Assessment of lower urinary tract function in children with Down syndrome.

BACKGROUND: Despite the fact that functional lower urinary tract symptoms are common among people with Down syndrome (DS), their voiding function has not been studied precisely. Our goal was to assess the lower urinary tract functions in DS. METHODS: Fifty-five DS children aged 5-15 years old and 35 age-matched control children were evaluated by ultrasonography and uroflowmetry. RESULTS: Eleven (20%) DS children had no uresiesthesia, 21 (38%) were urinated under guidance, nine (16%) urinated fewer than three times a day, two (4%) urinated more than 10 times a day, three (5%) used diapers, and 26 (47%) had urinary incontinence. Seven (13%), 15 (27%), and 10 (18%) DS children had weak, prolonged and intermittent urination, respectively, and seven (13%) had urination with straining. In contrast, none of the control subjects had urinary problems. In the uroflowmetrical analysis, 10 (18%), 20 (37%), 11 (20%) and five (9%) DS children showed "bell-shaped," "plateau," "staccato" and "interrupted" patterns, respectively; the remaining nine (16%) could not be analyzed. In contrast, 21 (60%), one (3%), four (11%), three (9%) and two (6%) control subjects showed bell-shaped, tower-shaped, plateau, staccato and interrupted patterns, respectively; the remaining four (11%) could not be analyzed. Residual urine was demonstrated in four (7%) DS children and one (3%) control child. CONCLUSIONS: Lower urinary tract symptoms and abnormal uroflowmetry findings, which can lead to further progressive renal and urinary disorders, are common in DS children. Therefore, lower urinary tract functions should be assessed at the life-long regular medical check-ups for subjects with DS.

Efficacy of flutamide-combined androgen blockade therapy in advanced prostate cancer patients: a phase III randomized, comparative trial.

The efficacy of combined androgen blockade therapy consisting of flutamide, a nonsteroidal antiandrogen, plus an LH-RH agonist (F-CAB) was investigated in Japanese patients with untreated advanced prostate cancer (clinical stage D). The primary endpoint was overall survival (OS), while the secondary endpoints were disease-specific survival (DSS), progression- free survival (PFS), reduction of prostate specific antigen (PSA), anti-tumor effects, quality of life (QOL), and adverse drug reactions (ADRs). As of the median observation period of 1,293.5 days, the F-CAB significantly prolonged DSS and PFS relative to LH-RH monotherapy (log rank test: p=0.0343 and 0.0017, respectively). The results of this study indicate the potential of F-CAB as a useful treatment for untreated advanced prostate cancer. Although additional study is considered necessary to determine the daily dosage of flutamide, the anti-tumor effects obtained from this study indicated that 375 mg/day is appropriate as a daily dosage, and 250 mg/day can also be considered when concern exists regarding the occurrence of complications or the development of ADRs, including liver function disorders. [Funded by Nippon Kayaku Co., Ltd., Japic CTI-050101].

Renoprotective effects of telmisartan after unilateral renal ablation in rats.

