Significance of prophylactic urethrectomy at the time of radical cystectomy for bladder cancer.

BACKGROUND: Prophylactic urethrectomy at the time of radical cystectomy is frequently recommended for patients with bladder cancer at a high risk of urethral recurrence without definitive evidence. The present study attempted to clarify the survival benefits of performing prophylactic urethrectomy. METHODS: We identified 214 male patients who were treated by radical cystectomy with an incontinent urinary diversion in our seven institutions between 2004 and 2017. We used propensity score matching and ultimately identified 114 patients, 57 of whom underwent prophylactic urethrectomy (prophylactic urethrectomy group) and 57 who did not (non-prophylactic urethrectomy group). RESULTS: No significant differences were observed in the 5-year overall survival rate between the prophylactic urethrectomy and non-prophylactic urethrectomy groups in the overall. However, the local recurrence rate was significantly lower in the prophylactic urethrectomy group than in the non-prophylactic urethrectomy group (P = 0.015). In the subgroup of 58 patients with multiple tumours and/or concomitant carcinoma in situ at the time of transurethral resection of bladder tumour, the 5-year overall survival rate was significantly higher in the prophylactic urethrectomy group than in the non-prophylactic urethrectomy group (P = 0.021). A multivariate analysis revealed that performing prophylactic urethrectomy was the only independent predictor of the overall survival rate (P = 0.016). In those patients who were treated without neoadjuvant chemotherapy (n = 38), the 5-year overall survival rate was significantly higher in the prophylactic urethrectomy group than in the non-prophylactic urethrectomy group (P = 0.007). CONCLUSIONS: Prophylactic urethrectomy at the time of radical cystectomy may have a survival benefit in patients with multiple tumours and/or concomitant carcinoma in situ, particularly those who do not receive neoadjuvant chemotherapy.

TNFAIP2 expression induces epithelial-to-mesenchymal transition and confers platinum resistance in urothelial cancer cells.

Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for many types of cancer. However, the phenotypic hallmark of tumors often changes after CDDP treatment, with the acquisition of epithelial-to-mesenchymal transition (EMT) and platinum resistance. Furthermore, the mechanisms by which cancer cells acquire EMT under the control of CDDP remain unclear. Following an investigation of urothelial carcinoma (UC) before and after the acquisition of platinum resistance, we offer the new target TNFAIP2, which led to EMT and tumor invasion in platinum-treated UC cells. TNFAIP2 expression in cancer was examined at the protein and transcriptional levels. A potential target for TNFAIP2 during EMT was assessed by microarray. Clinically, upregulated TNFAIP2 expression was identified as a significant predictor of mortality following surgery in three different cohorts of patients with UC (n = 156, n = 119, and n = 54). Knockdown of TNFAIP2 resulted in upregulation of E-cadherin expression and downregulation of TWIST1 expression, which decreased motile function in platinum-resistant UC cells. TNFAIP2 overexpression led to downregulation of E-cadherin expression and upregulation of TWIST1 expression in platinum-naïve UC cells. Clinical investigation of matched pre- and post-CDDP-treated UC sections confirmed upregulation of TNFAIP2 expression in CDDP-treated tumors but downregulation of E-cadherin expression. Global gene expression analysis following TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-derived EMT acquisition in cancer cells. The present results suggest a relationship between TNFAIP2 and EMT in cancers under the control of CDDP, in which MTDH expression levels in cancer cells are vital for promoting TNFAIP2-derived EMT acquisition.

Sub-classification of patients with intermediate-risk metastatic renal cell carcinoma treated with targeted therapy.

