Identification of an immunotherapy-responsive molecular subtype of bladder cancer

BACKGROUND: Although various molecular subtypes of bladder cancer (BC) have been investigated, most of these studies have focused on muscle-invasive BC (MIBC). A few studies have investigated non-muscle-invasive BC (NMIBC) or NMIBC and MIBC together, but none has classified progressive NMIBC or immune checkpoint inhibitor (ICI)-based therapeutic responses in early-stage BC patients. METHODS: A total of 1,934 samples from seven patient cohorts were used. We performed unsupervised hierarchical clustering to stratify patients into distinct subgroups and constructed a classifier by applying SAM/PAM algorithms. We then investigated the association between molecular subtypes and immunotherapy responsiveness using various statistical methods. FINDINGS: We explored large-scale genomic datasets encompassing NMIBC and MIBC, redefining four distinct molecular subtypes, including a subgroup containing progressive NMIBC and MIBC with poor prognosis that would benefit from ICI treatment. This subgroup showed poor progression-free survival with the distinct features of high mutation load, activated cell cycle, and inhibited TGFβ signalling. Importantly, we verified that BC patients with this subtype were significantly responsive to an anti-PD-L1 agent in the IMvigor210 cohort. INTERPRETATION: Our results reveal an immunotherapeutic option for ICI treatment of highly progressive NMIBC and MIBC with poor prognosis. FUNDING: This research was supported by the National Research Foundation of Korea grant funded by the Korean government, a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea, and a grant from the KRIBB Research Initiative Program.ope

Safety and efficacy study with various doses of SS-cream in patients with premature ejaculation in a double-blind, randomized, placebo controlled clinical study

OBJECTIVES: SS-cream is a topical agent made from the extracts of natural products for treating premature ejaculation (PE). To determine the optimal clinical dosage of SS-cream on PE, we investigated the safety and efficacy of SS-cream with various doses. A double blind, randomized placebo controlled clinical study was performed. METHODS: Fifty patients completed the study. Mean age of the patients was 37.1+/-1.O y and mean ejaculatory latency was 1.35+/-0.07 min. Sexual satisfaction rate of both the partner and patient was 16.2%. Each patient was instructed to apply the different cream (placebo, SS-cream 0.05, 0.10, 0.15, 0.20 g) on glans penis 1 h before sexual intercourse in random fashion. The ejaculatory latency was measured by stop watch and the satisfaction rate of both partner and patient was also recorded two times in the screening period and after the application of each test drugs. Clinical efficacy was considered if ejaculatory latency was prolonged more than 2 min and sexual satisfaction rate increased more than 20% than that of pretest values. RESULTS: The mean ejaculatory latencies were significantly prolonged after using various test drugs (placebo 2.27+/-0.32, SS-cream 0.05 g 4.47+/-0.81, 0.10 g 5.34+/-0.79, 0.15 g 6.22+/-0.87, 0.20 g 11.06+/-1.17 min, respectively). Clinical efficacies evaluated by ejaculatory latency were placebo 18%, SS-cream 0.05 g 30%, 0.10 g 60%, 0.15 g 54%, 0.20 g 84%, respectively. The satisfaction rate was also significantly increased dose-dependently (placebo 26%, SS-cream 0.05 g 60%, 0.10 g 70%, 0.15 g 78%, 0.20 g 90%, respectively). A side effect such as local mild burning sensation was noted in 35/250 times (14%) and no adverse effect on sexual function and no systemic side effects were observed. From the result of logistic regression analysis on clinical efficacy, the ED50 of SS-cream was obtained as 0.10 g. SS-cream 0.20 g was effective in 84% without any serious systemic side effects. CONCLUSION: From the above results, our conclusions are that SS-cream is effective on the treatment of PE with a few local side effects and that clinical optimal dose of SS-cream is 0.20 g.ope

Comparison of Biochemical Recurrence After Robot-assisted Laparoscopic Radical Prostatectomy with Volatile and Total Intravenous Anesthesia