PURPOSE: The renoprotective function of the angiotensin II type 1 receptor blocker (ARB) is well-known in various studies, including the animal model of renal failure. However, detailed temporal changes of pathological and molecular findings after unilateral nephrectomy are not fully understood. The main purpose of this study was to clarify the renoprotective effects and pathological changes induced by the ARB in rat-remnant kidney (RK) tissues after unilateral nephrectomy, but not after a 5/6 nephrectomy. METHODS: Telmisartan, which is structurally and functionally unique among ARB, was used in this study. Three rat groups were examined: A) no ARB administrated (RK, n=21); B) continuous subcutaneous infusion of an ARB administrated (RK-ARB, n=21); and C) a sham-operated group (Sham). Renal function was evaluated by blood urea nitrogen (BUN) levels and creatinine clearance (Ccr). Fibrosis was evaluated by hydroxyproline levels and Masson's trichrome staining. Expressions of angiotensin II type 1 receptor (AT1R) and transforming growth factor beta (TGF-ß) were investigated by real-time polymerase chain reaction and Western blotting. RESULTS: There was no significant difference regarding body and kidney weight or pathological features evaluated by hematoxylin and eosin staining between the RK and RK-ARB groups. The Ccr in the RK group was significantly lower than that in the Sham group (P<0.01), but no significant difference was found between the RK-ARB and Sham groups. The fibrotic area increased significantly with time after nephrectomy in the RK group. Although a similar trend was found in the RK-ARB group, the percentage of fibrous area in the RK-ARB group was significantly lower than that in the RK group at each time point (P<0.01). AT1R mRNA levels in the RK group were regulated immediately compared with those in the RK-ARB group. Although expressions of the AT1R and TGF-ß were significantly higher in the RK-ARB group than in the Sham group, no significant differences were found between the RK-ARB and Sham group. CONCLUSION: The ARB had renoprotective effects after unilateral nephrectomy. The ARB effectively maintained Ccr. Our results also showed the possibility that fibrotic changes mediated by AT1R and TGF-ß play an important role in renal protection. Moreover, this is the first report on changes of AT1R expression after using the ARB telmisartan in kidney tissues after unilateral nephrectomy. Finally, our results suggest that ARB may be useful to prevent renal failure in patients treated with nephrectomy.

Semen quality of 1559 young men from four cities in Japan: a cross-sectional population-based study.

OBJECTIVES: To provide information of semen quality among normal young Japanese men and indicate the frequency of reduced semen quality. DESIGN: Cross-sectional, coordinated studies of Japanese young men included from university areas. The men had to be 18-24 years, and both the man and his mother had to be born in Japan. Background information was obtained from questionnaires. Standardised and quality-controlled semen analyses were performed, reproductive hormones analysed centrally and results adjusted for confounding factors. SETTING: Four study centres in Japan (Kawasaki, Osaka, Kanazawa and Nagasaki). PARTICIPANTS: 1559 men, median age 21.1 years, included during 1999-2003. OUTCOME MEASURES: Semen volume, sperm concentration, total sperm count, sperm motility, sperm morphology and reproductive hormone levels. RESULTS: Median sperm concentration was 59 (95% CI 52 to 68) million/ml, and 9% and 31.9% had less than 15 and 40 million/ml, respectively. Median percentage of morphologically normal spermatozoa was 9.6 (8.8 to 10.3)%. Small, but statistically significant, differences were detected for both semen and reproductive hormone variables between men from the four cities. Overall, the semen values were lower than those of a reference population of 792 fertile Japanese men. CONCLUSIONS: Assuming that the investigated men were representative for young Japanese men, a significant proportion of the population had suboptimal semen quality with reduced fertility potential, and as a group they had lower semen quality than fertile men. However, the definitive role-if any-of low semen quality for subfertility and low fertility rates remain to be investigated.

Tumor-associated stromal cells expressing E-prostanoid 2 or 3 receptors in prostate cancer: correlation with tumor aggressiveness and outcome by angiogenesis and lymphangiogenesis.

OBJECTIVE: To clarify the detailed pathologic roles of prostaglandin E(2) in prostate cancer tissues, the present study investigated the clinical significance and prognostic roles of the density of tumor-associated stromal cells expressing specific receptors for prostaglandin E2, termed "E-prostanoid (EP)1-4 receptors (EP1R-4Rs)." METHODS: The expression of each receptor was immunohistochemically examined in 114 formalin-fixed biopsy specimens. Correlations with clinicopathologic features were investigated in these specimens. Angiogenesis and lymphangiogenesis were measured by the percentage of CD34-stained vessels (microvessel density) and D2-40-stained vessels (lymph vessel density). The relationships between the density of each EPR-stained cells and the microvessel density or lymph vessel density were evaluated in 62 prostate cancer tissues obtained by radical surgery for more detailed analysis in a wider area of prostate cancer tissue. RESULTS: The density of tumor-associated cells with EP2R expression was positively associated with the N (P<.001) and M (P=.002) stages. Similarly, EP3R-positive stromal cell density was significantly associated with the N (P=.033) and M (P=.026) stages. The density of EP2R- and EP3R-stained cells correlated with the microvessel density (r=0.42, P<.001) and lymph vessel density (r=0.36, P=.012), respectively. A greater density of EP2R-stained cells was recognized as an independent predictor of progression (hazard ratio 7.26, P=.002) on multivariate analysis. CONCLUSION: EP2R- and EP3R-stained cells might play important roles in tumor progression, angiogenesis, and lymphangiogenesis in prostate cancer. The density of EP2R-stained stromal cells could offer a useful predictor of biochemical recurrence after radical surgery.

