Satoru Yoshihiro

Centrosome Hyperamplification Predicts Progression and Tumor Recurrence in Bladder Cancer

Purpose: Recent studies have reported that centrosome hyperamplification (CH) is closely related to chromosomal instability in bladder cancer. In this study, we investigated whether CH could be used as a prognostic biomarker for patients with bladder cancer. Experimental Design: CH was evaluated by immunohistochemistry in 50 bladder cancers (≤pT1: 43; ≥pT2: 7). In addition, numerical aberrations of chromosomes 7, 9, and 17 and gain of 20q13, on which the Aurora-A gene is located, were evaluated by fluorescence in situ hybridization, and DNA ploidy was assessed. Preliminary experiments on eight bladder cancer cell lines found that six had over 5% of CH cells associated with a gain of 20q13 and overexpression of Aurora-A; therefore, CH-positive cases (CH+) were defined as those having over 5% of cells with ≥3 centrosomes per cell. Results: CH+, 20q13 gain, chromosomal instability, and DNA aneuploidy were detected in 30 (60%), 18 (36%), 22 (44%), and 19 (38%) patients, respectively. There were significant differences in tumor number, grade, recurrence, and progression between the CH+ and CH− groups. The later had significantly higher recurrence-free and progression-free survivals than the former (P = 0.0028 and P = 0.0070, respectively, log-rank test). Multivariate analysis revealed that CH+ was the strongest predictor for tumor recurrence in nonmuscle invasive (pTa and pT1) bladder cancer (hazard ratio, 1.882; 95% confidence interval, 1.161–3.325; P = 0.0094). Conclusions: Detection of CH may provide crucial prognostic information about tumor recurrence in bladder cancer.

A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter is associated with conventional renal cell carcinoma

Matrix metalloproteinase (MMP)‐1 is associated with tumor cell invasion and metastasis, and its promoter polymorphism has been shown to influence the transcriptional level. Our study explored the association between this polymorphism and renal cell carcinoma in a Japanese population. DNA was extracted from peripheral blood and normal tissue of 119 patients with conventional renal cell carcinoma (RCC) and from 210 age‐ and sex‐matched healthy volunteers. Genotyping was carried out using direct sequencing. In the MMP‐1 gene promoter polymorphism, it was demonstrated that the frequency of the 2G/2G genotype, which is associated with higher enzyme activity, was significantly higher in patients with RCC than in controls (p = 0.0015; OR = 2.082; 95% CI 1.317–3.293). When stratified for gender, only men showed a significant association of the polymorphism with RCC (p = 0.0028; OR = 2.307; 95% CI 1.333‐3.990). However, no significant association was observed between the 2G/2G genotype and clinicopathologic parameters including age, gender, tumor grade and pathologic stage. Our present data suggest that the MMP‐1 promoter polymorphism may be linked to susceptibility for conventional RCC.

Two putative tumor suppressor genes on chromosome arm 8p may play different roles in prostate cancer

Although loss of heterozygosity (LOH) on the short arm of chromosome 8 has been frequently observed in human prostate cancer, the relationship between LOH and clinical background is poorly understood. Fluorescence in situ hybridization (FISH) was employed to evaluate the chromosomal deletion on 8p in 42 prostate cancers using a centromeric probe for chromosome 8, in combination with 4 cosmid probes spanning 8p12 to 8p22. Deletions for at least one locus on the 8p were observed in 29 (69.0%) tumors. The most frequently deleted regions were 8p22 (54.8%) and 8p21.3 (52.4%), in almost the same frequency. The second most frequently deleted region was 8p21.1-p21.2 (38.1%). Deletions of 8p22 and 8p21.3 significantly correlated with tumor grade (P=0.0034, Fishers exact probability test). A significantly higher frequency of the deletion on 8p21.1-p21.2 was observed in advanced prostate cancer (beyond capsular penetration or positive nodal metastases) than in localized prostate cancer (P=0.0033). In particular, deletion of 8p21.1-p21.2 was more frequently observed in the cases with lymph node metastases than without them (P=0.0029). No clinicopathological parameters had significant relation to deletions on 8p12. These results suggest that deletions on 8p22-p21.3 play an important role in tumor differentiation, while an 8p21.1-p21.2 deletion plays a role in the progression of prostate cancer.

Chromosome 16q24 Deletion and Decreased E-Cadherin Expression: Possible Association With Metastatic Potential in Prostate Cancer

Deletion of chromosome 16q is a frequent aberration in prostatic carcinoma, indicating the existence of candidate tumor suppressor genes involved in the pathogenesis of prostate cancer.

Allelic imbalance at 1p36 may predict prognosis of chemoradiation therapy for bladder preservation in patients with invasive bladder cancer.

Invasive bladder cancers have been treated by irradiation combined with cis-platinum (CDDP) as a bladder preservative option. The aim of this study was to find a marker for predicting patient outcome as well as clinical response after chemoradiation therapy (CRT) by investigating allelic loss of apoptosis-related genes. A total of 67 transitional cell carcinomas of the bladder treated by CRT (median dose: 32.4 Gy of radiation and 232 mg of CDDP) were studied. We investigated allelic imbalances at 14 loci on chromosomes 17p13 and 1p36 including the p53 and p73 gene regions by fluorescent multiplex PCR based on DNA from paraffin-embedded tumour specimens and peripheral blood. The response to CRT was clinical response (CR) in 21 patients (31%), partial response (PR) in 31 (46%), and no change(NC) in 15 (22%). There was no statistical correlation between treatment response and clinical parameters, such as tumour grade, stage, radiation dose, or CDDP dose. The frequencies of allelic imbalance for TP53 and TP73 were 21 and 56%, respectively; neither was correlated with clinical treatment response and tumour stage or grade. There was no statistical correlation between treatment response and allelic imbalance at the other 12 loci. We found a significant correlation between cancer-specific survival and an imbalance of D1S243 (P=0.0482) or TP73 (P=0.0013) using a Log-rank test, although other loci including TP53 did not correlate with survival (P=0.4529 Multivariate analysis showed performance status (P=0.0047), recurrence (P=0.0017), and radiation doses (P=0.0468) were independent predictive factors for cancer-specific survival. However, an allelic imbalance of TP73 was the most remarkable independent predictive factor of poor patient survival (P=0.0002, risk ratio: 3382). Our results suggest that the allelic loss of the p73 gene predicts a clinical outcome of locally advanced bladder cancer when treated by CRT.

