Circulating Tumour DNA and Its Prognostic Role in Management of Muscle Invasive Bladder Cancer: A Narrative Review of the Literature.

Current management of non-metastatic muscle invasive bladder cancer (MIBC) includes radical cystectomy and cisplatin-based neoadjuvant chemotherapy (NAC), offers a 5-year survival rate of approximately 50% and is associated with significant toxicities. A growing body of evidence supports the role of liquid biopsies including circulating tumour DNA (ctDNA) as a prognostic and predictive marker that could stratify patients according to individualised risk of progression/recurrence. Detectable ctDNA levels prior to radical cystectomy have been shown to be correlated with higher risk of recurrence and worse overall prognosis after cystectomy. In addition, ctDNA status after NAC/neoadjuvant immunotherapy is predictive of the pathological response to these treatments, with persistently detectable ctDNA being associated with residual bladder tumour at cystectomy. Finally, detectable ctDNA levels post-cystectomy have been associated with disease relapse and worse disease-free (DFS) and overall survival (OS) and might identify a population with survival benefit from adjuvant immunotherapy.

A narrative review of management of muscle-invasive bladder cancer perioperative period: will continuous and combined treatment be the new trend?

Background and Objective: With the emergence of immunotherapy and targeted therapies, there are more options for the perioperative period management of muscle-invasive bladder cancer (MIBC), and various types of clinical studies are emerging, leading to the need to explore ways to choose the optimal treatment modality. This review aims to synthesize past and present treatment modalities and to explore future trends in the perioperative period cares of MIBC for the benefit of clinical practitioners. Methods: A non-systematic, literature search was conducted between March 5, 2023 and November 30, 2023 on PubMed using "perioperative period", "MIBC", "chemotherapy", "radiotherapy", "immunotherapy", "targeted treatment" and "combination" as keywords, along with a search for ongoing clinical studies that were related to the perioperative period of MIBC on classic.clinicaltrials.gov, some latest conference abstracts were also included as references. Key Content and Findings: The trend towards benefit from adjuvant chemotherapy in perioperative chemotherapy is gradually being recognized. Neoadjuvant immunotherapy, including single-agent immunization, like programmed cell death protein 1 (PD-1) inhibitors, programmed cell death 1 ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, and double-immunization, has been confirmed by several clinical studies to be beneficial to clinical remission rates, and the combination regimen is superior to single-agent therapy. Targeted therapies such as antibody-drug conjugate (ADC) are entering MIBC perioperative studies. Multiple sequential and combination clinical studies are gradually disclosing preliminary data on efficacy and safety. Conclusions: Immunotherapy would become an essential perioperative treatment for MIBC, and continuous and integrated perioperative management may become the MIBC treatment mode of the future. ADC medicines will also be a hot research focus in the coming years.

Prospective evaluation of sexual health following radical cystectomy due to bladder cancer.

Background: There is a lack of data concerning sexual health following open radical cystectomy (RC), especially in elderly patients and women. Aim: To describe sexual health and its impact on general health as well as survival in patients undergoing standard open RC for the treatment of bladder cancer (BC). Due to limited data, subgroup analysis for elderly patients and women was performed. Methods: A prospective noninterventional clinical study was performed evaluating sexual health in RC with any kind of urinary diversion due to BC with a follow-up of 12 months after RC. The study was approved by the local ethics review board (A 2021-0175) and was registered at the German Clinical Trial Register (DRKS00026255). Assessment of sexual health was done with the following validated questionnaires: EORTC QLQ-C30 (for quality of life; European Organisation for Research and Treatment of Cancer), EORTC SH22 (for sexual health), and IIEF-5 (5-item International Index of Erectile Function). Outcomes: The standard measurements of EORTC QLQ-C30, EORTC SH22, and IIEF-5 as well as overall survival. Results: Thirty-two patients participated in the study with a mean age of 71.5 years (SD, 9.7): 25 (78.1%) were male and 7 (21.9%) were female. Overall there is a heterogenic picture for sexual health in the study population, but sexual satisfaction is significantly higher prior to surgery while the importance of a sex life stays high and stable. Interestingly, the general health score is significantly correlated to sexual satisfaction (Pearson's correlation; r = 0.522, P = .002) preoperatively but not following surgery: r = 0.103 (P = .665) after 3 months, r = 0.478 (P = .052) after 6 months, r = 0.276 (P = .302) after 9 months, and r = 0.337 (P = .202) after 12 months. The importance of a sex life is still essential for the patients, especially when recovering from RC; nearly the same can be reported for elderly patients. Unfortunately, the data for women are too limited to report robust results. Clinical Implications: Evaluation, advice, and monitoring of sexual health must be integrated into clinical practice, particularly in women. Strengths and Limitations: At least to our knowledge, this is the first systematic prospective evaluation of sexual health in patients with BC receiving RC. Due to the small sample size, there is a risk of selection bias. Conclusion: Sexual health is important for patients with BC receiving RC, and it is an essential part of quality of life, especially in elderly patients.