Thrombospondin-1-derived 4N1K peptide expression is negatively associated with malignant aggressiveness and prognosis in urothelial carcinoma of the upper urinary tract.

BACKGROUND: Thrombospondin (TSP) is a multi-functional protein that appears to have dual roles in cancer, that is, either as a promoter or a suppressor. 4N1K is a TSP-derived peptide that has been reported to be associated with neovascularity, cell survival, and invasion. There is a little information regarding its pathological roles in human cancer tissues. Our aim was to clarify clinical significance and prognostic value of 4N1K expression in patients with urothelial carcinoma of the upper urinary tract (UC-UUT). METHODS: We investigated 4N1K expression in 97 surgically excised, non-metastasized UC-UUT specimens and five normal tissues via immunohistochemistry. Microvessel density (MVD), lymph vessel density (LVD), cancer cell proliferation (PI), apoptotic index (AI), and matrix metalloproteinase (MMP)-9 expression was also determined. The relationships 4N1K expression and pT stage, grade, and prognosis were analysed. In addition, correlations with these cancer-related and TSP-related factors were also investigated. RESULTS: Strong and moderate 4N1K expression was found in normal urothelial tissues. Of the 97 specimens, 45 patients were positive for 4N1K expression, which was primarily located in the interstitial areas of the cancer tissue. 4N1K expression was negatively associated with pT stage (p = 0.003) and grade (p = 0.002). Survival analyses revealed that 4N1K is a predictor of metastasis-free (p = 0.036) and cause-specific survival (p = 0.009). 4N1K expression was closely associated with malignant behaviour, specifically MVD (p = 0.001), AI (p = 0.013), and MMP-9 expression (p = 0.036), but not PI and LVD, as determined via multivariate analysis models. CONCLUSIONS: 4N1K expression appears to be associated with cancer cell progression and survival in UC-UUT patients via the regulation of angiogenesis, apoptosis, and MMP-9 expression. There is a possibility that the 4N1K-peptide may be a useful marker and novel therapeutic target in patients with UC-UUT.

Use of low-dose combined therapy with gemcitabine and paclitaxel for advanced urothelial cancer patients with resistance to cisplatin-containing therapy: a retrospective analysis.

PURPOSE: The prognosis of patients with advanced and recurrent urothelial cancer (UC) is poor. Although cisplatin (CDDP)-containing chemotherapy is the most effective regimen in these patients, there is no other established chemotherapeutic regimen. We administered combination therapy with low-dose gemcitabine (GEM) and paclitaxel (PTX), named low-dose gemcitabine-paclitaxel (LD-GP) therapy, as salvage therapy for these patients. The aim was to evaluate the anti-tumoral effects, relief of pain, and toxicity of LD-GP therapy in patients with resistance to CDDP-containing therapy. PATIENTS AND METHODS: Thirty-five patients with advanced UC, previously treated with CDDP-containing regimens, were treated with LD-GP therapy (GEM, 700 mg/m(2) + PTX, 70 mg/m(2) on day 1 and 8, repeated every 28 days). Pain was measured on a visual analog scale before and after treatment. Pain relief and survival were compared between this and other treatment regimens. RESULTS: None of the patients had complete response to LD-GP therapy. Partial response and stable disease were seen in 25.7 and 62.9 % of patients, respectively. Kaplan-Meier curves showed better survival in patients with LD-GP therapy than with others (p = 0.034). Twenty-eight patients (80.0 %) had adequate pain relief, and only two patients needed to increase their analgesics. Other regimens demonstrated pain relief in 30.4 % of patients. Common toxicities included leukopenia, with five patients requiring granular colony-stimulating factor therapy (14.3 %). The most common non-hematologic toxicity was fatigue (n = 7, 17.1 %). CONCLUSIONS: LD-GP therapy is feasible and well tolerated as salvage therapy in patients with advanced UC with resistance to CDDP-containing therapy.

