Cases Of Muscle-invasive Bladder Cancer Research Articles

Monopolar versus bipolar transurethral resection of bladder Tumour: post-hoc analysis of a prospective trial

IntroductionPreviously, in a randomised trial we demonstrated bipolar transurethral resection of bladder tumor (TURBT) could achieve a higher detrusor sampling rate than monopolar TURBT. We hereby report the long-term oncological outcomes following study intervention.MethodsThis is a post-hoc analysis of a randomized phase III trial comparing monopolar and bipolar TURBT. Only patients with pathology of non-muscle invasive bladder cancer (NMIBC) were included in the analysis. Per-patient analysis was performed. Primary outcome was recurrence-free survival (RFS). Secondary outcomes included progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS).ResultsFrom the initial trial, 160 cases were randomised to receive monopolar or bipolar TURBT. 24 cases of non-urothelial carcinoma, 22 cases of muscle-invasive bladder cancer, and 9 cases of recurrences were excluded. A total of 97 patients were included in the analysis, with 46 in the monopolar and 51 in the bipolar group. The median follow-up was 97.1 months. Loss-to-follow-up rate was 7.2%. Regarding the primary outcome of RFS, there was no significant difference (HR = 0.731; 95%CI = 0.433–1.236; P = 0.242) between the two groups. PFS (HR = 1.014; 95%CI = 0.511–2.012; P = 0.969), CSS (HR = 0.718; 95%CI = 0.219–2.352; P = 0.584) and OS (HR = 1.135; 95%CI = 0.564–2.283; P = 0.722) were also similar between the two groups. Multifocal tumours were the only factor that was associated with worse RFS.ConclusionDespite the superiority in detrusor sampling rate, bipolar TURBT was unable to confer long-term oncological benefits over monopolar TURBT.

Evaluation of the Expression of Programmed Death-Ligand 1 and Its Role in Differentiating Low-Grade and High-Grade Urothelial Carcinoma.

Urothelial carcinoma (UC) is a common malignancy, predominantly affecting males. Many tumor cells use the interaction between programmed death-ligand 1 (PD-L1) and programmed death receptor (PD-1) to inactivate T-cells in the microenvironment and evade host immune response. Our study aims to evaluate the expression of PD-L1 in UC and correlate its expression with histomorphological parameters. After obtaining approval from the Institute Ethics Committee, we conducted a prospective observational study on transurethral resection of urinary bladder tumor (TURBT) and cystectomy specimens histopathologically diagnosed as UC between 2022 and 2023, comprising 50 cases. All standard protocol was followed and immunohistochemistry (IHC) was done using PD-L1 with rabbit anti-human PD-L1 monoclonal antibody (Clone: IHC411; Biogenics Inc., San Francisco, CA, USA). Results: Among the 50 cases of UC, the majority were papillary type (35 cases), high grade (28 cases), and non-muscle invasive (30 cases). Among the cases studied, 15 of them showed PD-L1 positivity; 55% of the cases of muscle-invasive bladder cancer were found to be positive for PD-L1 out of which the results were statistically significant. PD-L1 expression by IHC staining can differentiate between muscle-invasive and non-muscle-invasive UC cases. This observation allows for further exploring the potential role of immune checkpoint inhibitors in adjuvant and neoadjuvant therapy, especially in muscle-invasive cases of UC.

Determining the clinicopathological significance of the VI-RADS ≧4 group: a retrospective study.

The Vesical Imaging Reporting and Data System (VI-RADS) is widely used for predicting muscle-invasive bladder cancer (MIBC). This study aimed to determine the clinicopathological significance of the VI-RADS ≧4 (VI≧4) group. Patients who underwent transurethral resections of bladder tumors during the study period and preoperative magnetic resonance imaging were considered. The patients were pathologically diagnosed with urothelial carcinoma (UC). We first compared the results of patients with VI-RADS scores of 3 and 4 to determine the cut-off score for MIBC; thereafter, the patients were divided into the VI≧4 and VI-RADS ≦3 (VI≦3) groups using VI-RADS. The clinicopathological significance of the VI≧4 group was examined retrospectively by comparing the characteristics of each group. In total, 121 cases were examined, of which 28 were pathologically diagnosed with MIBC. Of the 28 MIBC cases, three (10.7%) had a VI-RADS score of ≦3, and 25 (89.3%) had a VI-RADS score of ≧4. Of the 93 NMIBC cases, 86 (92.5%) had a VI-RADS score of ≦3, and seven (7.5%) had a VI-RADS score of ≧4. The diagnostic performance of the VI-RADS with a cut-off score of 4 was 89.3% for sensitivity, 92.5% for specificity, and an area under the curve (AUC) of 0.91. Contrastingly, for a cut-off score of 3, the sensitivity was 89.3%, specificity was 62.0%, and AUC was 0.72. A VI-RADS score of ≥ 4 could predict MIBC. In the VI≧4 group, 30 of 32 (93.8%) patients had high-grade tumors. The VI≧4 group had significantly more high-grade bladder cancers than the VI≦3 group (p < 0.001 OR = 31.77 95%CI:8.47-1119.07). In addition, the VI≧4 group had more tumor necrosis (VI≧4 vs VI≦3, p < 0.001 OR = 7.46 95%CI:2.61-21.34) and more UC variant cases (VI≧4 vs VI≦3, p = 0.034 OR = 3.28 95%CI:1.05-10.25) than the VI≦3 group. This study suggests that VI-RADS has a high diagnostic performance in predicting MIBC and that VI-RADS could diagnose high-grade tumors, necrosis, and UC variants.