Performance of VI-RADS in predicting muscle-invasive bladder cancer after transurethral resection: a single center retrospective analysis.

PURPOSE: To assess VIRADS performance and inter-reader agreement for detecting muscle-invasive bladder cancer (MIBC) following transurethral resection of bladder tumor (TURBT). METHODS: An IRB-approved, HIPAA-compliant, retrospective study from 2016 to 2020 included patients with bladder urothelial carcinoma who underwent MRI after TURBT, and cystectomy within 3 months without post-MRI treatments. Three radiologists blinded to pathology results independently reviewed MR images and assigned a VI-RADS score. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of VI-RADS were assessed for diagnosing MIBC using VI-RADS scores ≥ 3 and ≥ 4. Inter-reader agreement was assessed using Gwet's agreement coefficient (AC) and percent agreement. RESULTS: The cohort consisted of 70 patients (mean age, 68 years ± 11 [SD]; range 39-85; 58 men) and included 32/70 (46%) with MIBC at cystectomy. ROC analysis revealed an AUC ranging from 0.67 to 0.77 and no pairwise statistical difference between readers (p-values, 0.06, 0.08, 0.97). Percent sensitivity, specificity, PPV, NPV and accuracy for diagnosing MIBC for the three readers ranged from 81.3-93.8, 36.8-55.3, 55.6-60.5, 77.3-87.5, and 62.9-67.1 respectively for VI-RADS score ≥ 3, and 78.1-81.3, 47.4-68.4, 55.6-67.6, 72.0-78.8 and 61.4-72.9 respectively for VI-RADS score ≥ 4. Gwet's AC was 0.63 [95% confidence interval (CI): 0.49,0.78] for VI-RADS score ≥ 3 with 79% agreement [95% CI 72,87] and 0.54 [95%CI 0.38,0.70] for VI-RADS score ≥ 4 with 76% agreement [95% CI 69,84]. VIRADS performance was not statistically different among 31/70 (44%) patients who received treatments prior to MRI (p ≥ 0.16). CONCLUSION: VI-RADS had moderate sensitivity and accuracy but low specificity for detection of MIBC following TURBT, with moderate inter-reader agreement.

First case report of robot-assisted radical cystectomy and intracorporeal urinary diversion using the hinotori Surgical Robot System.

Background: The field of robotic surgery is still continuously advancing, with several cutting-edge robotic systems currently under development. This study aimed to present the methodology and perioperative outcomes of robot-assisted radical cystectomy (RARC) and intracorporeal urinary diversion (ICUD) in patient with muscle invasive bladder cancer (MIBC) by utilizing the hinotori Surgical Robot System, a recently developed robot-assisted surgical platform. Case Description: A 79-year-old man with MIBC, cT2N0M0, received RARC and ICUD after two courses of neoadjuvant chemotherapy. We performed RARC and ICUD using hinotori, with a total operation time of 476 minutes. The insufflation time was 424 minutes, and the console time was 396 minutes. Total blood loss was 562 mL and no blood transfusion was necessary. During the perioperative period, a paralytic ileus occurred, although no severe adverse events were observed. The pathological examination showed ypT0N0M0, and no recurrence was observed by computed tomography scan up to 8 months postoperatively. Conclusions: This report demonstrates the successfully implementation of RARC and ICUD using the hinotori system, without perioperative adverse effects. While further exploration is required to assess the long-term and large-scale implications of RARC and ICUD using hinotori on oncologic and functional outcomes, these initial findings suggest that the hinotori Surgical Robot System holds promise as an application for RARC and ICUD in patients with MIBC.

