Management Of Bladder Cancer Research Articles

The urothelial gene regulatory network: understanding biology to improve bladder cancer management.

The urothelium is a stratified epithelium composed of basal cells, one or more layers of intermediate cells, and an upper layer of differentiated umbrella cells. Most bladder cancers (BLCA) are urothelial carcinomas. Loss of urothelial lineage fidelity results in altered differentiation, highlighted by the taxonomic classification into basal and luminal tumors. There is a need to better understand the urothelial transcriptional networks. To systematically identify transcription factors (TFs) relevant for urothelial identity, we defined highly expressed TFs in normal human bladder using RNA-Seq data and inferred their genomic binding using ATAC-Seq data. To focus on epithelial TFs, we analyzed RNA-Seq data from patient-derived organoids recapitulating features of basal/luminal tumors. We classified TFs as "luminal-enriched", "basal-enriched" or "common" according to expression in organoids. We validated our classification by differential gene expression analysis in Luminal Papillary vs. Basal/Squamous tumors. Genomic analyses revealed well-known TFs associated with luminal (e.g., PPARG, GATA3, FOXA1) and basal (e.g., TP63, TFAP2) phenotypes and novel candidates to play a role in urothelial differentiation or BLCA (e.g., MECOM, TBX3). We also identified TF families (e.g., KLFs, AP1, circadian clock, sex hormone receptors) for which there is suggestive evidence of their involvement in urothelial differentiation and/or BLCA. Genomic alterations in these TFs are associated with BLCA. We uncover a TF network involved in urothelial cell identity and BLCA. We identify novel candidate TFs involved in differentiation and cancer that provide opportunities for a better understanding of the underlying biology and therapeutic intervention.

Phase II Trial of Concurrent Nivolumab and Radiation Therapy for Muscle-Invasive Bladder Cancer of Older or Chemotherapy-Ineligible Patients

Bladder cancer is predominantly a disease of older individuals. Concurrent chemotherapy and radiation is a bladder-sparing strategy for management of muscle-invasive bladder cancer; however, many patients are not candidates for chemotherapy due to comorbidities or impaired performance status. We conducted a study in a chemotherapy-ineligible patient population with the objectives of evaluating the safety, efficacy, and quality-of-life effect of the combination of nivolumab and radiation therapy in patients with localized/locally advanced urothelial cancer. Eligible patients had muscle-invasive bladder cancer and were not candidates for standard chemoradiation strategy due to at least one of the following: performance status of 2, creatinine clearance ≤60 mL/min, cardiac disease, neuropathy, and intolerance to previous treatment. Creatinine clearance ≥40 mL/min, normal marrow, and liver function were required. The primary endpoint was progression-free survival at 12 months. Nivolumab was started within 3 days of radiation therapy and administered at a dose of 240 mg intravenously every 2 weeks for a maximum of 6 months. Radiation therapy was per standard of care for bladder cancer. Imaging and cystoscopy and biopsy evaluation were required at months 3, 6, and 12 and then annually until progression. Twenty patients were enrolled, with a median age of 78.5 years (range, 58-95 years); 80% of patients were >70 years of age, and 8 (40%) were >80 years of age. Median creatinine clearance was 52 mL/min. Nine patients (48%) were progression free at 12 months. Median progression-free survival was 11.4 months (90% CI, 7.5-23.7 months), and median overall survival was 15.6 months (90% CI, 9.1-26.1 months). Concurrent nivolumab and radiation therapy is tolerable but demonstrated limited efficacy in an older population with multiple comorbidities. Immune correlates demonstrated that patients with baseline programmed cell death ligand 1 combined prognostic score ≥5% had numerically longer progression-free survival.

