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We used real-world and large-scale data to assess the clinical efficacy and safety of pembrolizumab in older patients with advanced urothelial carcinoma (UC).A total of 608 patients who received pembrolizumab for the treatment of chemoresistant UC were retrospectively analyzed. All patients were histologically diagnosed with pure UC. Using propensity score matching (PSM) (ECOG performance status, site of metastasis, hemoglobin level and neutrophil-to-lymphocyte ratio, 1:1 matching), the overall survival (OS) and adverse events (AEs) of patients75 and ≥75 years old were compared.The median follow-up (IQR) period was 16.1 (9.9-20.5) months. After PSM, there were 215 patients each in the aged75 years and aged ≥75-year-old groups. The median OS of all patients was estimated to be 10.4 months (95% confidence interval [CI] = 8.8-12.1). After PSM, the median OS was 7.8 months (95% CI = 5.2-10.4) in the75-year-old group and 10.4 months (95% CI = 7.3-13.5) in the ≥75-year-old group (P = 0.186). Any-grade AEs were more frequently reported in the ≥75-year-old group in comparison to the age75-year-old group (55.3% vs. 41.9%, P = 0.007), whereas there was no significant difference between the two groups in the incidence of grade ≥3 AEs (10.2% vs. 12.6%, P = 0.544). The objective response rate, defined as complete remission or a partial response, was 22.8% in the75-year-old group and 25.1% in the ≥75-year-old group (P = 0.651).The present study demonstrates that age does not affect the efficacy and safety of pembrolizumab treatment for advanced chemoresistant UC. Pembrolizumab treatment should not be avoided based on chronological age; however, close monitoring for the development of treatment-related AE should be considered for older patients.

Supplementary Figure 1 from Molecular Features of Hormone-Refractory Prostate Cancer Cells by Genome-Wide Gene Expression Profiles

Supplementary Table 1 from Molecular Features of Hormone-Refractory Prostate Cancer Cells by Genome-Wide Gene Expression Profiles

Supplementary Figure 1 Legend from Molecular Features of Hormone-Refractory Prostate Cancer Cells by Genome-Wide Gene Expression Profiles

One of the most critical issues in prostate cancer clinic is emerging hormone-refractory prostate cancers (HRPCs) and their management. Prostate cancer is usually androgen dependent and responds well to androgen ablation therapy. However, at a certain stage, they eventually acquire androgen-independent and more aggressive phenotype and show poor response to any anticancer therapies. To characterize the molecular features of clinical HRPCs, we analyzed gene expression profiles of 25 clinical HRPCs and 10 hormone-sensitive prostate cancers (HSPCs) by genome-wide cDNA microarrays combining with laser microbeam microdissection. An unsupervised hierarchical clustering analysis clearly distinguished expression patterns of HRPC cells from those of HSPC cells. In addition, primary and metastatic HRPCs from three patients were closely clustered regardless of metastatic organs. A supervised analysis and permutation test identified 36 up-regulated genes and 70 down-regulated genes in HRPCs compared with HSPCs (average fold difference > 1.5; P < 0.0001). We observed overexpression of AR, ANLN, and SNRPE and down-regulation of NR4A1, CYP27A1, and HLA-A antigen in HRPC progression. AR overexpression is likely to play a central role of hormone-refractory phenotype, and other genes we identified were considered to be related to more aggressive phenotype of clinical HRPCs, and in fact, knockdown of these overexpressing genes by small interfering RNA resulted in drastic attenuation of prostate cancer cell viability. Our microarray analysis of HRPC cells should provide useful information to understand the molecular mechanism of HRPC progression and to identify molecular targets for development of HRPC treatment. [Cancer Res 2007;67(11):5117–25]

The metastatic burden is a critical factor for decision‐making in the treatment of metastatic hormone‐sensitive prostate cancer (HSPC). This study aimed to develop and validate a novel risk model for survival in patients with de novo low‐ and high‐burden metastatic HSPC. The retrospective observational study included men with de novo metastatic prostate cancer who were treated with primary androgen‐deprivation therapy at 30 institutions across Japan between 2008 and 2017. We created a risk model for overall survival (OS) in the discovery cohort (n = 1449) stratified by the metastatic burden (low vs high) and validated its predictive ability in a separate cohort (n = 951). Based on multivariate analyses, lower hemoglobin levels, higher Gleason grades, and higher clinical T‐stage were associated with poor OS in low‐burden disease. Meanwhile, lower hemoglobin levels, higher Gleason grade group, liver metastasis, and higher extent of disease scores in bone were associated with poor OS in patients with high‐burden disease. In the discovery and validation cohorts, the risk model using the aforementioned parameters exhibited excellent discriminatory ability for progression‐free survival and OS. The predictive ability of this risk model was superior to that of previous risk models. Our novel metastatic burden‐stratified risk model exhibited excellent predictive ability for OS, and it is expected to have several clinical uses, such as precise prognostic estimation., This study developed and validated a novel metastatic burden‐stratified risk model in de novo metastatic hormone‐sensitive prostate cancer. This novel metastatic burden‐stratified risk model exhibited excellent predictive ability for overall survival, and it is expected to have several clinical uses, such as precise prognostic estimation.

Metastatic burden is a critical factor for therapy decision‐making in metastatic hormone‐sensitive prostate cancer. The present study aimed to identify prognostic factors in men with high‐ or low‐metastatic burden treated with primary androgen‐deprivation therapy. The study included 2450 men with de novo metastatic prostate cancer who were treated with primary androgen‐deprivation therapy at 30 institutions across Japan between 2008 and 2017. We investigated the prognostic value of various clinicopathological parameters for progression‐free survival (PFS) and overall survival (OS) in patients stratified by low‐ or high‐metastatic burden. Among the 2450 men, 841 (34.3%) and 1609 (65.7%) were classified as having low‐ and high‐metastatic burden, respectively. Median PFS of the low‐ and high‐burden groups were 44.5 and 16.1 months, respectively, and the median OS was 103.2 and 62.7 months, respectively. Percentage of biopsy‐positive core, biopsy Gleason grade group, T‐stage, and N‐stage were identified to be differentially prognostic. M1a was associated with worse PFS than was M1b in the low‐burden group, whereas lung metastasis was associated with better PFS and OS than was M1b in the high‐burden group. Differential prognostic factors were identified for patients with low‐ and high‐burden metastatic prostate cancer. These results may assist in decision‐making to select the optimal therapeutic strategies for patients with different metastatic burdens., This study investigated prognostic factors according to metastatic burden, and found that prognostic impact of some factors was different. This finding may be valuable in decision‐making to select the optimal therapeutic strategies for patients with different metastatic burdens.

