benson MC
TI - Neo-adjuvant chemotherapy and bladder preservation in locally advanced transitional cell carcinoma of the bladder.
SO - Ann Oncol 1999 Nov;10(11):1269-70

13
UI - 10631456
AU - Sternberg CN; Pansadoro V; Calabro F; Marini L; van Rijn A; Carli PD;
TI - Giannarelli D; Platania A; Rossetti A Neo-adjuvant chemotherapy and bladder preservation in locally advanced transitional cell carcinoma of the bladder.
SO - Ann Oncol 1999 Nov;10(11):1301-5
AD - San Raffaele Scientific Institute, Rome, Italy. sternbc@roma.hsr.it
BACKGROUND: The possibility of bladder preservation as well as the utility of neo-adjuvant chemotherapy for invasive bladder cancer are controversial issues. The purpose of this study was the evaluation of neo-adjuvant M-VAC chemotherapy and bladder preservation in patients with locally advanced transitional cell carcinoma of the bladder. PATIENTS AND METHODS: Eighty-seven consecutive evaluable patients with T2-T4aNxM0 TCC of the bladder were treated with three cycles of neo-adjuvant M-VAC chemotherapy. After three cycles of M-VAC, 42 patients had TURB alone, 13 patients underwent partial cystectomy, and 32 patients were to undergo radical cystectomy. RESULTS: Forty (51%) patients were T0 at the TURB following M-VAC. Thirty (71%) patients who had chemotherapy and TURB alone are alive; at a median follow-up of 54+ months (8(+)-109+). Twenty-four (57%) have maintained an intact bladder. Of 13 responding patients with monofocal lesions who underwent partial cystectomy, 8 patients (62%) are alive with a functioning bladder, at a median follow-up of 80+ months (16-107+ months). At a follow-up of 32 months (7-121+ months), 20 (63%) patients in the radical cystectomy group are alive. In patients who had downstaging to T0 or superficial disease, median follow-up is 55 months (10-121+ months) and five-year survival is 71%. Patients who failed to respond (T2 or greater after chemotherapy), at a median follow-up of 24 months (7-103+ months), had five-year survival of only 29%. CONCLUSIONS: Bladder sparing in selected patients on the basis of response to neo-adjuvant chemotherapy is a feasible approach which must be confirmed in prospective randomized trials.

14
UI - 11125364
AU - Herr HW; Donat SM
TI - Outcome of patients with grossly node positive bladder cancer after pelvic lymph node dissection and radical cystectomy.
SO - J Urol 2001 Jan;165(1):62-4; discussion 64
AD - Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
PURPOSE: Should the surgeon proceed with surgery when grossly positive nodes are found at cystectomy? To answer this question, we determine the outcome of patients after radical surgery alone for grossly node positive bladder cancer. MATERIALS AND METHODS: A total of 84 patients with grossly node positive (N2-3) bladder cancer found at cystectomy underwent extended pelvic lymph node dissection and have been followed for up to 10 years. The end point of study was disease specific survival. RESULTS: Of the 84 patients 20 (24%) survived and 64 (76%) died of disease. Median survival time was 19 months for all patients and 10 years for surviving patients. Of 53 patients with clinical stage T2 (organ confined) tumors 17 (32%) survived versus 3 of 31 (9.7%) with stage T3 (extravesical) tumors. CONCLUSIONS: A proportion of patients with grossly node positive bladder cancer can be cured with radical cystectomy and thorough pelvic lymph node dissection.

