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Objective: We aimed to elucidate risk factors for intravesical recurrence of high-grade T1 bladder cancer in the second transurethral resection era., Methods: The analysis included 73 patients with high-grade T1 bladder cancer on initial transurethral resection. The median follow-up period was 49.2 months. Recurrence-free survival, progression-free survival and risk factors related to the presence of residual tumors or recurrence-free survival were statistically analyzed., Results: The pathological findings for second transurethral resection were pT0 36 (49%), pTis/a 21 (29%), pT1 13 (18%) and pT2 3 (4%), respectively. The risk factor for residual tumors at second transurethral resection was the presence of concomitant carcinoma in situ at the initial transurethral resection (P < 0.01). The bladder was preserved in all 57 patients with pT0/is/a tumors on second transurethral resection, and 43 patients (75%) received intravesical BCG therapy. Of these patients, 3-year recurrence-free survival and 3-year progression-free survival rates were 81 and 96%, respectively. In addition, the presence of pTis/a residual tumors on second transurethral resection had a significant impact on the recurrence. Five of the 13 patients with pT1 on second transurethral resection were immediately treated by radical cystectomy or radiation therapy combined with chemotherapy, and two (25%) of the eight who were treated by intravesical BCG therapy had progression including distant metastasis., Conclusions: High recurrence-free survival and progression-free survival were achieved by a second transurethral resection and intravesical BCG therapy in the patients with pT0/is/a on the second transurethral resection. In this group, the residual tumors at second transurethral resection are risk factors for intravesical recurrence.

Background: The insulin-like growth factor-1 (IGF-1) plays an important role in growth of prostate cancer (PCa) cells and facilitating the development and progression of PCa. This study aimed to evaluate the association of polymorphisms in three linkage disequilibrium (LD) blocks of the IGF-1 on the survival of metastatic PCa patients., Methods: A total of 215 patients with bone metastases at initial presentation were included in this study. The cytosine-adenine (CA) repeat polymorphism and rs12423791 were selected as representative polymorphisms in the LD blocks 1 and 2, respectively. Haplotype in the LD block 3 was analyzed using two tag single nucleotide polymorphisms (SNPs), rs6220 and rs7136446. Cancer-specific survival rate was estimated from the Kaplan-Meier curve, and the survival data were compared using the log-rank test., Results: Cancer-specific survival was significantly associated with the CA repeat polymorphism, rs12423791, and rs6220 (P = 0.013, 0.014, and 0.014, respectively). Although rs7136446 had no significant association with survival, the haplotype in the LD block 3 was significantly associated with cancer-specific survival (P = 0.0003). When the sum of the risk genetic factors in each LD block (19-repeat allele, C allele of rs12423791, or C-T haplotype) was considered, patients with all the risk factors had significantly shorter cancer specific-survival than those with 0-2 risk factors (P = 0.0003)., Conclusions: Polymorphisms in the IGF-1, especially a haplotype in the LD block 3, are assumed to be genetic markers predicting the outcome of metastatic PCa.

The aim of this study was to evaluate the clinical factors, drug-related genetic polymorphisms, and human leukocyte antigen (HLA) types to determine the association with sorafenib-induced high-grade skin rash (HGSR) in Japanese patients with advanced renal cell carcinoma (RCC). A total of 55 patients with advanced RCC treated with sorafenib were analyzed retrospectively. Of these, 33 patients were subjected to HLA typing and polymorphism analyses of CYP3A5, ABCB1, ABCC2, and UGT1A1, which are involved in the metabolism and membrane transport of sorafenib. Grade 3 or higher SR developed in 12 (22%), and a higher incidence was observed in female patients than in male patients (40 vs. 15%, P=0.046). The initial dose, initial dose per body weight, and initial dose per body surface area in patients with HGSR were significantly higher than those in patients without HGSR. Patients with the ABCC2 -24CC genotype were at a significantly higher risk of SR than those with the CT genotype (35 vs. 0%, P=0.032). HLA-A*24 was significantly associated with the occurrence of HGSR (P=0.049). Our finding suggested that women, higher initial dose per body weight or body surface area, the ABCC2 -24CC genotype, and HLA-A*24 are associated with the risk of sorafenib-induced HGSR in Japanese RCC patients.

Objective: To achieve better cosmesis, less invasiveness, and less morbidity in donor nephrectomy without using specialized instruments, which is usually required in the laparoendoscopic single-site (LESS) procedure, we performed laparoendoscopic plus one trocar donor nephrectomy (LEPODN)., Methods: From October 2010 to December 2011, 20 living renal transplantation donors underwent the LEPODN procedure. Their mean age, body mass index (BMI), and preoperative creatinine clearance were 55.7 years, 23.2, and 118.4 mg/min, respectively. The GelPort laparoscopic system was inserted through a 5-6 cm pararectal incision at the umbilicus level. A subcostal 5-mm right-hand working trocar was placed under the left costal arch. The graft kidney was extracted using a retrieval bag. A 5-mm diameter drain was placed via a right-hand working trocar. Operative data of LEPODN were retrospectively compared to those of standard laparoscopic donor nephrectomy (standard-LDN, n = 27) previously performed at our hospital., Results: The procedure was technically successful in all 20 patients. The mean operative time in the LEPODN group was significantly shorter than that in the standard-LDN group (229.1 vs 249.8 minutes, P = .033). Mean blood loss and warm ischemic time in the LEPODN group were 39.4 mL and 272.4 seconds, respectively. The mean serum creatinine concentrations of the recipients 7 and 30 days after operation were 1.57 and 1.13 mg/dL, respectively. These results were not significantly different from those in the standard-LDN group., Conclusion: The LEPODN procedure was feasible and performed without specialized instruments by surgeons experienced in only standard laparoscopic nephrectomy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

The majority of deaths associated with solid tumors are caused by tumor metastasis. To prevent metastasis, it is vital to understand its detailed process. In hematogenous metastasis of bladder cancer, some cancer cells disseminating into blood circulation extravasate into the lung tissues to form metastases. To study the molecular basis of the lung metastasis of bladder cancer, we employed an in vivo selection system that mimics hematogenous metastasis of bladder cancer on a low-metastatic bladder cancer cell line (KK-47). We have successfully isolated a high-metastatic bladder cancer subline, KK-47HM4, from KK-47 cells. We characterized KK-47HM4 in in vitro experimental systems. No significant difference in growth rate and susceptibility to NK cell attack between KK-47 and KK-47HM4 cells was observed. However, KK-47HM4 exhibited the higher capacities of Matrigel Matrix invasion and transendothelial invasion than KK-47. These results suggest that the extravasation of KK-47HM4 cells was enhanced among the multiple steps of the lung metastasis of bladder cancer. Our cDNA microarray analysis identified 67 genes whose expression was up- or downregulated in KK-47HM4 cells compared with KK-47 cells. This analysis data implied that one possible cause for enhanced extravasation of KK-47HM4 is its higher adhesion to extracellular matrix proteins. KK-47HM4 is the first bladder cancer subline with enhanced extravasation potential using the in vivo selection system. The information provided by our cDNA microarray analysis using KK-47HM4 will be useful for further investigation into the molecular basis of extravasation of cancer cells.

Purpose: We evaluated the perioperative serum levels of inflammatory cytokines in patients with prostate cancer (PCa) treated with open or laparoscopic radical prostatectomy (RP) and assessed the surgical stress based on the cytokine levels in addition to conventional clinical stress markers after surgery., Patients and Methods: One hundred sixty-five patients who received RP for clinically localized PCa were enrolled. Serum levels of interleukin (IL)-10, IL-6, tumor necrosis factor-α, IL-1β, IL-8, and IL-12p70 were quantitatively measured using a multiplex bead array at three time points (i.e., before the operation [pre-OP], immediately after the operation [post-OP], and on postoperative Day 1 [POD1]). The perioperative changes in serum stress markers, including cytokines, were compared between patients who underwent open and laparoscopic RP, and the predictors for high levels of postoperative cytokines were assessed., Results: The median age and estimated blood loss were significantly lower in the laparoscopic RP group than in the open RP group (P=.003 and P<.01, respectively). In all patients, body temperature, white blood cell count, and serum IL-10 and IL-6 levels were significantly higher at post-OP and POD1 than at pre-OP. Patients who underwent laparoscopic RP had significantly lower levels of serum IL-10, IL-6, and IL-1β at post-OP and POD1 than those who underwent open RP. Multivariate regression analyses showed that the surgical group (open versus laparoscopic) was an independent influencing factor on the levels of serum IL-6 and IL-10 at POD1 (P=.031 and P<.004, respectively) among various clinical perioperative parameters., Conclusions: Several inflammatory cytokines, particularly IL-6 and IL-10, are potential surgical stress markers in patients with PCa treated with RP. Based on cytokine production, our data support the view that laparoscopic RP is less invasive than open RP.

