Membranous Expression of Heart Development Protein with EGF-like Domain 1 Is Associated with a Good Prognosis in Patients with Bladder Cancer.

OBJECTIVE: To investigate the correlation between total protein expression of heart development protein with EGF-like domain 1 (HEG1) and clinicopathological characteristics in patients with bladder cancer (BC) after radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively analyzed data from 110 patients who underwent RC at Kitasato University Hospital. And we prepared an anti-HEG1 monoclonal antibody W10B9, which can detect total HEG1 protein. HEG1 protein expression in tumor cells was evaluated separately for membrane and cytoplasmic staining using immunohistochemistry. RESULTS: Membranous HEG1 expression was associated with absent lymphovascular invasion (p < 0.01) and low pT stage (p < 0.01). Kaplan-Meier analysis revealed that the membranous HEG1-positive group had significantly long recurrence-free survival (RFS) (p < 0.01) and cancer-specific survival (p = 0.01). Expression of membranous HEG1 was identified as an independent prognostic factor for RFS (p = 0.04). There were no significant differences between cytoplasmic HEG1 expression and clinicopathologic factors including prognosis. CONCLUSION: The expression of membranous HEG1 could serve as a favorable prognostic indicator in patients with BC treated with RC.

Expression of S100A16 Is Associated with Biological Aggressiveness and Poor Prognosis in Patients with Bladder Cancer Who Underwent Radical Cystectomy.

S100 calcium binding protein A16 (S100A16) is expressed in various cancers; however, there are few reports on S100A16 in bladder cancer (BC). We retrospectively investigated clinical data including clinicopathological features in 121 patients with BC who underwent radical cystectomy (RC). Immunohistochemical staining was performed to evaluate S100A16 expression in archived specimens. Cases with >5% expression and more than moderate staining intensity on cancer cells were considered positive. S100A16 expression was observed in 54 patients (44.6%). Univariate analysis showed that S100A16 expression was significantly associated with age, pT stage, recurrence, and cancer-specific death. Kaplan-Meier analyses showed that patients with S100A16 expression had shorter overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) than those without S100A16 expression. In multivariate analysis, pT stage was an independent prognostic factor for OS and lymph node metastasis for CSS and RFS. S100A16 expression may be a biomarker of a biologically aggressive phenotype and poor prognosis in patients with BC who underwent RC. The PI3k/Akt signaling pathway is probably associated with S100A16 and may be a therapeutic target.

Gemcitabine-Paclitaxel Chemotherapy for Patients with Advanced Urothelial Cancer Refractory to Cisplatin-Based Chemotherapy: Predictive Role of PGK1 for Treatment Response to Cytotoxic Chemotherapy.

An investigation of alternatives to immune checkpoint inhibitors for advanced urothelial cancer (aUC), with biologic information, is urgently needed. Clinical data for 53 patients who received gemcitabine-paclitaxel therapy (GP) as 2nd-line chemotherapy for aUC refractory to platinum-based chemotherapy were retrospectively reviewed. The efficacy and tolerability of GP were evaluated, and the predictive value of phosphoglycerate kinase 1 (PGK1) immunostained in surgical specimens was investigated for treatment outcomes in 1st- and 2nd-line chemotherapy. GP was associated with an objective response rate of 35.8% and a median overall survival duration of 12.3 months. Multivariate analysis showed that PS2 and 1st- and 2nd-line non-response are independent predictors of worse progression-free survival and that PS2 and 1st-line non-response are independent predictors of worse overall survival. Adverse events were manageable, and no therapy-related deaths occurred. Non-response rates to 1st-line chemotherapy were significantly higher in patients with a high expression of PGK1 in the nucleus than in those with low expression (p = 0.006). Our study demonstrates the efficacy and tolerability of 2nd-line GP for patients with aUC who are refractory to platinum-based chemotherapy. Moreover, PGK1 in the nucleus was predictive values for resistance to platinum-based chemotherapy in aUC.

DJ-1 Expression Might Serve as a Biologic Marker in Patients with Bladder Cancer.

