IDH2 stabilizes HIF-1α-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer.

Drug resistance contributes to poor therapeutic response in urothelial carcinoma (UC). Metabolomic analysis suggested metabolic reprogramming in gemcitabine-resistant urothelial carcinoma cells, whereby increased aerobic glycolysis and metabolic stimulation of the pentose phosphate pathway (PPP) promoted pyrimidine biosynthesis to increase the production of the gemcitabine competitor deoxycytidine triphosphate (dCTP) that diminishes its therapeutic effect. Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1α expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity. Since the expression of key metabolic enzymes, such as TIGAR, TKT, and CTPS1, were affected by IDH2-mediated metabolic reprogramming and related to poor prognosis in patients, IDH2 might become a new therapeutic target for restoring chemosensitivity in chemo-resistant urothelial carcinoma.

Vasohibin-1 Expression Can Predict Pathological Complete Remission of Advanced Bladder Cancer with Neoadjuvant Chemotherapy.

BACKGROUND AND PURPOSE: Neoadjuvant chemotherapy (NAC) is a well-established standard practice in invasive bladder cancer (BCa), however patient selection remains challenging. High expression of vasohibin-1 (VASH1), an endogenous regulator of angiogenesis, has been reported in high-grade and advanced BCa; however, its prognostic value for chemotherapy outcomes remains unexplored. In this study, we sought to identify biomarkers of chemotherapy response focusing on the relationship between angiogenesis and tissue hypoxia. METHODS: Forty Japanese patients with BCa who underwent NAC and radical cystectomy were included in the present analysis. We compared the immunohistochemical expression of CD34, VASH1, and carbonic anhydrase 9 (CA9) between patients who achieved tumor clearance at operation (ypT0) and those with residual disease after cystectomy. RESULTS: There were 19 patients in the ypT0 group, while the remaining 21 patients had residual tumors at operation. Patients in the ypT0 group had high microvessel density (p = 0.031), high VASH1 density (p < 0.001), and stronger CA9 staining (p = 0.046) than their counterparts. Multivariate analysis identified microvessel and VASH1 density as independent predictive factors for pathological ypT0 disease (p = 0.043 and 0.002, respectively). The 5-year recurrence-free survival rate was higher in the high VASH1 density group than in the low VASH1 density group (66.3% vs. 33.3%, p = 0.036). CONCLUSION: VASH1 density is a potential therapeutic biomarker for chemotherapy response in BCa.

Prediction of pathological up-staging after radical nephroureterectomy in patients with upper tract urothelial carcinoma.

PURPOSE: The diagnostic accuracy of computed tomography urography for upper tract urothelial carcinoma is high; however, difficulties are associated with precisely assessing the T stage. Preoperative tumor staging has an impact on treatment options for upper tract urothelial carcinoma. We herein attempted to identify preoperative factors that predict pathological tumor up-staging, which will facilitate the selection of treatment strategies. MATERIALS AND METHODS: We retrospectively identified 148 patients with upper tract urothelial carcinoma who underwent computed tomography urography preoperatively followed by radical nephroureterectomy without preoperative chemotherapy at our institution between 2000 and 2021. Preoperative factors associated with cT2 or lower to pT3 up-staging were examined using a multivariate logistic regression analysis. RESULTS: Ninety out of 148 patients were diagnosed with cT2 or lower, and 22 (24%) were up-staged to pT3. A multivariate analysis identified a positive voided urine cytology (HR 4.69, p = 0.023) and tumor length ≥ 3 cm (HR 6.33, p = 0.003) as independent predictors of pathological tumor up-staging. CONCLUSIONS: Patients diagnosed with cT2 or lower, but with preoperative positive voided urine cytology and/or tumor diameter ≥ 3 cm need to be considered for treatment as cT3.

Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).

Effectiveness and safety of primary prophylaxis of G-CSF during chemotherapy for prostate cancer, Japanese clinical guideline for appropriate use of G-CSF: clinical practice guidelines for the use of G-CSF 2022.

