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Background/aim Expression of human leukocyte antigen (HLA) class I and II and CD74, which functions as a chaperone of MHC class II, play essential roles in T-cell recognition. The aim of this study was to elucidate the association between the HLAs and CD74, and their correlation with the infiltrated immune cells in renal cell carcinoma (RCC). Materials and methods We retrospectively investigated the expression of HLA-A/B/C, HLA-DR, and CD74 in 38 patients with advanced RCC (T3/T4), and evaluated their correlations with CD4 and CD8-positive T-cell infiltration using immunohistochemistry. Results The expression of HLA-A/B/C, HLA-DR, and CD74 on cancer cells was observed in 37, 20, and 31 patients, respectively. The density of CD8- and CD4-positive T cells showed a positive correlation with HLA-DR expression. The density of CD4-positive lymphocytes was significantly associated with CD74 expression. Conclusion The expression of HLA-DR, rather than CD74, on cancer cells was potentially associated with the anti-cancer immune microenvironment.

Background and Objectives: This study’s objective was to examine patients treated with robot-assisted radical prostatectomy (RARP) for intermediate-risk prostate cancer (IR-PCa), and to identify preoperative risk factors for biochemical recurrence (BCR) in these patients in Japan. Materials and Methods: We conducted a retrospective multicenter cohort study of patients with PCa who underwent RARP at 10 institutions in Japan. A total of 3195 patients were enrolled in this study. We focused on patients with IR-PCa who underwent RARP. We obtained data on pre- and postoperative covariates from the enrolled patients. Biochemical recurrence-free survival was the primary endpoint of this study. We also identified useful preoperative predictive factors for BCR in patients with IR-PCa after RARP. Results: A total of 1144 patients with IR-PCa were enrolled in this study. The median follow-up period was 23.7 months. At the end of the follow-up period, 94 (8.2%) patients developed BCR. The 2 and 3 year biochemical recurrence-free survival (BRFS) rates were 92.2% and 90.2%, respectively. Using the Kaplan–Meier method, Gleason grade (GG) 3 was significantly associated with poor BRFS compared with ≤GG 2. In multivariate analysis, GG 3 was a significant predictive factor for BCR in patients with IR-PCa. Conclusions: The results of the study indicated a significant relationship between GG 3 and post-RARP BCR in patients with IR-PCa.

A 69-year-old man underwent renal transplantation due to chronic renal failure of unknown cause in 1991. Furthermore, in 2012 he again underwent renal transplantation due to renal graft dysfunction with focal segmental glomerulosclerosis. After the second renal transplantation, his renal function has been stable. In 2019, he presented to the urology department with gross hematuria. Cystoscopy revealed a 2 cm vesical calculus at the dome of the bladder near the right lateral wall. Therefore, we performed transurethral lithotripsy using the holumium laser method. The vesical calculus was crushed, revealing a suture at the center, suggesting the suture as the cause. We tried to remove the suture during operation, however, it was impossible. Although the remaining suture posed a risk for calculus development, there has been no recurrence of a calculus for 6 months after the operation. This case reports a vesical calculus at the ureterovesical anastomotic site, wherein the core was an absorbable suture used during the initial renal transplantation. It should be taken into consideration that there is a possibility of anastomotic calculus occurrence with absorbable sutures, even long after renal transplantation.

We aimed to examine the relationship between D'Amico intermediate-risk and pathological grade group 1 (pGG1) after robot-assisted radical prostatectomy (RARP).In this retrospective multicenter cohort study, D'Amico intermediate-risk prostate cancer patients who did not receive neoadjuvant therapy, and underwent RARP at 10 institutions in Japan were examined for preoperative factors associated with pGG1.In total, we enrolled 1161 D'Amico intermediate-risk prostate cancer patients. The pGG1 and pGG ≥2 groups comprised 73 (6.3%), and 1088 (93.7%) cases, respectively. Biochemical recurrence-free survival (BCRFS) of the pGG1 group was equivalent to that of the D'Amico low-risk patients. Among the 3 D'Amico intermediate-risk factors (IRF), the pGG1-rate was 24% with prostate-specific antigen (PSA) of 10 to 20 ng/mL alone, and 30% with cT2b alone. Both groups had significantly higher pGG1-rates than other groups. Down-grading from biopsy GG ≥2 to pGG1 was relatively rare (3.9%). Patients with pGG1 were further stratified by prostate volume (PV) (cutoff, 40 cc) among patients with one IRF and PSA of 10 to 20 ng/mL. Patients with one IRF, PSA of 10 to 20 ng/mL, and PV40 cc had a relatively good BCRFS similar to that of the D'Amico low-risk group.Among intermediate-risk prostate cancer patients, those with pGG1 have a good prognosis. Downgrading from biopsy GG ≥2 is rare, and definitive treatment may be recommended for patients with biopsy GG ≥2. Patients with one IRF, PSA of 10 to 20 ng/mL, and PV40 cc who are eligible for RARP may be candidates for active surveillance.

We evaluated oncological outcomes of patients undergoing robot-assisted radical prostatectomy (RARP) for prostate cancer (PCa) and their perioperative complications in Japan. We investigated clinical and pathological covariates to predict biochemical recurrence (BCR) after RARP.A retrospective multicenter cohort study was conducted in RARP patients with PCa at 10 institutions in Japan. Pre- and postoperative covariates were collected from enrolled patients. The primary endpoint was defined as biochemical recurrence-free survival (BRFS). Additionally, the association between BCR and clinicopathological covariates was determined.We enrolled 2670 patients in this study. The median follow-up period was 26.0 months. RARP-related perioperative complications were identified in 198 patients (7.4%), including 69 patients (2.6%) with grade 3/4 complications according to the Clavien-Dindo classification. The 2-year BRFS was 88.0%. Using the Kaplan-Meier method, initial prostate-specific antigen (PSA) level of ≤7.6 ng/mL, biopsy and pathological Gleason score (GS) of ≤7, clinical and pathological T1/2, and low/intermediate risks according to the National Comprehensive Cancer Network risk classification, and negative surgical margin status had significant BRFS than their counterparts. In multivariate analysis, initial PSA, biopsy and pathological GS, clinical and pathological T stage, and surgical margin status significantly correlated with BCR after RARP.In this study, RARP achieved a lower incidence of perioperative complications than other studies.

Background Sarcoidosis is a multisystem inflammatory disorder and can affect any organ; however, ureteric involvement is extremely rare with only four cases reported in the literature to date, all of which were diagnosed with surgical ureteral resection including a nephroureterectomy. This study reports the first case of ureteric sarcoidosis controlled with medical therapy where a differential diagnosis was performed based on the diagnostic clue of hypercalcemia. A definitive diagnosis was established without surgical resection of the ureter. Case presentation A 60-year-old man presented with anorexia and weight loss. Blood tests showed renal dysfunction and hypercalcemia. Computed tomography revealed left hydronephrosis associated with left lower ureteral wall thickening, which showed high signal intensity on diffusion-weighted magnetic resonance imaging. Similarly, we detected a bladder tumor on cystoscopy, and a 2-cm-long stenosis was revealed by retrograde ureterography; therefore, ureteral cancer was suspected. Meanwhile, considering the clinical implication of hypercalcemia, a differential diagnosis of sarcoidosis was established based on elevated levels of sarcoidosis markers. Fluorodeoxyglucose positron emission tomography showed fluorodeoxyglucose accumulation in the left lower ureter, skin, and muscles, suggestive of ureteric sarcoidosis with systemic sarcoid nodules. For a definitive diagnosis, transurethral resection of the bladder tumor and ureteroscopic biopsy were performed. Histopathological examination revealed ureteric sarcoidosis with bladder urothelial carcinoma. Following an oral administration of prednisolone, hypercalcemia instantly resolved, the renal function immediately improved, and the left ureteral lesion showed complete resolution with no recurrence. Conclusions In this case, the co-occurrence of ureteral lesion with bladder tumor evoked a diagnosis of ureteral cancer. However, considering a case of ureteral lesion complicated with hypercalcemia, assessment for differential diagnosis was performed based on the calcium metabolism and sarcoidosis markers. In cases of suspected ureteric sarcoidosis from the assessment, pathological evaluation with ureteroscopic biopsy should be performed to avoid nephroureterectomy.

