Grade Non-muscle Invasive Bladder Cancer Research Articles

CDKN2A copy number alteration in bladder cancer: integrative analysis in patient-derived xenografts and cancer patients

Bladder cancer (BlCa) is an extensively heterogeneous disease that leads to great variability in tumor evolution scenarios and lifelong patients’ surveillance, emphasizing the need for modern minimally-invasive precision medicine. Herein, we have explored the clinical significance of copy-number alterations (CNAs) in BlCa. CNAs profiling was performed in 15 patient-derived xenografts (PDXs) and validated in TCGA-BLCA (n=408) and Lindgren et al. (n=143) cohorts. CDKN2A copy-number loss was identified as the most frequent CNA in bladder tumors, associated with reduced CDKN2A expression, tumors of papillary phenotype and prolonged PDX survival. Study’s screening cohort consisted of 243 BlCa patients and CDKN2A copy-number was assessed in genomic DNA and cell-free DNA (cfDNA) from 217 tumors and 189 pre-treatment serum samples, respectively. CDKN2A copy-number loss was correlated with superior disease-free and progression-free survival of non-muscle-invasive bladder cancer (NMIBC) patients. Moreover, higher CDKN2A index (CDKN2A/LEP ratio) in pre-treatment cfDNA was associated with advanced tumor stage, grade and short-term NMIBC progression to invasive disease, while multivariate models fitted for CDKN2A index in pre-treatment cfDNA offered superior risk-stratification of T1/high grade and EORTC high-risk patients, enhancing prediction of treatment outcome. CDKN2A copy-number status could serve as minimally-invasive tool in improving risk-stratification and supporting personalized prognosis in BlCa.

Long-term outcomes and cost savings of office fulguration of papillary Ta low-grade bladder cancer.

To assess whether office-based fulguration (OF) under local anaesthesia for small, recurrent, pathological Ta low-grade (LG) non-muscle-invasive bladder cancer (NMIBC) is an effective alternative to transurethral resection of bladder tumour (TURBT), avoiding the costs and risks of procedure, and anesthesia. Of 521 patients with primary TaLG NMIBC, this retrospective study included 270 patients who underwent OF during follow-up for recurrent, small, papillary LG-appearing tumours at a university centre (University Health Network, University of Toronto, Canada). We assessed the cumulative incidence of cancer-specific mortality (CSM) and disease progression (to MIBC or metastases), as well as possible direct cost savings. In the 270 patients with recurrent TaLG NMIBC treated with OF, the mean (sd) age was 64.9 (13.3) years, 70.8% were men, and 60.3% had single tumours. The mean (sd, range) number of OF procedures per patient was 3.1 (3.2, 1-22). The median (interquartile range) follow-up was 10.1 (5.8-16.2) years. Patients also underwent a mean (sd) of 3.6 (3.0) TURBTs during follow-up in case of numerous or bulkier recurrence. In all, 44.4% of patients never received intravesical therapy. The 10-year incidence of CSM and progression were 0% and 3.1% (95% confidence interval 0.8-5.4%), respectively. Direct cost savings in Ontario were estimated at $6994.14 (Canadian dollars) per patient over the study follow-up. This study supports that properly selected patients with recurrent, apparent TaLG NMIBC can be safely managed with OF under local anaesthesia with occasional TURBT for larger or numerous recurrent tumours, without compromising long-term oncological outcomes. This approach could generate substantial cost-saving to healthcare systems, is patient-friendly, and could be adopted more widely.

HMG co-reductase expression and response to intravesical Bacillus Calmette-Guérin in patients with high grade non-muscle invasive urinary bladder cancer receiving statins.

Cardiovascular disease affects over 7 million people in the UK and statins are often prescribed to mitigate cardiovascular risks. The effect of statins on a number of cancers is debated and their effect on Bacillus Calmette-Guérin (BCG) responsiveness in non-muscle invasive urinary bladder cancer (NMIBC) is not fully understood. This study aims to explore the difference in HMG Co-A reductase (HMGCR) expression in NMIBC on immunochemistry in BCG responders and non-responders while on statins. Three hundred and thirty-two cases of intravesical BCG treatment for high-risk NMIBC between November 2003 and December 2017 were identified. Patients taking statins for at least 12 months before the diagnosis of NIMBC and with a follow-up of at least 5 years were included. They were divided into BCG responders and non-responders. Tumour tissue from these patients was immunohistochemically stained and quantitative image analysis carried out to assess and compare HMGCR expression in the groups. This study showed a differential expression of HMGCR in responders vs. non-responders to BCG for high-risk NMIBC on statins. This data should form the basis of a further research and multi-centre study in a larger cohort, using HMGCR as a biomarker of response in patients on statins.

Preoperative Neutrophils to Lymphocytes Ratio in Predicting the Response to BCG in High Grade Non-Muscle Invasive Bladder Cancer

Background Urinary bladder cancer (BC) is a highly prevalent disease affecting more than 400, 000 new cases and 165, 000 deaths yearly, it is the ninth most common cancer in the world, the 13th cause of cancer deaths and the seventh most common cancer worldwide in men with marked male predominance. Aim of the Work To assess the role of preoperative Neutrophils to Lymphocytes Ratio as a predictor for the response to BCG in patients with Non-Muscle invasive Bladder Cancer in patients who underwent Trans-Uretheral Resection of Bladder Tumour (TURBT). Patients and Methods This retrospective cohort study was conducted at tertiary care hospital at Urology department, Ain Shams University hospitals from January 2020 to January 2022 and performed on a total of 46 patients with high grade non-Muscle invasive Bladder Cancer who underwent Trans-Urethral Resection of Bladder Tumor and took BCG course. Results Study results revealed that there was a highly statistically significant relation between preoperative NLR and pathological improvement during Follow up (p-value=0.00) in addition to Tstage and histological grade during Follow up, also there is a statistically significant relation between NLR and tumor size as well as the age of the patient. Conclusion Pre-TURBT NLR when it is high (above 3) is associated with an increased risk of disease recurrence and progression in patients with high grade NMIBC. Moreover, it is an independent predictor of disease recurrence and progression in patients treated with BCG for high grade NMIBC. Pre-TURBT NLR could be a useful blood-based biomarker to improve patients’ risk-stratification facilitating clinical decision-making regarding therapy and follow-up scheduling.

