Combination therapy with paclitaxel and gemcitabine after platinum-based chemotherapy in patients with advanced urothelial cancer.

OBJECTIVES: To evaluate the efficacy and tolerability of paclitaxel and gemcitabine therapy after platinum-based chemotherapy for patients with advanced urothelial carcinoma. METHODS: Consecutive patients with advanced urothelial carcinoma who received paclitaxel and gemcitabine therapy from December 2003 to March 2018 were retrospectively reviewed. The objective response for paclitaxel and gemcitabine therapy, progression-free survival and overall survival, and adverse events were evaluated. The reduction rate among each metastatic site and the associations between the clinical parameters and overall survival or progression-free survival were also assessed. RESULTS: We enrolled 58 patients. Complete and partial responses were observed in two (3.4%) and 15 patients (26%), respectively. The median progression-free survival and overall survival were 4.3 months (95% confidence interval 2.9-5.2) and 11.5 months (95% confidence interval 7.7-14.8), respectively. The objective response rates of primary site and metastases in lymph nodes, lung, bone, and liver were 6.0%, 37%, 23%, 0%, and 22%, respectively. Poor performance status (≥1), prior use of gemcitabine and the number of metastatic sites (≥2) were significantly associated with poor overall survival. Although three patients discontinued the treatment because of adverse events, there was no therapy-related death. CONCLUSIONS: Paclitaxel and gemcitabine therapy seems to be a valid option as a subsequent treatment after platinum-based chemotherapy for urothelial carcinoma, especially in patients with favorable performance status and no prior use of gemcitabine.

The third national Japanese antimicrobial susceptibility pattern surveillance program: Bacterial isolates from complicated urinary tract infection patients.

The antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using national surveillance data. The data consisted of 881 bacterial strains from eight clinically relevant species. The data were collected for the third national surveillance project from January 2015 to March 2016 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was undertaken with the cooperation of 41 medical institutions throughout Japan. Fluoroquinolone required a MIC90 of 2-64 mg/L to inhibit the 325 Escherichia coli strains tested and the proportion of levofloxacin resistant E. coli strains increased to 38.5% from 29.6% in 2011 and 28.6% in 2008. The proportion of levofloxacin resistant strains of Pseudomonas aeruginosa and Enterococcus faecalis decreased from previous reports and the proportion of multidrug-resistant P. aeruginosa and carbapenem-resistant Enterobacteriaceae remained low. Among methicillin-resistant Staphylococcus aureus (MRSA) strains, strains with reduced susceptibility to vancomycin (minimum inhibitory concentration, 2 µg/mL) increased to 14.7% from 5.5%. Bacterial strains that produced extended-spectrum ß-lactamase included E. coli (79 of 325 strains, 24.3%), Klebsiella pneumoniae (9 of 177 strains, 7.7%), and Proteus mirabilis (6 of 55 strains, 10.9%). The proportion of extended-spectrum ß-lactamase producing E. coli and K. pneumoniae strains increased from previous surveillance reports.

SLCO1B1, SLCO2B1, and SLCO1B3 polymorphisms and susceptibility to bladder cancer risk.

A variety of carcinogens are excreted in urine and may be actively transported by organic anion-transporting polypeptides that encoded by SLCOs. In this study, we evaluated whether single nucleotide polymorphisms (SNPs) in SLCO1B1, SLCO2B1, and SLCO1B3 are associated with bladder cancer susceptibility. Our results, for the first time, indicated that polymorphisms of SLCO1B1 rs2306283 might be associated with bladder cancer risk. Therefore, SNPs in SLCO1B1 may be potential biomarkers for assessing the risk of bladder cancer.

Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus.