BACKGROUND: International Metastatic Renal Cell Carcinoma Database Consortium model predicts the outcomes of metastatic renal cell carcinoma stratified into favorable, intermediate, and poor risk groups (FG, IG, and PG, respectively), with approximately 50% of patients being classified as IG. We aimed to generate better risk model based on the sub-classification of IG. METHODS: We analyzed records of 213 consecutive patients receiving molecular targeted therapy. Age, gender, histology, type of initial molecular targeted therapy, serum laboratory data, previous nephrectomy and immunotherapy, and metastatic sites were used for IG sub-stratification. Modified and original models were compared using a concordance correlation coefficient analysis. RESULTS: Median follow-up was 17.8 months. Serum albumin, serum C-reactive protein, and bone metastases were independent predictors of overall survival (OS) in IG. IG was sub-classified into low-, middle-, and high-risk IG according to the number of predictors. The following modified model was developed: modified FG (FG & low-risk IG), modified IG (middle-risk IG), and modified PG (PG & high-risk IG). Concordance indices for original and modified models were 0.68 and 0.73, respectively (P < 0.001). OS was significantly longer in modified PG treated with mammalian target of rapamycin inhibitors as second-line therapy than with tyrosine kinase inhibitors, whereas this was not observed in the original model. CONCLUSIONS: We successfully developed modified IMDC model using a two-step process: the original IMDC plus an IG sub-stratification, and demonstrated that it predicts outcomes more accurately than original model.

Impact of inflammatory marker levels one month after the first-line targeted therapy initiation on progression-free survival prediction in patients with metastatic clear cell renal cell carcinoma.

OBJECTIVES: Progression-free survival of first-line targeted therapy greatly influences the survival of patients with metastatic renal cell carcinoma. We evaluated whether post-treatment inflammatory markers and lactate dehydrogenase levels had impacts on progression-free survival prediction in addition to those of conventional predictors. METHODS: Two hundred and fifteen patients whose tumors were clear cell type and in whom first-line targeted therapies could be continued for >1 month were evaluated. Pretreatment clinical factors, pathological factors and laboratory data 1 month after targeted therapy initiation-including inflammatory markers (neutrophil count, neutrophil-to-lymphocyte ratio and C-reactive protein) and lactate dehydrogenase-were reviewed. To identify progression-free survival predictors, multivariate analyses were done. RESULTS: The 1-year progression-free survival rate was 47%. Female gender, Karnofsky performance status <80%, time from diagnosis to systemic treatment <12 months, pretreatment C-reactive protein >3.0 mg/dl and post-treatment neutrophil-to-lymphocyte ratio >3.0 were independent predictors for progression-free survival. In contrast, neither C-reactive protein increase nor neutrophil-to-lymphocyte ratio increase after targeted therapy initiation were independent predictors. Pretreatment lactate dehydrogenase, post-treatment lactate dehydrogenase and lactate dehydrogenase decline were not independent predictors. When all patients were stratified by these independent factors into three groups (0 risk vs. 1 or 2 risks vs. 3 or more risks), there were significant differences in progression-free survival rates between the groups (P < 0.0001). Furthermore, there were also significant differences in overall survival rates between the groups (P < 0.0001). CONCLUSIONS: Integration of post-treatment neutrophil-to-lymphocyte ratio value with pretreatment factors may lead to the establishment of effective predictive model for disease progression in patients with metastatic clear cell renal cell carcinoma who received first-line targeted therapies.

Increased vasohibin-1 expression is associated with metastasis and poor prognosis of renal cell carcinoma patients.

The microvascular density detected by markers of endothelial cells (ECs), such as CD31 and CD34, is considered to be a biomarker for angiogenesis, and it is generally associated with the malignant potential of solid tumors. However, there is a conflicting relationship between the microvascular density and prognosis in clear-cell renal cell carcinoma (ccRCC) patients. It may be explained by the suggestion that the microvascular density cannot fully reflect the angiogenic activity in ccRCC, as the markers of ECs are expressed by both quiescent and activated ECs. To investigate the real angiogenic activity, we examined vasohibin-1 (VASH1), a recently identified regulator of angiogenesis, which was demonstrated to be specifically expressed by ECs of newly formed blood vessels. Expression of VASH1 and CD34 were immunohistochemically examined in 116 primary untreated ccRCCs, 10 metastatic untreated ccRCCs, and 9 metastatic ccRCCs treated with sunitinib. ECs in the tumor microvessels were sporadically immunostained for VASH1, although no VASH1 staining was observed in the non-neoplastic renal tissues. CD34 was ubiquitously expressed by all ECs in both ccRCC and non-neoplastic renal tissues. Multivariate Cox analysis indicated that an elevated VASH1 density, but not microvascular density, was a significant and independent predictor of overall survival (odds ratio, 7.71; P=0.003). The microvascular density was significantly decreased in the sunitinib-treated metastases compared with untreated tumors (P=0.001). On the other hand, the VASH1 density was significantly higher in the metastatic ccRCCs treated with sunitinib compared with non-treated ones (P=0.010), indicating that VASH1 may be associated with the resistance of ECs to sunitinib treatment. Thus, VASH1 expression may reflect the actual activity of angiogenesis, and VASH1 can serve as a new prognostic and predictive biomarker in patients with ccRCC.