Management of high-grade papillary Ta or T1 bladder cancer after restaging transurethral resection: A retrospective study comparing Bacillus Calmette–Guerin therapy upfront versus a third resection

PurposePerforming restaging transurethral bladder resection (reTURB) for high-risk non-muscle invasive bladder cancer (NMIBC) reduces the risk of recurrence and tumour understaging. Management of residual high-grade papillary Ta or T1 after reTURB has changed this last 10years in international recommendations. This study aimed to compare the recurrence free survival according to the different management procedures performed. Materials and methodsPatients who underwent reTURB for initial high-risk NMIBC between 2011 and 2020 were included. Patients with residual high-grade papillary Ta or T1 tumour after reTURB were divided into two groups: BCG instillations upfront versus BCG following a third-look resection (3TURB). Patient and tumour characteristics, BCG instillations, recurrence-free survival were retrospectively analysed. ResultsA total of 162 high-risk patients were included. Sixty-one (37.7%) had residual high-grade papillary Ta or T1 at reTURB: 35 (21.6%) had BCG instillations upfront, 18 (11.2%) had a 3TURB and 8 (5%) had other management. The mean follow-up was 34.2weeks±20.2. Recurrence-free survival was significantly better in patients who underwent BCG instillations upfront (P<0.0043). Recurrence after BCG therapy following reTURB was significantly lower in patients with no residual NMIBC at 6 (92.5% vs. 72.4%, P<0.004) and 12months (85% vs. 67.3%, P<0.03). ConclusionsThe efficacy of intravesical BCG is compromised in case of residual tumour following TURB. The role of a 3TURB following a positive reTURB is not yet determined. This study has confirmed that residual tumor following reTURB is a negative predictive factor but could not demonstrate the value of a 3TURB compared to upfront BCG. Level of evidence3.

Initial management and survival of patients with primary metastatic bladder cancer before the immunotherapy era: a population-based study from Norway.

Before immunotherapy became part of the management of metastatic bladder cancer (mBC), systemic anti-cancer treatment comprised primarily of platinum-based chemotherapy. The objective of this study was to describe the characteristics, the initial management, overall survival (OS) and hospitalisations of patients with mBC before 2018 when immunotherapy for mBC was introduced in Norway. Material and methods: It is a nationwide population-based study of primary mBC patients (diagnosed 2008-16). Descriptive statistics were applied and stratified for four initial management options (≤150 days after BC diagnosis): chemotherapy, major local treatment (cystectomy/pelvic radiotherapy), multimodal treatment (chemotherapy and local) and no anti-cancer treatment beyond transurethral resection of bladder tumour (untreated). Group differences were evaluated by Chi-square and Kruskal-Wallis test; OS was estimated with Kaplan-Meier. Results: Of the 305 patients included, 76 (25%) patients had chemotherapy, 46 (15%) patients had major local treatment, 21 (7%) patients had multimodal treatment and 162 (53%) patients were untreated. Median OS ranged from 2.3 months (untreated) to 9.8 months (chemotherapy). Patients who received treatment had a higher rate of hospitalisation, with a median stay of three to four times that of untreated patients. Conclusion: Before immunotherapy, more than 50% of patients with primary mBC did not receive any initial anti-cancer therapy and had a poor survival. Patients treated with chemotherapy had inferior median OS compared to those treated with comparable systemic strategies in contemporary trials. Our results provide a basis for future research on treatment and survival after the introduction of immunotherapy for mBC, aiming to improve the care and outcome of patients with mBC.

Does Bladder Cancer Subtype Influence Pathologic Complete Response (pCR) and Pelvic Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) Response Evaluation After Neoadjuvant Chemotherapy? Pathological Perspective

IntroductionWe aimed to provide a pathological perspective on the management of muscle-invasive bladder cancer (MIBC) by correlating the prechemotherapy transurethral resection of bladder tumor findings and postchemotherapy radiologic evaluation with final radical cystectomy (RC) findings. Materials and MethodsThis retrospective study included 79 MIBC patients treated with neoadjuvant chemotherapy (NAC) and RC. Pelvic diffusion-weighted magnetic resonance imaging (DW-MRI) and pathologic reports were retrieved from our institutional database. All pathology slides were reviewed based on diagnostic criteria with high interobserver reproducibility. ResultsPathologic complete response (pCR) was confirmed in 32 patients (40.5%). The concordance and discordance between MRI and RC findings occurred in 68.3% and 31.7% of cases, respectively. The 21.5% of cases that were clinical CR (cCR) on MRI actually achieved pCR on RC specimens and 46.8% of cases that were non-cCR on MRI were actually non-pCR on RC specimens. In 19.0% of cases, RC findings were pCR, but MRI demonstrated residual tumor and the opposite was 12.7%. The greatest discrepancy between the 2 methods (75%, 3/4) was for the plasmacytoid subtype. Plasmacytoid histology was the most common histological subtype identified in RC specimens after NAC, followed by micropapillary and squamous histologies. ConclusionsWe found that all cases with plasmacytoid and micropapillary subtypes, and squamous differentiation did not show pCR. In particular, the largest discrepancy between MRI findings and RC pathology after NAC was seen in the plasmacytoid subtype. An accurate pathologic diagnosis based on strict criteria to identify histological subtypes of MIBC is necessary for proper treatment.