Response of recurrent urachal cancer to gemcitabine and cisplatin therapy: a case report and literature review.

Urachal cancer is a rare malignancy and the standard treatment is surgical resection. The prognosis of recurrent and metastatic urachal cancer is extremely poor because there is no established chemotherapy regimen. Here, the response of one patient with recurrent urachal cancer to combination chemotherapy of gemcitabine (GEM) and cisplatin (CDDP) (GC) is described. And the chemo- and radiotherapeutic regimens available for such patients are reviewed. A 67-year-old man diagnosed with stage IIIA urachal cancer underwent complete surgical resection. However, pelvic recurrence was detected on computed tomography (CT) 5 months after surgery. GC therapy was started immediately and resulted in a pronounced reduction in pelvic mass after three cycles. However, a follow-up CT scan taken 5 months later showed growth of the pelvic mass and new liver metastasis. He received GC therapy again, which resulted in reduction of the pelvic and liver metastatic masses after two cycles. However, the patient refused another course of GC therapy due to severe side-effects. Subsequent progression of the disease included spread in both regions, followed by death 16 months after recurrence. Various treatment strategies offer relatively long survival of patients with urachal cancer including those with recurrence and metastasis. Although further studies are necessary to determine its therapeutic efficacy, GC therapy may be a useful option in the treatment of urachal tumors, including recurrent tumours.

Clinical significance and predictive value of prostaglandin E2 receptors (EPR) 1 - 4 in patients with renal cell carcinoma.

BACKGROUND: The clinical significance of prostaglandin E2 receptor (EPR) expression in renal cell carcinoma (RCC) tissues remains unclear. Patients and Μethods: Four subtypes of EPRs were examined in 112 human RCC tissues by immunohistochemical and Western blot analysis. The relationships between EPR immunoreactivity score (IS) and various pathological features and survival were then analyzed. RESULTS: The IS of EP4R was significantly higher (p < 0.001) in cancer cells (mean = 2.7 and SD = 2.1) than in normal kidney tissues (1.8 and 1.2). EP4R expression correlated with pT stage, metastasis, and grade. EP2R expression was also associated with metastasis. Expressions of both EP2R and EP4R were found to be significant predictors for cause-specific survival on Kaplan-Meier survival analysis (p = 0.006 and 0.023, respectively). CONCLUSION: EP2R and EP4R may play important roles in malignant behavior. EP4R in particular was closely associated with pathological features, implicating this receptor as a potential therapeutic target in patients with RCC.

[Efficacy of naftopidil in patients with overactive bladder associated with benign prostatic hyperplasia: prospective randomized controlled study to compare differences in efficacy between morning and evening medication].

A total of 100 patients with benign prostatic hyperplasia (BPH) and overactive bladder (OAB) symptoms (BPH/OAB), enrolled between June 2006 to March 2008, were randomly divided into 2 groups of morning medication (M) and evening medication (E) groups, then 50 mg of naftopidil was given once a day after breakfast or supper for 8 weeks. Data were available for efficacy analysis on 80 patients (M group ; 43, E group ; 37). Naftopidil significantly improved the overall international prostatic symptom score ; from 19.2±7.9 to 11.7±5.8 in the M group and from 19.4±6.4 to 12.3±6.8 in the E group (p<0.0001), QOL score from 4.9±0.8 to 3.2±1.4 in the M group and from 5.0±0.8 to 3.6±1.3 in the E group (p<0.0001), and OAB symptom score from 7.8±2.6 to 5.0±2.5 in the M group (p<0.0001) and from 8.6±2.9 to 5.8± 3.3 in the E group (p<0.0001). There was no significant difference in the incidence of adverse effects between the M group (6.1%) and E group (2.2%). These results suggest that naftopidil improves storage symptoms as well as voiding symptoms regardless of timing of administration.