Underutilization of intravesical chemotherapy and immunotherapy for high grade non-muscle invasive bladder cancer in California between 2006–2018: Effect of race, age and socioeconomic status on treatment disparities

ObjectiveAmong patients diagnosed with non-muscle invasive bladder cancer (NMIBC), those with high risk disease have the greatest risk of recurrence and disease progression. The underutilization of intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) has been a longstanding concern in clinical practice. This study aimed to determine the disparities present in receipt of adjuvant intravesical chemotherapy and immunotherapy in treatment of patients with high grade NMIBC following initial transurethral resection of a bladder tumor (TURBT). MethodsThe California Cancer Registry data was used to identify 19,237 patients diagnosed with high grade NMIBC who underwent TURBT. Treatment variables include re-TURBT, re-TURBT and intravesical chemotherapy (IVC) and/or BCG. Independent variables include age, sex, race/ethnicity, neighborhood socioeconomic status (nSES), primary insurance payer and marital status at diagnosis. Multiple logistic regression and multinomial regression models were used to examine variation in the treatments received following TURBT. ResultsThe proportion of patients receiving TURBT followed by BCG was similar across all racial and ethnic groups (28%–32%). BCG therapy was higher in patients belonging to the highest nSES quintile (37% for highest vs. 23%–26% for the 2 lowest quintiles). In multiple variable analyses, receipt of any intravesical therapy (IVT) was influenced by nSES, age, marital status, race/ethnicity, and insurance type. Patients in the lowest nSES quintile had a 45% less likelihood of receiving IVT compared to the highest nSES group (OR [95%CI]: 0.55[0.49, 0.61]). Race/ethnicity differences in receipt of any adjuvant therapy were noted in the middle to lowest nSES quintile for Hispanic and Asian/Pacific Islander patients when compared to non-Hispanic White patients. When comparing variation in treatment by insurance type at diagnosis, those with Medicare or other insurance were 24% and 30% less likely to receive BCG after TURBT compared to those with private insurance, (OR [95%CI]: 0.76 [0.70, 0.82] and 0.70[0.62, 0.79]) respectively. ConclusionIn patients with a diagnosis of high risk NMIBC, disparities in utilization of BCG are seen based on SES, age, and insurance type.

Microscopic hematuria and pelvic ultrasonography could rule out flexible cystoscopy during surveillance for T1-low grade non-muscle invasive bladder cancer

ABSTRACT Purpose Cystoscopy (rigid/flexible [FC]) is the standard surveillance tool for non-muscle invasive bladder cancer (NMIBC). Nevertheless, it has its drawbacks. The objective of this study is to evaluate the performance of microscopic hematuria (MH), abdominal ultrasonography (US), and urine cytology (UC) as potential substitutes for FC in patients with T1-low-grade (T1-LG) NMIBC. Methods Over a 12-month period, patients attending our tertiary referral center for T1-LG NMIBC follow-up underwent urine analysis for MH and UC, and then US and FC were performed as outpatient surveillance procedures. Those with positive findings underwent inpatient rigid cystoscopy under anesthesia and biopsy. The negative predictive values (NPV) and sensitivity of different combinations of MH, UC, US, and FC were compared with the standard histopathology. Results In 218 evaluated patients, FC had the highest NPV (97.9%). However, this figure showed no statistically significant difference if compared with the combination of negative MH and US (93.8%) (difference = 0.04, p = 0.1) or the combination of MH, US, and UC (94.9%) (difference = 0.03, p = 0.2). The reported sensitivity results were similarly comparable between FC (94.2%) and the aforementioned combinations (90.4% and 92.3%; differences: 0.038 and 0.019; p = 0.4 and 0.7, respectively). Conclusions During the surveillance of NMIBC for patients diagnosed with T1-LG disease, the combination of MH/US has comparable sensitivity and NPV with FC. This non-invasive combination could be considered the first station that might preclude the need for FC in a considerable percentage of this group of patients.

Impact of intravesical Bacillus Calmette-Guérin and chemotherapy on the bladder microbiome in patients with non-muscle invasive bladder cancer.

Intravesical therapy (IVT), including Bacillus Calmette-Guérin (BCG), is the standard of care for high grade (HG) non-muscle invasive bladder cancer (NMIBC). Despite the use of IVT, many patients recur after treatment. The bladder microbiome and its role in disease processes has recently risen to prominence. We aim to characterize changes that occur in the bladder microbiome over the course of intravesical therapy and assess whether these changes correlate with outcomes in patients with NMIBC. Patients with NMIBC undergoing induction BCG or intravesical therapy were prospectively enrolled from January 2019 to March 2020. Patients with clinical T2 or greater pathology or active urinary tract infection at enrollment were excluded. Twenty-nine patients had catheterized (bladder) urine samples collected prior to induction intravesical therapy and prior to each IVT instillation. Twenty-seven received BCG while 2 received intravesical gemcitabine. Bacteria were identified using 16S ribosomal RNA gene sequencing. Bladder microbiome changes were evaluated and differences between patients who recurred and patients who did not recur after IVT were investigated. Across the 29 patients analyzed, bacterial richness decreased significantly following intravesical therapy (Richness, P=0.01). Evenness and overall diversity did not change significantly (Pielou, P=0.62; Shannon, P=0.13). Patients who experienced recurrence had a higher relative abundance of Aerococcus in their urine (P<0.01), while those who did not recur had significantly more Ureaplasma (P=0.01) and Escherichia/Shigella species (P=0.05). Patients with decreased levels of alpha diversity were more likely to fall within the non-recurrence cohort. IVT for NMIBC appears to change the urinary microbiome by decreasing richness while not altering evenness or overall diversity. The presence of Aerococcus species may be predictive of a poor cancer response to IVT, while the presence of Ureaplasma and Escherichia/Shigella may predict a favorable response to IVT. Further studies are warranted to elucidate and confirm the significance of changes in the bladder microbiome.