The Japanese surveillance committee conducted the first nationwide surveillance of antimicrobial susceptibility patterns of uropathogens responsible for female acute uncomplicated cystitis at 43 hospitals throughout Japan from April 2009 to November 2010. In this study, the causative bacteria (Escherichia coli and Staphylococcus saprophyticus) and their susceptibility to various antimicrobial agents were investigated by isolation and culturing of bacteria from urine samples. In total, 387 strains were isolated from 461 patients, including E. coli (n = 301, 77.8 %), S. saprophyticus (n = 20, 5.2 %), Klebsiella pneumoniae (n = 13, 3.4 %), and Enterococcus faecalis (n = 11, 2.8 %). S. saprophyticus was significantly more common in premenopausal women (P = 0.00095). The minimum inhibitory concentrations of 19 antibacterial agents used for these strains were determined according to the Clinical and Laboratory Standards Institute manual. At least 87 % of E. coli isolates showed susceptibility to fluoroquinolones and cephalosporins, and 100 % of S. saprophyticus isolates showed susceptibility to fluoroquinolones and aminoglycosides. The proportions of fluoroquinolone-resistant E. coli strains and extended-spectrum ß-lactamase (ESBL)-producing E. coli strains were 13.3 % and 4.7 %, respectively. It is important to confirm the susceptibility of causative bacteria for optimal antimicrobial therapy, and empiric antimicrobial agents should be selected by considering patient characteristics and other factors. However, the number of isolates of fluoroquinolone-resistant or ESBL-producing strains in gram-negative bacilli may be increasing in patients with urinary tract infections (UTIs) in Japan. Therefore, these data present important information for the proper treatment of UTIs and will serve as a useful reference for future surveillance studies.

Single dose 1 g ceftriaxone for urogenital and pharyngeal infection caused by Neisseria gonorrhoeae.

OBJECTIVES: To evaluate the efficacy of 1 g ceftriaxone in the treatment of urethritis, cervicitis and pharyngeal infection caused by Neisseria gonorrhoeae (N. gonorrhoeae) including the oral cephem-resistant strain with chimera penicillin-binding protein 2 (PBP-2) (cefozopran-resistant N. gonorrhoeae, CZRNG). METHODS: From September 2004 to November 2006, 67 patients (27 male and 40 female) who had genital infection and/or pharyngeal infection caused by N. gonorrhoeae were enrolled in this study at five participating centers in Japan. To detect the chimera PBP-2 gene, polymerase chain reaction (PCR) was performed using established primers against the altered penA of CZRNG isolates. All patients received a single 1 g dose of ceftriaxone. Efficacy was evaluated only in those who returned for examination and culture for N. gonorrhoeae between 3 and 14 days after the treatment. RESULTS: CZRNG isolates detected by PCR accounted for 41.7% (20/48) of urogenital infections and 60.0% (15/25) of pharyngeal infections in the treatment efficacy evaluable cases. 37 of 39 CZRNG isolates (94.9%) were multi-drug resistant isolates that had simultaneous resistance to penicillin, tetracycline, and ciprofloxacin. Nineteen patients had N. gonorrhoeae isolates in the urogenital area and pharynx simultaneously. Ceftriaxone treatment eradicated all N. gonorrhoeae isolates from 48 patients with genitourinary infection and 25 patients with pharyngeal infection. CONCLUSIONS: We report for the first time that ceftriaxone is effective in patients with gonococcal urethritis, cervicitis, and pharyngeal infection caused by CZRNG that has chimera PBP-2.

Lack of evidence for the association of E-cadherin gene polymorphism with increased risk or progression of prostate cancer.

BACKGROUND: E-cadherin is an epithelial cell adhesion molecule, and decreased E-cadherin expression in human prostate cancer is associated with tumor grade and advanced clinical stage. A -160 C-->A polymorphism in the promoter region of E-cadherin has been shown to decrease gene transcription. This allelic variation may be a potential genetic marker that can help identify those individuals at higher risk for invasive/metastatic disease. MATERIALS AND METHODS: We studied the effect of E-cadherin gene polymorphism on prostate cancer susceptibility in a case control study of 219 prostate cancer patients and 219 male controls, to determine whether this polymorphism is a biomarker for the risk and how aggressive the disease is. RESULTS: The genotype frequencies in the prostate cancer group were C/C: 0.607, C/A: 0.352, A/A: 0.041, and in the control group C/C: 0.671, C/A: 0.301, A/A: 0.027. A significant difference between the two groups was not found (p = 0.34), and the adjusted OR for A/A genotype was not statistically significant (OR = 1.66, 95% CI 0.58-4.78). Subdividing prostate cancer according to tumor differentiation and stage, we found no association between E-cadherin polymorphism and poor differentiation and invasiveness of prostate cancer. CONCLUSIONS: These data do not support an association between the E-cadherin genotype and the occurrence or progression of prostate cancer in Japanese populations.

Cytochrome P450 (CYP) 1A2, sulfotransferase (SULT) 1A1, and N-acetyltransferase (NAT) 2 polymorphisms and susceptibility to urothelial cancer.