Renal cell carcinoma (RCC) features altered lipid metabolism and accumulated polyunsaturated fatty acids (PUFAs). Elongation of very long-chain fatty acid (ELOVL) family enzymes catalyze fatty acid elongation, and ELOVL5 is indispensable for PUFAs elongation, but its role in RCC progression remains unclear. Here, we show that higher levels of ELOVL5 correlate with poor RCC clinical prognosis. Liquid chromatography/electrospray ionization-tandem mass spectrometry analysis showed decreases in ELOVL5 end products (arachidonic acid and eicosapentaenoic acid) under CRISPR/Cas9-mediated knockout of ELOVL5 while supplementation with these fatty acids partially reversed the cellular proliferation and invasion effects of ELOVL5 knockout. Regarding cellular proliferation and invasion, CRISPR/Cas9-mediated knockout of ELOVL5 suppressed the formation of lipid droplets and induced apoptosis via endoplasmic reticulum stress while suppressing renal cancer cell proliferation and in vivo tumor growth. Furthermore, CRISPR/Cas9-mediated knockout of ELOVL5 inhibited AKT Ser473 phosphorylation and suppressed renal cancer cell invasion through chemokine (C-C motif) ligand-2 downregulation by AKT-mTOR-STAT3 signaling. Collectively, these results suggest that ELOVL5-mediated fatty acid elongation promotes not only cellular proliferation but also invasion in RCC.

The present study aimed to evaluate the efficacy of the real‐world use of axitinib and to develop a prognostic model for stratifying patients who could derive long‐term benefit from axitinib. This was a retrospective, descriptive study evaluating the efficacy of axitinib in patients with metastatic renal cell carcinoma that had been treated with 1 or 2 systemic antiangiogenic therapy regimens at 1 of 36 hospitals belonging to the Japan Urologic Oncology Group between January 2012 and February 2019. The primary outcome was overall survival (OS). Using a split‐sample method, candidate variables that exhibited significant relationships with OS were chosen to create a model. The new model was validated using the rest of the cohort. In total, 485 patients were enrolled. The median OS was 34 months in the entire study population, whereas it was not reached, 27 months, and 14 months in the favorable, intermediate, and poor risk groups, respectively, according to the new risk classification model. The following 4 variables were included in the final risk model: the disease stage at diagnosis, number of metastatic sites at the start of axitinib therapy, serum albumin level, and neutrophil : lymphocyte ratio. The adjusted area under the curve values of the new model at 12, 36, and 60 months were 0.77, 0.82, and 0.82, respectively. The efficacy of axitinib in routine practice is comparable or even superior to that reported previously. The patients in the new model’s favorable risk group might derive a long‐term survival benefit from axitinib treatment., The accuracy of the overall survival predictions made after the initiation of axitinib treatment, area under the curve (AUC) values were calculated for each model. The adjusted AUC values at 12, 36, and 60 months after the initiation of axitinib were 0.77, 0.82, and 0.82, respectively, for the axitinib treatment prediction model, and 0.69, 0.67 and 0.56, respectively, for the International Metastatic Renal Cell Carcinoma Database Consortium model.

Renal cell carcinoma (RCC) is an aggressive genitourinary malignancy which has been associated with a poor prognosis, particularly in patients with metastasis, its major subtypes being clear cell RCC (ccRCC), papillary PCC (pRCC) and chromophobe RCC (chRCC). The presence of intracellular lipid droplets (LDs) is considered to be a hallmark of ccRCC. The importance of an altered lipid metabolism in ccRCC has been widely recognized. The elongation of very-long-chain fatty acid (ELOVL) catalyzes the elongation of fatty acids (FAs), modulating lipid composition, and is required for normal bodily functions. However, the involvement of elongases in RCC remains unclear. In the present study, the expression of ELOVL2 in ccRCC was examined; in particular, high levels of seven ELOVL isozymes were observed in primary tumors. Of note, elevated ELOVL2 expression levels were observed in ccRCC, as well as in pRCC and chRCC. Furthermore, a higher level of ELOVL2 was significantly associated with the increased incidence of a poor prognosis of patients with ccRCC and pRCC. The CRISPR/Cas9-mediated knockdown of ELOVL2 resulted in the suppression of the elongation of long-chain polyunsaturated FAs and increased LD production in renal cancer cells. Moreover, ELOVL2 ablation resulted in the suppression of cellular proliferation via the induction of apoptosis in vitro and the attenuation of tumor growth in vivo. On the whole, the present study provides new insight into the tumor proliferation mechanisms involving lipid metabolism, and suggests that ELOVL2 may be an attractive novel target for RCC therapy.

Renal mucinous tubular and spindle cell carcinoma (MTSCC) is a rare kidney cancer subtype with limited cases reported in the literature. Renal MTSCC has many similarities with papillary renal cell carcinoma (pRCC), and it is therefore often difficult to make a differential diagnosis between them. Herein, we report a case of renal MTSCC. The patient was a 76-year-old woman. Computed tomography revealed a left renal tumor. Magnetic resonance imaging (MRI) demonstrated an iso-intensity or high signal intensity mass on T2-weighted images, high signal intensity on diffusion-weighted images, and weak and gradual enhancement. We diagnosed the patient with left renal cell carcinoma (cT1bN0M0) and performed laparoscopic left nephrectomy in May 2019. The histopathological diagnosis was renal MTSCC. Six months after surgery, the patient remains free of recurrence and of metastasis. MRI is effective for the preoperative differentiation of renal MTSCC from pRCC since renal MTSCC presents an iso-intensity or high signal intensity on MRI T2-weighted images reflecting the mucin component in the intervening stroma within the tumor.

