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PURPOSE: A prognostic model for overall survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-1/PD-L1 inhibitors is necessary as existing models were constructed in the chemotherapy setting. MATERIALS AND METHODS: Patient level data were used from phase I/II trials evaluating PD-L1 inhibitors following platinum based chemotherapy for metastatic urothelial carcinoma. The derivation data set consisted of 2 phase I/II trials evaluating atezolizumab (405). Two phase I/II trials that evaluated avelumab (242) and durvalumab (198) comprised the validation data sets. Cox regression analyses evaluated the association of candidate prognostic factors with overall survival. Stepwise selection was used to select an optimal model using the derivation data set. Discrimination and calibration were assessed in the avelumab and durvalumab data sets. RESULTS: The 5 prognostic factors identified in the optimal model using the atezolizumab derivation data set were ECOG-PS (1 vs 0, HR 1.80, 95% CI 1.36-2.36), liver metastasis (HR 1.55, 95% CI 1.20-2.00), platelet count (HR 2.22; 95% CI 1.54-3.18), neutrophil-to-lymphocyte ratio (HR 1.94, 95% CI 1.57-2.40) and lactate dehydrogenase (HR 1.60, 95% CI 1.28-1.99). There was robust discrimination of survival between low, intermediate and high risk groups. The c-statistic was 0.692 in the derivation and 0.671 and 0.773 in the avelumab and durvalumab validation data sets, respectively. A web based interactive tool was developed to calculate the expected survival probabilities based on risk factors. CONCLUSIONS: A validated 5-factor model has satisfactory prognostic performance for survival across 3 PD-L1 inhibitors to treat metastatic urothelial carcinoma after platinum therapy and may assist in stratification, interpreting and designing trials incorporating PD-1/PD-L1 inhibitors in the post-platinum setting.

Background: Intravesical recurrence after radical nephroureterectomy (RNU) is a frequent event requiring intense cystoscopic surveillance. Recently, a prospective randomized clinical trial has shown that a single intravesical postoperative dose of mitomycin C (MMC) reduces the absolute risk of intravesical recurrence after RNU. Objective: The aim of the current study was to identify predictors of intravesical recurrence and to develop a tool to allow a risk-stratified approach supporting patient counseling for cystoscopic surveillance and postoperative intravesical MMC administration. Design, setting, and participants: We performed a retrospective analysis of 1839 patients with upper tract urothelial carcinoma (UTUC). The data set was split into a development cohort of 1261 patients from North America and a validation cohort of 578 patients from Europe. Interventions: RNU with bladder cuff excision was performed. The surgical approach was open in 1424 patients (77.4%) and laparoscopic in 415 patients (22.6%). Outcome measurements and statistical analyses: Univariable and multivariable Cox regression models addressed time to intravesical recurrence after RNU. We developed a nomogram for prediction of the probability of intravesical recurrence at 3, 6, 9, 12, 18, 24, and 36 mo. Predictive accuracy was quantified using the concordance index. Decision curve analysis was performed to evaluate the clinical benefit associated with the use of our nomograms. Results and limitations: With a median follow-up of 45 mo, intravesical recurrence occurred in 577 patients (31%). The probability of intravesical recurrence-free survival at 6, 12, 24, and 36 mo was 85% +/- 1%, 78% +/- 1%, 68% +/- 1%, and 47% +/- 2%, respectively. In multivariable Cox regression analysis, advanced age, male gender, ureteral tumor location, laparoscopic surgical technique, endoscopic distal ureteral management, previous bladder cancer, higher tumor stage, concomitant carcinoma in situ, and lymph node involvement were all significantly associated with intravesical recurrence (p values

We studied a series of superficial transitional cell carcinoma of the bladder to assess whether the Ki-67 labeling index predicts recurrence and progression in a cohort of patients treated by transurethral resection alone or receiving adjuvant intravesical bacillus Calmette-Guerin therapy (BCG).From 1989 to 1990, we prospectively studied 70 consecutive cases of superficial transitional cell carcinoma of the bladder using Ki-67 immunostaining. The tumors were 43 pTa and 27 pTl. Thirteen were treated with transurethral resection only and 57 received adjuvant intravesical BCG. The median follow-up times was 64 months. The threshold index values of Ki-67 for recurrence and progression were determined using ROC curves. The relative predictive values of the Ki-67 labeling index and tumor characteristics for recurrence and progression were evaluated using Cox's proportional hazards model.A cutoff value of 13% was determined. The recurrence free survival rate at 5 years was 68% for cases with a Ki-67 labeling index of 13 or higher and 71% for those with an index of less than 13 (NS). The progression-free survival rate at 5 years was 43% in cases with an index of 13 or higher and 89% in those with an index of less than 13 (p0.0001). Using multivariate analysis the Ki-67 labeling index is an independent risk factor for tumor progression with a relative risk of 4.61 (p0.05).When BCG is used for high and intermediate risk superficial bladder cancers, the Ki-67 labeling index is an independent predictive factor of progression but not of recurrence.