The overexpression of DJ-1 protein and its secretion into the bloodstream has been reported in various neoplasms. However, serum levels and the subcellular localization of DJ-1 have not been analyzed in detail in bladder cancer (BC). Our comprehensive analysis of these variables started with the measurement of DJ-1 in serum from 172 patients with BC, 20 patients with urolithiasis and 100 healthy participants. Next, an immunohistochemical study of DJ-1 expression and localization was conducted in 92 patients with BC, and associations with clinicopathologic factors and patient outcomes were evaluated. Serum DJ-1 was significantly higher in patients with BC than in those with urolithiasis or in healthy participants. Immunohistochemically, a cytoplasm-positive (Cy+) and nucleus-negative (N-) DJ-1 pattern was associated with age and pathologic stage. Log-rank tests indicated that the Cy+, N- pattern was significantly associated with overall survival (OS), recurrence-free survival (RFS), and cancer specific survival (CSS). In addition, the Cy+, N- pattern was an independent prognostic factor in the multivariate analysis adjusted for the effects of the clinicopathologic outcomes. The investigation of DJ-1 expression might help physicians to make decisions regarding further follow-up and additional treatments.

Expression of Membranous CD155 Is Associated with Aggressive Phenotypes and a Poor Prognosis in Patients with Bladder Cancer.

Objective: To investigate the relationship between clinicopathological findings and membranous CD155 (mCD155) or cytoplasmic CD155 (cCD155) expression in bladder cancer (BC). Methods: We retrospectively analyzed 103 patients with BC who underwent radical cystectomy between 1990 to 2015 at Kitasato University Hospital. Immunohistochemical staining was performed to evaluate CD155 expression in tumor cells. Cases with > 10% expression on the membrane or cytoplasm of tumor cells were positive. The Fisher's exact test was used for categorical variables and the Kaplan−Meier method was used for survival outcomes. Univariate and multivariate Cox regression hazard models were used to evaluate the survival risk factors. Results: Cases that were mCD155-positive were associated with high-grade tumors (p = 0.02), nodal status (p < 0.01), and pT stage (p = 0.04). No association with any clinicopathological factor was observed in the cCD155 cases. Kaplan−Meier analysis showed that mCD155-positive cases had shorter periods of recurrence-free survival (p = 0.015) and cancer-specific survival (p = 0.005). Only nodal status was an independent predictor for both cancer-specific survival and recurrence-free survival in multivariate analysis (p = 0.02 and p < 0.01, respectively). Conclusion: mCD155 expression may be a marker of an aggressive phenotype and a poor prognosis in patients with BC.

Serum Epiplakin Might Be a Potential Serodiagnostic Biomarker for Bladder Cancer.

Tumor markers that can be detected at an early stage are needed. Here, we evaluated the epiplakin expression levels in sera from patients with bladder cancer (BC). Using a micro-dot blot array, we evaluated epiplakin expression levels in 60 patients with BC, 20 patients with stone disease, and 28 healthy volunteers. The area under the curve (AUC) and best cut-off point were calculated using receiver-operating characteristic (ROC) analysis. Serum epiplakin levels were significantly higher in patients with BC than in those with stone disease (p = 0.0013) and in healthy volunteers (p < 0.0001). The AUC-ROC level for BC was 0.78 (95% confidence interval (CI) = 0.69-0.87). Using a cut-off point of 873, epiplakin expression levels exhibited 68.3% sensitivity and 79.2% specificity for BC. However, the serum epiplakin levels did not significantly differ by sex, age, pathological stage and grade, or urine cytology. We performed immunohistochemical staining using the same antibody on another cohort of 127 patients who underwent radical cystectomy. Univariate and multivariate analysis results showed no significant differences between epiplakin expression, clinicopathological findings, and patient prognoses. Our results showed that serum epiplakin might be a potential serodiagnostic biomarker in patients with BC.

Prognostic Impact of AHNAK2 Expression in Patients Treated with Radical Cystectomy.