MP63-14 PRELIMINARY RESULTS OF FIRST-IN-HUMAN CRYOTHERAPY FOR NON MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP63-14 PRELIMINARY RESULTS OF FIRST-IN-HUMAN CRYOTHERAPY FOR NON MUSCLE INVASIVE BLADDER CANCER Gilad Amiel, Omri Falik-Nativ, Kamil Malshy, Omer Sadeh, Michael Mullerad, Eyal Kochavi, and Azik Hoffman Gilad AmielGilad Amiel More articles by this author , Omri Falik-NativOmri Falik-Nativ More articles by this author , Kamil MalshyKamil Malshy More articles by this author , Omer SadehOmer Sadeh More articles by this author , Michael MulleradMichael Mullerad More articles by this author , Eyal KochaviEyal Kochavi More articles by this author , and Azik HoffmanAzik Hoffman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003321.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Initial treatment for Non-Muscle Invasive Bladder Cancer (NMIBC) mostly remains unchanged in recent decades. Utilizing cryotherapy with CO2 is commonly used to treat superficial papillary lesions of the skin for many years. Recently, we have proven its potential in treating urinary epithelial lesions in an animal model. In this study we present our preliminary phase 1 clinical experience and results in treating low grade papillary lesions of the bladder with cryoablation. METHODS: Following local IRB and Ministry of Health approval, 10 patients with up to 3 papillary lesions and a maximum of 10 mm in size were recruited. Exclusion criteria included previous high-grade disease and/or positive cytology. Following an initial routine cystoscopy, the bladder irrigation medium was replaced with CO2 insufflation, and each lesion was treated with 2 cycles of direct spraying of liquid CO2. Each cycle lasted 15 seconds, with 10 seconds of thawing between the treatment cycles. Follow-up cystoscopy and mandatory treatment site biopsy were performed 4-6 weeks after treatment. Routine surveillance with office cystoscopy was performed every 3 months for 1 year thereafter. RESULTS: 8 men and 2 women were included (age 57—89 years). Overall, 14 lesions were treated. No complications were noted during treatment or during follow-up (range 2-14 months). Pathological analysis of the treatment site 4-6 weeks after treatment detected residual low grade TCC only in the very first patient, attributed to suboptimal lesion freezing due to our initial learning curve. The other 13/14 biopsy sites were negative for cancer (93%). CONCLUSIONS: Initial results of cryotherapy utilizing CO2 spraying for small low grade NMIBC is safe and feasible. Pathological analysis confirms efficacy in tumor eradication. This novel treatment may be used as an office procedure and therefore, after further validation studies, offers a potential paradigm shift in the treatment of NMIBC. Source of Funding: Biotechnological Incubator Trendlines, Misgav, Israel © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e876 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Gilad Amiel More articles by this author Omri Falik-Nativ More articles by this author Kamil Malshy More articles by this author Omer Sadeh More articles by this author Michael Mullerad More articles by this author Eyal Kochavi More articles by this author Azik Hoffman More articles by this author Expand All Advertisement PDF downloadLoading ...

Clinical results of a phase 1 study of intravesical EG-70 in patients with BCG-unresponsive NMIBC.

512 Background: enGene is developing non-viral gene therapy platforms to deliver nucleic acids (plasmids) to epithelial mucosal tissues such as urothelium of urinary bladder. EG-70 is a nanoparticle formulation of plasmids that activates both innate and adaptive immune responses to activate the immune system within the bladder. The plasmid encodes both IL-12 and activators of the innate immune receptor RIG-I. EG-70 is administered intravesically to elicit local stimulation of anti-tumor immune responses providing durable efficacy in high grade non-muscle invasive bladder cancer (NMIBC) while avoidingsystemic toxicities. Methods: In the Phase 1 study(LEGEND; NCT04752722), escalating doses of EG-70 were administered intravesically to patients with BCG-unresponsive Carcinoma in situ (CIS) NMIBC on weeks 1 and 2 or weeks 1, 2, 5, 6 of 12-week treatment cycle. At the week 12 assessment, patients with stable disease (SD) or complete response (CR), as assessed by urine cytology, cystoscopy, and bladder biopsy, were allowed electively to remain on EG-70 for up to 3 additional 12-week cycles. Results: To date, 19 patients have been treated. There have been no DLTs. AEs (48 GR1, 17 GR 2 and 1 GR3) have been largely consistent with urinary tract instrumentation, and were not dose related. Eighteen patients have completed one cycle of EG-70, and 67% have achieved CR. Fifteen patients with CR or SD at the end of cycle 1 elected to receive additional treatment cycles (continuation rate of 15/18 ( 83%)). Durable CRs were seen at all dose levels. Patients who receive additional cycles are followed for durability of response (Table). Complete Response. Conclusions: These results demonstrate the safety, tolerability and durable therapeutic potential of intravesical EG-70 in patients with BCG-unresponsive CIS. A Phase 2 study will proceed in 2023. Clinical trial information: NCT04752722 . [Table: see text]

Sarcopenia Predicts Disease Progression in Patients with T1 High-grade Non–muscle-invasive Bladder Cancer Treated with Adjuvant Intravesical Bacillus Calmette-Guérin: Implications for Decision-making?