P234 - Comparing toxicity and short term outcomes of Hyperthermic Intravesical Chemotherapy with Mitomycin-C versus Intravesical Chemotherapy with Mitomycin-C alone in the management of intermediate risk non-muscle invasive bladder cancer

P234 - Comparing toxicity and short term outcomes of Hyperthermic Intravesical Chemotherapy with Mitomycin-C versus Intravesical Chemotherapy with Mitomycin-C alone in the management of intermediate risk non-muscle invasive bladder cancer

Predictive models of long-term survival outcomes following radical cystectomy.

Identifying the likelihood of life-threatening recurrence after radical cystectomy by reliable and user-friendly predictive models remains an unmet need in the clinical management of invasive bladder cancer. A total of 204 consecutive patients undergoing open radical cystectomy (ORC) for bladder cancer were retrospectively enrolled between May 2005 and August 2020. Clinicopathological and peri-ORC therapeutic data were extracted from clinical records. We explored predictive factors that significantly affected the primary endpoint of overall survival (OS) and secondary endpoints of cancer-specific survival (CSS) and recurrence-free survival (RFS). During a median follow-up of 3.9 years, 42 (20.6%) and 10 (4.9%) patients died due to bladder cancer and other causes, respectively. Five-year RFS, CSS, and OS were 66.5%, 77.6%, and 75.4%, respectively. Pathological T and N categories and lymphovascular invasion (LVI) significantly affected RFS by Cox regression analysis. Accordingly, clinical T and pathological N categories and LVI significantly affected CSS. Clinical T and pathological N categories, LVI, age, and ORC tumor grade significantly affected OS. Based on the assessment score for each independent risk factor, we developed the Gunma University Oncology Study Group (GUOSG) score, which predicts RFS, CSS, and OS. The GUOSG score classified four groups for RFS, three for CSS, and five for OS, with statistically significant distribution for nearly all comparisons. The GUOSG model is helpful to show individualized prognosis and functions as a risk-stratified historical cohort for assessing the lifelong efficacy of new salvage treatment regimens.

Effects of delayed diagnosis on tumor size, stage and grade in bladder cancer.

This study is planned based on the hypothesis that if bladder cancer is detected early, the disease would be less advanced and the possibility of treatment will increase, at least the recurrence-free survival will be longer. Regarding this hypothesis, it is aimed to investigate the effect of delayed diagnosis primarily on the disease factors. The study included 169 patients, who underwent TUR-BT with the suspicion of bladder cancer in the urology clinic of Afyonkarahisar Faculty of Medicine between April 2018 and April 2023. Demographic and clinical data of the patients were recorded and compared. It was observed that the delay in diagnosis was significantly longer in patients with tumors larger than 3cm compared to patients with tumors smaller than 3cm (p < 0.001). In the correlation analysis between tumor size, duration of diagnosis delay, age, T stage, and tumor grade, a low level of positive correlation was observed between tumor size and duration of diagnosis delay, and it was statistically significant (r = 0.215, p = 0.005). In our study, it was shown that the tumor size increases as the duration of diagnosis delay increases and this increase causes an increase of 0.088mm in the pathological size of the tumor in the 1-day delay period. Considering that tumor size changes the risk group of the disease in bladder tumors, and relatedly the follow-up and treatment process changes, we believe that these data will be valuable in the management of bladder cancer.

