Novel coumarone-derived(S,E)-4-(4-fluorobenzylidene)-3-phenylchroman-3-ol inhibits muscle-invasive bladder cancer cells by repressing the S and G2 cell cycle phases

Background:This study aimed to select compounds with unique inhibitory effects on muscle-invasive bladder cancer(MIBC)from coumarone derivatives with similar parent nuclear structures and to reveal their tumor-suppressive effects using various approaches.Methods:Bladder cancer cell lines SW780 and T24,as well as human normal bladder epithelial cell line SV-HUC-1 were selected as the study model,and these urinary system cells were co-incubated with various concentrations of(S,E)-4-(4-methylbenzylidene)-3-phenylchroman-3-ol,(S,E)-4-(4-isocyanobenzylidene)-3-phenylchroman-3-ol,(S,E)-4-(4-fluorobenzylidene)-3-phenylchroman-3-ol(FPO),and(S,E)-3-phenyl-4-(4-(trifluoromethoxy)benzylidene)chroman-3-ol.Cell activity was detected using cell counting kit-8.FPO showed the strongest inhibitory effect on MIBC cells;therefore,it was selected for further experiments.We monitored the FPO-induced T24 cell morphological changes with an inverted microscope.The FPO-inhibited migration of T24 cells was examined using a cell scratch assay.We detected the clonogenic ability of T24 cells through a clone formation test and evaluated their proliferative ability using a 5-ethynyl-2’-deoxyuridine fluorescence staining kit.The inhibitory effect of FPO against the cell cycle was monitored using flow cytometry,and its suppressive effect on the DNA replication ability of T24 cells was detected using double fluorescence staining(Ki67 and phalloidin).Results:Among the four candidate coumarone derivatives,FPO showed the most significant inhibitory effect on MIBC cells and was less toxic to normal urothelial cells.FPO inhibited T24 cell growth in time and dose-dependent manners(the half-inhibitory concentration is 8μM).FPO significantly repressed the proliferation,migration,and clonogenic ability of bladder cancer T24 cells.Cell mobility was significantly inhibited by FPO:30μM FPO almost completely repressed migration occurred at after 24 h treatment.Moreover,FPO significantly suppressed the clonogenicity of bladder cancer cells in a dose-dependent manner.Mechanistically,FPO targeted the cell cycle,arresting the S and G2 phases on bladder cancer T24 cells.Conclusion:We discovered a novel anticancer chemical,FPO,and proposed a potential mechanism,through which it suppresses MIBC T24 cells by repressing the cell cycle in the S and G2 phases.This study contributes to the development of novel anticancer drugs for MIBC.

A phase II study of neoadjuvant chemotherapy followed by organ preservation in patients with muscle-invasive bladder cancer

Objective:Conservative approaches in muscle-invasive bladder cancer(MIBC)have been evolved to avoid aggressive surgery,but are limited to elderly,frail,and patients medically unfit for surgery.Our study aimed to assess the response rate of neoadjuvant chemotherapy(NACT)before radiotherapy(RT)in MIBC patients.Methods:Forty patients with urothelial carcinoma of stage T2-T4a,N0,M0 were enrolled between November 2013 and November 2015,and treated with three cycles of NACT with gemcitabine-cisplatin.Post-NACT response was assessed using Response Evaluation Criteria in Solid Tumors(RECIST)criteria.Patients who achieved complete response(CR)and partial response(PR)>50%were treated with radical RT,and those who had PR<50%,stable disease(SD),and progressive disease(PD)underwent radical cystectomy(RC).Survival analysis was done with Kaplan-Meier method and point-to-time events were analyzed with Cox-proportional hazards regression model.Results:After NACT,35(87.5%)patients achieved either PR>50%or CR,and were treated with RT.Five(12.5%)patients who had PR<50%,SD,or PD underwent RC.All patients who received radiation showed CR after 6 weeks.Median follow-up was 43 months(range:10-66 months)and median overall survival(OS)was not reached.Three-year OS,local control,and disease-free survival were 70.1%,60.9%,50.6%,respectively,and 50%of patients preserved their functioning bladder.Three-year OS rate was 88.9%in patients who achieved CR to NACT,73.1%in patients with PR≥50%and 40%in patients with PR<50%.Conclusion:NACT followed by RT provides a high probability of local response with bladder preservation in CR patients.Appropriate use of this treatment regimen in carefully selected patients may omit the need for morbid surgery.