Identification of two mutations that cause defects in the ligninolytic system through an efficient forward genetics in the white-rot agaricomycete Pleurotus ostreatus.

White-rot fungi play an important role in the global carbon cycle because they are the species that almost exclusively biodegrade wood lignin in nature. Lignin peroxidases (LiPs), manganese peroxidases (MnPs) and versatile peroxidases (VPs) are considered key players in the ligninolytic system. Apart from LiPs, MnPs and VPs, however, only few other factors involved in the ligninolytic system have been investigated using molecular genetics, implying the existence of unidentified elements. By combining classical genetic techniques with next-generation sequencing technology, they successfully showed an efficient forward genetics approach to identify mutations causing defects in the ligninolytic system of the white-rot fungus Pleurotus ostreatus. In this study, they identified two genes - chd1 and wtr1 - mutations in which cause an almost complete loss of Mn2+ -dependent peroxidase activity. The chd1 gene encodes a putative chromatin modifier, and wtr1 encodes an agaricomycete-specific protein with a putative DNA-binding domain. The chd1-1 mutation and targeted disruption of wtr1 hamper the ability of P. ostreatus to biodegrade wood lignin. Examination of the effects of the aforementioned mutation and disruption on the expression of certain MnP/VP genes suggests that a complex mechanism underlies the ligninolytic system in P. ostreatus.

Effects of pex1 disruption on wood lignin biodegradation, fruiting development and the utilization of carbon sources in the white-rot Agaricomycete Pleurotus ostreatus and non-wood decaying Coprinopsis cinerea.

Peroxisomes are well-known organelles that are present in most eukaryotic organisms. Mutant phenotypes caused by the malfunction of peroxisomes have been shown in many fungi. However, these have never been investigated in Agaricomycetes, which include white-rot fungi that degrade wood lignin in nature almost exclusively and play an important role in the global carbon cycle. Based on the results of a forward genetics study to identify mutations causing defects in the ligninolytic activity of the white-rot Agaricomycete Pleurotus ostreatus, we report phenotypes of pex1 disruptants in P. ostreatus, which are defective in two major features of white-rot Agaricomycetes: lignin biodegradation and mushroom formation. Pex1 disruption was also shown to cause defects in the hyphal growth of P. ostreatus on certain sawdust and minimum media. We also demonstrated that pex1 is essential for fruiting initiation in the non-wood decaying Agaricomycete Coprinopsis cinerea. However, unlike P. ostreatus, significant defects in hyphal growth on the aforementioned agar medium were not observed in C. cinerea. This result, together with previous C. cinerea genetic studies, suggests that the regulation mechanisms for the utilization of carbon sources are altered during the evolution of Agaricomycetes or Agaricales.

Two new triterpenoids from the roots of Pinus densiflora.

Chemical investigation of the roots of Pinus densiflora led to the isolation of two new triterpenoids, (24S)-3ß-methoxy-24,25-epoxy-lanost-9(11)-ene (1) and 29-acetoxy-3α-methoxyserrat-14-en-21α-ol (2), together with three known serratene-type triterpenoids (3-5) and four known diterpenoids (6-9). Their structures were determined by spectroscopic analyses.

Relationship Between Increased Expression of the Axl/Gas6 Signal Cascade and Prognosis of Patients with Upper Tract Urothelial Carcinoma.

