Treatment Of Muscle-invasive Bladder Cancer Research Articles

Immune checkpoint inhibitor therapy as a neoadjuvant treatment for muscle-invasive bladder carcinoma

Abstract Background and objectives Immunotherapy has become a standard treatment for patients with advanced urothelial carcinoma, and neoadjuvant immunotherapy is being extensively explored. This review highlights the initial findings and key clinical therapeutic insights on immune checkpoint inhibitors in the early treatment of muscle-invasive bladder cancer across diverse patient populations. Materials and methods Relevant trials were retrieved from PubMed/MEDLINE and clinical trials databases. In addition, abstracts of major international oncology meetings (American Society of Clinical Oncology, American Association for Cancer Research, European Society of Medical Oncology, and European Council of Clinical Oncology) were reviewed until the European Society of Medical Oncology 2023 congress. The review also incorporated results from several exploratory investigations disclosed in recent years. Results This review focused on neoadjuvant immune checkpoint inhibitor monotherapy, combination therapy, and clinical biomarkers in relation to cisplatin-based chemotherapy tolerance. Most available literature consists of clinical investigations involving small sample, single-arm Phase II trials, with the primary endpoint being the pathologic complete response rate. The preliminary results from these studies are promising, demonstrating stage reduction rates comparable to or even exceeding those of standard chemotherapy, without compromising subsequent radical cystectomy. Conclusions Early results of immune checkpoint inhibitors in the neoadjuvant treatment of bladder cancer have demonstrated promising efficacy. However, these findings require confirmation in large Phase III clinical trials, with particular emphasis on long-term survival benefits and identifying patients who respond to treatment.

"Minho Technique" for Laparoscopic Radical Cystectomy with Intracorporeal Ileal Conduit.

Radical cystectomy (RC) with ileal conduit (IC) remains a main treatment for muscle-invasive bladder cancer (MIBC). Laparoscopy in this multistage surgery is quite demanding, so laparoscopic RC (LRC) with intracorporeal IC (IIC) is a technically exceptional procedure. We aim to simplify it, demonstrating our technique, step-by-step. We present a 4-port LRC with IIC and Bricker uretero-ileal anastomoses. The main difference is the immediate and complete posterior dissection, similar to the "Montsouris approach" for prostatectomy. A 70-year-old man with a 5 cm MIBC was subjected to our demonstrated procedure. The postoperative period was uneventful. Diet and ambulation: 2 days. Single-J stents removal: 4 weeks. MIBC N0 was confirmed. At 24 months, the patient is well, without complications (namely hydronephrosis or disease recurrence). LRC with IIC is demanding and requires laparoscopic expertise. However, if performed in a standardized fashion, as demonstrated through this case, and considering our center's experience, it seems feasible and safe with 4-port and standard material without a significant operative time increase, nor oncological or functional compromise.

Treatment preferences of patients with muscle invasive bladder cancer: A discrete choice experiment.

When faced with treatment options, patients are asked to participate in decision-making. We sought to determine which treatment aspects matter most for individuals treated for muscle invasive bladder cancer (MIBC), with an aim to improve understanding of patient preferences and what trade-offs patients are willing to accept. Our study consisted of a discrete choice experiment (DCE): a type of questionnaire used to elicit preferences in the absence of real-world choice. The DCE had five attributives, each with three levels. Participants were asked to complete a questionnaire in which they were asked to choose between two hypothetical MIBC treatments. The data were analysed using a conditional logit model, and preferences for, and trade-offs between, attributes were estimated. We recruited patients with MIBC who had either already completed, were undergoing or had yet to commence radical treatment for MIBC (n= 60). Participants indicated a strong preference for treatments that increased their life expectancy (p= <0.001), had a lower risk of long-term complications (p= <0.001) and less changes to their body image (p= <0.001). Changes to sexual wellbeing (p= 0.09) or an increase in acute side effects (p= 0.99) did not influence preferences. Patients were willing to accept treatments with higher risk of long-term complications to improve their life expectancy or body image. When deciding on the type of treatment, increased life expectancy is the most important consideration for people with MIBC. The risk of long-term complications and changes to overall body image as a result of treatment are also important. Our study also highlighted that patients are willing to accept a higher risk of long-term complications to improve other treatment outcomes. Understanding patient preferences is important for shared decision-making, which has an impact on quality of care for people living with MIBC.

Novel intravesical therapies and delivery systems for the management of bladder cancer.