Data regarding expression levels of AHNAK2 in bladder cancer (BCa) have been very scarce. We retrospectively reviewed clinical data including clinicopathological features in 120 patients who underwent radical cystectomy (RC) for BCa. The expression levels of AHNAK2 in the specimens obtained by RC were classified as low expression (LE) or high expression (HE) by immunohistochemical staining. Statistical analyses were performed to compare associations between the two AHNAK2 expression patterns and the prognoses in terms of recurrence-free survival (RFS) and cancer-specific survival (CSS). A Kaplan-Meier analysis showed that patients with HE had a significantly worse RFS and CSS than those with LE (hazard ratio [HR]: 1.78, 95% confidence interval [CI]: 1.02-2.98, p = 0.027 and HR: 1.91, 95% CI: 1.08-3.38, p = 0.023, respectively). In a multivariate analysis, independent risk factors for worse RFS and CSS were shown as HE (HR: 1.96, 95% CI: 1.08-3.53, p = 0.026 and HR: 2.22, 95% CI: 1.14-4.31, p = 0.019, respectively) and lymph node metastasis (HR: 2.04, 95% CI: 1.09-3.84, p = 0.026 and HR: 1.19, 95% CI: 1.25-4.97, p = 0.009, respectively). The present study showed that AHNAK2 acts as a novel prognostic biomarker in patients with RC for BCa.

High HNRNPA3 expression is associated with lymph node metastasis and poor prognosis in patients treated with radical cystectomy.

OBJECTIVE: We sought to identify heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) expression in bladder cancer and its relationship to clinicopathological findings and prognosis. METHODS: Immunohistochemical staining for HNRNPA3 was performed on 122 archived radical cystectomy specimens, with immunoreactivity being stratified on a 0 to 3 scale. The percentage of HNRNPA3 expressing tumor cells was calculated and multiplied by the staining score over an average of 5 areas to obtain a semiquantitative H-score (maximum value: 300). HNRNPA3 expression was categorized as high (≥80) or low (<80). RESULTS: The patients' median age was 70 years, and the median follow-up period was 39.4 months. High HNRNPA3 expression was significantly associated with lymph node metastasis (P= 0.014) and S100A8, S100A9 and uroplakin III expression (P= 0.028, 0.002, and 0.047, respectively). Log-rank tests indicated that high HNRNPA3 expression was significantly associated with disease progression and cancer-specific death (P= 0.013 and 0.006, respectively). In the Cox proportional hazards regression analysis, only lymph node metastasis was associated with disease progression and cancer-specific survival. CONCLUSION: HNRNPA3 may be a new biomarker to predict biologically aggressive cancers and determine the appropriate treatment modality in patients after radical cystectomy.

PD-L1 expression in tumor-infiltrating lymphocytes (TILs) as an independent predictor of prognosis in patients with pN0 bladder cancer undergoing radical cystectomy.

OBJECTIVES: Checkpoint inhibitors have led to a paradigm shift in urothelial carcinoma (UC) treatment. However, the relationship between PD-L1 expression status and oncological outcomes in UC patients remains uncertain. Here, we investigated the prognostic value of PD-L1 expression status in patients with UC of the bladder (UCB) who underwent radical cystectomy (RC). MATERIALS AND METHODS: We retrospectively analyzed pathological specimens from 97 UCB patients treated with RC from 1990 to 2015 at Kitasato University Hospital. Immunohistochemical staining using SP263 was performed to evaluate PD-L1 expression in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs). Kaplan-Meier plots and proportional Cox hazard ratios were examined to assess the relationship between PD-L1 expression and clinicopathological parameters and survival outcomes. RESULTS: Of the 97 specimens, 19.5% contained PD-L1-positive TCs, and 35.0% contained PD-L1-positive TILs. Regarding clinicopathological factors, PD-L1-positive TCs and TILs were significantly associated with high-grade tumors (TCs, P = 0.01; TILs, P = 0.003). Kaplan-Meier analyses showed that PD-L1-positive TCs were not correlated with survival rates. However, PD-L1-positive TILs were significantly associated with better recurrence-free survival (RFS; P = 0.03) and better cancer-specific survival (CSS; P = 0.02). Univariate analysis, but not multivariate analysis, CSS indicated that PD-L1-positive TILs were significant predictors of patient prognoses. Multivariate analysis showed that PD-L1-positive TILs independently predicted CSS in patients without lymph node metastasis (pN0). CONCLUSION: Positive PD-L1 expression is associated with high-grade tumors. PD-L1-positive TILs are independent predictors of favorable survival outcomes in surgically resected UCB patients at stage pN0.

