Diagnosing upper tract urothelial carcinoma: A review of the role of diagnostic ureteroscopy and novel developments over last two decades

Objective: The role of ureteroscopy in the diagnosis of upper tract urothelial carcinoma is yet to be fully determined. We aimed to provide an up to date evaluation of its role and the emerging technologies in the field.Methods: A literature search of the last two decades (from 24th May, 2001 to 24th May, 2021) was carried out identifying 147 papers for potential inclusion within this narrative review.Results: Diagnostic ureteroscopy is undeniably useful in its ability to visualise and biopsy indeterminate lesions, and to risk stratify malignant lesions that may be suitable for kidney sparing surgery. However, an increased risk of intravesical recurrence following nephroureterectomy when a prior diagnostic ureteroscopy has been performed, inadequate sampling at biopsy, complications from the procedure, and difficult ureteric access are all potential drawbacks. Furthermore, whilst generally an accurate diagnostic procedure, it risks missing carcinoma in-situ lesions. Despite this, evidence shows that routine use of ureteroscopy changes the management of patients in a large proportion of cases, preventing unnecessary surgery or facilitating kidney sparing surgery. The overall rate of complications is low, and improved biopsy techniques and the use of tissue biomarkers for improved staging and grading are encouraging. The risks of delays to definitive management and post-ureteroscopy intravesical recurrence do not seem to affect survival, and trials are in progress to determine whether intravesical therapy can mitigate the latter. Further promising techniques are being investigated to improve shortcomings, particularly in relation to improved diagnosis of carcinoma in situ and preoperative staging.Conclusion: Ureteroscopy has a role in the diagnosis of upper tract malignancy, though whether it should be used routinely is yet to be determined.

Oral microbiota in the oral-genitourinary axis:identifying periodontitis as a potential risk of genitourinary cancers

Periodontitis has been proposed as a novel risk factor of genitourinary cancers:although periodontitis and genitourinary cancers are two totally distinct types of disorders,epidemiological and clinical studies,have established associations between them.Dysbiosis of oral microbiota has already been established as a major factor contributing to periodontitis.Recent emerging epidemiological evidence and the detection of oral microbiota in genitourinary organs indicate the presence of an oral-genitourinary axis and oral microbiota may be involved in the pathogenesis of genitourinary cancers.Therefore,oral microbiota provides the bridge between periodontitis and genitourinary cancers.We have carried out this narrative review which summarizes epidemiological studies exploring the association between periodontitis and genitourinary cancers.We have also highlighted the current evidence demonstrating the capacity of oral microbiota to regulate almost all hallmarks of cancer,and proposed the potential mechanisms of oral microbiota in the development of genitourinary cancers.

Robot-assisted laparoscopic radical cystectomy with complete intracorporeal urinary diversion

Robot-assisted radical cystectomy with intracorporeal urinary diversion(RARCICUD)has only recently been explored as a viable surgical option for patients with muscle-invasive bladder cancer seeking satisfactory oncologic control while benefiting from minimally invasive surgical techniques.Inspired by earlier open and laparoscopic work,initial descriptions of RARC-ICUD were published in 2003,and have since been followed by multiple larger case series which have suggested promising outcomes for our patients.However,the rate of adoption has remained relatively slow when compared to other robotassisted procedures such as the radical prostatectomy,likely owing to longer operative times,operative complexity,costs,and uncertainty regarding oncologic efficacy.The operative technique for RARC-ICUD has evolved over the past decade and several high-volume centers have shared tips to improve efficiency and make the operation possible for a growing number of urologists.Though there are still questions regarding economic costs,effectiveness,and generalizability of outcomes reported in published data,a growing dataset has brought us ever closer to the answers.Here,we present our current operative technique for RARC-ICUD and discuss the state of the literature so that the urologist may hold an informed discussion with his or her patients.

Superselective embolisation of bilateral superior vesical arteries for management of intractable hematuria in context of metastatic bladder cancer

Hematuria due to locally advanced or metastatic bladder cancer is a common condition and is often a management problem.Percutaneous embolisation is a mini-invasive option to handle this situation.We report a case of a patient with a metastatic bladder cancer and who presented with an abundant hematuria and severe anemia.After failure of endoscopic resections and“flush”of radiotherapy haemostatic and refusal of cystectomy by the patient,he was treated by superselective embolisation of bilateral superior bladder arteries with excellent immediate results.The technique is safe and effective in the short term.The longterm effectiveness requires further investigation.

