Sadafumi Kawamura

Prospective Randomized Phase II Trial of a Single Early Intravesical Instillation of Pirarubicin (THP) in the Prevention of Bladder Recurrence After Nephroureterectomy for Upper Urinary Tract Urothelial Carcinoma: The THP Monotherapy Study Group Trial

PURPOSE We evaluated the efficacy of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma (UUT-UC). PATIENTS AND METHODS From December 2005 to November 2008, 77 patients clinically diagnosed with UUT-UC from 11 institutions participating in the Tohoku Urological Evidence-Based Medicine Study Group were preoperatively enrolled in this study. Patients were randomly assigned to receive or not receive a single instillation of THP (30 mg in 30 mL of saline) into the bladder within 48 hours after nephroureterectomy. Cystoscopy and urinary cytology were repeated every 3 months for 2 years or until the occurrence of first bladder recurrence. RESULTS Seventy-two patients were evaluable for efficacy analysis, 21 of whom had a subsequent bladder recurrence. Significantly fewer patients who received THP had a recurrence compared with the control group (16.9% at 1 year and 16.9% at 2 years in the THP group v 31.8% at 1 year and 42.2% at 2 years in the control group; log-rank P = .025). No remarkable adverse events were observed in the THP-treated group. Based on multivariate analysis, THP instillation (hazard rate [HR], 0.26; 95% CI, 0.07 to 0.91; P = .035) and open surgery (HR, 0.28; 95% CI, 0.09 to 0.84; P = .024) were independently predictive of a reduced incidence of bladder recurrence. CONCLUSION In this prospective randomized phase II study, a single intravesical instillation of THP seemed to reduce bladder recurrence after nephroureterectomy. A phase III, large-scale, multicenter study is needed to confirm these observations.

Glycolipid composition in bladder tumor: a crucial role of GM3 ganglioside in tumor invasion.

Glycolipids were extracted from primary bladder tumors of 14 patients and 2 normal counterparts. Their expression pattern was assessed by thin‐layer chromatography (TLC). The most remarkable change was massive accumulation of GM3 in superficial bladder tumors compared with invasive tumors. This change was also confirmed by immunohistochemistry using anti‐GM3 monoclonal antibody. The activities of glycosyltransferases responsible for GM3 synthesis (GM3 synthase, Gb3 synthase and GD3 synthase) were consistent with upregulated expression of GM3 in superficial tumors. It was suggested that the marked GM3 accumulation in superficial tumors was caused not only by upregulated GM3 synthase but also by downregulated activities of Gb3 and GD3 synthase. Histopathologic examination revealed an inverse correlation of the amount of GM3 expressed with invasive potential. Exogenously supplemented GM3 suppressed invasion potential in human bladder tumor cell lines (T‐24, KK‐47). These results indicate that the amount of GM3 expressed may serve as an indicator of the invasion potential of bladder tumor. Furthermore, new antiinvasion therapeutics may be possible by administration of GM3.

High energy underwater shock wave treatment on implanted urinary bladder cancer in rabbits

The effects of focused high energy shock waves (SW) on the implanted urinary bladder cancer in rabbits were examined. The bladder cancer was exposed to 2000 to 8000 shots of focused SW under ultrasound guidance. Although only focal necrosis of the tumor was seen in the one day SW exposure, wider and deeper tumor necrosis was observed in the tumors following serial SW (2000 to 6000 shots, for two to three days). Eight to 10 day serial SW exposure (6000 to 8000 shots) decreased the tumor growth in comparison with that of the control. Lung metastases examined by periodic chest X-ray after SW treatment revealed that SW did not promote lung metastases. Pathological findings were also in accord with the X-ray examinations. Polyclonal antibody type 4 collagen was used for immunohistochemical staining of vascular wall in bladder cancer. Vascular wall destruction, not found in spontaneous necrotic tumor, were clearly visible in SW induced necrotic area. SW induces vascular damage in the tumor, which may be the primary cause promoting the tumor necrosis.

Pathological and biochemical outcomes after radical prostatectomy in men with low-risk prostate cancer meeting the Prostate Cancer International: Active Surveillance criteria.

Active surveillance has been widely accepted as a treatment tool for low‐risk prostate cancer, and use of the Prostate Cancer Research International: Active Surveillance (PRIAS) criteria can select smaller and less aggressive tumours in low‐risk disease. The study shows the pathological outcomes of radical prostatectomy for patients with low‐risk disease who met the PRIAS criteria. It found that ∼20% had unfavourable pathological features and only 30% satisfied insignificant cancer criteria with pT2 stage, a Gleason score ≤6 and tumour volume <2.5 mL. It concludes that close follow‐up including repeat biopsy or MRI is necessary to minimize unexpected progression of disease.

Mass screening for prostate cancer: a comparative study in Natori, Japan and Changchun, China

OBJECTIVES To study the natural background of prostate cancer in Japan and China, mass checks with prostate-specific antigen (PSA)-based screenings were performed using identical procedures in Natori, Japan and Changchun, China. METHODS For 7 years (1995 to 2001) in Natori, Japan, and for 3 years (1998 to 2000) in Changchun, China, 2212 Japanese and 3566 Chinese men older than 55 years were mass checked by PSA-based screening (serum PSA cutoff value 4.1 ng/mL). RESULTS The PSA-positive rates (PSA 4.1 ng/mL or greater) and cancer detection rates in the screened persons of Natori and Changchun were 8.5% and 5.2% (P <0.0005) and 2.1% and 0.8% (P <0.0001), respectively. When the number of cancer cases detected was adjusted to a 100% biopsy rate for men who were PSA positive in both cities, the cancer detection rate was estimated at 2.3% and 1.3% in Natori and Changchun, respectively. This difference was also significant (P <0.01). CONCLUSIONS The results indicate that the percentage of PSA-positive men 55 years or older in Changchun was lower than that in Natori. The analysis of the results suggests that the prostate cancer incidence and prevalence in Changchun, China are lower than those in Natori, Japan.