The Role of Checkpoint Inhibitor Expression Directly on Exfoliated Cells from Bladder Cancer: A Narrative Review.

Bladder cancer (BCa) is a common type of cancer that affects the urinary bladder. The early detection and management of BCa is critical for successful treatment and patient outcomes. In recent years, researchers have been exploring the use of biomarkers as a non-invasive and effective tool for the detection and monitoring of BCa. One such biomarker is programmed death-ligand 1 (PD-L1), which is expressed on the surface of cancer cells and plays a crucial role in the evasion of the immune system. Studies have shown that the PD-L1 expression is higher in BCa tumors than in healthy bladder tissue. Additionally, PD-L1 expression might even be detected in urine samples in BCa patients, in addition to the examination of a histological sample. The technique is being standardized and optimized. We reported how BCa patients had higher urinary PD-L1 levels than controls by considering BCa tumors expressing PD-L1 in the tissue specimen. The expression of PD-L1 in urinary BCa cells might represent both a diagnostic and a prognostic tool, with the perspective that the PD-L1 expression of exfoliate urinary cells might reveal and anticipate eventual BCa recurrence or progression. Further prospective and longitudinal studies are needed to assess the expression of PD-L1 as a biomarker for the monitoring of BCa patients. The use of PD-L1 as a biomarker for the detection and monitoring of BCa has the potential to significantly improve patient outcomes by allowing for earlier detection and more effective management of the disease.

The Impact of Travel Time on Trimodal Therapy Compared to Cystectomy for Bladder Cancer.

Neoadjuvant chemotherapy followed by radical cystectomy (RC) and Transurethral Resection of Bladder Tumor (TURBT) followed by concurrent chemoradiation therapy (trimodal therapy, TMT) are both evidence-based approaches to the management of muscle-invasive bladder cancer, and no randomized evidence conclusively supports the use of one treatment over another. Literature suggests that increasing distance to radiation therapy (RT) facilities reduces the likelihood that patients will receive RT, though this has not been evaluated in bladder cancer. We hypothesize that greater travel time between a patient's home and their closest RT facility is associated with a lower likelihood of undergoing TMT. Clinical data and the locations of patient residences and surgical facilities performing RC were obtained from the California Cancer Registry. RT facility locations were compiled from state regulatory databases and dosimetric accrediting bodies. Travel time was identified using the Google Distance Matrix API. California patients diagnosed with T2-4N0 bladder cancer in 2018-2019 who underwent TMT (> = 55Gy) or RC were included in this analysis. Chi-square tests, Kruskal-Wallis tests, and univariate and multivariate logistic regressions were performed to assess factors associated with an increased likelihood of receipt of TMT, and to compare travel times for patients receiving TMT vs RC. A total of 536 patients met inclusion criteria, and 27.1% underwent TMT. Patients receiving TMT were more likely to be older, White, male, and live further from their nearest RT facility. After adjusting for age, sex, and race/ethnicity, patients undergoing TMT were more likely than RC patients to live more than 30 minutes away from the nearest RT facility (OR 1.53, p = 0.21, ref<15 minutes). On multivariate analysis, patients receiving TMT were less likely than surgical patients to live 30-60 minutes or >60 minutes from their treatment facility ((OR 0.5, p-value<0.01, and OR 0.23, p-value <.001), ref: <30 minutes). Only 26.2% of patients who received TMT were treated at their nearest RT facility, while 13.3% of patients undergoing RC were treated at their nearest surgical facility. In a modern cohort of bladder cancer patients in California, about a quarter of T2-4N0 patients are undergoing bladder preservation. Patients undergoing TMT lived further from their nearest RT facility than patients undergoing surgery. Surgical patients were more likely to live >30 minutes from their treating facility than TMT patients. A minority of patients underwent treatment at the facility nearest to them, regardless of treatment modality chosen. Taken together, this suggests that proximity to the nearest RT facility may not be associated with a higher likelihood of undergoing TMT. Examination of actual treatment facilities (as opposed to the closest facility) shows that patients are traveling further for surgical care than TMT.

