High-order interactions among genetic polymorphisms in nucleotide excision repair pathway genes and smoking in modulating bladder cancer risk.

Polymorphisms in nucleotide excision repair (NER) genes may cause variations in DNA repair capacity and increase susceptibility to bladder cancer through complex gene-gene and gene-smoking interactions. We applied two data mining approaches to explore high-order gene-gene and gene-environment interactions among 13 polymorphisms in nine major NER genes in 696 bladder cancer patients and 629 controls. Individually, only the XPD D312N variant genotypes exhibited a slightly increased risk for bladder cancer. In classification and regression tree analysis, we observed gene-gene interactions among CCNH V270A, ERCC6 M1097V and RAD23B A249V in ever smokers: smokers with the variant alleles at these three loci had an almost 30-fold increased risk of bladder cancer [odds ratio (OR): 29.6, 95% confidence interval (CI): 9.3-93.7]. When evaluating combined effect of above four single nucleotide polymorphisms, we found a significant gene dosage effect for increased bladder cancer risk with increasing numbers of unfavorable genotypes. Compared with individuals with less than 2 unfavorable genotypes, those with 2 unfavorable genotypes and more than 2 unfavorable genotypes exhibited increased bladder cancer risk with ORs of 1.14 (95% CI: 0.87-1.51) and 2.15 (95% CI: 1.56-2.97), respectively (P < 0.001). The risks were more evident in ever smokers with ORs of 1.43 (95% CI: 1.02-2.01) and 3.40 (95% CI: 2.24-5.15), respectively (P < 0.001). In multifactor dimensionality reduction (MDR) analysis, the five-factor model including smoking, CCNH V270A, ERCC6 M1097V, RAD23B A249V and XPD D312N had the best ability to predict bladder cancer risk. The contributions of these polymorphisms may jointly affect bladder cancer risk through gene-gene and gene-smoking interactions.

E-cadherin promoter polymorphism (C-160A) and risk of recurrence in patients with superficial bladder cancer.

Tumor recurrence is a hallmark of superficial bladder cancer. Currently, a molecular marker for bladder cancer recurrence is lacking. E-cadherin plays an important role in epithelial development and in the establishment and maintenance of cell-cell adhesion and tissue architecture. The purpose of this study is to investigate the association of an E-cadherin promoter polymorphism (CDH1c-160a) with the risk of bladder cancer recurrence. This study included 302 patients with superficial bladder cancer. Genomic DNA was extracted from peripheral blood lymphocytes and genotyping was performed using Taqman assay. Clinical data were collected by medical chart review. Cox proportional hazard model was used to estimate the hazard ratios (HRs) associated with genotypes while adjusting for age, gender, smoking status, tumor stage and grade where appropriate. During a median follow-up of 27.65 months, 151 patients experienced disease recurrence. Subsequent analyses were restricted to Caucasians only due to the small sample size of other ethnic groups (13 in recurrence group and 15 in non-recurrence group). Among the 274 Caucasian patients, 138 developed recurrence during the same length of follow-up time. In Caucasian patients, having at least one variant A allele conferred a 32% reduction in recurrence risk (adjusted HR: 0.68; 95% CI: 0.48-0.96). The median recurrence-free survival for patients carrying at least one variant A allele was significantly longer than that for patients with a homozygous CC genotype (40.4 vs 12.5 months, p=0.04). Our findings suggest that the E-cadherin promoter polymorphism may be a valuable molecular marker for bladder cancer recurrence.

In vivo gene therapy of human bladder cancer with PTEN suppresses tumor growth, downregulates phosphorylated Akt, and increases sensitivity to doxorubicin.