Aims: Recurrence after cancer surgery is a major concern in patients with cancer. Growing evidence from preclinical studies has revealed that various anesthetics can influence the immune system in different ways. The current study compared the long-term biochemical recurrence of prostate cancer after robot-assisted laparoscopic radical prostatectomy (RALP) in terms of selection of anesthetic agent between total intravenous anesthesia (TIVA) with propofol/remifentanil and volatile anesthetics (VA) with sevoflurane or desflurane/remifentanil. Methods: We followed up oncologic outcomes of patients who underwent RALP from two previous prospective randomized controlled trials, and the outcomes of those who received TIVA (n = 64) were compared with those who received VA (n = 64). The follow-up period lasted from November 2010 to March 2019. Results: Both TIVA and VA groups showed identical biochemical recurrence-free survivals at all-time points after RALP. The following predictive factors of prostate cancer recurrence were determined by Cox regression: colloid input [hazard ratio (HR)=1.002, 95% confidence interval (CI): 1.000-1.003; P = 0.011], initial prostate-specific antigen level (HR=1.025, 95% CI: 1.007-1.044; P = 0.006), and pathological tumor stage 3b (HR=4.217, 95% CI:1.207-14.735; P = 0.024), but not the anesthetic agent. Conclusions: Our findings demonstrate that both TIVA with propofol/remifentanil and VA with sevoflurane or desflurane/remifentanil have comparable effects on oncologic outcomes in patients undergoing RALP.ope

Prognostic value of prostate volume in non-muscle invasive bladder cancer

There is evidence that a history of benign prostatic hyperplasia increases the incidence of bladder cancer, and treatment with 5-alpha reductase inhibitor or androgen deprivation therapy reduces recurrence of non-muscle invasive bladder cancer. We aimed to evaluate whether prostate volume affects its prognosis. We reviewed medical records of men who underwent transurethral resection of bladder tumor due to non-muscle invasive bladder cancer from January 2012 to December 2017. Patients were divided into two groups based on prostate volume measured by computed tomography (group 1: 264 patients with ≤ 30 mL, group 2: 124 patients with > 30 mL). Propensity score matching analysis was used for adjust selection bias, and then assessed recurrence-free survival and progression-free survival. With a median follow up duration of 52 months, group 1 showed higher 5-year recurrence-free and progression-free survival (69.3% vs 47.0%, p = 0.001; 96.7% vs 87.7%, p = 0.002). Further, cox-regression analysis showed that tumor size (HR = 1.292 p < 0.001), multifocal tumor (HR = 1.993, p < 0.001), adjuvant intravesical therapy (chemotherapy: HR = 0.580, p = 0.037 and bacillus Calmette-Guérin: HR = 0.542, p = 0.004) and prostate volume (HR = 2.326, p < 0.001) were significant predictors of recurrence-free survival. Prostate volume (HR = 2.886, p = 0.014) was also associated with PFS with age (HR = 1.043, p = 0.044) and tumor grade (HR = 3.822, p = 0.013). We conclude higher prostate volume is associated with worse recurrence and progression-free survival in non-muscle invasive bladder cancer.ope

Urethral realignment with maximal urethral length and bladder neck preservation in robot-assisted radical prostatectomy: Urinary continence recovery

PURPOSE: To evaluate early recovery of urinary continence after robot-assisted radical prostatectomy (RARP) with urethral realignment using bladder neck preservation (BNP) and maximal urethral length preservation (MULP). METHODS: Patients who underwent RARP between 2014 and 2017 owing to prostate cancer with a Gleason score ≤ 7 (3+4), ≤ cT2c stage, and prostate-specific antigen level < 20 ng/ml were investigated. Patients with tumors of the bladder neck or apex on magnetic resonance imaging were excluded. A total of 266 patients underwent the operation using the standard method between 2014 and 2015 (group 1), while 305 patients underwent urethral realignment between 2016 and 2017 (group 2). Continence was defined as wearing no pad or one security pad. RESULTS: The continence rates immediately after Foley catheter removal, at 2 weeks, and at 1, 3, 6, and 12 months after operation in group 2 were 46.9%, 63.0%, 73.4%, 90.1%, 94.8%, and 98.7%, respectively. The continence rate at 1 month in group 2 was significantly higher than that in group 1 (65.4% versus 73.4%, p = 0.037). The multivariate regression analysis showed that age and surgical method were factors affecting early continence recovery. The positive surgical margin rates were 18.0% and 14.8% in groups 1 and 2, respectively (p = 0.288). Biochemical recurrence occurred in 14.7% and 8.2% in groups 1 and 2, respectively (p = 0.015). CONCLUSION: Urethral realignment using BNP and MULP resulted in rapid continence recovery and good oncological results after RARP in young patients with a Gleason score ≤ 7 and organ-confined disease.ope