PURPOSE: Arylamines are suspected to be the primary causative agent of urothelial cancer in tobacco smoke. In the human liver, arylamines are N-hydroxylated by a cytochrome P450 (CYP)1A2-catalyzed reaction, which produces a substrate for O-esterification that can be catalyzed by N-acetyltransferases (NAT) or sulfotransferases (SULT). Recently, several polymorphisms of CYP1A2, SULT1A1, and NAT2 that affect their activities have been reported. METHODS: In this study, 306 Japanese patients with urothelial transitional cell carcinoma and 306 healthy controls were compared for frequencies of CYP1A2, SULT1A1, and NAT2 genotypes. RESULTS: The frequencies of NAT2 intermediate or slow acetylator genotype were significantly higher in the urothelial cancer patients than in the healthy control subjects [odds ratio (OR) = 1.49, 95% confidence interval (95% CI) 1.06-2.09, OR = 3.23, 95% CI 1.72-6.08, respectively]. Stratifying by amount of smoking, among subjects who consumed >33.5 pack-years and carried the SULT1A1 *1/*1 or NAT2 slow acetylator genotype, the OR was 1.73 (95% CI 1.01-2.97) whereas it was 7.31 (95% CI 1.90-28.05) in non-smokers who carried the homozygous wild genotype, respectively. The relationships between CYP1A2, SULT1A1, and NAT2 polymorphisms and clinical findings including tumor differentiation, stage, and recurrence rate were analyzed. Only associations between NAT2 genotype and pathological findings were admitted, and the higher OR of NAT2 intermediate and slow acetylator genotype was more likely to present to a low-grade tumor (G1) among heavy-smokers. CONCLUSIONS: Our results suggest that SULT1A1 *1/*1 and NAT2 slow acetylator genotypes might modulate the effect of carcinogenic arylamines contained in tobacco smoke, and that the modulation of NAT2 intermediate and slow acetylator genotype has a tendency to present a higher risk for highly differentiated tumors among heavy-smokers.

E-cadherin gene polymorphism and risk of urothelial cancer.

The E-cadherin is important in cell-cell adhesion and in the development and maintenance of the epithelial phenotype. A -160C-->A polymorphism in the promoter region of E-cadherin has been shown to decrease gene transcription. This allelic variation may be a potential genetic marker that can help identify those individuals at higher risk for invasive/metastatic disease. We studied the effect of E-cadherin gene polymorphism on urothelial cancer susceptibility in a case control study of 314 urothelial cancer patients and 314 age-sex matched controls, to determine whether this polymorphism is a biomarker for the risk and how aggressive the disease is. The frequency with which the subjects carried E-cadherin A/A genotype was significantly higher in the urothelial cancer patients than in the healthy control subjects (OR=2.32, 95% CI 1.03-5.22). Subdividing urothelial cancer according to tumor differentiation and stage, we found no association between E-cadherin polymorphism and poorly-differentiation and invasiveness of urothelial cancer. Furthermore, no significant association between E-cadherin polymorphism and recurrence rate of urothelial cancer patients was found. The present study demonstrates for the first time that E-cadherin A/A genotype may be associated with susceptibility to urothelial cancer, but not with the progression of disease.

N-acetyltransferase-2 gene polymorphism as a possible biomarker for prostate cancer in Japanese men.

BACKGROUND: The purpose of this study was to determine the frequency of a polymorphism of the candidate metabolic enzyme N-acetyltransferase-2 (NAT2) in Japanese prostate cancer patients and Japanese non-cancer controls, in order to determine if an association exists between NAT2 genotype and the occurrence, clinical stage and grade of prostate cancer. METHODS: In the present case-control study, 111 patients with prostate cancer and 152 controls were genotyped for the NAT2 polymorphism using the polymerase chain reaction-based restriction fragment length polymorphism method. The NAT2 genotypes (slow or rapid acetylator genotype) were determined by the combination of three known NAT2 mutant alleles (M1, M2, M3) and the wild-type allele. RESULTS: The NAT2 slow acetylator genotype was statistically higher among prostate cancer patients (17.1%) compared with controls (8.6%) (Odds ration (OR) = 2.21; 95% confidence interval (CI), 1.04-4.69; P = 0.0289). In addition, there was a statistically increased risk of prostate cancer among smokers with the NAT2 slow genotype (OR = 3.78: 95% CI, 1.48-9.66; P = 0.0041). Furthermore, the NAT2 slow acetylator genotype was significantly higher among prostate cancer patients with locally advanced and metastatic disease (22.7%) compared with controls (8.6%) (OR = 3.14; 95% CI, 1.40-7.06; P = 0.0051). Lastly, the NAT2 slow acetylator genotype was significantly higher among prostate cancer patients with high-grade tumors (31.4%) compared with controls (8.6%) (OR = 4.90; 95% CI, 1.97-12.20; P = 0.0010). CONCLUSION: These data demonstrate that the NAT2 slow acetylator genotype plays an important role in determining the risk of developing prostate cancer in Japanese men and is also associated with more clinically advanced and pathologically aggressive disease. Furthermore, a possible interaction between the NAT2 slow acetylator genotype and smoking status was suggested.