The PTEN gene, located on chromosome 10, is a phosphatase in the phosphatidylinositol 3'-kinase (PI3'K)-mediated signal transduction pathway. PTEN inhibits the activation of Akt, a serine-threonine kinase involved in proliferative metabolic and antiapoptotic pathways, and has tumor suppressive properties. We created a PTEN adenoviral vector, Ad-MMAC, to assess the role of PTEN in the treatment of bladder cancer. Direct injection of Ad-MMAC into established subcutaneous UM-UC-3 (PTEN deleted, upregulation of phosphorylated Akt) and UM-UC-6dox (wild-type PTEN, upregulation of phosphorylated Akt) tumors in nude mice resulted in PTEN expression, apoptosis, and significantly decreased growth compared to Ad-CTR- or Phosphate-buffered saline (PBS)-treated tumors. UM-UC-3 tumors completely disappeared in all of mice treated with Ad-MMAC, but PBS- and Ad-CTR-treated UM-UC-3 tumors continued to grow rapidly. UM-UC-14 tumors (wild-type PTEN) were transiently suppressed by Ad-MMAC. Downregulation of vascular endothelial growth factor and decreased microvessel density were seen in tumors treated with Ad-MMAC in vivo. Combination therapy with Ad-MMAC and doxorubicin improved the in vivo efficacy of PTEN gene therapy in the doxorubicin-resistant cell line UM-UC-6dox. Treatment with Ad-MMAC and doxorubicin completely eradicated established UM-UC-6dox tumors in three of 10 mice. UM-UC-14 tumors were transiently suppressed by this combined treatment. These data demonstrate that PTEN gene therapy can effectively treat bladder cancers that have genomic alterations in PTEN. Furthermore, tumors that exhibit drug resistance associated with expression of phosphorylated Akt can be effectively treated with PTEN gene therapy and chemotherapy.

Genetic mapping and DNA sequence-based analysis of deleted regions on chromosome 16 involved in progression of bladder cancer from occult preneoplastic conditions to invasive disease.

Histologic and genetic mapping with 30 hypervariable markers mapped to chromosome 16 were performed on 234 DNA samples of five cystectomy specimens from patients with invasive bladder cancer. Allelic losses of individual markers were related to microscopically identified precursor conditions in the entire bladder mucosa and invasive cancer. Their significance for the development and progression of neoplasia from in situ preneoplastic conditions to invasive disease was analysed by the nearest neighbor algorithm and binomial maximum likelihood analysis. Using this approach we identified five distinct regions of allelic losses defined by their flanking markers and predicted size as follows. p13.3(D16S418-D16S406, 1.2 cM), p13.1(D16S748-D16S287, 12.9 cM), q12 1(D16S409-D16S514, 24.0 cM), q22.1 (D16S496-D16S515, 5.4 cM), and q24 (D16S507-D16S511, 5.9 cM and D16S402-D16S413, 17.4 cM). The regions mapping to p13.1 and q24 were involved in early intraurothelial phases of bladder neoplasia such as mild to moderate dysplasia. On the other hand the deleted region mapping to p13.3 was involved in progression of severe dysplasia/carcinoma in situ to invasive bladder cancer. Testing of markers that exhibited statistically significant LOH in relation to progression of neoplasia from precursor conditions to invasive cancer on 28 tumors and voided urine samples from 25 patients with bladder cancer revealed that q12.1 showed LOH in 46.4% of tumor and 32.0% of voided urine samples. The LOH of a single marker D16S541 could be detected in approximately 28% of tumors and 20% of voided urine samples of patients with bladder cancer. These data imply that the deleted region centered around marker D16S541 spanning approximately 10 cM and flanked by D16S409 and D16S415 contains a novel putative tumor suppressor gene or genes playing an important role in the development of human bladder cancer. To facilitate more precise positional mapping and identification of pathogenetically relevant genes, we analysed of human genome contig and sequence databases spanning the deleted regions. Multiple known candidate genes and several smaller gene-rich areas mapping to the target regions of chromosome 16 were identified.

Mapping and genome sequence analysis of chromosome 5 regions involved in bladder cancer progression.