Bladder cancer is a substantial burden for public health worldwide. A risk-adapted treatment strategy is required for non muscle-invasive (NMIBC) and muscle-invasive bladder cancer (MIBC). To date, treatment includes surgery with or without peri-operative local or systemic treatment. The aim of this review was to explore novel intravesical therapies and delivery systems emerging in NMIBC and MIBC. Several novel intravesical therapies and delivery systems for NMIBC and MIBC treatment recently emerged. Hyperthermic intravesical chemotherapy (HIVEC) allows a reasonable cancer control in selected high-risk NMIBC. Novel intravesical drugs such as nadofaragene firadenovec, Oncofid-P-B or Nogapendekin alfa-inbakicept seem to be safe and well tolerated. However, their efficacy in high-risk NMIBC should be further investigated. Hydrogels appear to be safe, well tolerated and potentially efficient in primary chemoablation in selected cases of low-grade intermediate-risk NMIBC tumors. Drug-releasing intravesical systems (drug-RIS) such as TAR-200 are safe and well tolerated, providing high partial and complete response rate in both NMIBC and MIBC patients. The armamentarium for the treatment of bladder cancer patients is expanding, notably with HIVEC, hydrogels, drug-RIS and novel therapies. However, accurate patients' selection is key to prevent disease progression in any bladder-sparing strategy, and radical cystectomy remains the gold-standard to date.

Follow-up strategies after trimodal treatment for muscle-invasive bladder cancer: a systematic review

PurposeOptimal follow-up strategies following trimodal treatment for muscle invasive bladder cancer play a crucial role in detecting and managing relapse and side-effects. This article provides a comprehensive summary of the patterns and risk factors of relapse, functional outcomes, and follow-up protocols.MethodsA systematic literature search on PubMed and review of current guidelines and institutional follow-up protocols after trimodal therapy were conducted.ResultsOut of 200 identified publications, 43 studies (28 retrospective, 15 prospective) were selected, encompassing 7447 patients (study sizes from 24 to 728 patients). Recurrence rates in the urinary bladder varied between 14–52%; 3–16% were muscle-invasive while 11–36% were non-muscle invasive. Nodal recurrence occurred at 13–16% and distant metastases at 15–35%. After 5 and 10 years of follow-up, around 60–85% and 45–75% of patients could preserve their bladder, respectively. Various prognostic risk factors associated with relapse and inferior survival were proposed, including higher disease stage (> c/pT2), presence of extensive/multifocal carcinoma in situ (CIS), hydronephrosis, multifocality, histological subtypes, incomplete transurethral resection of bladder tumor (TURBT) and incomplete response to radio-chemotherapy. The analyzed follow-up guidelines varied slightly in terms of the number, timing, and types of investigations, but overall, the recommendations were similar.ConclusionRandomized prospective studies should focus on evaluating the impact of specific follow-up protocols on oncological and functional outcomes following trimodal treatment for muscle-invasive bladder cancer. It is crucial to evaluate personalized adaption of follow-up protocols based on established risk factors, as there is potential for improved patient outcomes and resource allocation.

Perioperative complications of orthotopic neobladder after radical cystectomy for carcinoma of urinary bladder: A Retrospective Study

Background: The gold standard treatment for muscle-invasive bladder cancer is radical cystectomy (RC) with urinary diversion. Urinary diversion is performed in either as continent or incontinent forms. Orthotopic neobladder has the benefits of continent reservoir with voiding from the urethra. The mortality and morbidity rates ranged from 0 to 9.0% and 30 to 70%, respectively in various reports. For surgical outcome assessment, Clavien-Dindo classification is widely accepted for classification of complications of most of the surgical procedures. This study will be helpful to identify the potential complications and possibly minimize the morbidity and mortality of this surgery in the future. Materials and Methods: Data of 20 consecutively enrolled patients who underwent radical cystectomy and orthotopic neobladder form January 2023 to July 2024 at Urology unit of B.P. Koirala Memorial Cancer Hospital were taken for study from hospital medical records. The various demographic data and perioperative parameters were recorded. The early complications were defined as the complications during the period of hospitalization and up to 30 days of surgery, they were enlisted and then classified according to Clavein-Dindo Classification and the continence was reviewed at 1 month of surgery after catheter removal and after 3 months of surgery. Data was entered in SPSS 27 software and analyzed. Results: Complications were seen in 18 (90%) patients out of which 1 (5%) patients had Grade I complication, 12 (60%) patients had Grade II, 3 (15%) patients had grade IVA and 2(10%) had died. 5 (25%) patients developed high grade(≥ Grade III) complications. Mortality rate was 5%. Conclusion: Radical cystectomy with any forms of diversion is associated with high rate of morbidity and mortality. In order to identify and minimize the complications of this surgery in future, Clavein-Dindo classification is the standardized way of reporting the complications.