PURPOSE: Axl, which is in the TAM family of receptor tyrosine kinases, and its ligand, growth arrest-specific gene 6 (Gas6), have been associated with worse prognoses after the surgical treatment of some types of cancers. We herein investigated the biological significance of the protein expression of Axl and Gas6 on the outcomes of patients with upper tract urothelial carcinoma (UTUC). METHODS: The protein expression of Axl and Gas6 was evaluated by immunohistochemistry, and their relationships with clinicopathological features were investigated in surgical specimens obtained from 161 patients who had been surgically treated for UTUC. RESULTS: Axl labeling was strong in 67 of 161 (42 %) cases, while Gas6 labeling was strong in 72 of 161 (45 %) cases. The strong expression of Axl correlated with that of Gas6. A high pathological stage (p = 0.009), strong expression of Gas6 (p = 0.038), and strong expression of Axl (p = 0.016) were independent factors for predicting worse cancer-specific survival (CSS). In a subgroup analysis of patients with pT < 2 (N = 53), no significant difference in CSS was observed between patients weakly and strongly expressing Axl/Gas6. In contrast, a subgroup analysis of patients with pT ≥ 2 (N = 108) revealed that the expression levels of Axl and Gas6 correlated with CSS. CONCLUSION: The protein expression of Axl and its ligand Gas6 may be a useful indicator for a worse clinical outcome in UTUC patients, especially patients with pT ≥ 2, who underwent radical nephroureterectomy.

High Absolute Monocyte Count Predicts Poor Clinical Outcome in Patients with Castration-Resistant Prostate Cancer Treated with Docetaxel Chemotherapy.

BACKGROUND: The association of peripheral monocyte count and prostate cancer progression is not well characterized. OBJECTIVE: Our aim was to investigate the prognostic value of absolute monocyte count (AMC), which is thought to modulate immune response in the tumor microenvironment, in castration-resistant prostate cancer (CRPC) patients treated with docetaxel chemotherapy. METHODS: We retrospectively reviewed the medical records of 214 CRPC patients who received docetaxel therapy and were used as the training and validation set. Docetaxel at a dose of 75 mg/m2 was administered every 3 or 4 weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). RESULTS: In the training set, the median age was 73.0 years, and the median prostate-specific antigen (PSA) value was 31.7 ng/ml at initial treatment. The median OS and PFS were 23.0 months (range 1.20-84.0) and 11.2 months (range 3.6-78.0), respectively. According to multivariable Cox regression analysis, AMC ≥400/uL, PSA level ≥20 ng/ml, and Hb <10 mg/dL were associated with increased risk of PSA progression [hazard ratio (HR) 2.06, p = 0.005; HR 2.39, p = 0.002; and HR 2.38, p = 0.024, respectively]. Moreover, multivariate analysis for OS indicated that AMC ≥400/uL, pretreatment PSA level ≥20 ng/ml, presence of visceral metastasis, and alkaline phosphatase ≥284 U/L were independent prognostic factors for shortened OS (HR 2.07, p = 0.004; HR 2.18, p = 0.007; HR 2.11, p = 0.011; and HR 1.67, p = 0.048, respectively). According to the validation set, high AMC remained an independent prognostic factor for PFS and OS (HR 2.26, p = 0.001; and HR 3.10, p < 0.001, respectively). CONCLUSIONS: Elevated monocyte counts were associated with aggressive tumor features and poor survival outcomes of patients with CRPC treated with docetaxel chemotherapy.

Patient age was an independent predictor of cancer-specific survival in male patients with upper tract urothelial carcinoma treated by radical nephroureterectomy.