BackgroundSkeletal muscle loss (sarcopenia) has been linked to cancer cachexia and can predict survival in several tumors, including advanced genitourinary malignancies. ObjectiveTo investigate the predictive and prognostic role of sarcopenia in patients with T1 high grade (HG) non-muscle invasive bladder cancer (NMIBC) treated with adjuvant intravesical Bacillus Calmette-Guerin (BCG). Design, setting, and participantsOncological outcomes were evaluated for 185 patients with T1 HG NMIBC treated with BCG at two European referral centers. Sarcopenia, identified from computed tomography scans performed within 2 mo after surgery, was defined as a skeletal muscle index of <39 cm2/m2 for women and <55 cm2/m2 for men. Outcome measurements and statistical analysisThe main endpoint was the association between sarcopenia and disease recurrence and progression. Kaplan-Meier curves and multivariable Cox models were built, and the clinical value of any association was assessed using Harrell’s C index and decision curve analysis (DCA). Results and limitationsSarcopenia was present in 130 patients (70%). On multivariable Cox regression analyses that accounted for the effect of standard clinicopathological prognosticators, sarcopenia was independently associated with disease progression (hazard ratio 3.41; p = 0.02). Addition of sarcopenia to a standard model for prediction of disease progression improved the discrimination of the model from 62% to 70%. DCA revealed superior net benefits for the proposed model in comparison to the strategies of treating all or no patients with radical cystectomy, and in comparison to the existing predictive model. Limitations are inherent to the retrospective design. ConclusionsWe demonstrated the prognostic role of sarcopenia in T1 HG NMIBC. Pending external validation, this tool could be easily incorporated into existing nomograms for prediction of disease progression to improve clinical decision-making and patient counseling. Patient summaryWe looked at the role of loss of skeletal muscle (sarcopenia) as a factor in predicting prognosis for stage T1 high-grade non–muscle-invasive bladder cancer. We found that sarcopenia is a ready-to-use, cost-free marker that could be used to guide treatment and follow-up in this disease, although the results need to be confirmed in other studies.

Bladder EpiCheck urine test in the follow-up of NMIBC: a cost analysis.

In the Netherlands yearly more than 5000 patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). With a specificity of 88.0% and a negative predictive value (NPV) for high grade NMIBC of 99.3%, the Bladder EpiCheck (BE) urine test may be used in NMIBC to reduce the burden of follow-up cystoscopies. In this study a cost analysis of the BE follow-up strategy in the Dutch healthcare system was performed. In half of the follow-up appointments, BE was used as a rule-in for cystoscopy. In addition, the possible delay in recurrence detection was estimated. A cost calculation tool was developed using Microsoft Excel. The BE strategy results in an estimated cost reduction of 8%, 4% and 9% in low, intermediate and high risk patients, respectively. In the Netherlands this may result in a cost reduction of approximately 1.6 million euro per year. The estimated delay in the detection of recurrent disease would be 3.9, 1.7 and 1.3months in low, intermediate and high risk NMIBC patients respectively. To conclude, the BE can be used to reduce the costs of NMIBC follow-up, with a small delay in diagnosis of recurrent disease.

Predictive clinico-pathological factors to identify BCG, unresponsive patients, after re-resection for T1 high grade non-muscle invasive bladder cancer.

Seventy-five percent of bladder cancers are non-muscle invasive. The treatment strategy includes the transurethral resection of bladder tumor (TURB) followed by intravesical immunotherapy with the bacillus of Calmette-Guerin (BCG) or chemotherapy, depending on the grade of bladder tumor. Despite a proper BCG intravesical instillations schedule, up to 40% of patients present a failure within 2 years. The aim of this retrospective study was to investigate the predictive factors in the response to BCG in patients with a high-grade non-muscle invasive bladder cancer diagnosis. Patients with non-muscle invasive bladder cancer from 13 hospitals and academic institutions were identified and treated, from January 1, 2002, until December 31, 2012, with TURB and a subsequent re-TURB for restaging before receiving BCG. Follow-up was performed with urine cytology and cystoscopy every 3 months for 1 year and, successively every 6 months. Univariate and multivariate Cox regression models addressed the response to BCG therapy. Kaplan-Meier overall survival (OS) and cancer-specific survival (CSS) estimates were determined for BCG responsive vs. BCG unresponsive patients. A total of 1,228 patients with non-muscle invasive bladder cancer were enrolled. Of 257 (20.9%) patients were BCG unresponsive. Independent predictive factors for response to BCG were: multifocality (HR: 1.4; 95% CI 1.05-1.86; P = 0.019), lymphovascular invasion (HR: 1.75; 95% CI 1.22-2.49; P = 0.002) and high-grade on re-TURB (HR: 1.39; 95% CI 1.02-1.91; P = 0.037). Overall survival was significantly reduced in BCG-unresponsive patients compared to BCG-responsive patients at 5 years (82.9% vs. 92.4%, P < 0.0001) and at 10 years (44.2% vs. 74.4%, P < 0.0001). Similarly, cancer-specific survival was reduced in BCG-unresponsive patients at 5 years (90.6% vs. 97.3%, P < 0.0001) and at 10 years (72.3% vs. 87.2%, P < 0.0001). Multifocality, lymphovascular invasion, and high-grade on re-TURB were independent predictors for response to BCG treatment. BCG-unresponsive patients reported worse oncological outcomes.