Successful treatment of solitary bladder plasmacytoma:A case report

BACKGROUND Plasmacytoma is a rare neoplastic disorder that arises from B-lymphocytes.Solitary bladder plasmacytoma,a type of solitary extramedullary plasmacytoma,is even rarer.Treatments for solitary extramedullary plasmacytoma include surgery,chemotherapy,and radiation.However,there are no clinical trials or guidelines specifying which treatment might represent the gold standard.CASE SUMMARY We herein report a case of a 51-year-old woman with solitary bladder plasmacytoma(SBP).There remains no consensus regarding the optimal treatment for SBP.However,we successfully treated her with transurethral resection of bladder tumor followed by postoperative radiotherapy(50 Gy/25 F).The patient remained free of tumor recurrence at a 7-mo follow-up.CONCLUSION Radiation is the potential main treatment for SBP.However,surgery is also necessary.

Small cell carcinoma of the urinary bladder without gross hematuria： a case report

Small cell carcinoma of the urinary bladder （SCCB） is a rare and aggressive form of bladder cancer with poor prognosis. Hematuria is the main symptom of this malignancy, and most patients have a history of smoking. The disease incidence of malignant bladder tumors in China is approximately 0.74%. Early and accurate diagnosis of SCCB can ensure timely and appropriate treatment of this malignant disease. Oncologic surgery is the standard treatment; however, it may not be a curative approach. Chemotherapy and/or radiotherapy should be performed following surgical removal. This case report describes a patient with a single neoplasm diagnosed as SCCB that arose because of recurrence of bladder cancer after bladder tumor resection. In contrast to previously reported cases, this patient had no gross hematuria and no history of smoking.

XIAP as a prognostic marker of early recurrence of nonmuscular invasive bladder cancer

Background Dysregulation of apoptosis has been implicated not only in carcinogenesis and tumor progression but also in tumor recurrence. We investigated whether the expression of X-linked inhibitor of apoptosis （XIAP） might predict early recurrence in patients with non-muscular invasive bladder cancer. Methods The cohort comprised 176 consecutive patients with primary superficial bladder cancer treated with transurethral resection. Immunohistochemical staining using the standard avidin-bioUn-peroxidase technique and RT-PCR were used to detect XIAP protein and mRNA expressions in cancer tissues. The relationship between XIAP expression and clinicopathological characteristics, cancer recurrence were analyzed. Results XIAP expression was observed in 108 cases （61.4%） and no expression in 68. There was no correlation between XIAP expression rate and the tumor pathological grade, but was an apparent trend toward the increased XIAP levels from well （G1） to poor （G3） differentiated cancer. Eighty-two （46.6%） patients experienced tumor recurrence at a mean of 28.6 months of the follow-up; 66 of them expressed XIAP （61.1%） and 16 were XIAP negative （23.5%）. Twelve patients presented with invasive disease at the time of relapse and all of them expressed XIAP. Patients without XIAP expression or with low tumor grades had significantly higher recurrence-free survival than those with XIAP expression （log rank test ,P=-0.0015） or high tumor grades （log rank test P〈0.001）. Multivariate analysis revealed that XIAP expression, tumor grade, and tumor number were independent predictors for the recurrence of non-muscular invasive bladder cancer （P=-0.004, 0.016, and 0.043, respectively）. Conclusions XIAP may be considered as a new independent prognostic marker for early recurrence of non-muscular invasive bladder cancer.

Inhibition of telomerase with human telomerase reverse transcriptase antisense enhances tumor necrosis factor-a-induced apoptosis in bladder cancer cells