Neutrophil-to-lymphocyte ratio (NLR) was reported to be associated with prognosis of urothelial cancer (UC) patients receiving systemic chemotherapy or immunotherapy. However, it has not been elucidated how preceding first-line chemotherapy affects NLR and subsequent second-line pembrolizumab treatment. This multicenter study analyzed 458 patients with metastatic UC who received first-line chemotherapy and second-line pembrolizumab with regard to pre-chemotherapy and pre-pembrolizumab NLR in association with the efficacy of chemotherapy and pembrolizumab treatment. NLR was increased in 47% while decreased in 53% of patients before and after first-line chemotherapy. High pre-chemotherapy NLR (≥ 3) was significantly associated with unfavorable overall (OS, P = 0.0001) and progression-free (P

Background We retrospectively analyzed castration-resistant prostate cancer (CRPC) patients treated with secondary hormonal therapies (SHTs) prior to docetaxel therapy. Methods The cases of 73 CRPC patients who underwent docetaxel therapy in 2005–2011 at four hospitals in Ibaraki, Japan were analyzed. We determined the cause-specific survival (CSS) from the start of docetaxel therapy and the time point of CRPC diagnosis, and we compared the CSS achieved with/without prior classical SHTs, which were defined as low-dose steroid and estramustine phosphate. Results Of the 73 enrolled patients, 26 underwent docetaxel therapy (DOC group), and 47 underwent SHTs (SHTs-DOC group) as the initial treatment for CRPC. In the docetaxel therapy, the rate of prostate-specific antigen responses were higher in the DOC group compared with the SHTs-DOC group (76.9% vs. 44.7%, P = 0.0066). The median CSS from the docetaxel therapy initiation was not significant but longer in the DOC group than in the SHTs-DOC group (23.4 months vs. 16.6 months, P = 0.0969). However, the median CSS from the time of CRPC diagnosis did not significantly differ between the DOC and SHTs-DOC groups (23.4 months vs. 24.7 months, P = 0.9233). In a univariate analysis, pain and visceral metastasis appeared to be risk factors for the CSS in the SHTs-DOC group. The patients with pain and/or visceral metastasis had significantly poorer survival than those without these factors in the SHTs-DOC group (31.5 months vs. 16.8 months, P = 0.0053). Conclusion The induction of SHTs prior to docetaxel therapy is an acceptable treatment option with some survival benefits for CRPC patients without pain and visceral metastases.

p16INK4a (p16) is a key molecule in bladder tumor (BT) development. We previously reported that a p16 antitumor peptide inhibited the growth of subcutaneous BT grafts in mice through restoration of p16 function using a Wr-T peptide transporter system. In the present study, the efficacy of mouse p16 peptide administration in a mouse lung metastasis model for BT and also the toxicity of peptides by cardiac peptide injection were evaluated. Mouse lung metastases were developed by tail vein injection of a p16-deficient MBT-2 cell line. Six-week-old C3H/He female mice were divided into three groups: A control group (n=12) receiving no treatment; a group treated once on the 3rd experimental day (n=12); and a group treated three times on the 3rd, 5th and 7th experimental days (n=10) with an injection of a mixture of 80 nmol mouse p16 peptide and 50 nmol Wr-T into the tail vein. At the 14th experimental day, the lung metastases were histologically evaluated. Lung metastases were observed in 100% (12/12), 41.7% (5/12) and 30% (3/10) of the aforementioned three groups, respectively. The number and area of metastatic lung tumors were significantly different between control and treatment groups (control vs. triple treatment group for the number and area, P=0.0029 and P=0.0296, respectively). Immunohistochemistry demonstrated that phosphorylated retinoblastoma (Rb) protein was decreased in lung tumors of the treatment groups, compared with the control group. The toxicity of p16 peptide transduction was evaluated by using low-dose treatment (three dosages) and high-dose treatment (two dosages) on three male and three female C3H/He mice in early and late experimental phases. In low and high dose groups, no notable change was determined in body weight or blood analyses in early or late phases following mouse p16 peptide administration. In addition, no notable change was observed histologically in bone marrow of treatment groups. To conclude, systemic p16 peptide administration decreased lung tumor development in a mouse metastatic BT model without severe adverse events, as assessed by blood analyses and histological evaluation.

Radical cystectomy remains the gold standard for treatment of muscle-invasive bladder cancer. Robot-assisted radical cystectomy has technical advantages over laparoscopic radical cystectomy and has emerged as an alternative to open radical cystectomy. Despite the advancements in robotic surgery, experience with total intracorporeal reconstruction of urinary diversion remains limited. Most surgeons have carried out the hybrid approach of robot-assisted radical cystectomy and extracorporeal reconstruction of urinary diversion, as intracorporeal reconstruction of urinary diversion remains technically challenging. However, intracorporeal reconstruction of urinary diversion might potentially proffer additional benefits, such as decreased fluid loss, reduction in estimated blood loss and a quicker return of bowel function. The adoption of intracorporeal ileal neobladder reconstruction has hitherto been limited to high-volume academic institutions. In the present review, we compare the totally intracorporeal robot-assisted radical cystectomy approach with open radical cystectomy and robot-assisted radical cystectomy + extracorporeal reconstruction of urinary diversion in muscle-invasive bladder cancer patients.

What's known on the subject? and What does the study add? It is known that a prostate cancer gene 3 (PCA3) urine assay is superior to serum PSA level or PSA-related indices for predicting a positive biopsy result in European and US men. This is the first report on PCA3 in a large cohort of Japanese men. The diagnostic value of the PCA3 score in Japanese men was similar to those reported in European and US men. The study concludes that a combination of PSA density and PCA3 score may be useful for selecting patients who could avoid an unnecessary biopsy. Objective To examine the diagnostic performance of the prostate cancer gene 3 (PCA3) score for prostate cancer in Japanese men undergoing prostate biopsy. Patients and Methods This Japanese, multicentre study included 647 Asian men who underwent extended prostate biopsy with elevated prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE). Urine samples were collected after DRE. The PCA3 score was determined using a PROGENSA PCA3 assay and correlated with biopsy outcome. Its diagnostic accuracy was compared with that of serum PSA level, prostate volume (PV), PSA density (PSAD), and free/total PSA ratio (f/t PSA). Results A total of 633 urine samples were successfully analysed (the informative rate was 98%). Median PSA was 7.6 ng/mL. Biopsy revealed cancer in 264 men (41.7%). The PCA3 score for men with prostate cancer was significantly higher than that for men with negative biopsies (median PCA3 score: 49 vs. 18; P < 0.001). The rate of positive biopsy was 16.0% in men with a PCA3 score of