Background: Dietary patterns including high-fat diet (HFD) and high-carbohydrate diet (HCD) play an important role in prostate cancer progression. However, which of these diets have the greatest effect on tumor progression and its underlying mechanisms remains unclear., Methods: We investigated the effects of different diets on prostate cancer cell growth and the relevant circulating factors including serum insulin, growth factors, and inflammatory cytokines using the in vivo and ex vivo model., Results: The tumor growth of prostate cancer LNCaP xenograft was significantly higher in the HFD group than in the HCD and control diet (CD) groups (P = 0.01; HFD vs. HCD, P = 0.025; HFD vs. CD, P = 0.003). The mean level of the serum monocyte chemoattractant protein-1 (MCP-1) in the HFD group was significantly higher than that in the HCD and CD groups (P = 0.024; HFD vs. HCD, P = 0.033; HFD vs. CD, P = 0.001). The mRNA levels of CC chemokine receptor 2 (CCR2), which is an MCP-1 receptor, and the expression of activated Akt were the highest in the HFD group. Furthermore, serum from HFD-fed mice enhanced the proliferation of two PCa cells and CCR2 knockdown inhibited HFD-induced proliferation of LNCaP cells., Conclusions: An HFD enhanced prostate cancer cell growth more strongly than an HCD or CD. MCP-1/CCR2 signaling may be involved in an HFD-induced prostate cancer progression., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: This study investigated pharmacokinetic and pharmacogenetic differences between a modified-release once-daily formulation of tacrolimus (Tac-QD) and the original formulation requiring twice-daily intake (Tac-BID) in de novo renal transplant recipients., Methods: Forty-seven and 25 patients who received Tac-BID and Tac-QD, respectively, were enrolled. The pharmacokinetics and CYP3A5 6986A>G and ABCB1 3435C>T pharmacogenetics of each formulation were analyzed on day 28 posttransplantation., Results: The dose-adjusted trough level (C0) and area under the concentration-time curve (AUC0-24) of tacrolimus were approximately 25% lower for Tac-QD than Tac-BID. However, there was a good correlation between the AUC0-24 and C0 in the Tac-BID and Tac-QD groups (r=0.575, P<0.001; and r=0.638, P<0.001, respectively) and a similar coefficient in each regression equation. The dose-adjusted AUC0-24 was approximately 25% lower in carriers of the CYP3A*1 allele (CYP3A5 expressers), but not individuals with the CYP3A*3/*3 genotype (nonexpressers), for TAC-QD than Tac-BID. In the Tac-QD group, the interpatient variability for dose-adjusted parameters was small, and the interquatile ranges of dose-adjusted parameters differed between CYP3A5 expressers and nonexpressers and did not overlap. The ABCB1 polymorphism was not associated with any pharmacokinetic parameters of Tac-QD., Conclusions: C0-guided monitoring may lead to similar AUC0-24 values for both formulations. However, to maintain the same AUC0-24 value, a higher dose of Tac-QD than Tac-BID may be needed, especially for CYP3A5 expressers, in the early stage posttransplantation. The narrow interindividual variability of Tac-QD pharmacokinetics and its difference between CYP3A5 expressers and nonexpressers might contribute to a dosing strategy based on CYP3A5 genotype.

Background and Purpose: Whether the retroperitoneal approach (RA) or the transperitoneal approach (TA) for performing laparoscopic donor nephrectomy (LDN) in kidney transplant donors is less invasive is unclear. In this study, we compared the clinical outcome and systemic inflammatory marker levels between RA and TA to assess surgical invasiveness., Patients and Methods: We enrolled 105 donors (RA: 41, TA: 64) who underwent LDN in our hospital. Evaluation of both approaches included comparison of conventional clinical parameters and preoperative, immediate postoperative, and 1-day postoperative levels of the following circulating inflammatory cytokines: Tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, IL-10, and IL-12p70., Results: The frequency of right nephrectomy being performed was significantly lower in the TA than in the RA group (3/64 vs 12/41, P<0.001). Other clinical parameters in the TA group, including the frequency of surgical complications and incidence of delayed graft function, were comparable to those in the RA group. Immediate and 1-day postoperative mean serum IL-6 levels were significantly higher in the RA than in the TA group (P=0.023 and 0.044, respectively). The 1-day postoperative mean serum IL-10 level was also significantly higher in the RA than in the TA group (P=0.041). Meanwhile, the mean serum IL-6 and IL-10 levels were not associated with surgical duration or estimated intraoperative blood loss., Conclusions: Conventional clinical parameters related to surgical invasiveness were comparable in both approaches, thus indicating that both LDN approaches were similar and equally effective as minimally invasive procedures. The clinical significance of the higher postoperative mean serum IL-6 and IL-10 levels in the RA group remains to be clarified in a future study.

Background: The present study investigated the prevalence and predictors for the development of hyperuricemia within 1 year after transplantation and their associations with genetic polymorphisms and graft outcome in patients taking tacrolimus and mycophenolate mofetil., Methods: One hundred twenty-one renal allograft recipients transplanted between January 2001 and March 2009 were studied. Patients with serum uric acid concentrations above 7.0 mg/dL within 1 year after transplantation were defined as having hyperuricemia, and all were treated with allopurinol. Genetic polymorphisms of nitric oxide synthase, angiotensin-converting enzyme, methylenetetrahydrofolate reductase, and 3 uric acid transporters were examined., Results: At 1 year after transplantation, 46 (38%) recipients developed hyperuricemia. Male gender, higher body mass index, long-term pretransplantation dialysis, and hypertension were associated with the development of hyperuricemia. The estimated glomerular filtration rate (eGFR) at 1 year after transplantation was lower in the patients with hyperuricemia than in those without. There were no differences in graft survival between the two groups. The pharmacokinetics of tacrolimus and mycophenolic acid and 6 polymorphisms were not associated with hyperuricemia. In the multivariate analysis, male gender, long-term pretransplantation dialysis (>36 months), and eGFR (<60 mL/min) were independently associated with the development of hyperuricemia., Conclusion: The incidence of hyperuricemia in our cohort was 38%. Male gender and long-term pretransplantation dialysis were predictors for the development of hyperuricemia. The eGFR was lower in patients with hyperuricemia, but graft survival did not differ between the patients with hyperuricemia treated with alloprinol and those without hyperuricemia. We could not define the significance of the pharmacokinetics of immunosuppressants and genetic risk factors for hyperuricemia.

Purpose: Obesity has been considered a potential risk factor for complications during laparoscopic surgery. The purpose of this study is to retrospectively investigate the association of various obesity indices and intraoperative factors in laparoscopic donor nephrectomy., Patients and Methods: This study included 70 and 44 patients who underwent laparoscopic donor nephrectomy by a transperitoneal approach and retroperitoneal approach, respectively. We measured fat thickness and fat areas on preoperative computerized tomography (CT) images. The median value of fat thickness or of the subcutaneous fat area, visceral fat area, perirenal fat area, or total fat area among subjects was used as a cutoff to define fatty and non-fatty groups. The operative time and estimated blood loss were then compared between the two groups., Results: In the transperitoneal approach group, there was no statistically significant difference in any of the indices or intraoperative factors between the fatty and non-fatty groups defined using any of the fat parameters. In the retroperitoneal approach group, patients in the fatty group categorized by perirenal fat thickness and visceral fat area had significantly greater estimated blood loss than those in the non-fatty group. Also, in the retroperitoneal approach group, patients in the fatty group categorized by perirenal fat area had significantly greater estimated blood loss and longer operating time than those in the non-fatty group (P=.02 and P=.014, respectively)., Conclusions: The results indicate that the visceral fat, and in particular the perirenal fat area measured using CT scan imaging, influences operating time and estimated blood loss after retroperitoneal approach surgery but not in transperitoneal approach surgery. In donors with a high volume of perirenal fat, the transperitoneal approach may be recommended for laparoscopic nephrectomy.