15
UI - 12082860
AU - von der Maase H; Steven K
TI - [Urinary bladder cancer]
SO - Ugeskr Laeger 2002 Jun 3;164(23):3052-6
AD - Arhus Universitetshospital, Arhus Kommunehospital, onkologisk afdeling. hvdm@oncology.dk

16
UI - 12195748
AU - Wester K; Sjostrom A; de la Torre M; Carlsson J; Malmstrom PU
TI - HER-2--a possible target for therapy of metastatic urinary bladder carcinoma.
SO - Acta Oncol 2002;41(3):282-8
AD - Division of Experimental Urology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. kenneth.wester@genpat.uu.se
Human epidermal growth factor receptor 2, HER-2, is overexpressed in various tumours, e.g. breast- and bladder tumours. The aim of this study was to predict the potential use of HER-2 receptors as targets in systemic treatment of disseminated bladder tumours. HER-2 expression was assessed in bladder carcinoma metastases and the corresponding primary tumours, and subsequently compared with the EGFR expression. HER-2 and EGFR expression was analysed by immunohistochemistry in formalin-fixed, paraffin-embedded tissues from 21 patients with metastatic bladder carcinoma. HER-2 was overexpressed in 81% of the primary tumours and in 67% of the metastases. All HER-2-positive metastases were from HER-2-positive primary tumours. The results for EGFR were 71% of both primary and metastases-positive tumours. In 90% of the primary tumours and 86% of the metastases, at least one of the receptors was overexpressed. These results suggest that HER-2 targeted therapy can be considered as an alternative or a complement to other modalities in the treatment of metastatic urinary bladder carcinoma.

17
UI - 12197223
AU - Bellmunt J; Cos J; Cleries R; Perez M; Ribas A; Eres N; Murio JE;
TI - Margarit C; Baselga J Feasibility trial of methotrexate-paclitaxel as a second line therapy in advanced urothelial cancer.
SO - Cancer Invest 2002;20(5-6):673-85
AD - Medical Oncology Service, Hospital General Universitari Vall d'Hebron, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain. bellmunt@hg.vhebron.es
To evaluate the clinical value of the concurrent use of methotrexate administered immediately before paclitaxel, we investigated the efficacy and toxicity of this two-drug combination administered as palliative second line therapy in patients with advanced urothelial cancer. The design of the schedule and sequence used was based on our previous preclinical data from a comparative study on sequential combinations of paclitaxel and methotrexate in a human bladder cancer cell line. As a confirmation study, we further extended our analysis of in vitro synergism. Twenty patients with advanced transitional cell carcinoma of the urinary tract previously treated with platinum-based therapy, with adequate renal function and a performance status > or = 60 were considered eligible. They received therapy with methotrexate 30 mg/m2 administered as an intravenous bolus, followed immediately by paclitaxel 175 mg/m2 given as a 3-hr infusion, both on day 1 every 21 days. Therapy was given on a compassionate-use basis until either disease progression was documented or the patient became intolerant to therapy. In vitro data were further analyzed using the median-effect principle and the combination index method. Twenty patients with metastatic (16 patients) or locally advanced disease (four patients) received a median of three cycles of therapy. Of the 19 patients assessable for response, there were six partial responses and seven disease stabilizations with no complete responses. Median duration of response was 3 months (range, 2-7) and median survival was 5 months. Three patients developed grade 3-4 neutropenia, one patient had grade 3 anemia, four patients had grade 2-3 sensory neuropathy, and three patients had myalgias. Eighteen patients developed alopecia. Gastrointestinal toxicity was mild. One patient died after the first cycle due to pulmonary thrombo-embolism and could not be evaluated for response. The synergistic in vitro effect of the concurrent combination was confirmed in analyses performed under mutually exclusive and mutually nonexclusive criteria. In conclusion, the combination of methotrexate and paclitaxel at this dose and sequence is feasible and active as a palliative therapy in patients with advanced urothelial cancer previously treated with platinum-based therapies. This schedule merits further investigation in a phase-II trial.