Objectives The aim of this study was to compare 29 muscle-invasive bladder cancer patients who received neoadjuvant chemotherapy (NAC) followed by immediate robot-assisted radical cystectomy (RARC) with those who underwent minimum-incision endoscopic RC (MIE-RC). Methods We retrospectively reviewed the charts of 430 consecutive patients who underwent RC and bilateral pelvic node dissection (PLND) between May 1994 and July 2016. Our study focused on patients with MIBC who had histologically confirmed stage T2-T4aN0M0 urothelial carcinoma of the bladder and received NAC prior to surgery. Accordingly, 225 patients were included in this analysis, of whom, 29 underwent RARC (RARC group) and 196 underwent MIE-RC (MIE-RC group). The primary endpoints in this study were the positive surgical margin (PSM) rate and lymph node (LN) count. Results In the RARC group, 20 patients underwent RARC with intracorporeal urinary diversion and nine patients underwent RARC with extracorporeal urinary diversion. The median surgical duration for RC and bilateral PLND was 125 min in the RARC group and 98 min in the MIE-RC group (P < 0.001). The rate of PSM was 0% in the RARC group and 0.5% in the MIE-RC group. The median LN counts were 15 in the RARC group and 18 in the MIE-RC group. No intra-operative complication or mortality was associated with RARC or MIE-RP. All complications were grade 2 according to the Clavien-Dindo classification. Conclusions Our initial experience with NAC followed by RARC appears to be favorable, with acceptable operative and perioperative clinical outcomes when compared with those of MIE-RC.

OBJECTIVE • To conduct a preclinical evaluation of the ability of natural killer cells to cytolyze bladder cancer cells that were modified to show enhanced expression of natural-killer group 2, member D (NKG2D) ligands by R8-liposome-bacillus Calmette-Guein (BCG)-cell wall skeleton (CWS) treatment. MATERIALS AND METHODS • The T24 cells and RT-112 cells were co-cultured with R8-liposome-BCG-CWS and BCG for 2, 4, or 6 h, and then the surface expression of NKG2D ligands was analyzed using TaqMan real-time quantitative RT-PCR. • Peripheral blood mononuclear cells were obtained with a conventional preparation kit, and then lymphokine-activated killer (LAK) cells were generated from these purified peripheral blood mononuclear cells via interleukin-2 stimulation. • The anti-tumour effect of LAK cells against untreated and R8-liposome-BCG-CWS co-cultured with cells of the human bladder cancer cell lines T24 and RT-112 was analyzed using the cytotoxic WST-8 assay method at 4 h of culture at various effector/target (E : T) ratios. RESULTS • Major histocompatibility complex class I-related chain B (MICB) expression was increased ≈1.5-fold on T24 cells and RT-112 cells with BCG. • UL-16-binding protein (ULBP) 1 expression was also increased ≈1.5-fold on T24 cells and RT-112 cells with BCG. R8-liposome-BCG-CWS increased the surface expression of MICB 2.2-fold on T24 cells but did not increase it significantly on RT-112 cells. • ULBP1 expression was increased ≈2.2-fold on RT-112 cells, although no differences were observed between the expression of ULBP2 and 3 with R8-liposome-BCG-CWS. • T24 cells that were co-cultured with R8-liposome-BCG-CWS showed an ≈1.3-fold increase in sensitivity to cytolysis by LAK cells at an E : T ratio of 4 and RT-112 cells showed an ≈1.4-fold increase at an E : T ratio of 2. CONCLUSIONS • In the present study, the induction of surface NKG2D ligands by R8-liposome-BCG-CWS rendered cancer cells more susceptible to cytolysis by LAK cells. • T24 cells and RT-112 cells, even when cultured singly in the absence of immune cells, can directly respond to R8-liposome-BCG-CWS. • The results obtained in the present study may therefore indicate a novel adoptive immunotherapy against bladder cancers.

Lymph node metastasis is one of the most important factors for tumor dissemination. Quantifying microRNA (miRNA) expression using real-time PCR in formalin-fixed, paraffin-embedded (FFPE) lymph node can provide valuable information regarding the biological research for cancer metastasis. However, a universal endogenous reference gene has not been identified in FFPE lymph node. This study aimed to identify suitable endogenous reference genes for miRNA expression analysis in FFPE lymph node. FFPE lymph nodes were obtained from 41 metastatic cancer and from 16 non-cancerous tissues. We selected 10 miRNAs as endogenous reference gene candidates using the global mean method. The stability of candidate genes was assessed by the following four statistical tools: BestKeeper, geNorm, NormFinder, and the comparative ΔCt method. miR-103a was the most stable gene among candidate genes. However, the use of a single miR-103a was not recommended because its stability value exceeded the reference value. Thus, we combined stable genes and investigated the stability and the effect of gene normalization. The combination of miR-24, miR-103a, and let-7a was identified as one of the most stable sets of endogenous reference genes for normalization in FFPE lymph node. This study may provide a basis for miRNA expression analysis in FFPE lymph node tissue.

Objectives: To estimate the risk of intravesical recurrence in patients with primary urothelial cancer of the upper urinary tract. Methods: Ninety patients who underwent radical nephroureterectomy for clinically localized urothelial cancer of the upper urinary tract were initially considered. Those with a previous and/or concomitant history of bladder cancer, and those who had previously received systemic chemotherapy were excluded. Overall, data from 60 patients with no evidence of bladder cancer and distant or lymph node metastasis were retrospectively reviewed. The clinical course and the risk pattern of intravesical recurrence were estimated by using a smoothing technique on estimated hazard function plots. Multivariate analysis was carried out using a Cox proportional hazards regression model. Results: Mean patient age was 64.7 years. Median follow up was 51.3 months. Thirty patients (50%) had intravesical recurrence during the follow-up period. The peak of intravesical recurrence was detected in the early period (less than 2.5 years) after surgery. The intravesical recurrence hazard became lower afterwards. Nevertheless, it persisted over a long period of time. On univariate and multivariate analyses, none of the clinical or pathological parameters had a statistically significant impact on intravesical recurrence. Conclusions: Even if an intravesical recurrence in patients with upper urinary tract urothelial cancer is more likely in the early period, it persists over a long period of time. This might reflect different mechanisms of recurrence, having a significant impact on the definition of the optimal treatment and follow-up schedules.