Selective identification of men with clinically significant prostate cancer (sPC) is a pivotal issue. Development of a risk model for detecting sPC based on the prostate imaging reporting and data system (PI-RADS) for bi-parametric magnetic resonance imaging (bpMRI) and clinical parameters in a Japanese cohort is expected to prove beneficial. We retrospectively analyzed clinical parameters and bpMRI findings from 773 biopsy-naïve patients between January 2011 and December 2016. A risk model was established using multivariate logistic regression analysis and presented on a nomogram. Discrimination of the risk model was compared using the area under the receiver operating characteristic curve. Statistical differences between the predictive model and clinical parameters were analyzed using DeLong test. sPC was detected in 343 men (44.3%). Multivariate logistic regression analysis to predict sPC revealed age (P = 0.002), log prostate-specific antigen (P P P P

Two patients with late recurrence of renal cell carcinoma were observed long term without treatment. Case 1 is an 83-year-old woman who underwent right nephrectomy at 57 years of age following a renal tumor diagnosis. Histopathological results revealed clear cell renal cell carcinoma, G2, pT1aN0M0. Pancreatic metastasis developed at age 71, and pancreatic tail excision was performed. A metastatic lesion appeared again at the head of the pancreas at age 74. The patient has been followed by observation only for 9 years without any new lesions. Tumor doubling time calculated from abdominal ultrasonography was 13.3 months.Case 2 is a 91-year-old male. At 78 years of age, right nephrectomy and inferior vena cava tumor embolectomy were performed for renal tumor. Histopathological results revealed clear cell renal cell carcinoma, G2, pT3bN0M0. Left adrenal metastasis appeared at age 84, and the patient has been followed for 7 years without new lesions. Tumor doubling time calculated from abdominal computed tomography (CT) images was 14.1 months.In both patients, no symptoms due to tumor recurrence ever appeared, and their activities of daily living (ADL) were maintained fairly well. In the case of solitary late recurrence in elderly renal cancer patients, observation may be a treatment option that avoids adverse effects and complications caused by treatment. In addition, it appears possible to predict the need for subsequent treatment by calculating the doubling time using several sequential CT images obtained after recurrence. If a new recurrent metastatic lesion appears or if the doubling time during a 2-to 3-year follow-up period is relatively short, however, new treatment should be considered without delay.

Background To assess the prophylactic efficacy of postoperative single intravesical instillation with pirarubicin (THP) and mitomycin C (MMC) for low-risk non-muscle-invasive bladder cancer (NMBC). Patients and methods A total of 103 clinically low-risk NMBC patients were preoperatively randomized into either THP (n=49) or MMC (n=54) groups. The primary endpoint was recurrence-free survival. Results The median follow-up periods of the THP and MMC groups were 955 and 1008 days, respectively (p=0.76). Twelve patients (24.5%) in the THP group and 7 (13%) in the MMC group had bladder cancer recurrences. The two-year recurrence-free survival of the THP group and the MMC group was 77.8% and 86.4%, respectively (p=0.20). Neither groups had severe toxicity. Conclusion In low-risk NMBC, the prophylactic effect against postoperative single intravesical instillation with THP was not superior to that with MMC.

The aim of this study was to investigate the efficacy and safety of tadalafil add-on therapy with αPatients with persistent storage symptoms refractory to αOf the 75 patients recruited to the study, 38 and 37 were assigned to the tadalafil and solifenacin groups, respectively. There were no significant difference in baseline characteristics between the two groups. The change in the amount of residual urine volume was significantly larger in the solifenacin- than tadalafil-treated group; other parameters, including lower urinary tract symptoms and uroflowmetry measures, did not differ significantly between the two groups. Seven (18%) and 12 (32%) patients in the tadalafil and solifenacin groups, respectively, discontinued treatment because of adverse events. The main reasons for discontinuation in the tadalafil group were stomach discomfort or nausea and dizziness or vertigo; voiding difficulty and constipation were the main reasons for discontinuation in the solifenacin group. There was no significant difference in blood pressure fluctuations from baseline between the two groups.Tadalafil add-on therapy was not inferior to solifenacin add-on therapy in terms of effect and safety. Therefore, tadalafil could be an alternative add-on drug for patients with persistent lower urinary tract symptoms refractory to α

Objective: To determine the diagnostic accuracy of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for detecting metastasis and its impact on patient management with upper tract urothelial carcinoma (UTUC). Patients and Methods: Consecutive patients with UTUC underwent 18F-FDG PET/CT after CT for initial staging (n = 47) and for restaging at recurrence (n = 9). Diagnostic accuracy for detecting metastases with PET/CT and CT was compared statistically. The impact of PET/CT on patient management was assessed by comparing questionnaires that were completed by the attending physicians before and after PET/CT. Results: In the lesion-based analysis, 142 lesions were diagnosed as metastases. The sensitivity of PET/CT was significantly better than that of CT (85 vs. 50%, p = 0.0001). In the patient-based analysis, 22 patients were diagnosed as having metastases. The sensitivity/specificity/accuracy of PET/CT tended to be superior to those of CT, but these values were not significantly different (95, 91, and 93% vs. 82, 85, and 84%; p = 0.25, 0.50, and 0.063, respectively). The clinicians changed their assessments of disease extent and management plans in 18 (32%) and 11 (20%) patients, respectively, based on the PET/CT results. Conclusions: The diagnostic accuracy of PET/CT for detecting metastasis was superior to that of CT. PET/CT provided additional information to the CT-based staging, which had an impact on patient management.

To determine the indications for post-chemotherapy consolidative surgery in patients with clinical lymph node (LN) metastatic (cN+) urothelial carcinoma (UC). Sixty UC patients with measurable cN+ but without detectable systemic visceral/bone dissemination received induction platinum-based chemotherapy. Consolidative surgery was offered to all patients except for those with progressive disease. We retrospectively analyzed the clinicopathological response to induction chemotherapy and identified prognostic factors for overall survival (OS). The primary cancer site was the urinary bladder in 31 patients (52 %) and upper urinary tract in 29 (48 %). The median number of chemotherapy courses was 4. Forty-five patients (75 %) showed a clinically objective response to the induction chemotherapy. Fifty-one patients (85 %) underwent subsequent consolidative surgery. Histopathological analysis indicated pT0 status in 10 (20 %) and pN0 in 17 (33 %). When all 60 patients were considered, clinical tumor response was found to be significantly correlated with achievement of pathological complete response. At the median follow-up of 22 months, the median progression-free survival and OS periods were excellent: 18.6 and 31.6 months, respectively. In the multivariate analysis, clinical tumor response was found to be an independent pre-surgical prognostic factor for OS, and pathologically negative lymph node, negative resection margin, more LNs removed, and negative lymphovascular invasion were found to be independent post-surgical prognostic parameters for OS. The median OS in induction chemotherapy followed by consolidative surgery was very encouraging. Our results suggest that achieving a good clinical response to pre-surgical induction chemotherapy is a good indication for subsequent consolidative surgery in UC patients with cN+ to improve OS through a good pathological response.

Objective To assess the change in disease-specific health-related quality of life and to evaluate patient-perceived satisfaction after radical prostatectomy (RP) or intensity-modulated radiotherapy (IMRT) with androgen deprivation therapy (ADT) for patients with high-risk prostate cancer (PCA) that has been defined by the European Association of Urology guideline. Methods Between 2006 and 2010, 150 patients with high-risk PCA who underwent either RP (n = 97) or IMRT with ADT (n = 53) were enrolled in this prospective health-related quality of life study. Disease-specific health-related quality of life at baseline, 3, 6, 12, and 24 months and patient-perceived satisfaction at 12 and 24 months after these treatments were estimated using the Expanded Prostate Cancer Index Composite. Results Urinary bother and irritation and obstruction scores did not change significantly between both treatment groups throughout the 2-year follow-up. ADT greatly influenced sexual and hormonal functions and bothers in patients who received IMRT with ADT. The patient-perceived satisfaction at 12 months after the treatments was approximately 80% in both treatment groups, and there was no significant difference between the 2 groups. At 12 months after the treatments, urinary function ( P = .001) was identified as the most significant predictor of patient-perceived satisfaction, although it was not associated with the treatment type. Conclusion The majority of patients with high-risk PCA who received RP or IMRT with ADT reported high patient-perceived satisfaction after the treatments. This study showed that improvement in urinary function might contribute to patient-perceived satisfaction after the treatments.

Resection of metastatic lesions (metastasectomy) is performed for highly selected patients with metastatic urothelial carcinoma (mUC). This study aimed to identify the clinicopathologic factors associated with oncologic outcome for patients who underwent metastasectomy for mUC. This analysis included 37 UC patients who underwent metastasectomy with curative intent at nine Japanese hospitals. The primary end point was cancer-specific survival. The Kaplan–Meier method with the log-rank test and the multivariable Cox proportional hazards model addressed the relationship between clinical characteristics and survival. Metastasectomy was performed for pulmonary (n = 23), nodal (n = 7), and other (n = 7) metastases. The median survival time was 35.4 months (interquartile range [IQR] 15.5, not reached) from the detection of metastasis and 34.3 months (IQR 13.1, not reached) from metastasectomy. The 5-year cancer-specific survival rate after detection of metastasis was 39.7%. In the multivariate analysis, the time from primary surgery to detection of metastasis (time-to-recurrence [TTR]) of 15 months or longer (hazard ratio [HR] 0.23; p = 0.0063), no symptoms of recurrence (HR 0.23; p = 0.0126), and serum C-reactive protein (CRP) levels lower than than 0.5 mg/dl (HR 0.24; p = 0.0052) were significantly associated with better survival. Long-term survival could be achieved for some patients with mUC who underwent metastasectomy. Lung and lymph nodes were predominant sites for metastasectomy. Symptoms, TTR, and CRP value were identified as associated with survival and should be taken into account when metastasectomy is considered.