Comparative real-world survival outcomes of muscle-invasive bladder cancer treated with bladder-only vs. whole-pelvis concurrent chemoradiation.

Elective pelvic nodal irradiation for patients with muscle-invasive bladder cancer (MIBC) undergoing trimodal therapy (TMT ) is controversial. In patients with node-negative (N0) MIBC, the benefit of elective whole-pelvis concurrent chemoradiation (WP-CCR) compared to bladder-only (BO )-CCR has not been demonstrated. Using real-world data from the National Cancer Database (NCDB ), we sought to compare the overall survival (OS ) between BO-CCR and WP-CCR for MIBC. Using the 2020 NCDB Participant User File, we identified cases of MIBC diagnosed between 2017 and 2019. We selected patients with clinical T2-T4aN0M0 disease receiving CCR as first-line treatment. CCR was defined as transurethral resection of bladder tumor followed by ≥40 Gy radiation to the bladder with concurrent single- or multiple-agent chemotherapy. Based on elective nodal irradiation status, patients were stratified as having received BO-CCR vs. WP-CCR. OS analysis was performed using summary three-month conditional landmark, inverse probability treatment weighting (IPTW)-adjusted Kaplan-Meier estimates, and Cox regression. A total of 604 patients receiving CCR for MIBC were identified: 367 (60.8%) BO-CCR and 237 (39.2%) WP-CCR. Before IPTW, the groups were imbalanced in terms of baseline characteristics. The median followup of the weighted population was 42.3 months (interquartile range 18.1-49.1 months). In IPTW-adjusted Cox proportional hazards regression analysis, WP-CCR was associated with a significant OS benefit compared to BO-CCR (adjusted hazard ratio 0.72, 95% confidence interval 0.54-0.96, p=0.026). In the setting of CCR for N0 MIBC, this retrospective NCDB analysis revealed that WP-CCR was associated with a benefit in OS compared to BO-CCR.

Proposal for a Novel Histological Scoring System as a Potential Grading Approach for Muscle-invasive Urothelial Bladder Cancer Correlating with Disease Aggressiveness and Patient Outcomes

BackgroundGrading of muscle-invasive bladder cancer (MIBC) according to the current World Health Organization (WHO) criteria is controversial due to its limited prognostic value. All MIBC cases except a tiny minority are of high grade. ObjectiveTo develop a prognostic histological scoring system for MIBC integrating histomorphological phenotype, stromal tumor-infiltrating lymphocytes (sTILs), tumor budding, and growth and spreading patterns. Design, setting, and participantsTissue specimens and clinical data of 484 patients receiving cystectomy and lymphadenectomy with curative intent with or without adjuvant chemotherapy. Histomorphological phenotypes, sTILs, tumor budding, and growth and spreading patterns were evaluated and categorized into four grade groups (GGs). GGs were correlated with molecular subtypes, immune infiltration, immune checkpoint expression, extracellular matrix (ECM) remodeling, and epithelial-mesenchymal transition (EMT) activity. Outcome measurements and statistical analysisGGs were associated with overall (OS), disease-specific (DSS), and progression-free (PFS) survival in univariable and multivariable analyses. Association with biological features was analyzed with descriptive statistics. Results and limitationsIntegration of two histomorphological tumor groups, three sTILs groups, three tumor budding groups, and four growth/spread patterns yielded four novel GGs that had high significance in the univariable survival analysis (OS, DSS, and PFS). GGs were confirmed as independent prognostic predictors with the greatest effect in the multivariable Cox regression analysis. Correlation with molecular data showed a gradual transition from basal to luminal subtypes from GG1 to GG4; a gradual decrease in survival, immune infiltration, and immune checkpoint activity; and a gradual increase in ECM remodeling and EMT activity. ConclusionsWe propose a novel, prognostically relevant, and biologically based scoring system for MIBC in cystectomies applicable to routine pathological sections. Patient summaryWe developed a novel approach to assess the aggressiveness of advanced bladder cancer, which allows improved risk stratification compared with the method currently proposed by the World Health Organization.

Development and Internal Validation of a Nomogram Predicting Overall Survival Based on Log ODDS of Positive Lymph-Nodes for Post Radical Cystectomy Patients in Muscle Invasive Carcinoma of Bladder.

To develop and validate a nomogram based on LODDS (Log ODDS of positive lymph-nodes) for prediction of overall survival (OS) in post radical cystectomy (RC) patients of muscle invasive bladder cancer (MIBC). Data was retrospectively collected from 282 cases of MIBC that underwent RC from 2011 to 2017 at our institute. Significant independent predictors were identified using Cox regression model and incorporated into a nomogram to predict 1, 2, and 4-year OS. Multivariate analysis showed that Neo-Adjuvant Chemo-Therapy (NACT) (P< .001), LODDS (P< .001), T-stage (Pi=.001), CCI (Charlson Comorbidity Index) (P=.034) and grade (P=.003) were independent predictors of OS. The C-index of nomogram (0.740) was higher than that of the American Joint Committee on Cancer (AJCC) staging system (0.614). The bias-corrected calibration plots showed that the predicted risks were in excellent accordance with the actual risks. The results of NRI, IDI, and DCA exhibited superior predictive capability and higher clinical use of the nomogram. A simple, easy to use nomogram to predict OS in cases of MIBC has been constructed. To best of our knowledge, LODDS has been incorporated for the first time. It has superior predictive ability and higher clinical use than AJCC system. It would help the clinicians for better patient counselling, planning follow-up strategies and designing a clinical trial for newer adjuvant therapy (eg immunotherapy) in post radical cystectomy patients of MIBC.

