High-grade T1 Research Articles

Phase 2 pilot trial of tislelizumab plus low-dose nab-paclitaxel for extensive very high-risk non-muscle-invasive bladder cancer.

Combinations of immune checkpoint inhibitors and nab-paclitaxel have improved outcomes in advanced urothelial carcinoma and muscle-invasive bladder cancer. This study evaluates the safety and efficacy of tislelizumab combined with low-dose nab-paclitaxel in extensive very high-risk (VHR) non-muscle-invasive bladder cancer (NMIBC). TRUCE-02 was a single-arm phase 2 trial that included 63 patients with visually incomplete resection and/or high-volume high-grade T1 tumors (with or without carcinoma in situ), who were ineligible for or declined radical cystectomy. Patients received intravenous tislelizumab (200 mg on day 1) and nab-paclitaxel (200 mg on day 2) every 3 weeks, with assessment approximately 3 months after initial administration. The primary endpoint was the complete response rate of high-risk disease. Main secondary endpoints included safety and duration of complete response. The safety analysis included all 63 patients and the efficacy analysis included 59 patients. Thirty-seven patients [62.7%; 95% confidence interval (CI), 49.1-75.0%] achieved a complete response of high-risk disease, with a 24-month sustained response rate of 96.3% (95% CI, 89.4-100.0%). Grade 3-4 treatment-related adverse events occurred in nine patients (14%), with no fatal events reported. Tislelizumab plus low-dose nab-paclitaxel was well-tolerated and showed promising antitumor activity, making it a potential alternative for extensive VHR NMIBC patients who are ineligible for or decline radical cystectomy.

Oncological outcomes and prognostic implications of T1 histo-anatomic substaging in the management of high-Grade non-muscle invasive bladder cancer: results from a large single centre series.

This study aimed to comprehensively evaluate the prognostic value of T1 histo-anatomic substaging (T1a/T1b) for high grade (HG) non-muscle invasive bladder cancer (NMIBC) over a large single-centre cohort. Patients with primary HG T1 NMIBC were identified from our Institutional database, between 2011 and 2022. Data from diagnosis to repeated transurethral resection of bladder tumour (RE-TURBT), bacillus Calmette-Guérin (BCG) treatment and follow-up were collected. Patients were stratified based on histo-anatomic landmark into T1a (invasion above the Muscularis Mucosa-MM) and T1b (into/beyond MM). Kaplan-Meier curves and multivariate Cox regression analyses were used to assess the impact of histo-anatomic substaging on recurrence-free survival (RFS), cancer-specific survival (CSS), and progression-free survival (PFS). Substaging was feasible in 88% of cases. The median (IQR) follow-up was 40 (17-72) months. T1b patients had larger initial tumours (> 3cm: 43.2% vs. 26.1%, p < 0.001), while upstaging to muscle-invasive bladder cancer (MIBC) at RE-TURBT was more frequent in T1b than in T1a (5.9% vs. 1.5%, p = 0.02). T1b patients without BCG induction had worse RFS and PFS (all p ≤ 0.02) compared to T1a, while no differences were observed in patients who received complete BCG induction. At Multivariate analysis, completing at least a BCG induction course was associated with better outcomes across all endpoints. Invasion of the MM in primary T1 NMIBC is associated with a higher risk of upstaging to MIBC. Patients who received full BCG induction had similar outcomes regardless of substaging, whereas T1b patients without BCG induction experienced higher recurrence and progression rates.

Clinical management of patients with colorectal intramucosal carcinoma compared to high-grade dysplasia and T1 colorectal cancer.

In the colorectum, intramucosal carcinoma (IMC), like high-grade dysplasia (HGD), should be resected endoscopically. We were interested to understand how real-world treatment of IMC cases compares to management of HGD and T1 colorectal cancer (CRC). A multicenter cohort study was conducted. Through pathology databases, all patients diagnosed between 2010 and 2019 with HGD, IMC, or T1 CRC polyps at 3 hospitals in a regional Canadian center were identified. The primary outcome was the proportion of surgical management of IMC compared to HGD after complete endoscopic resection. Secondary outcomes were the proportion of synchronous advanced neoplasia (SAN) and the adjusted hazard ratios (aHRs) for metachronous advanced neoplasia (MAN) in the 3 groups among patients eligible for follow-up. We identified 753 patients with IMC or HGD on a first pathology diagnosis, including 601 after complete endoscopic resection. Patients with IMC were more likely to undergo surgery after complete endoscopic resection compared to patients with HGD (10.5% [6 of 57] vs 0% [0 of 544], P< .001). A total of 455 patients had follow-up endoscopy and pathology (mean age, 67.1 years; 42.2% female; median follow-up, 3.4 years): 269 with HGD, 60 with IMC, and 126 with T1 CRC. Proportions of SAN were 24.2%, 26.7%, and 25.4% (P= .908). Compared to HGD, patients with IMC and T1 CRC had similar MAN risks (aHR, 0.82 [95% CI, 0.43-1.59] and aHR, 1.16 [95% CI, 0.66-2.05], respectively). No lymph node findings were positive (0 of 363), and no metastasis occurred among patients with IMC. Patients diagnosed with colorectal IMC were more likely to undergo surgery after complete endoscopic resection than when HGD was diagnosed, although they were not at increased risk of SAN or MAN in this study, and the known risk of nodal metastasis with colorectal IMC is small (0%-2%). Unless a patient diagnosed with IMC is particularly concerned with this small risk, complete endoscopic resection should be considered the definitive treatment for IMC and should not be followed by surgery.