Efficacy and safety of dutasteride on prostate cancer risk reduction in Asian men: the results from the REDUCE study.

OBJECTIVE: A post hoc analysis of Asian men in the REDUCE study was conducted to investigate whether the outcomes were in line with those of the overall population. METHODS: REDUCE was a 4-year international, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Inclusion criteria were men between 50 and 75 years of age, a serum prostate-specific antigen level of 2.5-10.0 ng/ml (50-60 years) or 3.0-10.0 ng/ml (>60 years), and a single, negative prostate biopsy (6-12 cores) within 6 months before enrollment. The primary endpoint was biopsy-detectable prostate cancer. This post hoc analysis included subjects who were recorded as Asian. RESULTS: A total of 134 Asians, including 57 Japanese, were randomized to the study treatment. During the study period, the incidence of prostate cancer in the placebo and dutasteride groups was 19.6% (11/56) and 9.3% (5/54), respectively (relative risk reduction, 54%; 95% confidence intervals, -27 to 83%, P = 0.12), in the Asian subpopulation. Fewer tumors with the Gleason scores of 7-10 and 8-10 were detected among dutasteride-treated men. Although the incidences of drug-related sexual adverse events were higher in the dutasteride group, only in rare occasions did they lead to drug discontinuation. CONCLUSIONS: The incidence of prostate cancer in the dutasteride group was lower than that in the placebo group, although the difference was not significant. These results paralleled those for the overall population and support the value of dutasteride for prostate cancer risk reduction in Asian men with an increased risk of prostate cancer.

Green tea polyphenol suppresses tumor invasion and angiogenesis in N-butyl-(-4-hydroxybutyl) nitrosamine-induced bladder cancer.

BACKGROUND: Green tea polyphenol (GTP) suppresses malignancy in bladder cancer cell lines. However, the detail of its anti-carcinogenic effect in vivo is not fully understood. This study investigated the effect of GTP on bladder tumor size and angiogenesis in mice given N-butyl-(-4-hydroxybutyl) nitrosamine (BBN), with and without GTP. METHODS: Eight-week-old female C3H/He mice were treated with and without 0.05% BBN solution for 14 or 24 weeks. In addition, they were also treated with and without 0.5% GTP solution for the same periods. Histopathological diagnosis was established using hematoxylin and eosin staining, and microvessel density (MVD) was estimated by counting CD34- and von Willebrand factor-positive vessels in the tumor area. RESULTS: At 14 weeks, cancer cells were detected in BBN and BBN+GTP mice [5/14 (35.7%) and 3/14 (21.4%), respectively, p=0.678]. At 24 weeks, the incidence of cancer cells was also similar between the groups (BBN+GTP: 61.9% vs. BBN: 82.6%; p=0.179). However, the frequency of invasive tumors in BBN+GTP mice was significantly lower (23.8%; p=0.030) than in those given BBN alone (65.2%). Tumor volume and MVD of intratumoral and stromal region in the BBN+GTP group were also significantly lower than in BBN mice. CONCLUSION: The results showed that GTP had no anti-carcinogenic effect, but inhibited tumor growth and invasion in mice with established bladder cancer, at least in part through the regulation of angiogenesis. Our data suggest that GTP seems to suppress tumor development in bladder cancer.

Human papillomavirus genotypes in penile cancers from Japanese patients and HPV-induced NF-κB activation.