At present, there are no predictors of tumour behaviour for grade (G) 2 pTa transitional cell carcinomas (TCC) of the bladder. Here we analyse the prognostic relevance of histopathological grading and the immunohistochemical detection of p53 and p21/WAF1.70 patients were newly diagnosed with G2 pTa TCC of the bladder based on transurethral resection specimens. Two pathologists, blinded with respect to the clinical outcome, confirmed the initial grade and subclassified the G2 lesions into G2a and G2b carcinomas based on the degree of nuclear atypia and the number of mitoses. Immunoreactivity for p53 and p21/WAF1 was evaluated semiquantitatively.There were 52 G2a and 18 G2b tumours, mean follow-up was 49.2 months. Of all patients, 31.4% remained tumour-free, 48.6% recurred with the same tumour grade and stage, and 20.0% showed tumour progression. Patients with G2a tumours developed tumour progression in 13% in contrast to 39% with G2b lesions (p = 0.037). Of 21 p53-positive tumours, 33% (7/21) developed progressive disease, whereas 14% (7/49) of p53-negative patients showed tumour progression (p = 0.102). Neither p21/WAF1 expression alone nor the combination of p53 and p21/WAF1 correlated with clinical outcome.The more detailed grading system but not p53 or p21/WAF1 immunohistochemistry was found to be an independent prognostic factor for tumour progression.

p21(waf1/cip1) protein is a cyclin-dependent kinase inhibitor able to arrest the cell at the G1 phase by inhibiting DNA replication through interaction with proliferating cell nuclear antigen (PCNA). Experimental analyses of human bladder cancer cell lines show that p21 might be considered a tumour suppressor gene since it is able to induce apoptosis like p53. The prognostic value and expression of p21(waf1/cip1) is incompletely studied in bladder cancer at present.The expression of p21 protein was immunohistochemically analysed in paraffin-embedded specimens of 186 patients with primary transitional cell bladder tumours. The results of immunohistochemical analysis were related to known prognostic factors and complete long clinical follow-up data (over 11 years).The expression of p21(waf1/cip1) protein was significantly related to DNA ploidy, S phase fraction, mitotic index, apoptotic index, morphometric nuclear factors, and the expression of p53 and PCNA proteins, whereas it was unrelated to grade or TNM classification. In univariate survival analysis, the expression of p21(waf1/cip1) protein was not significantly related to prognosis. Independent prognostic factors were T category, papillary status and mitotic index.The results indicate that although the expression of p21(waf1/cip1) protein is related to indicators of cell proliferation, apoptosis and p53 expression, it has no better prognostic value than already established prognostic factors in bladder cancer.

OBJECTIVE: To investigate p53 and c-jun oncoproteins and proliferating cell nuclear antigen (PCNA) in transitional cell urinary bladder carcinomas (TCCs) and to determine their relationships to tumour grade, stage and survival. MATERIALS AND METHODS: The expression of p53, c-jun and PCNA was studied using immunohistochemistry in formalin-fixed, paraffin-embedded tissues in a series of 110 TCCs. RESULTS: 58% of our cases were positive for p53 and 88% for c-jun. A statistically very significant correlation (p < 0.0001) was observed between p53 and c-jun (r = 0.781), p53 and PCNA (r = 0.772), c-jun and PCNA (r = 0.831) as well as between each of the two oncoproteins and the histological grade and clinical stage (p < 0.001). There was no correlation of either p53, PCNA or c-jun with clinical outcome in terms of patients survival. CONCLUSION: p53 and c-jun proteins' overexpression are strongly related to rapid tumour cell proliferation and hence with aggressive growth in urinary bladder TCC. PCNA score remains an important prognostic index in transitional cell carcinoma of the bladder. Eur Urol

The CD44 cell adhesion molecule is a surface glycoprotein mainly expressed in lymphoid tissues. Recently, abnormal variants of CD44 including alternatively-spliced large molecular variants, have been reported in many neoplastic tissues. We studied the variation in the size of CD44 molecules in 25 transitional cell carcinomas and 11 normal transitional epithelial tissues, using the reverse transcriptase-polymerase chain reaction (RT-PCR) followed by electrophoresis and Southern blot hybridization. Whereas 23 of 25 (92.0%) tumor tissues expressed CD44 splice variants with large molecular size, only 1 of 11 (9.1%) normal tissues expressed the abnormal variants. Urine sediments from 5 of 7 (71.4%) patients also was positive for the CD44 splice variants. CD44 splice variants are increased markedly in human transitional cell carcinoma. In conclusion, detection of CD44 splice variants using the RT-PCR, which is a convenient molecular biological technique, may be useful in combination with other diagnostic methods such as cytology, flow cytometry, and tumor antigens.

