Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209.

BACKGROUND: This study aimed to determine the clinical benefit of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. PATIENTS AND METHODS: Patients with MIBC (T2-4aN0M0) were randomised to receive two cycles of neoadjuvant MVAC followed by radical cystectomy (NAC arm) or radical cystectomy alone (RC arm). The primary end point was overall survival (OS). Secondary end points were progression-free survival, surgery-related complications, adverse events during chemotherapy, proportion with no residual tumour in the cystectomy specimens, and quality of life. To detect an improvement in 5-year OS from 45% in the RC arm to 57% in the NAC arm with 80% power, 176 events were required per arm. RESULTS: Patients (N = 130) were randomly assigned to the RC arm (N = 66) and the NAC arm (N = 64). The patient registration was terminated before reaching the initially planned number of patients because of slow accrual. At the second interim analysis just after the early stoppage of patient accrual, the Data and Safety Monitoring Committee recommended early publication of the results because the trial did not have enough power to draw a confirmatory conclusion. OS of the NAC arm was better than that of the RC arm, although the difference was not statistically significant [hazard ratio 0.65, multiplicity adjusted 99.99% confidence interval 0.19-2.18, one-sided P = 0.07]. In the NAC arm and the RC arm, 34% and 9% of the patients had pT0, respectively (P < 0.01). In subgroup analyses, OS in almost all subgroups was in favour of NAC. CONCLUSIONS: This trial showed a significantly increased pT0 proportion and favourable OS of patients who received neoadjuvant MVAC. NAC with MVAC can still be considered promising as a standard treatment. UMIN CLINICAL TRIALS REGISTRY IDENTIFIER: C000000093.

Prognostic significance of CD45RO+ memory T cells in renal cell carcinoma.

BACKGROUND: Memory T cells are well known to have a critical role for host defense in humans. However, their role in actual human cancer remains largely unknown. In this study, we tried to reveal the clinical importance of tumour-infiltrating CD45RO+ memory T cells in renal cell carcinoma (RCC). METHODS: We analysed 105 patients with RCC, who received radical or partial nephrectomy. Those were 65 in TNM stage I, 7 in stage II, 15 in stage III, and 18 in stage IV, respectively. CD45RO expression was evaluated by immunohistochemistry. CD4 and CD8 expressions were also systematically assessed in the same manner. RESULTS: Patients with higher TNM stage or high nuclear grade were found to have higher densities of CD45RO. Furthermore, CD45RO status was positively correlated with preoperative C-reactive protein level. In prognostic analysis, CD45RO+lo patients had a significantly better prognosis than CD45RO+hi patients. There was also a significant difference between CD4+lo and CD4+hi groups, whereas no significant difference was observed in CD8 T-cell status. Finally, multivariate analysis revealed that CD45RO+ status was the independent prognostic factor for patient overall survival. CONCLUSION: CD45RO+ memory T-cell status has a significant independent prognostic value, indicating that the adaptive immune response is functionally critical in human RCC.

Lead aerosol pollution in the High Sierra overrides natural mechanism which exclude lead from a food chain.

Most of the lead contained in sedge and voles (mountain meadow mice) within one of the most pristine, remote valleys in the United States is not natural but came from smelter fumes and gasoline exhausts. In a food chain, natural mechanisms do not allow lead to accompany the bulk of the nutritive metals as they proceed to higher trophic levels. This exclusion can be expressed quantitatively by a comparison of lead/calcium ratios at successive trophic levels. This ratio decreased by an overall factor of 200 in proceeding from rock, to soil moisture, to sedge, to vole. This factor would have been 1200 if lead aerosols had not collected on sedge leaves and circtumvented the tendency by sedge to exclude lead from the nutritive metals it absorbed from soil moisture.

Prostatic volume and volume-adjusted prostate-specific antigen as predictive parameters for prostate cancer patients with intermediate PSA levels.