The causal relationship between chronic inflammation and cancer is widely accepted. Numerous investigations have identified nuclear factor-κB (NF-κB) as an important modulator in driving chronic inflammation to cancer. This study aimed to determine the prevalence of human papillomavirus (HPV) in penile cancer in Japanese patients and whether NF-κB is subsequently overexpressed in penile cancer. Thirty-four specimens of penile tissue (16 malignant and 18 benign cases) were examined to determine the association of HPV infection. An in situ hybridization (ISH) method was used to detect and localize HPV-DNA. A sensitive HPV polymerase chain reaction (PCR) procedure was used for the detection of HPV-DNA, and DNA sequencing was used to identify the HPV genotype. HPV-DNA was detected in 37.5 and 75% of cases of penile cancer, using ISH and PCR, respectively. Our efforts to detect HPV genotypes were unsuccessful as HPV-DNA could not be extracted from these materials. Using ISH, a prevalence of 68.2% of HPV infection was found in penile cancer in Kenyan patients in east Africa. In the present study, all 9 HPV-positive cases, (100%) were NF-κB-positive in the nucleus and/or cytoplasm. In contrast, of the 25 HPV-negative cases, 15 (60%) were NF-κB-positive in the nucleus and/or cytoplasm. Therefore, ISH is a method which is able to prove infection of a large quantity of HPV more effectively when compared with PCR. Thus, a large quantity of HPV infection leads to the activity of NF-κB. The most prevalent genotype was the HPV-22 found in 83.3% of the penile cancer cases. In addition, HPV-11 was found in 81.8% of the non-cancer cases. For cases with a high level of infection, the activity of NF-κB increased compared with those with a low level of HPV infection.

Expression of matrix metalloproteinase-10 in non-metastatic prostate cancer: Correlation with an imbalance in cell proliferation and apoptosis.

Matrix metalloproteinases (MMPs) are associated with cell invasion under various physiological and pathological conditions. Among MMPs, MMP-10 is reported to correlate with a high pT stage and progression in a variety of cancer types. However, the clinical and pathological significance of MMP-10 in human prostate cancer tissues remains unclear. This study aimed to clarify the role of MMP-10 in non-metastatic prostate cancer. Sixty-three specimens were obtained by radical prostatectomy. MMP-10 expression, Ki-67, CD34 and apoptotic cells were examined using an immunohistochemical technique and the terminal deoxynucleotidyl transferase-mediated nick end-labeling method. The proliferation index (PI), apoptotic index (AI), microvessel density (MVD) and cell renewal index (CRI=PI/AI) were calculated. The relationship between MMP-10 expression and clinicopathological features, as well as PI, AI, MVD and CRI were investigated. MMP-10 was mainly detected in cancer cell cytoplasm, and the proportion of MMP-10-expressing cancer cells (median 13.8%) was significantly higher (P<0.001) than non-tumoral gland cells (2.4%). Similarly, the proportion of MMP-10-expressing cancer cells was significantly higher (P=0.007) in stage pT3 (median 22.3%) than in pT2 (11.3%) tumors and was correlated with blood vessel invasion (P=0.025). In addition, its expression level correlated significantly with CRI (r=0.34, P=0.001), but not with PI, AI or MVD. Multivariate analysis identified MMP-10 expression to be closely associated with pT stage (OR 3.76, 95% CI 1.14-12.34, P=0.029). Our results suggest that the overexpression of MMP-10 produces an imbalance in cancer cell proliferation and apoptosis, thereby contributing to cancer cell progression of non-metastatic prostate cancer.

Clinical significance and prognostic value of S100A4 and matrix metalloproteinase-14 in patients with organ-confined bladder cancer.

Various therapeutic modalities are available for treatment of bladder cancer, and their effectiveness and patient outcome often depend on cancer cell invasiveness. However, the mechanisms underlying the early steps of bladder cancer cell invasion remain unknown. This study aimed to clarify the relationships between S100A4 expression and bladder cancer invasion of surrounding muscles, prognosis and expression of matrix metalloproteinase (MMP)-14 in patients with organ-confined bladder cancer. S100A4 and MMP-14 expression was analyzed in 85 cases of organ-confined (pTa, pT1 and pT2) bladder cancer using immunohistochemical technique. The expression levels were compared among the pTa, pT1 and pT2 tumors. In addition, the predictive values of S100A4 or MMP-14 expression for muscle invasion, metastasis and survival were investigated, as was the possible correlation between the expression of the two proteins. The proportion of S100A4-positive cancer cells in pT2 tumors (53%) was significantly higher (p<0.001) than in pTa (38.7%) or pT1 (40.9%) tumors; there was no difference between pTa and pT1. The results were similar for MMP-14 expression, which was significantly correlated with S100A4 expression (r=0.360, p<0.001). S100A4 expression predicted metastasis-free survival (p=0.009), but not cause-specific survival. The results implicated S100A4 in the early steps of muscle invasion via MMP-14, but not for mucosal invasion. S100A4 is therefore a potential therapeutic target for bladder cancer, and its expression is a risk factor for muscle invasion in patients with superficial tumors. In addition, S100A4 expression may be a useful prognostic factor for metastasis in patients with organ-confined bladder cancer.