Radiogenomics of muscle invasive bladder cancer.

e16587 Background: Accurate staging of Muscle Invasive Bladder Cancer (MIBC) is essential to ensure optimal treatment (e.g., radical cystectomy vs. bladder preservation). However, currently about 1/3 of patients are overstaged and 1/3 are understaged. There is a pressing need of accurate noninvasive staging for MIBC to assist clinical decision making. Methods: In this preliminary study, an extensive radiogenomic analysis of MIBC cases was performed to identify potential indicators of MIBC stages, and to automate the staging process. A total of 28 MRI scans and their matched transcriptomic profiles were obtained from subjects diagnosed with MIBC at different stages. In the genomics, a bulk RNA-seq from FFPE tissues was performed that identified 3 major clusters, high, intermediate, and low infiltrating immune cells and fibroblasts. This was followed by a bioinformatic analyses, such as pathway enrichment and gene set enrichment analyses, 15 most significant signatures were identified for stage categorization of MIBC (Fig. 1). In the radiomics, several hundred image-based features from bladder tumor in MRI were extracted and analyzed. The tumors were manually outlined and grouped into lower-stage (stage I and II) and higher-stage (stage III and IV) by the trained radiologists. Using various statistical tests, several radiomic features (e.g., heterogeneity, inverse contrast, entropy) were inferred as significant at discriminating the two groups (Fig. 2). A naïve Bayes machine learning model was then used to integrate such features and perform automated binary classification of cases into their true class. A 4-fold cross validation was performed in which a unique 75% and 25% of 28 cases were used for training and testing of the model respectively. Results: The model performance was assessed in terms of prediction (binary classification) of stages as mean sensitivity, specificity, and accuracy, reaching 84%, 86%, and 86% respectively. Conclusions: The radiogenomics of MIBC provides insight into features associated with cancer stages. Assisted with AI, the discriminative features can accurately stage MIBC. Source of Funding: Cedars-Sinai Cancer Internal Funds: Developmental Funds for Investigator Initiated Trials Using Advanced Imaging Methods.

Hypoxia Is Associated with Increased Immune Infiltrates and Both Anti-Tumour and Immune Suppressive Signalling in Muscle-Invasive Bladder Cancer.

Hypoxia and a suppressive tumour microenvironment (TME) are both independent negative prognostic factors for muscle-invasive bladder cancer (MIBC) that contribute to treatment resistance. Hypoxia has been shown to induce an immune suppressive TME by recruiting myeloid cells that inhibit anti-tumour T cell responses. Recent transcriptomic analyses show hypoxia increases suppressive and anti-tumour immune signalling and infiltrates in bladder cancer. This study sought to investigate the relationship between hypoxia-inducible factor (HIF)-1 and -2, hypoxia, and immune signalling and infiltrates in MIBC. ChIP-seq was performed to identify HIF1α, HIF2α, and HIF1β binding in the genome of the MIBC cell line T24 cultured in 1% and 0.1% oxygen for 24 h. Microarray data from four MIBC cell lines (T24, J82, UMUC3, and HT1376) cultured under 1%, 0.2%, and 0.1% oxygen for 24 h were used. Differences in the immune contexture between high- and low-hypoxia tumours were investigated using in silico analyses of two bladder cancer cohorts (BCON and TCGA) filtered to only include MIBC cases. GO and GSEA were used with the R packages "limma" and "fgsea". Immune deconvolution was performed using ImSig and TIMER algorithms. RStudio was used for all analyses. Under hypoxia, HIF1α and HIF2α bound to ~11.5-13.5% and ~4.5-7.5% of immune-related genes, respectively (1-0.1% O2). HIF1α and HIF2α both bound to genes associated with T cell activation and differentiation signalling pathways. HIF1α and HIF2α had distinct roles in immune-related signalling. HIF1 was associated with interferon production specifically, whilst HIF2 was associated with generic cytokine signalling as well as humoral and toll-like receptor immune responses. Neutrophil and myeloid cell signalling was enriched under hypoxia, alongside hallmark pathways associated with Tregs and macrophages. High-hypoxia MIBC tumours had increased expression of both suppressive and anti-tumour immune gene signatures and were associated with increased immune infiltrates. Overall, hypoxia is associated with increased inflammation for both suppressive and anti-tumour-related immune signalling and immune infiltrates, as seen in vitro and in situ using MIBC patient tumours.