We present the clinical course of a ureteroiliac arterial fistula in a patient who had been managed by ureteral stenting for 8 years for severe ureteral stricture after abdominoperineal resection with pelvic irradiation for advanced rectal cancer. A multidisciplinary team approach including provocative angiography and an endovascular stent saved the life of the patient. Ureteroarterial fistula is a rare complication of a long-term indwelling ureteral stent that is potentially fatal unless a prompt diagnosis and adequate therapy are provided. Heightened awareness and a high index of suspicion for this condition are required to make an early diagnosis.

Introduction Several recent studies suggested that the prevalence of erectile dysfunction (ED) was higher in men with metabolic syndrome (MS). Aim We analyzed the impact of MS on the responsiveness to sildenafil. Methods A total of 133 ED patients were evaluated for the prevalence of MS and graded on severity of ED. MS was diagnosed according to the International Diabetes Federation (IDF) definition. The severity of ED was evaluated by the International Index of Erectile Function (IIEF) questionnaire. Hormonal parameters were measured for all patients, and the IIEF questionnaire was conducted after administration of eight tablets of 50-mg doses of sildenafil. If the scores to questions 3 and 4 of the IIEF were 4 or higher after administration, the patients were defined as responders to sildenafil. Main Outcome Measures To clarify the negative impact of MS on the responsiveness to sildenafil. Results The mean age of the patients was 56.9 years, and 25 patients were diagnosed with MS. The IIEF-erectile function score and the response rate for sildenafil decreased as the number of MS components increased. Logistic regression analysis showed that the presence of MS along with severity of ED and history of pelvic surgery were significant independent risk factors of nonresponse for sildenafil. The hazard ratio for the presence of MS was 3.30 (95% confidence interval [CI]: 1.17–9.73). No meaningful association was observed between total testosterone or free testosterone levels and MS in this population. Conclusion We demonstrated the negative impact of MS on the responsiveness to sildenafil. Erectile function and response rate for sildenafil decreased as the number of MS components increased. Suetomi T, Kawai K, Hinotsu S, Joraku A, Oikawa T, Sekido N, Miyanaga N, Shimazui T, and Akaza H. Negative impact of metabolic syndrome on the responsiveness to sildenafil in Japanese men.

Background: We previously reported that weekly treatment with docetaxel alone is useful for and well tolerated by patients with hormone-refractory prostate cancer (HRPC). Here, we compare it with the regimen of docetaxel once every 3 weeks (q3w) plus daily prednisone (PSL) based on a TAX 327 trial in order to clarify the efficacy and toxicity of docetaxel regimens in Japan. Methods: Thirty-two patients with HRPC were treated with docetaxel weekly (regimen 1) or docetaxel q3w plus PSL daily (regimen 2) at Tsukuba University Hospital and the changes in serum prostate-specific antigen (PSA), tumor size and survival were evaluated. The dose of docetaxel in regimen 1 was based on our previous report and that of regimen 2 was modified from a TAX 327 trial. Results: A .50% decrease in PSA was observed in 53% of the patients with a median time to progression of 3.5 months and 69% with 8.5 months with regimens 1 and 2, respectively. Patients who received regimen 2 had a significantly better survival rate than those who received regimen 1. Myelosuppression and neuropathy were statistically more frequent in regimen 2 than in regimen 1. Conclusion: A regimen of docetaxel q3w with PSL daily was associated with a high rate of PSA reduction and prolongation of patient survival. Although docetaxel has not been approved in Japan yet, this treatment is considered feasible for Japanese patients with HRPC.

We analyzed the correlation between interferon-alpha (IFNalpha) response and gene expression profiles to predict IFNalpha sensitivity and identified key molecules regulating the IFNalpha response in renal cell carcinoma (RCC) cell lines. To classify eight RCC cell lines of the SKRC series into three subgroups according to IFNalpha sensitivity, that is, sensitive, resistant and intermediate group, responses to IFNalpha (300-3000 IU/mL) were quantified by WST-1 assay. Microarray, followed by supervised hierarchical clustering analysis, was applied to selected genes according to IFNalpha sensitivity. In order to find alteration of expression profiles induced by IFNalpha, sequential microarray analyses were performed at 3, 6, and 12 h after IFNalpha treatment of RCC cell lines and mRNA expression level was confirmed using quantitative real time polymerase chain reaction. According to the sequential microarray analysis between IFNalpha-sensitive and -resistant line, seven genes were selected as candidates for IFNalpha-sensitivity-related genes in RCC cell lines. Among these seven genes, we further developed a model to predict tumor inhibition with four genes, that is, adipose differentiation-related protein, microphthalmia associated transcription factor, mitochondrial tumor suppressor 1, and troponin T1 using multiple linear regression analysis (coefficient=0.948, P=0.0291) and validated the model using other RCC cell lines including six primary cultured RCC cells. The expression levels of the combined selected genes may provide predictive information on the IFNalpha response in RCC. Furthermore, the IFNalpha response to RCC might be modulated by regulation of the expression level of these molecules.

Background: We retrospectively evaluated the effects of tumor size and microvascular tumor invasion on the clinical outcomes of patients who had undergone radical nephrectomy for renal cell carcinoma (RCC). Methods: One-hundred and sixty-two patients who received radical nephrectomy for localized or locally invasive RCC from1989 to 2002 were included. We evaluated a new cut-off value for tumor size by dividing patients into groups by tumor diameter from 3.0 to 7.0 cm in 1.0 cm increments and compared the prognosis with that predicted by the 2002 TNM classification. We also re-classified localized microvascular tumor invasion as invasive disease. Results: Univariate analyses showed a 5.0 cm cut-off provided the greatest difference in recurrence (p ¼ 0.004) and survival (p ¼ 0.001). Microvascular invasion made no significant difference in tumor recurrence and tumor-specific survival. However, in the new categories used in this study, survival in the locally invasive group was poor compared with the localized group. Conclusion: Our study showed that a tumor diameter of 5.0 cm might be the critical size to determine the prognosis of patients with localized RCC. Microvascular invasion seemed to have the necessity of re-evaluation in the TNM classification for patients with RCC.