18
UI - 12197246
AU - Petrylak DP
TI - Salvage therapy for platinum-refractory urothelial cancer: designing new clinical trials.
SO - Cancer Invest 2002;20(5-6):855-6

19
UI - 12133057
AU - Aveyard P; Adab P; Cheng KK; Wallace DM; Hey K; Murphy MF
TI - Does smoking status influence the prognosis of bladder cancer? A systematic review.
SO - BJU Int 2002 Aug;90(3):228-39
AD - Department of Public Health and Epidemiology, University of Birmingham, UK. p.n.aveyard@bham.ac.uk
OBJECTIVE: To summarize, in a systematic review, the evidence for the effect of stopping smoking on recurrence, cancer-specific and all cause-mortality among smokers with newly diagnosed bladder cancer. MATERIALS AND METHODS: Two electronic databases and the reference lists of identified primary studies and reviews were searched. Studies were included if a hazard ratio and its confidence intervals could be extracted. A predefined set of study characteristics was extracted which defined whether studies were giving valid prognostic data on the effects of smoking in reasonably homogenous cohorts. The results of studies were synthesized qualitatively. RESULTS: Fifteen relevant studies were identified; former and current smokers were combined in many studies. Many studies produced information on prognosis that was confounded by the mixing of incident and prevalent cases. Only three studies examined the influence of smoking on prognosis in only incident cases, most of whom had superficial disease. Of these, only one was of high quality. These three studies and the other 12 showed suggestive evidence that continued smoking or a lifetime of smoking constitutes a moderate risk factor for recurrence and death, and that stopping smoking could favourably change this. However, the evidence base for this is weak because of the methodological shortcomings and because most studies' results were not statistically significant. A life-table model showed that if stopping smoking altered the prognosis, the size of the benefit would be clinically worthwhile. CONCLUSION: There is suggestive evidence that stopping smoking might favourably alter the course of bladder cancer, but this is insufficient for clinicians to inform patients that doing so will improve their prognosis, and for providing specialized services to assist in stopping smoking to patients with bladder cancer.

20
UI - 12100923
AU - Shipley WU; Kaufman DS; Zehr E; Heney NM; Lane SC; Thakral HK; Althausen
TI - AF; Zietman AL Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer.
SO - Urology 2002 Jul;60(1):62-7; discussion 67-8
AD - Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
OBJECTIVES: To evaluate the outcomes of patients with muscle-invasive Stage T2-4a bladder carcinoma managed by transurethral surgery and concurrent chemoradiation. METHODS: A total of 190 patients were treated on institutional prospective protocols using concurrent cisplatin-containing chemotherapy and radiotherapy after rigorous transurethral resection of the bladder tumor. Patients were re-evaluated by repeated biopsy and urine cytologic analysis after 40 Gy, with the initial tumor response guiding subsequent therapy. One hundred twenty-one patients with a complete response by cytologic and histologic examination and those medically unfit for cystectomy received boost chemoradiation to 64 to 65 Gy. Those patients without a complete response were advised to undergo radical cystectomy. A total of 66 patients (35%) ultimately underwent radical cystectomy; 41 for less than a complete response and an additional 25 for recurrent invasive tumors. The median follow-up was 6.7 years for all surviving patients. RESULTS: The 5 and 10-year actuarial overall survival rate was 54% and 36%, respectively (Stage T2, 62% and 41%; Stage T3-T4a, 47% and 31%, respectively). The 5 and 10-year disease-specific survival rate was 63% and 59% (Stage T2, 74% and 66%; Stage T3-T4a, 53% and 52%), respectively. The 5 and 10-year disease-specific survival rate for patients with an intact bladder was 46% and 45% (Stage T2, 57% and 50%; Stage T3-T4a, 35% and 34%), respectively. The pelvic failure rate was 8.4%. No patient required cystectomy because of bladder morbidity. CONCLUSIONS: The 10-year overall survival and disease-specific survival rates are comparable with the results reported for contemporary radical cystectomy for patients of similar clinical and pathologic stage. One third of patients treated on protocol with the goal of bladder sparing ultimately required a cystectomy. A trimodality approach with bladder preservation based on the initial tumor response is, therefore, safe, with most long-term survivors retaining functional bladders.