Machine Learning-Based Detection of Bladder Cancer by Urine cfDNA Fragmentation Hotspots that Capture Cancer-Associated Molecular Features.

cfDNA fragmentomics-based liquid biopsy is a potential option for noninvasive bladder cancer (BLCA) detection that remains an unmet clinical need. We assessed the diagnostic performance of cfDNA hotspot-driven machine-learning models in a cohort of 55 BLCA patients, 51 subjects with benign conditions, and 11 healthy volunteers. We further performed functional bioinformatics analysis for biological understanding and interpretation of the tool's diagnostic capability. Urinary cfDNA hotspots-based machine-learning model enabled effective BLCA detection, achieving high performance (area under curve 0.96) and an 87% sensitivity at 100% specificity. It outperformed models using other cfDNA-derived features. In stage-stratified analysis, the sensitivity at 100% specificity of the urine hotspots-based model was 71% and 92% for early (low-grade Ta and T1) and advanced (high-grade T1 and muscle-invasive) disease, respectively. Biologically, cfDNA hotspots effectively retrieved regulatory elements and were correlated with the cell of origin. Urine cfDNA hotspots specifically captured BLCA-related molecular features, including key functional pathways, chromosome loci associated with BLCA risk as identified in genome-wide association studies, or presenting frequent somatic alterations in BLCA tumors, and the transcription factor regulatory landscape. Our findings support the applicability of urine cfDNA fragmentation hotspots for noninvasive BLCA diagnosis, as well as for future translational study regarding its molecular pathology and heterogeneity.

Tumor immune microenvironment dynamics and outcomes of prognosis in non-muscle-invasive bladder cancer.

Agents that target PD-1 and PD-L1 have been developed in the treatment of bladder cancer (BC). However, the diversity of immune cell infiltration in non-muscle-invasive BC (NMIBC) and the dynamics of the microenvironment as it progresses to muscle-invasive/metastatic disease remains unknown. To assess tumor immune activity, hierarchical clustering was applied to 159 BC samples based on cellular positivity for the defined immune cellular markers (CD3/CD4/CD8/FOXP3/CD20/PD-1/PD-L1/LAG3/TIGIT), divided into two clusters. There was a "hot cluster" (25%) consisting of patients with a high expression of these markers and a "cold cluster" (75%) comprising those without. The expression of CD39, CD44, CD68, CD163, IDO1, and Ki67 was significantly higher in tumors in the hot cluster. Immunologically, high-grade T1 tumors were significantly hotter, whereas tumors that had progressed to muscle invasion turned cold. However, a certain number of high-grade NMIBC patients were in the cold cluster, and these patients had a significantly higher risk of disease progression. Using an externally available TCGA dataset, RB1 and TP53 alterations were more frequently observed in TCGA hot cluster; rather FGFR3, KDM6A, and KMT2A alterations were common in TCGA cold/intermediate cluster. Analyses of recurrent tumors after BCG therapy revealed that tumor immune activity was widely maintained before and after treatment, and high FGFR3 expression was detected after recurrence in tumors initially classified into the cold cluster. Collectively, we revealed the dynamics of the tumor microenvironment in BC as a whole and identified candidate molecules as therapeutic targets for recurrent NMIBC, e.g., after BCG therapy.

Predicting Response to Intravesical Bacillus Calmette-Guérin in High-Risk Nonmuscle-Invasive Bladder Cancer Using an Artificial Intelligence-Powered Pathology Assay: Development and Validation in an International 12-Center Cohort.