OBJECTIVE: We hypothesized that there may be a prognostic difference in age between the genders and evaluated the influence of gender-adjusted age on prognosis in upper tract urothelial carcinoma patients. METHODS: A total of 839 patients with upper tract urothelial carcinoma from a retrospective multi-institutional cohort were included. The patients were divided into four groups consisting of males (N = 610) and females (N = 229) according to age ((i) <60 years, (ii) 60-69.9 years, (iii) 70-79.9 years and (iv) ≥80 years), and we evaluated the associations of patient age and gender with clinicopathological features and oncological outcomes following radical nephroureterectomy. The median follow-up duration was 34 months. RESULTS: Disease recurrence occurred in 249 patients and 192 patients died of upper tract urothelial carcinoma. The 3-year cancer-specific survival rates were (i) 84.3%, (ii) 80.2%, (iii) 77.1% and (iv) 71.5% in the entire patient population (P = 0.001); (i) 84.5%, (ii) 81.1%, (iii) 76.8% and (iv) 69.7% in males (P = 0.010); and (i) 83.3%, (ii) 76.9%, (iii) 77.7% and (iv) 72.9% in females (P = 0.287), respectively. No significant differences between disease recurrence and age were found in the male or female population. In multivariate analysis, older age was an independent predictor of cancer-specific survival, in addition to advanced pT stage, the presence of lymphovascular invasion and lymph node involvement in males. In contrast, age was not associated with cancer-specific survival in females, while high grade, advanced pT stage, the presence of lymph node involvement and multifocal tumor were independent predictors. CONCLUSION: The results indicate that gender-adjusted age might be a new prognostic factor in upper tract urothelial carcinoma patients.

Impact of an adjuvant chemotherapeutic regimen on the clinical outcome in high risk patients with upper tract urothelial carcinoma: a Japanese multi-institution experience.

PURPOSE: Current guidelines do not yet provide any recommendations for adjuvant chemotherapy in patients with upper tract urothelial carcinoma managed with radical nephroureterectomy. We evaluated whether an adjuvant chemotherapeutic regimen would affect the clinical outcome in patients with high risk upper tract urothelial carcinoma. MATERIALS AND METHODS: We identified 873 patients who had undergone radical nephrouretectomy for localized upper tract urothelial carcinoma at 14 Japanese institutions between 1993 and 2011. We assessed whether the type of regimen, such as methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and cisplatin, in an adjuvant setting, could affect the subsequent clinical outcome of patients with upper tract urothelial carcinoma. RESULTS: On multivariate analysis pathological T stage, tumor grade, lymphovascular invasion and lymph node involvement were prognostic factors for recurrence-free survival and cancer specific survival. We defined 229 patients with 3 or more of these factors as the high risk group. In an analysis according to adjuvant regimen, Kaplan-Meier curves showed that the 1 and 2-year recurrence-free survival rates in the methotrexate, vinblastine, doxorubicin and cisplatin treated group were 71.4% and 47.9%, which were significantly higher than in the gemcitabine and cisplatin treated group (48.2% and not reached, p=0.022) or those not treated with adjuvant chemotherapy (53.4% and 39.6%, p=0.039). Similar results were observed in terms of cancer specific survival. CONCLUSIONS: Our study showed that pT3-4, tumor grade 3, positive lymphovascular invasion and lymph node involvement were independent risk factors for disease mortality in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. In the high risk group methotrexate, vinblastine, doxorubicin and cisplatin adjuvant chemotherapy contributed to improve subsequent mortality compared to gemcitabine and cisplatin or no adjuvant chemotherapy.

Dual PI3K/mTOR inhibitor NVP-BEZ235 sensitizes docetaxel in castration resistant prostate cancer.