Core 2 β-1,6-N-acetylglucosaminyltransferase (C2GnT) forms an N-acetylglucosamine branch in O-glycans (core 2 O-glycans) of cell surface glycoproteins. C2GnT-expressing bladder tumors acquire highly metastatic phenotypes by surviving longer in host blood circulation. However, the detailed mechanisms underlying this increased survival remain unclear. In this study, we report that the expression of C2GnT in bladder tumors positively correlates with tumor progression and that bladder tumor cell-surface mucin 1 (MUC1) carrying core 2 O-glycans plays an important role in the evasion from natural killer (NK) cell attack. In C2GnT-expressing bladder tumor cells, heavily core 2 O-glycosylated MUC1 carries poly-N-acetyllactosamine in its O-glycans and galectin-3 binds to MUC1 through this poly-N-acetyllactosamine. The binding of galectin-3 to poly-N-acetyllactosamine in MUC1 core 2 O-glycans attenuates the interaction of the tumor cells with NK cells and interferes with the access of tumor necrosis factor-related apoptosis-inducing ligand to the tumor cell surface. These effects of MUC1 carrying core 2 O-glycans on NK cell attack facilitate C2GnT-expressing tumor cells to evade NK cell immunity and survive longer in host blood circulation. We reveal that MUC1 carrying core 2 O-glycans thus functions as a molecular shield against NK cell attack, thereby promoting bladder tumor metastasis.

Background: In 2003, the Japanese Urological Association (JUA) and Japanese Society of Endourology (JSE) established a urological laparoscopic skill qualification system, called the Endoscopic Surgical Skill Qualification System in Urological Laparoscopy of JUA and JSE (ESSQSJJ). The main goal of the system is to decrease the prevalence of complications associated with laparoscopic surgery. To validate the qualification system, perioperative outcome and the prevalence of complications in different types of urological laparoscopic surgery performed by accredited surgeons were evaluated., Methods: One hundred thirty-six surgeons who obtained the qualification in 2004 were prospectively asked to submit intraoperative and postoperative data of their latest 20 cases at the end of 2009, along with the number of laparoscopic urological surgeries performed in each year for a 5-year period (2004-2009). Intraoperative and postoperative complications were graded according to the Satava classification and modified Clavien classification, respectively., Results: Data of 2,590 urological laparoscopic surgeries of 130 surgeons, including 904 laparoscopic radical nephrectomies, 430 laparoscopic nephroureterectomies, 390 laparoscopic adrenalectomies, 320 laparoscopic radical prostatectomies, and 170 laparoscopic partial nephrectomies, were analyzed. Complications were noted in 97 (3.7%) patients. Major intraoperative complications (grade II or III) occurred in 32 (1.2%) patients, and major postoperative complications (grade III or higher) occurred in 24 (0.9%) patients. The prevalence of conversion to open surgery, allogeneic transfusion, and perioperative mortality was 2.5%, 1.6%, and 0%, respectively. The number of surgeries performed by each qualified surgeon or the role of the surgeon (main operator vs. mentor/instructor) in the surgery did not affect the prevalence of intraoperative complications or postoperative complications. The open conversion rate was significantly higher in surgeons with a low surgical volume., Conclusions: ESSQSJJ can ensure urological laparoscopic surgeons who can perform various types of urological laparoscopic surgeries with a low prevalence of perioperative complications and reasonable outcomes.

Objectives: Docetaxel-based chemotherapy is effective in patients with castration-resistant prostate cancer (CRPC). This phase II study assessed the outcome and predictive factors for prognosis and toxicity following intermittent chemotherapy with docetaxel, estramustine phosphate, and carboplatin (DEC) in patients with CRPC., Methods: Thirty-five patients were treated with a DEC regimen that consisted of a 28-day cycle of drugs as follows: docetaxel (60 mg/m(2) on day 1), carboplatin (AUC 5 on day 1) and estramustine phosphate (560 mg daily). Treatment was continued intermittently. The end point was to test the effect of DEC on the response rate and overall survival (OS). Statistical correlations between the outcomes and predictive factors, including clinical parameters and 8 single-nucleotide polymorphisms (SNPs) related to drug metabolism, were assessed., Results: Prostate-specific antigen levels decreased by more than 30% in 65.7% of the patients. The median OS following DEC was 17.8 months, and the median total time of chemotherapy holiday was 7.7 months (range 1.7-35.8). On multivariate analysis, serum lactate dehydrogenase (LDH) was an independent prognostic factor for OS (p = 0.007). On SNP analysis, patients carrying the TT genotype of the ABCB1 C3435T polymorphism showed a significantly more severe leukocytopenia during the first cycle of DEC therapy compared to patients with the CC + CT genotype (p = 0.036)., Conclusion: Combination chemotherapy with DEC has a potential effect on CRPC with acceptable toxicity. Serum LDH may be a promising predictor of prognosis, and the ABCB1 C3435T polymorphism may be a genetic predictor of the severity of leukocytopenia in patients with CRPC treated with DEC.

Unlabelled: Study Type--Therapy (case series). Level of Evidence 4. What's known on the subject? and What does the study add? A randomized prospective phase III clinical trial for systemic treatment-naïve metastatic renal cell cancer (RCC) patients demonstrated the superiority of sunitinib over interferon with an acceptable safety profile. However, a commonly asked question is whether patients with RCC in clinical trials are representative of those with this disease being seen in ordinary clinical practice. To our knowledge, this is the first report of sunitinib for the Japanese patients with metastatic RCC in ordinary clinical practice. The estimated median PFS and OS in this study were 9.3 and 32.2 months, respectively. The application of the MSKCC model distinctly separated OS curves (P<0.001), suggesting that MSKCC prognostic factors might be still valid to predict survival in metastatic RCC in the era of molecular targeted therapy., Objectives: • To report the treatment efficacy and safety profile of sunitinib for patients with metastatic renal cell carcinoma (RCC) in ordinary clinical practice. • In addition, to investigate the prognostic clinicopathological factors in these patients., Patients and Methods: • The present study consisted of native Japanese patients with metastatic RCC, comprising 29 pretreated and 34 systemic treatment-naïve patients. • Univariate and multivariate analyses were performed by the log-rank test and the Cox proportional hazards model, respectively., Results: • Estimated median progression-free survival and overall survival (OS) were 9.3 months (95% confidence interval, CI, 5.0-13.7) and 32.2 months (95% CI, 24.4-40.0), respectively. • Among the patients pretreated before sunitinib, two patients were treated with initialized systemic therapy with sorafenib and the remaining 27 were initialized with interferon-α. • The OS from the initial systemic therapy of the patients in pretreated groups was 79.6 months (95% CI, 14.6-144.5). • The application of the Memorial Sloan-Kettering Cancer Center model distinctly separated the OS curves (P < 0.001). • The most common grade 3 adverse events were fatigue (53%), thrombocytopaenia (48%), hand-foot syndrome (16%), anaemia (20%), hypertension (10%) and leucopaenia (9%), although these events were manageable and reversible., Conclusions: • Sunitinib has a favourable efficacy/safety profile for Japanese metastatic RCC patients in clinical practice. • The estimated median OS was >2 years with acceptable tolerability. • The median OS from the initial systemic therapy of the pretreated patients was >6 years. • Memorial Sloan-Kettering Cancer Center prognostic factors still appear to be valid for predicting survival in metastatic RCC in the era of molecular targeted therapy., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