Magnetic resonance radiographic features which might lead to misdiagnosis of muscle-invasive bladder cancer based on vesical imaging reporting and data system: the application experience of a single center.

Background: The Vesical Imaging Reporting and Data System (VI-RADS) has been widely used for diagnosing muscle-invasive bladder cancer (MIBC), yet instances of misdiagnosis persist. However, limited research discusses the factors affecting its accuracy. This study aimed to evaluate the diagnostic efficacy of the VI-RADS in our center and to preliminarily identify possible magnetic resonance imaging (MRI) characteristics of misdiagnosis. Methods: From January 2018 to February 2023, a consecutive series of 211 participants pathologically diagnosed with bladder cancer (BC) who underwent an MRI exam were retrospectively enrolled. MRI was interpreted by 2 radiologists with different levels of experience, the diagnostic performance was validated using the receiver operating characteristic (ROC) curve, and VI-RADS ≥4 was considered to indicate MIBC-positive status. The clinical and radiographic characteristics of the true-positive (TP), true-negative (TN), false-positive (FP), and false-negative (FN) groups were analyzed using Kruskal-Wallis test or Fisher exact test. Results: With VI-RADS ≥4 as the cutoff value, the area under the ROC curves (AUCs) were 0.951 (0.912-0.976) and 0.847 (0.791-0.893) for the more-experienced reader and less-experienced reader, respectively, with good interobserver agreement (κ=0.74105). The median tumor size in the TP (more experienced: 57 cases; less experienced: 44 cases) and FP (more experienced: 8 cases; less experienced: 9 cases) groups was larger than that in the TN (more experienced: 141 cases; less experienced: 139 cases) group for the more-experienced reader (TP: 28 mm; FP: 31 mm; TN: 19 mm; P<0.001 and P=0.031, respectively) and the less-experienced reader (TP: 31 mm; FP: 28 mm; TN: 19 mm; P<0.001 and P=0.042, respectively). The tumor base in the TP and FP groups was larger than that in the TN group for the more-experienced reader (TP: 37 mm; FP: 48 mm; TN: 15 mm; both P<0.001) and for the less-experienced reader (FP: 42 mm; FP: 36 mm; TN: 15 mm; P<0.001 and P=0.022, respectively). The median tumor base in the TP group was larger than that in the FN group for the less-experienced reader (TP: 42 mm; FN: 17 mm; P=0.004). Conclusions: We observed good to excellent AUCs with good interobserver agreement among radiologists with different levels of expertise using VI-RADS. Large tumor size and wide tumor base affected the accuracy of VI-RADS in MIBC diagnosis.

Bladder cancer course, four genetic high-risk variants, and histopathological findings.

Urinary bladder cancer, a smoking and occupation related disease, was subject of several genome-wide association studies (GWAS). However, studies on the course of the disease based on GWAS findings differentiating between muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC) are rare. Thus we investigated 4 single nucleotide polymorphisms (SNPs) detected in GWAS, related to the genes coding for TACC3 (transforming, acidic coiled-coil containing protein 3), for FGFR3 (fibroblast growth factor receptor 3), for PSCA (prostate stem cell antigen) and the genes coding for CBX6 (chromobox homolog 6) and APOBEC3A (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A). This study is based on 712 bladder cancer patients and 875 controls from 3 different case control studies in Germany. The 4 SNPs of interest (PSCA rs2294008 and rs2978974, FGFR3-TACC3 rs798766, and CBX6-APOBEC3A rs1014971) were determined by real-time polymerase chain reaction. The distribution of the 4 SNPs does not vary significantly between cases and controls in the entire study group and in the 3 local subgroups, including two former highly industrialized areas and a region without such history. Also, no significant differences in the bladder cancer subgroups of MIBC and NMIBC were observed. The 4 investigated SNPs do not noticeably contribute differently to the bladder cancer risk for the bladder cancer subgroups of MIBC and NMIBC.

Bladder-sparing approaches for muscle invasive bladder cancer: a narrative review of current evidence and future perspectives.

