Advanced Urinary Bladder Cancer Research Articles

Targeting Chemoresistance in Advanced Bladder Cancers with a Novel Adjuvant Strategy.

Advanced urinary bladder cancer is characterized by rapid progression and development of therapy resistance. About 30% of the patients are diagnosed with high-grade tumors (grade > T2a). A typical nonsurgical treatment is systemic chemotherapy using cisplatin (C) and gemcitabine (G). However, treatment failure and subsequent disease progression are common in treated patients, and adjuvant therapies are not significantly effective. The therapeutic potential of a molecular hybrid of ursolic acid (UA), a pentacyclic-triterpene conjugated to N-methyl piperazine (UA4), was tested on both naïve (WT) and gemcitabine-resistant (GemR) variants of two human invasive bladder cancer cell lines, 5637 and T24. UA4 killed 5637 (4 µmol/L), T24 (4 µmol/L) WT, and GemR cells in vitro at equal potency. Pretreatment with UA4 followed by G synergistically killed WT and GemR cells by >50% compared with G followed by UA4. Oral gavage of UA4 (100 mg/kg) inhibited WT and GemR tumor growth in athymic mice. UA4 + G was more effective against GemR tumors than either drug alone. Studies revealed cytotoxic autophagy as a mechanism of UA4 cytotoxicity. UA4 induced moderate apoptosis in T24 but not in 5637 cells. Mitochondrial integrity and function were most affected by UA4 because of high levels of reactive oxygen species, disruption of mitochondrial membrane, and cell cycle arrest. These effects were enhanced in the UA4 + G combination. UA4 was well-tolerated in mice, and oral gavage led to a serum level >1 µmol/L with no systemic toxicity. These results show the potential of UA4 as a nontoxic alternative treatment for high-grade bladder cancer.

Endoscopic balloon cryoablation against single instillation after transurethral resection of bladder cancer: A multicenter, randomized, controlled noninferiority trial.

e16561 Background: Cryotherapy is a prevalent percutaneous ablative therapy for solid tumors. However, studies on the clinical practice of endoscopic cryotherapy for intraluminal malignancies are lacking. We aim to explore the feasibility of endoscopic cryotherapy for bladder cancer. Methods: In this multicenter, randomized, parallel controlled, non-inferiority trial, we compared endoscopic balloon cryoablation (EBCA) with a single instillation (SI) of pirarubicin after transurethral resection (TUR).Men or women aged 18-85 years with a clinical diagnosis of bladder cancer (tumor number no more than 3 and maximal tumor size no more than 3 cm) were included. The exclusion criteria were as follows: locally advanced urinary bladder cancer (clinical stage T3 or T4), lymph node involvement (N1) or distant metastasis (M1), severe organ dysfunction, severe coagulation disorder, sepsis, concomitant neoplastic malignancy and other conditions unsuitable for surgery or intravesical chemotherapy. Women in pregnancy or lactation were also excluded. Eligible participants were randomly assigned (1:1) to the TUR-EBCA or TUR-SI group. The primary endpoint was the residual-free rate at repeated TUR. A non-inferiority test was used to compare the primary endpoint with a chosen margin of 10%. The secondary endpoints included the recurrence-free survival (RFS), progression-free survival (PFS) and adverse events. Results: We recruited 227 participants between November, 2017, and September, 2020. In total, 205 patients received EBCA or SI after TUR, of whom 163 completed all the required interventions and follow-up. In the per-protocol analyses, 75 (91.5%) of 82 patients had no residual tumor in the TUR-EBCA group compared with 61 (76.5%) of 81 in the TUR-SI group (risk difference 14.9%; 95% confidence interval [CI] 0.03 to 0.27, P < 0.001), meeting the criteria for non-inferiority. Similar results were found in the after intention-to-treat analysis. After a median follow-up of 21 months, the TUR-EBCA group had better RFS(HR = 0.49; 95% confidence interval [CI] 0.24 to 0.99; Log-rank P = 0.046) and PFS (HR = 0.25; 95% confidence interval [CI] 0.08 to 0.77; Log-rank P = 0.0092). There were no significant differences in the SAEs rate (3.0% vs. 3.9%, p = 0.52). Conclusions: EBCA is a safe and effective adjuvant alternative to TUR for bladder cancer with the potential advantage of “energetically resecting” the tumor base. Clinical trial information: NCT02760953.

