Shigeru Sakano

Overexpression of Polo-Like Kinase 1 (PLK1) and Chromosomal Instability in Bladder Cancer

Polo-like kinase 1 (PLK1) participates in bipolar spindle formation and entry into mitosis. Chromosomal instability (CIN) is caused by abnormalities in spindle formation and chromosome segregation. In this study, we investigated the relationship of PLK1 overexpression to CIN, and compared the PLK1 status with clinicopathological parameters in 101 human urothelial carcinomas of the urinary bladder. Expression of PLK1 and the number of centrosomes were assessed by immunohistochemistry. Numerical aberrations of chromosomes 7, 9 and 17 spots that allowed estimation of CIN were evaluated by fluorescence in situhybridization, and DNA ploidy was assessed by laser scanning cytometry. Cancers with a large intercellular variation in centromere copy number were defined as CIN cancers.Tumors with PLK1 overexpression were associated more frequently with CIN (p < 0.0001), DNA aneuploidy (p = 0.0007) and centrosome amplification (p = 0.0013) than those without. Overexpression of PLK1 was significantly related to higher pathological grade (p = 0.0024), multiple tumors (p = 0.0241) and positive urine cytology (p = 0.0192). These data suggest that a high level expression of PLK1 confers tumor progression advantages to urothelial cancer cells, although other factors are also involved.

Nucleotide excision repair gene polymorphisms may predict acute toxicity in patients treated with chemoradiotherapy for bladder cancer

AIMS Platinum-based chemoradiotherapy (CRT) as bladder conservation therapy has shown promising results for muscle-invasive bladder cancer. However, treatment-related toxicity remains a major consideration in therapeutic planning. Some common polymorphisms in genes involved in DNA repair (encoding enzymes that repair DNA damaged by platinum agents and ionizing radiation) are reported to result in modulation of the repair capacity. We investigated associations between functional genetic polymorphisms involved in DNA repair and acute toxicity of CRT to determine the predictive value of these polymorphisms for toxicity. MATERIALS & METHODS The study group comprised of 101 bladder cancer patients treated with platinum-based CRT, and seven polymorphisms in XPC (Lys939Gln, rs2228001), XPD (Lys751Gln, rs13181), XPG (Asp1104His, rs17655), XRCC1 (Arg399Gln, rs25487), XRCC3 (Thr241Met, rs861539), TP53 (Arg72Pro, rs1042522) and MDM2 (SNP309, T>G, rs2279744) were genotyped. RESULTS More than two total variant alleles in nucleotide excision repair genes, including XPC, XPD and XPG, were significantly associated with grade 3 or 4 neutropenia (adjusted odds ratio [aOR]: 6.8; 95% CI: 2.0-26; p = 0.0026). There were no significant associations between any genotypes and grade 2 or greater nausea/vomiting or diarrhea. Any grade 3 or 4 hematological toxicity was significantly associated with the Gln/Gln or Lys/Gln + Gln/Gln genotypes of XPC compared with Lys/Lys (aOR: 10; 95% CI: 2.0-65; p = 0.0070 or aOR: 6.3; 95% CI: 1.9-29; p = 0.0069; respectively). CONCLUSION These results suggest that nucleotide excision repair gene polymorphisms, especially in XPC, might potentially be predictive factors for acute toxicity of CRT for bladder cancer, helping individual patient selection for bladder conservation therapy. However, further studies with larger sample sizes are needed to draw final conclusions.

ADENOCARCINOMA DEVELOPING IN AN ILEAL CONDUIT

We report a case of adenocarcinoma that developed in an ileal conduit 18 years after cystectomy for transitional cell carcinoma of the bladder. The only presenting sign was gross hematuria. Retrograde ileal loopography and endoscopy of the ileal loop were useful in the diagnosis. To our knowledge adenocarcinoma arising in an ileal conduit after a radical procedure for transitional cell carcinoma of the bladder has not been reported previously. The literature regarding malignancies that arise in portions of intestinal segments used as conduits is reviewed and carcinogenesis is discussed.

Clinical significance of lymphovascular invasion in upper urinary tract urothelial cancer

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.

Association of TP53 and MDM2 polymorphisms with survival in bladder cancer patients treated with chemoradiotherapy

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)

Risk of concomitant carcinoma in situ determining biopsy candidates among primary non‐muscle‐invasive bladder cancer patients: Retrospective analysis of 173 Japanese cases

Objectives:  To determine candidates for bladder biopsies among Japanese primary non‐muscle‐invasive bladder cancer patients according to the risk of concomitant carcinoma in situ (CIS).