Expression of X-linked inhibitor of apoptosis protein in human prostate cancer specimens with and without neo-adjuvant hormonal therapy.

PURPOSE: X-linked inhibitor of apoptosis (XIAP) has high affinity and strong inhibitory activity on apoptosis-related caspase-3. The relationships between expression of XIAP and cleaved caspase-3, and response to neo-adjuvant hormonal therapy (NHT) remain elusive. The aim was to investigate whether NHT influences with XIAP expression in prostate cancer patients. In addition, the relationship between XIAP expression and apoptosis in patients who did or did not receive NHT was also investigated. METHODS: Eighty-three patients who had undergone radical prostatectomy were examined retrospectively and divided into NHT group (n = 40) and non-NHT group (n = 43). Immunohistochemistry was used to analyze the expressions of XIAP and cleaved caspase-3. The apoptotic cells reconfirmed the number of terminal deoxynucleotidyl transferase-mediated nick and labeling (TUNEL)-positive cells. RESULTS: In the non-NHT group, the proportion of TUNEL-positive cells correlated with expression of cleaved caspase-3 (r = 0.592, P < 0.001), and the expression of XIAP correlated negatively with that of cleaved caspase-3 and TUNEL-positive cells (r = -0.464, P < 0.001 and r = 0.431, P = 0.002, respectively). The expression of cleaved caspase-3, but not that of XIAP, was higher in NHT group than non-NHT group (P = 0.017). In the NHT group, there was no significant correlation between XIAP expression and cleaved caspase-3 expression or the proportion of TUNEL-positive cells. CONCLUSIONS: NHT did not influence XIAP expression. We speculate that the inhibition of XIAP expression may reinforce the apoptotic effect of NHT and improve the prognosis in patients with prostate cancer.

[Secondary endocrine therapy with oral estrogen for relapsed prostate cancer].

We report clinical outcomes of secondary endocrine therapy with oral estrogen for relapsed prostate cancer. A total of 18 patients were treated with oral estrogen as a secondary endocrine therapy for relapsed prostate cancer between February 2002 and December 2007. One mg/day of ethinylestradiol was administered orally and the dose was increased to 3 mg/day if necessary. A decrease of serum prostate specific antigen (PSA) level was seen in all of the 15 patients who were able to take ethinylestradiol without severe side effects. The PSA level was decreased more than 50% in 11 out of 15 (73.3%) patients. Median re-relapse-free survival was 15 (3-32) months. This effectiveness was as good as intravenous high-dose diethylstilbestrol diphosphate (DES-DP) treatment which was used as a secondary endocrine therapy for relapsed prostate cancer at our institute previously. Oral administration of ethinylestradiol is effective and outpatients can be treated at a low cost, so it should be considered as one of the treatment options for relapsed prostate cancer after initial endocrine therapy.

E1AF expression is associated with extra-prostatic growth and matrix metalloproteinase-7 expression in prostate cancer.