Research Progress of Neoadjuvant Chemotherapy in Advanced Bladder Cancer

Systemic treatment, commonly referred to as chemotherapy, is a fundamental approach for treating muscle-invasive bladder cancer (MIBC) and metastatic bladder cancer. Neoadjuvant chemotherapy has recently become a standard treatment for MIBC, significantly reducing tumor recurrence rates and improving patient outcomes. Patients may receive adjuvant chemotherapy involving various drug combinations to improve prognosis following surgery. MIBC patients who are unwilling or unable to undergo radical cystectomy and instead opt for bladder-sparing surgery may benefit from systemic chemotherapy combined with radiotherapy, wherein chemotherapy proves more impactful than radiotherapy. Over the past 30 years, cisplatin-based chemotherapy has been the main approach for treating metastatic bladder cancer. Recent advancements in the molecular understanding of bladder cancer have led to the use of targeted therapies, which have shown promising results. Immunotherapy for MIBC has only recently emerged, with clinical trial results indicating that immunotherapy offers better efficacy and fewer side effects for metastatic bladder cancer. In recent years, basic research on bladder cancer has been burgeoning, and clinical treatment methods have been improving accordingly. This article reviews the development of systemic treatment for bladder cancer.

Image directed redesign of bladder cancer treatment pathways: the BladderPath RCT.

Transurethral resection of bladder tumour has been the mainstay of bladder cancer staging for >60 years. Staging inaccuracies are commonplace, leading to delayed treatment of muscle-invasive bladder cancer. Multiparametric magnetic resonance imaging offers rapid, accurate and non-invasive staging of muscle-invasive bladder cancer, potentially reducing delays to radical treatment. To assess the feasibility and efficacy of the introducing multiparametric magnetic resonance imaging ahead of transurethral resection of bladder tumour in the staging of suspected muscle-invasive bladder cancer. Open-label, multistage randomised controlled study in three parts: feasibility, intermediate and final clinical stages. The COVID pandemic prevented completion of the final stage. Fifteen UK hospitals. Newly diagnosed bladder cancer patients of age≥18 years. Participants were randomised to Pathway 1 or 2 following visual assessment of the suspicion of non-muscle-invasive bladder cancer or muscle-invasive bladder cancer at the time of outpatient cystoscopy, based upon a 5-point Likert scale: Likert 1-2 tumours considered probable non-muscle-invasive bladder cancer; Likert 3-5 possible muscle-invasive bladder cancer. In Pathway 1, all participants underwent transurethral resection of bladder tumour. In Pathway 2, probable non-muscle-invasive bladder cancer participants underwent transurethral resection of bladder tumour, and possible muscle-invasive bladder cancer participants underwent initial multiparametric magnetic resonance imaging. Subsequent therapy was determined by the treating team and could include transurethral resection of bladder tumour. Feasibility stage: proportion with possible muscle-invasive bladder cancer randomised to Pathway 2 which correctly followed the protocol. Intermediate stage: time to correct treatment for muscle-invasive bladder cancer. Between 31 May 2018 and 31 December 2021, of 638 patients approached, 143 participants were randomised; 52.1% were deemed as possible muscle-invasive bladder cancer and 47.9% probable non-muscle-invasive bladder cancer. Feasibility stage: 36/39 [92% (95% confidence interval 79 to 98%)] muscle-invasive bladder cancer participants followed the correct treatment by pathway. Intermediate stage: median time to correct treatment was 98 (95% confidence interval 72 to 125) days for Pathway 1 versus 53 (95% confidence interval 20 to 89) days for Pathway 2 [hazard ratio 2.9 (95% confidence interval 1.0 to 8.1)], p = 0.040. Median time to correct treatment for all participants was 37 days for Pathway 1 and 25 days for Pathway 2 [hazard ratio 1.4 (95% confidence interval 0.9 to 2.0)]. For participants who underwent chemotherapy, radiotherapy or palliation for multiparametric magnetic resonance imaging-diagnosed stage T2 or higher disease, it was impossible to conclusively know whether these were correct treatments due to the absence of histopathologically confirmed muscle invasion, this being confirmed radiologically in these cases. All patients had histological confirmation of their cancers. Due to the COVID-19 pandemic, we were unable to realise the final stage. The multiparametric magnetic resonance imaging-directed pathway led to a substantial 45-day reduction in time to correct treatment for muscle-invasive bladder cancer, without detriment to non-muscle-invasive bladder cancer participants. Consideration should be given to the incorporation of multiparametric magnetic resonance imaging ahead of transurethral resection of bladder tumour into the standard pathway for all patients with suspected muscle-invasive bladder cancer. The improved decision-making accelerated time to treatment, even though many patients subsequently needed transurethral resection of bladder tumour. A proportion of patients can avoid transurethral resection of bladder tumour completely, reducing costs and morbidity, given the much lower cost of magnetic resonance imaging and biopsy compared to transurethral resection of bladder tumour. Further work to cross-correlate with the recently developed Vesical Imaging-Reporting and Data System will improve accuracy and aid dissemination. Longer follow-up to examine the effect of the pathway on outcomes is also required. Incorporation of liquid deoxyribonucleic acid-based biomarkers may further improve the quality of decision-making and should also be investigated further. This study is registered as ISRCTN 35296862. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135775) and is published in full in Health Technology Assessment; Vol. 28, No. 42. See the NIHR Funding and Awards website for further award information.