Objectives To assess the detection rate of putative Lynch syndrome-associated upper urinary tract urothelial cancer among all upper urinary tract urothelial cancers and to examine its clinicopathological characteristics. Methods A total of 143 patients with upper urinary tract urothelial cancer who had received total nephroureterectomy were immunohistochemically stained for the expression of mismatch repair proteins MLH1, PMS2, MSH2 and MSH6. For all suspected mismatch repair-deficient cases, MMR genetic testing was recommended and clinicopathological features were examined. Results Loss of mismatch repair proteins was found in seven patients (5%) who were thus categorized as putative Lynch syndrome-associated upper urinary tract urothelial cancer. Five of these patients showed dual loss of MSH2/MSH6. Two patients were confirmed to be MSH2 germline mutation carriers. Histologically, all seven tumors were low-grade atypical urothelial carcinoma and showed its unique histological features, such as an inverted papilloma-like growth pattern and a villous to papillary structure with mild stratification of tumor cells. Six tumors had no invasion of the muscularis propria. No recurrence or cancer-related deaths were reported in these seven patients. Just three patients met the revised Amsterdam criteria. Conclusions This is the first report that universally examined mismatch repair immunohistochemical screening for upper urinary tract urothelial cancers. The prevalence (5%) of putative Lynch syndrome-associated upper urinary tract urothelial cancers is much higher than we had expected. We ascertained that putative Lynch syndrome-associated upper urinary tract urothelial cancers were clinically in the early stage and histologically classified into low-grade malignancy with its characteristic pathological features. The clinicopathological characteristics that we found in the present study could become additional possible markers in the diagnosis of Lynch syndrome-associated upper urinary tract urothelial cancers.

Objective To evaluate the long-term effect of the processus vaginalis transection method, which we previously developed to prevent postradical prostatectomy inguinal hernia. Methods Our hernia prevention procedure is designed to prevent postoperative indirect hernias. The procedure is performed in the following order: (1) the spermatic cord is isolated and mobilized in the pelvis, (2) the vas deferens is isolated from the spermatic cord and ligated, and (3) the processus vaginalis is dissected free of the other spermatic cord elements, mainly spermatic vessels, ligated near the peritoneum, and transected. Between February 2006 and August 2008, 435 consecutive patients underwent the inguinal hernia prevention procedure concurrently with open radical retropubic prostatectomy. The control group comprised 433 patients who had undergone radical retropubic prostatectomy without hernia prevention immediately before the introduction of this hernia prevention procedure was introduced (between January 2001 and January 2006). Results No significant complications associated with the hernia prevention procedure were observed, except for a few minor peritoneal injuries that were easily repaired during surgery. An inguinal hernia developed postoperatively in 109 of the 433 control patients (25.2%) during the median follow-up of 68 months. In contrast, 4 of the 435 patients (0.9%) who underwent the hernia prevention procedure developed an inguinal hernia during the median follow-up of 42 months. Conclusion The processus vaginalis transection method is safe and effective in the long-term prevention of postradical prostatectomy inguinal hernia.

This study investigated the significance of urological surgical intervention for viral hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 1, 024 patients underwent allo-HSCT at our medical center between January 2006 and July 2014. In the 6 patients (0.58%) who required urological surgical treatment for viral HC, we retrospectively analyzed patient characteristics and outcomes. Two patients underwent nephrostomy for bilateral hydronephrosis due to bladder tamponade. One of these patients showed no improvement in renal function, graft versus host disease worsened and he died on postoperative day (POD) 5. The other patient displayed improved renal function but hematuria did not improve, and total cystectomy was required. To control bleeding, we performed transurethral electrocoagulation (TUC) on 3 patients, and total cystectomy was performed on 2 patients. All 3 patients who underwent TUC had BK virus HC. Two of these patients experienced marked improvement in hematuria from immediately after surgery. Hemostasis was only temporary in the other patient, who eventually died due to septicemia on POD 24. The 2 patients who underwent total cystectomy had adenovirus HC. Both experienced secondary hemorrhage postoperatively and required further surgery. Eventually, one died due to postoperative bleeding on POD 1, and one died due to postoperative pneumonia on POD 57. Urological surgical treatment for HC was effective in some cases, but the ultimate outcome greatly depends on the general condition of the patient and treatment of the underlying hematological disorder. TUC may be considered for HC (particularly BK virus HC), but total cystectomy (especially inaden ovirus HC) should be avoided.

Objectives To investigate the intratumoral heterogeneity of BAP1 and PBRM1 expression at the primary site and metastatic sites and to evaluate whether BAP1 and PBRM1 expression in metastatic sites of clear cell renal cell carcinoma (ccRCC) has prognostic value. Methods and materials We collected paired samples from the primary site and the first metastatic site in 41 patients with ccRCC. Immunohistochemistry analyses were performed for the expression of BAP1 and PBRM1 proteins. We retrospectively analyzed the associations between the expression of BAP1 and PBRM1 and overall survival (OS). Results The most common first metastatic sites were lung (68.3%) and lymph node (12.2%). BAP1 protein expression was negative in 8 (19.5%) primary sites and in 11 (26.8%) metastatic sites. PBRM1 protein expression was negative in 9 (22.0%) primary sites and in 11 (26.8%) metastatic sites. The incidences of intratumoral heterogeneity for BAP1 and PBRM1 protein expression in primary/metastatic sites were 9.8%/2.4% and 24.4%/7.3%, respectively. The concordance rates between primary and metastatic sites for BAP1 and PBRM1 protein expression were 82.9% and 63.4%, respectively. Median OS from the first occurrence of metastasis in patients with BAP1-positive and BAP1-negative metastatic sites were 97 months (95% CI: 58–136) and 51 months (95% CI: 13–82), respectively (P = 0.0077). Median OS in patients with PBRM1-positive and PBRM1-negative metastatic sites were 82 (95% CI: 42–97) and 120 (95% CI: 52–120) months, respectively (P = 0.25). Conclusion Intratumoral heterogeneity of BAP1 protein expression is more frequent in primary tumor than in metastatic sites. The loss of BAP1 protein expression in metastatic sites predicts poor prognosis in patients with ccRCC.

Background The role of lymph node dissection (LND) for upper tract urothelial carcinoma (UTUC) patients remains controversial. The aim of this study was to evaluate the effect of LND on clinical outcomes during radical nephroureterectomy (RNU) and to determine prognostic factors of survival. Patients and Methods From 1985 to 2013, 404 patients with UTUC underwent RNU; 5 patients who received neoadjuvant chemotherapy were excluded. Among them, 182 (46%) were pathologically negative for lymph node metastasis (pN0), 177 (44%) were non-LND (pNx), and 40 (10%) were positive for lymph nodes metastasis (pN1/2). Results The 5-year disease-free survival (DFS) and cancer-specific survival (CSS) rate were higher in pN0 patients than in pNx patients and in pN1/2 patients. According to multivariate analysis, non-LND was an independent predictive factor of DFS (hazard ratio [HR], 1.91; P = .004) and CSS (HR, 2.28; P = .003). In the subgroup with muscle-invasive UTUC, the 5-year DFS and CSS rates were higher in pN0 patients than in pNx patients. However, there was no statistical difference between pN0 and pNx groups in terms of DFS and CSS in the pT2 cases. DFS and CSS times were significantly prolonged in the pN0 group in the locally advanced UTUC patients (≥pT3). Conclusion In the ≥pT3 subgroup, the 5-year DFS and CSS were significantly prolonged in the pN0 group, but there were no statistical differences between pN0 and pNx groups in terms of DFS and CSS in the pT2 subgroup. LND for patients with locally advanced UTUC might improve disease prognosis.