Lack of Selectin-Dependent Adhesion in Prostate Cancer Cells Expressing Sialyl Lex

Background Recently, it has been reported that upregulation of the oligosaccharide sialyl Lex (SLex) in prostate cancer is associated with hormone‐resistant, aggressive disease. However, it is not clear that SLex expressed on prostate cancer cells has a biological function related to metastatic potential.

Impact of body mass index on clinicopathological outcome and biochemical recurrence after radical prostatectomy

Background:Accumulating evidence suggests that obesity is associated with tumor progression in prostate cancer (PCa) patients after radical prostatectomy (RP). We conducted a retrospective multicenter study to determine the effect of body mass index (BMI) on the clinicopathological characteristics and biochemical recurrence of PCa in Japanese men who underwent RP.Methods:The medical records of 1257 men with PCa treated by RP without neoadjuvant therapy at four medical institutes between 2001 and 2009 were retrospectively reviewed. Patients were categorized into four groups using the World Health Organization (WHO) BMI classification and BMI quartiles. Associations of the various BMI categories with clinicopathological characteristics and biochemical recurrences were statistically evaluated. Biochemical recurrence was defined as a PSA level of >0.2 ng ml–1.Results:Of the 1257 patients, 230 (18.3%) experienced biochemical recurrence during the median follow-up period of 49 months. The median BMI was 23.8 kg m–2, and 1.4% patients were underweight, 65.4% were of normal weight, 30.9% were overweight and 2.4% were obese (WHO classification). Preoperative PSA levels and PSA density (PSAD) tended to decrease as BMI increased. Pathological characteristics did not differ significantly among BMI categories. As per the WHO classification and quartile categories, biochemical recurrence rate was comparable among the BMI groups. After adjusting for other pre- and postoperative covariables, multivariate Cox proportional hazards analysis revealed that a high BMI did not have an independent impact on biochemical recurrence-free survival.Conclusions:Underweight Japanese PCa patients treated by RP had higher preoperative PSA levels and PSAD. High BMI was not associated with adverse pathological findings or increased biochemical recurrence rate in Japanese PCa patients treated with RP. Racial differences may exist in the relationship between obesity and outcomes of RP in PCa patients.

Increased sialidase activity in serum of cancer patients: Identification of sialidase and inhibitor activities in human serum

Aberrant sialylation in glycoproteins and glycolipids is a characteristic feature of malignancy. Human sialidases, which catalyze the removal of sialic acid residues from glycoconjugates, have been implicated in cancer progression. They have been detected in a wide variety of human cells and tissues, but few studies have focused on their existence in human serum. Among the four types identified to date, we previously demonstrated that plasma membrane‐associated ganglioside sialidase (NEU3) is markedly upregulated in various human cancers, including examples in the colon and prostate. Here, using a sensitive assay method, we found a significant increase of sialidase activity in the serum of patients with prostate cancer compared with that in healthy subjects having low activity, if any. Activity was apparent with gangliosides as substrates, but only to a very limited extent with 4‐methylumbelliferyl sialic acid, a good synthetic substrate for sialidases other than human NEU3. The serum sialidase was also almost entirely immunoprecipitated with anti‐NEU3 antibody, but not with antibodies for other sialidases. Interestingly, sera additionally contained inhibitory activity against the sialidase and also against recombinant human NEU3. The sialidase and inhibitor activities could be separated by exosome isolation and by hydrophobic column chromatography. The serum sialidase was assessed by a sandwich ELISA method using two anti‐NEU3 antibodies. The results provide strong evidence that the serum sialidase is, in fact, NEU3, and this subtype may, therefore, be a potential utility for novel diagnosis of human cancers.

Glycolipid expression in prostatic tissue and analysis of the antigen recognized by antiprostatic monoclonal antibody APG1

The expression patterns of glycolipid from prostatic hyperplasia, prostatic cancer and normal prostate tissue were observed. A further analysis of antigen recognized by mouse monoclonal antibody APG1, which was gained by immunizing glycolipids extracted from human prostate cancer, was also performed. In cancer tissue, both of the lactosyl and globoside series glycolipids were found to be generally reduced, although in the ganglioside series, GM3 and GD3 were not reduced and only the glycolipids with longer chains than GD2 were found to be reduced. These results indicated that the inhibition of sugar chain elongation, but not sialylation, was the main synthetic change occurring with carcinogenesis of the human prostate. APG1 reacted with only two bands near GM2 and GD2 of the ganglioside fraction on a thin-layer chromatography plate, but it did not react with any of the known gangliosides of the ganglioside series including GM2 and GD2. Histochemically, APG1 showed intense reaction only in frozen tissue sections of human prostate, and the reactivity decreased with the increasing grade of cancer. Therefore, this antigen was considered to be a prostate-specific and differentiated antigen reacting with nonganglioseries gangliosides.

The Effect of High‐energy Underwater Shock Waves on Implanted Urinary Bladder Cancer in Rabbits

We have examined the effects of high‐energy shock waves (HESW) on implanted urinary bladder cancer in rabbits. The bladder cancer was exposed to 2000 to 6000 shots of focused HESW under ultrasound guidance. Although only focal necrosis of the tumor was seen in the one‐day HESW exposure (2000 shots), wider and deeper necrosis was observed in the tumors following serial HESW (4000 or 6000 shots; 2 or 3 days). These results indicate that serial HESW exposure has destructive effects on implanted bladder cancer in rabbits.