21
UI - 12168852
AU - Tei Y; Matsuyama H; Wada T; Kurisu H; Tahara M; Naito K
TI - In vitro antitumor activity of bropirimine against urinary bladder tumor cells.
SO - Anticancer Res 2002 May-Jun;22(3):1667-71
AD - Department of Urology, Yahaguchi University School of Medicine, Ube, Japan.
BACKGROUND: Bropirimine is an orally-active immunostimulant that has an antitumor effect on superficial transitional cell carcinoma of the bladder. The mechanism of its antitumor effect has not yet been clarified. MATERIALS AND METHODS: The cytokine-mediated antiproliferative activity of bropirimine was tested against cultured KK-47 and 724 cells using a modified human clonogenic tumor assay. Perpheral blood mononuclear cells (PBMCs) obtained from five healthy volunteers were co-cultured with bropirimine and the levels of various cytokines, including IFN-alpha, gamma, IL-1beta and TNF-alpha in the supernatants, were quantified. RESULTS: Colony formation by both cell lines was directly inhibited by bropirimine in a dose-dependent manner. In co-cultures of bropirimine and PBMCs, the inhibition of colony formation by both cell lines was not enhanced compared with the effect of bropirimine alone. No significant elevation of cytokines was detected in the presence of PBMCs. CONCLUSION: The results obtained suggest that bropirimine is like to have direct antitumor activity rather than a cytokine-mediated antitumor effect.

22
UI - 12187064
AU - Nishiyama T; Tanikawa T; Tomita Y; Takahasi K
TI - Neoadjuvant chemotherapy with sequential methotrexate and 5-fluorouracil scheduling, epirubicin and cisplatin for locally advanced bladder cancer.
SO - Oncology 2002;63(1):1-5
AD - Department of Urology, Niigata University School of Medicine, Niigata, Japan. nkh@niigata-inet.or.jp
INTRODUCTION: Transitional cell carcinoma of the bladder is moderately sensitive to chemotherapy. Notably, the methotrexate, doxorubicin, vinblastine and cisplatin regimen was found to produce a high overall response rate and a modest survival advantage. However, toxicity was significant and the therapy rarely results in long-term disease-free survival. In several clinical series, sequentially delivered methotrexate and 5-fluorouracil followed by leucovorin rescue in expectation of a biochemical modulation has a higher response rate. METHODS: The combination chemotherapy using sequential methotrexate and 5-fluorouracil scheduling, epirubicin and cisplatin (MFAP regimen) for locally advanced bladder cancer was evaluated in a neoadjuvant setting. Thirty-seven patients (32 males and 5 females) were enrolled in this study. RESULTS: Six (16.2%) of the patients had complete responses and 26 (70.3%) had partial responses to the therapy amounting to a response rate of 86.5%. At follow-up, 10 of 13 patients (76.9%) who underwent bladder preservation had not developed muscle-invasive recurrence of the disease and kept their bladder. There is no statistical difference of the survival rate between the cystectomy group and the bladder preservation group (p = 0.86). Toxicity was relatively mild but with some severe myelotoxic effects. CONCLUSIONS: MFAP represents an active regimen in the treatment of locally advanced bladder cancer with a moderate toxicity profile. Copyright 2002 S. Karger AG, Basel

23
UI - 12209686
AU - Vaughn DJ; Manola J; Dreicer R; See W; Levitt R; Wilding G
TI - Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group.
SO - Cancer 2002 Sep 1;95(5):1022-7
AD - Abramson Cancer Center, University of Pennsylvania, Philadelphia 19104, USA. djv@mail.med.upenn.edu
BACKGROUND: Chemotherapy options for the patients with advanced urothelial carcinoma and renal dysfunction are limited. The authors performed a Phase II trial of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction. METHODS: Forty-two patients were accrued; 37 eligible patients were treated. Patients received paclitaxel 225 mg/m(2) over three hours followed by carboplatin targeted area under the concentration-time curve = 6 mg/mL. minute every three weeks for up to six cycles. RESULTS: The median number of cycles received was four (range, one to six). The objective response rate was 24.3% (95% confidence interval, 11.9-41.7%). The median progression free survival was 3 months and the median overall survival was 7.1 months. The number of poor prognostic risk factors (Eastern Cooperative Oncology Group performance status > 1 or lung, liver, or bone metastases) significantly predicted for survival. The most common > or = 1 Grade 3 toxicities included granulocytopenia (60%) and neurotoxicity (35%). CONCLUSIONS: Paclitaxel/carboplatin is a chemotherapy option for patients with advanced urothelial carcinoma and renal dysfunction. Future trials in chemotherapy development for this patient population are warranted. Copyright 2002 American Cancer Society.