1722P - Loss of SWI/SNF chromatin remodelling complex is linked to advanced urinary bladder cancer

1722P - Loss of SWI/SNF chromatin remodelling complex is linked to advanced urinary bladder cancer

116 Chemoinduced downstaging as a potential surrogate marker of efficacy and of increased survival following neoadjuvant chemotherapy of locally advanced urothelial urinary bladder cancer

116 Chemoinduced downstaging as a potential surrogate marker of efficacy and of increased survival following neoadjuvant chemotherapy of locally advanced urothelial urinary bladder cancer

Cytogenetic characterization of an N-butyl-N-(4-hydroxybutyl) nitrosamine-induced mouse papillary urothelial carcinoma

Chemically-induced urinary bladder cancer in rodents has long been used as a reliable model to study the biopathology of urinary bladder neoplasia and to develop therapeutic strategies against human tumors. Knowledge of the genetic basis underlying carcinogenesis would greatly enhance usability and usefulness of this model for the purposes of comparative pathology. However, little is known about the cytogenetic characteristics of rodent urinary bladder tumors. Accordingly, pathological and negative control specimens were collected for cytogenetic evaluation, from an ongoing mouse urinary bladder N-butyl-N-(4-hydroxybutyl) nitrosamine-induced carcinogenesis study. Histopathological analysis characterized the pathological sample as a papillary urothelial carcinoma. Conventional cytogenetic analysis revealed the presence of 66.3 % tetraploid cells. Fluorescent in situ hybridization using chromosome paint probes allowed the detection of a reciprocal translocation involving chromosomes 4 and 14 (containing the murine homologues to human p16 and retinoblastoma tumor-suppressor genes) in 42 % of tetraploid cells. The control sample showed no histological or cytogenetic changes. CDKN2A and RB1 loss of heterozygosity is associated with human early and advanced urinary bladder cancer, respectively. Thus, the present data paves the way for further studies concerning the molecular mechanisms of urinary bladder carcinogenesis.

774: COX2 Expression is Frequent in Advanced Urinary Bladder Cancer with Features of Genomic Instability

You have accessJournal of UrologyDiscussed Poster, Monday, May 23, 2005, 1:00 - 5:00 pm1 Apr 2005774: COX2 Expression is Frequent in Advanced Urinary Bladder Cancer with Features of Genomic Instability Stefan Denzinger, Leoni Kunz-Schughart, Frauke Bataille, Robert Stoehr, Ronald Simon, Guido Sauter, Thomas C. Gasser, Wolf Wieland, Arndt Hartmann, and Peter J. Wild Stefan DenzingerStefan Denzinger More articles by this author , Leoni Kunz-SchughartLeoni Kunz-Schughart More articles by this author , Frauke BatailleFrauke Bataille More articles by this author , Robert StoehrRobert Stoehr More articles by this author , Ronald SimonRonald Simon More articles by this author , Guido SauterGuido Sauter More articles by this author , Thomas C. GasserThomas C. Gasser More articles by this author , Wolf WielandWolf Wieland More articles by this author , Arndt HartmannArndt Hartmann More articles by this author , and Peter J. WildPeter J. Wild More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)34943-7AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "774: COX2 Expression is Frequent in Advanced Urinary Bladder Cancer with Features of Genomic Instability." The Journal of Urology, 173(4S), p. 210 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 173Issue 4SApril 2005Page: 210 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Stefan Denzinger More articles by this author Leoni Kunz-Schughart More articles by this author Frauke Bataille More articles by this author Robert Stoehr More articles by this author Ronald Simon More articles by this author Guido Sauter More articles by this author Thomas C. Gasser More articles by this author Wolf Wieland More articles by this author Arndt Hartmann More articles by this author Peter J. Wild More articles by this author Expand All Advertisement PDF DownloadLoading ...

Aberrations of the Chk2 tumour suppressor in advanced urinary bladder cancer.