The object of the study was to examine the usefulness of volume-adjusted prostate-specific antigen (PSA) parameters for prediction of prostate cancer in the patients with intermediate PSA levels. The subjects were 235 patients with intermediate PSA levels (range: 4.1-10.0 ng/ml) whose prostate volume (PV) and prostate transition zone volume (TZV) were evaluated between August 1996 and April 2004. PSA, PV, TZV, PSA density (PSAD) (PSA/PV) and PSA transition zone density (PSATZD) (PSA/TZV) were assessed with the receiver operating characteristic (ROC) curve and the area under the curve (AUC). Simple and multivariate logistic regression analyses were used to analyze the odds ratios of age, PSA, PSAD, PSATZD, PV, TZV, digital rectal examination (DRE) and transrectal ultrasonography (TRUS) findings. Fifty-five patients (23.4%) of 235 patients had biopsy-proven prostate cancer. The univariate analysis revealed significant differences in the mean values of age, PSAD, PSATZD, PV, TZV and DRE between the patients with cancer and the non-cancer patients. The ROC curve analysis revealed that PV, TZV, PSAD and PSATZD had significant predictive values as compared with that of PSA. However, there was no difference in AUC between them. The stepwise logistic regression analysis showed that the age, PV, PSATZD and DRE had significant predictive values, and that PSATZD had the most predictive power. In conclusion, both PSAD and PSATZD had significant predictive values in discriminating prostate cancer. Furthermore, the stepwise logistic regression analysis showed that PSATZD had the strongest predictive value.

Pharmacokinetic modelling of [2-13C]uracil metabolism in normal and DPD-deficient dogs.

A physiologically based pharmacokinetic (PBPK) model to simulate the plasma concentration and 13CO2 exhalation after [2-13C]uracil administration to DPD-suppressed dogs was developed. Simulation using this PBPK model should be useful in clinical situations where DPD-deficient patients at risk are to be detected with [2-13C]uracil as an in vivo probe.

Enhancement by urine of urinary bladder carcinogenesis.

The role of urine as a tumor-enhancing agent in urinary bladder carcinogenesis was investigated by using the heterotopically transplanted rat urinary bladder. Bladders removed from rats initiated with the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine in drinking water for 4 or 10 weeks were heterotransplanted to syngeneic rats. These heterotopically transplanted bladders receiving repeated instillations of normal rat urine subsequent to transplantation had a higher incidence of carcinoma than did those receiving 0.9% NaCl solution. These results suggest that normal urine may contain tumor promoter(s).

In vitro induction of ornithine decarboxylase in urinary bladder carcinoma cells.

The induction of ornithine decarboxylase by normal rat urine in bladder cancer cell cultures was tested in view of recent observations that urine acts as a tumor promoter. Addition of urine up to 15% in final concentration to culture medium resulted in a 10-fold increase in ornithine decarboxylase activity over the control. The stimulatory factor(s) contained in urine appears heat stable and may be multiple. 12-O-Tetradecanoylphorbol-13-acetate, a potent promoter in mouse skin carcinogenesis, induced a 39-fold increase in ornithine decarboxylase activity, the best response among the various substances tested. This suggests that it may act as a promoter of bladder cancer.

Induction of tumors in heterotopic bladder by topical application of N-methyl-N-nitrosourea and N-butyl-N-(3-carboxypropyl)nitrosamine.

The heterotopic urinary bladder with a communicating reservoir is a potentially useful model for bladder carcinogenesis studies. As a test of whether such bladders will develop transitional cell carcinomas after chronic carcinogenic stimuli, two carcinogens, N-methyl-N-nitrosourea and N-butyl-N-(3-carboxypropyl)nitrosamine, were instilled repeatedly into the reservoir connected with the heterotopic bladder. Transitional cell carcinomas developed in 25 of 33 heterotopic bladders exposed to cumulative doses of 1.5, 3.0, or 6.0 mg of N-methyl-N-nitrosourea for between 20 and 30 weeks, while heterotopic bladders exposed to cumulative doses of 150 or 300 mg of N-butyl-N-(3-carboxypropyl)nitrosamine failed to develop tumors. However, 11 of 27 rats with heterotopic bladders that were exposed to N-butyl-N-(3-carboxypropyl)nitrosamine for over 20 weeks developed tumors in their homotopic or natural bladders. N-Methyl-N-Nitrosourea probably acted directly on the bladder epithelial cells to induce neoplastic change. The reason(s) for the development of tumors in homotopic but not heterotopic bladders when N-butyl-N-(3-carboxypropyl)nitrosamine was administered directly into the heterotopic bladders could not be ascertained from these studies.

Urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in dogs.