Comparison of the survival outcomes between primary and secondary muscle-invasive bladder cancer: a propensity score-matched study

Background:Studies have classified muscle-invasive bladder cancer(MIBC)into primary(initially muscle-invasive,PMIBC)and secondary subtypes(initially non-muscle-invasive but progresses,SMIBC),for which controversial survival outcomes were demonstrated.This study aimed to compare the survival outcomes between PMIBC and SMIBC patients in China.Methods:Patients diagnosed with PMIBC or SMIBC at West China Hospital from January 2009 to June 2019 were retrospectively included.Kruskal-Wallis and Fisher tests were employed to compare clinicopathological characteristics.Kaplan-Meier curves and Cox competing proportional risk model were used to compare survival outcomes.Propensity score matching(PSM)was employed to reduce the bias and subgroup analysis was used to confirm the outcomes.Results:A total of 405 MIBC patients were enrolled,including 286 PMIBC and 119 SMIBC,with a mean follow-up of 27.54 and 53.30 months,respectively.The SMIBC group had a higher proportion of older patients(17.65%[21/119]vs.9.09%[26/286]),chronic disease(32.77%[39/119]vs.22.38%[64/286]),and neoadjuvant chemotherapy(19.33%[23/119]vs.8.04%[23/286]).Before matching,SMIBC had a lower risk of overall mortality(OM)(hazard ratios[HR]0.60,95%confidence interval[CI]0.41-0.85,P=0.005)and cancer-specific mortality(CSM)(HR 0.64,95%CI 0.44-0.94,P=0.022)after the initial diagnosis.However,higher risks of OM(HR 1.47,95%CI 1.02-2.10,P=0.038)and CSM(HR 1.58,95%CI 1.09-2.29,P=0.016)were observed for SMIBC once it became muscle-invasive.After PSM,the baseline characteristics of 146 patients(73 for each group)were well matched,and SMIBC was confirmed to have an increased CSM risk(HR 1.83,95%CI 1.09-3.06,P=0.021)than PMIBC after muscle invasion.Conclusions:Compared with PMIBC,SMIBC had worse survival outcomes once it became muscle-invasive.Specific attention should be paid to non-muscle-invasive bladder cancer with a high progression risk.

Cryoablation techniques in bladder cancer: A review

Bladder cancer(BC)ranks as the tenth most common cancer globally.Histopathologically,BC is broadly categorized into urothelial and non-urothelial BC.Urothelial carcinoma represents over 90%of BC in most regions worldwide.The standard treatment procedure for diagnosing and treating non-muscle-invasive bladder cancer(NMIBC)is transurethral resection of bladder tumors(TURBT).Currently,the standard of care for muscle-invasive bladder cancer(MIBC)is neoadjuvant chemotherapy followed by radical cystectomy.Cryoablation therapy is a medical technique that uses extremely low temperatures to destroy diseased tissue.This treatment serves as a therapeutic tool for both benign and malignant diseases in organs such as the kidney,prostate gland,lung,liver,and breast,and is particularly effective for unresectable tumors,offering less trauma,quick recovery,good tolerability,and symptom control.However,cryoablation has its limitations.Over the past few years,cryoablation therapy has emerged as a new method for treating early BC.This treatment is minimally invasive,precise,and offers quick recovery,providing patients with a new treatment option.Although randomized studies are still limited,increasing evidence suggests its potential application in bladder cancer combined with transurethral resection(TURBT)or medication.Cryoablation is not standard therapy for bladder cancer.Treatment decisions should be discussed by a multidisciplinary team of urologists,oncologists,and interventional physicians and require more randomized controlled trials to define patient selection criteria and treatment approaches.

Treatment trends of muscle invasive bladder cancer: Evidence from the Surveillance, Epidemiology, and End Results database, 1988 to 2013

Objective:Guidelines for muscle-invasive bladder cancer(MIBC)recommend that patients receive neoadjuvant chemotherapy with radical cystectomy as treatment over radical cystectomy alone.Though trends and practice patterns of MIBC have been defined using the National Cancer Database,data using the Surveillance,Epidemiology,and End Results(SEER)program have been poorly described.Methods:Using the SEER database,we collected data of MIBC according to the American Joint Commission on Cancer.We considered differences in patient demographics and tumor charac-teristics based on three treatment groups:chemotherapy(both adjuvant and neoadjuvant)with radical cystectomy,radical cystectomy,and chemoradiotherapy.Multinomial logistic regression was performed to compare likelihood ratios.Temporal trends were included for each treatment group.Kaplan-Meier curves were performed to compare cause-specific sur-vival.A Cox proportional-hazards model was utilized to describe predictors of survival.Results:Of 16728 patients,10468 patients received radical cystectomy alone,3236 received chemotherapy with radical cystectomy,and 3024 received chemoradiotherapy.Patients who received chemoradiotherapy over radical cystectomy were older and more likely to be African American;stage III patients tended to be divorced.Patients who received chemotherapy with radical cystectomy tended to be males;stage II patients were less likely to be Asian than Caucasian.Stage III patients were less likely to receive chemoradiotherapy as a treatment op-tion than stage II.Chemotherapy with radical cystectomy and chemoradiotherapy are both un-derutilized treatment options,though increasingly utilized.Kaplan-Meier survival curves showed significant differences between stage II and III tumors at each interval.A Cox proportional-hazards model showed differences in gender,tumor stage,treatment modality,age,andmarital status.Conclusion:Radical cystectomy alone is still the most commonly used treatment for muscle-invasive bladder cancer based on temporal trends.Significant disparities exist in those who receive radical cystectomy over chemoradiotherapy for treatment.