The purpose of the present study was to determine the genomic profile of renal cell carcinoma (RCC) in end-stage renal disease (ESRD) by analyzing genomic copy number aberrations. Seventy-nine tumor samples from 63 patients with RCC-ESRD were analyzed by array comparative genomic hybridization using the Agilent Whole Human Genome 4 × 44K Oligo Micro Array (Agilent Technologies Inc., Palo Alto, CA, USA). Unsupervised hierarchical clustering analysis revealed that the 63 cases could be divided into two groups, Clusters A and B. Cluster A was comprised mainly of clear cell RCC (CCRCC), whereas Cluster B was comprised mainly of papillary RCC (PRCC), acquired cystic disease (ACD)-associated RCC, and clear cell papillary RCC. Analysis of the averaged frequencies revealed that the genomic profiles of Clusters A and B resembled those of sporadic CCRCC and sporadic PRCC, respectively. Although it has been proposed on the basis of histopathology that ACD-associated RCC, clear cell papillary RCC and PRCC-ESRD are distinct subtypes, the present data reveal that the genomic profiles of these types, categorized as Cluster B, resemble one another. Furthermore, the genomic profiles of PRCC, ACD-associated RCC and clear cell papillary RCC admixed in one tissue tended to resemble one another. On the basis of genomic profiling of RCC-ESRD, we conclude that the molecular pathogenesis of CCRCC-ESRD resembles that of sporadic CCRCC. Although various histologic subtypes of non-clear cell RCC-ESRD have been proposed, their genomic profiles resemble those of sporadic PRCC, suggesting that the molecular pathogenesis of non-CCRCC-ESRD may be related to that of sporadic PRCC., (© 2011 Japanese Cancer Association.)

We have previously reported multiple loci associated with prostate cancer susceptibility in a Japanese population using a genome-wide association study (GWAS). To identify additional prostate cancer susceptibility loci, we genotyped nine SNPs that were nominally associated with prostate cancer (P < 1 × 10(-4)) in our previous GWAS in three independent studies of prostate cancer in Japanese men (2,557 individuals with prostate cancer (cases) and 3,003 controls). In a meta-analysis of our previous GWAS and the replication studies, which included a total of 7,141 prostate cancer cases and 11,804 controls from a single ancestry group, three new loci reached genome-wide significance on chromosomes 11q12 (rs1938781; P = 1.10 × 10(-10); FAM111A-FAM111B), 10q26 (rs2252004; P = 1.98 × 10(-8)) and 3p11.2 (rs2055109; P = 3.94 × 10(-8)). We also found suggestive evidence of association at a previously reported prostate cancer susceptibility locus at 2p11 (rs2028898; P = 1.08 × 10(-7)). The identification of three new susceptibility loci should provide additional insight into the pathogenesis of prostate cancer and emphasizes the importance of conducting GWAS in diverse populations.

We investigated the inhibitory effect of sunitinib, a newly approved multitargeted tyrosine kinase inhibitor, against the progression of renal cell cancer (RCC) bone metastases in vivo. In vitro cell proliferation was determined using the MTS assay. To investigate the inhibitory effects of sunitinib in vivo, we established luciferase-labeled ACHN(Luc) cells derived from papillary RCC. Mice in which ACHN(Luc) cells had been transplanted into the left ventricle to establish bone metastases were treated orally with 40 mg/kg/day sunitinib or vehicle control for 3 weeks. Growth of the cancer cells was monitored using an in vivo imaging system. In addition, 16 patients with metastatic RCC were treated with sunitinib, and serum and urine levels of amino-terminal telopeptide (NTx) were measured as markers of bone resorption. Sunitinib did not inhibit the growth of RCC cells in vitro at clinically or experimentally achievable serum levels (100 nM-1 μM). To investigate the inhibitory effect of sunitinib in vivo, we established luciferase-labeled human RCC cells (ACHN(Luc) ). Sunitinib prevented the growth of ACHN(Luc) RCC cells in the bone metastatic mouse model. The number of osteoclasts in sunitinib-treated mice was significantly less than that in control mice. Serum and urine levels of NTx in patients with metastatic RCC declined significantly during the first 4 weeks of sunitinib treatment (p = 0.027). Sunitinib is a potent anticancer agent for RCC bone metastases, at least for papillary RCC., (Copyright © 2011 UICC.)

The sulfamethoxazole (SMX)-trimethoprim drug combination is routinely used as prophylaxis against Pneumocystis pneumonia during the first 3 to 6 months after renal transplantation. The objective of this study was to examine the impact of N-acetyltransferase 2 (NAT2) and CYP2C9 polymorphisms on the pharmacokinetics of SMX in 118 renal transplant recipients. Starting on day 14 after renal transplantation, patients were administered 400 mg/day-80 mg/day of SMX-trimethoprim orally once daily. On day 14 after the beginning of SMX therapy, plasma SMX concentrations were determined by a high-performance liquid chromatography method. The SMX area under the concentration-time curve from 0 to 24 h (AUC(0-24)) for 15 recipients with the NAT2 slow acetylator genotype (NAT2 5/ 6, - 6/ 6, - 6/ 7, and - 7/ 7) was significantly greater than that for 56 recipients with the NAT2 rapid acetylator genotype (homozygous for NAT2 4) (766.4 ± 432.3 versus 537.2 ± 257.5 μg-h/ml, respectively; P = 0.0430), whereas there were no significant differences in the SMX AUC(0-24) between the CYP2C9 1/ 1 and - 1/ 3 groups. In a multiple regression analysis, the SMX AUC(0-24) was associated with NAT2 slow acetylator polymorphisms (P = 0.0095) and with creatinine clearance (P = 0.0499). Hepatic dysfunction in NAT2 slow acetylator recipient patients during the 6-month period after SMX administration was not observed. SMX plasma concentrations were affected by NAT2 polymorphisms and renal dysfunction. Although standard SMX administration to patients with NAT2 slow acetylator polymorphisms should be accompanied by monitoring for side effects and drug interaction effects from the inhibition of CYP2C9, SMX administration at a low dose (400 mg) as prophylaxis may not provide drug concentrations that reach the level necessary for the expression of side effects. Further studies with a larger sample size should be able to clarify the relationship between SMX plasma concentration and side effects.

Background: To assess the outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with a high risk of localized prostate cancer (PCa)., Methods: Complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m2) with estramustine phosphate (560 mg) were given to 18 PCa patients before radical prostatectomy. Subsequently, the clinical and pathological outcomes were analyzed., Results: No patients had severe adverse events during chemohormonal therapy, and hence they were treated with radical prostatectomy. Two patients (11.1%) achieved pathological complete response. Surgical margins were negative in all patients. At a median follow-up of 18 months, 14 patients (77.8%) were disease-free without PSA recurrence. All 4 patients with PSA recurrence had pathologic T3b or T4 disease and 3 of these 4 patients had pathologic N1 disease., Conclusion: We found that neoadjuvant chemohormonal therapy with complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy was safe, feasible, and associated with favorable pathological outcomes in patients with a high risk of localized PCa.

Transforming growth factor (TGF) β is a pro-fibrotic cytokine. While three isoforms (TGF-β1, 2 and 3) are known, the functional differences between them are obscure. To investigate the roles of TGF-β isoforms during liver fibrogenesis, male Wistar rats were administrated carbon tetrachloride (CCl4) subcutaneously twice a week for two months. Livers were excised and sectioned for histochemical examinations. These livers were also used to quantitate the expression of genes associated with fibrogenesis, including TGF-β isoforms, as well as those associated with retinoid metabolism. Expression levels of Tgfb1 and Tgfb3 were up-regulated in CCl4-treated rat livers while that of Tgfb2 was not changed. The mRNAs for lecithin-retinol acyltransferase (Lrat) and retinoic acid hydroxylase, Cyp26a1, were also elevated. By immunohistochemical staining, TGF-β3 protein was found to be localized mainly in liver parenchymal cells (hepatocytes). These results indicate that retinoid mobilization likely takes place within the rat's liver following CCl4 treatment, and suggest the possibility that the expression of Tgfb mRNA is regulated by retinoic acid receptors. Reporter analyses of a region of the Tgfb3 gene were performed using the rat liver parenchymal cell line, RLC-16, and a positively responsive region was identified within its intron.