PURPOSE: Effective therapeutic strategies that can achieve long-term improvement in patients with castration resistant prostate cancer are urgently needed. We recently reported that the activated PI3K/Akt/mTOR signaling pathway induced by docetaxel explains resistance to docetaxel in castration resistant prostate cancer. In this study we explored the efficacy of NVP-BEZ235, a dual PI3K and mTORC1/2 inhibitor, for docetaxel resistant castration resistant prostate cancer. MATERIALS AND METHODS: We used the 2 human castration resistant prostate cancer cell lines C4-2 and C4-2AT6. At our laboratory C4-2AT6 cells were established from C4-2 under androgen ablated treatment for 6 months. We investigated the efficacy of NVP-BEZ235 monotherapy and NVP-BEZ235 combined with docetaxel in vitro and in vivo. RESULTS: Increased phosphorylated Akt in C4-2AT6 cells was significantly inhibited by NVP-BEZ235 in a dose and time dependent manner. WST cell proliferation assay results in C4-2AT6 cells revealed that combined administration of NVP-BEZ235 and docetaxel had significant, synergistically greater cytotoxicity than NVP-BEZ235 or docetaxel monotherapy. Combined NVP-BEZ235 (40 mg/kg) and docetaxel (4 mg/kg) in vivo in a castrated mouse xenograft model inhibited C4-2AT6 tumor growth to a greater degree than in the monotherapy groups. Also, NVP-BEZ235 showed significant efficacy with docetaxel at a low concentration in vivo, suggesting that NVP-BEZ235 effectively decreased resistance to docetaxel. CONCLUSIONS: Results suggest that inhibition of the PI3K/Akt/mTOR signaling pathway by NVP-BEZ235 can overcome docetaxel resistance in human castration resistant prostate cancer. Our findings provide a molecular basis for the clinical use of combined administration of NVP-BEZ235 and docetaxel in patients with castration resistant prostate cancer.

Metastatic behavior of upper tract urothelial carcinoma after radical nephroureterectomy: association with primary tumor location.

PURPOSE: To investigate the site-specific pattern of disease recurrence and/or metastasis and the associated patient outcomes after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). METHODS: A total of 733 patients with UTUC from a retrospective multi-institutional cohort were included, with a median follow-up of 34 months. Associated patient outcomes were analyzed by multivariate analysis. To evaluate the influence of primary tumor location, we divided it into four areas: renal pelvis, and upper, middle, and lower ureter. RESULTS: A total of 218 patients experienced disease recurrence, with the majority of relapses occurring within the first 3 years. Cumulative incidence rates of first disease recurrence at 1 and 3 years were 18.9 and 29.8 %, respectively. Of these patients, 38.5 % developed distant recurrence; 17.4 % experienced both local and distant recurrences; and 44.0 % developed isolated local recurrence. The predominant sites of distant metastasis were lung, liver, and bone. Multivariate analysis revealed that the prevalence of local recurrence and lung metastasis was significantly associated, with primary tumor location being independent of other clinicopathological variables. Lower/middle ureter tumors had a higher rate of local recurrence in the pelvic cavity, and renal pelvic tumors had a higher prevalence of distant relapse in the lungs. Similar results were obtained when rerunning the data set by excluding patients who received adjuvant chemotherapy (n = 131). CONCLUSIONS: This multi-institutional study provided a detailed picture of metastatic behavior after RNU, and primary tumor locations were associated with unique patterns of metastatic spread in UTUC patients.

A multi-institutional validation of the prognostic value of the neutrophil-to-lymphocyte ratio for upper tract urothelial carcinoma treated with radical nephroureterectomy.

BACKGROUND: To externally validate the prognostic impact of preoperative neutrophil-lymphocyte ratio (pre-NLR) in patients with upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy (RNU). METHODS: A total of 665 patients from 12 institutions were included. The median follow-up was 28 months. Associations between pre-NLR level and outcome were assessed using multivariate analysis. A pre-NLR level of >3.0 was defined as elevated. RESULTS: Pre-NLR levels were elevated in 184 patients (27.7 %), and pre-NLR elevation was significantly associated with worse pathological features such as tumor grade 3, advanced pT stage, positive lymphovascular invasion (LVI), and lymph node involvement in RNU specimens. The 5-year recurrence-free and cancer-specific survival rates were 57.0 % (p < 0.001) and 60.2 % (p < 0.001), respectively, in patients with elevated pre-NLR, and 69.2 and 77.3 %, respectively, in their counterparts. Multivariate analysis showed that elevated pre-NLR was an independent risk factor for predicting subsequent disease recurrence (p = 0.037; hazard ratio (HR) 1.38) and cancer-specific mortality (p = 0.036;, HR 1.47), although the addition of pre-NLR slightly improved the accuracies of the base model for predicting both disease recurrence and cancer-specific mortality to 79.8 % (p = 0.041) and 83.0 % (p = 0.039), respectively (gain in predictive accuracy: 0.2 and 0.1 %, respectively). CONCLUSION: This multi-institutional study revealed that elevated pre-NLR was significantly associated with worse pathological features such as tumor grade 3, advanced pT stage, positive LVI, and lymph node involvement in RNU specimens, and elevated pre-NLR was an independent risk factor of disease recurrence and cancer-specific mortality in UTUC patients treated with RNU.