Clinicopathological, radiological, and histological studies were performed on urinary bladder neoplasia induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in five adult beagle dogs and in ten adult mongrel dogs. Tumors of the urinary bladder developed in dogs given various daily doses of BBN p.o. for different periods. The latent period of tumor induction was 4 years in dogs receiving a daily dose of 80 mg of BBN, 2 to 2.5 years in dogs receiving a daily dose of 160 mg of BBN, and 1.5 years in dogs receiving a daily dose of 240 mg of BBN. The total dose of BBN ingested by the dogs until the first tumors were observed by urological examinations was nearly the same in all groups, 100 to 140 g. These results suggest that there is a correlation between dose and induction time, but further dose-response studies are required. Histologically, tumors of the urinary bladder were transitional cell papillomas or transitional cell carcinomas resembling morphologically those found in human cases. It is possible to observe the process of development of urinary bladder tumors from initial lesions to invasive tumors using routine urological examinations. We believe that this experimental model is valuable for clinicopathological studies of urinary bladder tumors.

Primary structure of a constituent polypeptide chain of the chlorocruorin from Sabellastarte indica.

A 16 kDa polypeptide chain (chain E) was isolated from the giant extracellular chlorocruorin from the polychaete Sabellastarte indica by reverse-phase chromatography, and the N-terminal 19 amino-acid residues was determined by an automated protein sequencer. The cDNA of Sabellastarte chain E was amplified by polymerase chain reaction (PCR), and the complete nucleotide sequence of 1205 bp was determined. The open reading frame is 498 nucleotides in length and encodes a protein with 165 amino-acid residues. Comparison of the cDNA-derived amino-acid sequence with the protein sequence shows that Sabellastarte chain E has a signal peptide of 16 residues at the N-terminus, the mature protein consisting of 149 amino-acid residues with a calculated molecular mass of 16636 Da. The amino-acid sequence of Sabellastarte chain E shows 42-49% sequence identity with the corresponding chains of the giant hemoglobins from Tylorrhynchus (polychaete, Annelida), Lumbricus (oligochaete, Annelida), Lamellibrachia (Vestimentifera) and Oligobrachia (Pogonophora). Thus, we conclude that chlorocruorin with chlorocruorohaem falls into the 'hemoglobin/myoglobin family'. This is the first complete sequence of a globin polypeptide chain of a chlorocruorin.

Pentosidine and its deposition in renal tissue in renal transplantation.

BACKGROUND: Advanced glycation end products (AGEs) accumulate in lesions of arteriosclerosis, Alzheimer's disease, rheumatoid arthritis, diabetic retinopathy, and diabetic nephropathy. Among AGEs, chemical quantification and immunohistologic methods for pentosidine have been established. Free pentosidine-eliminated by renal excretion- is mainly affected by renal function. In this study, we measured concentrations of plasma free and total pentosidine and immunohistologically investigated kidney graft biopsy specimens in patients after renal transplantation to investigate the renal function, plasma free and total pentosidine, and its relationship with deposition in the renal tissue. PATIENTS AND METHODS: In 28 patients who underwent renal transplantation from 1996 to 2003, we measured the time course of plasma concentrations of free pentosidine, total pentosidine, and serum creatinine starting right after renal transplantation. Thirty-four graft biopsy specimens were immunohistologically investigated using anti-pentosidine antibody. Plasma free and total pentosidine, and serum creatinine were measured at the same time. RESULTS: Plasma free and total pentosidine were positively correlated with serum creatinine. Plasma free pentosidine and serum creatinine reached nadir values on day 34.2 +/- 14.2, when the blood concentrations were 5.1 +/- 1.6 pmol/mL and 1.7 +/- 0.7 mg/dL, respectively. Plasma total pentosidine reached a nadir on day 116.5 +/- 39.7 when the plasma concentration was 4.0 +/- 1.5 pmol/mg. We correlated the time required to reach the nadir of plasma free and total pentosidine concentrations. However, neither the concentration of plasma free nor plasma total pentosidine at nadir correlated with serum creatinine. The intensity of immunostaining with anti-pentosidine antibody in proximal tubular cells was graded as weakly positive, positive, or strongly positive. Significant differences were obtained among plasma free pentosidine values between the weakly positive and strongly positive groups. CONCLUSIONS: Renal transplantation improves renal function and decreases renal excretion of free pentosidine. Accordingly, total pentosidine also decreases. However, the concentrations of plasma free and total pentosidine at nadir varied among individuals; the blood concentrations were not determined by renal function alone. It was suggested that deposition of pentosidine in proximal tubular cells was more severe among patients with higher plasma free pentosidine and serum creatinine values.