Electronic nose to distinguish bladder cancer by urinary odour feature: A pilot study.

BACKGROUND: No study has yet investigated the use of electronic nose (eNose) technology to reveal pattern recognition of urological diseases, including bladder cancer. OBJECTIVE: We sought to determine the diagnostic performance of the eNose in recognizing urinary odour in patients with bladder cancer. METHODS: The eNose is a commercially available model equipped with two sensors. The angle of the two sensors (θ) depends on the kinds of chemical substances, thus defining θ as the feature of odour. Quantity of odour is the number of θ detected during a measurement. Urine samples were from 36 untreated patients with bladder cancer, 29 with urolithiasis, 10 with urinary tract infection (UTI), and 27 healthy volunteers. RESULTS: Based on ROC analysis of the quantity in patients with bladder cancer, an optimal cut-off value for θ of 49, 48, and 55 was applied to compare with samples from the healthy volunteer, urolithiasis and UTI groups, respectively. There were significantly differences between bladder cancer and the other conditions using these specific points (p< 0.0001, respectively). The resulting diagnostic sensitivity was 61.4%, 45.6%, and 60.8%, and specificity was 52.8%, 68.4%, and 90.2%, respectively. The AUC for bladder cancer was 0.565, 0.548, and 0.909, respectively. CONCLUSION: The eNose is a small, portable, rapid, low cost, and noninvasive instrument for distinguishing bladder cancer from other benign conditions.

Long-term mood/antidepressant effects of quetiapine extended-release formulation: an open-label, non-controlled extension study in Japanese patients with bipolar depression.

BACKGROUND: In an 8-week, randomized, placebo-controlled, double-blind study, an extended-release formulation of quetiapine, quetiapine XR, demonstrated efficacy and safety in Japanese patients with bipolar depression. Bipolar disorder is a chronic disease requiring continuous treatment. METHODS: This was a long-term (52-week), open-label, non-controlled extension study to evaluate the long-term safety and efficacy of quetiapine XR in Japanese patients with bipolar depression who had previously completed the initial 8-week double-blind study. Efficacy was determined by the Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Depression Scale 17-item (HAM-D17), and Clinical Global Impressions-Bipolar scale (CGI-BP). Safety evaluations included analysis of adverse events, clinical laboratory measures, vital signs, Drug-induced Extrapyramidal Symptoms Scale, Young Mania Rating Scale, and the Columbia Suicide Severity Rating Scale. RESULTS: The mean (SD) MADRS total score decreased from 30.9 (6.9) at baseline to 16.1 (10.6) at week 8, and eventually to 9.1 (8.7) at week 52. The sustained efficacy of quetiapine XR treatment was also shown using HAM-D17 total scores, CGI-BP-Severity and Change evaluations. The most common adverse events were somnolence, nasopharyngitis, and thirst. Long-term treatment with quetiapine XR caused no substantial changes in the safety profiles, including clinical laboratory parameters, and no new safety concerns were identified. CONCLUSIONS: The efficacy of quetiapine XR was sustained long-term and no new safety concerns were identified in Japanese patients with bipolar depression. TRIAL REGISTRATION: ClinicalTrials.gov Registration: NCT01725308. Date of registration; 12th November 2012 (retrospectively registered).

TROY expression is associated with pathological stage and poor prognosis in patients treated with radical cystectomy.