Background Telomerase activity is found in 85%-90% of all human cancers but not in their adjacent normal cells. Human telomerase reverse transcriptase （hTERT） is an essential component in the telomerase complex that plays an important role in telomerase activity. This study investigated the effect of the telomerase inhibition with an hTERT antisense oligodeoxynucleotide （ODN） in bladder cancer cells （T24） on tumor necrosis factor-α （TNF-α）-induced apoptosis. Methods Antisense phosphorothioate oligodeoxynucleotide （AS PS-ODN） was synthesized and purified. Telomerase activity was measured by polymerase chain reaction enzyme-linked immunoassay （PCR-ELISA）. hTERT mRNA expression was measured by reverse transcription polymerase chain reaction （RT-PCR） assay and a gel-image system. hTERT protein was detected by immunochemistry and flow cytometry. Cell viability was measured by the 3-（4, 5-dimethylthiazol-2-yl）-2, 5-Diphenyltetrazolium （MTT） assay. Cell apoptosis was observed by a morphological method and determined by flow cytometry. Results AS PS-ODN significantly inhibited telomerase activity and decreased the levels of hTERT mRNA which preceded the decline in the telomerase activity. AS PS-ODN significantly reduced the percentage of positive cells expressing hTERT protein following the decline of hTERT mRNA levels. There was no difference seen in the telomerase activity, hTERT mRNA expression or the protein levels between the sense phosphorothioate oligodeoxynucleotide （SPS-ODN） and the control group. AS PS-ODN treatment significantly decreased the cell viability and enhanced the apoptotic rate of T24 cells in response to TNF-α while there was no difference in cell viability and apoptotic rate between the S PS-ODN and the control group. Conclusions AS PS-ODN can significantly inhibit telomerase activity by downregulating the hTERT mRNA and protein expression. Treatment with AS PS-ODN may be a potential and most promising strategy for bladder cancer with telomerase activity.

Association of chromosome 7 aneuploidy measured by fluorescence in situ hybridization assay with muscular invasion in bladder cancer

Background:The preoperative prediction of muscular invasion status is important for adequately treating bladder cancer(BC)but nevertheless,there are some existing dilemmas in the current preoperative diagnostic accuracy of BC with muscular invasion.Here,we investigated the potential association between the fluorescence in situ hybridization(FISH)assay and muscular invasion among patients with BC.A cytogenetic-clinical nomogram for the individualized preoperative differentiation of muscle-invasive BC(MIBC)from non-muscle-invasive BC(NMIBC)is also proposed.Methods:All eligible BC patients were preoperatively tested using a FISH assay,which included 4 sites(chromosome-specific centromeric probe[CSP]3,7,and 17,and gene locus-specific probe[GLP]-p16 locus).The correlation between the FISH assay and BC muscular invasion was evaluated using the Chi-square tests.In the training set,univariate and multivariate logistic regression analyses were used to develop a cytogenetic-clinical nomogram for preoperative muscular invasion prediction.Then,we assessed the performance of the nomogram in the training set with respect to its discriminatory accuracy and calibration for predicting muscular invasion,and clinica usefulness,which were then validated in the validation set.Moreover,model comparison was set to evaluate the discrimination and clinical usefulness between the nomogram and the individual variables incorporated in the nomogram.Results:Muscular invasion was more prevalent in BC patients with positive CSP3,CSP7 and CSP17 status(OR[95%CI],2.724[1.555 to 4.774],P<0.001;3.406[1.912 to 6.068],P<0.001 and 2.483[1.436 to 4.292],P=0.001,respectively).Radiologydetermined tumor size,radiology-determined clinical tumor stage and CSP7 status were identified as independent risk factors of BC muscular invasion by the multivariate regression analysis in the training set.Then,a cytogenetic-clinical nomogram incorporating these three independent risk factors was constructed and was observed to have satisfactory discrimination in the training(AUC 0.784;95%CI:0.715 to 0.853)and validation(AUC 0.743;95%CI:0.635 to 0.850)set.The decision curve analysis(DCA)indicated the clinical usefulness of our nomogram.In models comparison,using the receiver operator characteristic(ROC)analyses,the nomogram showed higher discriminatory accuracy than any variables incorporated in the nomogram alone and the DCAs also identified the nomogram as possessing the highest net benefits at wide range of threshold probabilities.Conclusion:CSP7 status was identified as an independent factor for predicting muscular invasion in BC patients and was successfully incorporated in a clinical nomogram combining the results of the FISH assay with clinical risk factors.