Prostate specific antigen (PSA) is widely used as a diagnostic biomarker for prostate cancer (PC). However, due to its low predictive performance, many patients without PC suffer from the harms of unnecessary prostate needle biopsies. The present study aims to evaluate the reproducibility and performance of a genetic risk prediction model in Japanese and estimate its utility as a diagnostic biomarker in a clinical scenario. We created a logistic regression model incorporating 16 SNPs that were significantly associated with PC in a genome-wide association study of Japanese population using 689 cases and 749 male controls. The model was validated by two independent sets of Japanese samples comprising 3,294 cases and 6,281 male controls. The areas under curve (AUC) of the model were 0.679, 0.655, and 0.661 for the samples used to create the model and those used for validation. The AUCs were not significantly altered in samples with PSA 1-10 ng/ml. 24.2% and 9.7% of the patients had odds ratio <0.5 (low risk) or >2 (high risk) in the model. Assuming the overall positive rate of prostate needle biopsies to be 20%, the positive biopsy rates were 10.7% and 42.4% for the low and high genetic risk groups respectively. Our genetic risk prediction model for PC was highly reproducible, and its predictive performance was not influenced by PSA. The model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA, which should be confirmed in future clinical studies.

We report an extremely rare case of a 69-year-old man having a retroperitoneal carcinoid tumor associated with multiple endocrine neoplasia (MEN) type 1. The patient whose son and daughter were previously diagnosed with MEN type 1 was admitted to the Department of Endocrinology at our hospital for evaluation of this disorder. Computed tomography (CT) and ultrasonography revealed a parathyroid and retroperitoneal tumor (43 mm x 34 mm). The patient did not consent to surgical management of the tumor; however three years later, a follow-up CT revealed tumor enlargement (55 mm x 50 mm). We were unable to rule out a malignancy, and subsequently resected the tumor. A pathological diagnosis of retroperitoneal carcinoid was made. No local recurrence or metastasis have been observed for 21 months.

Fibroblast growth factor-inducible 14 (Fn14), a transmembrane receptor binding to the multifunctional cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is known to modulate many cellular activities including cancer progression. Here, we demonstrated the significant role of Fn14 in invasion, migration and proliferation of androgen-independent prostate cancer (AIPC) cells. Fn14 and its ligand TWEAK were highly expressed in two AIPC cell lines, DU 145 and PC-3, whereas expression was weak in androgen-sensitive LNCaP cells. Fn14 knockdown using small-interfering RNAs attenuated migration, invasion and proliferation and enhanced apoptosis in the AIPC cell lines. Both forced overexpression of Fn14 by stable Fn14 complementary DNA transfection to PC-3 cells (PC-3/Fn14) and ligand activation by recombinant TWEAK in PC-3 cells enhanced invasion. Fn14 was shown to modulate expression of matrix metalloproteinase (MMP)-9, and MMP-9 mediated the invasive potential influenced by Fn14 in PC-3 cells. In vivo, subcutaneous xenografts of PC-3/Fn14 grew significantly faster than xenograft of PC-3/Mock, and the invasive capacity in PC-3/Fn14 was found to be higher than that of PC-3/Mock as evaluated in an invasion model of the diaphragm. Furthermore, the messenger RNA expressions of MMP-9 in PC-3/Fn14 xenografts were significantly higher than those in PC-3/Mock xenografts. Clinically, high expression of Fn14 was significantly associated with higher prostate-specific antigen recurrence rate in patients who underwent radical prostatectomy. In conclusion, the overexpression of Fn14 may contribute to multiple malignant cellular phenotypes associated with prostate cancer (PCa) progression, in part via MMP-9. TWEAK-Fn14 signaling may be a novel therapeutic target of PCa.

The Clinical Research Office of the Endourological Society (CROES) conducts large-scale, international, multicenter clinical trials in the field of endourology. One of the major challenges that these trials pose is to ensure that data collected remotely and online within a very short time frame are valid and reliable. This editorial describes a formal process for auditing the data by the CROES Audit Committee. The audit process presented is largely based on an automatic scoring system, which takes into consideration several parameters to determine the quality of the data and of the participating institution. This process is dynamic in nature and offers live monitoring of both patient data and study centers.

Abnormal survivin expression has been reported to be involved in many types of cancer. A single-nucleotide polymorphism (SNP), C-31G, located in the promoter region of survivin reportedly may alter the mRNA level, while the significance of the nonsynonymous SNP A9194G in exon 4 has not yet been clarified. Here, the association between the two survivin SNPs and bladder cancer susceptibility and progression was investigated in 235 patients with bladder cancer and 346 healthy controls. Regarding the C-31G SNP, subjects with the CC genotype had a significantly higher risk of bladder cancer compared to those with the GG + CG genotype [odds ratio (OR) = 1.85, p = 0.001]. Regarding the A9194G SNP, the presence of the G allele was associated with a significantly reduced risk with a gene dosage effect (OR = 0.69, p = 0.002). Using the C-A haplotype as a reference, the G-G haplotype was associated with a significantly lower risk (OR = 0.11, p = 0.00006), indicating the cooperative effect of the two SNPs. Immunohistological evaluation of surgical specimens showed that cancer cells of the C-31G CC genotype had significantly higher nuclear survivin expression than those of the C-31G GG + CG genotype. With reverse transcriptase-polymerase chain reaction analysis, a significantly higher survivin mRNA expression level was observed in surgical specimens with an increase in the number of the C-31G C allele (p = 0.016). These results indicate that the two SNPs have a significant and cooperative influence on bladder cancer susceptibility., (Copyright © 2010 UICC.)

Background: To evaluate the efficacy and toxicity of a combination chemotherapy consisting of gemcitabine, carboplatin, and docetaxel (GCD) in patients with advanced urothelial carcinoma (UC) as a phase II trial., Materials and Methods: Patients with metastatic or locally advanced unresectable UC were eligible for this trial. All enrolled patients were considered to be "unfit" for cisplatin-based chemotherapy, or to have methotrexate, vinblastine, doxorubicin, cisplatin (MVAC)-refractory UC. The chemotherapy regimen consisted of gemcitabine 1000 mg/m(2) on days 1 and 8, and carboplatin (with a target area under the curve of 5) and docetaxel 70 mg/m(2) on day 1; this was repeated every 21 days., Results: Thirty-five patients were enrolled, with a median age of 68 years. A total of 89 cycles were administered (median, 2 cycles). Major toxicities were Grade 3/4 neutropenia in 28 (80.0%) patients and Grade 3/4 thrombocytopenia in 18 (51.5%). An objective response rate (ORR) was 11 of 21 patients (52.4%), including a complete response in 1 (4.8%). The median overall survival (OS) was 13.1 months (1-year survival rate, 60%) and the median progression-free survival (PFS) was 5.0 months. Among 16 patients who had previously received MVAC, the ORR, the median PFS, the median OS and 1-year survival rate was 56.3%, 5.0 months, 12.6 months and 54%, respectively., Conclusions: GCD chemotherapy is active and well tolerated as a first- or second-line therapy for patients with advanced UC. Response rate, duration and survival did not differ between those with and without a history of MVAC treatment.

We report a case of Xp11.2 translocation renal cell carcinoma (RCC) whose lung metastases were effectively treated with sunitinib. A 43-year-old woman presenting with upper abdominal pain was diagnosed with a left renal tumor. Laparoscopic left radical nephrectomy was performed. Histopathological examination of the surgical specimen revealed a clear-cell carcinoma of the left kidney. Two years later, multiple lung metastases were detected and the patient was treated daily with 50 mg sunitinib. A computed tomography scan performed after 2 cycles of sunitinib treatment revealed partial regression of these metastases. The partial regression has been maintained for >3 years. In retrospective evaluation of the primary RCC, tumor cells showed strong nuclear staining for transcription factor E3 (TFE3) protein and TFE3 split-fluorescence in-situ hybridization revealed translocation involving the TFE3 gene. These findings strongly support diagnosis of Xp11.2 translocation RCC.