Association of genotypes of carcinogen-activating enzymes, phenol sulfotransferase SULT1A1 (ST1A3) and arylamine N-acetyltransferase NAT2, with urothelial cancer in a Japanese population.

Carcinogenic aromatic amines such as 4-aminobiphenyl, which is contained in tobacco smoke, are one of the causal factors of urothelial epithelial cancers. 4-Aminobiphenyl has been shown to be bioactivated through N-hydroxylation by hepatic cytochrome (CYP) 1A2 and subsequently through O-sulfation and O-acetylation by phenol sulfating sulfotransferase, ST1A3 (SULT1A1), and arylamine N-acetyltransferase, NAT2, respectively. In a case-control study for urothelial epithelial cancers, low activity alleles of NAT2 are overall high-risk alleles (OR 2.11; 95% CI 1.08-4.26). Wild-type ST1A3*1 ((213)Arg) alleles were slightly overrepresented in nonsmoking urothelial cancer patients (82.6% vs. 69.7%) and in smoking cancer patients (76.7% and 74.3%) compared to a variant ST1A3*2 ((213)His) allele. In combination of ST1A3 and NAT2 genotypes for analyses of urothelial cancer risk, the highest OR of 2.45 (95% CI 1.04-5.98) was obtained with ST1A3*1 and NAT2 slow genotype among the 4 combinations. Recombinant ST1A3*1 enzyme showed a tendency of catalyzing higher in vitro 3'-phosphoadenosine 5'-phosphosulfate-dependent DNA adduct formation than ST1A3*2 (2.84 +/- 0.49 and 2.22 +/- 0.11 adducts/10(8) nucleotides). Combined analyses of different alleles of carcinogenic aromatic amine-activating phase II enzymes were applied to urothelial cancer risk for the first time and showed the highest risk combination of ST1A3 and NAT2 alleles.

Association of vitamin D receptor gene polymorphism with renal cell carcinoma in Japanese.

Molecular epidemiologic studies have reported a relationship between 1alpha,25 dihydroxyvitamin D3 (1,25(OH)2D3) and the development and progression of malignant tumors. (1,25(OH)2D3) exerts its biological activity by binding the vitamin D receptor (VDR), while recent studies have demonstrated that VDR gene polymorphisms affect serum levels of (1,25(OH)2D3). Serum levels of (1,25(OH)2D3) are reported to be significantly lower in patients with renal cell carcinoma (RCC) compared to non-cancer control patients. The purpose of this study was to investigate the TaqI VDR polymorphism in Japanese RCC patients and non-cancer controls in order to determine if an association exists between VDR genotype and the risk of developing RCC as well as clinical risk factors. A total of 102 RCC patients and 204 controls were genotyped for a previously described TaqI restriction fragment length polymorphism (RFLP) of the VDR gene. Products were digested into T allele or the t allele according to the absence or presence of a TaqI restriction site. Individuals were classified as TT, Tt or tt. The genotype TT was statistically more frequent among RCC patients (80.4%) compared to controls (61.8%) (OR = 2.54; 95% CI, 1.44-4.46; p = 0.0006). In addition, the occurrence of the genotype TT was significantly higher in patients with rapid-growth-type group (92.1%) compared to slow-growth-type group (73.4%) (OR = 4.22; 95% CI, 1.15-15.53; p = 0.0175). These data demonstrate that VDR genotype plays an important role in determining the risk of developing more aggressive RCC in Japanese.

A case of von Hippel-Lindau disease with bilateral pheochromocytoma, renal cell carcinoma, pelvic tumor, spinal hemangioblastoma and primary hyperparathyroidism.