Background and Objective: In recent years, the application of less-invasive "bladder-sparing" trimodal therapy (TMT) in selected muscle-invasive bladder cancer (MIBC) patients unfit for or who declined radical cystectomy (RC) has been increasing. This review aims to summarize the current evidence and future perspectives of bladder-sparing therapy for MIBC. Methods: A non-systematic Medline/PubMed literature search was conducted on July 2022 with the following keywords 'MIBC', 'bladder-sparing', 'chemotherapy', 'radiotherapy', 'trimodal', 'multimodal', and 'immunotherapy'. Key Content and Findings: All monotherapies are inferior to RC or combination therapy and should not be routinely used for curative intent. Radiotherapy (RT) alone has been shown to have poorer outcomes when compared to chemoradiotherapy. The ideal selection criteria for TMT include good bladder function and capacity, clinical stage within cT2, complete transurethral resection of bladder tumor (TURBT), no prior history of pelvic RT, no extensive carcinoma in situ (CIS), and absence of hydronephrosis. The emergence of immunotherapy may further increase the effect of bladder-sparing therapy. Novel predictive biomarkers are awaited for more precise patient selection and better oncological outcomes. Conclusions: TMT is a well-tolerated and offers a curative alternative approach to RC for selected patients with localized MIBC. Appropriate patient selection and a multi-disciplinary approach is crucial in achieving good oncologic control with bladder-sparing therapy.

An innovative risk index based on neutrophils and macrophages can effectively predict prognosis and immunotherapy response in patients with muscle-invasive bladder cancer.

Background: This study aimed to establish an innovative prognostic risk index based on tumor-infiltrating immune cells (TIICs) for patients with muscle-invasive bladder cancer (MIBC). Methods: We used the CIBERSORT algorithm to calculate the abundance of immune cells in MIBC samples from the The Cancer Genome Atlas (TCGA) database. Univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression analysis, and stepwise regression analysis were used to identify the included immune cells. Then, we constructed the risk index based on these cells through multivariate Cox regression analysis. By the risk index formula, we obtained the risk score of each patient and divided the patients into high-risk and low-risk groups. Kaplan-Meier (K-M) curve was used for survival analysis between groups. The receiver operating characteristic (ROC) curve was used to measure the prediction accuracy of the index. We validated the performance of the index in the IMvigor210 immunotherapy cohort. In addition, we established a nomogram combining the index and clinical characteristics. Finally, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of differential genes between groups. Results: The risk index we constructed consists of three variables, including M0 macrophages, M2 macrophages, and neutrophils. K-M curve showed that the risk score had good risk stratification performance. Moreover, the risk score correlates with the patient's response to chemotherapy and immunotherapy. The nomogram has good accuracy and clinical benefit. GO and KEGG enrichment analysis revealed the tumor-promoting molecular mechanism of the index. Conclusions: The risk index based on TIICs can facilitate individualized treatment of MIBC patients by predicting prognosis and immunotherapy response.

Fibronectin-1: A Predictive Immunotherapy Response Biomarker for Muscle­Invasive Bladder Cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is characterized as bladder tumors that infiltrate into the muscle layer, along with multiple metastasis and poor prognosis. Numerous research studies have been performed to identify the underlying clinical and pathological alterations that occur. However, few studies have revealed the molecular mechanism of its progression based upon the immunotherapy response. Our present study was designed to identify biomarkers which may predict the immunotherapy response by investigating the tumor microenvironment (TME) in MIBC. METHODS: The transcriptome and clinical data of MIBC patients were obtained and analyzed with R version 4.0.3 (POSIT Software, Boston, MA, USA) ESTIMATE package. Differentially expressed immune-related genes (DEIRGs) were identified and further analyzed via the protein-protein interaction network (PPI). Meanwhile, univariate Cox analysis was utilized to screen out the prognostic DEIRGs (PDEIRGs). Then, the PPI core gene was matched with PDEIRGs to obtain the target gene-fibronectin-1 (FN1). Human MIBC and control tissues were collected and FN1 was measured with Quantitative Reverse Transcription PCR (qRT-PCR) and Western-Blot. Finally, the relationship between FN1 expression level and MIBC was validated through survival, univariate Cox, multivariate Cox, Gene Set Enrichment Analysis (GSEA) and correlation analysis of tumor infiltrating immune cells. RESULTS: TME DEIRGs were identified and the target gene FN1 was obtained. The higher expression of FN1 was confirmed in MIBC tissues via bioinformatics analysis, qRT-PCR and Western-Blot. Moreover, higher FN1 expression correlated with reduced survival time and FN1 expression was further favorably correlated with clinic-pathological features (grade, TNM stage, invasion, lymphatic and distant metastasis). Additionally, the genes in the high FN1 expression group were mainly enriched in immune-related activities and macrophage M2, T cell CD4, T cell CD8 and T cell follicular helper cells were correlated with FN1. Finally, it was observed that FN1 was closely related to key immune checkpoints. CONCLUSIONS: FN1 was identified as a novel and independent prognostic factor for MIBC. Our data also suggests FN1 can predict MIBC patients' response to immune checkpoints inhibitors.