Objective: The RENAL nephrometry scoring system characterizes tumors according to their size, growth pattern, location and nearness to the renal sinus or collecting system. The current study aims to evaluate the RENAL nephrometry scoring system in adopting nephron-sparing surgery (NSS) for cT1 renal cancer. Methods: Clinicopathological data of 200 consecutive patients who had undergone radical nephrectomy (RN) or NSS for clinical stage T1 renal cell cancer at our single institution during 2005-2009 were investigated retrospectively. Results: Of 200 patients, 103 were scheduled for RN, whereas 97 were planned to undergo NSS, 9 of whom actually underwent RN. Those who were planned to undergo NSS were younger and had smaller tumors (p < 0.001). The median RENAL score was significantly lower among those who were originally assigned to NSS (5, range 4-10) versus RN (8, range 4-11) (p < 0.001). Three months after surgery, the renal function of patients who had been scheduled for NSS was significantly better than in those treated by RN (p < 0.001). Conclusions: This study suggests that the RENAL nephrometry scoring system is a useful tool in adopting NSS for cT1 renal cancer and that objective decision-making for NSS was possible.

C-reactive protein (CRP) was an independent prognostic factor for metastatic renal cell carcinoma in the cytokine era. However, the impact of CRP on the survival of metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors has not yet been investigated. Therefore, we further evaluated the prognostic impact of CRP for patients with metastatic renal cell carcinoma treated with molecular-targeted agents of tyrosine kinase inhibitors.Fifty-two patients were treated with tyrosine kinase inhibitors for metastatic renal cell carcinoma at our institution. Overall, 31 and 21 patients were administered sunitinib and sorafenib, respectively. The prognostic value of all variables, including CRP, for overall survival was assessed using the Cox proportional hazards model.The median baseline CRP level was 4.9 mg/l. In multivariate analysis, CRP was an independent predictor for overall survival as both continuous and categorical variable. The median overall survival times of patients with non-elevated CRP concentration (8 mg/l) were not reached, compared with those of patients with elevated CRP concentration (8 mg/l or greater) of 15.9 months. There was a significant difference in overall survival rates between the two groups, with 1- and 3-year overall survival rates of 92.8 and 69.3% versus 50.2 and 22.9% for the non-elevated CRP group and the elevated CRP group (p = 0.003), respectively.CRP has a significant impact on overall survival of patients with metastatic renal cell carcinoma carcinoma treated with tyrosine kinase inhibitors.

We analyzed the pathological findings, surgical margin, the first site of local or distant recurrence, treatment for postoperative recurrence and the characteristics of 25 patients who were surgically treated for retroperitoneal sarcomas between December 2000 and January 2014. The median tumor diameter was 11 cm. The pathological diagnosis was liposarcoma (n = 14), leiomyosarcoma (n = 7) and others (n = 4). Tumors were resected en-bloc with adjacent organs in 17 of the patients. In median follow up period of 39 months, 11 of the 14 patients with liposarcoma experienced local tumor recurrence and distant metastasis did not precede local recurrence in any of these patients. Leiomyosarcoma recurred in all patients and distant metastases appeared before local recurrence in four of them. The five-year recurrence-free and over all survival rates were 28 and 58%, respectively. The recurrence-free and overall survival rates significantly differed between well-differentiated and other subtypes of liposarcoma (both p0.05). The overall survival was significantly better for patients with a tumor diameter of11 cm than for those with ≥ 11 cm (p 0.05). Furthermore, overall survival was significantly better for patients who were able to undergo re-operation at the time of recurrence than for those who could not (p0.005). Although we resected adjacent organs when the margin was insufficient, the rate of local recurrence was high in liposarcoma. On the other hand, the rate of distant metastasis was high in leiomyosarcoma.

Objective: It was the aim of this study to assess the outcome of prostate cancer patients with preoperative prostate-specific antigen (PSA) levels ≧100 ng/ml who were treated with antegrade radical prostatectomy with intended wide resection (aRP). Patients and Methods: Eighteen patients who underwent aRP had an initial PSA level ≧100 ng/ml. Overall survival, disease-specific survival and biochemical progression-free survival (bPFS) rates were determined, and predictors of treatment outcome were examined. Results: The median serum PSA level was 159.5 ng/ml. All patients but one had received neoadjuvant androgen deprivation therapy (ADT), while only 2 patients received adjuvant ADT. Five patients were classified as stage pT2, 6 as pT3a, 6 as pT3b and 1 as pT4. Four patients had locoregional lymph node metastases. Twelve patients developed PSA failure. Eight of them received salvage ADT. The estimated 10-year bPFS rate was 25.0% and the overall survival and disease-specific survival rates were 92.9 and 100%, respectively, at a median follow-up of 6 years. Multivariate analysis revealed only the clinical stage to be predictive of bPFS based on preoperative variables. On the other hand, surgical margin status, extracapsular extension and organ-confined disease were identified as being significant postoperative predictors. Conclusions: This study showed a comparatively satisfactory outcome for clinically non-metastatic prostate cancer with PSA levels ≧100 ng/ml treated by aRP.

Objectives Renal cell carcinoma (RCC) is characterized by a propensity for extension into the renal vein and inferior vena cava (IVC) and is associated with poor prognosis. BAP1 mutation, which occurs in about 15% of patients with clear cell RCC (ccRCC), also predicts poor prognosis. The aim of this study was to elucidate the association between BAP1 protein expression and clinicopathological outcomes in patients with nonmetastatic ccRCC with an IVC tumor thrombus (IVCTT). Material and methods Thirty-five patients with nonmetastatic ccRCC with an IVCTT who underwent radical nephrectomy and tumor thrombectomy at our institution from 1999 to 2010 were retrospectively evaluated. Immunohistochemical (IHC) analyses were performed for the expression of BAP1 protein, and the associations between the expression of BAP1 and clinical outcomes were assessed. Survival analyses were performed using the Kaplan-Meier method and log-rank test. Multivariate analyses of the associations between disease-free survival (DFS) and clinical variables including BAP1 protein expression, tumor size, Karnofsky performance status (KPS) score, and the extension level of the tumor thrombus were performed using a Cox proportional hazard model. Results The median follow-up time was 58.8 months (range: 2–130 months). The median age was 68 years (range: 37–80 years). The median size of the primary tumor was 9.6 cm (range: 3.0–15.0 cm). The IVCTT extended above and below the diaphragm in 10 (28.6%) and 25 (71.4%) patients, respectively. The KPS score was>80 in 23 patients (65.7%). BAP1 protein expression on IHC was positive in 24 cases (68.8%) and negative in 11 cases (31.2%). The median overall survival in cases with BAP1-negative and -positive tumor on IHC staining were 44.7 and 81.5 months, respectively (P = 0.052). BAP1-negative tumor on IHC staining was associated with a significantly shorter DFS than BAP1-positive tumor (median DFS = 10.0 vs. 26.0 months, respectively; P = 0.011). Multivariate analysis showed that only BAP1-negative tumor on IHC staining was significantly associated with shorter DFS (P = 0.004). Conclusions Patients whose tumors had loss of BAP1 protein expression were significantly associated with poor prognosis in patients with ccRCC with an IVCTT who underwent radical nephrectomy and tumor thrombectomy.

OBJECTIVE To investigate the longitudinal alteration of health-related quality of life (HRQL) up to 5 years after radical perineal prostatectomy (RPP) among Japanese patients with localized prostate cancer. PATIENTS AND METHODS In all, 194 patients who had RPP were included in this longitudinal survey. The validated RAND 36-Item Health Survey (SF-36) and the University of California, Los Angeles Prostate Cancer Index (UCLA-PCI) were used to evaluate the HRQL. RESULTS Among the UCLA-PCI urinary domains, urinary function scores decreased at 3 months after RPP, but they increased 6 months after RPP. Likewise, urinary bother showed a transient decrease at 3 months, but had returned to the baseline level 6 months after RPP. Sexual function (SF) was drastically decreased at 3 months after RPP, but had slightly increased 1 year after RPP. Patients who had a nerve-sparing (NS) RPP showed better SF-related HRQL than those who did not at 6 months after RPP. This favourable alteration involving SF-related HRQL was closely associated with the NS procedure, but not with the patient age. Multivariate analysis showed that later recovery of SF was essentially related to the use of NS RPP, while early recovery of sexual bother was closely related to the patient age. CONCLUSIONS Our results confirmed the positive effect of RPP on the long-term HRQL in Japanese patients. Although NS surgery conferred the benefit of the recovery of SF, older Japanese patients were not greatly concerned about their decreased SF-related HRQL. The current results provide primary evidence for predicting the alteration of HRQL and understanding the effect of patient age and NS surgery on HRQL after RPP.