Genomic aberrations in renal cell carcinomas detected by restriction landmark genomic scanning.

In order to reveal and characterise genetic events occurring in renal tumorigenesis, samples of sporadic renal cell carcinomas (RCCs) were examined using restriction landmark genomic scanning (RLGS), an electrophoretic separation technique which detects gene amplification and deletion. We were able to find two fragments frequently amplified and 10 others commonly showing reduced signal intensity within the 16 tumour samples analysed. These altered spots were located on chromosomes 2, 3, 9-12, 16, 17 and 18 according to chromosomal assigned RLGS. A subset of reduced fragments appeared to be correlated to tumour type and were located within a new chromosomal region, suggesting genetic specificity within the process of renal carcinogenesis.

Infrequent somatic alteration of p16/MTS1 in human primary superficial bladder cancers.

Although superficial bladder cancer, usually presenting as low grade transitional cell carcinomas, are easily resected by transurethral intervention, their frequent recurrence and progression of satage or grade of the recurrent tumors in some cases is a major problem in urology. Deletion of chromosome 9, bands 9p21-22 in bladder cancers including the lowest grade and stage, suggest potential location of candidate tumor suppressor genes. Recently, p16/MTS1 was isolated from 9p21-22 as a multiple tumor suppressor gene, which regulates the cyclin dependent kinase 4 in the G1/S phase of the cell cycle. In the present study, somatic alterations of p16/MTS1 were examined concentrating on histologically defined superficial bladder carcinomas by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) technique using paraffin embedded materials. Infrequent alterations of p16/MTS1 in superficial bladder cancers, one deletion and one silent mutation in 15 cases, were detected. The results suggest that p16/MTS1 mutation is not involved in the development of superficial urinary bladder carcinomas.

Development of sarcomas in heterotopically transplanted rat urinary bladder unit exposed to glucuronic acid conjugate of N-hydroxy-4-aminobiphenyl.

The glucuronic acid conjugate of N-hydroxy-4-aminobiphenyl was tested for carcinogenicity using a heterotopically transplanted rat urinary bladder (HTB) diverted from urine flow. A low-grade transitional cell carcinoma developed in 1 of 16 HTB and sarcoma surrounding the Ommaya reservoir connected to HTB in 8 of 16 rats. This unexpected high incidence of sarcomas, not previously observed in HTB-carcinogenesis model, suggested that the glucuronide conjugate of N-hydroxy-4-aminobiphenyl is a locally active carcinogen to mesenchymal cells.

Strain variation in renal carcinogenesis by N-ethyl-N-hydroxyethylnitrosamine in F1 (Wistar-Fischer) rats.

The present study was conducted to compare the incidences of renal tumors in Wistar (W), Fischer (F) and F1 rats (WF: female Wistar rats x male Fischer rats; FW: female Fischer rats x male Wistar rats) induced by N-ethyl-N-hydroxyethylnitrosamine (EHEN). Levels of 8-OHdG in renal DNA were also investigated in Wistar and Fischer rats. After 2000 ppm of EHEN was administered orally for 2 weeks, the animals were fed basal diet until week 32. Wistar males and females demonstrated significantly higher sensitivity regarding induction of renal lesions, while both WF and FW rats had similar incidences, generally intermediate between those for the two parent strains. The formation of 8-OHdG was maximal 60-180 min after an intraperitoneal dose of 750 mg/kg to Wistar and Fischer rats, which correlates with the increase tending to the incidence of renal tumors in male and female Wistar and Fischer rats. The results suggest that EHEN induction of renal tumors is related to oxygen radical damage and that the genes in the Wistar strain responsible for the sensitivity are not inherited in a sex-dependent fashion, despite the male being more susceptible.

Alcohol intake and serum lipids in a Japanese population.