Long-Term Results of Bladder Preservation With Twice-Daily Radiation Plus 5-Fluorouracil/Cisplatin or Daily Radiation Plus Gemcitabine for Muscle-Invasive Bladder Cancer—Updated Report of NRG/RTOG 0712: A Randomized Phase 2 Trial

Purpose5-FU/cisplatin and twice-daily radiation (FCT) or gemcitabine and once daily radiation (GD) are effective chemoradiation (CRT) regimens for bladder sparing treatment of muscle-invasive bladder cancer (MIBC). This trial evaluated these regimens and demonstrated efficacy with either regimen at 3 years. With further follow-up, longer term results are reported here. Methods and MaterialsPatients with cT2-4a MIBC were randomized to FCT or GD. Patients had a transurethral resection and induction CRT to 40 Gy. Patients with a complete response (CR) received consolidation CRT to 64 Gy. Others had cystectomy. Adjuvant gemcitabine/cisplatin chemotherapy was administered. The primary endpoint was freedom from distant metastasis (FDM). This updated analysis reports 7-year data. Toxicity and efficacy endpoints, including bladder intact distant metastasis free survival (BI-DMFS) were also assessed. ResultsFrom 12/2008 to 4/2014, 70 patients were enrolled; 66 eligible for analysis, 33 per arm. Median follow-up was 9.1 years for eligible living patients. At 7 years, FDM was 65% and 73% for FCT and GD, respectively. BI-DMFS was 58% (95% CI: 41 – 76) and 68% (95% CI: 51-84), respectively. The post-hoc hazard ratio of 0.75 (95% CI: 0.37-1.55) showed no difference between treatments (p=0.44). Overall survival at 7 years was 48% and 59%. There were 4 and 5 cystectomies performed for FCT and GD, respectively. In the FCT arm, there were 5 (16%), 1 (3%) and 0 grade 3, 4 and 5 late toxicities reported. In the GD arm, there were 7 (23%), 0 and 0. ConclusionsBoth regimens maintained high FDM rates at 7 years. Cystectomy rates were low and overall survival rates high on both arms. Late toxicity rates were low. Either gemcitabine and daily radiation or a cisplatin-based regimen are effective bladder sparing therapies.

Efficacy and safety of radical cystectomy with ileal conduit for muscle-invasive bladder cancer in the elderly: a multicenter retrospective study.

Radical cystectomy with ileal conduit is the current mainstay of treatment for muscle-invasive bladder cancer and is also a high-risk procedure. Existing studies have limited targeted assessment of the efficacy and safety of this procedure, and the patient population appropriate for this procedure is still poorly defined. We sought to longitudinally analyze differences in the efficacy and safety of radical cystectomy with ileal conduit by age subgroups to assess whether the age factor should be used as an exclusion criterion when selecting this procedure. We retrospectively examined the clinicopathological data of patients with MIBC treated with RC with IC at the Cancer Hospital of Harbin Medical University between February 2014 and October 2023. Additionally, we utilized clinical and pathological data from the SEER database (2000-2020) for external validation of our findings. Patients were categorized into elderly (≥70 years at diagnosis) and non-elderly (<70 years) groups. Statistical analyses included t-tests, non-parametric tests for continuous data, chi-square tests for categorical data, and Kaplan-Meier survival analysis. In this study, 152 patients were included: 119 were categorized as non-elderly and 33 as elderly. For external validation, data from 416 patients in the SEER database were analyzed, with 172 classified as non-elderly and 244 as elderly. The results indicated that elderly patients were more likely to require ICU transfer postoperatively but exhibited a lower incidence of stoma inflammation. Additionally, both the data from our center and the external validation from the SEER database showed a concordance in cancer-specific survival (CSS) between the elderly and non-elderly groups. The efficacy of RC with IC was comparable in both elderly and non-elderly patients. For longitudinal age subgroups, RC with IC for both elderly and non-elderly MIBC had good efficacy and safety, and good quality of life after surgery. Although there are surgical and perioperative risks in elderly patients, there is no significant difference compared with non-elderly patients. In elderly patients requiring RC for bladder cancer, IC should remain the preferred mode of urinary diversion, and old age should not be used as an absolute exclusion criterion for IC.