There are few markers to identify those likely to recur or progress after treatment with intravesical bacillus Calmette-Guérin (BCG). We developed and validated artificial intelligence (AI)-based histologic assays that extract interpretable features from transurethral resection of bladder tumor digitized pathology images to predict risk of recurrence, progression, development of BCG-unresponsive disease, and cystectomy. Pre-BCG resection-derived whole-slide images and clinical data were obtained for high-risk nonmuscle-invasive bladder cancer cases treated with BCG from 12 centers and were analyzed through a segmentation and feature extraction pipeline. Features associated with clinical outcomes were defined and tested on independent development and validation cohorts. Cases were classified into high or low risk for recurrence, progression, BCG-unresponsive disease, and cystectomy. Nine hundred forty-four cases (development: 303, validation: 641, median follow-up: 36 months) representative of the intended use population were included (high-grade Ta: 34.1%, high-grade T1: 54.8%; carcinoma in situ only: 11.1%, any carcinoma in situ: 31.4%). In the validation cohort, "high recurrence risk" cases had inferior high-grade recurrence-free survival vs "low recurrence risk" cases (HR, 2.08, P < .0001). "High progression risk" patients had poorer progression-free survival (HR, 3.87, P < .001) and higher risk of cystectomy (HR, 3.35, P < .001) than "low progression risk" patients. Cases harboring the BCG-unresponsive disease signature had a shorter time to development of BCG-unresponsive disease than cases without the signature (HR, 2.31, P < .0001). AI assays provided predictive information beyond clinicopathologic factors. We developed and validated AI-based histologic assays that identify high-risk nonmuscle-invasive bladder cancer cases at higher risk of recurrence, progression, BCG-unresponsive disease, and cystectomy, potentially aiding clinical decision making.

Bladder-Preserving Trimodality Treatment for High-Grade T1 Bladder Cancer: Results From Phase II Protocol NRG Oncology/RTOG 0926.

To investigate the use of radiation with radiosensitizing chemotherapy following repeated transurethral resection (trimodality therapy) as an alternative to radical cystectomy in T1 bladder cancer which has failed Bacillus Calmette-Guerin (BCG). Patients with recurrent T1 bladders who had failed BCG and were recommended to undergo cystectomy were treated with trimodality therapy. The primary end point was 3-year freedom from cystectomy. Secondary end points were distant metastasis at 3 and 5 years, local recurrence, disease-specific and overall survival (OS), and safety. This single-arm phase II study enrolled 37 patients. Efficacy and safety were evaluated in 34 patients after three exclusions. The median follow-up was 5.1 years. The 3-year freedom from cystectomy rate was 88% (lower one-sided 97.5% confidence limit [CI], 72%), meeting the primary study goal. OS at 3 and 5 years was 69% (95% CI, 54 to 85) and 56% (95% CI, 39 to 74), respectively. The distant metastasis rates at 3 and 5 years were 12% (95% CI, 4 to 26) and 19% (95% CI, 7 to 34), respectively. Eight patients died due to urothelial cancer, 12 exhibited local recurrence at 3 years (cumulative incidence: 32%; 95% CI, 17 to 48), 18 experienced grade 3 adverse events, mostly hematological, and one developed grade 4 neutropenia. Trimodality therapy is an effective potential alternative to radical cystectomy for recurrent high-grade T1 urothelial cancer of the bladder. At 3 years, 88% of the patients remained free of cystectomy.

Bowel function, quality of life, and mental health of patients with high-grade intraepithelial neoplasia or T1 colorectal cancer after organ-preserving versus organ-resection surgeries: a cross-sectional study at a Chinese tertiary care center.

This study aimed to determine the postoperative intestinal functioning, quality of life (QoL), and psychological well-being of patients treated either with organ-preserving surgery (OPS) or organ-resection surgery (ORS) for high-grade intraepithelial neoplasia (HIN) or T1 colorectal cancer (CRC). This cross-sectional study was conducted at a single tertiary care center. In total, 175 eligible individuals with T1 CRC or HIN were divided into the OPS (n = 103) or ORS (n = 72) group based on whether the relevant segment of the intestine was preserved or resected. Intestinal function was evaluated using low anterior resection syndrome (LARS) scores. QoL was evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ)-C30 and EORTC-QLQ-CR29. Psychological status was evaluated using the Fear of Progression Questionnaire-Short Form and the Self-rating Anxiety and Depression scales. Propensity score matching (PSM) was used to minimize the influence of potential confounders. Overall, 130 of 175 patients (74.29%) responded to the questionnaires; 56 and 74 were in the ORS and OPS groups, respectively. Thirty-five patient pairs were successfully matched through PSM. The mild and severe LARS rates were significantly higher in the ORS group than in the OPS group (P < 0.001). The EORTC-QLQ-C30 and EORTC-QLQ-CR29 scores revealed significantly better physical, role, and emotional functioning and an overall improved state of health (with multiple reduced symptom scores) in the OPS group than in the ORS group (P < 0.05). Significantly more patients were depressed in the ORS group than in the OPS group (P = 0.034), whereas anxiety or fear of disease progression did not differ significantly between the groups. OPS for the treatment of HIN or T1 CRC was found to be more advantageous for patients in terms of improved intestinal function, QoL, and psychological status than was ORS.