BACKGROUND: Docetaxel (DTX) is commonly used as a primary chemotherapy, and cabazitaxel (CBZ) has shown efficacy in patients who are DTX resistant. Primary prophylactic granulocyte colony stimulating factor (G-CSF) therapy is currently used with CBZ treatment in routine clinical care in Japan. METHODS: In this study, we performed a systematic review following the Minds guidelines to investigate the effectiveness and safety of primary prophylaxis with G-CSF during chemotherapy for prostate cancer and to construct G-CSF guidelines for primary prophylaxis use during chemotherapy. A comprehensive literature search of various electronic databases (PubMed, Cochrane Library, and Ichushi) was performed on January 10, 2020, to identify studies published between January 1990 and December 31, 2019 that investigate the impact of primary prophylaxis with G-CSF during CBZ administration on clinical outcomes. RESULTS: Ultimately, nine articles were included in the qualitative systematic review. Primary G-CSF prophylaxis during CBZ administration for metastatic castration-resistant prostate cancer was difficult to assess in terms of correlation with overall survival, mortality from infection, and patients' quality of life. These difficulties were owing to the lack of randomized controlled trials comparing patients with and without primary prophylaxis of G-CSF during CBZ administration. However, some retrospective studies have suggested that it may reduce the incidence of febrile neutropenia. CONCLUSION: G-CSF may be beneficial as primary prophylaxis during CBZ administration for metastatic castration resistant prostate cancer, and we made a "weak recommendation to perform" with an annotation of the relevant regimen.

Potential therapeutic effects of adjuvant chemotherapy after neoadjuvant chemotherapy for locally advanced muscle-invasive bladder cancer.

BACKGROUND: Although the administration of neoadjuvant chemotherapy has been associated with improved prognosis in patients with muscle-invasive bladder cancer, the therapeutic effects of adjuvant chemotherapy remain unknown in real-world settings. Therefore, we herein evaluated the clinical outcomes of adjuvant chemotherapy in pT3/4 muscle-invasive bladder cancer patients. MATERIALS AND METHODS: Among 587 bladder cancer patients who underwent radical cystectomy, 200 with a pathological T3 or higher muscle-invasive bladder cancer were included in the present analysis. Recurrence-free survival and cancer-specific survival were assessed by multivariate Cox regression analysis. RESULTS: Median age was 73 years, and the median follow-up duration was 17 months. The 5-year cancer-specific survival rate was 53.6% in 66 patients treated with adjuvant chemotherapy, which was significantly higher than that in those without adjuvant chemotherapy (34.0%, P = 0.025). The absence of adjuvant chemotherapy (hazard ratio = 2.114, P = 0.004) and lymphovascular invasion (hazard ratio = 2.203, P = 0.011) was identified as independent prognostic indicators for cancer-specific death. In patients treated without neoadjuvant chemotherapy (n = 143), the absence of adjuvant chemotherapy (hazard ratio:1.887, P = 0.030) remained an independent indicator for cancer-specific death. For those treated with adjuvant chemotherapy without neoadjuvant chemotherapy, three or more adjuvant chemotherapy cycles were independently associated with favourable outcome (hazard ratio = 0.240, P = 0.009). In contrast, for neoadjuvant chemotherapy-treated patients (N = 57), adjuvant chemotherapy was not independently associated with disease recurrence or cancer-specific death. CONCLUSION: Adjuvant chemotherapy was associated with improvements in the prognosis of patients, even in those with pT3 or higher muscle-invasive bladder cancer. Although three or more cycles of adjuvant chemotherapy were effective for muscle-invasive bladder cancer patients treated without neoadjuvant chemotherapy, no therapeutic advantages were observed with additional adjuvant chemotherapy in patients treated with neoadjuvant chemotherapy.

How long should urologists observe patients with prostate cancer after radical prostatectomy? Weibull analysis.