BACKGROUND: New biomarkers may help us provide individualized prognosis and allow risk-stratified clinical decision making about radical treatment. OBJECTIVES: This study aimed to determine the tumor necrosis factor of receptor superfamily 19 (TROY) expression in urothelial carcinoma and its relationship to clinicopathological findings. METHODS: Immunohistochemical staining for TROY was carried out in 136 archival radical cystectomy specimens with immunoreactivity being stratified on a 0-9 scale. Expression scores for TROY were further stratified into negative (score 0) and positive (score 1 or greater). Median age was 65 years, and the median follow-up period was 50.7 months. RESULTS: Expression of TROY was significantly associated with the pathological stage (p= 0.019) and expression of nestin (p= 0.013). Log-rank tests indicated that expression of TROY was significantly associated with disease progression and cancer-specific mortality (p= 0.044 and 0.008, respectively). In multivariate Cox regression analysis, lymph node status was the only independent prognostic factor for disease progression and cancer-specific survival. Expression of TROY was a marginal prognostic factor for cancer-specific survival. CONCLUSIONS: TROY may therefore be a new molecular marker to aid in identifying and selecting patients undergoing radical cystectomy who could potentially benefit from multimodal treatment.

Correction to: Multi-center, randomized, double-blind, placebocontrolled study of quetiapine extended-release formulation in Japanese patients with bipolar depression.

The original version of this article contained a mistake in Table 5. Correct version is presented here.

Multi-center, randomized, double-blind, placebo-controlled study of quetiapine extended-release formulation in Japanese patients with bipolar depression.

RATIONALE: Quetiapine fumarate is an atypical antipsychotic indicated for various mental disorders, but it has not been studied in Japanese patients with bipolar depression. OBJECTIVES: To evaluate the efficacy and safety of quetiapine XR (extended release) in Japanese patients with bipolar depression. METHODS: In this multi-center, randomized, double-blind, placebo-controlled, fixed-dose study of 431 Japanese adults with bipolar I or II disorder, efficacy was determined by analyzing the mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary end points included MADRS response and remission rates, Hamilton Depression Scale 17-Item (HAM-D17), and Clinical Global Impressions-Bipolar (CGI-BP) scale scores. Safety was determined by monitoring adverse events and clinical assessments. RESULTS: This study revealed a statistically significantly greater decrease in MADRS total score after 8 weeks of quetiapine XR 300 mg/day monotherapy compared with placebo (- 12.6 vs. - 10.1; p = 0.034). There were also improvements in MADRS response (44.1 vs. 35.6%) and remission (38.0 vs. 26.6%) rates as well as in HAM-D17 and CGI-BP scale scores compared with placebo. In the subgroup analysis of patients with bipolar I or II disorder, the adjusted mean changes in MADRS total score compared to placebo were - 2.3 and - 2.1, respectively. Adverse events occurred in 149 patients (83.2%) receiving quetiapine XR 300 mg/day and in 81 patients (45.8%) receiving placebo. The most common adverse events were somnolence and thirst, which is consistent with the previously reported safety profile. CONCLUSIONS: Once-daily monotherapy with quetiapine XR is an effective and well-tolerated treatment for bipolar depression in Japanese patients.

Increased protein level of PEPT1 intestinal H+-peptide cotransporter upregulates absorption of glycylsarcosine and ceftibuten in 5/6 nephrectomized rats.

In chronic renal failure (CRF), dietary protein is one of the factors that deteriorates residual renal functions. Numerous studies have indicated that the products of protein digestion are mainly absorbed as small peptides. However, how small peptides are absorbed in CRF remains poorly understood. H(+)-coupled peptide transporter (PEPT1/SLC15A1) plays an important role in the absorption of small peptides and peptide-like drugs in the small intestine. Because dietary protein intake is one of the risk factors for renal failure, the alteration of intestinal PEPT1 might have implications in the progression of renal disease as well as the pharmacokinetics of peptide-like drugs. In this study, we examined the alteration of intestinal PEPT1 in 5/6 nephrectomized (5/6 NR) rats, extensively used as a model of chronic renal failure. Absorption of [(14)C]glycylsarcosine and ceftibuten was significantly increased in 5/6 NR rats compared with sham-operated rats, without a change in intestinal protease activity. Western blot analysis indicated that the amount of intestinal PEPT1 protein in 5/6 NR rats was increased mainly at the upper region. On the other hand, the amount of intestinal PEPT1 mRNA was not significantly different from that of sham-operated rats. These findings indicate that the increase in absorption of small peptides and peptide-like drugs, caused by the upregulation of intestinal PEPT1 protein, might contribute to the progression of renal failure as well as the alteration of drug pharmacokinetics.