24
UI - 12187204
AU - Rajala P; Kaasinen E; Raitanen M; Liukkonen T; Rintala E; The
TI - Finnbladder Group Perioperative single dose instillation of epirubicin or interferon-alpha after transurethral resection for the prophylaxis of primary superficial bladder cancer recurrence: a prospective randomized multicenter study--FinnBladder III long-term results.
SO - J Urol 2002 Sep;168(3):981-5
AD - Divisions of Urology, Turku University Hospital, Turku, Finland.
PURPOSE: We evaluated the long-term efficacy of a single dose of interferon or epirubicin administered immediately after transurethral resection compared with transurethral resection alone for primary superficial bladder cancer recurrence. MATERIAL AND METHODS: A total of 200 patients with primary superficial stages Ta to T1, grades 1 to 3 bladder cancer were randomized into 3 treatment groups, including transurethral resection alone, transurethral resection plus 50 milliunits interferon-alpha2b and transurethral resection plus 100 mg. epirubicin. The primary end point was time to first recurrence. RESULTS: At a median followup of 72 months we observed a sustained effect of a single epirubicin instillation compared with other treatments. To date only 46% of the patients in group 3 have experienced recurrence in contrast to 73% and 68% in groups 1 and 2, respectively (p = 0.002). At 72 months the Kaplan-Meier disease-free estimates were 24%, 31% and 51% in groups 1 to 3, respectively (p = 0.002). The Cox multivariate model revealed a more than 2-fold relative risk of recurrence in group 1 versus group 3 (p <0.001). Other significant variables predicting recurrence were grade and the number of tumors. CONCLUSIONS: A single perioperative instillation of 100 mg. epirubicin causes a significant and sustained decrease in primary superficial bladder cancer recurrence, whereas a single dose of 50 milliunits interferon-alpha2b is ineffective for prophylaxis.

25
UI - 11981270
AU - Patton SE; Hall MC; Ozen H
TI - Bladder cancer.
SO - Curr Opin Oncol 2002 May;14(3):265-72
AD - Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. spatton@wfubmc.edu
Bladder cancer is a common and chemotherapy-responsive tumor, related to tobacco smoking, environmental arsenic exposure, industrial dye exposure, and parasitic schistosomiasis exposure. Both reduction of carcinogen exposure and chemoprevention, possibly with cyclooxygenase 2 inhibitors, should reduce the incidence. The search for the ideal screening and monitoring test continues with some promising new candidates, including survivin. Although 10-year survival can be achieved in 87% of early-stage patients with muscle-invasive disease rendered T(0) and 57% of those rendered T(1) at second look after transurethral resection bladder tumor, most still require radical cystectomy. Continued improvements in surgical techniques permit gains in quality of life after the procedure. Ten-year survival can still be achieved with cystectomy in the face of grossly positive lymph nodes in 32% of T(2) and 10% of T(3) patients. A recent meta-analysis indicates that preoperative irradiation is unlikely to be beneficial, but definitive chemoradiation can produce significant 5-year survival rates in nonoperative candidates and those desiring bladder preservation. The Intergroup now has preliminary data from a Southwest Oncology Group-based trial showing a significant benefit for neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin. The regimen of gemcitabine and cisplatin is equally efficacious with less toxicity than methotrexate, vinblastine, doxorubicin, and cisplatin. It has been adopted as the standard arm in a phase III trial for advanced bladder cancer, comparing it with the triplet of gemcitabine, paclitaxel, and cisplatin. Other active agents in bladder cancer include ifosfamide, carboplatin, docetaxel, and vinorelbine, and various doublets of these agents are being tested in phase II trials, with promising results.