Characterization of the tumor-infiltrating immune repertoire in muscle invasive bladder cancer.

Introduction: Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease with several taxonomic molecular subtypes showing different genetic, clinical, and epidemiological profiles. It has been suggested that MIBC-subtypes follow different tumorigenesis pathways playing decisive roles at different stages of tumor development, resulting in distinct tumor microenvironment containing both innate and adaptive immune cells (T and B lymphocytes). We aim to characterize the MIBC tumor microenvironment by analyzing the tumor-infiltrating B and T cell repertoire according to the taxonomic molecular subtypes. Methods: RNAseq data from 396 MIBC samples included in TCGA were considered. The subtype information was collected from the international consensus taxonomic classification describing six subtypes: Basal/Squamous-like (Ba/Sq), Luminal papillary (LumP), Luminal non-Specify (LumNS), Luminal unstable (LumU), Stroma-rich, and Neuroendocrine-like (NE-like). Using MiXCR, we mapped the RNA read sequences to their respective B-cell receptor (BCR) and T-cell receptor (TCR) clonotypes. To evaluate the BCR and TCR differences among subtypes, we compared diversity measures (richness and diversity) using a Wilcoxon test and we performed a network analysis to characterize the clonal expansion. For the survival analysis stratified by subtypes, Cox regression models adjusted for age, region, and pathological stage were performed. Results: Overall, we found different patterns of tumor-infiltrating immune repertoire among the different MIBC subtypes. Stroma-rich and Ba/Sq tumors showed the highest BCR and TCR infiltration while LumP showed the lowest. In addition, we observed that the Ba/Sq and Stroma-rich tumors were more clonally expanded than the Luminal subtypes. Moreover, higher TCR richness and diversity were significantly associated with better survival in the Stroma-rich and Ba/Sq subtypes. Discussion: This study provides evidence that MIBC subtypes present differences in the tumor microenvironment, in particular, the Ba/Sq and the Stroma-rich are related with a higher tumoral-infiltrating immune repertoire, which seems to be translated into better survival. Determining the causes of the different tumoral-infiltrating immune repertoire according to the MIBC molecular subtypes will help to improve our understanding of the disease and the distinct responses to immunotherapy of MIBC.

Fibronectin-1: A Predictive Immunotherapy Response Biomarker for Muscle Invasive Bladder Cancer

Background: Muscle-invasive bladder cancer (MIBC) is characterized as bladder tumors that infiltrate into the muscle layer, along with multiple metastasis and poor prognosis. Numerous research studies have been performed to identify the underlying clinical and pathological alterations that occur. However, few studies have revealed the molecular mechanism of its progression based upon the immunotherapy response. Our present study was designed to identify biomarkers which may predict the immunotherapy response by investigating the tumor microenvironment (TME) in MIBC. Methods: The transcriptome and clinical data of MIBC patients were obtained and analyzed with R version 4.0.3 (POSIT Software, Boston, MA, USA) ESTIMATE package. Differentially expressed immune-related genes (DEIRGs) were identified and further analyzed via the protein-protein interaction network (PPI). Meanwhile, univariate Cox analysis was utilized to screen out the prognostic DEIRGs (PDEIRGs). Then, the PPI core gene was matched with PDEIRGs to obtain the target gene-fibronectin-1 (FN1). Human MIBC and control tissues were collected and FN1 was measured with Quantitative Reverse Transcription PCR (qRT-PCR) and Western-Blot. Finally, the relationship between FN1 expression level and MIBC was validated through survival, univariate Cox, multivariate Cox, Gene Set Enrichment Analysis (GSEA) and correlation analysis of tumor infiltrating immune cells. Results: TME DEIRGs were identified and the target gene FN1 was obtained. The higher expression of FN1 was confirmed in MIBC tissues via bioinformatics analysis, qRT-PCR and Western-Blot. Moreover, higher FN1 expression correlated with reduced survival time and FN1 expression was further favorably correlated with clinic-pathological features (grade, TNM stage, invasion, lymphatic and distant metastasis) (AU)