The relationship between the mean nuclear area, standard deviation of the nuclear area, the mean area of the 10 largest nuclei in a section (NA10), volume-corrected mitotic index (M/V index), DNA index (DI) and S-phase fraction (SPF) were assessed in a panel of 222 transitional cell bladder tumors. The relations between the morphometric variables and DI (p less than 0.0001), and between the morphometric variables and SPF (p less than 0.0001) were highly significant. Pearson's correlation coefficients between NA10 and DI (r = 0.413) and between SPF and the M/V index (r = 0.536) were also highly significant (p less than 0.0001). The SPF could be estimated reliably by morphometric methods, whereas the estimation of DI is not perfect. The combination of morphometric variables allowed a more reliable estimation of flow cytometric parameters. The results suggest that DI and SPF can be semiquantitatively estimated in routine histopathological sections by simple morphometric methods.

We assessed the incidence of upper urinary tract tumors (UUTTs) after cystectomy for invasive or superficial transitional cell carcinoma (TCC) of the bladder. The risk factors, patients' characteristics and evolution of those who developed UUTTs are analyzed.From August 1980 to February 1994, 568 radical cystectomies were performed for TCC of the bladder: in 469 instances (82.5%) due to invasive tumor (T2-T4), and in 99 cases (17.5%) for superficial tumor (Ta, T1, Tis). All patients were followed for at least 5 years or until death. A retrospective study of patients who developed UUTTs has been performed. A revision of bladder tumor and UUTT characteristics, and the intervals between both is also evaluated.26 patients (4.5%) developed UUTTs: 11 of the 99 patients cystectomized for superficial TCCs (11.1%); 6 of the 392 patients with primary invasive TCC (1.5%), and 9 of the 77 (11.6%) patients with invasive tumors and a prior history of superficial TCC. The interval to the development of UUTT was higher after cystectomy for superficial tumor. TCCs of the bladder that subsequently developed UUTTs were high grade in 84%, multifocal in 80%, or had carcinoma in situ in 65%, tumor in the prostatic urethra in 52%, and involvement of the distal ureter in 57%. Twenty-two UUTTs (84%) were located in the calyces or the renal pelvis, 3 were bilateral (11.5%), 14 multiple (58%) and 4 superficial (16%). With a median follow-up time of 18 (range 3-103) months, 14 patients (53.8%) died of tumor, 2 were alive with disease, 2 were lost for follow-up, and 8 (30%) were alive and free of disease.We found that patients cystectomized for superficial or invasive TCC with a prior history of superficial TCC have a higher incidence of UUTTs. These cases require follow-up with annual urography or loopography.

To determine conventional computed tomography (CT) signs in the diagnosis and staging of upper urinary tract tumors (UUTTs).Retrospective study was made of the CTs of 82 patients diagnosed with UUTTs. Nine CT signs were defined and compared with the pathology of the surgical specimen. A chi2 test was used for statistical analyses.We reviewed the CTs of 93 UUTTs in 82 patients, of which 36% were invasive and 12% had positive lymph nodes. Renal parenchymal invasion was found in 82% of high-grade and in 18% of low-grade tumors (p = 0.001). 94% of the tumors with signs of renal parenchymal invasion were invasive (p0.001), as well as 88% of those appearing as renal masses (p = 0.005), with a global sensitivity of 64% and specificity of 97%. The CT sensitivity and specificity of detecting infiltration of the ureter was 67 and 77%, respectively, and no sign was statistically significant. The detection of lymph node involvement had a sensitivity of 87.5% and a specificity of 98%.CT offers good sensitivity (87.5%) and specificity (98%) in the detection of lymph node involvement, and 64% sensitivity and 97% specificity for the detection of renal tumor invasion.