Abstract 2058: Effect of route of Bacillus-Calmette Guerin administration on systemic immune responses in a murine model of non-muscle invasive bladder cancer

Abstract Background: Bladder cancer is the 5th most common cancer worldwide, with the most common type being non-muscle invasive bladder cancer (NMIBC). Treatment for high grade NMIBC includes resection of the bladder tumor followed by repeated intravesical administration of Bacillus-Calmette Guérin (BCG), the live-attenuated form of Mycobacterium bovis. Unfortunately, 60-70% of patients will experience disease recurrence. Our current understanding is that BCG acts within the local bladder tumor microenvironment and draining lymph nodes, leading to the activation of a systemic immune response. Using a murine model of NMIBC, here we investigated whether different routes of BCG administration alter the systemic immune response to BCG and affect tumor size. Methods: To establish syngeneic orthotopic bladder tumors in a mouse model, female C57Bl/6 mice were catheterized and 2.5 x 105 mouse bladder cancer cells (MB49) were instilled into the bladder. Beginning on day 7, mice received either intravesical, intravenous (IV) or intraperitoneal (IP) BCG (8 mg/ml) or saline once weekly for three weeks and bladders were imaged through ultrasound. At endpoint (day 23), tumors, tumor draining lymph nodes (tdLNs), spleen, and bone marrow were harvested and stored. Immune composition of the various lymphoid organs was evaluated using polychromatic flow cytometry. Ex vivo responsiveness to lipopolysaccharide (LPS) was assessed in bone marrow cells by measuring cytokine levels in culture supernatants. Results: Mice treated with IV BCG had significantly smaller tumor volumes when compared to intravesical BCG treatment. Ex vivo LPS stimulation of bone marrow from BCG-treated mice, regardless of administration route, led to increased release of pro-inflammatory cytokines compared with saline controls. IP and IV BCG treatment skewed immune microenvironments of secondary lymphoid organs towards a cytotoxic phenotype compared with intravesical BCG treatment. Within the lymphoid compartment of tdLNs, the proportion of CD8+ T cells was significantly increased while the proportion of CD4+ T cells was significantly decreased in mice treated with IV and IP BCG compared with intravesical BCG. Conversely, the proportion of CD11b+ dendritic cells (DCs) was significantly increased in tdLNs from mice receiving intravesical BCG compared with BCG administered IV or IP. Within the spleen, the proportion of CD8+CD11b- DCs were significantly increased in the DC compartment following IP BCG treatment compared to other treatment routes. Conclusion: This provides evidence that route of BCG administration affects the immune composition of secondary lymphoid organs that may be associated with anti-tumor responses. A better understanding of the mechanism of BCG immunotherapy will lead to novel approaches to optimize anti-tumor immune responses and, consequently, improved patient outcomes. Citation Format: Arielle Grossman, Aline Atallah, Tiziana Cotechini, Jean-Francois Pare, Robert Siemens, Charles H. Graham. Effect of route of Bacillus-Calmette Guerin administration on systemic immune responses in a murine model of non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2058.

Intravesical MgSO4 for the treatment of BCG refractory T1 G3 bladder cancer: Preliminary results on efficacy and safety.

An urgent need of therapy exists for patients with high-risk non-muscle invasive bladder cancer (NMIBC) for whom Bacillus Calmette-Guérin (BCG) refractory treatment has failed. We investigated the role of intravesical magnesium sulfate (MgSO4) therapy in the management of BCG refractory T1 high grade (G3) NMIBC. Between January 2018 and July 2021, we performed a prospective trial enrolling participants with T1 G3 NMIBC refractory in BCG therapy. All patients included were considered ineligible for or have refused to undergo radical cystectomy. Subjects are enrolled into a single treatment group of a fixed dose of intravesical MgSO4. The intravesical solution was given for 3 h bi-weekly × 6 then once per week for 12 months. Cystoscopic surveillance was performed every 3 months. Endoscopic resection was performed if suspicious findings were identified on surveillance cystoscopy to establish pathologic diagnosis. Oncological outcomes and any side effects were reported during follow-up. A total of 8 patients who received intravesical MgSO4 for refractory TG3 tumors were included in our study. The median follow-up time was 29 months (range from 23 to 36). 62.5% of the patients (5/8) achieved a complete response to intravesical MgSO4, while 25% of the patients (2/8) had a partial response and 12.5% (1/8) had persistent disease. None of the patients had disease progression. None of the patients experienced hypermagnesemia. In patients with pTG3 tumors who were refractory to BCG therapy, intravesical MgSO4 was a well-tolerated and potentially effective regimen.