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.

The allelic loss of chromosome 3p25 with c-myc gain is related to the development of clear-cell renal cell carcinoma.

To explore the role of allelic losses at 3p25 and genetic alterations of chromosome 8, we investigated the relationships between genetic alterations in these chromosomal regions and clinicopathologic findings (such as tumor size and grade), by employing fluorescence in situ hybridization (FISH). Fifty Japanese clear‐cell renal cell carcinomas (RCCs) were examined by dual‐color FISH using cosmid DNA probes for 3p25.1–25.3 combined with probes for chromosome 3 centromere, 8p12, 8p21.1, 8p21.3, 8p22 and 8q24.12–24.13 (c‐myc), and chromosome 8 centromere. Deletion at 3p25.1–25.3 was detected in 38 patients (76%), while 8p12 deletion, 8p21.1 deletion, 8p21.3 deletion, 8p22 deletion and c‐myc gain were detected in 23 (46%), 25 (50%), 25 (50%), 25 (50%), and 20 patients (40%), respectively. There was a significant correlation between 8p21.1 deletion, 8p21.3 deletion and 8p21.1 deletion with c‐myc gain and tumor grade (p = 0.04, 0.04 and 0.02, respectively). Deletions at 8p21.1 and 8p21.3 with 3p deletion were significantly related to tumor grade; the statistical significance was identical to that of sole 8p deletion with tumor grade. The deletion at 3p25.1–25.3 with c‐myc gain showed a significant correlation with tumor size, indicating an association with tumor progression. Our results suggest that the allelic loss of chromosome 3p25 with c‐myc gain is related to the development of clear‐cell RCC.

Numerical aberrations of chromosome 9 in bladder cancer. A possible prognostic marker for early tumor recurrence.

To investigate whether nonrandom aberrations of chromosomal numbers could predict tumor recurrence in patients with bladder cancer, archival urine cytology specimens (Giemsa-stained) from patients previously treated for transitional cell carcinoma of the urinary bladder were studied retrospectively by fluorescence in situ hybridization. A total of 48 patients (pTis, 6; pTa, 2: pT1, 32; and pT2-4, 8) were consecutively enrolled in this study, and numerical aberrations of chromosomes 9 and 17 were investigated. Cytology was diagnosed as negative for malignancy in 18 patients and positive in 30 patients. Twenty-seven of the 48 patients (56%) had one or more chromosomal aberrations. The frequency of numerical aberrations of chromosome 17 was correlated with increasing stage and grade, whereas loss of copies of chromosome 9 (monosomy) was frequently observed at a lower stage and grade. Chromosomal aberrations were detected in 9 (50%) of 18 patients with negative or equivocal cytology (class I, II, or III) by the Papanicolaou classification. Of eight patients with negative or equivocal cytology who developed tumor recurrence, four (50%) showed monosomy 9 and one (14%) showed a numerical aberration of chromosome 17. All six patients who showed monosomy of chromosome 9 developed tumor recurrence within 12 months, whereas four of the nine patients who did not show monosomy of this chromosome developed recurrence within 12 months (P<0.05, Fisher test). These results suggest that monosomy of chromosome 9 might be a prognostic marker for early tumor recurrence in patients with negative or equivocal cytology specimens.

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

Clinical significance of lymph node dissection in renal cell carcinoma

Objective To identify the role of lymph node dissection in renal cell carcinoma (RCC). Material and methods A total of 100 patients (66 males, 34 females) were enrolled in the study. The mean age and tumor size were 61.4 years and 5.8 cm, respectively. A total of 41 patients (41%) had tumors <4 cm in diameter. The pathological status was pT1, pT2 and pT3 in 60, 11 and 29 patients, respectively. Results In total, lymph node metastases were found in seven cases (7%). Of 40 patients with pT1a tumors (tumor size <4 cm), one (2.5%) had lymph node metastasis. Patients with lymph node metastases had significantly larger tumors than those without (8.9 vs 5.5 cm; p<0.05). Regarding patient outcome, 33 (33%) had tumor progression (alive with disease, n=14; disease-specific death, n=19) after a median follow-up period of 54.0 months. In univariate analysis, 15/18 prognostic markers [tumor size, tumor grade, pT, pN and M categories, stage, microscopic venous invasion (V category), microscopic lymphatic invasion (Ly category), pathological tumor infiltration pattern (INF category), plasma fibrinogen, C-reactive protein, immunosuppressive acidic protein, α-2 globulin and erythrocyte sedimentation rates at 1 and 2 h] were common significant predictors of tumor progression. A Cox hazard model revealed tumor size, tumor grade and pathological stage to be independent prognostic factors. Conclusions Tumor size is a crucial prognostic factor for tumor progression, and lymph node dissection may be omitted in T1a tumors.