Tomoyuki Ishibe

Neoadjuvant Chemotherapy for Locally Advanced Urothelial Cancer of the Upper Urinary Tract

Cisplatin-based multiple-drug chemotherapy is currently considered the most effective treatment for advanced and metastatic urothelial cancers. We treated 15 patients with locally advanced urothelial cancers of the upper urinary tract using the cisplatin-based multiple-drug regimen in a neoadjuvant setting. The regimens administered were: M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin); MEC (methotrexate, etoposide and cisplatin), or M-VEC (methotrexate, vinblastine, epirubicin and cisplatin). Total nephroureterectomy was performed in all patients and response was evaluated pathologically Of 15 patients 2 (13%) achieved a pathological complete response, 6 (40%) a pathological partial response, for an overall response rate of 53% (95% confidence limits 29-77%). The median durations of response were 54 months for patients with a pathological complete response and 15.5 months for patients with a pathological partial response. One of six patients with a pathological partial response and 4 of 7 with no remission died of cancer. While a positive relationship between the pathological response and prognosis was observed, adequate follow-up is needed to assess the ability of neoadjuvant chemotherapy to improve the prognosis of patients with locally advanced urothelial cancer of the upper urinary tract.

Immunohistochemical analysis of proliferating cell nuclear antigen, p53 protein and nm23 protein, and nuclear DNA content in transitional cell carcinoma of the bladder

Transitional cell carcinoma (TCC) of the bladder displays an unpredictable biologic behavior and the morphologic methods of grading tumor malignancy are often insufficient to predict the clinical outcome of patients with TCC of the bladder. Thus, the new indicator should reliably reflect prognosis. In this study, the authors determined the prognostic significance of proliferating cell nuclear antigen (PCNA), p53 protein, and nm23 protein, as well as nuclear DNA content in specimens with TCC of the bladder.

Clinical significance of immunohistochemically detectable p53 protein in renal cell carcinoma

OBJECTIVE To elucidate the clinical significance of p53 protein in renal cell carcinoma (RCC). MATERIALS AND METHODS The p53 protein in the paraffin-embedded materials taken from 72 patients with RCCs was evaluated immunohistochemically and was compared with the histological findings, expression of proliferating cell nuclear antigen (PCNA), genetic instability as assessed by 2c deviation index (2cDI) and 5c exceeding rate (5cER) as well as clinical outcome. RESULTS The p53 positivity was demonstrated only in a localized and/or focal area of the cancerous tissue. The positive rate of p53 protein was 40.3% in this study. The p53 protein significantly correlated with nuclear grade as well as PCNA expression (p < 0.001 and p < 0.01, respectively). Although there was a wide scatter of 2cDI and 5cER values between p53 positive and negative RCCs, the RCC with positive p53 exhibited significantly higher values in 2cDI as well as 5cER, as compared to that with negative p53 (p < 0.02 and p < 0.005, respectively). However, some of the RCCs with negative p53 showed relatively higher values in 2cDI and 5cER. Using univariate analysis, the prognostic relevance was noted in T, N, M categories, age and p53 positivity, while it was not in 2cDI, 5cER and PCNA expression. Multivariate analysis demonstrated that N category and p53 positivity were independently significant indicators in predicting survival. CONCLUSIONS The presence of p53 protein might reflect the genetic instability already occurred. The p53 positivity reflecting a high cellular proliferation could afford an additional but useful information when predicting survival in patients with RCC.

Limitations of ureteroscopy in diagnosis of invasive upper tract urothelial cancer.