Background: Elastography is a diagnostic imaging technique that evaluates the hardness of a lesion. It is expected to become a new diagnostic modality for prostate cancer. The aim of this study was to examine the usefulness of elastography in the diagnosis of prostate cancer. Methods: A total of 29 patients with untreated, histologically proven prostate cancer were examined using an elastographic imaging technique. The patient was scanned in the dorsosacral position and the prostate was manually compressed with a transrectal ultrasonic probe. The echo signals from inside the tissue were measured before and after the tissue compression and an elastogram was generated by spatially differentiation of the displacement distribution. Results: Elastography depicted the cancer lesion as a harder tissue than the surrounding normal prostatic tissue. Elastography successfully detected 93% (27 patients) of the untreated prostate cancer lesions. Detection of cancer lesions using elastography was significantly higher than by digital rectal examination (59%; 17 patients) and transrectal ultrasonography (55%; 16 patients). Conclusion: Elastography has great potential as a useful modality for diagnosis of prostate cancer. Differentiation between cancerous and normal tissues can be expected to become more accurate as a result of technical advances in the quantification of tissue hardness.

Small-cell carcinoma of the prostate (SCCP) is a rare entity. Many treatment modalities have been done, but thus far no uniform treatment has been clearly established. We carried out combination chemotherapy with gemcitabine, docetaxel, and carboplatin (GDC) regimen (for two patients with refractory SCCP. Case 1 involved a 53-year-old man diagnosed with SCCP after receiving hormone therapy for prostate cancer (stage D1). Six cycles of GDC chemotherapy was applied. Initially the primary site reduced according with a decline of neuro-specific enolase and with relief of the symptoms; however, bone disease occurred and he died of cancer 13 months after diagnosis of SCCP. Case 2 involved a 69-year-old man complaining of severe anal pain. He underwent a biopsy and a huge prostate tumor showing SCCP was showed. He had pelvic node metastases but no distant lesions, and received four cycles of GDC chemotherapy. He was discharged after receiving subsequent radiotherapy and remained stable for a while; however, he died of possible drug-induced hepatitis. This is the first report of chemotherapy with GDC against patients with SCCP. This regimen raised the possibility that it would intensify the outcome, which had been poorly achieved.

Background Combination of bleomycin, etoposide and cisplatin (BEP) remains the standard chemotherapy for testicular cancer. Since the development of BEP in the 1980s, there has been a considerable advance in supportive therapies, such as granulocyte colony-stimulating-factor and 5-HT3 antagonists. Therefore, we re-evaluated the completion and toxicity of BEP combined with modern supportive care. Methods The medical records of all 42 testicular cancer patients who received induction chemotherapy at Tsukuba University Hospital were reviewed. Toxicities during the induction chemotherapy were graded according to the Japanese CTCAE v3.0. Results Dose reduction was needed in only three patients. The subsequent chemotherapy was started at the planned 3 week interval or within 3 days of postponement in 89% of the treatment cycles. The average relative dose intensity (RDI) of bleomycin was 0.95, while that for etoposide and cisplatin was 0.97. There was no death due to toxicity. The most frequent toxicity was leukopenia (grade 3 in 44% and grade 4 in 55%). Post-chemotherapy diffusion capacity was significantly decreased in 30% of patients. Two patients developed bleomycin-induced pneumonitis, but recovered successfully. Sixteen patients received second line or salvage chemotherapy after BEP, subsequently. The overall 5 year cause-specific survival rate was 85%. Conclusion BEP with high RDIs is acceptable if combined with modern supportive care, with acceptable toxicity profile in most patients.

A 54-year-old man received combination chemotherapy with nedaplatin and irinotecan as salvage chemotherapy for refractory non-seminomatous testicular cancer. The patient developed abdominal pain and high fever on Day 21 after the initiation of chemotherapy. Computed tomography revealed thickening of the terminal ileum wall and paralytic ileus. The patient recovered with intensive supportive management including broad-spectrum antibiotics, bowel rest with gastric intubation and intravenous gamma-globulin. Neutropenic colitis has been thought to be a serious gastrointestinal complication associated with chemotherapy for hematological malignancy. The mortality rate is as high as 21-48% according to a recent review. The present case indicates that the neutropenic colitis can occur under neutropenic conditions induced by the standard-dose chemotherapy for solid cancer.

Purpose: Most patients with advanced testicular cancer can be cured with cisplatin-based chemotherapy. Therefore, the long-term effects of the treatment are clinically important. In the present study, we evaluated the serum creatinine and cholesterol levels of long-term survivors of testicular cancer. Methods: Serum creatinine and cholesterol levels were determined in 23 testicular cancer patients who had received cisplatin-based chemotherapy more than 5 years earlier. They were compared with a control group of 16 patients who did not receive chemotherapy. In addition, follow-up data of beyond 10 years after the initial treatment was obtained from 17 patients. We also analysed the trends of both serum creatinine and cholesterol determinations over 10 or more years using a generalized linear model. Results: There was no significant difference in the serum creatinine and cholesterol levels 5 years after the treatment between the chemotherapy and control groups. Analysis using a generalized linear model showed a significant trend toward an increase in serum creatinine in patients who had developed renal dysfunction during chemotherapy (P = 0.0024). The elevation of the serum creatinine level was mainly observed during the first 5 years. In addition, a significant trend toward an increase in serum cholesterol was revealed in both the chemotherapy and control groups. Conclusions: Patients who have developed renal dysfunction during chemotherapy may be at risk of gradually increasing serum creatinine levels even after it has become normal. Although further analysis is needed, we recommend long-term follow up in the survivors of metastatic testicular cancer patients treated with cisplatin-based chemotherapy.

BACKGROUND To evaluate the significance of the presence of circulating renal cell carcinoma (RCC) cells in the development of metastases, the authors extended a previous study to quantify cadherin-6 mRNA levels in association with the pattern of metastasis. METHODS Cadherin-6 mRNA levels were measured in peripheral blood samples from 66 patients with RCC, including 55 patients who had newly diagnosed RCC (43 without metastases and 12 with metastases) and 11 patients who had recurrent RCC. For quantitative polymerase chain reaction analysis, a cutoff value was determined in blood samples from 25 healthy volunteers and was verified in samples from 5 healthy controls and from 10 patients who had other malignancies. The correlation between the site of metastases and the cadherin-6 mRNA level was analyzed, and a follow-up study (median, 39 months) to track subsequent metastases was performed after patients underwent nephrectomy. RESULTS Cadherin-6 was found in 69.9% of patients with metastases and in 34.9% of patients without apparent metastases (P = 0.0099). In the group of patients with recurrent RCC, patients who had only pulmonary metastases had a significantly lower positivity rate (25.0%) compared with patients who had distant metastases (85.7%; P = 0.044). Among 43 patients with newly diagnosed RCC, 5 of 15 patients who were positive for cadherin-6 had metastases after nephrectomy, whereas only 2 of the 28 patients with negative cadherin-6 status had recurrent disease (P = 0.0398). In addition, the recurrence-free survival of patients who were positive for cadherin-6 was poorer compared with the survival of patients who were negative for cadherin-6 (P = 0.062). CONCLUSIONS The quantification of cadherin-6 mRNA in peripheral blood may be a significant predictive marker for current and future metastases. However, subsequent metastases did not always correlate with levels of cadherin-6 mRNA. This may have been due either to the small numbers of circulating tumor cells or to the low levels cadherin-6 mRNA in circulating tumor cells. Cancer 2004. © 2004 American Cancer Society.