Checkpoint kinase 2 (Chk2) is a tumour suppressor and signal transducer in genome integrity checkpoints that coordinate cell-cycle progression with DNA repair or cell death in response to DNA damage. Defects of Chk2 occur in subsets of diverse sporadic malignancies and predispose to several types of hereditary carcinomas. However, the status of Chk2 in tumours of the urinary bladder remains unknown. Here, we report that among 58 advanced (grade T2-T4) human bladder carcinomas, immunohistochemical analysis revealed tumour-specific reduction or lack of Chk2 protein in 6 (10.3%) cases. Genetic analysis of the latter subset showed that a Chk2-negative carcinoma #668 harboured a truncating mutation 1100delC, in one Chk2 allele and loss of the corresponding second allele. The 1100delC mutation was also found in the germ line of this patient. Sequencing of TP53 in tumour #668 identified two missense mutations. Furthermore, the vast majority of the tumours showed 'unscheduled' activatory phosphorylation on Thr68 of Chk2 in the absence of any DNA-damaging treatment. Our results indicate that the otherwise dormant DNA damage signal transducer Chk2 is aberrantly and constitutively activated in invasive urinary bladder carcinomas, and that such likely proapoptotic checkpoint signalling can be disabled by inactivation of Chk2 and/or p53 tumour suppressors in subsets of these tumours.

The prevalence and clinicopathologic correlate of p16 INK4a, retinoblastoma and p53 immunoreactivity in locally advanced urinary bladder cancer

The purpose of the study was to investigate the prognostic value and clinicopathological correlate of tumor p53, p16 and Rb protein expression in patients with locally advanced urinary bladder cancer. Sixty-five patients (44 men and 21 women; 40 to 84 yrs old) with locally advanced urinary bladder cancer (21 pT2, 27pT3, 17pT4) undergoing radical cystectomy and bilateral pelvic lymph node dissection were followed up for 2 to 116 months (mean ± SD: 30.02 ± 6.46 months). Immunohistochemical staining for p53, Rb and p16 proteins were performed on surgically obtained, formalin fixed and paraffin embedded tissue sections. Thirty of the tumors (46.2%) were p53 +, 52 of the tumors (80%) were p16 − and 41 (63%) were Rb −. Only 5 of the tumors (7.7%) had normal expression of all three proteins. The tumor expression status of p53 could not be correlated with p16 ( P = 1.000) or Rb ( P = 1.000). Only a marginal inverse relationship was found between the expression of p16 and Rb ( P = 0.056). Higher grade tumors had significantly lower percentage of p16 abnormality ( P = 0.05), while higher grade (not higher stage) tumors had higher percentage of Rb abnormality ( P = 0.0245). Univariate analysis showed that tumor expression of Rb or p16, alone or combined, had no predictive value on progression-free and disease-specific survival. It did, however, show a significant correlation between progression-free survival and tumor p53 and LN status ( P = 0.032 and P = 0.0304) and a significant correlation between tumor stage disease-specific survival ( P = 0.042). Multivariate analysis showed tumor stage and nodal status to be two significant independent indicators for progression-free survival ( P = 0.0038 and P = 0.0049) and disease-specific survival ( P = 0.0066 and P = 0.0484). It was also noteworthy that, after receiving postoperative adjuvant systemic M-VEC chemotherapy, patients with node-positive p53-normal tumors had significantly better progression-free and disease-specific survivals than those with node-positive p53-abnormal tumors ( P = 0.036 and P = 0.0479, respectively). This study has found tumor expression of p53, p16 and Rb proteins in locally advanced bladder cancer to be frequently abnormal. Although multivariate analysis showed tumor stage and nodal status to be the only two statistically significant parameters, p53 may also serve as an additional prognostic predictor of the outcome of postoperative adjuvant systemic chemotherapy in patients with regional lymph node tumor involvement. Such patients with p53-normal tumors experienced significantly better progression-free and disease-specific survivals than those with p53-abnormal tumors.

Molecular cytogenetic alterations associated with rapid tumor cell proliferation in advanced urinary bladder cancer.