Ki67 and BUBR1 May Discriminate Clinically Insignificant Prostate Cancer in the PSA Range <4 ng/ml

OBJECTIVE We aimed to evaluate the Epstein criteria and the eligibility criteria for active surveillance in the Prostate Cancer Research International study by using immunohistochemical staining. METHODS We reviewed the clinicopathological data of 119 patients who underwent prostate biopsy, with prostate-specific antigen levels being ≤4 ng/ml. The data of patients with detected prostate cancer were compared with those of patients with clinically significant prostate cancer. To discriminate insignificant prostate cancer, immunohistochemical staining for Ki67, p53, bcl-2, BUBR1, PTEN and E-cadherin was performed. RESULTS Ki67, BUBR1 and E-cadherin staining showed significant correlation with the Gleason score. Ki67 and BUBR1 staining showed significant correlations with the Epstein criteria, and Ki67, BUBR1 and E-cadherin staining correlated with the Gleason score and Prostate Cancer Research International criteria. The sensitivity and specificity of Ki67 or BUBR1 staining in discriminating the prostate cancer cases classified as clinically insignificant according to the Epstein criteria were 62.5 and 84.2%, or 57.1 and 100%, respectively. The sensitivity and specificity of Ki67, BUBR1 or E-cadherin staining in discriminating prostate cancer cases classified as clinically insignificant according to the Prostate Cancer Research International criteria were 75 and 87.5%, 66.7 and 100% or 50 and 100%, respectively. The predictive accuracy of Ki67 and BUBR1 staining was equivalently high in relation to both sets of criteria (77.6 and 83.3%, respectively). CONCLUSIONS These data could provide pathological evidence to support the suitability of the Epstein and Prostate Cancer Research International criteria. Ki67 and BUBR1 may be potential markers in selecting candidates for active surveillance.

Risk group stratification to predict recurrence after transurethral resection in Japanese patients with stage Ta and T1 bladder tumours: validation study on the European Association of Urology guidelines

Study Type – Therapy (case series) 
Level of Evidence 4

Association between DNA Repair Gene Polymorphisms and p53 Alterations in Japanese Patients with Muscle-Invasive Bladder Cancer

Objective: DNA repair enzymes play a vital role in protecting the genome from carcinogens, several of which can cause mutations in the TP53 gene in bladder cancer. Some single nucleotide polymorphisms (SNPs) in DNA repair genes reportedly modulate the repair capacity. This study aimed to clarify the effect of these functional SNPs on the alteration of p53 in muscle-invasive bladder cancer. Methods: We investigated the association between SNPs in xeroderma pigmentosum complementation groups C (XPC), D and G and X-ray repair cross-complementing group 1 and 3 genes, and p53 expression and allelic imbalance at the TP53 locus in Japanese patients with muscle-invasive bladder cancer. p53 expression and the allelic imbalance were evaluated using immunohistochemistry and a microsatellite marker, respectively. Results: Positive p53 expression was significantly less frequent in patients with the CC genotype of the XPC gene than in those with the AA or AC genotype (p = 0.0005). C alleles of the XPC gene were also less frequent in patients with positive p53 expression (p = 0.01). Conclusion: Our results suggested that the XPC polymorphism might affect p53 alteration and the molecular pathway defined by the p53 alteration in the development of muscle-invasive bladder cancer.

The loss of 8p23.3 is a novel marker for predicting progression and recurrence of bladder tumors without muscle invasion

There are few reliable markers to distinguish tumors with aggressive characteristics from others at the time of initial diagnosis in non-muscle-invasive bladder cancer. The purpose of this study was to identify a genomic marker that allows the prediction of prognosis for non-muscle-invasive bladder cancers. We screened the genome-wide copy number in 41 patients with non-muscle-invasive urothelial carcinoma of the bladder by array-based comparative genomic hybridization using arrays spotted with 4,030 bacterial artificial chromosome clones. A loss of 8p23.3 (clone 923) was correlated significantly with a higher histological grade (P = 0.0026) and advanced pathological stage (P = 0.0148). Both recurrence-free and progression-free survival rates were lower in patients with tumors without 8p23.3, compared with those with 8p23.3 (P = 0.0146 and 0.0473, respectively; log-rank test). These data suggest that the loss of 8p23.3 is a novel genomic marker allowing estimation of biological characteristics of non-muscle-invasive bladder cancer.