We hypothesized that the administration of the superoxide dismutase (SOD) mimetic Tempol (4-hydroxy-2, 2, 6, 6-tetramethylpiperidine 1-oxyl) may reverse diabetes-induced erectile dysfunction. To test this hypothesis, reactive oxygen species-related genes (SOD1, SOD2, GP x 1, CAT, NOS2, NOS3) were tested, erectile functional studies and immunohistochemical analysis were carried out in diabetic rats treated with or without Tempol. Thirty Sprague-Dawley (3-4 months old) rats were divided into three groups (n=10 each), 20 with diabetes (diabetic control and Tempol treatment) and 10 healthy controls. At 12 weeks after the induction of diabetes by streptozotocin and Tempol treatment, all groups underwent in vivo cavernous nerve stimulation. Rat crura were harvested and the expression of antioxidative defense enzymes were examined by semi-quantitative reverse transcriptase PCR (RT-PCR). To confirm the RT-PCR results, we carried out immunohistochemistry (IHC) for catalase (CAT) and iNOS (NOS2). Nitration of tyrosine groups in proteins was also examined by IHC. Mean intracavernous pressure in the diabetic group was significantly lower than in the healthy controls (P

OBJECTIVE To evaluate the effectiveness of adjuvant chemotherapy in patients with pathological Stage T3 bladder cancer who had undergone radical cystectomy, and to determine the prognostic survival factors for adjuvant chemotherapy treatment. METHODS From January 1990 to October 2013, 202 patients underwent radical cystectomy and pelvic lymphadenectomy. Among them, 65 patients with non-organ-confined disease (pT3, N0-3, M0) diagnosed were investigated in this study. Thirty-one patients (48%) were treated with adjuvant chemotherapy and the remaining 34 patients (52%) were not. RESULTS Median age of all patients was 66 years, and median follow-up was 26.1 months. For all pT3 patients, overall survival and disease-free survival times were similar in the adjuvant chemotherapy and non-adjuvant chemotherapy groups. However, in the pT3b subgroup, median overall survival (47.0 vs. 10.6 months) and median disease-free survival (35.5 vs. 5.3 months) times were significantly prolonged for those who underwent adjuvant chemotherapy (P = 0.009 and 0.025). In patients with pathological lymph node metastatic (pN+), median overall survival (30.1 vs. 6.4 months) and median disease-free survival (15.7 vs. 3.5 months) times were significantly prolonged in the adjuvant chemotherapy group (P = 0.016 and 0.027). In addition, according to multivariate analysis in pT3b and/or pN+ subgroup patients, adjuvant chemotherapy status was an independent predictive factor for overall survival and disease-free survival. CONCLUSION Adjuvant chemotherapy did not significantly improve overall survival and disease-free survival when compared with all patients with pT3 who had received radical cystectomy in the non-adjuvant chemotherapy group. However, in the pT3b and pN+ subgroup, adjuvant chemotherapy demonstrated statistically significant benefits regarding overall survival and disease-free survival. Although these results could not support adjuvant chemotherapy use for all pT3 patients, the pT3b substage and/or pN+ may help identify patients with pT3 who could benefit from adjuvant chemotherapy.

The outcome of surveillance for Japanese patients with clinical stage I testicular germ cell cancer (GCC) was investigated in the multi-detector computed tomography (MDCT) era.The medical records of 92 Japanese patients with stage I GCC, who received treatment in our institution between March 1999 and February 2013, were reviewed. As six patients requested and received prophylactic chemotherapy and two patients seriously deviated from surveillance schedule, these patients were excluded from the study. Data from a total 84 patients were analyzed,The median follow-up period following diagnosis was 5.1 years (inter-quartile range: IQR, 2.3-7.7 years). Of the 84 patients, eight (9.5 %) had a recurrence of their cancer in this observation period. Regarding histologic subtypes, the recurrence rates were five (9.3 %) of the 54 patients with seminoma and three (10 %) of the 30 patients with nonseminomatous germ cell tumor (NSGCT). All eight patients who experienced a recurrence did so within 2 years; they all underwent induction chemotherapy and remain alive at the time of writing, with no evidence of disease. Among 31 seminoma patients with a tumor more than 4 cm in size and rete testis invasion, cancer recurred in three (9.7 %) during the surveillance period. On the other hand, among the 13 patients with NSGCT and vascular invasion, three (23 %) experienced a recurrence, whereas the figure was zero for the 11 (0 %) patients without vascular invasion.Fewer than 10 % of Japanese patients with stage I testicular GCC suffered a recurrence in the 5-year observation period of this study. The risk of occult disease, which will result in relapse, might be decreased in the MDCT era. All patients must be fully informed of the anticipated recurrence rate and the potential risks of exposure to chemotherapy agents.

Purpose: We hypothesized that combined methylation analysis of Wnt antagonist genes could serve as a panel of biomarkers for diagnosis, staging, and prognosis in renal cell carcinoma (RCC). Experimental Design: Samples (n = 62) of RCC and corresponding normal renal tissue (NRT) were analyzed using methylation-specific PCR for methylation of six Wnt antagonist genes (sFRP-1, sFRP-2, sFRP-4, sFRP-5, Wif-1, and Dkk-3). To increase the sensitivity/specificity of RCC detection, the methylation score (M score) for multigene methylation analysis was developed. Receiver operator characteristic curve analysis was used to determine the optimal sensitivity/specificity of the M score. In addition, the M score was compared with the clinicopathologic outcome. Thirty-three serum DNA samples were also used to investigate the methylation status of Wnt antagonist genes. Results: The methylation levels of all Wnt antagonists were significantly higher in RCC than in NRT. In multivariate regression analysis, the methylation level of sFRP-1 was a significant independent predictor of RCC, whereas for sFRP-2 and sFRP-4 there was a trend toward significance as independent predictors. The M score of Wnt antagonist genes was significantly higher in RCC than in NRT. Overall, the M score had a sensitivity of 79.0% and a specificity of 75.8% (area under the curve, 0.808) as a diagnostic biomarker. In addition, the M score could significantly distinguish grade, pT category, M category, and overall survival of RCC patients. The M score was independent of age and gender in predicting overall survival by the Cox proportional hazards model. In RCC patients, 72.7% of the methylation-specific PCR results had identical methylation in samples of tumor and serum DNA. No serum DNA in normal controls showed aberrant methylation of the Wnt antagonist genes. In addition, the methylation status of Wnt antagonist genes in serum DNA was significantly correlated with tumor grade and stage. Conclusions: This is the first report showing that M score analysis of Wnt antagonist genes can serve as an excellent epigenetic biomarker panel for detection, staging, and prognosis of RCC using serum DNA.

Purpose: Bcl-2 inhibits apoptosis, and its overexpression is associated with hormone refractory prostate cancer (HRPC). Bak and Bax are in the Bcl-2 family and counteract the antiapoptotic function of Bcl-2. Taxane-induced (paclitaxel and its analogue docetaxel) phosphorylation of Bcl-2 abolishes the potential antiapoptotic effect of Bcl-2. We hypothesized that (a) survival benefit in HRPC patients treated with taxanes is determined by the presence of Bcl-2 protein and (b) altered expression of Bak and Bax protein caused by genetic mutation is associated with biological aggressiveness of prostate cancer. Experimental Design: Forty localized prostate cancer and 30 HRPC cases were used in this study. Surgical specimens of localized prostate cancer and biopsy specimens of HRPC were used for immunostaining of Bcl-2, Bak, and Bax as well as DNA extraction. Mutations in the Bak and Bax genes were screened by single-strand conformational polymorphism, and confirmed by direct DNA sequencing. Results: Bcl-2–positive HRPC showed longer cause-specific survival in comparison with the counterparts. Multivariate analysis revealed that the level of Bcl-2 expression before treatment with taxane-based chemotherapy was an independent predictor for cause-specific survival (P < 0.01) and baseline prostate-specific antigen level was an independent predictor for progression-free survival (P < 0.01). Bax gene mutation was found in only one HRPC specimen. Conclusions: Bcl-2 expression in addition to prostate-specific antigen measurement before treatment could identify HRPC patients who may benefit from taxane-based chemotherapy. Mutation of the Bak and Bax genes is a rare event in prostate cancer.

DNA repair gene alterations have been shown to cause a reduction in DNA repair capacity and may influence an individual’s susceptibility to carcinogenesis. Single nucleotide polymorphisms (SNPs) of DNA repair genes have been shown to cause a reduction in repair activity. We hypothesized that SNPs of DNA repair genes may be a risk factor for renal cell carcinoma (RCC). To test this hypothesis, DNA samples from 112 cases of renal cell cancer and healthy controls (n = 180) were analyzed by PCR-RFLP to determine the genotypic frequency of six different polymorphic loci on five DNA repair genes (XRCC1, XPC, ERCC1, XRCC3, and XRCC7). The χ2 test was applied to compare the genotype frequency between patients and controls. We found that the frequency of 399Gln variant at XRCC1 Arg399Gln was significantly higher in RCC cases than in controls (OR = 2.83, 95%CI = 1.24–6.49, P = 0.01). The frequency of T–A haplotype of XRCC1 194 Trp and XRCC1 399Gln was significantly higher in RCC than controls. No differences in genotypes were observed at the other sites. This is the first report on SNPs of DNA repair genes in renal cell carcinoma that suggests XRCC1 399Gln polymorphism may be a risk factor for RCC. Our present data suggest that the XRCC1 399Gln allele may be linked to susceptibility for RCC.