A rare case of von Hippel-Lindau (VHL) disease with bilateral pheochromocytomas, right renal cell carcinoma, right pelvic carcinoma, spinal hemangioblastoma and primary hyperparathyroidism is described. A 78-year-old woman had a history of hypertension from her forties. She suffered from headache and body weight loss. Abdominal CT revealed bilateral adrenal tumors and right external renal tumors enhanced in early stage. MIBG scintigraphy exhibited a high accumulation of tracer in both adrenal glands. On the basis of the radiographic findings and endocrinological results, the patient was diagnosed as having bilateral pheochromocytomas and right renal cell carcinoma. A bilateral adrenectomy was performed, followed by surgery for resection of the renal cell carcinoma. The other resected right kidney showed a clear cell subtype that was determined to be renal cell carcinoma, and proved that the pelvic tumor was transient cell carcinoma. Spinal MRI showed spinal hemangioblastoma. von Hippel-Lindau (VHL) gene mutation for the patient was found. We diagnosed the patient as VHL because of the existence of spinal hemangioma and a VHL disease gene. Parathyroid echo revealed a hypoechoic space on the back of the left lobe, and serum calcium and intact PTH to be elevated. The patient was diagnosed as primary hyperparathyroidism. We report the first case of a patient with VHL disease complicated with bilateral pheochromocytomas, right renal cell carcinoma, right renal pelvic carcinoma and primary hyperparathyroidism. The life expectancy of affected individuals has been less than 50 years. Since the prognosis may be improved by an early diagnosis, affected individuals with VHL complexes should undergo cranial, spinal MRI and abdomen CT. The families may benefit from presymptomatic detection of affected gene carriers and the exclusion of at-risk family members by negative test results.

Genetic polymorphisms ofCYP2A6 andCYP2E1 with tobacco smoking is not associated with risk of urothelial cancer.

OBJECTIVES: To elucidate the association between genetic polymorphisms ofCYP2a6 andCYP2E1 and urothelial cancer susceptibility. METHODS: A total of 137 Japanese patients with urothelial cancer and 217 Japanese healthy controls, frequency-matched for age and gender, were selected. The polymorphisms ofCYP2A6 andCYP2E1 were analyzed by PCR-RFLP, and cigarette smoking histories were obtained through interviews RESULTS: The frequency ofCYP2A6 homozygote deletion genotype was 2.9% in the patients, compared with 3.2% in the controls (OR=0.84, 95% CI 0.24-2.96). The frequencies ofCYP2E1 C1/c2 andC2/c2 were 27.7% and 4.4% in the patients, compared with 35.5% and 6.0% in the controls (OR=0.68, 95% CI 0.42-1.09, OR=0.67, 95% CI 0.24-1.84, respectively). No statistically significant differences were observed when theCYP2A6 homozygote deletion genotype and theCYP2E1 genotypes were examined relative to smoking status. CONCLUSIONS: Our data indicate that neither a relationship between genetically impaired nitrosamine metabolism and tobacco-smoking consumption, nor urothelial cancer risk related to theCYP2A6 deletion genotype andCYP2E1 Rsa I genotype was found in Japanese population.

[Faropenem 300 mg 3 times daily versus levofloxacin 100 mg 3 times daily in the treatment of urinary tract infections in patients with neurogenic bladder and/or benign prostatic hypertrophy].

Faropenem (FRPM) is an only penem antibiotics. Though it has been reported that FRPM had good efficacy (overall efficacy rate: 82.0%) against patients with complicated urinary tract infection, FRPM has not been frequently used for UTI patients. This multicenter clinical study was designed to compare FRPM 300 mg 3 times daily to Levofloxacin (LVFX), which is the standard treatment for patients with UTI, 100 mg 3 times daily for 7 days in the treatment of urinary tract infections in patients with neurogenic bladder and/or benign prostatic hypertrophy. A total of 60 patients with significant bacteriuria and pyuria were included in this study. Overall efficacy rate (excellent plus moderate) was achieved in 90.6% (29/32) of patients treated with FRPM versus 82.1% (23/28) of those treated with LVFX. The ratios of eliminated bacteriuria and cleared pyuria were 71.9% and 56.3% of patients treated with FRPM, and 64.3% and 75.0% of those treated with LVFX. These data were not significant difference. In conclusion, FRPM 300 mg 3 times daily is at least as effective as LVFX 100 mg 3 times daily in patients with complicated urinary tract infection.