BACKGROUND: Previous epidemiological and clinical studies have shown that alcohol, which increases high density lipoprotein (HDL) cholesterol levels, has an anti-atherogenic effect. But data on the effects of alcohol on low density lipoprotein (LDL) cholesterol are scarce. In this paper a cross-sectional study on the associations of alcohol in graded doses with serum lipids in a Japanese population is presented. METHODS: The daily alcohol intake of 832 Japanese men aged 35-59 was determined and the subjects were divided into five categories according to their daily alcohol consumption. The associations of alcohol intake and the kind of alcoholic beverage with serum lipids were determined by multiple regression analyses taking into consideration the differences of other confounding factors, i.e. age, body mass index (BMI) and smoking. RESULTS: Serum triglycerides and HDL-cholesterol were higher (P < 0.001) with higher alcohol intake while LDL-cholesterol was lower (P < 0.01). In multiple regression analysis, after adjusting for age, BMI and number of cigarettes smoked per day, HDL-cholesterol and the ratio of HDL-cholesterol to LDL-cholesterol were found to have a significant positive relationship with daily alcohol consumption (P < 0.001) and LDL-cholesterol to have a significant negative relationship (P < 0.001). The kind of alcoholic beverage had no significant relationship with serum HDL-cholesterol and LDL-cholesterol; however, serum triglycerides were found to be significantly lower in those who drank beer (P < 0.05). CONCLUSIONS: Alcohol drinkers have a higher HDL-cholesterol level and lower LDL-cholesterol level than non-drinkers. This anti-atherogenic lipid profile in alcohol drinkers may be explained by the effect of alcohol on serum lipids independent of age, BMI and smoking.

Retrograde ejaculation caused by incomplete paralysis of pelvic nerve.

A case of retrograde ejaculation is reported. Initially, it was considered idiopathic, but various examinations revealed subclinical neurogenic bladder with hypotonic detrusor and normal external urethral sphincter. This was due to incomplete paralysis of the pelvic nerve and the normal activity of the pudendal nerve. Normal antegrade ejaculation was obtained by bilateral pudendal nerve block. Some cases of idiopathic retrograde ejaculation are ascribable to neurogenic bladder; and urodynamic examination is essential in the diagnosis of this disease.

Prospective randomized study of prophylaxis of superficial bladder cancer with epirubicin: the role of a central pathology laboratory. Nara Uro-oncology Research Group. (NUORG).

The preliminary results of a multi-institutional prospective randomized study of the prophylaxis of superficial bladder cancer using epirubicin (protocol NUORG SBT-003) are reported. The subjects were 129 patients with untreated superficial bladder cancer (< or = T1b, < or = G2) who were randomized into 2 groups: a transurethral resection (TUR)-alone group (63 patients) and a TUR + intravesical epirubicin (20 mg/40 ml, 30 times/2 years) group (66 patients). The nonrecurrence rate observed in the epirubicin group was significantly higher than that seen in the control group. To unify the pathological diagnosis, a central pathology laboratory (CPL) was set up for extramural review. The correspondence of the pathological diagnosis of TUR-Bt specimens between the CPL and the local pathology laboratory (LPL) was 70.5% in grading and 51.9% in staging. There was a tendency for overdiagnosis by the LPL for both the grade and the stage of tumors. However, differing interpretations by pathologists seem to exert little influence on the nonrecurrence rate at interim analysis. Further observation will be necessary to clarify the prophylactic efficacy of low-dose, long-term periodic intravesical epirubicin instillation and the influence of the disagreement in pathological findings between the CPL and the LPL on the analysis of the results.

Prophylactic treatment for superficial bladder cancer following transurethral resection.

A total of 130 primary cases with superficial bladder cancer were entered in the prospective randomized group study. The prophylactic treatments compared consisted in intravesical instillation of adriamycin (20 mg/-40 ml or 30 mg/30 ml), mitomycin C (20 mg/40 ml) or thio-TEPA (30 mg/30 ml), and noninstillation treatments with etretinate or tegafur; control patients were also studied. All agents were administered for 2 years. Recurrences were significantly suppressed in the instillation groups compared with control and non-instillation groups. Significant suppression of recurrence was observed in stage 1 or grade 2 disease treated with prophylactic instillation administered over the first 24 months of a 48-month observation period. These results may indicate the clinical usefulness of prophylactic instillation, but the long-term effect of intravesical instillation is still uncertain. A long-term follow-up study is therefore necessary.