A cohort profile of the Graham Roberts study cohort.

Purpose: The Graham Roberts Study was initiated in 2018 and is the first Trials Within Cohorts (TwiCs) study for bladder cancer. Its purpose is to provide an infrastructure for answering a breadth of research questions, including clinical, mechanistic, and supportive care centred questions for bladder cancer patients. Participants: All consented patients are those aged 18 or older, able to provide signed informedconsent and have a diagnosis of new or recurrent bladder cancer. All patients are required to have completed a series of baseline questionnaires. The questionnaires are then sent out every 12 months and include information on demographics and medical history as well as questionnaires to collect information on quality of life, fatigue, depression, overall health, physical activity, and dietary habits. Clinical information such as tumor stage, grade and treatment has also been extracted for each patient. Findings to date: To date, a total of 125 bladder cancer patients have been consented onto the study with 106 filling in the baseline questionnaire. The cohort is made up of 75% newly diagnosed bladder cancer patients and 66% non-muscle invasive bladder cancer cases. At present, there is 1-year follow-up information for 70 patients, 2-year follow-up for 57 patients, 3-year follow-up for 47 patients and 4-year follow-up for 19 patients. Future plans: We plan to continue recruiting further patients into the cohort study. Using the data collected within the study, we hope to carry out independent research studies with a focus on quality of life. We are also committed to utilizing the Roberts Study Cohort to set up and commence an intervention. The future studies and trials carried out using the Roberts Cohort have the potential to identify and develop interventions that could improve the prevention, diagnosis, and treatment of bladder cancer.

Multiomics analysis of ferroptosis-related molecular subtypes in muscle-invasive bladder cancer immunotherapy.

Background: The purpose of this study was to identify the ferroptosis-related molecular subtypes in muscle invasive bladder cancer (MIBC) associated with the tumor microenvironment (TME) and immunotherapy. Methods: Expression profiles and corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) dataset. Nonnegative matrix factorization (NMF) analysis was performed to identify two molecular subtypes based on 41 ferroptosis-related prognostic genes. The differences between the two subtypes were compared in terms of prognosis, somatic mutations, gene ontology (GO), cytokines, pathways, immune cell infiltrations, stromal/immune scores, tumor purity and response to immunotherapy. We also constructed a risk prediction model using multivariate Cox regression analysis to analyze survival data based on differentially expressed genes (DEGs) between subtypes. In combination with clinicopathological features, a nomogram was constructed to provide a more accurate prediction for overall survival (OS). Results: Two molecular subtypes (C1 and C2) of MIBC were identified according to the expression of ferroptosis-related genes. The C2 subtype manifested poor prognosis, high enrichment in the cytokine-cytokine receptor interaction pathway, high abundance of immune cell infiltration, immune/stromal scores and low tumor purity. Additionally, C2 is less sensitive to immunotherapy. The risk prediction model based on five pivotal genes (SLC1A6, UPK3A, SLC19A3, CCL17 and UGT2B4) effectively predicted the prognosis of MIBC patients. Conclusions: A novel MIBC classification approach based on ferroptosis-related gene expression profiles was established to provide guidance for patients who are more sensitive to immunotherapy. A nomogram with a five-gene signature was built to predict the prognosis of MIBC patients, which would be more accurate when combined with clinical factors.

Diffusion-weighted MRI to determine response and long-term clinical outcomes in muscle-invasive bladder cancer following neoadjuvant chemotherapy.