Evaluation of short-term outcomes of neoadjuvant chemotherapy followed by radical cystectomy in muscle-invasive bladder cancer: a single Egyptian institution experience

Background and aimNeoadjuvant chemotherapy (NAC) before radical cystectomy (RC) became the standard of care for muscle-invasive bladder cancer (MIBC) in the last few years. We aimed to evaluate the radiological, pathological responses to NAC, and the 30-day surgical outcomes after RC in MIBC.Patients and methodsA retrospective cohort study involving adult patients with localized urothelial MIBC who received NAC followed by RC at the National Cancer Institute of Egypt (NCI-E) for 2 years (2017 and 2018). Out of 235 MIBC cases, we recognized 72 patients (30%) who fitted the eligibility criteria.ResultsA cohort of 72 patients with a median age of 60.5 years (range 34–87). Hydronephrosis, gross extravesical extension (cT3b), and radiologically negative nodes (cN0) were depicted initially in 45.8, 52.8, and 83.3% of patients, respectively. Gemcitabine and cisplatin (GC) was the rampant NAC employed in 95.8%. Radiological evaluation post NAC using RECIST v1.1 revealed a response rate (RR) of 65.3% in bladder tumor and progressive disease in the former and lymph nodes encountered in 19.4 and 13.9%, respectively. The median time from the end of NAC to surgery was 8.1 weeks (range 4–15). Open RC and ileal conduit were the most common types of surgery and urinary diversion, respectively. Pathological down-staging was encountered in 31.9%, and only 11 cases (15.3%) achieved pathological complete response (pCR). The latter was significantly correlated with the absence of hydronephrosis, low-risk tumors, and associated bilharziasis (p = 0.001, 0.029, and 0.039, respectively). By logistic regression, the high-risk category was the only independent factor associated with a poor likelihood of achieving pCR (OR 4.3; 95% CI 1.1–16.7; p = 0.038). Thirty-day mortality occurred in 5(7%) patients, and 16(22%) experienced morbidity, with intestinal leakage being the most frequent complication. cT4 was the only significant factor associated with post-RC morbidity and mortality compared to cT2 and cT3b (p = 0.01).ConclusionsOur results are further supporting the radiological and pathological benefits of NAC in MIBC, evidenced by tumor downstaging and pCR. The complication rate after RC is still considerable; hence, more larger studies are necessary to postulate a comprehensive risk assessment tool for patients who would get the maximum benefit from NAC, hoping to accomplish higher complete response rates with ultimately increased adoption of the bladder preservation strategies.

Intratumoral Heterogeneity of Molecular Subtypes in Muscle-invasive Bladder Cancer—An Extensive Multiregional Immunohistochemical Analysis

BackgroundMolecular bladder cancer (BC) subtypes define distinct biological entities and were shown to predict treatment response in neoadjuvant and adjuvant settings. The extent of intratumoral heterogeneity (ITH) might affect subtyping of individual patients. ObjectiveTo comprehensively assess the ITH of molecular subtypes in a cohort of muscle-invasive BC. Design, setting, and participantsA total of 251 patients undergoing radical cystectomy were screened. Three cores of the tumor center (TC) and three cores of the invasive tumor front (TF) of each patient were assembled in a tissue microarray. Molecular subtypes were determined employing 12 pre-evaluated immunohistochemical markers (FGFR3, CCND1, RB1, CDKN2A, KRT5, KRT14, FOXA1, GATA3, TUBB2B, EPCAM, CDH1, and vimentin). A total of 18 072 spots were evaluated, of which 15 002 spots were assessed based on intensity, distribution, or combination. Outcome measurements and statistical analysisAllocation to one of five different molecular subtypes—urothelial like, genomically unstable, small-cell/neuroendocrine like, basal/squamous cell carcinoma like, and mesenchymal like—was conducted for each patient for the complete tumor, individual cores, TF, and TC separately. The primary objective was to assess the ITH between the TF and TC (n = 208 patients). The secondary objective was the evaluation of multiregion ITH (n = 191 patients). An analysis of the composition of ITH cases, association with clinicopathological parameters, and prognosis was conducted. Results and limitationsITH between the TF and TC was seen in 12.5% (n = 26/208), and ITH defined by at least two different subtypes of any location was seen in 24.6% (n = 47/191). ITH was more frequent in locally confined (pT2) versus advanced (pT ≥3) BC stages (38.7% vs 21.9%, p = 0.046), and pT4 BC presented with significantly more basal subtypes than pT2 BC (26.2% vs 11.5%, p = 0.049). In our cohort, there was no association of subtype ITH with prognosis or accumulation of specific molecular subtypes in ITH cases. The key limitations were missing transcriptomic and mutational genetic validation as well as investigation of ITH beyond subtypes. ConclusionsSeveral molecular subtypes can be found in nearly every fourth case of muscle-invasive BC, when using immunohistochemistry. ITH must be given due consideration for subtype-guided strategies in BC. Genomic validation of these results is needed. Patient summaryDifferent molecular subtypes can be found in many cases of muscle-invasive bladder cancer. This might have implications for individualized, subtype-based therapeutic approaches.