Clinical practice guideline on bladder cancer(Part Ⅲ)

Bladder cancer(BC)has become a significantly prevalent disease in China,with an incidence rate of 5.80 per 100000 in 2015,ranking it as the thirteenth most common type of cancer within the nation.This illness presents a serious public health concern,highlighting the imperative need to unify the standards for diagnosis and treatment to improve patient outcomes.The section of the clinical practice guideline in question is dedicated to addressing muscle-invasive bladder cancer(MIBC)and metastatic BC.The primary treatment strategies for MIBC are well-defined:preoperative(neoadjuvant)chemotherapy combined with radical cystectomy stands as the conventional treatment protocol.For patients with locally advanced MIBC,integrating systemic and local therapies is advocated to enhance treatment effectiveness.In cases of metastatic BC,the focus shifts to systemic treatment supplemented by supportive care measures.The guideline also succinctly presents the pros and cons of various urinary diversion surgeries,which are critical considerations following radical cystectomy.It provides an in-depth exploration of the treatment modalities for metastatic urothelial carcinoma of the bladder.Additionally,this part delves into the integrated approach to treatment and the use of radiotherapy in bladder preservation for localized disease.Moreover,it offers a concise overview of the classification,diagnosis,and therapeutic approaches for nonurothelial carcinoma of the bladder.Lastly,this part emphasizes the importance of recommended posttreatment follow-up for MIBC patients to ensure comprehensive and ongoing care management.

Adjuvant chemotherapy after radical cystectomy:Do all patients who need chemotherapy after surgery actually receive it?

Background:Compliance with the guideline recommendations for neoadjuvant chemotherapyin patients with muscle-invasive bladder cancer is incomplete.The adjuvant chemotherapy approach has the advantage of pathology-based decision-making,allowing for patient selection.In addition,radical surgery is not delayed and treatment-related toxicity does not impair surgical fitness.The proportion of patients who completed chemotherapy after cystectomy among those who were fit and in need of treatment were evaluated.The reasons for not completing adjuvant chemotherapy were determined.Materials and methods:We retrospectively evaluated all patients who had undergone radical cystectomy at our center over thelast 7 years.Indications for adjuvant chemotherapy included pathological T>2,any node+,or surgical margin involvement.Only patients who were fit for chemotherapy before surgery were included in the study.Results:Of the 52 patients with muscle-invasive bladder cancer,14 received neoadjuvant chemotherapy or unfit for chemotherapy were excluded.Of the remaining 38 patients,14(37%)had bladder-confined cancers and did not require additional chemotherapy.Of the 24 patients who needed chemotherapy and were fit to receive it,8 patients completed treatment(33%),and 3 discontinued treatment due to toxicity.Twelve patients(50%)declined chemotherapy,whereas 1 patient became unfit for chemotherapy after surgery.Conclusions:While the adjuvant chemotherapy approach could save unnecessary treatment in 37%of patients,two-thirds of those who needed chemotherapy did not complete it.Patient refusal was the primary reason for not receiving treatment.

Natural bioactive compounds:a potential therapeutic strategy to sensitize bladder cancer to cisplatin treatment?

Bladder cancer(BC)is the tenth most common cancer,and its incidence is steadily rising worldwide,with the highest rates in developed countries.Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the standard therapy for patients with muscle-invasive bladder cancer.However,less than 50%of patients initially respond to this treatment and nearly all of them eventually develop resistance,which is an important barrier to long-term survival.Therefore,there is an urgent need to understand the mechanisms of cisplatin resistance in BC and develop ways to counteract them.Several preclinical studies have demonstrated that naturally derived bioactive compounds,such as phytochemicals and flavonoids,can enhance the antitumor activity of cisplatin,with minimal side effects,by targeting different pathways involved in cisplatin sensitivity and resistance.However,their poor bioavailability has been one of the main problems for their successful introduction into clinical practice.At present,however,many new formulations with greatly increased bioavailability are under study in several clinical trials with encouraging results.