High-resolution HLA-DRB1 and DQB1 genotyping in Japanese patients with testicular germ cell carcinoma.

We report for the first time the frequency distributions of HLA-DRB1 and -DQB1 genes in 55 patients with testicular germ cell carcinoma (TGC) using the modified PCR-RFLP method and compare the results with those for 1216 healthy Japanese control subjects. The modified PCR-RFLP method produced accurate, reproducible cleavage patterns that are easily discriminated. HLA-DRB1*0410 was the susceptibility allele (RR = 3.26, P = 0.006) and DQB1*0602 appears to be a candidate protective allele (RR = 0.26, P = 0.02) for TGC in the Japanese. None of the HLA-DRB1 and -DQB1 alleles showed a specific tendency for histological type or clinical stage of the tumours. Previous studies based on serotyping methods failed to show these allelic associations. High-resolution genotyping is essential because the peptide-binding domain of MHC class II molecules is determined more precisely by their genotypes than by their serotypes. In addition, inherent technical difficulties and typing errors of up to 25% make serotyping inefficient. Our results suggest that high-resolution genotyping is a useful genetic marker to determine risk for TGC.     

Prophylactic effect of UFT in combination with intravesical chemotherapy on the recurrence of superficial bladder tumor]

The influence of N1-(2-tetrahydrofuryl)-5-fluorouracil plus uracil (UFT) on the recurrence of superficial bladder tumors was evaluated in a randomized clinical study. Group A (n = 196) underwent transurethral resection (TUR) and the intravesical chemoprophylaxis, while group B (n = 193) received 400 mg per a day of UFT orally for 6 months in addition to the instillation therapy. These adjuvant therapy was started one week after TUR. Consequently, 30 patients in group B showed UFT-related toxicity and administration of UFT was discontinued in 10 of them. In addition, 87 patients in group B did not complete the 6-month course of UFT administration. Comparison of 2-year actuarial non-recurrence curves revealed no significant difference between groups A and B. However, UFT seemed to have a favorable prophylactic effect when recurrence rates were compared among those patients with recurrent tumors (generalized Wilcoxon: p = 0.1277), and those with recurrent multiple tumors (p = 0.0847).     

Clinical significance of nonpalpable prostate cancer with favorable biopsy features in Japanese men

OBJECTIVE: To assess the clinical significance of nonpalpable localized prostate cancers with relatively favorable six sextant biopsy features in Japanese men. PATIENTS AND METHODS: 136 nonpalpable prostate cancers of which biopsy features confined to (1) a Gleason score of 6 or less, (2) one or two positive cores per six sextant cores, and (3) 50% or less involvement of any positive core were collected. The Gleason score, tumor extension, and cancer volume were compared with preoperative serum PSA and PSA density for the patients who underwent radical prostatectomy. PSA doubling time was measured for the patients who were treated expectantly. RESULTS: Treatments chosen for 136 patients with favorable biopsy features were radical prostatectomy alone for 48 and with preoperative androgen deprivation for 30, radiation to the prostate for 12, androgen deprivation therapy for 21, and watchful waiting for 25. Of 48 patients who underwent radical prostatectomy without androgen deprivation therapy, 25% had nonorgan-confined cancers. Seven cancers (14.6%) were Gleason score of 7, but no cancers were 8 or greater. Among 42 prostatectomy specimens for which cancer volume was measured, 22 (52.4%) had cancer volume >0.5 cm(3). Pretreatment serum PSA levels were correlated neither with the Gleason score, tumor extension nor cancer volume. There was only one nonorgan-confined cancer in the 23 cancers for which PSA density was <0.2 ng/ml/g. The ability of PSA density to predict cancer volume <0. 5 cm(3) was 0.61 using a cut-off of 0.2 ng/ml/g. Of the 25 patients treated expectantly, the PSA doubling time was less than 2 years for 3 patients, while it was stable or fluctuated for 13. CONCLUSIONS: Tumor extension can be predicted based on PSA density in nonpalpable prostate cancer with favorable biopsy features, but predictability of cancer volume based on PSA or PSA density is not satisfactorily high. New parameters or biomarkers that complement needle biopsy findings are needed to predict clinical significance of T1c prostate cancer with favorable biopsy features.     