Utilization of neoadjuvant chemotherapy for muscle-invasive bladder cancer in elderly patients: a retrospective cohort study.

Neoadjuvant chemotherapy (NAC) improves overall survival in muscle-invasive bladder cancer (MIBC). Older patients often do not receive NAC due to its potential toxicities. We examined treatment patterns of elderly MIBC patients as well as impact of NAC on survival in this population. The National Cancer Database was queried from 2006 to 2019 for stage T2-T4a MIBC patients ≥ 80years old. Treatment exposures (extirpative surgery; chemotherapy; radiation) were ascertained. Kaplan-Meier survival curves were generated based on treatment modalities (no treatment; radiation only; chemotherapy only; chemoradiation; surgery only; NAC with surgery). Multivariable Cox proportional hazards regression assessed associations with overall survival (OS). The cohort included 16,391 patients (mean age 86years); 51% received treatment. MIBC treatment was less common with advancing age; patients receiving NAC then surgery were younger and had lower comorbidity scores. From 2006 to 2019, more patients received chemoradiation, while rates of NAC rose modestly. Median OS for the NAC with surgery group was 48months versus 9months for the no treatment group. Log-rank tests showed significantly improved survival in the NAC with surgery group compared to the surgery only group, while Cox proportional hazards regression analysis showed highest survival benefit in the NAC with surgery group. Only half of elderly MIBC patients received treatment, with fewer undergoing curative intent. NAC with surgery was associated with the greatest survival benefit. While our findings should be taken in the context of potential selection bias and patient preferences, they support NAC as part of shared-decision making regardless of age.

Abstract IA006: Towards ctDNA-guided treatment of muscle-invasive bladder cancer

Abstract Cancer cells release cell-free DNA with tumor-specific molecular alterations into circulation, known as circulating tumor DNA (ctDNA). Numerous studies have underscored the biomarker potential of ctDNA in detecting minimal residual disease across various cancer types, including bladder cancer. The rapid clearance of ctDNA from circulation, typically under two hours, makes it an ideal candidate for real-time monitoring of tumor burden following surgical interventions and throughout oncological treatments. For ctDNA measurements to be effectively incorporated into clinical decision-making, it is crucial to conduct ctDNA-guided intervention trials that demonstrate tangible clinical benefits. Current trials focusing on muscle-invasive bladder cancer (MIBC) are supported by recent exploratory sub-analyses of completed clinical trials, which have shown that ctDNA can effectively guide treatment decisions in this context. Beyond guiding adjuvant treatments, ctDNA holds potential for directing bladder preservation strategies, potentially in combination with urinary tumor-derived DNA (utDNA) measurements. The need for treatment de-escalation, such as in neoadjuvant chemotherapy (NAC), is underscored by the observation that a significant proportion of patients undergo treatments that result in considerable adverse effects without achieving pathologic response. Traditional decision-making in cancer treatment, largely reliant on imaging-based criteria like the Response Evaluation Criteria in Solid Tumors (RECIST), often does not adequately reflect the ultimate clinical endpoint of overall survival. A ctDNA-based measure that considers ctDNA dynamics during treatment could serve as a superior tool or complement to current strategies. In conclusion, ctDNA has demonstrated significant promise as a biomarker in both retrospective and prospective studies for risk assessment in MIBC. The clinical value of ctDNA-guided treatment will soon be determined by ongoing clinical trials (TOMBOLA, IMvigor011, MODERN). In my presentation I will address the potential clinical impact of ctDNA analyses, the technological aspects involved, how urine analyses may supplement these findings, and future directions in the field. Citation Format: Lars Dyrskjøt. Towards ctDNA-guided treatment of muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA006.