Independent predictors for bladder outcomes after treatment of intravesical recurrence following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma.

BACKGROUND: Few studies have described the clinical courses and outcomes in the bladder after treatment of intravesical recurrence after radical nephroureterectomy (RNU) in patients with primary upper tract urothelial carcinoma (UTUC). We investigated the indicators for predicting subsequent bladder outcomes after treatment of intravesical recurrence after RNU. METHODS: A total of 241 patients with primary UTUC (pTa-4N0M0) who experienced intravesical recurrence after RNU were included. Of these patients, 101 (41.9 %) underwent Bacillus Calmette-Guérin treatments, whereas 49 (20.3 %) underwent intravesical chemotherapy. The median follow-up period after initial transurethral resection of the bladder tumor was 33 months. Relationships with bladder outcomes were analyzed by using multivariable analysis. RESULTS: Ninety-six patients experienced intravesical recurrence, and bladder progression was observed in 13. Cumulative incidence rates of intravesical recurrence at 1 and 5 years after treatment of the first intravesical recurrence were 31.0 and 48.4 %, whereas those of bladder progression at 1 and 5 years thereafter were 2.4 and 8.0 %. Multivariate analysis showed that the number of recurrent tumors and pT1 tumors at the time of the first intravesical relapse were independent risk factors for subsequent intravesical recurrence. With respect to bladder progression, multivariate analysis showed that pT1 tumors, the appearance of concomitant carcinoma-in situ at the time of the first intravesical relapse, and the absence of the Bacillus Calmette-Guérin treatment were independent risk factors. CONCLUSIONS: This retrospective study presents a detailed picture of further bladder outcomes after intravesical recurrence after RNU in primary UTUC patients. The results may assist physicians to develop a more rational protocol in bladder surveillance.

[Synchronous male bladder cancer and breast cancer - a case report].

A 74-year-old man complained of blood in his urine over a 1-week period beginning in early October 2013, and was examined in the urology department of our hospital. A thorough examination revealed bladder cancer, and surgery was planned after two cycles of preoperative gemcitabine plus cisplatin chemotherapy. A chest computed tomography (CT) performed to evaluate the response to chemotherapy revealed a mass in the right breast. The patient had previously complained about the same site, and mammography and ultrasonography had suggested the possibility of a malignant mammary gland tumor. The results of aspiration cytology were Class V, and based on that finding, a diagnosis of cancer of the right breast was made. In February 2014, we performed a mastectomy, while preserving the pectoral muscles, along with sentinel node biopsy, total cystectomy, urethrectomy, pelvic lymph node dissection, and ureteroileal anastomosis. The histopathological diagnosis of the right breast tumor was invasive ductal carcinoma[scirrhous carcinoma, ly (+), v (-), g (+), f (+), s (+), nuclear grade 1=atypia 2+mitosis 1, EIC (-), ICT (-), NCAT (-)]. A micrometastatic tumor measuring approximately 1mm was observed in the sentinel lymph node. The breast disease was classified as pT1N1mi(sn)M0, Stage IIA, and the tumor was ER (+), PgR (+), HER2/neu (2+), and FISH (-). The bladder cancer was diagnosed as urothelial carcinoma, non-papillary, invasive G2>G3, pT2a; no pelvic lymph node metastases were detected, and it was classified as pT2aN0M0, Stage II. Synchronous male breast cancer and bladder cancer is a very rare condition, and we report the case with a review of the literature.