Do we need a re-TUR after en bloc resection of T1 stage bladder cancer?

BackgroundA second look trans-urethral resection of the bladder (re-TUR) is recommended after the diagnosis of T1 high grade (T1HG) bladder cancer. Few studies have evaluated the results of re-TUR after a first en bloc resection (EBR) and none of them have specifically reported the pathological results on the field of previous T1 disease.ObjectiveTo report the rate of upstaging and the rate of residual disease (RD) on the field of T1HG lesions resected with EBR.Materials and methodsBetween 01/2014 and 06/2022, patients from 2 centers who had a re-TUR after an EBR for T1HG urothelial carcinoma were retrospectively included. Primary endpoint was the rate of RD including the rate of upstaging to T2 disease on the scar of the primary resection. Secondary endpoints were the rate of any residual disease outside the field.ResultsSeventy-five patients were included. No muscle invasive bladder cancer lesions were found after re-TUR. Among the 16 patients who had a RD, 4 were on the resection scar. All of these lesions were papillary and high grade. RD outside the field of the first EBR was observed in 12 patients.ConclusionAfter EBR of T1HG disease, none of our patients had an upstaging to MIBC. However, the rate of RD either on and outside the field of the EBR remains quite significant. We suggested that predictive factors of residual papillary disease (number of tumors at the initial TUR and concomitant CIS) might be suitable to select patient who will benefit of the re-TUR.

Intravesical Gemcitabine and Docetaxel Therapy for BCG-Naïve Patients: A Promising Approach to Non-Muscle Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) therapy for patients with non-muscle invasive bladder cancer (NMIBC) faces limitations in efficacy and significant side effects, aggravated by a recent global shortage. In this prospective clinical study, we report the outcomes of sequential intravesical administration of gemcitabine and docetaxel (Gem/Doce) as a first-line treatment for BCG-naïve patients with high-risk NMIBC (HR NMIBC). From October 2019 until April 2022, we enrolled 52 patients and followed the treatment protocol set forth by the University of Iowa. Follow-up assessments were conducted every 3 months. In this cohort, 25 (48.1%) patients were diagnosed with high-grade T1 (T1HG) bladder cancer, 10 (19.2%) patients had carcinoma in situ (CIS), and 17 (32.7%) patients had a combination of T1HG+CIS. The median time to first recurrence in the T1HG, CIS, and T1HG+CIS groups was 11, 10.5, and 8.8 months, respectively. The recurrence-free survival was 98.1%, 94.2%, and 80.8% at 6, 9, and 12 months, respectively. The rate of progression-free survival was 100%, 98.1%, and 92.3% at 6, 9, and 12 months, respectively. We demonstrated the safety and efficacy of Gem/Doce therapy in BCG-naïve patients with HR NMIBC during a one-year follow-up. Further research with extended follow-ups, as well as direct comparisons of Gem/Doce with other anticancer agents, is essential.

Comparative efficacy of Bacillus Calmette-Guérin instillation and radical cystectomy treatments for high-risk non-muscle-invasive urothelial cancer classified as high-grade T1 in initial and repeat transurethral resection of bladder tumor.

To compare the differential therapeutic effects of Bacillus Calmette-Guérin (BCG) instillation and radical cystectomy (RC) for high-risk non-muscle-invasive urothelial cancer (NMIBC) classified as high-grade T1 in initial and repeat transurethral resection of bladder tumors (TURBT) and to construct a prediction model. We retrospectively analyzed the clinical data of patients with malignant bladder tumors treated at the First Affiliated Hospital of Soochow University from January 2016 to December 2017 and compared the differences in 1-year, 2-year, 3-year, 5-year, and comprehensive overall survival (OS) and progression-free survival (PFS) between BCG instillation treatment and RC treatment. Survival curves were drawn to show differences in OS and PFS between the two groups. Concurrently, univariate and multivariate COX analyses were performed to identify risk factors affecting OS and PFS, and a nomogram was created. In total, 146 patients were included in the study, of whom 97 and 49 were in the BCG and RC groups, respectively. No statistical differences were observed in the 1- and 2-year OS and PFS between the two groups, whereas significant statistical differences were found in the 3-year, 5-year, and comprehensive OS and PFS. Survival curves also confirmed the statistical differences in OS and PFS between the BCG and RC groups. Multivariate COX analysis revealed that the treatment method, concomitant satellite lesions, and albumin-to-alkaline phosphatase ratio (AAPR) were independent risk factors affecting OS and PFS. The nomogram that was further plotted showed good predictive ability for OS and PFS. For patients who exhibit high-level T1 pathology after both initial and repeat TURBT, especially those with low AAPR, and concomitant satellite lesions, choosing RC as a treatment method offers a better prognosis.