The efficacy of ureteroscopic evaluation of upper tract abnormalities was evaluated in 40 patients. Twenty-eight patients presented with a radiologic filling defect, 9 with a filling defect and hematuria and 3 individuals exhibited hematuria alone. Cold cup biopsies revealed transitional cell carcinoma in 7 of 9 patients with papillary tumors and in 2 of 3 with nonpapillary tumors. Four patients without ureteroscopic diagnosis of urothelial cancer were found to have invasive tumors on subsequent nephroureterectomy. Of 15 patients with upper tract urothelial cancer, 12 were treated with total nephroureterectomy. Three individuals with grade 1 neoplasms received conservative ureteroscopic ablative therapy. Ureteroscopy is effective when combined with biopsy in the diagnosis and treatment of papillary lesions, but exhibits a low sensitivity in patients with invasive lesions.

Urethral caruncle with coexistence of intestinal heterotopia. A case report

Urethral caruncle is one of the benign disorders which occurs frequently after the menopause. We describe a case of urethral caruncle with intestinal heterotopia, in which infiltration by lymphocytes, invagination of the urethral transitional epithelium causing nest formation, lumen formation, hypervascularity as well as teleangiectasia were observed, suggesting the occurrence of metaplasia in the transitional epithelium preceding the intestinal heterotopia. The aetiology and clinical significance of urethral caruncle exhibiting intestinal heterotopia are discussed.

Immunohistochemistry of p53 Protein in Transitional-Cell Carcinoma of the Bladder Using an Image Analyzer

The p53 protein is known to be the product of the tumor suppressor gene p53. To elucidate the biological characteristics of p53 protein in transitional-cell carcinoma (TCC) of the bladder, the positive rate (PR) and positive intensity (PI) of p53 immunostaining in 72 TCCs of the bladder were quantified and compared with clinicopathological findings, prognosis and expression of proliferating-cell nuclear antigen (PCNA). The immunoreactivity for p53 and PCNA was evaluated using the CAS 200 Image Analyzer (Cell Analysis System, Elmhurst, Ill., USA). Intense immunoreactivity for p53 protein was observed not only near the basal cell layer but also at the invasive border. Both PR and PI of p53 were significantly correlated with histological grade (p < 0.05 and P < 0.02, respectively), histological stage (p < 0.02 and p < 0.02, respectively). Both PR and PI of p53 were significantly higher in patients who died of bladder cancer and in patients who developed metastatic progression. Using a univariate analysis, the survival was significantly short in subjects with high PR (> 40%) or high PI (> 70%) of p53 (p < 0.01 in both cases). However, using a multivariate analysis, the prognostic value of p53 immunoreactivity was not superior to histological stage. These findings suggested that, although p53 immunoreactivity appears to be related to proliferative activity in TCCs of the bladder, the prognostic relevance of p53 immunoreactivity was rather limited when evaluating the biological attitude of individual TCC of the bladder.

Association of nm23 protein levels in human prostates with proliferating cell nuclear antigen expression at autopsy.

OBJECTIVE To investigate nm23-H1 gene expression in the human prostate. METHODS The nm23-H1 protein levels of normal prostatic tissues, latent cancers of the prostate and primary and metastatic sites of clinical prostate cancers from autopsied men were evaluated using immunohistochemical analysis. Cell proliferation in serial sections using proliferating cell nuclear antigen immunoreactivity was also estimated. RESULTS Intense nm23-H1 staining was observed in metastatic sites of clinical prostate cancers. The incidence of intense nm23-H1 staining cells in primary sites of clinical prostate cancers was significantly higher than that found in latent cancers and normal prostates (p < 0.01). The staining pattern of nm23-H1 was heterogeneous in latent cancers of the prostate. A significant relationship was observed between nm23-H1 staining and positive proliferating cell nuclear antigen staining (p < 0.01). CONCLUSIONS These results seem to indicate that the nm23-H1 gene expression is related to cell proliferation and tumor metastatic potential, and appear to show the existence of a biologically different population of cells within the latent cancer.

Evaluation of the argyrophilic nucleolar organizer region, nuclear DNA content and mean nuclear area in transitional cell carcinoma of bladder using a quantitative image analyzer.

