Prognostic value of pre-treatment risk stratification and post-treatment neutrophil/lymphocyte ratio change for pembrolizumab in patients with advanced urothelial carcinoma.

BACKGROUND: Pembrolizumab is effective in a limited number of patients with advanced urothelial carcinoma (UC). Therefore, we evaluated the prognostic value of clinical biomarkers following pembrolizumab treatment in patients with advanced UC. METHODS: We retrospectively reviewed the medical records of 121 patients with platinum-refractory advanced UC who received pembrolizumab. Inflammation-based prognostic scores before and 6 weeks after the treatment were recorded. The categorical variables influencing overall survival (OS) and objective response rate (ORR) were analyzed. RESULTS: Multivariate analyses showed that pretreatment Eastern Cooperative Oncology Group (ECOG) performance score (PS), presence of only lymph node metastasis (only LN mets), C-reactive protein (CRP), and neutrophil/lymphocyte ratio (NLR) were independent prognostic factors for OS (P = 0.0077; RR = 2.42, P = 0.0049; RR = 0.36, P = 0.0047; RR = 2.53, and P = 0.0079; RR = 2.33, respectively). The pretreatment risk stratification using ECOG PS, only LN mets, CRP, and NLR was used for estimating the OS (P < 0.0001) and ORR (P < 0.0001). Furthermore, changes in NLR in response to pembrolizumab were significantly associated with the OS (P = 0.0002) and ORR (P = 0.0023). This change was also significantly correlated with OS even in the high-risk group stratified by this pretreatment risk stratification (P = 0.0069). CONCLUSIONS: This pretreatment risk stratification may be used for estimating the OS and ORR of patients with advanced UC treated with pembrolizumab. If changes in NLR in response to pembrolizumab treatment improve, pembrolizumab should be continued.

Identification of curable high-risk prostate cancer using radical prostatectomy alone: who are the good candidates for undergoing radical prostatectomy among patients with high-risk prostate cancer?

BACKGROUND: Currently, there is no consensus regarding which patients with high-risk prostate cancer (PCa) would benefit the most by radical prostatectomy (RP). We aimed to identify patients with high-risk PCa who are treatable by RP alone. METHODS: We retrospectively reviewed data on 315 patients with D'Amico high-risk PCa who were treated using RP without neoadjuvant or adjuvant therapy at the institutions of the Yamaguchi Uro-Oncology Group between 2009 and 2013. The primary endpoint was biochemical progression-free survival (bPFS) after RP. Risk factors for biochemical progression were extracted using the Cox proportional hazard model. We stratified the patients with high-risk PCa into 3 subgroups based on bPFS after RP using the risk factors. RESULTS: At a median follow-up of 49.9 months, biochemical progression was observed in 20.5% of the patients. The 2- and 5-year bPFS after RP were 89.4 and 70.0%, respectively. On multivariate analysis, Gleason score (GS) at biopsy (≥ 8, HR 1.92, p < 0.05) and % positive core (≥ 30%, HR 2.85, p < 0.005) were independent predictors of biochemical progression. Patients were stratified into favorable- (0 risk factor; 117 patients), intermediate- (1 risk factor; 127 patients), and poor- (2 risk factors; 57 patients) risk groups, based on the number of predictive factors. On the Cox proportional hazard model, this risk classification model could significantly predict biochemical progression after RP (favorable-risk, HR 1.0; intermediate-risk, HR 2.26; high-risk, HR 5.03; p < 0.0001). CONCLUSION: The risk of biochemical progression of high-risk PCa after RP could be stratified by GS at biopsy (≥ 8) and % positive core (≥ 30%).

BUBR1 overexpression predicts disease-specific survival after nephroureterectomy in patients with upper tract urothelial carcinoma.

OBJECTIVE: To date, there are few reliable markers to distinguish tumors with aggressive characteristics in upper tract urothelial carcinoma. The purpose of this study was to identify a biomarker related to genetic instability (chromosomal instability or microsatellite instability) with prognostic value, in patients with upper tract urothelial carcinoma. METHODS: Expression of chromosomal instability-related markers (BUBR1, p53, polo-like kinase 1) and microsatellite instability-related markers (mismatch repair proteins, MLH1 and MSH2) were assessed by immunohistochemistry in 100 patients who had radical nephroureterectomy for upper tract urothelial carcinoma. Numerical aberrations of chromosomes 7, 9 and 17 were evaluated by fluorescence in situ hybridization, which allowed an estimation of the degree of chromosomal instability. BUB1B copy number was examined by array-based comparative genomic hybridization in 32 patients with upper tract urothelial carcinoma. RESULTS: BUBR1 status was most significantly correlated with chromosomal instability-related and low mismatch repair parameters, according to the molecular biomarkers examined. Overexpression of BUBR1 is frequently detected in tumors with higher histological grade (P < 0.0001) and is significantly associated with chromosomal instability (P = 0.0071). Array-based comparative genomic hybridization revealed that no tumors (0%) showed BUB1B amplification and gain, indicating that overexpression of BUBR1 was independent of BUB1B copy number. For disease-specific survival, BUBR1 overexpression, lymphovascular invasion, pathological tumor stage, pathological lymph node involvement and low MSH2 expression were significant prognostic factors in univariate analyses. In multivariate analyses, BUBR1 overexpression was an independent prognostic factor for disease-specific survival (P = 0.0483, risk ratio 3.76, 95% confidence interval: 1.01-18.43). CONCLUSIONS: BUBR1 may have significant potential as a biomarker for estimating disease-specific survival in patients with upper tract urothelial carcinoma treated by radical nephroureterectomy.