Bladder Cancer during Pregnancy: A Review of the Literature.

Bladder malignancy represents the fourth most common cancer in men and the eighth in women in the western world. Women under 75 years of age have a risk of 0.5-1% of developing bladder cancer. The diagnosis usually occurs between 65 and 70 years of age, whereas the mortality rate for women varies from 0.5 to 4 per 100,000 every year. Nulliparous women present a greater risk than women who have given birth. The risk is further decreased when parity increases. Theoretically, hormonal changes occurring during pregnancy play a protective role. Smoking and occupational exposure to specific chemicals are the most common risk factors of bladder cancer. Other risk factors such as chronic urinary tract inflammation, cyclophosphamide, radiotherapy, and familial correlation have been reported. The aim of this review is to highlight a rare combination, which is the co-existence of bladder malignancy and pregnancy. We present thirteen different cases of women who were diagnosed with malignant bladder tumors during their pregnancy. A review of the literature was conducted, focusing on the unspecific symptoms, possible diagnostic tools, and suitable treatment modalities. The management of bladder cancer in pregnancy is a challenging process. The fragile balance between the possible complications of pregnancy and maternal health is yet to be discussed.

Elucidating the Associated Biological Function and Clinical Significance of RHOJ Expression in Urothelial Carcinoma.

Urothelial cancer, a common urinary system malignancy, often presents treatment challenges due to metastasis and chemotherapy side effects. Angiogenesis, crucial for tumor growth, has become a target for drug development. This study explores the expression, prognostic value, and clinical correlation of RHOJ in the TCGA BLCA, GSE31684, and GSE32894 datasets. We identify common differentially expressed genes across these databases and utilize g:Profiler and Cytoscape ClueGO for functional assessment. Further, we perform a gene set enrichment analysis (GSEA) using Hallmark gene sets and use the imsig package for immune cell infiltration analysis. Our analysis indicates that RHOJ expression levels significantly impact survival rates, tumor progression, and immune response in urothelial tumors. High RHOJ expression correlated with poor prognosis, advanced disease stages, and an increase in monocyte population within the tumor microenvironment. This aligns with current literature indicating a key role of immune infiltration in bladder cancer progression and treatment response. Moreover, the GSEA and imsig results further suggest a potential mechanistic link between RHOJ expression and immune-related pathways. Considering the increasing emphasis on immunotherapeutic strategies in bladder cancer management, our findings on RHOJ's potential as a diagnostic biomarker and its association with immune response open new avenues for therapeutic interventions.

Occurrence of Distant Metastasis During Bladder Presevation in T1 high-grade Bladder Cancer: Report of Three Cases

We report three patients with T1 high-grade (HG) bladder cancer who suffered from distant metastasis during bladder preservation. The patients were a 48-year-old female (Case 1), a 75-year-old female (Case 2) and an 82-year-old male (Case 3) with the chief complaint of asymptomatic gross hematuria. The histopathological diagnoses of the initial transurethral resection of the bladder tumor (TURBT) and second TURBT were urothelial carcinoma, pT1, HG and no malignancy in all three patients. Bladder tumors of all patients revealed sessile growth pattern and no presence of carcinoma in situ. Case 2 and 3 did not receive BCG vesical instillation after the second TURBT. Lymph node metastases appeared in Case 1 and Case 2 and lung metastasis appeared in Case 3. Tumor budding (TB) was positive in Case 1 and Case 2. Variant histology (VH) of nested morphology was detected in Case 1 and VH of inverted morphology in Case 2 and Case 3. Twenty-four months after the initial TURBT, Case 1 died due to cancer progression after cisplatin-based chemotherapy and pembrolizumab therapy. Thirty-three and 11 months after the initial TURBT, Case 2 and Case 3 were alive without cancer progression after cisplatin-based chemotherapy and/or pembrolizumab therapy, respectively. The two patients with T1 HG bladder cancer with TB had lymphatic metastasis and the patient without TB had hematogenous metastasis. Nested morphology is reportedly categorized as high-risk disease and inverted morphology as low-risk disease. TB might be correlated with lymphatic metastasis in T1 HG bladder cancer, and TB should be considered in the management of T1 HG bladder cancer. In the case of VH, the guidelines should be followed during the treatment decision of T1 HG bladder cancer.

