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Objective Radical cystectomy remains the standard treatment for muscle-invasive bladder cancer; however, a substantial number of patients with muscle-invasive bladder cancer are not appropriate candidates to radical cystectomy due to co-morbidities or anxiety regarding bladder preservation. Trimodal bladder-sparing therapy is an intelligent and attractive treatment option for such patients. We established a novel treatment strategy using trimodal treatment with gemcitabine and cisplatin. Methods Patients diagnosed with muscle-invasive bladder cancer by transurethral resection of bladder tumor and who wished for bladder preservation were recruited. The regimens were gemcitabine 300 mg/m2 and cisplatin 30 mg/m2 in day 1 and concomitant irradiation 1.8 Gy/Fr, five fractions per week. Irradiation was administered to the true pelvis up to 36 Gy and was then boosted to the entire bladder until a total of 54 Gy. Transurethral resection of bladder tumor was also performed after chemoradiotherapy to evaluate pathological response to treatment. We evaluated treatment efficacy and survival, safety of chemoradiotherapy with gemcitabine and cisplatin. Results Thirty-eight patients were enrolled, and three patients were excluded. Pathological complete response after chemoradiotherapy was observed in 31 patients, and the 5-year bladder-intact metastasis-free survival rate was 76%. The 5-year cancer-specific and overall survival rates for chemoradiotherapy were 85 and 75%, respectively, which were not significantly different from those for radical cystectomy (73 and 71%, respectively). Grade 3/4 adverse events included neutropenia (63%), anemia (18%) and thrombocytopenia (37%); however, treatment-related deaths were not observed. Conclusions Chemoradiotherapy using gemcitabine and cisplatin for muscle-invasive bladder cancer is effective for local cancer control and shows no significant difference in oncological prognosis compared with radical cystectomy.

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

724 Background: Nivolumab is a standard treatment for previously treated advanced renal-cell carcinoma (RCC). However, nivolumab is effective in only a limited number of patients; therefore, we evaluated the prognostic value of several biomarkers, including inflammation-based prognostic scores and changes in these scores following nivolumab treatment in Japanese patients with metastatic RCC. Methods: We retrospectively reviewed the medical records of 65 patients with previously treated metastatic RCC and who received nivolumab. MSKCC and IMDC risk, inflammation-based prognostic scores, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and Glasgow prognostic score before and 6 weeks after the treatment were recorded. Categorical variables influencing disease-specific and overall survival were compared using Cox proportional-hazards regression models. Results: Univariate analysis showed that MSKCC risk score ( P = 0.0052), lactate dehydrogenase (LDH) ( P = 0.0266), LMR ( P = 0.0113), and PLR ( P = 0.0017) had a significant effect on disease-specific survival. Multivariate analyses showed that PLR and LDH were found to be independent prognostic factors for disease-specific survival ( P = 0.0008, RR = 7.95, 95% CI, 2.16–51.64 and P = 0.0123, RR = 3.92, 95% CI, 1.37–10.80, respectively). The combination of PLR and LDH was the most significant prognostic biomarker in metastatic RCC for disease-specific ( P < 0.0001) and overall ( P < 0.0001) survival. Changes in LMR and PLR in response to nivolumab were significant prognostic factors for disease-specific survival ( P < 0.0001 and P = 0.0477, respectively). Conclusions: The combination of PLR and LDH may be a potential biomarker for estimating disease-specific and overall survival in Japanese patients with metastatic RCC treated by nivolumab. If changes of inflammation-based prognostic scores in response to nivolumab treatment might be improved, nivolumab treatment should be continued.

Recent studies have reported that lymphovascular invasion (LVI) is a predictor of patient prognosis in upper urinary tract urothelial carcinoma (UUTUC). DNA copy number aberrations (DCNAs) identified by array-based comparative genomic hybridization (aCGH) had not previously been examined in UUTUC. We therefore examined DCNAs in UUTUC and compared them with DCNAs in LVI. We applied aCGH technology using DNA chips spotted with 4,030 BAC clones to 32 UUTUC patients. Frequent copy number gains were detected on chromosomal regions 8p23.1 and 20q13.12, whereas frequent copy number losses were detected on chromosomal regions 13q21.1, 17p13.1, 6q16.3, and 17p11.2. DCNAs occurred more frequently in tumors with LVI than in those without it (P = 0.0002), and this parameter was more closely associated with LVI than with the tumor grade or pT stage. Disease-specific survival rate was higher in tumors without LVI than in those with it (P = 0.0120); however, tumor grade and stage were not significant prognostic factors of patient outcome. These data support our hypothesis that tumors with LVI have more genetic alterations in terms of total numbers of DCNAs than those without, and provide proof that aggressive adjuvant therapy should be considered for UUTUC patients with LVI.