OBJECTIVES: There is no recommended observation time for patients who have undergone radical prostatectomy for prostate cancer. This study was undertaken to determine the postoperative observation time by investigating the hazard rate for prostate-specific antigen failure and other-cause death using Weibull analysis. METHODS: We included 612 patients who underwent laparoscopic radical prostatectomy for localized prostate cancer between June 2002 and December 2017. Risk classification was categorized by the D'Amico risk classification, and the patients were divided into three age groups: <60, 60-69 and ≥70 years. The hazard rates at each point were derived using Weibull analysis. The optimal observation time after laparoscopic radical prostatectomy was determined as the intersection point at which the hazard rate of other-cause death overtakes the hazard rate of prostate-specific antigen failure. RESULTS: In all groups classified by age, the hazard rate of other-cause deaths increased over time. In contrast, the hazard rate of prostate-specific antigen failure decreased gradually. The ≥70 years age group showed the highest hazard rate. The hazard rate of prostate-specific antigen failure was highest in the high-risk group. The patients aged ≥70 and 60-69 years in the low-risk group were recommended 6 years 6 months and 14 years 8 months, respectively, for observation. The remaining patients were recommended >25 years of postsurgical observation. CONCLUSIONS: The observation time after laparoscopic radical prostatectomy could be estimated by comparing the estimated hazard rates of prostate-specific antigen failure and other-cause death based on Weibull analysis. Urologists should pay attention to age and risk classifications for optimal postoperative observation.

Profiling the Biological Characteristics and Transitions through Upper Tract Tumor Origin, Bladder Recurrence, and Muscle-Invasive Bladder Progression in Upper Tract Urothelial Carcinoma.

To evaluate biological characteristics and transitions of upper tract urothelial carcinoma (UTUC) through metachronous bladder tumors after radical nephroureterectomy (RNU), we conducted immunohistochemical (IHC) staining of tumor specimens of UTUC tumor origin, non-muscle-invasive bladder cancer (NMIBC) and MIBC progressed after intravesical recurrence (IVR), and bladder primary MIBC. Fibroblast growth factor receptor 3 (FGFR3), p53, cytokeratin 5/6 (CK5/6), and CK20 were stained to examine expression rates. After expression assessment with heatmap clustering, the overexpression of four biomarkers from UTUC origin to metachronous MIBC progression was analyzed with clinicopathological variables. We found that high CK20 and low CK5/6 expression were both observed in UTUC tumor origin and subsequent NMIBC after RNU. By investigating molecular expression in the IVR specimen, we observed that low pT stage bladder recurrence occupied the majority of CK20 high CK5/6 low expression, but would change to CK20 low CK5/6 high expression as it progressed to MIBC. UTUC metachronous MIBC has different characteristics compared with bladder primary MIBC, which comprises favorable biological features such as high FGFR3 expression, and follows favorable prognosis compared to those without FGFR3 expression. The present study demonstrated that the biological characteristics of UTUC tumor origin shifts from luminal to basal-like features with progression to MIBC, but FGFR3 expression taken over from UTUC origin may comprise a favorable entity compared to primary MIBC.

The clinicopathological characteristics of muscle-invasive bladder recurrence in upper tract urothelial carcinoma.

This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.

Role of Previous Malignancy History in Clinical Outcomes in Patients with Initially Diagnosed Non-Muscle Invasive Bladder Cancer.

INTRODUCTION: Our aim is to evaluate whether previous non-urothelial malignant history affects the clinical outcomes of patients with non-muscle invasive bladder cancer (NMIBC). PATIENTS AND METHODS: We identified 1097 cases treated by transurethral resection of bladder tumors for initially diagnosed NMIBC at our four institutions between 1999 and 2017. We compared clinical characteristics and outcomes between NMIBC patients with and without previous non-urothelial malignant history and investigated whether smoking status and treatment modality for previous cancer affected NMIBC outcomes. RESULTS: A total of 177 patients (16.1%) had previous non-urothelial malignant history (malignant history group). The 5-year recurrence-free survival rate and the 5-year progression-free survival rate in the malignant history group was 46.4% and 88.3%, respectively, which was significantly lower than that in the counterpart (60.2% p = 0.004, and 94.5% p = 0.002, respectively). A multivariate Cox regression analysis identified previous non-urothelial malignant history as an independent risk factor for tumor recurrence (p = 0.001) and stage progression (p = 0.003). In a subgroup of patients who were current smokers (N = 347), previous non-urothelial malignant history was associated with tumor recurrence and stage progression. In contrast, previous non-urothelial malignant history was not associated with tumor recurrence or stage progression in ex-smokers or non-smokers. In a subgroup analysis of NMIBC patients with previous prostate cancer history, those treated with androgen deprivation therapy had a significantly lower bladder tumor recurrence rate than their counterparts (p = 0.027). CONCLUSIONS: Previous history of non-urothelial malignancy may lead to worse clinical outcome in patients with NMIBC, particularly current smokers.