We studied the evolution of allelic losses on chromosome 5 by whole-organ histologic and genetic mapping in 234 mucosal DNA samples of 5 cystectomy specimens with invasive bladder cancer and preneoplastic changes in adjacent urothelium. The frequency of alterations in individual loci was verified on 32 tumors and 29 voided urine samples from patients with bladder cancer. Finally, deleted regions on chromosome 5 were integrated with the human genome contigs and sequence-based databases. Deleted regions on chromosome 5 involved in intraurothelial phases of bladder neoplasia defined by their nearest flanking markers and predicted size were identified as follows: q13.3-q22 (D5S424-D5S656; 38.8 centimorgan [cM]); q22-q31.1 (D5S656-D5S808; 19.2 cM), q31.1-q32 (D5S816-SPARC; 11.5 cM), and q34 (GABRA1-D5S415; 6.4 cM). The two most frequently deleted neighbor markers (D5S2055 and D5S818) mapping to q22-q31.1 defined a 9 cM region, which may contain genes that play an important role in early phases of urinary bladder carcinogenesis. Human genome database analysis provided an accurate map of deleted regions with positions of 138 known genes and revealed several smaller gene-rich areas representing putative targets for further mapping. The strategic approach presented here, which combines whole-organ histologic and genetic mapping with analysis of the rapidly emerging human genome sequence database, facilitates identification of genes potentially involved in early phases of bladder carcinogenesis.

Radical cystectomy for invasive bladder cancer in the octogenarian.

The incidence of bladder cancer increases with age. As the population lives longer, an increasing number of patients 80 years of age or older will develop invasive bladder cancer. In this study, we reviewed the outcome of 33 patients age 80 years or older treated with radical cystectomy and ileal conduit urinary diversion. Five patients received neoadjuvant chemotherapy, and 2 had salvage cystectomy after failure of external beam radiation therapy. The median age was 82 years, and the median hospital stay was 12 days. There were no perioperative deaths. Twenty-seven complications occurred in 20 patients (60.6%), of which 17 were minor (63%) and 10 were major (37%). There was no difference in the rate of complications in patients receiving neoadjuvant treatment compared to the group treated with cystectomy alone. The median survival was 3.5 years. Our results demonstrate that radical cystectomy and ileal conduit urinary diversion should not be withheld from patients on the basis of age.

Connexin 26 enhances the bystander effect in HSVtk/GCV gene therapy for human bladder cancer by adenovirus/PLL/DNA gene delivery.

Herpes simplex thymidine kinase/ganciclovir (HSVtk/GCV) gene therapy has been used for the treatment of a variety of cancers. Its efficacy is enhanced by the bystander effect that helps overcome the delivery problems commonly observed in current gene therapy. Connexins encode proteins that produce gap junctions, which enable intercellular communication and the bystander effect. We previously demonstrated that decreased Cx 26 expression and loss of gap junctional intercellular communication were associated with human bladder cancer. To investigate the efficacy of the bystander effect in HSVtk/GCV gene therapy, the Cx 26 gene was introduced into UM-UC-3 and UM-UC-14 bladder cancer cell lines by an adenovirus poly-L-lysine conjugate using a multigenic expression plasmid that expressed both the HSVtk and Cx 26 genes. We found significantly increased cytotoxicity in HSVtk/GCV gene therapy after introduction of the HSVtk and Cx 26 genes together compared with the cytotoxicity seen after introduction of the HSVtk gene and LacZ genes in vitro and in vivo. Cytotoxicity correlated with Cx 26 expression and the induction of functional gap junctions. This study indicates that combination gene therapy with co-expression of the HSVtk and Cx 26 genes potentiates HSVtk/GCV gene therapy through the bystander effect.

Cystectomy in the elderly.

Invasive bladder cancer is a disease of the elderly. With the elderly population rapidly growing and living longer than ever before, a larger number of patients 75 years of age or older will develop invasive bladder cancer. Currently available data indicate that well-selected elderly patients, even those 80 years old or older, do not have a significantly higher risk of morbidity or mortality from cystectomy than do younger patients. Cystectomy in patients of advanced age requires a multidisciplinary team approach and increased vigilance in the perioperative period but can be performed safely. Most elderly patients diagnosed with invasive bladder cancer, if left untreated by cystectomy, will die of the disease and not from competing age-related illness. Therefore, radical cystectomy should not be withheld from elderly patients on the basis of age alone.