A meta-analysis of randomized trials of maintenance bacillus Calmette-Guerin instillation efficacy against recurrence of T1G3 bladder tumor

Meta-analysis was used to determine whether maintenance intravesical bacillus Calmette-Guerin(BCG)could reduce recurrence after transurethral resection of tumor 1 grade 3(T1G3)superficial bladder cancer.All available published data of randomized clinical trials comparing transurethral resection plus intravesical BCG to either resection alone or resection plus another treat-ment on the treatment results in patients with superficial bladder cancer of T1G3 were selected for analysis.Both the fixed effects model and random effects model were applied,and the odds ratio(OR)with its 95%confidence interval(CI)was used as the effect size estimate.Sensitivity analysis and publication bias determination were performed by funnel plots and comparing ORs of different models.Within the follow-up period,375 of 915(41.0%)BCG-treated patients and 332 of 733(45.3%)non-BCG-treated patients developed tumor recurrence.In the combined results,a statistically signifi-cant difference in the ORs for tumor recurrence between the two treatment groups was found(randomized model combined effect OR 0.58,95%CI 0.41 to 0.83,P 50.003).The stratified meta-analysis did not show any statistically significant confounding effects on the results when strati-fied by BCG strains.The randomized model combined effect OR of Pasteur F and other strains were 0.50(95%CI 0.26 to 0.95,P 50.04)and 0.63(95%CI 0.40 to 0.99,P 50.04),respectively.Therefore,we came to the conclu-sion that adjuvant maintenance instillation BCG com-bined with transurethral resection of bladder tumor(TURBT)is an effective conservative treatment for pre-venting recurrence of T1G3 bladder cancer.

PD-1/L1 inhibitors can improve but not replace chemotherapy for advanced urothelial carcinoma:A systematic review and network meta-analysis

Background:Programmed cell death-1/ligand 1 inhibitors are a new treatment strategy for advanced urothelial carcinoma.Therefore,a comparative evaluation of their efficacy and toxicity compared with chemotherapy is necessary.Methods:We comprehensively searched PubMed,Web of Science,Embase,and Cochrane Library databases and performed a meta-analysis of randomized controlled trials up to July 2021.We considered overall survival as the primary outcome,and progression-free survival,objective response rate,and treatment-related adverse events as secondary outcomes.Results:Overall,3584 patients from five studies were evaluated.Compared with first-line chemotherapy,programmed cell death-1/ligand 1 inhibitors were significantly associated with worse progression-free survival(p<0.001)and adverse objective response rates(p<0.001).However,the treatments were not significantly different in terms of overall survival(p=0.33).Compared with second-line chemotherapy,programmed cell death-1/ligand 1 inhibitors significantly improved overall survival(p<0.001),and there was no statistically significant difference in progression-free survival(p=0.89)or objective response rate(p=0.34).Compared with chemotherapy,programmed cell death-1/ligand 1 inhibitors were well tolerated(first-line chemotherapy:p<0.001;second-line chemotherapy:p<0.001).Conclusions:The efficacy of programmed cell death-1/ligand 1 inhibitors in patients with advanced urothelial carcinoma is not superior to that of first-line platinum-based chemotherapy but is better than second-line chemotherapy;however,programmed cell death-1/ligand 1 inhibitors are safer than first-and second-line chemotherapy and have a broader prospect for use in combination therapy.

Mechanism of apoptotic induction on T24 cells by honokiol and its synergistic anticancer effect in combination with hydroxycamptothecin

OBJECTIVE:To investigate the mechanism of honokiol(HNK)on bladder cancer cells and its synergistic anticancer effect with hydroxycamptothecin(HCPT).METHODS:Control,HNK,HCPT,and HNK plus HCPT groups were established.The morphological characteristics of T24 cells were examined microscopically.The maximal experimental concentration of HNK and HCPT were determined according to IC10 detected by MTT.T24 cell viability and the percentage of apoptotic cells were assessed on the basis of MTT and flow cytometric analysis.The expression of caspase-3,caspase-9,phosphorylated nuclear factor-kappa B(NF-κB)-p65,Akt,and extracellular signal-regulated kinase(ERK)proteins were analyzed by Western blot.RESULTS:Apoptosis in T24 cells was observed microscopically in both the HNK and HCPT groups and even more obvious in the HNK plus HCPT groups.The percentage of T24 cell viability decreased down to 19.41%,and the percentage of apoptotic cells rose to 54.08% when treated with HNK plus HCPT in an HNK dose-dependent manner.The induction of caspase-3 and caspase-9 proteins and the inhibition of phosphorylation of NF-κB-p65,Akt,and ERK proteins in T24 cells were demonstrated in the HNK groups,and more significantly in the HNK plus HCPT groups,but not in the HCPT group.CONCLUSION:The anticancer effect of HNK may be due to the activation of the caspase pathway and inhibition of phosphorylation of NF-κB,Akt,and ERK.HNK in combination with HCPT produces a synergistic cell-killing effect on bladder cancer cells.