PD36-02 A COMPOSITE BIOMARKER APPROACH TO SPARE NEOADJUVANT CHEMOTHERAPY IN SELECT MUSCLE-INVASIVE BLADDER CANCER PATIENTS

You have accessJournal of UrologyCME1 Apr 2023PD36-02 A COMPOSITE BIOMARKER APPROACH TO SPARE NEOADJUVANT CHEMOTHERAPY IN SELECT MUSCLE-INVASIVE BLADDER CANCER PATIENTS Joep De Jong, A. Gordon Robertson, Nick Beije, John Martens, Ellen Zwarthoff, Arno Van Leenders, Ewan Gibb, and Joost Boormans Joep De JongJoep De Jong More articles by this author , A. Gordon RobertsonA. Gordon Robertson More articles by this author , Nick BeijeNick Beije More articles by this author , John MartensJohn Martens More articles by this author , Ellen ZwarthoffEllen Zwarthoff More articles by this author , Arno Van LeendersArno Van Leenders More articles by this author , Ewan GibbEwan Gibb More articles by this author , and Joost BoormansJoost Boormans More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003334.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Clinical guidelines recommend neoadjuvant chemotherapy (NAC) for the treatment of muscle-invasive bladder cancer (MIBC). However, NAC prior to radical cystectomy (RC) is associated with treatment-related toxicity and confers a modest survival benefit. Here, we aimed to identify MIBC patients who may avoid NAC by combining circulating tumor cell status and molecular subtypes in a composite biomarker approach. METHODS: TURBT tissue specimen were collected from clinical stage T2-T4aN0-N1M0 MIBC cases that were included within the CirGuidance study (NL3954), a prospective trial that analyzed circulating tumor cell (CTC) status in a patient’s blood sample using the CELLSEARCH system. For the present study, transcriptome-wide expression profiling was performed on 234 TURBT samples using an array-based approach. Molecular subtypes, long non-coding RNA (lncRNA) based FGFR3+ status and gene signatures were determined as described previously (de Jong et al., Genome Med. 2019). The primary endpoint of this study was cancer-specific mortality (CSM), calculated as the date of study inclusion till date of bladder cancer related death. Median follow-up was 28.8 (IQR: 16.6-40.2) months. RESULTS: Of 234 patients, 21 (9%) were treated with NAC and RC, while 213 (91%) received RC alone. A CTC-negative status was observed in 172 (81%) of RC-only cases. Molecular subtyping identified 28 luminal FGFR3+ cases with high FGFR3, SHH and p53 pathway activity, and lower EMT hallmark scores. Adjusting for clinical risk factors, both CTC and FGFR3+ status were significant predictors for cancer specific mortality on MVA (p<0.05). Of interest, the subgroup of FGFR3+ cases that were CTC-negative (N=26) showed most favorable outcomes with only one CSM event after a median of 33.4 (IQR: 24.8-44.5) months of follow-up. CONCLUSIONS: Using a composite biomarker approach of blood-based CTC status and molecular subtyping, we identified a biologically distinct subgroup of MIBC with favorable prognosis after RC-only, validating the performance of a previously developed lncRNA based FGFR3+ classifier. Clinical trials which withhold NAC from CTC-negative, FGFR3+ MIBC patients are warranted. Source of Funding: Gene expression profiles were generated using the Decipher Bladder assay © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e980 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joep De Jong More articles by this author A. Gordon Robertson More articles by this author Nick Beije More articles by this author John Martens More articles by this author Ellen Zwarthoff More articles by this author Arno Van Leenders More articles by this author Ewan Gibb More articles by this author Joost Boormans More articles by this author Expand All Advertisement PDF downloadLoading ...

LBA03-05 RADIOGENOMICS OF MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023LBA03-05 RADIOGENOMICS OF MUSCLE INVASIVE BLADDER CANCER Touseef Ahmad Qureshi, Xingyu Chen, Yibin Xie, Kaoru Murakami, Toru Sakatani, Makito Miyake, Takashi Kobayashi, Simon Knott, Debiao Li, Charles Rosser, and Hideki Furuya Touseef Ahmad QureshiTouseef Ahmad Qureshi More articles by this author , Xingyu ChenXingyu Chen More articles by this author , Yibin XieYibin Xie More articles by this author , Kaoru MurakamiKaoru Murakami More articles by this author , Toru SakataniToru Sakatani More articles by this author , Makito MiyakeMakito Miyake More articles by this author , Takashi KobayashiTakashi Kobayashi More articles by this author , Simon KnottSimon Knott More articles by this author , Debiao LiDebiao Li More articles by this author , Charles RosserCharles Rosser More articles by this author , and Hideki FuruyaHideki Furuya More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003426.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Accurate staging of Muscle Invasive Bladder Cancer (MIBC) is essential to ensure optimal treatment (e.g., radical cystectomy vs. bladder preservation). However, currently about 1/3 of patients are overstaged and 1/3 are understaged. There is a pressing need of accurate noninvasive staging for MIBC to assist clinical decision making. METHODS: In this preliminary study, an extensive radiogenomic analysis of MIBC cases was performed to identify potential indicators of MIBC stages, and to automate the staging process. A total of 28 MRI scans and their matched transcriptomic profiles were obtained from subjects diagnosed with MIBC at different stages. In the genomics, a bulk RNA-seq from FFPE tissues was performed that identified 3 major clusters, high, intermediate, and low infiltrating immune cells and fibroblasts. This was followed by a bioinformatic analyses, such as pathway enrichment and gene set enrichment analyses, 15 most significant signatures were identified for stage categorization of MIBC (Fig. 1). In the radiomics, several hundred image-based features from bladder tumor in MRI were extracted and analyzed. The tumors were manually outlined and grouped into lower-stage (stage I and II) and higher-stage (stage III and IV) by the trained radiologists. Using various statistical tests, several radiomic features (e.g., heterogeneity, inverse contrast, entropy) were inferred as significant at discriminating the two groups (Fig. 2). A naïve Bayes machine learning model was then used to integrate such features and perform automated binary classification of cases into their true class. A 4-fold cross validation was performed in which a unique 75% and 25% of 28 cases were used for training and testing of the model respectively. RESULTS: The model performance was assessed in terms of prediction (binary classification) of stages as mean sensitivity, specificity, and accuracy, reaching 84%, 86%, and 86% respectively. CONCLUSIONS: The radiogenomics of MIBC provides insight into features associated with cancer stages. Assisted with AI, the discriminative features can accurately stage MIBC. Source of Funding: Cedars-Sinai Cancer Internal Funds: Developmental Funds for Investigator Initiated Trials Using Advanced Imaging Methods © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1193 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Touseef Ahmad Qureshi More articles by this author Xingyu Chen More articles by this author Yibin Xie More articles by this author Kaoru Murakami More articles by this author Toru Sakatani More articles by this author Makito Miyake More articles by this author Takashi Kobayashi More articles by this author Simon Knott More articles by this author Debiao Li More articles by this author Charles Rosser More articles by this author Hideki Furuya More articles by this author Expand All Advertisement PDF downloadLoading ...