Among 190 patients operated on for transitional cell cancer of the renal pelvis and/or ureter from 1976 to 1990, 95 had their tumor studied by flow cytometry. Of these, the prognostic significance of the DNA ploidy pattern with respect to the standard pathologic features was assessed in a retrospective analysis, where survival information were updated to October 1991 and the mean follow-up of patients exceeded 5.5 years (longest follow-up: 15.5 years). Five and ten-year survival probabilities for the whole group were, respectively, 65.5 and 51%. Patients with a diploid tumor had significantly better survival rates than patients with tetraploid/aneuploid cancer (p less than 0.00001). The impact of the DNA ploidy on survival was confirmed by a multivariate analysis of prognostic factors, where only tumor grade (p less than 0.0001), tumor stage (p less than 0.0001), number of neoplastic foci (p = 0.022) and nuclear DNA pattern (p less than 0.068) had a significant influence on survival. In the group of patients with low-stage (pTa-pT1) and low-grade (G1-G2) transitional cell cancer of the upper urinary tract, the DNA analysis was unable to identify any subset of patients at higher risk for disease progression.

DNA flow cytometry (FCM) was performed from multiple samples in 60 transitional cell bladder carcinomas (TCC) to detect intratumoral heterogeneity of DNA index (DI). The samples for analysis were selected randomly and they were paraffin-embedded peroperative biopsy specimens from the primary TCCs. Intratumoral heterogeneity of DI was found in 12 of 60 (20%) samples. All WHO grade I tumors were diploid whereas 12 of 41 (29%) WHO grade II-III tumors showed a heterogeneous DI. DI heterogeneity was related to WHO grade (p = 0.004), mitotic frequency (p = 0.002), inflammatory cell infiltration (ICI; p = 0.003) and nonpapillar growth pattern (p = 0.06). In multivariate analysis, the WHO grade (p = 0.027) and the degree of ICI (p = 0.041) were independently related to heterogeneous DI. The results show that (a) many of the WHO grade II-III TCCs are composed of diploid and aneuploid cell populations; (b) the presence of dense ICI and TCCs may lead to false diploid DI. Consequently, the analysis of multiple samples is recommended in WHO grade II-III tumors to detect aneuploidy particularly when dense ICIs are present.

The effects of intravesical doxorubicin on cells in superficial transitional cell carcinomas and adjacent urothelium were studied by electron microscopy. Nucleolar segregation, vacuolation of the cytoplasms, mitochondrial abnormalities and the breakdown of secondary lysosomes leading to autolysis were the main patterns of damage. Cell loss was by desquamation from the surface and random cell death in the deeper cell layers of the tumour and urothelium.

Mortality among 139 patients with transitional cell tumour of the bladder was studied. Tumours were reevaluated according to the grading system recommended by WHO. The absolute 5-year survival of histologically benign papilloma cases was 68%, of grade I carcinoma cases 64%, of grade II carcinoma cases 42% and of grade III carcinoma patients 34%. Clinical staging (UICC), however, would have been more effective than histological grading (WHO) for prognostic purposes. 3 of the 14 patients with histologically benign papilloma in this study developed grade I carcinoma during follow-up periods of between 4.5 and 24 years. Following radical treatment all recurrences were papillomas. The study suggests that histological grading should be used to complement clinical staging in prognosis and that with half-yearly check-ups and elimination of any tumours thus detected, patients with papilloma rarely develop carcinomas of higher grade than grade I.

A critical reevaluation of the preoperative classification in 96 patients with transitional cell bladder carcinomas of grade 3 (WHO) and clinical category T2 has been performed. As a result of incomplete biopsies and clinical data, it was possible to reclassify only 49 tumors (51%). 43 of these seemed to be of a lower stage than originally proposed. In addition downstaging after preoperative irradiation occurred in 77 patients (80%). In view of the uncertainties in the present series, a return to a simplified preoperative classification for clinical purposes is proposed--e.g. tumors with mucosal growth, tumors with muscle infiltration, tumors extending outside the bladder.

The authors report the preliminary data concerning a multicentric study on ablative effects of 4'-epi-doxorubicin (EPR) on superficial bladder cancer. Forty-six patients affected by multiple transitional cell superficial bladder carcinoma were treated by transurethral resection of all but one tumor, left as a marker lesion. Subsequently, an intensive local treatment with EPR and 3-month control cystoscopies with biopsies were performed. In the 47% of cases the control cystoscopy and pathology assessed the complete disappearance of marker lesions without any new occurrence whereas it is interesting to observe that the breakdown of the complete remissions into primary (67%) versus recurrent (37%) and in intravesical unpretreated (55%) versus pretreated (31%) showed important differences. It may be concluded that EPR shows a real activity against transitional cell superficial bladder carcinoma.