Evaluating the Oncological Outcomes of Pure Laparoscopic Radical Nephroureterectomy Performed for Upper-Tract Urothelial Carcinoma Patients: A Multicenter Cohort Study Adjusted by Propensity Score Matching.

PURPOSE: To evaluate the oncological feasibility of pure laparoscopic radical nephroureterectomy (p-LRNU) for upper tract urothelial carcinoma (UTUC) compared with conventional LRNU (c-LRNU) using a propensity-adjusted multi-institutional collaboration dataset. METHODS: Among the 503 UTUC patients who underwent RNU, we identified 219 who underwent c-LRNU (laparoscopic nephrectomy with open bladder cuff resection) and 72 who underwent p-LRNU (dissecting the kidney, ureter, and bladder cuff under complete laparoscopy). We adopted a propensity score (PS) matching method to achieve homogeneity with respect to patient backgrounds. PS matching-adjusted Cox-regression analysis was performed to evaluate the risk factors that influenced oncological outcomes. RESULTS: Sixty-eight p-LRNU and 68 c-LRNU patients were matched. Overall, 51 (37.0%) developed intravesical recurrence (IVR), 21 (15.4%) had disease recurrence, and 20 (14.7%) died. Patients who underwent p-LRNU had a significantly shorter operation time and less blood loss than those who underwent c-LRNU. Although no significant differences in 3-year recurrence-free survival were found between the two methods, atypical recurrence sites were observed in the p-LRNU group, including the brain, sigmoid colon, vagina, and peritoneum. Regarding IVR, the 3-year IVR-free survival rate was 41.8% in the p-LRNU group, which was significantly lower than that in the c-LRNU group (66.6%, p = 0.004). Multivariate analysis demonstrated that a history of bladder cancer, ureteral cancer, and p-LRNU were independent risk factors for subsequent IVR. CONCLUSION: Although p-LRNU is less invasive, the current technique may increase the incidence of atypical disease recurrence and subsequent IVR due to extravesical and intravesical tumor dissemination.

Conditional Survival and Time of Biochemical Recurrence of Localized Prostate Cancer in Japanese Patients Undergoing Laparoscopic Radical Prostatectomies.

PURPOSE: Using conditional survival (CS) analysis, we investigated whether the duration of survival without biochemical recurrence (BCR) of prostate cancer after laparoscopic radical prostatectomies (LRP) affected the BCR rate. We also investigated the impact of well-known risk factors for BCR. METHODS: Between 2002 and 2014, 627 consecutive patients underwent LRPs at our institution. Prostate-specific antigen (PSA) concentrations above 0.2  ng/mL were defined as BCR. Conditional BCR-free survival rates were determined through Kaplan-Meier analysis. Assessment of potential BCR risk factors was performed using a Cox proportional hazard analysis. RESULTS: The 10-year BCR-free rates after LRP increased to 82.4%, 84.5%, 86.6%, 90.1%, and 94.7% in patients surviving 1, 2, 3, 5, and 7.5 years without BCR, respectively. Multivariate analyses of age, PSA concentrations, neoadjuvant therapy, and pathological findings were performed for all patients. In all patients, positive surgical margins (PSM) and Gleason Grade Groups (GG) ≥ 4 were independent risk factors for BCR (p < 0.001, hazard ratio [HR] = 2.45; and p < 0.001, HR = 2.83, respectively,). Similarly, PSM and GG ≥ 4 were significant risk factors in patients surviving 1-5 years without BCR. No clear risk factors were observed in patients surviving > 5 years without BCR after LRPs. CONCLUSIONS: The BCR-free rate increased with time after LRP. It is recommended that patients with PSM, GG ≥ 4, or with both factors are strictly monitored for 5 years postoperatively. CS analysis is particularly useful for predicting the postoperative course of patients.

Clinical utility of the Vesical Imaging-Reporting and Data System for muscle-invasive bladder cancer between radiologists and urologists based on multiparametric MRI including 3D FSE T2-weighted acquisitions.