Invasive urinary bladder carcinomas are characterized by a high number of cytogenetic alterations which are thought to pinpoint the location of critical genes, some of which may be involved in cell cycle control. To identify genomic alterations that may affect such genes the proliferative activity (Ki67 labeling index) was assessed in 93 invasively growing bladder carcinomas analyzed by comparative genomic hybridization. Only a few changes were significantly associated with rapid tumor cell proliferation, including 3p+ (p=0.0357), 6p+ (p=0.003), 8q+ (p=0.0273), and 11q- (p=0.0329). Among these alterations 6p+ is of particular interest because high level 6p22 amplifications occur frequently in bladder cancer. The particular strong association between 6p+ and a high tumor cell proliferation being independent of grade and stage suggests that a putative oncogene on 6p22 involved in cell cycle regulation.

Partially wedged radiation beams.

To increase dose homogeneity within certain radiotherapy targets, we defined a partially wedged radiation beam as a beam with wedge modification in one part of the field only. Partially wedged beams may be beneficial in cases with curved surfaces inside parts of the beam only, where they may compensate for missing tissue and/or for variations in depth to the target region. Possible sites suitable for partially wedged beams include urinary bladder and tangential breast irradiation. Customized partially wedged beams were delivered applying dynamic collimation techniques. Two different linear detector arrays, a semiconductor diode array and an ionization chamber array, were used independently in the same standard water tank to verify that the partially wedged beams were delivered according to the definition. Dose calculations of partial wedge fields were implemented in our treatment planning system and compared with the measured dose distributions. We re-planned a representative treatment plan for both advanced urinary bladder cancer and tangential breast irradiation using partially wedged beams. For both patients the target dose homogeneity was improved, and the doses to surrounding critical normal tissues were reduced.

Patterns of Chromosomal Imbalances in Advanced Urinary Bladder Cancer Detected by Comparative Genomic Hybridization

To identify genetic changes linked to bladder cancer progression we analyzed 90 invasive transitional cell carcinomas (37 pT1 and 53 pT2-4) by comparative genomic hybridization. The most frequent alterations included 1q+ (37%), 5p+ (24%), 6q- (19%), 8p-(29%), 8q+ (37%), 9p- (31%), 9q- (23%), 11p-(24%), 11q- (22%), 17q+ (29%), and 20q+ (28%). Interestingly, there were three groups of alterations that frequently occurred together (9p- and 11q13+/ 20q+ and 11q13+ or 17q+/1q+ and 3p+ or 11q-). These loci might carry genes that interact with each other in specific molecular pathways. There were remarkable genetic similarities between minimally and deeply invasive tumors of different histological grades, including a similar number of aberrations per tumor and an equal frequency of most individual alterations. However, deletions of 5q, 6q, and 15q and gains of 5p, 7p, and Xq were significantly more frequent in pT2-4 than in pT1 carcinomas. These loci may harbor genes that are important for bladder cancer progression.

Phase II study of a new combined primary chemotherapy regimen, intravenous methotrexate and vincristine and intraarterial Adriamycin and cisplatin, for locally advanced urinary bladder cancer: preliminary results

A phase II study of a new combination therapy was performed using intraarterial (i.a.) cisplatin and Adriamycin in combination with i.v. methotrexate and vincristine for 27 patients with invasive urinary bladder carcinoma of stages T2-3NOMO, and the therapeutic effects were assessed. Methotrexate (20 mg/m2) was given i.v. on days 1,15, and 22, and vincristine (0.7 mg/m2) was injected i.v. on day 2 before i.a. infusion therapy and on days 15 and 22. The i.a. chemotherapy was performed after both superior gluteal arteries had been embolized using 3- or 5-mm stainless-steel coils. A mixture of cisplatin (50-70 mg/m2) and Adriamycin (20 mg/m2) was infused i.a. via both internal iliac arteries over a period of 20-30 min. Angiotensin II (mean dose, 21 micrograms) was simultaneously infused i.a. in 15 of 27 patients. In 24 of the 27 patients, at least 2 cycles of full-dose chemotherapy were completed. The dose was decreased in the remaining 3 patients because of their poor health status and advanced age. Among the 27 patients, 9 and 14 had complete (CR) and partial responses (PR), respectively; 3 manifested no change (NC), and 1 had progressive disease (PD). The objective response rate (CR+PR) was 85.2%. Among the 27 patients staged T2-3 NOMO, 6 (CR, 1; PR, 5) underwent total cystectomies and 18 (CR, 8; PR, 8; NC, 2) had transurethral resection of a bladder tumor (TUR-Bt) or partial resections following chemotherapy. The remaining 3 diminished-dose patients had no surgery. Of the 27 patients, 22 were alive after a median follow-up period of 21+ (range, 7-48+) months. No significant side effect was observed except for lower extremity paresthesias in 5 patients (18.5%). These results point to the effectiveness of this therapy and to the possibility of urinary bladder preservation in patients with invasive, advanced urinary bladder cancers.