To search for reliable parameters that reflect the biological potential of bladder cancer, the argyrophilic nucleolar organizer region (AgNOR), nuclear DNA content and mean nuclear area (MNA) were studied in paraffin-embedded materials of 75 primary transitional cell carcinomas (TCCs) using a quantitative image analyzer, and were also compared with histological findings and prognosis. The AgNOR parameters studied were the mean AgNOR count (C-AgNOR) and the percentage of cells exhibiting more than 4 AgNOR dots within nuclei (P-AgNOR), whereas the DNA parameters were the 2c deviation index (2cDI) and 5c exceeding rate (5cER). These 5 parameters significantly correlated with the histological grade (p < 0.0001, respectively). Similarly, these 5 parameters correlated with the histological stage, but the correlation was higher in 2cDI and 5cER (p < 0.0001, respectively) in comparison with the AgNOR parameters and MNA. Using univariate analysis, the prognostic relevance was noted in all but P-AgNOR. The 5cER value could discriminate histological grade-II tumors in relation to prognosis, whereas the remaining parameters could not. In addition, the significant difference between noninvasive and invasive tumors was noted in 2cDI and 5cER (p < 0.05, respectively), but not in C-AgNOR, P-AgNOR and MNA. These results suggest that (i) 2cDI and 5cER exhibit superiority over the AgNOR parameters and MNA in predicting survival, and (ii) in histological grade-II tumors, evaluation of the 5cER value is most important when predicting survival as well as judging the necessity for further aggressive treatment in patients with TCCs of the bladder.

Organisms in the Prostate and Antibiotics in the Treatment of Postoperative Infections

On 24 benign prostatic hyperplasia patients with preoperatively sterile urine, who also had no history of urinary tract infection, the organisms in the prostate obtained through transurethral resection as well as in the anterior urethra were isolated. In 17 patients out of 24, organisms obtained in the prostate were identical to those in the anterior urethra; therefore, it can be concluded that another 7 patients had organisms in the prostate itself before the operation. These results would suggest that sterile urine did not indicate sterile prostate and that organisms in the prostate did not always ascend from the urethra. In the patients who preoperatively received transurethral catheterizations, Streptococcus faecalis was the most predominantly isolated organism in the prostate, which was highly sensitive to ABPC and minocycline and lower to cephems. On the other hand, in the patients with no history of catheterizations, Staphylococcus epidermidis was the most commonly isolated one, which was highly sensitive to ABPC and minocycline as well as cephems. So, in the treatment of the cases with infectious symptoms after transurethral resection of the prostate, ABPC or minocycline should be selected as first-choice drugs rather than cephems.

Relationship of genetic instability with immunoreactivities for p53 protein and proliferating cell nuclear antigen in transitional cell carcinoma of the bladder

OBJECTIVE To elucidate the relationship between genetic instability and tumor development in transitional cell carcinoma (TCC) of the bladder. METHODS The genetic instability as assessed by 2c deviation index (2cDI) and 5c exceeding rate (5cER) was compared with immunoreactivities for p53 protein and proliferating cell nuclear antigen (PCNA) in specimens obtained from 65 patients with primary untreated TCCs. RESULTS Both p53 and PCNA immunoreactivities significantly correlated with histological grade as well as stage. The immunoreactivity of p53 significantly correlated with that of PCNA, while a dissociation of the positive correlation between p53 immunoreactivity and PCNA expression was noted in the TCCs with high 2cDI value (> or = 2.0) and/or high 5cER (> or = 10%). In addition, PCNA expression became higher as the genetic instability increased, however, the p53 immunoreactivity was not parallel with the change of genetic instability. Moreover, some TCCs with high genetic instability (2cDI > or = 2.0 and 5cER > or = 10%) showed concomitant expression of high PCNA and low p53 protein, whose clinical outcome was poor in general. CONCLUSIONS The inactivation of p53 may represent a rather early event in the development of TCC of the bladder. However, the proliferative activity in itself rather than the effect due to a specific alteration in p53 plays an important role in the development and progression in TCC of the bladder.