Rotatable Bi-Channel En Bloc Resection of Bladder Tumor for Non-Muscle-Invasive Bladder Cancer in an Ex Vivo Porcine Model.

En bloc resection of bladder tumor (ERBT) is a promising alternative for non-muscle-invasive bladder cancer management. However, the tumor characteristics and surgeon's experience influence its application. Therefore, in this pilot study, we developed a technique called "rotatable bi-channel en bloc resection of bladder tumor (RBC-ERBT)" and assessed its feasibility, efficacy, and safety compared with those of conventional ERBT. In an ex vivo porcine bladder model, 160 bladder lesions of varying morphologies (exophytic and flat) and sizes (1 and 2 cm) were created and evenly distributed across different locations. A total of 160 procedures were performed, with the ERBT and RBC-ERBT group each exhibiting 80 lesions. RBC-ERBT had a significantly higher technical success rate than ERBT (98.8% vs. 77.5%) for exophytic and flat lesions of both sizes and dome lesions. The procedure time was significantly shorter in the RBC-ERBT group, particularly for flat lesions, lesions with a 2 cm diameter, and lesions located at the dome. RBC-ERBT had a significantly lower piecemeal resection rate than ERBT (0% vs. 18.8%). The incidence of perforation or detrusor muscle sampling did not differ between the groups. Compared with conventional ERBT, RBC-ERBT offered improved success rates, reduced resection times, and effective management of challenging lesions.

Does Repeating Transurethral Resection of Bladder Tumors Change Treatment Plan for All T1 Tumors?

Background: The main problem in the proper management of non-muscle invasive bladder cancer (NMIBC) is the under-staging of lesions after initial transurethral resection of bladder tumor (TUBRT). Under staging is much more evident in T1 tumors when the detrusor muscle is absent. So, we evaluated under-staging and residual tumors in patients with complete initial TURBT whose initial pathological samples revealed the presence of the detrusor muscle. Methods: In this prospective study performed in Bahonar hospital, Kerman, Iran, from August 2018 to April 2020, 51 patients with newly diagnosed T1 bladder tumors were enrolled according to our criteria and underwent standard Re-TURBT about eight weeks after the initial TURBT. Results: Of 51 patients who underwent Re-TURBT, 12 (23.5%) had tumors, of whom eight had microscopic, and four had macroscopic tumors. None of them were upstaged or upgraded. There was a statistically significant relationship between the presence of tumors in Re-TURBT and the size of the primary tumor (&gt;3 cm) and the number of tumors (&gt;1). No changes were observed in the stage and grade of the disease, besides, the treatment plan of patients did not change despite imposing financial burdens on patients and the healthcare system. Conclusion: Re-TURBT is not necessary for all superficial bladder tumors, especially in the case of complete initial TURBT, and also in the presence of the detrusor muscle in the pathological sample and when the tumor is single and less than three centimeters in size.

Codelivery of ERCC2 small interfering RNA and cisplatin with macrophage-derived mimetic nanovesicles for enhanced bladder cancer treatment.

Cisplatin-based chemotherapy plays a vital role in the management of muscle-invasive bladder cancer (MIBC); however, off-tumor toxicity and resistance often lead to cancer recurrence and eventual treatment failure. The loss of function of the nucleotide excision repair gene excision repair cross-complementing rodent repair deficiency gene 2 ( ERCC2 ) in cancer cells correlates with sensitivity to cisplatin, while its overexpression causes cisplatin resistance. Small interfering RNA (siRNA) knockdown of ERCC2 combined with cisplatin treatment may improve therapeutic outcomes in patients with bladder cancer. Here, we aimed to develop macrophage-derived mimetic nanovesicles (MNVs) as a nanoplatform for the simultaneous delivery of cisplatin and ERCC2 siRNA for enhancing the efficacy of bladder cancer chemotherapy. The cellular uptake, gene down-regulation, tumor inhibition effects, and biosafety of the synthesized nanodrugs (MNV-Co) as a synergistic therapeutic strategy for MIBC were evaluated in vitro and in vivo . The results indicated high efficacy of MNV-Co against MIBC and low off-tumor toxicity. Furthermore, by down-regulating ERCC2 mRNA and protein levels, MNV-Co improved chemosensitivity, promoted cancer cell apoptosis, and effectively suppressed tumor growth. This study presents a potential approach for delivering cisplatin and ERCC2 siRNA concurrently to treat bladder cancer using a biomimetic nanosystem.

Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 Patients.

To evaluate our long-term experience with patients treated uniformly with radical cystectomy and pelvic lymph node dissection for invasive bladder cancer and to describe the association of the primary bladder tumor stage and regional lymph node status with clinical outcomes. All patients undergoing radical cystectomy with bilateral pelvic iliac lymphadenectomy, with the intent to cure, for transitional-cell carcinoma of the bladder between July 1971 and December 1997, with or without adjuvant radiation or chemotherapy, were evaluated. The clinical course, pathologic characteristics, and long-term clinical outcomes were evaluated in this group of patients. A total of 1,054 patients (843 men [80%] and 211 women) with a median age of 66 years (range, 22 to 93 years) were uniformly treated. Median follow-up was 10.2 years (range, 0 to 28 years). There were 27 (2.5%) perioperative deaths, with a total of 292 (28%) early complications. Overall recurrence-free survival at 5 and 10 years for the entire cohort was 68% and 66%, respectively. The 5- and 10-year recurrence-free survival for patients with organ-confined, lymph node-negative tumors was 92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83% and 78% for P1 tumors, respectively. Patients with muscle invasive (P2 and P3a), lymph node-negative tumors had 89% and 87% and 78% and 76% 5- and 10-year recurrence-free survival, respectively. Patients with nonorgan-confined (P3b, P4), lymph node-negative tumors demonstrated a significantly higher probability of recurrence compared with those with organ-confined bladder cancers (P < .001). The 5- and 10-year recurrence-free survival for P3b tumors was 62% and 61%, and for P4 tumors was 50% and 45% , respectively. A total of 246 patients (24%) had lymph node tumor involvement. The 5- and 10-year recurrence-free survival for these patients was 35%, and 34%, respectively, which was significantly lower than for patients without lymph node involvement (P < .001). Patients could also be stratified by the number of lymph nodes involved and by the extent of the primary bladder tumor (p stage). Patients with fewer than five positive lymph nodes, and whose p stage was organ-confined had significantly improved survival rates. Bladder cancer recurred in 311 patients (30%) . The median time to recurrence among those patients in whom the cancer recurred was 12 months (range, 0.04 to 11.1 years). In 234 patients (22%) there was a distant recurrence, and in 77 patients (7%) there was a local (pelvic) recurrence. These data from a large group of patients support the aggressive surgical management of invasive bladder cancer. Excellent long-term survival can be achieved with a low incidence of pelvic recurrence.

Recent advancements in the diagnosis and treatment of non-muscle invasive bladder cancer: Evidence update of surgical concept, risk stratification, and BCG-treated disease.

In the management of non-muscle invasive bladder cancer (NMIBC), disease progression and long-term control are determined by the intensity of delivered treatment and surveillance and the cancer cells' biological nature. This requires risk stratification-based postoperative management, such as intravesical instillation of chemotherapy drugs, Bacillus Calmette-Guérin (BCG), and radical cystectomy. Advancements in mechanical engineering, molecular biology, and surgical skills have evolved the clinical management of NMIBC. In this review, we describe the updated evidence and perspectives regarding the following aspects: (1) advancements in surgical concepts, techniques, and devices for transurethral resection of the bladder tumor; (2) advancements in risk stratification tools for NMIBC; and (3) advancements in treatment strategies for BCG-treated NMIBC. Repeat transurethral resection, en-bloc transurethral resection, and enhanced tumor visualization, including photodynamic diagnosis and narrow-band imaging, help reduce residual cancer cells, provide accurate diagnosis and staging, and sensitive detection, which are the first essential steps for cancer cure. Risk stratification should always be updated and improved because the treatment strategy changes over time. The BCG-treated disease concept has recently diversified to include BCG failure, resistance, refractory, unresponsiveness, exposure, and intolerance. A BCG-unresponsive disease is an extremely aggressive subset unlikely to respond to a rechallenge with BCG. Numerous ongoing clinical trials aim to develop a future bladder-sparing approach for very high-risk BCG-naïve NMIBC and BCG-unresponsive NMIBC. The key to improving the quality of patient care lies in the continuous efforts to overcome the clinical limitations of bedside management.