Recent studies have reported that centrosome amplification is closely related to chromosomal instability and patient prognosis in human malignancies. The purpose of this study was to elucidate the relationship between centrosome amplification and genomic alterations in urothelial carcinomas. Centrosomes were evaluated by immunohistochemistry using anti-γ-tubulin antibody. Array-based comparative genomic hybridization technology using DNA chips spotted with 4030 bacterial artificial chromosome clones was applied to 70 urothelial carcinomas to examine DNA copy number aberrations. Studying aberrations in the number of chromosomes 7, 9, and 17 using fluorescence in situ hybridization allowed the estimation of the degree of chromosomal instability. DNA copy number gains at 20p12.2, 5p15.2, 5p15.31, and 17q25.3 and losses at 17p12, 8p22, 2q37.3, 5q31.1, and 2q37.3 were more frequent in tumors with centrosome amplification than in those without it. The total numbers of DNA copy number aberrations and frequency of chromosomal instability were also larger in tumors with centrosome amplification than in those without it (P = .0263 and P < .0001, respectively). These parameters were more closely associated with centrosome amplification than with the subjectively assigned tumor grade (P = .0405 and P = .0020, respectively). Thus, these data suggest that centrosome amplification may have great potential as a biomarker for improved objective classification of urothelial carcinoma and estimation of prognosis.

Platinum-based chemoradiotherapy (CRT) as bladder conservation therapy has shown promising results for muscle-invasive bladder cancer. However, CRT might diminish survival as a result of the delay in cystectomy for some patients with non-responding bladder tumors. Because the p53 tumor suppression pathway, including its MDM2 counterpart, is important in chemotherapy- and radiotherapy-associated effects, functional polymorphisms in the TP53 and MDM2 genes could influence the response to treatment and the prognosis following CRT. We investigated associations between two such polymorphisms, and p53 overexpression, and response or survival in bladder cancer patients treated with CRT. The study group comprised 96 patients who underwent CRT for transitional cell carcinoma of the bladder. Single nucleotide polymorphisms (SNPs) in TP53 (codon 72, arginine > proline) and MDM2 (SNP309, T > G) were genotyped using PCR-RFLP, and nuclear expression levels of p53 were examined using immunohistochemistry. None of the genotypes or p53 overexpression was significantly associated with response to CRT. However, patients with MDM2 T / G + G / G genotypes had improved cancer-specific survival rates after CRT (P = 0.009). In multivariate analysis, the MDM2 T / G + G / G genotypes, and more than two of total variant alleles in TP53 and MDM2, were independently associated with improved cancer-specific survival (P = 0.031 and P = 0.015, respectively). In addition, MDM2 genotypes were significantly associated with cystectomy-free survival (P = 0.030). These results suggest that the TP53 and MDM2 genotypes might be useful prognostic factors following CRT in bladder cancer, helping patient selection for bladder conservation therapy. (Cancer Sci 2009; 100: 2376–2382)

The incidence of prostate cancer and the resultant mortality rates in Japanese men are lower compared with the rates for Caucasians; however, the Gleason score at diagnosis is higher in Japanese men compared with Caucasians. Loss of 13q is one of the most common chromosomal alterations in prostate cancer. To elucidate the difference in the rate of loss of 13q between Japanese and Caucasian men, we examined the allelic imbalance (AI) on chromosome 13q in 32 Japanese and 39 German prostate cancer patients with a fluorescent polymerase chain reaction technique using 12 microsatellite markers. Benign and malignant histology was identified by a single pathologist and laser capture microdissection was used to gather cancer cells. Although there were no statistical differences in patient background characteristics, the frequency of AI at 13q14 (D13S1253) and at 13q21 (D13S166) was significantly higher in Japanese patients compared with German patients (p = 0.0128 and p = 0.0078, respectively). The frequency of AI at 13q14 was significantly higher in tumors with high Gleason scores (GS) compared with tumors with low GS (p = 0.0478). The present observations suggest that the frequency of genetic alterations at 13q14 may underlie differences in the biological behavior of prostate cancer between Japanese and Caucasian populations.

Introduction: Few studies have examined the prognostic significance of common laboratory variables in Japanese patients with localized clear cell renal cell carcinoma (CCRCC). We evaluate the prognostic significance of preoperative laboratory variables in Japanese patients with localized CCRCC. Patients and Methods: The study included 110 Japanese patients who were pathologically confirmed as nonmetastatic CCRCC (pT1–3 N0M0) after radical nephrectomy at our institution. We assessed the clinical (including laboratory measurements) and pathological findings, with the survival rates after surgery. Results: Tumor stage and erythrocyte sedimentation rate (ESR) were identified as significant independent prognostic factors of progression-free survival in multivariate analysis. As for the prognostic factors for disease-specific survival, tumor stage and ESR had prognostic significance both in univariate and multivariate analyses. When the analysis was limited to pT1, multivariate analysis showed that only ESR was an independent prognostic factor for disease-specific survival. Conclusions: Preoperative ESR is an independent prognostic factor in Japanese patients with localized CCRCC, especially in patients with pT1.