Clinical significance of lymphovascular invasion in upper urinary tract urothelial cancer.

OBJECTIVES: To clarify the significance of lymphovascular invasion (LVI) in patients with pT3N0M0 upper urinary tract (UUT) urothelial carcinoma (UC) relative to prognosis in terms of disease-specific survival, as LVI, which implies both blood vessel and lymph vessel involvement, is reportedly a poor prognostic factor in patients with UUT-UC. PATIENTS AND METHODS: The clinical records of 90 patients who had surgery for UUT-UC were reviewed retrospectively. The median patient age was 71 years and the median follow-up was 42 months. The prognostic significances of LVI (with vs without), T stage (< 1 vs 2-4), grade (1-2 vs 3), N stage (0 vs 1-2), age (< or = 70 vs > 70 years), gender and tumour location (renal pelvis vs ureter) for survival time were evaluated. RESULTS: LVI of UUT-UC was found in 34 patients (37.8%). There were significantly higher frequencies of LVI with advancing stage and lymph node metastasis. Kaplan-Meier analysis showed that LVI was strongly associated with disease-specific survival in all patients (P < 0.001) and in patients with pT3N0M0 disease (P < 0.001). Univariate analyses showed that LVI, T stage, N stage and tumour grade were significantly related to disease-specific survival in all patients (P < 0.001, < 0.001, 0.003 and 0.007, respectively). Multivariate analysis using Cox proportional hazards model showed that LVI was the only prognostic factor with independent significance for disease-specific survival (P < 0.001). CONCLUSIONS: LVI appears to be an important and independent prognostic factor for UUT-UC in patients treated by nephroureterectomy. Our data suggest that the LVI status might be a predictive marker for disease-specific survival in patients with T3N0M0 UTT-UC.

DNA repair gene polymorphisms may be associated with prognosis of upper urinary tract transitional cell carcinoma.

Upper urinary tract transitional cell carcinoma (UUT-TCC) is quite an uncommon disease, and its prognosis differs among individuals irrespective of tumor stage. DNA repair gene polymorphisms are reported to result in the modulation of the repair capacity and might influence the prognosis of UUT-TCC. We examined the associations between functional polymorphisms in five DNA repair genes, and the prognosis of UUT-TCC in 103 UUT-TCC patients. Variant alleles in xeroderma pigmentosum complementation group C, more than three total variant alleles in all DNA repair genes studied and more than two total variant alleles in three nucleotide excision repair genes were independently associated with improved overall and disease-specific survival of UUT-TCC patients in multivariate analysis (P = .0063 and P = .0005 for xeroderma pigmentosum complementation group C, P = .016 and P = .0016 for all genes, and P = .0053 and P = .018 for nucleotide excision repair genes, respectively). These results suggest that some DNA repair gene polymorphisms may preoperatively be valuable as prognostic factors for UUT-TCC beyond tumor stage and grade, helping to provide optimal treatment strategies for individual patients.

Chromosome 20q13.2 gain may predict intravesical recurrence after nephroureterectomy in upper urinary tract urothelial tumors.

PURPOSE: Amplification or gain of copy number of chromosome 20q13.2 has been implicated as a causal factor for chromosome instability. We investigated the impact of chromosomal instability and its causative molecular markers, 20q13.2 gain and centrosome amplification, on patient outcome in upper urinary tract transitional cell carcinoma (UUT-TCC). EXPERIMENTAL DESIGN: The number of centrosomes was assessed by immunohistochemistry. Numerical aberrations of chromosomes 7, 9, and 17 that allowed the estimation of chromosomal instability and 20q13.2 gain were evaluated by fluorescence in situ hybridization in 96 frozen specimens from UUT-TCC and compared with clinicopathologic background and patient outcome. RESULTS: Chromosomal instability, 20q13.2 gain, and centrosome amplification were detected in 62 of 96 (64.6%), 61 of 96 (63.5%), and 45 of 90 (50.0%) tumors, respectively. 20q13.2 Gain was significantly associated with tumor stage (P = 0.042), chromosomal instability (P < 0.0001), and centrosome amplification (P < 0.0001). Kaplan-Meier analysis showed that 20q13.2 gain was strongly associated with intravesical recurrence-free survival in all patients (P = 0.0050), as well as in patients with grade 2 tumors (P = 0.0011, log-rank test). On multivariate analysis, 20q13.2 gain was found to be the sole independent prognostic factor predicting subsequent intravesical recurrence (hazard ratio, 1.65; 95% confidence interval, 1.03-2.90; P = 0.036). CONCLUSIONS: 20q13.2 gain was strongly associated with a reduced time to intravesical recurrence in all patients. Our data suggest that 20q13.2 gain may be a predictive marker of intravesical recurrence in patients with UUT-TCC.