Absence of p53 Overexpression and Favorable Response to Cisplatin-based Neoadjuvant Chemotherapy in Urothelial Carcinomas

It has been controversial whether cancer cells harboring loss or inactivation of the tumor suppressor p53 are resistant or sensitive to DNA-damaging agents including cisplatin and doxorubicin. Overexpression of mdm2 oncoprotein, a negative regulator of p53, is assumed to be an alternative to p53 dysfunction. Archival urothelial carcinoma specimens obtained from 60 patients prior to cisplatin-based chemotherapy were immunohistochemically studied for overexpression of p53 and mdm2. Thirty-two patients (group I) were treated with chemotherapy in the neoadjuvant setting, while 28 patients (group II) underwent chemotherapy for distant metastases or inoperable locoregional tumors. In group I, the responsiveness was correlated with staining status of p53 ( P =0.0225) and the combination of p53 and mdm2 ( P =0.0497). Negative staining of p53 and negative for both p53 and mdm2 could have predicted favorable response to chemotherapy in 16 of 18 (88.9%) and in 12 of 13 (92.3%) tumors, respectively. On the other hand, p53-positive and p53 and/or mdm2-positive staining could have predicted poor response only in 7 of 14 (50.0%) and 8 of 19 (42.1%) tumors, respectively. Disease-specific survival of the p53-negative group was significantly superior to that of the p53-positive group ( P =0.0086). Difference in survival did not become more significant when overexpression of mdm2 was taken into consideration ( P =0.0456). In contrast, in group II, there was no correlation of responsiveness to chemotherapy or survival with p53- or p53/mdm2-staining status. The patients with urothelial carcinomas negative for overexpression of p53 will benefit from neoadjuvant chemotherapy. From clinical viewpoint, however, p53 status alone or the combination of p53 and mdm2 status is not enough to identify those patients who will not benefit from the treatment.     

National trend of management of benign prostatic hyperplasia in Japan during 1990s: analysis of national health statistics

To review the contemporary management of benign prostatic hyperplasia (BPH) in Japan during 1990s, we analyzed several nationwide health statistics by the Ministry of Health and Welfare of Japan. The cross-sectional surveys revealed that the estimated total number of patients receiving treatment increased from 202,000 in 1987, to 335,000 and 590,000, respectively, in 1995 and 1998. Approximately 73-80% of patients were men aged 65 years or over and 94-98% 55 years or older. Urologists treated two thirds of the BPH patients. The incidence of prostatectomies remained relatively stable at 50,000/year (3.0-3.8 prostatectomies/1,000 men aged 55 or over). The average hospital stay in 1996 was 24.7 days. The total cost of BPH therapy nearly doubled between 1988 and 1998. The ratio of outpatient to inpatient costs ranged from 1.5 to 2.2 and 60% of the outpatient cost was spent for medical therapy. The total value of the market for medical therapy increased from 30-40 billion yen in 1989 to more than 80 billion yen in 1998. The application of alpha-blockers increased from 243,000 men (70% of all patients) in 1995 to 452,000 (77%) in 1998, whereas the number of patients taking antiandrogens, plant extracts and antispasmodic agents/Ca antagonists (for pollakisuria), respectively, remained relatively stable at 60,000-70,000, 180,000 and 300,000. Because Japan is a rapidly aging society and men aged 55 or older are expected to increase from 15 million in 1995 to 21 million in 2010, cost-effective treatment guidelines for the Japanese BPH patients are needed.     

Increased expression of CYR61, an extracellular matrix signaling protein, in human benign prostatic hyperplasia and its regulation by lysophosphatidic acid

Lysophosphatidic acid (LPA) is an endogenous lipid growth factor that is thought to play important roles in cell proliferation and antiapoptosis and therefore may have roles in the development and progression of benign prostatic hyperplasia (BPH). CYR61 (CCN1), on the other hand, is a growth factor-inducible immediate early gene that functions in cell proliferation, differentiation, and extracellular matrix synthesis. Here we show the close relationship between LPA-induced expression of CYR61 and prostate enlargement. CYR61 mRNA and protein were dramatically up-regulated by 18:1 LPA (oleoyl-LPA) within 1 and 2 h, respectively, in both stromal and epithelial prostatic cells. G protein-coupled receptors, i.e. Edg-2, Edg-4, and Edg-7, for LPA were also expressed in both stromal and epithelial prostatic cells. Furthermore, on DNA microarray analysis for normal and BPH patients, CYR61 was found to be related to the development and progression of BPH, regardless of symptoms. Although CYR61 mRNA was synthesized in hyperplastic epithelial cells, in many cases of BPH, CYR61 protein was detected in both the epithelial and stromal regions of BPH patient tissues. The functional contribution of CYR61 to prostatic cell growth was demonstrated by recombinant CYR61 protein and anti-CYR61 neutralizing antibodies, which inhibited CYR61-dependent cell spreading and significantly diminished cell proliferation, respectively. In conclusion, these data support the hypothesis that LPAs induce the expression of CYR61 by activating G proteincoupled receptors and that CYR61 acts as a secreted autocrine and/or paracrine mediator in stromal and epithelial hyperplasia, demonstrating the potential importance of this signaling mechanism in the disease.