Early experience with sequential intravesical gemcitabine and docetaxel for micropapillary variant non-muscle invasive bladder cancer

BackgroundGuidelines lack clear recommendations regarding conservative management of micropapillary (MP) variant non-muscle invasive bladder cancer (NMIBC). Bladder-sparing therapy using intravesical Bacillus Calmette-Guerin (BCG) has been reported although there are concerns regarding recurrence and progression with this approach. Due to the ongoing BCG shortage, we have utilized sequential intravesical gemcitabine and docetaxel (Gem/Doce) as primary therapy for NMIBC, including some cases with limited MP urothelial carcinoma (MPUC). To compare oncologic outcomes of patients with non-muscle invasive MPUC and conventional UC treated with Gem/Doce. MethodsA secondary analysis of 138 patients with high-risk NMIBC treated with intravesical Gem/Doce from January 2011 to December 2021 was performed. Oncologic outcomes were compared in patients with or without MPUC using the Kaplan-Meier method. ResultsMedian follow-up (f/u) for all patients was 23 months (IQR 13–34). There were 129 patients with pure UC and 9 with MPUC. In those with MPUC, all were high-grade (HG), 8/9 were stage T1, 7/9 had a focal MP component (extent < 10%), 3/9 had concomitant CIS, and 2/9 had lymphovascular invasion. All MPUC tumors were re-resected, and 4 had T0, 3 had T1 HG, 1 had Ta HG, 1 had carcinoma in situ (CIS); none had residual MP or LVI tumors before Gem/Doce treatment. The 24-month high-grade recurrence-free survival was 89% and 80% in patients with MPUC and pure UC, respectively. Survival outcomes did not significantly differ between patients with and without MPUC. Four patients with MPUC experienced recurrent NMIBC after Gem/Doce, and all were treated successfully with rescue sequential intravesical valrubicin and docetaxel (Val/Doce). Pathology of these four recurrent patients revealed more aggressive histologic features in the original tumor including: multifocal tumor (3/4), T1 HG disease (4/4), concomitant CIS (2/4), and moderate MP variant extent (30%) (1/4). No patient with MPUC underwent cystectomy, experienced progression, or died at last follow-up (median f/u of 43 months). ConclusionsGem/Doce with Val/Doce rescue appears to have activity against carefully selected non-muscle invasive MPUC with favorable histology. Larger prospective trials are needed to validate these results.

A Phase 2 Trial of Intravesical Gemcitabine and Docetaxel in the Treatment of Bacillus Calmette-Guérin‒Naïve Nonmuscle-Invasive Urothelial Carcinoma of the Bladder.

Combination intravesical gemcitabine and docetaxel (GemDoce) has demonstrated efficacy as second-line therapy for patients with bacillus Calmette-Guérin (BCG)‒unresponsive nonmuscle-invasive urothelial carcinoma of the bladder (NMIBC). In the context of widespread BCG shortages, we performed a phase 2 prospective trial to assess GemDoce for BCG-naïve NMIBC. This study is a prospective, single-arm, open-label phase 2 trial for patients with BCG-naïve high-risk NMIBC. Intravesical GemDoce was given weekly for 6 weeks as induction followed by monthly maintenance therapy for 2 years among responders. The primary end point was 3-month complete response, and key secondary end points included adverse events (AEs) and 12-month recurrence-free survival. Twenty-five patients were enrolled between August 2020 and August 2022 with median follow-up of 19.6 months. The pretreatment pathologic stages were high-grade (HG) T1 with carcinoma in situ (CIS; n = 7), HGT1 without CIS (n = 6), HGTa (n = 9), and CIS alone (n = 3). The 3-month complete response rate was 100% and recurrence-free survival at 12 months was 92%. Two patients with pretreatment HGT1 had HGT1 recurrences at 9 and 12 months. No patients progressed to T2 disease, underwent radical cystectomy, or had any radiographic evidence of progressive disease. Grade 1 AEs were common (23/25 patients) including hematuria, urinary frequency, urgency, and fatigue. Five patients (20%) experienced a grade 3 AE including hematuria and UTI. In this single-arm phase 2 trial, GemDoce was well tolerated with promising efficacy for patients with BCG-naïve high-risk NMIBC.