Abstract B020: Development of novel Src-targeting strategies to block bladder cancer invasive progression

Abstract Background: Treatment of muscle-invasive bladder cancer remains challenging and, BCG, one of the few treatments that prevents progression of high-risk non-muscle invasive tumors to invasive metastatic disease, is difficult to obtain. Thus, development of new treatment approaches to block progression to muscle invasive disease is essential. We find that TRIM29 (tripartite motif containing 29, also known as ATDC), drives bladder cancer invasive progression through modulation of focal adhesions containing FAK and c-Src (Src). Despite this, literature has reported conflicting effects of Src knockdown and Src kinase inhibition on migration, perhaps due to separable pro- and anti-invasive functions of Src in bladder cancer. Hypothesis: Src drives bladder cancer invasive progression specifically through its tyrosine kinase activity within focal adhesions. Methods: We used 2D live cell migration assays and 3D spheroid invasion assays to test dasatinib, highly specific, novel conformation inhibitors of Src, a novel Src PROTAC, and siRNA against Src on bladder cancer migration and invasion. Results: Dasatinib and our novel conformation-specific inhibitors inhibited Src kinase activity and both siRNA and the novel PROTAC reduced total Src expression in vitro. Neither dasatinib, conformation inhibitors, siRNA, nor the PROTAC impacted bladder cancer cell viability in UM-UC5, UM-UC9 or UM-UC14 cell lines. Interestingly, we found that inhibiting Src’s kinase activity with either dasatinib or conformation-specific inhibitors abrogated bladder cancer migration. Conclusion: These results point to the selective importance of Src in regulating bladder cancer migration and invasion. They also suggest that novel Src targeting agents have potential clinical utility in the prevention of bladder cancer invasive progression. Citation Format: Nicole A. Jerome, Yin Wang, Marian L. Henderson, Luke Broses, Kathleen C. Day, Mark L. Day, Matthew B. Soellner, Phillip L. Palmbos. Development of novel Src-targeting strategies to block bladder cancer invasive progression [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B020.

Robot-Assistant Radical Cystectomy as a Modern Method of Personalized Treatment for Patients with Muscle-Invasive Bladder Cancer

Introduction. Radical cystectomy (RC) is the “gold standard” treatment for muscle-invasive bladder cancer (MIBC). Robot-assisted RC (RARC) can act as a safe and effective method of treating MIBC.The aim of the study was to analyze our own experience with the use of RARC with intraoperative indocyanine green fluorescence (ICG) and postoperative determination of tumor macrophage levels in the treatment of patients with MIBC.Materials and methods. A study was conducted at the Clinic of the Bashkir State Medical University with the participation of 202 patients aſter RARC. 30 patients underwent intraoperative ICG fluorescence testing. The levels of tumor macrophages in the removed macropreparations were determined in all patients. In the postoperative period, a survival analysis was performed.Results. The sensitivity of the ICG fluorescence method was 94.4 %, and the specificity was 83.3 %. High levels of expression of macrophage markers CD68 and CD163 significantly predominate in the group with the cN+ stage (according to the clinical TNM classification, there are signs of damage) (p = 0.027 and p = 0.018, respectively). ICG fluorescence of regional lymph nodes (100 %) was observed in all patients with high CD68 and CD163 levels. A significant decrease in survival was recorded in patients with high pathomorphological stage T (pT according to the TNM classification) (r = 0.952, p &lt; 0.05) and statistically significant survival rates were obtained for pT1–pT4 groups (p &lt; 0.05 for overall, cancer-specific and recurrence-free survival (OS, CSS, RFS, respectively)).Discussion. More and more studies are appearing in the world literature proving the effectiveness of RARC in the treatment of patients with MIBC. Compared with open and laparoscopic techniques, better surgical and comparable oncological results are demonstrated.Conclusion. The results of the analysis of the RARC’s own experience indicate the effectiveness of this method of treating MIBC. The use of ICG fluorescence and verification of tumor macrophages makesit possible to provide personalized care to oncourological patients.

Advances in Urinary Diversion: From Cutaneous Ureterostomy to Orthotopic Neobladder Reconstruction-A Comprehensive Review.

Bladder cancer ranks as the 10th most prevalent cancer globally with an increasing incidence. Radical cystectomy combined with urinary diversion represents the standard treatment for muscle-invasive bladder cancer, offering a range of techniques tailored to patient factors. Overall, urinary diversions are divided into non-continent and continent. Among the first category, cutaneous ureterostomy and ileal conduit represent the most common procedures while in the second category, it could be possible to describe another subclassification which includes ureterosigmoidostomy, continent diversions requiring catheterization and orthotopic voiding pouches and neobladders. In this comprehensive review, urinary diversions are described in their technical aspects, providing a summary of almost all alternatives to urinary diversion post-radical cystectomy.