MP59-06 PD-L1 EXPRESSION AND BCG RESPONSE IN NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 May 2022MP59-06 PD-L1 EXPRESSION AND BCG RESPONSE IN NON-MUSCLE INVASIVE BLADDER CANCER Solomon Woldu, Thomas Gerald, Vitaly Margulis, Daniel Halstuch, Yaara Ber, Karin Lifshitz, David Margel, Yair Lotan, and Liwei Jia Solomon WolduSolomon Woldu More articles by this author , Thomas GeraldThomas Gerald More articles by this author , Vitaly MargulisVitaly Margulis More articles by this author , Daniel HalstuchDaniel Halstuch More articles by this author , Yaara BerYaara Ber More articles by this author , Karin LifshitzKarin Lifshitz More articles by this author , David MargelDavid Margel More articles by this author , Yair LotanYair Lotan More articles by this author , and Liwei JiaLiwei Jia More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002642.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Intravesical bacillus Calmette Guerin (BCG) is the standard of care adjuvant therapy for high risk non-muscle invasive bladder cancer (NMIBC), yet many patients experience recurrence or disease progression. The mechanism of BCG is thought to be related to stimulation of immune surveillance. Relatedly, systemic immune checkpoint inhibition is being utilized in advanced bladder cancer and approved for BCG unresponsive NMIBC. We sought to determine the association between PD-L1 expression and BCG treatment. METHODS: We identified 102 BCG-naïve patients with high grade (HG) NMIBC treated with BCG. All patients underwent initial transurethral resection (TUR). Dako 22c3 assay was used to determine PD-L1 expression. Patients were defined as PD-L1 positive if the combined positive score > 0. BCG unresponsiveness was defined by presence of HG disease at 6 months following adequate BCG (one induction and maintenance cycle or two induction cycles) for pT1 or 12 months for CIS or presence of pT1 at 3 months after induction. HG relapse was defined as HG disease after being followed for 6 months after BCG. RESULTS: The median follow-up was 57 months. Median number of BCG maintenance cycles was 1, and 17 (16.7%) patients underwent immediate reinduction BCG. PD-L1 expression was observed in 5.9% of pTa, 30.0% of pT1, and 3.6% of CIS. BCG unresponsiveness and HG relapse were observed in 32 (35.6%) and 29 (34.5%), respectively. On univariate analysis, PD-L1 expression was inversely associated with BCG unresponsiveness (OR=0.11; 95% CI 0.01-0.90) but not HG relapse (OR=0.30; 95% CI 0.06-1.44). The sensitivity, specificity, positive predictive value, and negative predictive value of PD-L1 expression for BCG responsiveness were 22%, 97%, 93%, and 41%, respectively. PD-L1 positive patients had a post-test probability of BCG responsiveness of 93%. On multivariate regression, pT1 (OR = 0.16; 95% CI 0.05-0.60), CIS (OR=0.25; 95% CI 0.07-0.86), and PD-L1 expression (OR=15.63; 95% CI 1.78-142.86) were associated with BCG responsiveness. CONCLUSIONS: PD-L1 expression in HG NMIBC was low, and those with PD-L1 expression at initial TUR were more likely to harbor invasive disease. Patients with PD-L1 expression were more likely to demonstrate BCG responsiveness. These findings suggest a role of PD-L1 in the immune surveillance mechanism of BCG at initial diagnosis and may assist in predicting response to BCG in patients with HG NMIBC. Further investigation is needed to determine if additional immune checkpoint markers have strong correlation with BCG response, particularly among patients without PD-L1 expression. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e1003 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Solomon Woldu More articles by this author Thomas Gerald More articles by this author Vitaly Margulis More articles by this author Daniel Halstuch More articles by this author Yaara Ber More articles by this author Karin Lifshitz More articles by this author David Margel More articles by this author Yair Lotan More articles by this author Liwei Jia More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP54-01 DISCORDANCE BETWEEN CLINICAL AND PATHOLOGIC CARCINOMA IN SITU FOR TURBT AND RADICAL CYSTECTOMY IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER: IMPLICATIONS FOR BCG UNRESPONSIVE CLINICAL TRIAL DESIGN AND INTERPRETATION

You have accessJournal of UrologyCME1 May 2022MP54-01 DISCORDANCE BETWEEN CLINICAL AND PATHOLOGIC CARCINOMA IN SITU FOR TURBT AND RADICAL CYSTECTOMY IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER: IMPLICATIONS FOR BCG UNRESPONSIVE CLINICAL TRIAL DESIGN AND INTERPRETATION Manuel R. de Jesus Escano, Carissa Chu, Song Jiang, Wesley Yip, Nima Almassi, Peter Reisz, Andrew Lenis, Nicole Benfante, Eugene Cha, Timothy F Donahue, Guido Dalbagni, Alvin Goh, Bernard Bochner, and Eugene Pietzak Manuel R. de Jesus EscanoManuel R. de Jesus Escano More articles by this author , Carissa ChuCarissa Chu More articles by this author , Song JiangSong Jiang More articles by this author , Wesley YipWesley Yip More articles by this author , Nima AlmassiNima Almassi More articles by this author , Peter ReiszPeter Reisz More articles by this author , Andrew LenisAndrew Lenis More articles by this author , Nicole BenfanteNicole Benfante More articles by this author , Eugene ChaEugene Cha More articles by this author , Timothy F DonahueTimothy F Donahue More articles by this author , Guido DalbagniGuido Dalbagni More articles by this author , Alvin GohAlvin Goh More articles by this author , Bernard BochnerBernard Bochner More articles by this author , and Eugene PietzakEugene Pietzak More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002633.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The FDA recommends non-muscle invasive bladder cancer (NMIBC) trials stratify patients into two groups: carcinoma in situ (CIS) with or without papillary disease (CIS±Ta/T1) and papillary only disease (Ta/T1). Complete response rate is used as indicator of drug efficacy for approval in Phase II BCG unresponsive trials, yet limited data supports this classification. Moreover, effects of TURBT on response rate is not well stablished in NMIBC trials. To address this, we analyzed the concordance of CIS between TURBT and corresponding radical cystectomy (RC) specimens in NMIBC patients. METHODS: Patients treated with immediate RC at our center for high grade NMIBC between 2005-2015. Pre-RC TURBT/EUA and RC were performed at our center for study inclusion. Enhanced cystoscopy techniques during TURBTs were recorded. BCG unresponsive was defined using FDA criteria. BCG relapsing was defined as prior BCG treatment, but not meeting BCG unresponsive criteria. Clinical CIS (cCIS) was defined as histologic CIS in TURBT specimen, and pathologic CIS (pCIS) as histologic CIS in RC specimen. RESULTS: Of 610, 302 (49%) were BCG naïve and 308 (51%) had prior BCG. 358 (59%) had positive cCIS, 419 (69%) had positive pCIS, and 486 (80%) had any CIS (either+cCIS or +pCIS). In those with +cCIS, 289 (81%) had residual pathologic CIS (+cCIS/+pCIS), while eradication of CIS (+cCIS/−pCIS) was seen in 69 (19%). For those without cCIS at TURBT, concordance with RC (−cCIS/−pCIS) was seen in 124 (49%), while occult pathologic CIS (−cCIS/+pCIS) was detected in 128 (51%). In those BCG unresponsive (n=99), eradication of CIS by TURBT was seen in 16% (8/51) who would have been included in CIS±Ta/T1 cohorts, while occult pathologic CIS was seen in 52% (25/48). A similar frequency of CIS eradication (18%) and occult pathologic CIS (46%) was seen in the BCG relapsing subgroup. CONCLUSIONS: We report the potential utility of CIS as a marker of residual disease. Based on our findings, >15% of NMIBC patients in single-arm FDA registration trials might experience complete responses from the effects of TURBT alone, raising concerns about the interpretation of these trials. Furthermore, occult pathologic CIS was found in half of NMIBC patients who would incorrectly be placed into the papillary Ta/T1 only cohort of current NMIBC clinical trial stratification schema. Better measures of residual CIS after TURBT are needed to improve patient stratification and drug efficacy evaluations in NMIBC trials. Source of Funding: SKC for Prostate and Urologic Cancers, NIH/NCI to MSKCC through CCSG award #P30 CA008748, MJ and HRK CMO, MSKCC SPORE in BC P50-CA221745, MSKCC SPORE CE A., MSKCC Dept. of Surgery FR A., Bochner-Fleisher Scholars in BC Award, NIH/NCATS #UL1-TR-002384, NIH/NCI K12 Paul Calabresi CD A. for C Onc (K12 CA184746), Wofchuck Family A © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e926 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Manuel R. de Jesus Escano More articles by this author Carissa Chu More articles by this author Song Jiang More articles by this author Wesley Yip More articles by this author Nima Almassi More articles by this author Peter Reisz More articles by this author Andrew Lenis More articles by this author Nicole Benfante More articles by this author Eugene Cha More articles by this author Timothy F Donahue More articles by this author Guido Dalbagni More articles by this author Alvin Goh More articles by this author Bernard Bochner More articles by this author Eugene Pietzak More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP54-04 A PHASE II STUDY OF CHECK POINT INHIBITOR, DURVALUMAB (MEDI4736) FOR BACILLUS CALMETTE-GUERIN UNRESPONSIVE CARCINOMA IN SITU OF THE BLADDER