OBJECTIVES: To investigate the clinical utility of the Vesical Imaging-Reporting and Data System (VI-RADS) by comparing its diagnostic performance for muscle-invasive bladder cancer (MIBC) between radiologists and urologists based on multiparametric MRI, including three-dimensional (3D) fast spin-echo (FSE) T2-weighted acquisitions. METHODS: This study included 66 treatment-naïve patients (60 men, 6 women; mean age 74.0 years) with pathologically proven bladder cancer who underwent multiparametric MRI, including 3D FSE T2-weighted imaging, before transurethral bladder tumour resection between January 2010 and November 2018. The MRI scans were categorised according to the five-point VI-RADS score by four independent readers (two board-certified radiologists and board-certified urologists each), blinded to the histopathological findings. The VI-RADS scores were compared with the postoperative histopathological diagnosis. Interobserver agreement was assessed using weighted kappa coefficients. ROC analysis and generalised estimating equations were used to evaluate the diagnostic performance. RESULTS: Forty-nine (74.2%) and 17 (25.8%) tumours were confirmed to be non-MIBC and MIBC, respectively, based on pathological examination. The interobserver agreement was good-to-excellent between all pairs of readers (range, 0.73-0.91). The urologists' sensitivity/specificity values for DCE-MRI VI-RADS scores were significantly lower than those of radiologists. No significant differences were observed for the overall VI-RADS score. The AUC for the overall VI-RADS score was 0.94, 0.92, 0.89, and 0.87 for radiologists 1 and 2 and urologists 1 and 2, respectively. CONCLUSIONS: The VI-RADS score, based on multiparametric MRI including 3D FSE T2-weighted acquisitions, can be useful for radiologists and urologists to determine the bladder cancer muscle invasion status preoperatively. KEY POINTS: • VI-RADS (using multiparametric MRI including 3D FSE T2-weighted acquisitions) achieves good to excellent interobserver agreement and has similar diagnostic performance for detecting muscle invasion by both radiologists and urologists. • The diagnostic performance of the overall VI-RADS score is high for both radiologists and urologists, particularly due to the dominant effect of diffusion-weighted imaging on the overall VI-RADS score. • The sensitivity and specificity values of the T2WI VI-RADS scores for four readers in our study (using 3D FSE T2-weighted acquisitions) were similar (with slightly higher specificity values) to previously published results (using 2D FSE T2-weighted acquisitions).

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.

Guideline adherence for radical cystectomy significantly affects survival outcomes in non-muscle-invasive bladder cancer patients.

BACKGROUND: The relationship between guideline adherence for radical cystectomy of non-muscle-invasive bladder cancer and patient prognoses currently remains unclear. We investigated whether guideline adherence at the time of non-muscle-invasive bladder cancer affects the oncological outcomes of bladder cancer patients who underwent radical cystectomy. METHODS: Among 267 cTa-4N0-2M0 bladder cancer patients, 70 who underwent radical cystectomy under the non-muscle-invasive bladder cancer or muscle-invasive bladder cancer status that progressed from non-muscle-invasive bladder cancer were identified. Patients who followed the guidelines from initial transurethral resection of bladder tumors to radical cystectomy were defined as the guideline adherent group (n = 52), while those who did not were the guideline non-adherent group (n = 18). RESULTS: In the guideline non-adherent group, 8 (44.4%) out of 18 were diagnosed with highest risk non-muscle-invasive bladder cancer for Bacillus Calmette Guérin-naïve patients and 7 (38.9%) had a Bacillus Calmette Guérin unresponsive tumor status. Five-year recurrence-free survival and cancer-specific survival rates for the guideline non-adherent group vs guideline adherent group were 38.9% vs 69.8% (P = 0.018) and 52.7% vs 80.1% (P = 0.006), respectively. A multivariate analysis identified guideline non-adherence as one of independent indicators for disease recurrence (hazard ratio = 2.81, P = 0.008) and cancer-specific death (hazard ratio = 4.04, P = 0.003). In a subgroup analysis of 49 patients with cT1 or less non-muscle-invasive bladder cancer at the time of radical cystectomy, guideline non-adherence remained an independent prognostic factor for cancer-specific survival (hazard ratio = 3.46, P = 0.027). CONCLUSIONS: Guideline adherence during the time course of the non-muscle-invasive bladder cancer stage may result in a favorable prognosis of patients who receive radical cystectomy. Even under non-muscle-invasive bladder cancer status, radical cystectomy needs to be performed with adequate timing under guideline recommendations.

Site-specific differences in survival among upper and lower tract urothelial carcinoma patients treated with radical surgery.