26
UI - 11984073
AU - Pu YS; Hour TC; Chen J; Huang CY; Guan JY; Lu SH
TI - Arsenic trioxide as a novel anticancer agent against human transitional carcinoma--characterizing its apoptotic pathway.
SO - Anticancer Drugs 2002 Mar;13(3):293-300
AD - Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei, Taiwan 100, ROC. yspu@ha.mc.ntu.edu.tw
Arsenic trioxide (As(2)O(3)) has been shown to be an active agent against acute promyelocytic leukemia. Little is known about its therapeutic efficacy in human transitional carcinomas. In this study, the arsenic-mediated apoptotic pathway in transitional carcinoma cells was investigated. Three bladder transitional carcinoma cell lines were used, including a parental sensitive line and two resistant daughter lines (cisplatin and As(2)O(3) resistant). The As(2)O(3)-mediated cytotoxicity to the three cell lines was studied in vitro in the presence or absence of buthionine sulfoximine (BSO), a chemotherapy modulator. In results, although a lesser extent of apoptosis was seen in cells treated with As(2)O(3) alone, more significant apoptotic events were observed in the combined treatment of As(2)O(3) and non-toxic concentrations of BSO (up to 10 microM). These included the accumulation of sub-G(1) fractions and internucleosomal DNA breakdown, which were preceded by production of reactive oxygen species, loss of mitochondrial membrane potential and activation of caspase-3. In conclusion, As(2)O(3) in the presence of BSO may be an active agent against both chemonaive and cisplatin-resistant transitional carcinomas. The As(2)O(3)-mediated cytotoxicity appeared to go through the conventional apoptotic pathway. Our results have clinical implications and warrant further investigation.

27
UI - 11125362
AU - Colombo R; Bertini R; Salonia A; Da Pozzo LF; Montorsi F; Brausi M;
TI - Roscigno M; Rigatti P Nerve and seminal sparing radical cystectomy with orthotopic urinary diversion for select patients with superficial bladder cancer: an innovative surgical approach.
SO - J Urol 2001 Jan;165(1):51-5; discussion 55
AD - Department of Urology, Scientific Institute H. San Raffaele, Milan, Italy.
PURPOSE: Radical cystectomy is advocated for high risk patients with superficial bladder cancer. To preserve complete urinary continence, normal sexual function and fertility in young patients, we developed an innovative technique based on nerve and seminal sparing radical cystectomy. MATERIALS AND METHODS: Radical cystectomy was recommended for 8 patients with superficial bladder cancer that was not conservatively manageable. Average patient age was 44 years (range 36 to 48), and all patients were extremely anxious to maintain potency and fertility. The surgical procedure consisted of transurethral resection of the prostate, pelvic iliac lymph node dissection and extraperitoneal radical cystectomy performed while preserving the vas deferens seminal vesicles and neurovascular bundles. Urinary diversion was accomplished with a W-shaped ileal reservoir anastomosed to the prostatic capsule. RESULTS: Patients were generally discharged from the hospital 15 days after surgery, and postoperative morbidity was limited. Daytime and nighttime continence was immediate and complete after catheter removal. Normal erectile function was clinically documented in all patients while fertility potential with semen retrieval via urine was recorded in 7. The quality of life, as reported by the patients, was highly satisfactory at 18-month followup. CONCLUSIONS: The surgical approach we describe should be considered in young men with clinical, superficial bladder tumors refractory to conservative treatment who wish to maintain potency and fertility, and to guarantee as good a quality of life as possible. To ensure oncological success scrupulous patient selection is a primary step of this procedure.