Low Cubilin/Myeloperoxidase ratio as a promising biomarker for prognosis of high-grade T1 bladder cancer

PurposeT1 bladder cancer is known for its high progression and recurrence rates. Identifying aggressive tumours at the non-muscle-invasive stage is crucial to allow early interventions and subsequently increase patient survival. This study aimed to investigate the potential of the cubilin/myeloperoxidase (CUBN/MPO) ratio as a high-grade T1 bladder cancer biomarker.MethodsUrine samples were collected from 30 patients who underwent transurethral resection of the tumour with high-grade T1 bladder cancer (June 2015 to December 2019) before surgery. The urinary proteome was analysed using high-resolution mass spectrometry and the CUBN/MPO ratio was calculated. The primary outcome was the recurrence during the follow-up (around 31.5 months after resection). Univariate Cox regression and Kaplan–Meier curves were used for data analysis.ResultsPatients with a low CUBN/MPO ratio exhibited upregulated MPO and/or downregulated CUBN. This group of patients had a higher incidence of disease recurrence and progression. Low CUBN/MPO ratio was significantly associated with a higher likelihood of recurrence, progression, and death. It is worth noting that this study was exploratory and conducted on a small sample size, so further research is needed to validate these findings in larger cohorts.ConclusionThis study highlights the potential of the CUBN/MPO ratio as a prognostic biomarker for high-grade T1 bladder cancer.

Abstract 7648: COL6A1 expression as a potential prognostic biomarker for risk stratification of T1HG bladder cancer: Unveiling the aggressive nature of a distinct non-muscle invasive subtype

Abstract Introduction and Objectives: T1 high grade (T1HG) bladder cancer (BC) is a type of non-muscle invasive BC (NMIBC) that is recognized as an aggressive subtype with a heightened propensity for progression. Current risk stratification methods for NMIBC rely on clinicopathological indicators; however, these approaches do not adequately capture the aggressive nature of T1HG BC. Thus, new, more accurate biomarkers for T1HG risk stratification are needed. Here, we enrolled three different patient cohorts and investigated expression of COL6A1, a key component of the extracellular matrix, at different stages and grades of BC, with a specific focus on T1HG BC. Materials and Methods: Samples from 298 BC patients were subjected to RNA sequencing and real-time PCR. Results: We found that T1HG BC and muscle invasive BC (MIBC) exhibited comparable expression of COL6A1, which was significantly higher than that by other NMIBC subtypes. In particular, T1HG patients who later progressed to MIBC had considerably higher expression of COL6A1 than Ta, T1 low-grade patients, and patients that did not progress, highlighting the aggressive nature and higher risk of progression associated with T1HG BC. Moreover, Cox and Kaplan-Meier survival analyses revealed a significant association between elevated expression of COL6A1 and poor progression-free survival of T1HG BC patients (multivariate Cox hazard ratio, 16.812; 95% confidence interval, 3.283-86.095; P=0.001 and P=0.0002 [log-rank test]). Conclusion: These findings suggest that COL6A1 may be a promising biomarker for risk stratification of T1HG BC, offering valuable insight into disease prognosis and guidance of personalized treatment decisions. Citation Format: Xuan-Mei Piao, Young Joon Byun, Chuang-Ming Zheng, Seon-Kyu Kim, Seong-Hwan Park, Kyungchan Min, Hansoo Park, Sungmin Moon, Kyeong Kim, Ho Won Kang, Won Tae Kim, Seok Joong Yun. COL6A1 expression as a potential prognostic biomarker for risk stratification of T1HG bladder cancer: Unveiling the aggressive nature of a distinct non-muscle invasive subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7648.

Abstract 4558: A triterpenoid derivative has strong antitumor activities in gemcitabine-resistant advanced bladder cancer models and promotes immune cell infiltration in a high grade murine syngeneic model

Abstract Bladder cancer (BC) presents a formidable challenge in treatment and patient survival, requiring particular attention to advanced stages, such as muscle-invasive stage (MIBC), due to its potential for rapid progression and substantial impact on patient morbidity and mortality. The five-year survival rate for MIBC is a meager 30%, which drops further down to 8% once tumors metastasize. Advanced bladder cancers (High grade T1) are treated with intravesical therapy with Gemcitabine and Cisplatin (G+C) combination and Stage T2 are treated neoadjuvant with G+C and cystectomy, thereby decreasing the quality of life for patients with BC. Furthermore, tumors progress beyond responding to other chemotherapy regimens such as dose-dense treatment with Methotrexate +Vinblastine + Adriamycin and Cis-platin (MVAC), all of which will further decrease the quality of life with persistent adverse toxicity. Our laboratory has developed a novel compound derived from the pentacyclic triterpenoid, Ursolic acid, termed N-methyl piperazine conjugated-Ursolic acid, or UA4, and have demonstrated its antitumor activities against both Gem-Sensitive (Gem-S) and Gem-Resistant (Gem-R) human advanced BC cell lines, T24 and 5637. We tested the combination of Gem, UA4 and Gem + UA4 in a murine non-MIBC model (MB49) to investigate the role of immune cell infiltration during tumor development and treatment response. UA4 treatment was equally effective in chemo-sensitive and chemo-resistant cell lines at dosages between 4-5µM. Previous in vitro mechanistic studies on UA4 and UA4+Gem combination treatments revealed cell death occurred through apoptosis and autophagy, along with a highly selective form of mitochondrial-mediated autophagy (mitophagy). These findings were confirmed with transmission electron microscopy ultrastructural analysis, cell cycle phase analyses, excess, changes in mitochondrial membrane potential and reactive oxygen species measurements. Gem-S and Gem-R xenografts in athymic mice further supported UA4’s efficacy in vivo, demonstrating a significant reduction in both tumor weight and volume following oral gavage (100mg/kg), with mice exhibiting no signs of systemic toxicity. Combination treatment with UA4 and Gem synergistically increased antiproliferative activity. MB49 syngeneic mice model further supported UA4 as an effective therapy, and immunofluorescence assays with immune-related markers, suggested an anti-inflammatory effect in vivo. Overall, we demonstrate UA4 has a potential to be used as an efficacious, non-toxic compound for further adjuvant use in clinical settings. Citation Format: Juliette Rose Seremak, Kunj Bihari Gupta, Siva S. Panda, Bal L. Lokeshwar. A triterpenoid derivative has strong antitumor activities in gemcitabine-resistant advanced bladder cancer models and promotes immune cell infiltration in a high grade murine syngeneic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4558.