BACKGROUND: It currently remains unclear whether the location of primary tumours affects the clinical outcomes of patients with locally advanced urothelial carcinoma in the urinary tract. The aim of the present study was to compare prognostic differences between bladder urothelial carcinoma and upper tract urothelial carcinoma, particularly pT3 or higher tumours. METHODS: In total, 307 patients with pT3 or higher urothelial carcinoma without distant metastasis who underwent radical cystectomy for bladder urothelial carcinoma (N = 127, 41.4%) or radical nephroureterectomy for upper tract urothelial carcinoma (N = 180, 58.6%) at Keio University Hospital and three affiliated hospitals between 1994 and 2017 were enrolled. Oncological outcomes were compared between bladder urothelial carcinoma and upper tract urothelial carcinoma using Cox regression analysis. RESULTS: Significantly higher rates of male patients, smokers, neoadjuvant chemotherapy, lymph node involvement and lymphovascular invasion were observed in the bladder urothelial carcinoma group. The incidence of regional lymph node or local recurrence was higher in patients with bladder urothelial carcinoma than in those with upper tract urothelial carcinoma, while that of lung metastasis was lower. In all patients, bladder urothelial carcinoma was independently associated with disease recurrence (hazard ratio (HR) 1.504, P = 0.035) in addition to neoadjuvant chemotherapy and lymphovascular invasion. Bladder urothelial carcinoma was also independently associated with cancer death (HR = 1.998, P = 0.002) as well as lymphovascular invasion. Following the exclusion of patients who received neoadjuvant chemotherapy, bladder urothelial carcinoma remained an independent risk factor for disease recurrence and cancer death (HR = 1.702, P = 0.010 and HR = 1.888, P = 0.013, respectively). CONCLUSIONS: Bladder urothelial carcinoma may follow worse prognosis compared to upper tract urothelial carcinoma, particularly that with a high pathological stage.

Effects of transurethral resection under general anesthesia on tumor recurrence in non-muscle invasive bladder cancer.

BACKGROUND: The effects of the type of anesthesia (spinal (SA) vs. general (GA)) used for transurethral resection of bladder tumor (TURBT) on non-muscle invasive bladder cancer (NMIBC) recurrence and progression are controversial and our aim is to investigate their associations. METHODS: We identified 300 NMIBC patients who underwent initial TURBT with SA or GA. Cox's regression analysis was performed to examine the effects of anesthesia on tumor recurrence. RESULTS: Among 300 patients, 153 (51.0%) received GA and 147 (49.0%) SA. The 5-year recurrence-free survival (RFS) rate was 59.9% in the GA group, which was significantly lower than that in the SA group (74.4%, p = 0.029). GA (HR 1.57, p = 0.048), male sex (HR 2.72, p = 0.012), and tumor multiplicity (HR 1.96, p = 0.006) were independently associated with tumor recurrence. In a subgroup of 137 patients with high-risk NMIBC, the 5-year RFS rate was 50.3% in the GA group, which was significantly lower than that in the SA group (77.6%, p = 0.020), and GA remained an independent indicator of tumor recurrence (HR 2.35, p = 0.016). However, no significant differences were observed in the RFS rates of low- to intermediate-risk NMIBC patients between the GA and SA groups. CONCLUSIONS: The RFS rate was lower in NMIBC patients who received GA during TURBT than in those who received SA. Volatile anesthesia may increase tumor recurrence, particularly in high-risk NMIBC patients, which may be due to the inhibition of the immune response system during surgery.

Role of the MUC1-C oncoprotein in the acquisition of cisplatin resistance by urothelial carcinoma.