Objective: This study aims to determine local treatment response and long-term survival outcomes in patients with localised muscle-invasive bladder cancer (MIBC) patients receiving neoadjuvant chemotherapy (NAC) using diffusion-weighted MRI (DWI) and apparent diffusion coefficient (ADC) analysis. Methods: Patients with T2-T4aN0-3M0 bladder cancer suitable for NAC were recruited prospectively. DWI was performed prior to NAC and was repeated following NAC completion. Conventional response assessment was performed with cystoscopy and tumour site biopsy. Response was dichotomised into response (15.5% was associated with significant improvement in OS (HR, 0.40; 95% CI, 0.19-0.86; p=0.0179), bCSS (HR, 0.26; 95% CI, 0.08-0.82; p=0.0214), PFS (HR, 0.16; 95% CI, 0.05-0.48; p=0.0012), and time to cystectomy (HR, 0.19; 95% CI, 0.07-0.47; p=0.0004). Conclusions: Quantitative ADC analysis can successfully identify NAC response and improved long-term clinical outcomes. Multi-centre validation to assess reproducibility and repeatability is required before testing within clinical trials to inform MIBC treatment decision making. Advances in knowledge: We successfully demonstrated that measured change in DWI can successfully identify NAC response and improved long-term survival outcomes.

Impact of the time of surgical delay on survival in patients with muscle-invasive bladder cancer.

Background and objectives: Patients with muscle-invasive bladder cancer (MIBC) often experience a waiting period before radical surgery for numerous reasons; however, the COVID-19 outbreak has exacerbated this problem. Therefore, it is necessary to discuss the impact of the unavoidable time of surgical delay on the outcome of patients with MIBC. Methods: In all, 165 patients from high-volume centers with pT2-pT3 MIBC, who underwent radical surgery between January 2008 and November 2020, were retrospectively evaluated. Patients' demographic and pathological information was recorded. Based on the time of surgical delay endured, patients were divided into three groups: long waiting time (> 90 days), intermediate waiting time (30-90 days), and short waiting time (≤ 30 days). Finally, each group's pathological characteristics and survival rates were compared. Results: The median time of surgical delay for all patients was 33 days (interquartile range, IQR: 16-67 days). Among the 165 patients, 32 (19.4%) were classified into the long waiting time group, 55 (33.3%) into the intermediate waiting time group, and 78 (47.3%) into the short waiting time group. The median follow-up period for all patients was 48 months (IQR: 23-84 months). The median times of surgical delay in the long, intermediate, and short waiting time groups were 188 days (IQR: 98-367 days), 39 days (IQR: 35-65 days), and 16 days (IQR: 12-22 days), respectively. The 5-year overall survival (OS) rate for all patients was 58.4%, and that in the long, intermediate, and short waiting time groups were 35.7%, 61.3%, and 64.1%, respectively (P = 0.035). The 5-year cancer-specific survival (CSS) rates in the long, intermediate, and short waiting time groups were 38.9%, 61.5%, and 65.0%, respectively (P = 0.042). The multivariate Cox regression analysis identified age, time of surgical delay, pT stage, and lymph node involvement as independent determinants of OS and CSS. Conclusion: In patients with pT2-pT3 MIBC, the time of surgical delay > 90 days can have a negative impact on survival.

Anti-Metastatic Effect of Pyruvate Dehydrogenase Kinase 4 Inhibition in Bladder Cancer via the ERK, SRC, and JNK Pathways.

Bladder cancer is a common global cancer with a high percentage of metastases and high mortality rate. Thus, it is necessary to identify new biomarkers that can be helpful in diagnosis. Pyruvate dehydrogenase kinase 4 (PDK4) belongs to the PDK family and plays an important role in glucose utilization in living organisms. In the present study, we evaluated the role of PDK4 in bladder cancer and its related protein changes. First, we observed elevated PDK4 expression in high-grade bladder cancers. To screen for changes in PDK4-related proteins in bladder cancer, we performed a comparative proteomic analysis using PDK4 knockdown cells. In bladder cancer cell lines, PDK4 silencing resulted in a lower rate of cell migration and invasion. In addition, a PDK4 knockdown xenograft model showed reduced bladder cancer growth in nude mice. Based on our results, PDK4 plays a critical role in the metastasis and growth of bladder cancer cells through changes in ERK, SRC, and JNK.