Cost-utility of Initial Management of High-grade T1 Bladder Cancer With Intravesical BCG vs Immediate Radical Cystectomy

ObjectivesTo compare the cost-utility of initial management of high-grade T1 non-muscle invasive bladder cancer (HGT1 NMIBC) with intravesical BCG versus immediate radical cystectomy. High risk NMIBC patients may climb a costly ladder of treatments, culminating in radical cystectomy for oncologic or symptomatic benefit in up to one-third. This high healthcare resource utilization presents a challenging dilemma in balancing sufficiently aggressive management with cost, toxicity, and quality-of-life. MethodsCost-utility of initially managing HGT1 with intravesical BCG and early radical cystectomy with ileal conduit urinary diversion was compared using decision-analytic Markov models. Five-year oncologic outcomes, adverse event rates, and published utility values were extracted from literature. Costs were calculated from a US Medicare perspective in 2021 US dollars. Sensitivity analysis identified drivers of cost and break-even points for recurrence and progression. ResultsMean costs were $26,093 for intravesical BCG and $39,720 for immediate radical cystectomy, though cystectomy generated a gain of 2.2 QALYs compared to intravesical BCG. Immediate cystectomy was a more cost-effective management strategy for HGT1 NMIBC with an ICER of $7120/QALY.The costs associated with cystectomy, TURBT, and BCG toxicity had the greatest impact on ICER. One-way sensitivity analysis demonstrated that intravesical BCG became a cost-effective management strategy if the five-year recurrence rate of HG T1 was less than 56% or the five-year progression rate to MIBC was less than 4%. ConclusionsAt current prices, treatment of high-grade T1 NMIBC with early radical cystectomy is more cost-effective management strategy than initial treatment with intravesical BCG.

Comparing Clinical Efficacy of Different Bacillus Calmette-Guérin Strains in Patients With T1 High Grade Bladder Cancer.

This study aimed to compare the clinical efficacy of two different Bacillus Calmette-Guérin (BCG) strains, TICE strain (OncoTICE) and Connaught strain (ImmuCyst), as a first line intravesical instillation therapy in patients with T1 high grade bladder cancer. Patients with newly diagnosed T1 high-grade bladder cancer who underwent transurethral resection of bladder tumor (TURBT) followed by intravesical instillation therapy were enrolled. The effects of BCG strain on recurrence, progression, and side effects were analyzed using Kaplan-Meier and Cox proportional hazards models. Among 147 patients, 53 patients received Connaught strain and 94 patients received TICE strain. The completion rate of induction instillation was 92.45% in the Connaught group and 91.49% in the TICE group (p=1.00). The three-year recurrence-free survival rate was 71.7% in the Connaught group and 63.83% in the TICE group (p=0.33), whereas the three-year progression-free survival rate was 96.23% in the Connaught group and 89.36% in the TICE group (p=0.21). On Cox regression test, carcinoma in situ and ≥eight lesions were significant predictors for recurrence. No significant difference was observed in recurrence and progression between the two BCG regimens. The complication rates according to the Cleveland Clinic grading system showed no significant difference between the two groups (p=0.13). Both the Connaught and TICE strains of BCG demonstrated comparable three-year recurrence-free survival rates and three-year progression-free survival rates for T1 high grade bladder cancer, as well as comparable adverse events. Due to the global BCG shortage, further strain comparisons are essential for clinical validation.

The Effect of Lymphovascular Invasion on Short-Term Tumor Recurrence and Progression in Stage T1 Bladder Cancer.