Combination chemotherapy of methotrexate, actinomycin D and cisplatin (MAP) is reported to be effective against gestational choriocarcinoma.Eight patients with metastatic testicular cancer who had elevated beta-hCG were treated with MAP. They included three refractory cases and two relapsed cases. An additional three patients received MAP as part of the induction therapy. The MAP therapy consisted of methotrexate (10 mg/m2) on days 1-5, actinomycin D (0.01 mg/kg) on days 1-5 and cisplatin (70 mg/m2) on day 1.In all three refractory patients, MAP failed to achieve tumor marker normalization. However, the elevated tumor markers normalized after MAP in the two cases of relapse. Of these two, one patient relapsed again 7 months after MAP and was subsequently salvaged with high-dose chemotherapy. The other patient relapsed and died of the disease 30 months after receiving MAP. Of the three patients who received MAP as part of the induction chemotherapy, one with pure choriocarcinoma achieved tumor marker normalization after MAP and is still alive without disease progression. In the other two patients, MAP failed to achieve marker normalization and the patients received high-dose chemotherapy. The toxicities were mainly bone marrow suppression and mucositis, which were almost acceptable.The results demonstrated the limited efficacy of MAP as salvage therapy. In addition, the efficacy of MAP as part of induction chemotherapy was negligible. However, there might be some role for MAP as a salvage therapy for patients with pure choriocarcinoma.

Background Paclitaxel, ifosfamide and cisplatin (TIP) has been tested with successful results on metastatic testicular cancer in Western countries. Because paclitaxel, the key drug of this regimen, has not been approved for testicular cancer in Japan, there are no established data concerning TIP. The purpose of this study was to assess the feasibility of a TIP regimen for Japanese patients with advanced germ cell cancer. Methods Eight patients with advanced germ cell cancer were treated with TIP that was originally reported by Motzer et al (1). The treatment was used for three refractory cases and two late relapse cases as salvage therapy and for three poor-risk cases with extra-pulmonary visceral metastases as a part of induction chemotherapy. TIP consisted of paclitaxel 175 mg/m(2) by 24 h infusion on day 1, followed by ifosfamide 1.2 g/m(2) infusions over 2 h and cisplatin 20 mg/m(2 )given over 2 h on days 2-6. Results Five patients (62%) achieved a disease-free status after chemotherapy and surgical resection of residual tumor. Three of five patients have remained continuously free from disease progression at a median follow-up duration of 24 months and one additional patient is currently free of evidence of disease. Most patients developed grade 3 or 4 leukocytopenia and thrombocytopenia; however, they could be managed with routine supportive care. Sensory neuropathy was frequently seen, but no patient experienced over grade 3 neurotoxicity. Conclusions TIP regimen as salvage chemotherapy is feasible for Japanese patients with advanced germ cell cancer. TIP as a part of induction chemotherapy for poor-risk patients is also feasible; however, larger and longer-term follow-up studies are needed to define the role of TIP in this setting.

Multiple occurrence or recurrence after transurethral resection is an important characteristic of superficial bladder tumors. To study bladder carcinogenesis, we focused on detection of telomerase activation, which was investigated in several human cancers, including bladder tumors. We experimentally examined the telomerase activity during bladder carcinogenesis, especially in precancerous lesions, induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in rats. Male Wistar rats were given 0.05% BBN in water from the age of 8 weeks to 24 weeks. Subgroups were euthanized at 4, 8, 10, 12, 18, and 24 weeks after BBN administration. Using the stretch PCR method, telomerase activity was semiquantified in exfoliated bladder epithelial cells. In addition, telomere length in each subgroup was measured by southern hybridization for the terminal restriction fragment using a (TTAGGG)(4) probe. Statistical analyses were performed using analysis of variance and Fisher's PLSD test. Epithelial cells of normal bladder in the control groups and those of diffuse hyperplasia, which was a reversible change at 4 weeks, expressed no telomerase activity. In contrast, telomerase activity significantly increased in the stage after nodular hyperplasia, an irreversible change at 8 weeks, then elevated with carcinogenesis. However, telomere length was still preserved by the 12th week, and was shortened at 18 and 24 weeks. These results suggest that telomerase activation is probably induced independent of telomere shortening during bladder carcinogenesis in the rat, and might be a biological tumor marker of irreversible preneoplastic lesions, which evolve into bladder tumors in the rat.

Purpose: We have previously demonstrated that the AgNOR count in proliferating cells is a predictor of tumor recurrence in superficial bladder tumor (J. Urol. 162 (1999), 63–68). In the present study, we evaluate the type of AgNOR associated with cell cycles as a prognostic factor in invasive bladder tumor using a double staining technique employing both AgNOR and MIB-1 labelling.Materials and methods: Forty-four paraffin sections of invasive bladder tumors were stained simultaneously with AgNOR and MIB-1. The number of AgNORs in proliferating (MIB-1 positive) or resting (MIB-1 negative) cells were counted from a total of 100 nuclei. Correlations between MIB-1 associated AgNOR count and clinicopathological parameters were statistically analyzed.Results: The AgNOR count in proliferating cells (proliferating NOR) was significantly higher than that in resting cells (resting NOR) (p< 0.01). The resting NOR in tumors with distant metastases was significantly higher than that in tumors without metastases (p< 0.05). Patients with a low resting NOR tumor had a better prognosis than those with a high resting NOR tumor, whereas the proliferating NOR was not associated with survival. Survival analysis revealed that the resting NOR was the most powerful prognostic marker in patients with invasive bladder tumor (p< 0.05).Conclusions: Resting NOR had a predictive value in the prognosis of patients with invasive bladder tumor. Keywords: Transitional cell carcinoma, invasive, resting cell, AgNORs, MIB-1