Systems Drug Design for Muscle Invasive Bladder Cancer and Advanced Bladder Cancer by Genome-Wide Microarray Data and Deep Learning Method with Drug Design Specifications.

Bladder cancer is the 10th most common cancer worldwide. Due to the lack of understanding of the oncogenic mechanisms between muscle-invasive bladder cancer (MIBC) and advanced bladder cancer (ABC) and the limitations of current treatments, novel therapeutic approaches are urgently needed. In this study, we utilized the systems biology method via genome-wide microarray data to explore the oncogenic mechanisms of MIBC and ABC to identify their respective drug targets for systems drug discovery. First, we constructed the candidate genome-wide genetic and epigenetic networks (GWGEN) through big data mining. Second, we applied the system identification and system order detection method to delete false positives in candidate GWGENs to obtain the real GWGENs of MIBC and ABC from their genome-wide microarray data. Third, we extracted the core GWGENs from the real GWGENs by selecting the significant proteins, genes and epigenetics via the principal network projection (PNP) method. Finally, we obtained the core signaling pathways from the corresponding core GWGEN through the annotations of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway to investigate the carcinogenic mechanisms of MIBC and ABC. Based on the carcinogenic mechanisms, we selected the significant drug targets NFKB1, LEF1 and MYC for MIBC, and LEF1, MYC, NOTCH1 and FOXO1 for ABC. To design molecular drug combinations for MIBC and ABC, we employed a deep neural network (DNN)-based drug-target interaction (DTI) model with drug specifications. The DNN-based DTI model was trained by drug-target interaction databases to predict the candidate drugs for MIBC and ABC, respectively. Subsequently, the drug design specifications based on regulation ability, sensitivity and toxicity were employed as filter criteria for screening the potential drug combinations of Embelin and Obatoclax for MIBC, and Obatoclax, Entinostat and Imiquimod for ABC from their candidate drugs. In conclusion, we not only investigated the oncogenic mechanisms of MIBC and ABC, but also provided promising therapeutic options for MIBC and ABC, respectively.

Impact of sarcopenia in bladder preservation therapy for muscle-invasive bladder cancer patients: a narrative review.

Background and Objective: Muscle-invasive bladder cancer (MIBC) is a biologically aggressive disease and its prognosis is poor. Radical cystectomy (RC) with urinary diversion and lymph node dissection is the gold standard treatment for MIBC patients. Accumulating evidence indicates that sarcopenia, the degenerative and systemic loss of skeletal muscle mass, is a significant predictor of higher rates of mortality and perioperative complications following RC. Recently, bladder preservation therapy has been offered as an alternative in appropriately selected MIBC patients who desire to preserve their bladders and those unfit or unwilling for RC. Here, we performed a narrative review on the impact of sarcopenia on oncological outcomes and complication rates in MIBC patients treated with bladder preservation therapy. Methods: A literature review was performed using the PubMed and Scopus databases. Key Content and Findings: We identified two studies reported the impact of sarcopenia on responses to trimodal therapy and survival outcomes in MIBC patients. Consolidative partial cystectomy was performed in patients who achieved clinical complete response (CR) to trimodal therapy in one of the two studies. In both studies, CR rates to trimodal therapy are comparable between sarcopenic and non-sarcopenic patients. Sarcopenia was not significantly associated with shorter survival after completing bladder preservation therapy in either study. For complication rates of bladder preservation therapy, one study showed equivalent complication rates of consolidative partial cystectomy between sarcopenic and non-sarcopenic patients. In addition, in another small series of trimodal therapy, sarcopenic patients showed a higher rate of complications of trimodal therapy compared with non-sarcopenic patients. Conclusions: According to the result of our literature review, sarcopenia would not affect responses to trimodal therapy and prognosis in MIBC patients treated with bladder preservation therapy. Although the effect of sarcopenia on complication rates of bladder preservation therapy is inconclusive due to limited evidence, bladder preservation therapy could be a viable alternative option in carefully selected MIBC patients regardless of the presence of sarcopenia.