CDK2 and CDK4 targeted liensinine inhibits the growth of bladder cancer T24 cells

Bladder cancer (BCa) is a urinary tumor with limited treatment options and high mortality. Liensinine (LIEN), a natural bisbenzylisoquinoline alkaloid, has shown excellent anti-tumor effects in numerous preclinical studies. However, the anti-BCa effect of LIEN remains unclear. To the best of our knowledge, this is the first study to investigate the molecular mechanism of LIEN in the management of BCa. First, we identified the treatment-related targets of BCa; those that repeatedly occur in more than two databases, including GeneCards, Online Mendelian Inheritance in Man, DisGeNET, Therapeutic Target Database, and Drugbank. The SwissTarget database was used to screen LIEN-related targets, and those with a probability >0 were possible LIEN targets. The prospective targets of LIEN in the treatment of BCa were then determined using a Venn diagram. Second, we discovered that the PI3K/AKT pathway and senescence mediated the anti-BCa action of LIEN by using GO and KEGG enrichment analysis to explore the function of LIEN therapeutic targets. A protein-protein interaction network was created using the String website, and six algorithms of the CytoHubba plug-in were then used in Cytoscape to assess the core targets of LIEN for the therapy of BCa. The outcomes of molecular docking and dynamics simulation demonstrated that CDK2 and CDK4 proteins were the direct targets of LIEN in the management of BCa, among which CDK2 was more stable in binding to LIEN than CDK4. Finally, in vitro experiments showed that LIEN inhibited the activity and proliferation of T24 cells. The expression of p-/AKT, CDK2, and CDK4 proteins progressively decreased, while the expression and fluorescence intensity of the senescence-related protein, γH2AX, gradually increased with increasing LIEN concentration in T24 cells. Therefore, our data suggest that LIEN may promote senescence and inhibit proliferation by inhibiting the CDK2/4 and PI3K/AKT pathways in BCa.

Bibliometric analysis of the association between drinking water pollution and bladder cancer.

Bladder cancer has become an increasingly intractable health problem worldwide. Long-term drinking water pollution is known to promote its occurrence. This study aimed to analyze the research status, hot spots, and future trends of drinking water pollution and bladder cancer through extensive bibliometric examination to provide reference data for better prevention and management of bladder cancer. The Scopus database developed by Elsevier was browsed for articles that met the predefined criteria using the search terms related to drinking water and bladder cancer. Included articles were further evaluated by year of publication, subject category, institution, article type, source journal, authors, co-authorship networks, and text mining of titles by R software packages tm, ggplot2 and VOSviewer software. In total, 687 articles were selected after a comprehensive literature search by the Scopus database, including 491 research articles, 98 review articles, 26 conference papers, 23 letters and 49 other documents. The total number of articles published showed an upward trend. The United States has the largest number of published articles (345 articles), institutions (7/10) and funding sponsors (top 5). The journal with the most publications was Environmental Health Perspectives, with 46 published. The highest number of citations up to 2330 times for a single article published in 2007 on the journal of Mutation Research. Professor Cantor K.P. was the highest number of publications with 35 articles and Smith A.H. was the most cited author with the number of citations reaching 6987 times overall and 225 times per article. The most frequent keywords excluding the search subject were "arsenic", "chlorination", "trihalomethane", and "disease agents". This study is the first systematic bibliometric study of the literature publications on drinking water pollution and bladder cancer. It offers an overall and intuitive understanding of this topic in the past few years, and points out a clear direction research hotspots and reveals the trends for further in-depth study in future.