Combined Cisplatin and Radiation Therapy for Advanced Bladder Cancer

Since September 1985, 44 patients with advanced urinary bladder cancer have been treated by combined cisplatin and full-dose radiotherapy. The patients were 32 males and 12 females, and their ages ranged from 33 to 83 years, with a median of 67.4 years. Radiotherapy consisting of a tumor dose of 50-60 Gy was administered with cobalt-60. Cisplatin was infused 5 days at a daily dose of 20 mg on the 1st and 4th weeks of treatment. Of the 39 evaluable patients 27 (69.2%) achieved a complete response. Toxicity was also evaluated for those 44 patients. Mainly gastrointestinal toxicity was noted: loss of appetite in 28 (64%), nausea and/or vomiting in 21 (48%), and diarrhea in 8 (18%). Leukocytopenia was noted in 16 (33%) and mild thrombocytopenia in 5 (11%). Mild dermatitis was noted in 8 (18%).

Neues, nicht chirurgisch implantierbares Katheter-Port-System zur lokoregionalen Chemotherapie des fortgeschrittenen Harnblasenkarzinoms

A new method to treat advanced urinary bladder cancer with locoregional chemotherapy has been developed which can be implanted by the radiologist. So far 3 patients with urinary bladder cancer invading the surrounding anatomical structures were treated. A 5F catheter is introduced into the internal iliac artery by the translumbar approach. Then, this catheter is exchanged with a coaxially assembled catheter port system over a guide wire. A subcutaneous tunnel through the puncture site is formed to receive the port. 10 mg mitomycin were infused three times at intervals of one to three weeks. Computed tomograms and cytoscopy showed complete disappearance of the tumour.

Chemotherapy in advanced urinary bladder cancer

In our investigation of different chemotherapy protocols, the best results in recent years were obtained with a combination of cisplatinum and doxorubicin in patients with recurrent urinary bladder cancer. This applied both to the local bladder tumor and the metastases. With respect to the cases of advanced localized bladder cancer, refined surgery or more developed equipment in radiotherapy, even developing new particles or rays, presumably will give only marginal effects on eradication of the tumor. A new approach may be to give a combined therapy of CDDP and doxorubicin before surgery and/or radiotherapy; a pilot study is going on in Stockholm. Experience so far has shown that CDDP together with radiotherapy or after preoperative irradiation followed by cystectomy is not tolerable to the patients. Between 40 and 50 per cent of them failed to fulfill the treatment.

Methotrexate: an active drug in bladder cancer.

Forty-nine patients with transitional urothelial tract tumors received methotrexate: 0.5-1.0 mg/kg I.V. Q W (40 patients) or 250 mg/M2 in a 2-hour infusion with citrovorum factor rescue 24 hours later (nine patients). Eleven (26%, 95% confidence limits 13-39%) of 42 patients with bidimensionally measurable metastases achieved partial remission. Most responses occurred within 2-3 weeks and persisted for a median duration of six months (range, 2-20). Response rates were increased to 38% (6/16 patients, 95% confidence limits 18-65%) in patients who had no prior chemotherapy, and a 90-100% performance status (50, 5/10 patients, 95% confidence limits 22-78%) compared with 19% (5/26, 95% confidence limits 8-37%) in patients who had prior chemotherapy and a less than or equal to 80% performance status (19%, 6/32 cases, 95% confidence limits 9-32%). Toxicity included mucositis and myelosuppression. A review of the literature coupled with the present data suggest that methotrexate is as active as cisplatin in the treatment of patients with advanced urinary bladder cancer.