28
UI - 11547095
AU - John H; Hauri D
TI - Re: Nerve and seminal sparing radical cystectomy with orthotopic urinary diversion for select patients with superficial bladder cancer: an innovative surgical approach.
SO - J Urol 2001 Oct;166(4):1402

29
UI - 12085284
AU - Leissner J; Allhoff EP; Hohenfellner R; Wolf HK
TI - [Significance of pelvic lymphadenectomy for the prognosis after radical cystectomy]
SO - Zentralbl Chir 2002 Apr;127(4):315-21
AD - Urologische Universitatsklinik der Otto-von-Guericke-Universitat, Magdeburg, Germany. joachim.leissner@medizin.uni-magdeburg.de
OBJECTIVE: In contrast to other carcinomas such as breast or colon cancer, there are no guidelines regarding the number and location of lymph nodes to be removed during radical surgery in patients with invasive bladder carcinoma. The therapeutic effect of pelvic lymphadenectomy and its influence on tumour staging has not been documented yet. METHODS: Here we present an evaluation of pelvic lymph nodes from 484 patients who underwent radical cystectomy with curative intention between 1986 and 1999. The number of lymph nodes was correlated with the depth of invasion of the primary tumour, occurrence of nodal metastases, clinical outcome, the operating surgeon, and the pathologist. RESULTS: There were 484 patients with a mean age of 62.7 years. Clinical follow up was available from 321 patients with a mean follow up period of 35.9 months. The average number of lymph nodes removed was 14.3 (range: 1-46). The number of lymph nodes removed varied significantly between different surgeons and did not correlate with the pathologists. There was a significant correlation between the number of lymph nodes removed and the tumour-free survival in pT2 or pT3 tumours and in patients without lymph node metastases. Multivariate analysis revealed that pT-category (p < 0.01), pN-category (p < 0.01), and the total number of lymph nodes removed (p = 0.04) were the most important factors affecting survival. CONCLUSION: The more extensive lymphadenectomy significantly improved the prognosis of patients with invasive bladder cancer and therefore, represents a potentially curative procedure. The results indicate a need for a standardised lymph node dissection.

30
UI - 9812938
AU - van der Meijden AP
TI - Bladder cancer.
SO - BMJ 1998 Nov 14;317(7169):1366-9
AD - Department of Urology, Bosch Medicentrum, PO Box 90153, 5200 ME 's-Hertogenbosch, Netherlands. urology.bmc@tip.nl

31
UI - 12194991
AU - Lopez-Beltran A; Luque RJ; Mazzucchelli R; Scarpelli M; Montironi R
TI - Changes produced in the urothelium by traditional and newer therapeutic procedures for bladder cancer.
SO - J Clin Pathol 2002 Sep;55(9):641-7
AD - Department of Pathology, Reina Sofia University Hospital and Faculty of Medicine, 14004 Cordoba, Spain.
A handful of traditional and newer therapeutic procedures, such as chemotherapy, immunotherapy, radiotherapy, photodynamic and laser treatment, and gene therapy, are used to treat epithelial malignancies of bladder origin. These treatment modalities, used either intravesically or systemically, produce morphological changes in the urothelial mucosa that can be mistaken for carcinoma. The pathologist must be able to separate toxic and drug related alterations from tumour related changes. The clinical history is usually invaluable in this assessment.

32
UI - 11718635
AU - Xiaoxu L; Jianhong L; Jinfeng W; Klotz LH
TI - Bladder adenocarcinoma: 31 reported cases.
SO - Can J Urol 2001 Oct;8(5):1380-3
AD - Department of Urology, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, 030001 Shanxi, P.R. of China.
SUMMARY: Retrospective review of 31 cases of bladder adenocarcinoma. METHODS: All patients diagnosed with adenocarcinoma of the bladder at the second affiliated hospital and commercial worker's hospital in Shanxi between 1985 and 1999 were reviewed. RESULTS: The cohort consisted of 31 patients, 25 with primary bladder adenocarcinoma, and 6 patients with urachal adenocarcinoma. Compared to the patients with primary adenocarcinoma, the urachal group were younger (67 versus 56 years), and more likely to be female (M:F 3:1 versus 1:2), and had a worse survival (45% versus 20% at 3 years). In the primary bladder

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