Background: Urinary bladder capacity is reduced in patients undergoing long-term dialysis, which may increase the risk of vesicoureteral reflux (VUR) to a transplanted kidney. This study investigated the correlations between dialysis duration, pretransplant and posttransplant bladder capacity, and prevalence of VUR to the graft., Methods: Voiding cystography was performed in 101 adult renal transplant recipients without neurogenic disorders immediately before and 1 year after transplantation to evaluate bladder capacity and VUR. Nonstented extravesical antireflux ureteroneocystostomy was performed in all patients., Results: The median dialysis duration and pretransplant bladder capacity were 32 months (range 1-426 months) and 120 mL (range 15-450 mL), and 21 patients (20.8%) underwent dialysis for more than 120 months, and 30 patients (29.7%) had a pretransplant bladder capacity of less than 80 mL. Dialysis duration was correlated with pretransplant bladder capacity (R=0.466, P<0.001). Bladder capacity expanded more than 6-fold from pretransplantation to posttransplantation, and all recipients had a bladder capacity greater than 150 mL at 1 year posttransplantation. Thirty patients had VUR to the graft. Dialysis duration longer than 60 months (P=0.021) and pretransplant bladder capacity of less than 130 mL (P=0.024) were associated with VUR. VUR was associated with lower graft function., Conclusions: Although bladder capacity decreased because of long-term dialysis, it exceeded 150 mL at 1 year posttransplantation. A small bladder can be used in renal transplantation, but it may increase the risk of VUR.

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ∼25% of the familial risk in this disease, have now been identified.

Aim: Tacrolimus is a substrate of CYP3A4 and CYP3A5. The present study investigated the impact of the CYP3A4*1/*1G polymorphism compared with CYP3A5 genotypes on the dose-adjusted pharmacokinetics of tacrolimus. The effects of the polymorphism on the variability in tacrolimus pharmacokinetics among patients with the CYP3A5*1 allele (CYP3A5 expresser) and among those with CYP3A5*3/*3 genotype (nonexpresser) were also studied., Materials & Methods: A total of 136 renal allograft recipients were given repeated doses of tacrolimus every 12 h. On day 28 after the renal transplantation, blood tacrolimus concentrations were measured, and dose-adjusted pharmacokinetics were determined and compared with the corresponding genotype., Results: The dose-adjusted AUC₀₋₁₂ and C₀ of tacrolimus were significantly lower in patients with the CYP3A4*1G allele and CYP3A5 expressers than those with the CYP3A4*1/*1 genotype and nonexpressers, respectively. In a multiple regression analysis, the dose-adjusted AUC₀₋₁₂ and C₀ values were associated with CYP3A4*1/*1 (p = 0.018 and 0.040, respectively) and CYP3A5*3/*3 (p < 0.001 each). The standardized regression coefficient for the AUC₀₋₁₂ of tacrolimus was approximately twofold less for CYP3A4*1/*1 than CYP3A5*3/*3. The lowest dose-adjusted AUC₀₋₁₂ was found in CYP3A5 expressers with the CYP3A4*1G allele., Conclusion: The CYP3A4*1/*1G polymorphism was associated with the pharmacokinetics of tacrolimus, however, its contribution to dose-adjusted pharmacokinetics was approximately twofold less than that of the CYP3A5*1/*3 polymorphism. Although its effect on CYP3A4 activity is not clear, CYP3A4*1/*1G may be a candidate for a polymorphism affecting the interindividual variability in tacrolimus pharmacokinetics among CYP3A5 expressers.

A 62-year-old female patient with a chief complaint of back pain and continuous fever was referred to our hospital. A computed tomography scan revealed a left renal tumor (76×54×67 mm) without a metastatic lesion. Laboratory examination showed an elevated white blood cell count of 23,200/μl. The patient underwent left radical nephrectomy and the histopathological diagnosis was spindle cell renal cell carcinoma (G3-4, pT4, pN2) with positive staining for granulocyte colony-stimulating factor. One month later, a computed tomography scan showed an enlarged locally recurrent tumor mass. Three cycles of combination chemotherapy consisting of gemcitabine (1,500 mg/m2, day 1) and doxorubicine (50 mg/m2, day 1) resulted in an 83% reduction of the tumor mass. A follow-up computed tomography scan after 2 weeks revealed rapid regrowth of the recurrent tumor. The patient died 199 days after the surgery. Combination chemotherapy consisting of gemcitabine and doxorubicin is a treatment option for patients with spindle cell renal cell carcinoma.

Introduction: Although specimen extraction site selection for laparoscopic donor nephrectomy (LDN) is relatively flexible and is mostly selected by surgeons from the patient's standpoint, the patient's request may differ from the medical worker's recommendation. The cosmetic aspect may also differ with age, gender, and the extent of medical knowledge. We performed an unsigned questionnaire assessment of individual preferences for LDN wound sites., Materials and Methods: Between August 2007 and October 2008, we surveyed LDN wound site preferences among 148 physicians, 263 nurses, and 266 outpatients of urology at Akita University Hospital. They were questioned for their age, gender, occupation (medical worker or not), and for the most preferred surgical wound site among the following: A, lower vertical midline: B, upper vertical midline: C, anterior subcostal: D, Pfannenstiel: E, Gibson: and F, subcostal flank. The valid response rate was 93.5% (677/724)., Results: Wound sites preferred (ranked in descending order) were F (48.3%), D (25.6%), E (10.5%), A (9.0%), C (5.2%), and B (1.4%). The subcostal flank incision was the most preferred in almost all the categories. Second preferences were Pfannenstiel incisions in women and incisions on the lower abdomen in men. Overall, flank and lower abdominal incisions tended to be preferred, and mid and upper abdominal incisions tended to be avoided. Medical workers selected the subcostal flank and Pfannenstiel incisions more frequently than outpatients. With increasing age, the selection rates of the Gibson and the lower vertical midline incisions increased, whereas the subcostal flank and the Pfannenstiel incisions decreased., Conclusions: The subcostal flank was the most preferred LDN sites. Age, gender, and the extent of medical knowledge may influence the individual preferences for LDN wound sites.

The O-glycan branching enzyme, core2 β-1,6-N-acetylglucosaminyltransferase (C2GnT), forms O-glycans containing an N-acetylglucosamine branch connected to N-acetylgalactosamine (core2 O-glycans) on cell-surface glycoproteins. Here, we report that upregulation of C2GnT is closely correlated with progression of bladder tumours and that C2GnT-expressing bladder tumours use a novel strategy to increase their metastatic potential. Our results showed that C2GnT-expressing bladder tumour cells are highly metastatic due to their high ability to evade NK cell immunity and revealed the molecular mechanism of the immune evasion by C2GnT expression. Engagement of an NK-activating receptor, NKG2D, by its tumour-associated ligand, Major histocompatibility complex class I-related chain A (MICA), is critical to tumour rejection by NK cells. In C2GnT-expressing bladder tumour cells, poly-N-acetyllactosamine was present on core2 O-glycans on MICA, and galectin-3 bound the NKG2D-binding site of MICA through this poly-N-acetyllactosamine. Galectin-3 reduced the affinity of MICA for NKG2D, thereby severely impairing NK cell activation and silencing the NK cells. This new mode of NK cell silencing promotes immune evasion of C2GnT-expressing bladder tumour cells, resulting in tumour metastasis.