Various carcinogenic metabolites, including catechol estrogens, play a role in malignant transformation. An enzyme that is capable of neutralizing the genotoxic effects of these compounds is catechol-O-methyltransferase (COMT). A variant form of this enzyme has been shown to reduce its activity by up to 4-fold; thus, we hypothesize that single nucleotide polymorphisms of the COMT gene can be a risk factor for benign prostatic hyperplasia (BPH) and prostate cancer. To test this hypothesis, the genetic distribution of three different COMT polymorphisms at codon 62 (C→T), codon 72 (G→T), and codon 158 (G→A) were analyzed in 131 normal healthy subjects, 134 BPH, and 178 sporadic prostate cancer samples from a Japanese population. Results of these experiments show that the variant genotype at codon 62 (P = 0.060) and codon 158 (P = 0.047) are risk factors for prostate cancer but not BPH when compared with normal controls. Odds ratio (OR) and 95% confidence interval (95% CI) for cancer were 3.24 and 1.38 to 7.61, respectively, for codon 62 T/T genotype when compared with wild type. At codon 158, the A/A variant for cancer had an OR of 3.00 with a 95% CI of 1.38 to 6.54 compared with wild type. Codons 62 and 158 were in linkage disequilibrium (LD), and when compared with the C-G haplotype, other types (C-A, T-G, T-A) were observed to be associated with prostate cancer (P = 0.040) but not BPH. Codon 72 on the other hand, was not in LD with either codon 62 or 158. The homozygous variant on codon 72 was rare in this Japanese population, and the heterozygous G/T at this codon was not associated with either prostate cancer or BPH. When evaluating the risk of COMT polymorphisms with stage or grade of cancer, no associations were observed for any of the genotypes with the exception of a tendency (P = 0.096) for the variant A allele on codon 158 to be correlated with higher stages (≥T3) of cancer. This is the first report that shows the polymorphisms of COMT to be associated with sporadic prostatic carcinogenesis. These results are important in understanding the role of COMT polymorphisms in the pathogenesis of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(2):238–44)

BACKGROUND Aberrant CpG methylation profiles of gene promoters and their correlation with advanced pathologic features have been well investigated in prostate carcinoma (PC). Several case–control and prospective studies have revealed a positive association between current smoking and PC. The authors hypothesized that smoking influences both progression and prognosis of PC through CpG hypermethylation of related genes. METHODS A total of 164 PC patients (52 current, 30 former, and 82 never smokers) and 69 benign prostatic hyperplasia (BPH) patients were examined by methylation-specific PCR (MSP) for 3 genes: adenomatous polyposis coli (APC), glutathione S-transferase pi (GSTP1), and multidrug resistance one (MDR1). The methylation status of representative samples was confirmed by bisulfite DNA sequencing analysis. The newly defined methylation score (M-score) of each sample is the sum of the corresponding log hazard ratio (HR) coefficients derived from multivariate logistic regression analysis for pathology (BPH vs. PC), and was related to clinical and pathologic outcome including smoking status. RESULTS The M-score was significantly higher in the current smokers than in never smokers (P = 0.008). Spearman rank correlation test demonstrated a significant correlation between pack-years smoked and M-score in PCs (P = 0.039). Significant correlation of the M-score methylation was observed with high pT category (P < 0.001), high Gleason sum (P < 0.001), high preoperative prostate-specific antigen (PSA) (P = 0.041), and advanced pathologic features. In addition, Gleason sum was significantly associated with PSA failure-free probability as a poor outcome (P = 0.020). CONCLUSIONS This is the first study to demonstrate significant correlation of the methylation status of multigenes with smoking status in PC. Smoking status may influence both progression and prognosis of PC through CpG hypermethylation of related genes. Cancer 2006. © 2005 American Cancer Society.

γ-Catenin is a cell adhesion molecule and a candidate mediator of Wnt signal transduction. We hypothesized that impaired regulation of γ-catenin through genetic and epigenetic pathways is associated with the pathogenesis of prostate cancer. To test this hypothesis, cytosine-phosphate-guanine methylation, loss of heterozygosity (LOH), and mutation status of the γ-catenin gene were analyzed in cultured prostate cancer cell lines, 180 localized prostate cancers, 69 benign prostatic hyperplasias, and 11 hormone refractory prostate cancers (HRPC). In prostate cancer cell lines (DuPro, LNCaP, ND-1, and PC3), γ-catenin mRNA transcripts were increased after 5-aza-2′-deoxycytidine treatment. In localized prostate cancer, γ-catenin expression was lower but prevalence of γ-catenin methylation was higher compared with benign prostatic hyperplasia. However, γ-catenin methylation did not correlate with Gleason sum, pT category, or capsular penetration. Among localized prostate cancers with positive γ-catenin methylation, the presence of LOH at chromosome 17q21 was closely related to down-regulation of γ-catenin mRNA expression. The γ-catenin mutations were not found in localized prostate cancers, whereas six mutations were found in five HRPCs within or close to the GSK-3β consensus motif phosphorylation site, among which four HRPCs showed strong nuclear γ-catenin accumulation. In these four HRPCs, Bcl-2 expression was increased, whereas the target of the Wnt signal, c-myc, was only expressed in one HRPC. Therefore, although epigenetic γ-catenin methylation is an early event in the development of prostate cancer, simultaneous events of epigenetic cytosine-phosphate-guanine methylation and genetic LOH may be responsible for functional loss of γ-catenin. The γ-catenin mutation related to Bcl-2 overexpression has a significant effect on the pathogenesis of HRPC. This is the first report to characterize the epigenetic and genetic regulation of γ-catenin in human prostate cancer.

Objectives To examine docetaxel (DTX)-based chemotherapy in paclitaxel (PTX)-based chemotherapy-resistant hormone-refractory prostate cancer (HRPC) to investigate the activity and degree of toxicity in a pilot study. We have previously reported on the effectiveness of combination chemotherapy with PTX, estramustine (EMP), and carboplatin against HRPC. Although many patients with HRPC initially responded to this PTX/EMP-based combination chemotherapy, most finally progressed to PTX-resistant status within a mean of less than 1 year. DTX is an inhibitor of microtubule depolymerization like PTX and has demonstrated activity against PTX-resistant metastatic tumors. Methods The subjects were 15 patients with HRPC who displayed disease progression while receiving PTX/EMP/carboplatin combination chemotherapy. The patients were treated with intravenous DTX 30 mg/m 2 weekly, oral EMP 10 mg/kg daily, and intravenous carboplatin (dosed to an area under the curve of 6) on day 1 of every 4-week cycle. Treatment was continued until disease progression or excessive toxicity. Results Each patient received a median of eight consecutive cycles. The prostate-specific antigen level decreased by 50% or more in 33.3% of patients and by 90% or more in 13.3%. The median follow-up was 49.6 weeks, with median time to progression of 25.0 weeks and median overall survival of 54.0 weeks. One patient died of interstitial pneumonitis. One patient developed secondary osteomyelodysplastic syndrome. The major severe toxicities were grade 3 or 4 anemia in 66.7% of patients, leukopenia in 26.7%, and thrombocytopenia in 40.0%. Conclusions The results of our study have shown that DTX is comparatively active for heavily pretreated patients with PTX-resistant HRPC. However, given the significant toxicities and small subject population, well-designed Phase I-II trials of the improved regimen are warranted.

The incidence and mortality of prostate cancer (PC) is approximately 2-fold higher among African-Americans as compared to Caucasians and very low in Asian. We hypothesize that inactivation of GSTP1 genes through CpG methylation plays a role in the pathogenesis of PC, and its ability to serve as a diagnostic marker that differs among ethnic groups. GSTP1 promoter hypermethylation and its correlation with clinico-pathological findings were evaluated in 291 PC (Asian = 170; African-American = 44; Caucasian = 77) and 172 benign prostate hypertrophy samples (BPH) (Asian = 96; African-American = 38; Caucasian = 38) using methylation-specific PCR. In PC cells, 5-aza-dC treatment increased expression of GSTP1 mRNA transcripts. The methylation of all CpG sites was found in 191 of 291 PC (65.6%), but only in 34 of 139 BPH (24.5%). The GSTP1 hypermethylation was significantly higher in PC as compared to BPH in each ethnic group (p < 0.0001). Logistic regression analysis (PC vs. BPH) showed that African-Americans had a higher hazard ratio (HR) (13.361) compared to Caucasians (3.829) and Asian (8.603). Chi-square analysis showed correlation of GSTP1 hypermethylation with pathological findings (pT categories and higher Gleason sum) in Asian PC (p < 0.0001) but not in African-Americans and Caucasian PC. Our results suggest that GSTP1 hypermethylation is a sensitive biomarker in African-Americans as compared to that in Caucasians or Asian, and that it strongly influences tumor progression in Asian PC. Ours is the first study investigating GSTP1 methylation differences in PC among African-American, Caucasian and Asian.