Identification of effective retinoids for inhibiting growth and inducing apoptosis in bladder cancer cells.

PURPOSE: Retinoids modulate the growth and differentiation of normal and malignant epithelial cells in vitro and in vivo, and inhibit bladder carcinogenesis in animal models. Retinoid analogs have been used in several clinical chemoprevention trials of superficial bladder cancer recurrence. There is a clear need to identify new effective retinoids and develop novel approaches for the chemoprevention and treatment of superficial bladder cancer. We investigated the effects of various retinoids on growth inhibition and apoptosis induction in bladder cancer cell lines. MATERIALS AND METHODS: Ten grades 1 to 3 bladder cancer cell lines and the 4 retinoids all-trans-retinoic acid, 9-cis retinoic acid, 4-(N-hydroxyphenyl) retinamide (4HPR) and LGD1069 were used in the study. We compared the ability of these retinoids to inhibit growth, induce apoptosis, affect the expression of nuclear retinoid receptors and modulate apoptosis related genes. RESULTS: Most bladder cancer cell lines did not express retinoic acid receptor beta and were resistant to the effect of all-trans-retinoic acid and 9-cis retinoic acid on growth inhibition and apoptosis induction, even at a concentration of 10(-5) M. The 2 cell lines that expressed retinoic acid receptor beta were constitutively sensitive to the growth inhibitory effect of all-trans-retinoic acid. 4HPR inhibited cell growth by about 90% in all but 1 cell line and induced apoptosis at a concentration of 10(-5) M after a 24-hour treatment. LGD1069 had virtually no effect. All-trans-retinoic acid and 4HPR induced retinoic acid receptor beta expression in 1 bladder cancer cell line. However, the effect of 4HPR on cell growth and apoptosis were not related to the constitutive expression of retinoic acid receptor beta. 4HPR decreased bcl-2 expression in 6 of 8 bladder cancer cell lines but did not change p53 gene expression. CONCLUSIONS: The results demonstrate that 4HPR is the most potent growth inhibitor and apoptosis inducer of the retinoids tested. Lack of retinoic acid receptor beta expression may be responsible for cell resistance to all-trans-retinoic acid but not to the other retinoids.

Differential expression of progression-related genes in the evolution of superficial to invasive transitional cell carcinoma of the bladder.

It is generally accepted that there are dichotomous biologic pathways that lead to the development of either: i) superficial papillary (Ta) transitional cell carcinoma (TCC) or ii) precursor lesions to muscle-invasive (CIS, T1) TCC and muscle-invasive (> or =T2) TCC. We investigated the expression of several progression-related genes to characterize the phenotype of these tumors within these divergent developmental pathways. Using a colorimetric in situ hybridization technique, we examined the expression of mRNAs of several progression-related genes in archival, pathologic specimens from 77 patients with bladder TCC. These genes included basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), interleukin (IL)-8, matrix metalloproteinase (MMP)-9, and epidermal growth factor receptor (EGFR). Relative gene expression was quantified using image analysis. Gene expression was normalized using poly (dT) and the expression of each factor in a panel of specimens of normal urothelium. Patients were stratified according to disease stage, and the level of gene expression among the stratified groups was compared. VEGF, bFGF, IL-8, and MMP-9 expression was increased in muscle-invasive compared with superficial papillary tumors, (p<0.05) and VEGF expression was increased in muscle-invasive tumors compared with CIS specimens (p<0. 05). bFGF, IL-8, and EGFR expression was increased in CIS specimens compared with superficial papillary tumors (p<0.05). The pattern of expression of bFGF, VEGF, IL-8, MMP-9, and EGFR represent the divergent developmental pathways in the pathogenesis of bladder TCC, which characterizes superficial or invasive bladder cancer. bFGF, IL-8, and EGFR appear to be upregulated in early precursor lesions (CIS), whereas VEGF appears to be upregulated at later stages in the development of muscle-invasive TCC.