You have accessJournal of UrologyCME1 May 2022MP54-04 A PHASE II STUDY OF CHECK POINT INHIBITOR, DURVALUMAB (MEDI4736) FOR BACILLUS CALMETTE-GUERIN UNRESPONSIVE CARCINOMA IN SITU OF THE BLADDER Roger Li, Kyle Rose, Michael Poch, Philippe Spiess, Scott Gilbert, Wade Sexton, and Jingsong Zhang Roger LiRoger Li More articles by this author , Kyle RoseKyle Rose More articles by this author , Michael PochMichael Poch More articles by this author , Philippe SpiessPhilippe Spiess More articles by this author , Scott GilbertScott Gilbert More articles by this author , Wade SextonWade Sexton More articles by this author , and Jingsong ZhangJingsong Zhang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002633.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) represents a difficult clinical scenario, for which radical cystectomy (RC) is standard of care. Many patients are either unfit or unwilling to undergo RC, and bladder preserving treatment options are limited. We aimed to investigate the efficacy of durvalumab, a PD-L1 inhibitor, in the treatment of BCG-unresponsive carcinoma in situ (CIS) containing NMIBC. METHODS: This was a single center, open-label, phase II study of patients with BCG-unresponsive CIS of the bladder. After enrollment, patients received IV Durvalumab 1500mg IV, every 4 weeks for a total of 12 months. Cystoscopy with for-cause biopsy was performed every 3 months during the 12-month administration period, then every 4 months for a second 12 month surveillance period. Patients were taken off study if disease persistence or progression to invasive disease occurred. The primary endpoint was complete response (CR) by mapping biopsy at 6 months. Secondary outcomes were the duration of complete response and recurrence free survival (RFS). Pre- and post-treatment PD-L1 status was determined by the SP263 assay. Adverse events were captured using CTCAE v4.03. RESULTS: Seventeen patients were enrolled and began durvalumab for BCG-unresponsive CIS-containing NMIBC. Median age was 77 years (IQR 69-79), 13 (76.5%) patients had CIS alone, and the median number of prior BCG instillations was 12 (IQR 12-12). Four patients came off of study after 3 month bladder biopsy demonstrating persistent high grade NMIBC. Among the 13 patients who underwent 6-month mapping biopsy, 3 (18%) patients had a 6-month CR with a median duration of response of 14 months. Three (18%) patients progressed to muscle invasive or metastatic disease and 9 (53%) underwent RC. No correlation was observed between PD-L1 expression and clinical response to durvalumab. Grade 1-2 treatment-related adverse events occurred in 11 patients; most frequently fatigue (35%), diarrhea (18%), pancreatic enzyme elevation (12%), rash (6%), and hypothyroidism (6%). CONCLUSIONS: Immune checkpoint inhibition with durvalumab in BCG-unresponsive CIS-containing NMIBC demonstrated a favorable safety profile, but a modest CR rate. Additional research is needed in a larger cohort to determine generalizable efficacy with immune checkpoint inhibitors, and to better understand the safety profile in NMIBC. Source of Funding: AstraZeneca © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e927 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Roger Li More articles by this author Kyle Rose More articles by this author Michael Poch More articles by this author Philippe Spiess More articles by this author Scott Gilbert More articles by this author Wade Sexton More articles by this author Jingsong Zhang More articles by this author Expand All Advertisement PDF DownloadLoading ...

Modified Glasgow Prognostic Score as a Predictor of Recurrence in Patients with High Grade Non-Muscle Invasive Bladder Cancer Undergoing Intravesical Bacillus Calmette-Guerin Immunotherapy.