Mucin 1 C-terminal subunit (MUC1-C) has been introduced as a key regulator for acquiring drug resistance in various cancers, but the functional role of MUC1-C in urothelial carcinoma (UC) cells remains unknown. We aimed to elucidate the molecular mechanisms underlying the acquisition of cisplatin (CDDP) resistance through MUC1-C oncoprotein in UC cells. MUC1-C expression was examined immunohistochemically in tumor specimens of 159 UC patients who received CDDP-based perioperative chemotherapy. As a result, moderate to high MUC1-C expression was independently associated with poor survival in UC patients. Using human bladder cancer cell lines and CDDP-resistant (CR) cell lines, we compared the expression levels of MUC1-C, multiple drug resistance 1 (MDR1), the PI3K-AKT-mTOR pathway, and x-cystine/glutamate transporter (xCT) to elucidate the biological mechanisms contributing to the acquisition of chemoresistance. MUC1-C was strongly expressed in CR cell lines, followed with MDR1 expression via activation of the PI3K-AKT-mTOR pathway. MUC1-C also stabilized the expression of xCT, which enhanced antioxidant defenses by increasing intracellular glutathione (GSH) levels. MUC1 down-regulation showed MDR1 inhibition along with PI3K-AKT-mTOR pathway suppression. Moreover, it inhibited xCT stabilization and resulted in significant decreases in intracellular GSH levels and increased reactive oxygen species (ROS) generation. The MUC1-C inhibitor restored sensitivity to CDDP in CR cells and UC murine xenograft models. In conclusion, we found that MUC1-C plays a pivotal role in the acquisition of CDDP resistance in UC cells, and therefore the combined treatment of CDDP with a MUC1-C inhibitor may become a novel therapeutic option in CR UC patients.

Risk for intravesical recurrence of bladder cancer stratified by the results on two consecutive UroVysion fluorescence in situ hybridization tests: a prospective follow-up study in Japan.

BACKGROUND: A previous comparative study in Japan has demonstrated that the two consecutive UroVysion tests are useful tools to detect the presence of bladder cancer during follow-up after transurethral resection, but they also presented their high rates of false-positive results. Here, we aimed to evaluate the relationship between the UroVysion tests and subsequent intravesical recurrence. METHODS: In the previous study, patients without bladder cancer during the first analysis showed the same examination set repeated 3 months later as the second analysis. In this follow-up study, 326 patients showed negative findings confirmed on cystoscopy during the second UroVysion test. Recurrence-free survival was assessed using a median follow-up of 27 months. RESULTS: In the two consecutive UroVysion tests, 214 patients (65.6%) showed negative UroVysion results in both tests, whereas 91 presented a positive result on either tests and 21 patients presented positive results in both tests. During the follow-up, 40 patients (12.3%) had an intravesical recurrence with non-muscle-invasive bladder cancer. The recurrence rates in patients with negative results in both tests, those with one positive result in either tests, and those with positive results in both tests were 8.4%, 16.5%, and 33.3%, respectively. The multivariate analysis indicated that the history of bladder cancer and the consecutive UroVysion test pattern were independent risk factors for recurrence. CONCLUSIONS: Our data confirmed the effectiveness of two consecutive UroVysion tests in predicting intravesical recurrence after TURBT. Further prospective studies would help determine an appropriate interval for cystoscopy follow-up.

Bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer: Its definition and future therapeutic strategies.

Bacillus Calmette-Guérin induction with or without maintenance is the gold standard therapy for intermediate-/high-risk non-muscle-invasive bladder cancer; however, one-third of patients treated with adequate bacillus Calmette-Guérin therapy do not achieve sufficient responses, and this is referred to as "bacillus Calmette-Guérin failure." The term, bacillus Calmette-Guérin failure, is ambiguous and includes a very heterogeneous population of patients. By strictly focusing on patients who are unlikely to benefit from additional bacillus Calmette-Guérin therapy and who need to be treated with radical cystectomy, the new concept of "bacillus Calmette-Guérin unresponsive" was recently proposed, and might accelerate the development of novel therapeutic options for bacillus Calmette-Guérin-unresponsive disease. A promising therapeutic strategy for bacillus Calmette-Guérin-unresponsive disease is the blockade of the programmed cell death-1/programmed cell death-ligand 1 pathway, which is considered to be activated by bacillus Calmette-Guérin therapy. Several large clinical trials have been carried out to assess the potential of programmed cell death-1/programmed cell death-ligand 1 blockade in bacillus Calmette-Guérin-naïve high-risk non-muscle-invasive bladder cancer and bacillus Calmette-Guérin-unresponsive disease. Furthermore, clinical trials that are targeting bacillus Calmette-Guérin-unresponsive disease with other strategies, such as vaccines, gene therapy, and targeted and cytotoxic therapies, are ongoing. The findings of these trials are awaited in order to establish appropriate bladder-sparing approaches for patients with bacillus Calmette-Guérin-unresponsive disease.