Combination cisplatin, 5-fluorouracil and radiation therapy for locally advanced unresectable or medically unfit bladder cancer cases: a Southwest Oncology Group Study.

PURPOSE: Patients with locally advanced bladder cancer or who are not medically fit for surgery are a therapeutic dilemma. Radiotherapy with or without single agent cisplatin has been the major therapeutic modality. A phase II Southwest Oncology Group trial investigated the efficacy and feasibility of 5-fluorouracil, cisplatin and radiation in this patient subset. MATERIALS AND METHODS: Eligible patients had muscle invasive bladder cancer (clinical stages T2-T4) with nodal involvement at or below the level of bifurcation of the iliac vessels, were medically or surgically inoperable, or refused cystectomy. Patients underwent pretreatment cystoscopy and detailed tumor mapping, and were treated with 75 mg. /m.2 cisplatin on day 1 and 1 gm./m.2 daily, 5-fluorouracil on days 1 to 4 and definitive radiotherapy. Chemotherapy was repeated every 28 days, twice during and twice after radiation. RESULTS: From October 1993 to April 1998, 60 patients were enrolled in study. Of the 56 eligible patients 34% had unresectable tumors, 21% were not medically fit for surgery and 45% refused cystectomy. Overall, 68% of the patients had clinical T3 tumors or greater and 22% had nodal metastasis. Treatment was completed as planned in 32 of 56 (57%) patients. The most frequent grade 3 or 4 toxicities were neutropenia, stomatitis or mucositis, diarrhea, neuropathy and nausea. There were 53 patients who were evaluable for response, although response was not determined for 18. The overall response rate was 51% (95% confidence interval [CI] 37 to 65) based on intent to treat with a complete response rate of 49% (95% CI 35 to 63). Estimated median survival of the 56 patients was 27 months (95% CI 21 to 40 months) with an overall 5-year survival of 32%. The 5-year survival of the 25 patients who refused surgery was 45%. CONCLUSIONS: Concurrent 5-fluorouracil, cisplatin and radiation therapy is feasible. Despite a promising complete response rate, the overall 5-year survival suggests the need for more effective systemic therapy. The 5-year survival of patients who refused cystectomy suggests that this combined modality may provide another alternative to cystectomy for these patients.

Connexin 26 gene therapy of human bladder cancer: induction of growth suppression, apoptosis, and synergy with Cisplatin.

The connexin 26 (Cx26) gene encodes a protein involved in gap junctional intercellular communication and is a putative tumor suppressor. We constructed a Cx26 adenovirus vector (Ad-Cx26) and used it to infect human bladder cancer cell lines UM-UC-3, UM-UC-6, UM-UC-14, and T24. Infection with Ad-Cx26 suppressed the growth of these cell lines in vitro and prevented tumor formation in vivo. Cell cycle accumulation or arrest at the G(1) phase was noted in UM-UC-3 cells and at the G(2)/M phase in UM-UC-6, UM-UC-14, and T24 cells. Apoptosis was noted in UM-UC-3, UM-UC-6, and UM-UC-14 cells both in vitro and in vivo. These effects were not seen with control adenovirus (Ad-CTR) or mock infection. Ad-Cx26 did not significantly alter the growth of the immortalized normal human bladder cell line SV-HUC. Direct injection of Ad-Cx26 into established UM-UC-3 and UM-UC-14 tumors in nude mice resulted in Cx26 expression, apoptosis, and significantly decreased growth compared with Ad-CTR treated tumors. Delayed resumption of tumor growth was associated with loss of Cx26 expression. Combination therapy with Ad-Cx26 and cisplatin resulted in decreased growth in vitro compared with either agent alone. We explored combination therapy with Ad-Cx26 and cisplatin to improve the in vivo efficacy of Cx26 gene therapy. In vivo therapy with Ad-Cx26 and cisplatin resulted in long-term suppression of tumor growth. These data demonstrate that combining gene and chemotherapy can result in dramatic synergy in vivo.

Extravesical cryosurgical approach for VX2 bladder tumor in rabbits.