Deficiency in the DNA mismatch repair (MMR) is frequently involved in various cancers. The hMSH3 gene is one of the human MMR genes whose role in bladder cancer is not known. We hypothesized that down-regulation of the hMSH3 gene might be involved in bladder cancer. In this study we analyzed this gene with regard to frame-shift mutation, single nucleotide polymorphism (SNP), a 9bp repeat in exon 1, loss of heterozygosity (LOH), immunohistochemistry, and methylation status in 102 bladder cancer samples. Immunohistochemistry revealed that hMSH3 expression in bladder cancer was significant decreased compared to normal epithelium (p0.0001). An inverse correlation with pathological grade was found. The frame-shift mutation in the (A) 8 tract was lacking in bladder cancer. There was no significantly difference between bladder cancer samples and healthy controls' with regard to SNP and the 9bp repeat. In bladder cancer, presence of the codon 222 polymorphism, LOH, and the 9bp repeats in exon 1 had a correlation with either pathological stage or pathological grade. Presence of the codon 1036 polymorphism had significant correlation with pathological stage and a trend to correlation with pathological grade. After 5-aza-dC treatment, MSH3 expression was significantly enhanced in TCC and UMUC bladder cancer cells when compared to untreated cells. This is the first report suggesting that genetic and epigenetic alterations in the human MSH3 gene might play a significant role in the progression of bladder tumors.

Recently, survival benefit by chemotherapy using paclitaxel (PTX) and the induction of thymidine phosphorylase (TP) by PTX have been reported in several solid tumors. On the other hand, TP confers antiapoptotic effect on tumor cells through inhibition of caspase-8 activation in vitro. On the basis of these previous observations, we hypothesized that (a) TP can be induced after PTX treatment in human prostate cancer (PC) and (b) blockade of PTX-induced TP expression can enhance the apoptotic processes in human PC cells. PTX was used to find TP expression in all eight hormone-refractory PC cases after chemotherapy; however, cleaved caspase-8 was not expressed after chemotherapy in the six hormone-refractory PC cases with strong TP expression. In PC cell lines (PC-3, DU 145, and LNCaP), TP expression after PTX treatment was clearly up-regulated in a dose-dependent manner. Cell viability of PC cell lines treated with PTX and TP antisense was significantly reduced in a time-dependent and dose-dependent manner compared with the PTX treatment alone. Likewise, apoptotic index of PC cells treated with PTX and TP antisense was significantly increased in comparison with PTX alone. After complete blockade of PTX-induced TP translation by TP antisense transfection, cleaved form of caspase-3 and poly(ADP-ribose) polymerase was increased, and this exaggeration of apoptosis also ran parallel with caspase-8 activation in a PTX dose-dependent manner. However, in PC cell lines treated with TP antisense alone, neither caspase-3 nor poly(ADP-ribose) polymerase was cleaved despite caspase-8 activation. These results indicate that PTX-induced TP up-regulation is associated with decreased caspase-8 activation. This study is the first report showing that blockade of PTX-induced TP expression could exaggerate the processing of apoptosis in PC cells treated with PTX. Our results provide preclinical evidence that TP could be a new molecular target for enhancing the potency of PTX-mediated apoptosis in PC cells.

Aim: To evaluate postoperative morbidity, functional results and health-related quality of life of patients with an orthotopic neobladder. Methods: A total of 37 patients with orthotopic neobladder (modified Studer method: 35 cases; Hautmann method: one case; sigmoid neobladder: one case) were included in the present study. Postoperative morbidity and neobladder function were analyzed. To determine quality of life, the Sickness Impact Profile questionnaire was used. The quality of life of patients who underwent orthotopic neobladder was compared with that of patients who underwent ileal conduit. Results: In 37 consecutive patients with neobladder reconstruction, early complications included 10 cases of pyelonephritis (27.0%) and one of stenosis of ureterointestinal anastomosis (2.7%). Two patients died of ARDS and sepsis following peritonitis and pneumonia in the perioperative period. Late complications included pyelonephritis in three patients (8.6%). In 32 cases, except for an early postoperative case and those that died, complete daytime and night-time continence was achieved in 31 patients (96.9%) and 16 patients (50.0%), respectively. Concerning health-related quality of life, the mean sum scores per category of the Sickness Impact Profile were calculated for 32 patients with orthotopic neobladder and 30 patients with ileal conduit. There were no significant differences in overall satisfaction, however, the scores for patients with orthotopic neobladder reconstruction were significantly higher than those for patients with ileal conduit in the three categories of emotions, feelings and sensation, social interaction and recreation. Conclusion: Orthotopic neobladder reconstruction exhibited good functional results with acceptable complications. Patients who underwent neobladder reconstruction were satisfied with their voiding. Assessment of quality of life using the Sickness Impact Profile questionnaire demonstrated that orthotopic neobladder improved their quality of life better than ileal conduit, especially with regard to mental, physical and social functioning in daily life.

OBJECTIVE To assess the correlation between angiogenesis and Doppler signal intensity using transrectal colour Doppler ultrasonography (CDUS) in patients with prostate cancer. PATIENTS AND METHODS The study comprised 56 patients who underwent radical prostatectomy and had untreated tumours with a volume of> 0.1 mL in the peripheral zone. CDUS images were recorded on videotape before surgery. The Doppler signal intensity in tumours was evaluated using the colour pixel intensity (PI). Microvessel density (MVD) and vascular endothelial growth factor (VEGF) immunoreactivity were determined in the prostatectomy specimens. Microvessels were identified by immunohistochemical staining of endothelial cells for CD31. RESULTS The PI in the tumour correlated with MVD (P

This report demonstrates a case of rhabdomyolysis as a result of the exaggerated lithotomy position during radical perineal prostatectomy. The pathogenesis, diagnosis, management, and preventive measures of rhabdomyolysis are also reviewed.

To analyze the relationships among the antitumor effect of chemothermotherapy, generation of reactive oxygen species (ROS), and expression of heat shock protein 70 (HSP-70) in the PC-3 prostate cancer cell line.Changes in cell proliferation, cell cycle fractions, intracellular ROS accumulation and HSP-70 expression were examined after thermotherapy of PC-3 cells at 41, 42, 43 and 44 degrees C and/or simultaneous treatment with Adriamycin for 1 h, using the trypan blue dye exclusion method, flow cytometry, fluorescent 2', 7'-dichlorofluorescein (DCF) assay, and Western blot analysis.A significant decrease in the number of viable cells was observed with chemothermotherapy compared with thermotherapy at 42, 43, or 44 degrees C (p0.05). DNA distribution histograms revealed cell accumulation in the S-G(2)/M phase after thermotherapy at 43 degrees C and after chemothermotherapy at 37, 41, 42 and 43 degrees C. After thermotherapy and chemothermotherapy at 44 degrees C, DNA histograms revealed no accumulation of cells with S-G(2)/M DNA content and cells exhibited a marked loss of viability. A significant increase in DCF production was observed with chemothermotherapy compared with thermotherapy at 42, 43 or 44 degrees C (p0.05, p0.01 and p0.01, respectively). HSP-70 levels increased linearly with increasing temperature. HSP-70 levels after thermotherapy and chemothermotherapy increased with time and reached plateaus at 30 min, whereas the level after thermotherapy at 44 degrees C decreased at 60 min.In conclusion, one possible synergism in cytotoxic effects of chemothermotherapy and Adriamycin could be evaluated by the relationship between ROS accumulation and HSP-70 expression in the PC-3 prostate cancer cell line.