Background: Routine therapeutic drug monitoring of mycophenolic acid (MPA) is generally performed using the area under the concentration-time curve from 0 to 12 hours (AUC0-12) with recommended values between 30 and 60 μg·h/mL., Objective: The aim of this study was to examine whether the monitoring of the MPA predose concentration (C0) in patients who are stable for >1 year after renal transplantation was practical and to determine factors that cause MPA C0 variability among patients., Methods: Eighty-six Japanese patients who had undergone renal transplantation and were taking tacrolimus and who had their MPA C0 analyzed >6 times by high-performance liquid chromatography for >1 year posttransplantation were enrolled., Results: Recipients with MPA AUC0-12 levels<30 μg·h/mL on day 28 and 1 year after transplantation had an MPA C0 of <2.0 μg/mL, with a sensitivity of 90.9% and a specificity of 70.7%. There was no significant difference in the mean dose-adjusted MPA C0>1 year after transplantation between subjects with either the UGT (1A1, 1A9, and 2B7) or drug transporter (SLCO1B3, ABCC2, and ABCG2) genotypes. However, in a multiple regression analysis, the dose-adjusted mean MPA C0>1 year after transplantation was significantly associated with age (P=0.0035), creatinine clearance (P=0.0001), and the dose-adjusted MPA AUC0-12 at 1 year (P=0.0147)., Conclusions: To keep the MPA AUC0-12>30 μg·h/mL, the plasma threshold for maintaining the MPA C0 with tacrolimus should be set >2.0 μg/mL as determined by high-performance liquid chromatography. For patients who are stable for >1 year after transplantation, continued monitoring of the MPA C0 using the same samples used to monitor the tacrolimus C0 and the additional assessment of the MPA AUC0-12 at the 1-year time point seem to be a viable option. If a change of the mycophenolate mofetil dose seems necessary based on the routine MPA C0 information, the determination of MPA AUC0-12 using a limited sampling strategy is recommended.

What Is Known and Objective: Tacrolimus, a widely used immunosuppressive agent in organ transplantation, has a narrow therapeutic window. It has been suggested that its interaction with lansoprazole could be dependent on polymorphisms of CYP3A5 and CYP2C19. The objective of this study was to investigate how, 1 year after renal transplantation, CYP3A5 and CYP2C19 polymorphisms, biochemical parameters and coadministration with lansoprazole, influenced tacrolimus pharmacokinetics., Methods: The pharmacokinetics of tacrolimus was studied 1 year after renal transplantation, in 75 recipients who were all receiving continuation treatment with 12-hourly oral tacrolimus, and 30 mg lansoprazole daily (Group 1; n = 20) or, 10 mg rabeprazole daily or no proton pump inhibitor (Group 2; n = 55)., Results: There were no significant differences in the dose-adjusted area under the plasma concentration-time curve (AUC(0-12)) and maximum plasma concentration (C(max)) of tacrolimus between CYP2C19 genotype groups, but there were significant differences between CYP3A5 genotypes groups (*1/*1 + *1/*3 vs. *3/*3 = 45·2 ± 20·0 vs. 71·0 ± 34·1 ng·h/mL/mg, P < 0·0001 and 6·3 ± 2·6 vs. 9·3 ± 7·0 ng/mL/mg, P = 0·0017, respectively) and between co-administration with and without lansoprazole (74·5 ± 34·0 vs. 52·4 ± 27·4 ng·h/mL/mg, P = 0·0054 and 10·9 ± 8·8 vs. 6·7 ± 3·0 ng/mL/mg, P = 0·0024, respectively). In a multiple regression analysis, the dose-adjusted AUC(0-12) and C(max) of tacrolimus were associated with CYP3A5*3/*3 and co-administration with lansoprazole., What Is New and Conclusion: CYP2C19 does not seem to contribute to the interaction between tacrolimus and lansoprazole. The long-term combination of tacrolimus and lansoprazole requires careful monitoring of patients with the CYP3A5*3/*3 genotype., (© 2010 The Authors. JCPT © 2010 Blackwell Publishing Ltd.)

A pathological diagnosis of a lesion in the ureteral wall is often attended with a difficulty. We report a case of a 54-year-old man who presented a thickening of the ureteral wall and diffuse swelling of paraaortic lymph nodes diagnosed as a non-Hodgkin lymphoma by a laparoscopic needle biopsy. This is a safe and useful technique by which target tissues can be surely obtained.

Background: This study investigated the increase in interstitial fibrosis (IF) from 0 hr to 1 month and 1 year posttransplantation in biopsy sections and assessed the risk of developing IF in 118 living kidney recipients., Methods: A quantitative analysis of IF was performed using computer-assisted imaging. The percent IF (%IF) in the cortical region at 0 hr was defined as the baseline, and the increases in %IF at 1 month and 1 year were calculated. Demographics, higher (regimen 1) and lower (regimen 2) target trough concentrations of tacrolimus, and the cytochrome P450 (CYP) 3A5 polymorphism were tested as risk factors., Results: The mean %IF at 0 hr, 1 month, and 1 year was 10.3%+/-4.2%, 15.0%+/-5.8%, and 19.0%+/-7.7%, respectively. %IF increased 1.7- and 2.2-fold from 0 hr to 1 month and 1 year posttransplantation, respectively. At 1 year, the increase was higher in patients with the CYP3A5*3/*3 genotype (nonexpressers), those treated with regimen 1, and those with a lower estimated glomerular filtration rate and higher body mass index. In a multivariate analysis, CYP3A5 nonexpression correlated with the development of IF (odds ratio 2.63, P=0.018). Tacrolimus blood levels in the early stage posttransplantation were higher in nonexpressers than CYP3A5 expressers in both regimens 1 and 2, despite therapeutic drug monitoring., Conclusions: The higher concentrations of tacrolimus, especially in the nonexpressers treated with regimen 1, might influence the development of IF. This study suggested that a new regimen with lower and narrow target trough levels of tacrolimus or a dosing strategy based on the CYP3A5 genotype is needed to reduce the risk of developing IF.

Although the characteristics and safety of radiocontrast media in peritoneal dialysis (PD) patients are not yet well defined, their use in PD patients is considered generally safe. In this study, we evaluated clearance and adverse events of iopamidol in PD patients. We measured the iopamidol concentration in the plasma, dialysate, and urine of 11 patients. Iopamidol clearance from patient plasma was delayed with a half-life of 33.3 h, and the elimination ratio was 83.6% for 96 h. We retrospectively investigated adverse events occurring in a total of 50 stable PD patients who underwent a total of 64 angiographic computed tomography (CT) scans. In 64 angiographic CT scans, two cases of adverse events were observed. Our results suggest that iopamidol can be eliminated by regular PD and careful observation for adverse events are necessary for the safe use of radiocontrast media.

Purpose: We investigated the clinical significance of chromogranin A and endothelin-1 polymorphism and expression in prostate cancer., Materials and Methods: We analyzed 2 CHGA polymorphisms by polymerase chain reaction-restriction fragment length polymorphism in DNA samples of 435 patients with prostate cancer and 316 age matched male controls. Chromogranin A and endothelin-1 expression was evaluated by immunohistochemistry in prostate specimens of 114 men with prostate cancer who underwent radical retropubic prostatectomy and in 27 with bladder cancer who underwent radical cystectomy and served as controls., Results: For the CHGA Glu264Asp polymorphism men with the GG genotype were at 2.05 times higher risk for prostate cancer than men with the CC genotype (p = 0.014). In men with prostate cancer higher chromogranin A immunohistochemistry grade was associated with higher stage and higher Gleason score (p = 0.011 and 0.044, respectively). Multivariate analysis showed that chromogranin A immunohistochemistry grade was an independent variable for predicting biochemical failure after radical prostatectomy (p = 0.023). Higher endothelin-1 expression was observed in prostate cancers (p = 0.011), especially those with a higher Gleason score (p = 0.042). There was no significant relationship between chromogranin A polymorphisms, and chromogranin A and endothelin-1 expression., Conclusions: Polymorphism and expression of chromogranin A and endothelin-1 have clinical significance in prostate cancer. Chromogranin A expression was an independent predictor of biochemical failure after prostatectomy in patients with localized prostate cancer., (2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

The risk of acute rejection in patients with higher exposure to mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), might be due to inosine 5'-monophosphate dehydrogenase (IMPDH) polymorphisms. The correlations with subclinical acute rejection, IMPDH1 polymorphisms and MPA exposure on day 28 post-transplantation were investigated in 82 Japanese recipients. Renal transplant recipients were given combination immunosuppressive therapy consisting of tacrolimus and 1.0, 1.5 or 2.0 g/day of MMF in equally divided doses every 12 hr at designated times. There were no significant differences in the incidence of subclinical acute rejection between IMPDH1 rs2278293 or rs2278294 polymorphisms (p = 0.243 and 0.735, respectively). However, in the high MPA night-time exposure range (AUC > 60 microg x h/ml and C(0 )> or = 1.9 microg/ml), there was a significant difference in the incidence of subclinical acute rejection between IMPDH1 rs2278293 A/A, A/G and G/G genotypes (each p = 0.019), but not the IMPDH1 rs2278294 genotype. In the higher daytime MPA exposure range, patients with the IMPDH1 rs2278293 G/G genotype also tended to develop subclinical acute rejection. In patients with the IMPDH rs2278293 A/A genotype, the risk of subclinical acute rejection episode tends to be low and the administration of MMF was effective. The risk of subclinical acute rejection for recipients who cannot adapt in therapeutic drug monitoring (TDM) of MPA seems to be influenced by IMPDH1 rs2278293 polymorphism. The prospective analysis of IMPDH1 rs2278293 polymorphism as well as monitoring of MPA plasma concentration after transplantation might help to improve MMF therapy.