A Retrospective Analysis of the Challenges of Urothelial Cancer Management during the COVID-19 Pandemic at a Single Academic Center in Romania.

The COVID-19 pandemic caused major changes in the healthcare sector due to adaptations required to hospitalize and treat an impressive number of patients. This retrospective study intended to collect reliable information on urothelial cancer patients in Romania. The primary objective was to compare the pre-pandemic and pandemic periods to observe the differences that occurred in the management of patients with urothelial carcinoma. The secondary objective was to determine the risk factors for urothelial cancer progression in the study cohort correlated with the COVID-19 pandemic. All patients that were diagnosed and treated at our clinic with a diagnosis of urothelial carcinoma (transitional cell carcinoma) during 2019-2021 were included in the current study. A total of 1122 eligible unique cases were identified during the study period. The number of patients who underwent intervention in the pre-pandemic year was 421, followed by a 22.6% decrease in 2020 to 326 cases and a 13.1% increase in 2021 to 375 cases. The proportion of muscle-invasive bladder cancer (MIBC) cases was significantly higher during the pandemic years, from 30.5% MIBC cases in 2019 to 37.4% in 2020 and 39.4% in 2021, suggesting a delay in presentations during the pandemic. Stage III and IV (TNM) cases were significantly more frequent, even though approximately 40% of all patients were operated on in stage I. The number of cystectomies increased significantly, from 5.2% in 2019 and 4.3% in 2020 to 10.1% in 2021, while the number of elective surgeries decreased, although no significant difference was observed regarding the in-hospital mortality and disease progression at six months. Patients with stage III and IV at presentation had the highest likelihood of disease progression at six months (HR = 5.61). Distant invasion was the second highest risk factor (HR = 5.13), followed by MIBC type (HR = 2.49). Nevertheless, the duration of hospitalization and year of diagnosis during the COVID-19 pandemic were not significant risk factors for cancer progression at six months. It can be concluded that there was a significant delay in patient presentations in 2020, and we advocate for increased public health awareness for urothelial cancer and increased attention toward the screening and management of these patients in the following years.

Comparative real-world survival outcomes of muscle-invasive bladder cancer treated with bladder-only vs. whole-pelvis concurrent chemoradiation.

488 Background: Elective nodal irradiation for patients with muscle-invasive bladder cancer (MIBC) undergoing trimodal therapy (TMT) is controversial. In patients with node-negative (N0) MIBC, the benefit of elective whole-pelvis concurrent chemoradiotherapy (WP-CCRT) compared to bladder-only (BO)-CCRT has not been demonstrated. Currently, the National Comprehensive Cancer Network (NCCN) guidelines do not recommend whether to include pelvic nodes in the radiation field. Using real-world data from the National Cancer Database (NCDB), we sought to compare the overall survival (OS) between BO-CCRT and WP-CCRT for MIBC. Methods: Using the 2019 NCDB Participant User File, we identified cases of MIBC diagnosed between 2017 and 2018. We selected patients with clinical T2-T4N0M0 disease receiving TMT as first-line treatment. TMT was defined as transurethral resection of bladder tumor followed by CCRT: 60–65 Gy of RT delivered to the bladder with concurrent single- or multiple-agent chemotherapy. Patients were stratified into BO-CCRT vs. WP-CCRT. Overall survival (OS) analysis was performed using Kaplan-Meier estimates and multivariable Cox proportional hazards regression analysis. The variables included in the multivariable Cox regression model were age, sex, race, comorbidity burden (as per the Charlson-Deyo comorbidity index), facility type, insurance status, median income quartile, rurality, distance from facility, and clinical T stage. Results: A total of 605 patients receiving TMT for MIBC were identified: 162 (26.8%) BO-CCRT and 443 (73.2%) WP-CCRT. The median follow-up time was 25.6 months (interquartile range [IQR]: 4.8-42.6) and 28.7 months (IQR: 3.0-51.6) for BO-CCRT and WP-CCRT, respectively. The median OS was 32.9 months (95% confidence interval [CI] 30.8 – not reached) and 48.3 months (95% CI 39.6 – not reached) for BO-CCRT and WP-CCRT, respectively. However, multivariable Cox regression analysis failed to find an association between WP-CCRT (hazard ratio [HR] 1.08, 95% CI 0.76-1.54) and improved OS, compared to BO-CCRT. Conclusions: Elective nodal-irradiation (WP-CCRT) in the setting of TMT for MIBC was not associated with a benefit in OS compared to BO-CCRT.