To evaluate the significance of chromosomal aberrations in renal cell carcinoma, fluorescence in situ hybridization (FISH) was used to determine its prevalence and correlation with clinical parameters of malignancy. In addition, correlation of chromosomal aberration with Ki 67 expression was analysed. We performed FISH with chromosome-specific DNA probes, and the signal number of pericentromeric sequences on chromosomes 3, 7, 9 and 17 was detected within interphase nuclei in touch preparations from tumour specimen. The incidence of loss of chromosome 3 was significantly higher than those of chromosomes 7, 9 and 17 (P < 0.001, P = 0.03 and P < 0.001 respectively). Hyperdiploid aberration of chromosomes 3 and 17 was significantly correlated with tumour stage (P = 0.03, P = 0.02 respectively), whereas hyperdiploid aberration of chromosome 9 was associated with nuclear grade (P = 0.04). Disomy of chromosome 7 was correlated with venous involvement (P = 0.04). Ki 67 expression was significantly associated with hyperdiploid aberration of chromosome 17 (P = 0.01), but not with aberration of chromosome 3. There was a significant relationship between hyperdiploid aberration of chromosome 7 and Ki 67 expression (P = 0.01). In conclusions, gain of chromosome 17 may reflect tumour development, and aberration of chromosome 7 may affect metastatic potential of malignancy, whereas loss of chromosome 3 may be associated with early stage of tumour development in renal cell carcinoma.

von Hippel-Lindau (VHL) gene mutations are detected in noninherited, sporadic human renal cell carcinomas (RCs) at a high frequency. We recently identified a germline mutation in the rat homologue of the human tuberous sclerosis (TSC2) predisposing RC gene in the Eker rat model, and in this study we searched for mutations of the Tsc2 gene in chemically induced non-Eker rat RCs.Chemically [N-ethyl-N-hydroxyethylnitrosamine (EHEN)]-induced non-Eker rat RC lines (designated as BP13 and BP36B) were subjected to PCR-single strand conformation polymorphism (PCR-SSCP) analysis using specific primers covering entire exons of Tsc2 gene (41 coding exons and one non-coding exon). We simultaneously searched for mutations of Vhl gene, a rat homologue of von Hippel-Lindau disease gene (VHL) as well as Tsc2 gene.BP36B showed an abnormal mobility shift from the normal tissue of the same rat in exon 35 on analysis by PCR-SSCP. This mutation was confirmed by direct sequencing and found to be a T-to-C transition at the second position of codon 1470, resulting in an amino acid change from leucine to proline (missense mutation).This is the first demonstration of Tsc2 gene somatic mutation in non-Eker rat RCs. Our present findings call attention to further investigation of the role of Tsc2 gene mutations in rat renal carcinogenesis and possible Tsc2 gene mutations in human RCs, especially of the non-clear cell type, which are not related to the VHL gene.

We report a case of inverted papilloma in the urinary bladder with special reference to its malignant potential. A 77-year-old male patient complaining of microhaematuria was subjected to cystoscopic examination, which showed a non-papillary pedunculated tumour at the postero-lateral wall, and was treated with transurethral resection. The histological findings of the specimen were compatible with inverted papilloma of the urinary bladder, except for the presence of low grade dysplastic changes in the tumour nuclei. We revealed the malignant potential of this tumour, analyzing and evaluating nuclear DNA content, proliferating cell nuclear antigen (PCNA) as well as p53 expression.

Background: This study re-evaluated the efficacy and tolerability of cisplatin, etoposide, and ifosfamide (VIP) combination chemotherapy as an alternative first-line regimen for patients with disseminated germ cell cancer (GCC) in this granulocyte colony-stimulating factor (G-CSF) era. Methods: The medical records of 91 consecutive patients with previously untreated disseminated GCC who received first-line VIP between 1995 and 2011 were retrospectively reviewed. Results: The 5-year overall survival rates for patients with good (n = 49), intermediate (n = 22) and poor (n = 20) prognoses according to the International Germ Cell Cancer Collaborative Group classification were 100, 79 and 83%, respectively. G-CSF was given to all patients, and no treatment-related deaths due to myelosuppression occurred. Conclusion: The present study is the first to examine the therapeutic outcomes and safety profile of first-line VIP after routine G-CSF use. VIP might be an alternative first-line regimen for patients with disseminated GCC in this G-CSF era.

BACKGROUND. Transitional cell carcinoma (TCC) of the bladder displays an unpredictable biologic behavior and the morphologic methods of grading tumor malignancy are often insufficient to predict the clinical outcome of patients with TCC of the bladder. Thus, the new indicator should reliably reflect prognosis. In this study, the authors determined the prognostic significance of proliferating cell nuclear antigen (PCNA), p53 protein, and nm23 protein, as well as nuclear DNA content in specimens with TCC of the bladder. METHODS. Paraffin embedded materials taken from 77 patients with nonmetastatic untreated TCC of the bladder (classified as pTa-3b, N0, M0) treated with total cystectomy were employed in this study. PCNA expression, p53 protein and nm23 protein immunoreactivities, and the parameters for nuclear DNA content such as 2c deviation index (2cDI) and 5c exceeding rate (5cER) were evaluated using a computer-assisted image analyzer, and the results were compared with histologic findings and clinical outcome. RESULTS. PCNA expression positively correlated with p53 protein and nm23 protein immunoreactivities, 2cDI value, and 5cER. In addition, histologic grade positively correlated with all of these five parameters. Similarly, pT category and disease progression positively correlated with all of the five parameters, except for nm23 protein immunoreactivity. In tumors with high genetic instability as judged by 2cDI and 5cER, both PCNA expression and p53 protein immunoreactivity were elevated, whereas nm23 protein immunoreactivity was not. However, the percent coefficient of variation in PCNA expression was smaller than that observed in p53 protein immunoreactivity in each group of genetic instabilities. In univariate analysis, prognostic potential was found with histologic grade, pT category, PCNA expression, p53 protein immunoreactivity, 2cDI value, and 5cER, but was not noted in nm23 protein immunoreactivity. Multivariate analysis indicated that quantity and intensity of PCNA expression (χ 2 = 8 ; P = 0.0047 for quantity and χ 2 = 8.71 ; P = 0.0032 for intensity) and 2cDI value (χ 2 = 5.52 ; P = 0.0019) were independent variables of histologic grade and pT category when predicting survival. However, p53 protein and nm23 protein immunoreactivities and 5cER were not of independent significance. CONCLUSIONS. The tumor growth fraction as assessed by PCNA immunostaining is an independently significant predictor for survival of patients with TCC of the bladder.

AIMS: To evaluate the expression of bcl-2 in transitional cell carcinoma (TCC) of the bladder; to compare bcl-2 expression with clinicopathological findings, p53 immunoreactivity, proliferating cell nuclear antigen (PCNA) expression, 2c deviation index (2cDI), 5c exceeding rate (5cER), and the mean nuclear area (MNA). METHODS: Cystectomy specimens from 77 patients with untreated, non-metastatic TCC of the bladder were studied. Expression of bcl-2, p53 and PCNA was detected immunohistochemically using the following monoclonal antibodies: bcl-2/124, DO-7 and PC10, respectively. Nuclear DNA content was analysed using static cytometry. RESULTS: Bcl-2 was expressed in 19 (24.7%) of 77 TCCs and in 74 (96.1%) of 77 normal samples of transitional epithelium (taken from normal tissue adjacent to the tumour in each case). In all cases, bcl-2 immunoreactivity was more intense in normal transitional epithelium than in TCC. In normal transitional epitehlium and superficial TCC bcl-2 immunoreactivity was observed at the basal layer, and not at the invasive front. Bcl-2 immunoreactivity was invesely correlated with histological grade and p53 immunoreactivity, and was not correlated with the pT category, disease progression, PCNA expression, 2cDI, 5cER, and the MNA. No significant correlation was found between bcl-2 expression and overall survival. CONCLUSIONS: Bcl-2 expression in TCC of the bladder seems to be associated with a less aggressive phenotype and does not play an important role in tumour progression.

OBJECTIVE To determine the relationship between growth fractions defined by proliferating cell nuclear antigen (PCNA), prostate-specific antigen (PSA) and alpha 1-antichymotrypsin (ACT) staining in prostate cancer. MATERIALS AND METHODS A total of 96 lesions, including 71 from prostate cancers and 25 from benign prostatic hyperplasia (BPH) were evaluated in microscopic sections of the prostatic tissues from 34 patients with prostate cancer. Immunohistochemical staining was performed with an avidin-biotin system using monoclonal anti-PCNA antibodies, polyclonal anti-PSA and anti-ACT antibodies. RESULTS There was a significant difference in the mean PCNA labelling index between tissue from prostate cancer (4.2 +/- 7.1) and BPH (0.5 +/- 1.1) (P = 0.002). The mean labelling index of PCNA tended to increase with increasing Gleason score. The proportion of cells positive for PSA was significantly higher in tissue from BPH than from prostate cancer (P = 0.005). While the proportion of cells immunostaining for ACT was significantly higher in tissue from BPH compared to that from prostate cancer (P = 0.02), there was no significant difference in the proportion of ACT-positive cells among prostate cancers of differing Gleason score. The mean labelling index of PCNA decreased significantly with the increase in the proportion of PSA-positive cells (P = 0.013). There was a significant relationship between the proportion of ACT- and PSA-positive cells (P = 0.001). CONCLUSION These results indicate a reciprocal relationship between cell growth and tumour differentiation in prostate cancer. Although the significance of ACT deserves further study, there was evidence for the complexing of PSA with ACT from the immunohistochemical studies.