Introduction: Because the normal ovary is assumed to be devoid of lymphoid tissue, it is unusual for it to be an initial manifestation of malignant lymphoma. This case is the first report, to our knowledge, of post-transplant lymphoproliferative disorder involving the ovary as an initial manifestation., Case Presentation: Twenty-nine weeks after a living renal transplantation, a 38-year-old Japanese female, whose ethnic origin was Asian, presented with abdominal pain and a chronic high fever. Computed tomography revealed a right ovarian tumor and liver metastases. The patient underwent oophrectomy based on the clinical diagnosis of liver metastasis from the primary ovarian tumor. The pathological diagnosis was Epstein-Barr Virus-associated post-transplant lymphoproliferative disorder. While ovarian malignant lymphoma has a poor prognosis, complete remission of liver involvement in this case was achieved only with a reduction of immunosuppressants., Conclusion: Clinicians should remember that malignant lymphoma could initially involve the ovary, especially if the patient is immunosuppressed after transplantation therapy.

Objective: The aim of this study was to assess the efficacy and safety of two different types of medical mushrooms in patients with prostate cancer in Japan., Methods: Patients with biochemical failure after radical treatment for non-metastasized prostate cancer were enrolled in this open-label study. For 6 months they ingested one of the two following supplements: Senseiro, containing extracts from the Agaricus blazei Murill mushroom; and Rokkaku Reishi, containing the Ganoderma lucidum mushroom. Levels of serum prostate-specific antigen (PSA) level and PSA doubling time were examined before and after study entry to assess the impact of these supplements on disease progression. The primary end-point of this study was partial response rate (50% or more decrease of serum PSA). Hormonal status, represented by serum testosterone levels, and toxicity were also assessed., Results: A total of 51 patients were enrolled following radical prostatectomy. Forty-seven completed the protocol and could be assessed. Thirty-two patients received Senseiro and the remaining 15 received Rokkaku Reishi. No partial response in terms of PSA was observed. Alteration of PSA doubling time did not correlate with that of serum testosterone levels. Serious adverse effects were not observed., Conclusions: No significant anticancer effects were observed with the intake of these two medical mushrooms.

Objectives: To examine Japanese patients who had received androgen-deprivation therapy (ADT) for longer periods, as it is known that ADT of patients with prostate cancer reduces their bone mineral density (BMD). However, our previous cross-sectional study revealed that short-term ADT (average, 23.5 months) does not significantly increase the prevalence of osteoporosis in Japanese patients., Methods: The subjects consisted of 201 native Japanese patients with prostate cancer. They comprised 113 ADT-treated and 88 hormone-naive patients. Lumbar spine, total hip, and femoral neck BMDs were measured by dual-energy x-ray absorptiometry and expressed in standard deviation units relative to the scores of young adult men (T-score) or age-matched men (Z-score). Serum levels of bone metabolism markers were also measured., Results: The ADT-treated patients had significantly lower BMD values, T-scores, and even Z-scores than the hormone-naive patients (P <.001). For patients who were hormone-naive, ADT-treated for less than 2 years, and ADT-treated for more than 2 years, the osteoporosis prevalence was 4.5% (4/88), 12.1% (4/33), and 10.8% (4/37), respectively. The ADT-treated patients had significantly higher serum amino-terminal telopeptide levels than the hormone-naive patients (P = .014), but significantly lower serum carboxy-terminal telopeptide of type-I collagen levels than the ADT-treated patients with bone metastasis (P <.001)., Conclusions: Our cross-sectional study confirmed that both ADT-treated and hormone-naive Japanese patients with prostate cancer have low rates of osteoporosis. These findings are different from those of studies in western countries. Genetic and hormonal or other environmental factors may result in population differences in the characteristics of prostate cancer and BMD., (Copyright 2010 Elsevier Inc. All rights reserved.)

Mel-18 is a member of the polycomb group (PcG) proteins, which are chromatin regulatory factors and play important roles in development and oncogenesis. This study was designed to investigate the clinical and prognostic significance of Mel-18 in patients with prostate cancer. A total of 539 native Japanese subjects consisting of 393 prostate cancer patients and 146 controls were enrolled in this study. Mel-18 genotyping was analyzed using a PCR-RFLP method and an automated sequencer using the GENESCAN software. Immunohistochemistry revealed that Mel-18 expression was diminished in high grade and high stage prostate cancers. Moreover, patients with positive Mel-18 expression had significantly longer PSA recurrence-free survival than patients negative for Mel-18 expression (p=0.038). A Mel-18 1805A/G SNP was located in the 3' untranslated region and was predicted to alter the secondary structure of the mRNA. Mel-18 mRNA expression of the 1805A allele was clearly higher than expression of the 1805G allele by allele specific quantitative RT-PCR. In multivariate analysis, a homozygous G allele genotype and negative Mel-18 expression were independent risk factors predicting high PSA recurrence after radical prostatectomy, with HRs of 2.757 (p=0.022) and 2.271 (p=0.045), respectively. Moreover, the G allele was also an independent predictor of poor cancer-specific survival with an HR of 4.658 (p=0.019) for patients with stage D2 prostate cancer. This is the first study to provide important evidence demonstrating that Mel-18 is a tumor suppressor and possible therapeutic target, as well as a diagnostic marker for poor prognosis in prostate cancer patients., (Copyright (c) 2009 UICC.)

Objective: The aim of this study was to elucidate the effect of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activating angiotensin receptor blocker (ARB) telmisartan and the non-PPAR-gamma activating ARB valsartan and candesartan on mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients., Methods: Recipients (n = 10 each group) were randomly given either 40 mg of telmisartan, 80 mg of valsartan or 8 mg of candesartan cilexetil for at least 6 months, and no ARB. Blood was sampled a year after transplantation., Results: Dose-adjusted maximum and trough plasma concentration of MPA co-administered with telmisartan were the lowest in all groups. The mean dose-adjusted area under the concentration curve from 0 to 12 h (AUC(0-12)) and AUC(0-6) of MPA co-administered with telmisartan were significantly lower than that without ARB (98 vs. 138 ng x h/mL/mg, P = 0.0353 and 63 vs. 96 ng x h/mL/mg, P = 0.0305). Coadministration of valsartan and candesartan did not alter MPA pharmacokinetics. The AUC ratio of MPA glucuronide (MPAG)/MPA co-administered with telmisartan was higher than that without ARBs, but not significantly (14.2 vs. 9.1). The mean maximum and minimum plasma concentrations of telmisartan (40 mg) after oral administration were 84 and 15 ng/mL, respectively, and that of valsartan (80 mg) 2220 and 441 ng/mL, respectively. Plasma concentrations of candesartan in most transplant patients were not observed 19 h after oral administration of candesartan cilexeil (8 mg)., Conclusions: The degree of drug interaction between MPA and telmisartan was significantly greater than that between MPA and valsartan or candesartan. Uridine diphosphate-glucuronosyltransferase (UGT) 1A9 has been identified as a PPAR-gamma target gene. UGT induction by telmisartan might stimulate MPA glucuronidation. A combination of telmisartan and mycophenolate mofetil might require periodic monitoring of MPA.