Incidental Diagnosis of Urothelial Bladder Cancer: Associations with Overall Survival.

We investigated whether an incidental diagnosis (ID) of bladder cancer (BC) was associated with improved survival. We retrospectively reviewed data of consecutive patients with no prior diagnosis of urothelial cancer who underwent a primary transurethral resection of bladder tumor (pTURBT) between January 2013 and February 2021 and were subsequently diagnosed with urothelial BC. The type of diagnosis (incidental or non-incidental) was identified. Overall, relative, recurrence-free, and progression-free survival rates (OS, RS, RFS, and PFS) after pTURBT were evaluated using the Kaplan-Meier curves and long-rank tests. A multivariable Cox regression model for the overall mortality was developed. A total of 435 patients were enrolled. The median follow-up was 2.7 years. ID cases were more likely to be low-grade (LG) and non-muscle-invasive. ID vs. non-ID was associated with a trend toward an improved 7-year OS (66% vs. 49%, p = 0.092) and a significantly improved 7-year OS, if incidental cases were limited to ultrasound-detected tumors (75% vs. 49%, p = 0.013). ID was associated with improved survival among muscle-invasive BC (MIBC) patients (3-year RS: 97% vs. 23%, p < 0.001), but not among other subgroups stratified according to disease stage or grade. In multivariable analysis, only age, MIBC, and high-grade (HG) cancer demonstrated an association with mortality. PFS and RFS among non-MIBC patients did not differ in regard to the type of diagnosis. Incidental diagnosis may contribute to an improved survival in BC patients, most probably in the mechanism of the relative downgrading of the disease, including the possible overdiagnosis of LG tumors. Nevertheless, in the subgroup analyses, we noted marked survival benefits in MIBC cases. Further prospective studies are warranted to gain a deeper understanding of the observed associations.

Clinical utility of vesical imaging-reporting and data system (VI-RADS) in non-muscle invasive bladder cancer (NMIBC) patients candidate for en-bloc transurethral resection: A prospective study.

To assess accuracy of vesical imaging-reporting and data system (VI-RADS) 5-point score in detection of muscle invasive bladder cancer and avoiding second look transurethral resection of the tumors (TURBT). Additionally, to assess safety and efficacy of bipolar en-block transurethral urethral resection of bladder tumor. Patients with bladder mass up to 5 cm were included in the study. VI-RADS 5-point score was done preoperative for all cases and postoperatively before second look TURBT. Patients were followed up for 12 months. In all, 80 cases were eligible for the study. Preoperative VI-RADS score at cutoff of 3 had sensitivity of 89.3 %, specificity 83.3 %, postive predective value (PPV) 92.6 %, negative predictive value (NPV) 76.9 %, accuracy of 87.5 %, while at cutoff 2 sensitivity was 82.1%, specificity 91.7%, PPV 95.8%, NPV 68.8%, accuracy of 85.0%. Operative time 28.8 ± 9.4 minutes, hemoglobin drop 0.3 ± 0.05 g/dl, catheterization time 2.8 ± 0.8 days, hospital stay 1.4 ± 0.4 days. No complications occurred. Recurrence in field of resection 3.75%. Detrusor muscle was available in 76 cases (95%). Postoperative VI-RADS score at cutoff of 3 had sensitivity of 78.6%, specificity 77.8%, PPV 84.6%, NPV 70.0%, accuracy of 78.3%. At cutoff 2 VI-RADS score sensitivity was 71.4%, specificity 77.8%, PPV 83.3%, NPV 63.6%, accuracy of 73.9%. VI-RADS 5-point score showed high sensitivity and specificity in preoperative discrimination of non-muscle invasive bladder cancer (NMIBC) from muscle invasive bladder cancer cases and in avoiding unnecessary second look TURBT. Bipolar en-block TURBT technique is both safe and efficacious in resecting NMIBC cases with low recurrence rate.

Are Preoperative Systemic Immune Index and Neutrophil-to-Lymphocyte Ratio Sufficient to Predict Lymph Node Positivity and Overall Survival in Muscle-Invasive Bladder Cancer Cases?

Are Preoperative Systemic Immune Index and Neutrophil-to-Lymphocyte Ratio Sufficient to Predict Lymph Node Positivity and Overall Survival in Muscle-Invasive Bladder Cancer Cases?

Identification of CNGB1 as a Predictor of Response to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer.