Abstract LB256: New mechanistic insights into cisplatin resistance in muscle-invasive bladder cancer

Abstract The standard of care for eligible patients with muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy. However, platinum-based treatments leave up to 70% of MIBC patients with residual disease, and the 5-year survival rate for these individuals is under 30%. Understanding cisplatin resistance mechanisms will improve MIBC treatment by developing more effective therapeutics and precision medicine strategies. We previously identified NPEPPS, an M1 aminopeptidase, as a novel and potentially targetable mediator of platinum drug response. Recently, we have established that NPEPPS controls platinum drug import through its interactions with volume regulated anion channels (VRACs), which have been shown to import cisplatin to cells directly. We have shown that NPEPPS interacts with key VRAC subunit SWELL1 at the cell membrane and that intact SWELL1 is required for NPEPPS-mediated platinum resistance. We further discovered that NPEPPS cannot bind SWELL1 when its enzymatic aminopeptidase function is disrupted genetically or pharmacologically. In vivo studies showed that catalytic-dead NPEPPS-mutant MIBC xenografts were sensitive to cisplatin treatment compared to NPEPPS-wildtype xenografts. Patient cohort data analysis supported the model that the expression of NPEPPS and its relative expression with VRAC proteins are associated with overall survival in treatment-resistant MIBC patients. These findings shed light on how bladder cancer cells resist chemotherapy by disrupting the transport of drugs into cells and suggest new ways to target NPEPPS to enhance the effectiveness of platinum-based therapeutics in treating bladder cancer. Citation Format: Lily Elizabeth R. Feldman, Saswat Mohapatra, Robert Jones, Charlene Tilton, Tahlita Zuiverloon, James Costello, Dan Theodorescu. New mechanistic insights into cisplatin resistance in muscle-invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB256.

MIR145 Core Promoter Methylation in Pretreatment Cell-Free DNA: A Liquid Biopsy Tool for Muscle-Invasive Bladder Cancer Treatment Outcome.

The lack of personalized management of bladder cancer (BlCa) results in patients' lifelong post-treatment monitoring with invasive interventions, underlying the urgent need for tailored and minimally invasive health care services. On the basis of our previous findings on miR-143/145 cluster methylation in bladder tumors, we evaluated its clinical significance in pretreatment cell-free DNA (cfDNA) of patients with BlCa. Methylation analysis was performed in our screening cohort (120 patients with BlCa; 20 age-matched healthy donors) by bisulfite-based pyrosequencing. Tumor recurrence/progression for patients with non-muscle-invasive bladder cancer, and progression and mortality for patients with muscle-invasive bladder cancer (MIBC) were used as clinical end point events in survival analysis. Bootstrap analysis was applied for internal validation of Cox regression models and decision curve analysis for assessment of clinical benefit on disease prognosis. Decreased methylation of MIR145 core promoter in pretreatment cfDNA was associated with short-term disease progression (multivariate Cox: hazard ratio [HR], 2.027 [95% CI, 1.157 to 3.551]; P = .010) and poor overall survival (multivariate Cox: HR, 2.098 [95% CI, 1.154 to 3.817]; P = .009) of patients with MIBC after radical cystectomy (RC). Multivariate models incorporating MIR145 promoter methylation in cfDNA with tumor stage clearly ameliorated patients' risk stratification, highlighting superior clinical benefit in MIBC prognostication. Reduced pretreatment cfDNA methylation of MIR145 core promoter was markedly correlated with increased risk for short-term progression and worse survival of patients with MIBC after RC and adjuvant therapy, supporting modern personalized and minimally invasive prognosis. Methylation profiling of MIR145 core promoter in pretreatment cfDNA could serve as a minimally invasive and independent predictor of MIBC treatment outcome and emerge as a promising marker for blood-based test in BlCa.