This study characterized the VX2 bladder cancer model in rabbits and tested the feasibility of treating bladder cancer by extravesical cryosurgery. After the growth characteristics of the VX2 bladder tumor model were determined, the VX2 tumor was inoculated into rabbits at the dome of the bladder. One week later, three freeze/thaw cycles were followed by immediate surgical repair. The control group underwent a sham operation without freezing. When the VX2 tumor is injected into the bladder wall, invasion and central necrosis occurred within I week, lymphatic metastases by 2 weeks, and lung metastases by 3 weeks after inoculation. By 4 weeks, all control rabbits had large VX2 tumors in their bladders and advanced lung metastases. Nine of the ten rabbits in the cryosurgical group had mild to moderate degrees of lung metastases, and six of them had relatively small local recurrences. One rabbit had no tumor in the bladder and only microscopic lung metastasis. The extravesical approach to cryosurgery employing bladder inversion is well tolerated. Cryosurgery exhibits modest efficacy in treating local tumors and delaying lung metastasis in this aggressive tumor model.

MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells.

The development and progression of bladder cancer is associated with multiple alterations in the genome, including loss of chromosome 10. Recently, MMAC1/PTEN, a phosphatidylinositol phosphatase, has been mapped to chromosome 10q23. We previously demonstrated that MMAC1/PTEN has tumor suppressive properties in glioblastoma and prostate cancer. To investigate the efficacy of gene therapy with MMAC1/PTEN, we examined whether the exogenous introduction of MMAC1/PTEN via an adenoviral vector (Ad-MMAC) can inhibit tumor growth and reverse drug resistance to doxorubicin in human bladder cancer cells. Human bladder cancer cell lines UM-UC-3 and T24 were infected with Ad-MMAC to induce exogenous expression of MMAC1/PTEN. The cells were then analysed for cell growth and expression of phosphorylated protein kinase B (Akt/PKB) and MMAC1/PTEN. UM-UC-6dox, a doxorubicin resistant subline, was infected with Ad-MMAC to evaluate its role in reversing drug resistance to doxorubicin. We found that MMAC1/PTEN suppressed tumor growth in UM-UC-3 and T24 cells with arrest in the G1 phase of the cell cycle. We also showed that gene therapy with MMAC1/PTEN abrogated phosphorylated Akt/PKB expression in UM-UC-3, T24 and UMUC-6dox cells, and restored doxorubicin sensitivity in UM-UC-6dox. These data demonstrate that MMAC1/PTEN can induce growth suppression and increase sensitivity to doxorubicin in bladder cancer cells and suggest that the MMAC1/PTEN gene and its pathways can be therapeutic targets for bladder cancer.

Management of patients with Bacilli Calmette-Guérin-refractory carcinoma in situ of the urinary bladder: cost implications of a clinical trial for valrubicin.

OBJECTIVE: This study was undertaken to identify the expected first- and second-year clinical costs associated with intravesical valrubicin therapy, using a decision analytic model, for patients with Bacilli Calmette-Guérin (BCG)-refractory carcinoma in situ (CIS) of the urinary bladder. BACKGROUND: Cancer of the urinary bladder is the fourth most common malignancy in men and the sixth most common noncutaneous carcinoma overall. One histopathologic stage of bladder cancer is CIS, for which BCG intravesical immunotherapy is the first-line therapy. Radical cystectomy has been recommended for patients with CIS who do not respond to or become refractory to therapy with BCG. Surgery, however, may not be appropriate for all patients, especially those who are ineligible for the lengthy procedure because of advanced age or comorbidities and those who prefer alternative nonsurgical management. For these groups, intravesical valrubicin therapy is a plausible alternative. METHODS: Models were developed and populated with data from 1 open-label study of 90 patients, information from the medical literature, and input from clinical experts. The analysis was conducted from the payor perspective for direct costs only. RESULTS: Our data indicate that first- and second-year expected costs for valrubicin therapy are $19,912 and $23,496, respectively. Expected cost for radical cystectomy was also evaluated, since some patients may have no other option if drug therapy fails. CONCLUSION: Our cost-consequence analysis and clinical data provide decision-makers with tools to aid in global budgetary projections of fractional and total expected health care costs associated with the management BCG-refractory CIS of the urinary bladder.