Simple SummaryChemotherapy is recommended prior to surgical removal of the bladder for muscle-invasive bladder cancer patients. Despite a survival benefit, some patients do not respond and experience substantial toxicity and delay in surgery. Therefore, the identification of chemotherapy responders before initiating therapy would be a helpful clinical asset. To date, there are no reliable biomarkers routinely used in clinical practice that identify patients most likely to benefit from chemotherapy and their identification is urgently required for more precise delivery of care. To address this issue, we compared gene expression profiles of biopsy materials from 30 chemotherapy-responder and -non-responder patients. This analysis revealed a novel signature gene set and CNGB1 as a simpler proxy as a promising biomarker to predict chemoresponsiveness of muscle-invasive bladder cancer patients. Our findings require further validation in larger patient cohorts and in a clinical trial setting.Cisplatin-based neoadjuvant chemotherapy (NAC) is recommended prior to radical cystectomy for muscle-invasive bladder cancer (MIBC) patients. Despite a 5–10% survival benefit, some patients do not respond and experience substantial toxicity and delay in surgery. To date, there are no clinically approved biomarkers predictive of response to NAC and their identification is urgently required for more precise delivery of care. To address this issue, a multi-methods analysis approach of machine learning and differential gene expression analysis was undertaken on a cohort of 30 MIBC cases highly selected for an exquisitely strong response to NAC or marked resistance and/or progression (discovery cohort). RGIFE (ranked guided iterative feature elimination) machine learning algorithm, previously demonstrated to have the ability to select biomarkers with high predictive power, identified a 9-gene signature (CNGB1, GGH, HIST1H4F, IDO1, KIF5A, MRPL4, NCDN, PRRT3, SLC35B3) able to select responders from non-responders with 100% predictive accuracy. This novel signature correlated with overall survival in meta-analysis performed using published NAC treated-MIBC microarray data (validation cohort 1, n = 26, Log rank test, p = 0.02). Corroboration with differential gene expression analysis revealed cyclic nucleotide-gated channel, CNGB1, as the top ranked upregulated gene in non-responders to NAC. A higher CNGB1 immunostaining score was seen in non-responders in tissue microarray analysis of the discovery cohort (n = 30, p = 0.02). Kaplan-Meier analysis of a further cohort of MIBC patients (validation cohort 2, n = 99) demonstrated that a high level of CNGB1 expression associated with shorter cancer specific survival (p < 0.001). Finally, in vitro studies showed siRNA-mediated CNGB1 knockdown enhanced cisplatin sensitivity of MIBC cell lines, J82 and 253JB-V. Overall, these data reveal a novel signature gene set and CNGB1 as a simpler proxy as a promising biomarker to predict chemoresponsiveness of MIBC patients.

Radical Cystectomies at the University Teaching Hospital, Lusaka: Baseline Characteristics, Short-term Complications, and Role of Nursing Care

Bladder cancer is the ninth most common cancer in the world and the 11th most common cancer in Zambia. Bladder cancer is of three histological types, Squamous cell cancer, Transitional cell cancer, and Adenocarcinoma. The most common histological type in Zambia is Squamous cell cancer accounting for 60 percent of cases of muscle-invasive bladder cancer. The treatment of muscle-invasive bladder cancer is radical cystectomy, Lymph node dissection, and urinary diversion. Globally, radical cystectomy is associated with high morbidity and mortality. The most common diversion used was uretero-sigmoidostomy, accounting for 60 percent of cases. In our case series, the most common complications were wound dehiscence, hypo-proteinemia, bowel ileus, deep vein thrombosis, and electrolyte imbalance. Identification and prevention of complications associated with this procedure play a crucial role in improving survival for these patients. The role of nursing staff in the early recognition of these complications cannot be overemphasized.

A combination of ssGSEA and mass cytometry identifies immune microenvironment in muscle-invasive bladder cancer.

BackgroundMuscle‐invasive bladder cancer (MIBC) is a heterogeneous disease with varying clinical courses and responses to treatment. To improve the prognosis of patients, it is necessary to understand such heterogeneity.MethodsWe used single‐sample gene set enrichment analysis to classify 35 MIBC cases into immunity‐high and immunity‐low groups. Bioinformatics analyses were conducted to compare the differences between these groups. Eventually, single‐cell mass cytometry (CyTOF) was used to compare the characteristics of the immune microenvironment between the patients in the two groups.ResultsCompared with patients in the immunity‐low group, patients in the immunity‐high group had a higher number of tumor‐infiltrating immune cells and greater enrichment of gene sets associated with antitumor immune activity. Furthermore, positive immune response‐related pathways were more enriched in the immunity‐high group. We identified 26 immune cell subsets, including cytotoxic T cells (Tcs), helper T cells (Ths), regulatory T cells (Tregs), B cells, macrophages, natural killer (NK) cells, and dendritic cells (DCs) using CyTOF. Furthermore, there was a higher proportion of CD45+ lymphocytes and enrichment of one Tc subset in the immunity‐high group. Additionally, M2 macrophages were highly enriched in the immunity‐low group. Finally, there was higher expression of PD‐1 and Tim‐3 on Tregs as well as a higher proportion of PD‐1+ Tregs in the immunity‐low group than in the immunity‐high group.ConclusionIn summary, the immune microenvironments of the immunity‐high and immunity‐low groups of patients with MIBC are heterogeneous. Specifically, immune suppression was observed in the immune microenvironment of the patients in the immunity‐low group.