E1AF is associated with malignant aggressiveness via regulation of matrix metalloproteinases (MMPs), which play pivotal roles in invasion through the degradation of extracellular matrix of tissues surrounding tumors. However, the clinical significance of E1AF and MMPs in patients with prostate cancer is not fully understood. We reviewed 50 tissue samples from patients with T2-3N0M0 prostate cancer who had undergone radical operation. Expression levels of E1AF, MMP-1, -3, -7, -9 and -14 were determined semiquantitatively by immunohistochemistry. The mean +/- SD percentage of E1AF-stained cancer cells was 8.56 +/- 5.22, and it was significantly higher (p < 0.001) than the E1AF-immunostaining index of normal cells (1.17 +/- 0.61). E1AF immunostaining index in pT3 (12.74 +/- 4.80) was significantly higher (p < 0.001) than that in pT2 (5.78 +/- 3.31). Although E1AF expression correlated with that of MMP-7 and MMP-9 (r = 0.47, p < 0.001 and r = 0.41, p = 0.004, respectively), multivariate analysis showed that E1AF correlated with only MMP-7 expression (OR = 5.81, 95% CI = 1.27-26.59, p = 0.023). Our results demonstrated that increased expression of E1AF is involved in tumor aggression of prostate cancer. This finding may be influenced by regulation of MMP-7. We speculate that E1AF is a possible target in treatment and prevention of tumor growth in prostate cancer.

Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival.

BACKGROUND: A previously reported, double-blind, randomized, multicenter phase 3 trial in 205 patients with stage C/D prostate cancer compared combined androgen blockade (CAB) with luteinizing hormone-releasing hormone agonist (LHRH-A) plus bicalutamide 80 mg versus LHRH-A plus bicalutamide-matching placebo (LHRH-A monotherapy). The analysis at a median follow-up of 2.4 years indicated that CAB significantly (P<.001) prolonged the time to progression and the time to treatment failure. In the current report, survival data from a long-term follow-up (median, 5.2 years) were analyzed. METHODS: All deaths irrespective of cause and all prostate cancer-specific deaths were recorded. The data were analyzed using Cox regression analysis and the log-rank test. RESULTS: At a median follow-up of 5.2 years, a significant overall survival advantage was observed in favor of CAB over LHRH-A monotherapy (Cox regression analysis: hazard ratio, 0.78; 95% confidence interval, 0.60-0.99; P=.0498; log-rank test: P=.0425). The difference in cause-specific survival between the 2 groups was not significant. The achievement of a prostate-specific antigen (PSA) nadir concentration

Phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor growth and prognosis in patients with bladder cancer: correlation with matrix metalloproteinase-2 and -7 and E-cadherin.

Hepatocyte growth factor receptor/c-Met is associated with malignant aggressiveness and survival in various cancers including bladder cancer. Although phosphorylation of hepatocyte growth factor receptor/c-Met is essential for its function, the pathologic significance of phosphorylated hepatocyte growth factor receptor/c-Met in bladder cancer remains elusive. We investigated the clinical significance of its expression, and its correlation with cancer cell progression-related molecules. The expression levels of 2 tyrosine residues of hepatocyte growth factor receptor/c-Met (pY1234/1235 and pY1349) were examined immunohistochemically in 133 specimens with nonmetastatic bladder cancer. We also investigated their correlation with matrix metalloproteinase-1, -2, -7, and -14; urokinase-type plasminogen activator; E-cadherin; CD44 standard, variant 3, and variant 6; and vascular endothelial growth factor. Expression of phosphorylated hepatocyte growth factor receptor/c-Met was detected in cancer cells, but was rare in normal urothelial cells. Although hepatocyte growth factor receptor/c-Met, pY1234/1235 hepatocyte growth factor receptor/c-Met, and pY1349 hepatocyte growth factor receptor/c-Met were associated with pT stage, multivariate analysis identified pY1349 hepatocyte growth factor receptor/c-met expression only as a significant factor for high pT stage. Expression of pY1349 hepatocyte growth factor receptor/c-Met was a marker of metastasis and (P = .001) and cause-specific survival (P = .003). Expressions of matrix metalloproteinase-2, matrix metalloproteinase-7, and E-cadherin correlated with pY1349 hepatocyte growth factor receptor/c-Met expression. Our results demonstrated that pY1349 hepatocyte growth factor receptor/c-Met plays an important role in tumor development, and its expression is a significant predictor of metastasis and survival of patients with bladder cancer. The results suggest that these activities are mediated, at least in part, by matrix metalloproteinase-2, matrix metalloproteinase-7, and E-cadherin.