Background: A systemic inflammatory marker, the modified Glasgow prognostic score (mGPS), could predict outcomes in non-muscle-invasive bladder cancer (NIMBC). We aimed to investigate the predictive power of mGPS in oncological outcomes in HG/G3 T1 NMIBC patients undergoing Bacillus Calmette–Guérin (BCG) therapy. Methods: We retrospectively reviewed patient’s medical data from multicenter institutions. A total of 1382 patients with HG/G3 T1 NMIBC have been administered adjuvant intravesical BCG therapy, every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months. The analysis of mGPS for recurrence and progression was performed using multivariable and univariable Cox regression models. Results: During follow-up, 659 patients (47.68%) suffered recurrence, 441 (31.91%) suffered progression, 156 (11.28%) died of all causes, and 67 (4.84%) died of bladder cancer. At multivariable analysis, neutrophil to lymphocyte ratio [hazard ratio (HR): 7.471; p = 0.0001] and erythrocyte sedimentation rate (ESR) (HR: 0.706; p = 0.006 were significantly associated with recurrence. mGPS has no statistical significance for progression (p = 0.076). Kaplan–Meier survival analysis showed a significant difference in survival among patients from different mGPS subgroups. Five-year OS was 93% (CI 95% 92–94), in patients with mGPS 0, 82.2% (CI 95% 78.9–85.5) in patients with mGPS 1 and 78.1% (CI 95% 60.4–70) in mGPS 2 patients. Five-year CSS was 98% (CI 95% 97–99) in patients with mGPS 0, 90% (CI 95% 87–94) in patients with mGPS 1, and 100% in mGPS 2 patients. Limitations are applicable to a retrospective study. Conclusions: mGPS may have the potential to predict recurrence in HG/G3 T1 NMIBC patients, but more prospective, with large cohorts, studies are needed to study the influence of systemic inflammatory markers in prediction of outcomes in NMIBC for a definitive conclusion.

PD-L1 expression and BCG response in nonmuscle invasive bladder cancer.

545 Background: Intravesical bacillus Calmette Guerin (BCG) is the standard of care adjuvant therapy for high risk non-muscle invasive bladder cancer (NMIBC), yet many patients experience recurrence or disease progression. The mechanism of action of BCG is believed to be related to stimulation of immune surveillance. Relatedly, systemic immune checkpoint inhibition is currently being utilized in advanced bladder cancer and approved for BCG unresponsive NMIBC. We sought to determine the association between PD-L1 expression and BCG treatment. Methods: We identified 102 BCG-naïve patients with high grade (HG) NMIBC treated with BCG. All patients underwent initial transurethral resection (TUR) for pathologic diagnosis. Dako 22c3 assay was used to determine PD-L1 expression. Patients were defined as PD-L1 positive if the combined positive score (CPS) &gt; 0. BCG unresponsiveness was defined by presence of high grade disease at 6 months following adequate BCG (one induction and maintenance cycle or two induction cycles) for pT1 or 12 months for CIS or presence of pT1 at 3 months following induction. HG relapse was defined as presence of any HG disease after being followed for 6 months after BCG. Results: The median follow-up time was 57 months. Median number of BCG maintenance cycles was 1, and 17 (16.7%) patients underwent immediate reinduction BCG. PD-L1 expression was observed 5.9% of pTa, 30.0% of pT1, and 3.6% of CIS. BCG unresponsiveness and HG relapse were observed in 32 (35.6%) and 29 (34.5%) patients, respectively. On univariate analysis, PD-L1 expression was inversely associated with BCG unresponsiveness (OR = 0.112; 95% CI 0.014-0.898) but not high grade relapse (OR = 0.296; 95% CI 0.061-1.440). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PD-L1 expression for BCG responsiveness were 22%, 97%, 93%, and 41%, respectively. The post-test probability of BCG responsiveness was 93% in patients positive for PD-L1 based on a positive likelihood ratio of 7.33 for PD-L1 expression. On multivariate regression, pT1 (OR = 0.159; 95% CI 0.045-0.600), CIS (OR = 0.247; 95% CI 0.071-0.857), and PD-L1 expression (OR = 15.625; 95% CI 1.779-142.857) were independently associated with BCG responsiveness. Conclusions: PD-L1 expression in HG NMIBC was low, and patients with PD-L1 expression at initial TUR were more likely to harbor invasive disease. Patients showing PD-L1 expression were more likely to demonstrate BCG responsiveness. These findings suggest a role of PD-L1 in the immune surveillance mechanism of BCG at initial pathologic diagnosis and may assist in predicting responses to BCG among patients with HG NMIBC. Further investigation is required to determine if additional immune checkpoint markers have strong correlation with BCG response, particularly among patients without PD-L1 expression.

Association of statin use and oncological outcomes in patients with first diagnosis of T1 high grade non-muscle invasive urothelial bladder cancer: results from a multicenter study.

We aimed to test the hypothesis that the immune-modulatory effect of statins may improve survival outcomes in patients with non-muscle invasive bladder cancer (NMIBC). We focused on a cohort of patients diagnosed with high risk NMIBC, that were treated with intravesical BCG immunotherapy. We included patients at first diagnosis of T1 high grade NMIBC after transurethral resection of bladder (TURB). All procedures were performed at 18 different tertiary institutions between January 2002 and December 2012. Univariable and multivariable models were used to test differences in terms of residual tumor, disease recurrence, disease progression and overall mortality (OM) rates. Overall, 1510 patients with T1 high grade NMIBC at TURB were included in our analyses. Of these, 402 (26.6%) were statin users. At multivariable analysis, statin use was associated with a higher rate of high-grade BC at re-TURB (OR: 1.37, 95%CI: 1.04-1.78; P=0.022), while at follow-up it was not independently associated with OM (HR: 0.71, 95%CI: 0.50-1.03; P=0.068) and disease progression rates (HR: 0.97, 95%CI: 0.79-1.19; P=0.753). Conversely, statin use has been shown to be independently associated with a lower risk of recurrence (HR:0.80, 95%CI: 0.67-0.95; P=0.009). The median recurrence-free survival was 47 (95%CI 40-49) months for those classified as non-statin users vs. 53 (95%CI 48-68) months in those classified as statin users. Statin daily intake do not compromise oncological outcomes in high risk NMIBC patients treated with BCG. Moreover, statin may have a beneficial effect on recurrence rates in this cohort of patients.