The involvement of E-cadherin in the progression of carcinoma is supported by a large number of studies showing an inverse relationship between E-cadherin immunoreactivity and tumor aggressiveness. However, the mechanisms leading to decreased E-cadherin immunoreactivity are still unclear. Comparison of Northern blotting and immunohistochemistry in a series of 49 frozen bladder tumors revealed that, in 16 of 23 tumors with abnormal staining, clear mRNA down-regulation occurred. In the 7 cases without mRNA down-regulation, no structural anomalies of E-cadherin could be detected by Southern blotting, Western blotting or PCR-SSCP. Western blotting confirmed that, in 6 of these tumors, E-cadherin was down-regulated at the protein level. This down-regulation was accompanied by down-regulation of α-catenin and, to a lesser extent, of β- or γ-catenin. However, Northern-blot analysis indicated that expression of the 3 catenins is maintained at the mRNA level. Thus our data show that, in bladder tumors, mRNA down-regulation accounts for about two thirds (16/23) of tumors with abnormal staining and that post-transcriptional down-regulation of E-cadherin occurs in 6/23 of these tumors. Int. J. Cancer 83:591–595, 1999. © 1999 Wiley-Liss, Inc.

It has been shown in many carcinomas that the proliferation rate and number of argyrophilic nucleolar organizer regions (AgNOR) are associated with tumor aggressiveness. However, in bladder tumor the significance of the correlation between the number of AgNOR and tumor behavior remains controversial. Therefore, it would be helpful if a new technique could be developed that would allow for more accurate AgNOR counting in association with tumor behavior. We established the simultaneous staining technique of AgNOR with Ki-67 labeling to reveal the significance of AgNOR count in superficial bladder tumor.A total of 50 paraffin sections of superficial bladder tumor were stained with AgNOR and Ki-67 (MIB-1). The numbers of AgNORs in proliferating (MIB-1 positive) or resting (MIB-1 negative) cells were counted from a total of 100 nuclei. Correlations between MIB-1 associated AgNOR count and clinicopathological parameters were statistically analyzed.The AgNOR count in proliferating cells was significantly higher than that in resting cells (p0.01), and the count significantly increased with tumor grade (p0.01). Based on recurrence-free survival analyses the local recurrence rate was significantly higher in patients with high proliferating cell NOR but not for those with resting or whole cells. However, no AgNOR score helped to select patients at high risk for disease progression.Proliferating cell NOR had a predictive value for local recurrence in patients with superficial bladder tumor.

A 69-year-old man was hospitalized for treatment of a left renal tumor. The tumor had originally been demonstrated as a simple renal cyst 4 years before. However, the size of the tumor decreased, and at the time of hospitalization, the tumor showed a solid, papillary component that was enhanced by contrast medium on computed tomography (CT) and had high signal intensity on T2-weighted magnetic resonance imaging (MRI). We diagnosed this tumor as a cystic renal cell carcinoma of the left kidney, cT1aN0M0, arising from the epithelium of a renal cyst, and performed a left partial nephrectomy. The pathological diagnosis was cavernous hemangioma of the left kidney. Generally, it is difficult to diagnose a cavernous hemangioma of the kidney preoperatively. This case is unusual because the configuration of this tumor changed within a few years. When we find a renal cyst with a solid component, renal cavernous hemangioma arising from the cyst wall should be considered in the differential diagnosis, and a conservative surgical approach should be considered.

The number of nucleolar organizer regions (NOR) of human bladder cancers was evaluated at the light- and electron-microscopic level. The average number of argyrophilic NOR (AgNOR), stained by the one-step silver colloid method, was measured in benign and malignant urothelial cells in the human urinary bladder using a light microscope. The average number of nucleolar fibrillar centers (FC) per nucleus was also calculated by quantitative ultrastructural morphometry in the specimens from the same patients. Statistical evaluations revealed that the average number of AgNOR per nucleus was significantly correlated with the elevation of tumor grade and stage (p < 0.05). An average FC number per nucleus also increased in association with tumor grade and stage (p < 0.05). Although the average number of FC was 5.6 times higher than that of AgNOR, the correlation between the average number of FC and AgNOR was statistically significant. In conclusion, these results suggested that the silver staining method was a useful and convenient tool for the evaluation of the differentiation and invasive potential of bladder cancer cells at the light-microscopic level.

Splenogonadal fusion is a rare congenital anomaly. We report herein a case of splenogonadal fusion associated with contra lateral testicular aplasia, and review the etiology, pathogenesis and management of this rare disease. As far as we know, this is the first reported case of splenogonadal fusion associated with testicular aplasia.

During the progression of many cancers, cell‐cell adhesion molecules, e.g., E-cadherin (EC), may be down-regulated. In a number of carcinomas, EC has been described as an independent prognostic variable. We have studied the expression of adhesion molecules participating in cadherin‐catenin complexes in renal cell carcinoma (RCC) specimens. Expression of EC, catenins and p120cas protein was examined in frozen tissue of 90 RCC specimens by immunohistochemistry, and these molecules were evaluated for their significance as prognostic markers. Staining was scored as normal (homogeneously positive at cell‐cell borders) or abnormal (heterogeneous or absent). A significant correlation between poor survival and decreased expression of a-, b -o r g-catenin was observed, whereas no association between survival and EC or p120cas expression was seen. Cox’s proportional hazard regression analysis showed that in patients with pT1-3N0M0 disease, reduced a-catenin expression correlated with poor survival, suggesting that a-catenin expression might be an independent prognostic indicator for patients of this group. Int. J. Cancer 74:523‐528, 1997. r 1997 Wiley-Liss, Inc.

We report a case of a 60-year-old man with necrotizing fasciitis complicated by streptococcal toxic shock syndrome. The patient had received high-dose chemotherapy and radiotherapy to the pelvis for relapsed seminoma 7 years previously. He had been in long-term remission. He was admitted to the Tsukuba University Hospital, Tsukuba-City, Ibaraki, Japan, with complaints of fever and localized erythema over the foreskin. The patient suffered from septic shock and multiple organ failure. Despite intensive care, he died 18 h after admission. Streptococcus pyogenes was isolated from both the wound and blood culture. To our knowledge, this is the first description of necrotizing fasciitis primarily affecting the penile skin.