Introduction Lymphovascular invasion (LVI) is the most important stage for tumor spread and metastasis. The role of LVI in transurethral resection is not yet clear. In this study, the progression and recurrences of patients who underwent transurethral resection bladder tumor (TUR-BT) and T1 high-grade tumor and concomitant LVI were detected in pathology results and were evaluated. Methods Our study included 58 patients, who underwent TUR-BT with the suspicion of bladder cancer and were pathologically diagnosed with T1 stage bladder cancer and who did not undergo radical surgery, in the Urology Clinic of Afyonkarahisar Health Sciences University, Turkey. The patient's age, gender, tumor size, tumor grade, presence of LVI, second resection, recurrence, and progression rates at three months and one year were compared. Results LVI was detected in the pathology specimens of nine (15.5%) of the 58 patients who were included in the study. When the one-year progression was evaluated, progression to T2 tumor was detected in six (66.7%) patients in the group with LVI and five (10.2%) patients in the group without LVI, and the progression was significantly higher in the group with LVI (p=0.001). In logistic regression analysis, the only significant predictor for one-year progression was the presence of LVI (p=0.001). Conclusion According to the results of our study, the presence of LVI in the pathology specimens of patients with T1 high grade significantly increases the progression. Suggesting radical cystectomy and neoadjuvant chemotherapy to patients with LVI in the early period seems to be a more accurate approach, considering the course of the disease.

A152 THE RISK OF UNFAVORABLE HISTOLOGIC FEATURES, LYMPH NODE METASTASIS AND METACHRONOUS ADVANCED NEOPLASIA IN PATIENTS WITH COLORECTAL INTRAMUCOSAL CARCINOMA

Abstract Background Very few studies have described the risk of unfavorable histologic features (UHFs), lymph node involvement (LNI), distant metastasis (DM) and metachronous advanced neoplasia (MAN) after the detection of colorectal intramucosal carcinoma (IMC). Aims This study aimed to determine the risk of UHFs, LNI, DM and MAN in patients with IMC, compared to high-grade dysplasia (HGD) or T1 colorectal cancer (CRC). Methods A retrospective cohort study was conducted. Through a pathology database search, we identified all consecutive patients with HGD (epithelial) (n=908) or either IMC (lamina propria or muscularis mucosa) or T1 CRC (submucosa) (n=496) diagnosed between 2010 and 2019 at the University of Montreal Hospital Center. We excluded patients with age ampersand:003C40 or ampersand:003E90, IBD, hereditary CRC or post-neoadjuvant therapy. Primary outcome was the risk of UHF, LNI and DM in IMC vs T1. Secondary outcome was the risk of MAN (metachronous advanced adenoma or advanced serrated lesion or CRC) in the IMC group, compared to HGD and T1. Files were reviewed for demographics and index and follow-up findings. The metachronous analysis excluded follow-ups ampersand:003C6 months, no follow-up or previous CRC. Follow-up continued until MAN or last colonoscopy within 10 y. Variables were compared between groups using ANOVA, chi-squared tests or Kruskal-Wallis tests, followed by post-hoc tests. We performed multivariate Cox regressions, adjusting for age, sex, family history of CRC, main lesion location, villous histology, adenomas ≥10 mm, and number of adenomas. Results The primary cohort included 90 patients with IMC (mean age 69.4 y., 44.4% female) and 207 with T1 CRC (mean age 69.8 y., 43.5% female), as well as 797 with HGD. The rates of lymphatic invasion, vascular invasion, intermediate differentiation/grade and mucinous histology were 2/90, 1/90, 7/90 and 4/90 in the IMC group compared to respectively 30/207 (2.2% vs 14.5%, pampersand:003C0.01), 15/207 (1.1% vs 7.2%, p=0.06), 68/207 (7.7% vs 32.9%, pampersand:003C0.01) and 15/207 in the T1 group (4.4% vs 7.2%, p=0.52). No other UHFs were present. No patients with IMC had LNI or DM. In the metachronous outcomes analysis, 464 patients were eligible (mean age 67.1 y., 42.2% female, median follow-up 3.0 y.): 274 with HGD, 58 with IMC and 132 with T1 CRC. Compared to HGD, patients with IMC had a lower likelihood of MAN (HR 0.46, 0.22-0.96), and T1 CRC had a similar likelihood of MAN (HR 0.65, 0.41-1.02). Compared to IMC, T1 CRC had a similar likelihood of MAN (HR 1.39, 0.63-3.09). Conclusions Patients with colorectal IMC have a small risk of UHFs, but LNI and DM were not identified in this cohort study and have not been reported. Patients with IMC and T1 CRC do not have an increased risk of MAN compared to patients with HGD. Funding Agencies None