Vesicoureteral Reflux in the Adult Uncomplicated Acute Pyelonephritis

Purpose: Acute pyelonephritis (APN) is mostly caused by ascending infection. Based on clinical and experimental studies, it is known that APN is caused by bacteria that ascends from the bladder through the ureter to the renal pelvis and parenchyma. Urinary reflux, bacterial virulence factors, and decreased ureteral peristalsis are some of the causes of ascending infection. We have tried to evaluate the significance of reflux in adult uncomplicated APN.Materials and Methods: Voiding cystourethrogram (VCUG) was performed in 71 female patients with APN who showed no structural abnormalities on either intravenous urogram or ultrasonogram from April 1998 to May 2000. VCUG was performed at cure phase (29.7±9.18 days, 20 patients) in the early days of the study and the date of performing VCUG was shortened gradually to resolved phase (13.8±2.13 days, 10 patients), subacute phase (6.60±1.84 days, 10 patients), and acute phase (2.42±0.51 days, 31 patients).Results: There were only 2 (2.8%) cases with vesicoureteral reflux among 71 female patients with uncomplicated APN. 1 ipsilateral grade 2 reflux was found among the 20 patients who underwent VCUG at cure phase. 1 case with ipsilateral grade 1 reflux was found at resolved phase. Reflux was not found in the groups where study was performed at subacute and acute phase. The cause of infection was found to be E. coli (55 patients, 77.5%), Enterococcus faecalis (3 patients, 4.2%), Klebsiella pneumoniae (2 patients, 2.8%), and S. aureus (1 patients, 1.4%).Conclusions: These results suggest that reflux may not be a significant factor causing ascending infection that leads to APN. More study on the pathophysiology of ascending infection to the upper urinary tract is warranted.ope

Analysis of Human V-erbA Related EAR-3 Gene Expression between Transitional Cell Carcinoma and Normal Tissue in Bladder Cancer

Purpose The prognosis of bladder cancer is related to tumor grade and stage. Because these pathological changes are preceded by molecular alterations, new molecular markers are needed in early diagnosis. New target molecular biomarkers can be differentially expressed genes (DEGs) between normal and cancer tissues. We tried to find a new DEG and demonstrated that it may be related to the development of the bladder cancer. Materials and Methods Cancer tissues were obtained from 39 patients with urothelial cell carcinoma, treated by transurethral resection of tumor (TURB) since 2002. Normal bladder tissues were obtained from the same patients during TURB. We compared the mRNA profiles between normal and cancer tissues using annealing control primer (ACP)-based Genefishing™ PCR to identify the DEGs in normal and cancer tissues of one same patient. To validate the result of ACP-based GeneFishing™ PCR, reverse transcription-polymerase chain reaction (RT-PCR) was performed on those of 39 patients. Results According to the result of ACP-based Genefishing™ PCR, EAR-3 gene was only present or markedly upregulated in normal tissue, compared with cancer tissues. The expression pattern that EAR-3 gene was downregulated in cancer tissues, irrespective of the clinicopathologic parameters was confirmed by RT-PCR in 39 patients. Conclusions EAR-3 gene was downregulated in cancer tissues, irrespective of clinicopathologic parameters, compared with normal tissues in the bladder of the same patient. Therefore, we suggested that EAR-3 gene may be also play a role in bladder cancer development.ope