Reproducibility of p53 immunohistochemistry in bladder tumors. National Cancer Institute, Bladder Tumor Marker Network.

The National Cancer Institute Bladder Tumor Marker Network conducted a study to evaluate the reproducibility of immunohistochemistry for measuring p53 expression in bladder tumors. Fifty paraffin blocks (10 from each of the five network institutions) were chosen at random from among high-grade invasive primary bladder tumors. Two sections from each block were sent to each laboratory for staining and scoring, and then all sections were randomly redistributed among the laboratories for a second scoring. Intra- and interlaboratory reproducibility was assessed with regard to both staining and scoring. For overall assessments of p53 positivity, the results demonstrated that intralaboratory reproducibility was quite good. Concordance across the five participating laboratories was high for specimens exhibiting no or minimal nuclear immunostaining of tumor cells or high percentages of tumor cells with nuclear immunoreactivities. However, there was a reduced level of concordance on specimens with percentages of stained tumor cells in an intermediate range. The discordancies were due mainly to staining differences in one of the five laboratories and scoring differences in another laboratory. These results indicate that some caution must be used in comparing results across studies from different groups. Standardization of staining protocols and selection of a uniform threshold for binary interpretation of results may improve assay reproducibility between laboratories.

The prognostic significance of S-phase analysis in stage Ta/T1 bladder cancer. A Southwest Oncology Group Study.

OBJECTIVES: An intergroup study (SWOG 8795) comparing two forms of adjunctive therapy (immuno and chemo), bacillus Calmette-Guerin (BCG) and mitomycin C (MMC), furnished preregistration index tumors for 244 patients with superficial, papillary stage Ta/T1 TCC. These were examined by flow cytometry to learn whether DNA ploidy or proliferation (low vs high S-phase fraction (SPF) helped to predict disease recurrence or progression. METHODS: Cell cycle analysis using commercially available (Multicycle) programs was performed on 249 Ta/T1 bladder cancers. Tumor grade, available for 223 cases, was assigned by a single study pathologist. The SWOG statistical office reviewed follow-up information and other data and performed statistical analysis. RESULTS: Disease recurrence occurred in half the cases studied. The most parsimonious model predictive of recurrence included only treatment arm and tumor grade, with the MMC arm and tumor grade greater than I indicating worse prognosis (p = 0. 014). Neither ploidy nor SPF predicted recurrence-free survival or contributed prognostic information that was additive to tumor grade. Within 5 years of follow-up, disease progression or death from bladder cancer occurred for 29/223 (13%) of patients. The most parsimonious model for progression-free survival included only grade greater than I (p<0.001) and high SPF (p = 0.029) (relative risk: tumor grade, 4.3, high SPF, 1.9). CONCLUSIONS: Knowledge of tumor proliferation (low versus high SPF) contributes prognostic information about tumor progression that is additive to tumor grade.

The utility of fibrin/fibrinogen degradation products in superficial bladder cancer.

Fibrin/fibrinogen degradation products are either absent or present at exceedingly low levels in the urine of healthy persons. Although various nonspecific inflammatory conditions of the urinary tract can result in detectable amounts of FDP in the urine, the presence of FDP is far more prevalent in urine from patients with bladder cancer. Urinary FDP levels tend to be higher in patients with tumors of increasing grade and stage. This correlation results in improved sensitivity in detecting more aggressive tumors. Current monoclonal antibody immunoassays are simple, rapid, and inexpensive, and can be performed on urine samples in the clinical setting. The overall accuracy of these immunoassays ranges from 75% to 80% (Table 1), suggesting that the urine FDP test should not be used alone for the surveillance of superficial bladder cancer. When assays for urine FDP are combined with urine cytology, the sensitivity for detecting tumors is improved. Prospective data are needed to determine whether using these tests in combination can safely permit a reduced frequency of endoscopic surveillance.