Patient characteristics and outcomes in metastatic upper tract urothelial carcinoma after radical nephroureterectomy: the experience of Japanese multi-institutions.

OBJECTIVES: To investigate oncological outcomes and prognostic factors in patients with upper tract urothelial carcinoma (UTUC) who experienced disease recurrence after radical nephroureterectomy (RNU). Few studies have focused on the clinical courses of patients who experienced disease recurrence after RNU. PATIENTS AND METHODS: A total of 204 UTUC patients who experienced disease recurrence from a retrospective multi-institutional cohort were included in the present study. Associated patient outcomes were analyzed using multivariate analysis. RESULTS: The mean time from RNU to first disease recurrence was 15.0 months and ≈90% of patients experienced disease recurrence within the first 3 years after RNU. During a median follow-up of 8.1 month after disease recurrence, 165 patients died from UTUC and five patients died from other causes. In the 204 cohorts, 1- and 3-year cancer-specific survival rates were 40.2% and 9.7%, respectively, and 1- and 3-year overall survival rates were 39.5% and 9.4%, respectively. After disease recurrence, 132 patients underwent systemic chemotherapy, and a subgroup analysis of patients who underwent systemic chemotherapy multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently prognostic of cancer-specific and overall survival after relapsing. According to three significant variables, 1- and 3-year cancer-specific survival rates were 72.7% and 20.8% in patients with no risk factors, 46.5% and 7.5% in patients with one risk factor, and 26.4% and 4.4% in patients with two or three risk factors, respectively (P < 0.001). CONCLUSIONS: Most patients died from UTUC within 3 years, even though systemic chemotherapies were administered after relapsing. Multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently related to poor survival after systemic chemotherapy.

The soybean F3'H protein is localized to the tonoplast in the seed coat hilum.

We previously isolated a soybean (Glycine max (L.) Merr.) flavonoid 3'-hydroxylase (F3'H) gene (sf3'h1) corresponding to the T locus, which controls pubescence and seed coat color, from two near-isogenic lines (NILs), To7B (TT) and To7G (tt). The T allele is also associated with chilling tolerance. Here, Western-blot analysis shows that the sf3'h1 protein was predominantly detected in the hilum and funiculus of the immature seed coat in To7B, whereas sf3'h1 was not detected in To7G. A truncated sf3'h1 protein isolated from To7G was detected only upon enrichment by immunoprecipitation. An analysis using diphenylboric acid 2-aminoethyl ester (DBPA) staining revealed that flavonoids accumulated in the hilum and the funiculus in both To7B and To7G. Further, the scavenging activity of the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical in methanol extracts from the funiculus and hilum of To7B was higher than that of To7G. Moreover, the enzymatic activity of F3'H was detected using microsomal fractions from yeast transformed with sf3'h1 from To7B, but not from To7G. These results indicate that sf3'h1 is involved in flavonoid biosynthesis in the seed coat and affects the antioxidant properties of those tissues. As shown by immunofluorescence microscopy, the sf3'h1 protein was detected primarily around the vacuole in the parenchymatic cells of the hilum in To7B. Further immunoelectron microscopy detected sf3'h1 protein on the membranous structure of the vacuole. Based on these observations, we conclude that F3'H, which is a cytochrome P450 monooxygenase and has been found to be localized to the ER in other plant systems, is localized in the tonoplast in soybean.

Renal cell carcinoma arising from a horseshoe kidney in a chronic hemodialysis patient.

A 60-year-old man undergoing hemodialysis for 13 years was referred to our department for evaluation of gross hematuria and a right renal mass. Voided urine cytology was negative. Computed tomography and magnetic resonance imaging demonstrated a right renal mass (32 × 22 × 20 mm in diameter). We clinically diagnosed the tumor as renal cell carcinoma staged T1aN0M0 arising from a horseshoe kidney, and performed right heminephrectomy. Pathological examination of the surgical specimen showed a grade 2, pT1a, clear cell carcinoma and negative surgical margin. To our knowledge, this is a rare case of a renal cell carcinoma arising from a horseshoe kidney in a chronic hemodialysis patient.