Impact of a bladder cuff excision during radical nephroureterectomy on cancer specific survival in patients with upper tract urothelial cancer in Korea: a retrospective, multi-institutional study

BACKGROUND: Radical nephroureterectomy (RNU) with bladder cuff excision (BCE) is the surgical principle adopted for the treatment of upper tract urothelial cancers (UTUCs). However, not all RNUs are performed with BCE. We quantified the prognostic impact of RNU with BCE on cancer-specific survival (CSS) in a large patient population. METHODS: In total, 505 patients with UTUC were enrolled from four different institutions. The clinicopathological parameters of patients who underwent RNU with and without BCE were compared. The Kaplan-Meier and multivariate Cox regression analyses were performed to assess the influence of BCE on CSS. RESULTS: In total, 60 (11.9%) patients had not undergone BCE during RNU. Compared to patients who underwent BCE, these patients were older and had more comorbidities. Patients with UTUC who had not undergone BCE were more likely to be associated with ≥pT3, margin positivity, and renal pelvis localization compared to patients who underwent BCE. Median follow-up periods were 30.5 months (range, 6-144 months). The Kaplan-Meier estimates revealed that BCE during RNU was not significantly associated with CSS in all UTUC patients and in the subgroup with renal pelvis localization; however, patients who underwent RNU without BCE had significantly worse CSS rates compared to patients who underwent RNU with BCE in the subgroup analysis of patients with ureteral cancer. Multivariate analysis identified BCE as an independent prognostic factor of CSS in patients with ureteral cancer. CONCLUSIONS: In the present study, RNU without BCE resulted in significantly worse CSS in ureteral cancer patients, which indicated that BCE should be mandatory in patients with ureteral cancer.ope

Establishment of a System to Evaluate the Efficacy of Functional Foods

There are many functional foods available nowadays. Functional foods are believed to promote health, physical activities, and satisfaction. However, their efficacy should be proved through both laboratory and clinical trials. To evaluate the efficacy, in vitro effects of specific animal model can be used as an objective laboratory screening test. In vivo function tests can be used as a preclinical animal study with or without administration of functional foods. In clinical trials, validated questionnaires and objective function tests can be used according to various study models. Therefore to validate the efficacy of any nutritional supplement, one or more laboratory results and validated clinical study are necessary. In conclusion, the safety and efficacy of functional foods should be decided based on a functional testing guideline, which can substantially decrease the incidence of drug overuse and protect the public health, accordingly.ope

Metabolic Pathway Signatures Associated with Urinary Metabolite Biomarkers Differentiate Bladder Cancer Patients from Healthy Controls.

PURPOSE: Our previous high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry study identified bladder cancer (BCA)-specific urine metabolites, including carnitine, acylcarnitines, and melatonin. The objective of the current study was to determine which metabolic pathways are perturbed in BCA, based on our previously identified urinary metabolome. MATERIALS AND METHODS: A total of 135 primary BCA samples and 26 control tissue samples from healthy volunteers were analyzed. The association between specific urinary metabolites and their related encoding genes was analyzed. RESULTS: Significant alterations in the carnitine-acylcarnitine and tryptophan metabolic pathways were detected in urine specimens from BCA patients compared to those of healthy controls. The expression of eight genes involved in the carnitine-acylcarnitine metabolic pathway (CPT1A, CPT1B, CPT1C, CPT2, SLC25A20, and CRAT) or tryptophan metabolism (TPH1 and IDO1) was assessed by RT-PCR in our BCA cohort (n=135). CPT1B, CPT1C, SLC25A20, CRAT, TPH1, and IOD1 were significantly downregulated in tumor tissues compared to normal bladder tissues (p<0.05 all) of patients with non-muscle invasive BCA, whereas CPT1B, CPT1C, CRAT, and TPH1 were downregulated in those with muscle invasive BCA (p<0.05), with no changes in IDO1 expression. CONCLUSION: Alterations in the expression of genes associated with the carnitine-acylcarnitine and tryptophan metabolic pathways, which were the most perturbed pathways in BCA, were determined.ope