Ileoneocystoplasty After Radical Cystectomy – Modification of the Method and Immediate Results

The objective: is to evaluate the effectiveness of the treatment of muscle-invasive bladder cancer (MIBC) by creating an artificial reservoir for the derivation of urine from segments of the small intestine of patients and to study urination and other functions of the urinary system in the postoperative period. Material and methods. During 2019-2020, the SI «Academician O.F. Vozianov Institute of Urology National Academy of Sciences of Ukraine» conducted examinations and treatments on nine patients diagnosed with MIBC at clinical stages T2aN0M0–T3bN0M0. All patients underwent laparoscopic cystectomy and lymphadenectomy, while a third of them underwent open bladder resection at other medical facilities. Among these, three patients received intracorporeal ileoneocystoplasty, whereas in six patients, the procedure involved a change in access from a median laparotomy. The implemented method of orthotopic ileoneocystoplasty during radical cystectomy involves creating an orthotopic artificial bladder from a previously resected segment of the ileum and anastomosing it with the proximal part of the urethra and the distal segments of the ureters. Notably, this method introduces several innovations: firstly, it allows for instrumental intestinal suturing in cases of endoscopic variants of radical cystoprostatectomy, and reduces the necessary length of the ileo-intestinal fragment to 50 cm. Secondly, it involves complete detubularization of the intestine fragment, asymmetrically during its middle 5 cm to form a cervical flap, and symmetrically along the contramesenteric edge for the remaining length. Thirdly, the medial edges of the right and left intestinal segments are initially fixed to the upper edge of the middle segment. Fourthly, after creating the eye of the neck of the future reservoir, the upper and middle thirds of the lateral edge of the right and left intestinal segments are fastened together. Fifthly, the original neck of the intestinal bladder is formed by performing vertical incisions of the pre-created eye of the neck of the reservoir at 12 and 6 o’clock to expand its diameter to 1.0–1.5 cm, followed by eversion and tubularization of the formed semicircles on the urethral catheters using 3–5 nodal sutures and a neck duplication maneuver with two nodal, superimposed parallel to the axis of the neck, sero-muscular sutures with a step between injection and needle puncture of 0.3–0.5 cm. Sixth, after forming the vesico-urethral anastomosis, the free edge of the cervical flap and the lower thirds of the lateral edge of the right and left intestinal segments are sutured, the adoral nd aboral intestinal openings are sealed, a cystostomy drainage is installed through the latter, and a reversible peritonization maneuver is performed. Results. According to the type of intervention, patients were divided into 2 groups: 1 group of open ileoneocystoplasty – 6 patients, 2 group of intracorporeal ileoneocystoplasty – 3 patients. According to the results of the operation, the average volume of the artificial reservoir immediately after the operation was: in group 1 – 180 ml ± 23 ml, in group 2 160 ml ± 50 ml. After 6 months, this volume increased and was 420 ± 68 ml in group 1, 380 ± 50 ml in group 2, which allowed patients to urinate 6-8 times a day and 2-3 times a night in some cases. The postoperative bed-day in group 2 was shorter on average by 7 days (7.2 ± 1.5 vs. 14.2 ± 4.2). In this study, there were no registered cases of leakage of the vesico-urethral anastomosis or its stenosis. Conclusions. Application of the proposed method of orthotopic ilioneocystoplasty during radical cystectomy will allow: – to reduce the total time of the operation in connection with the use of modern methods of intestinal suture provided for in its framework; – to compensate for the possible tension of the vesico-urethral anastomosis, which will lead to a decrease in the frequency and intensity of such postoperative complications and negative consequences as: leakage of the vesico-urethral anastomosis or its stenosis, as well as urinary incontinence at night; – thanks to the original maneuver of forming the neck of the ileal reservoir, reduce the hypermobility of the reconstructed bladder-urethral segment; – reduce the likelihood of metabolic disorders in the postoperative period due to the reduction of the length of the ileal segment removed from the patient; – to unify the technology of orthotopic ilioneocystoplasty within the framework of various approaches to performing radical cystectomy, among them: traditional «open», laparoscopic or robot-assisted.

Disitamab Vedotin Alone or in Combination With Immune Checkpoint Inhibitors in Bladder-Sparing Treatment of Muscle-Invasive Bladder Cancer: A Real-World Study

PurposeTo evaluate the efficacy and safety of a novel humanized anti-HER2 antibody, RC48-ADC (Disitamab vedotin, DV), the combination of RC48-ADC with PD-1 inhibitors was used to treat muscle-invasive bladder cancer (MIBC). This combination therapy has potential applications in both bladder preservation and neoadjuvant therapy for MIBC. MethodsPatients with MIBC underwent transurethral resection of bladder tumors followed by RC48-ADC alone or in combination with PD-1 inhibitors. Radiological and endoscopic evaluations were conducted 3 months later. The primary endpoint was objective response rate (ORR), with secondary endpoints including complete response rate (CR), partial response rate (PR), and bladder preservation rate. Treatment safety was assessed according to RECIST v1.1 criteria. ResultsEleven patients were enrolled, with a median follow-up of 19.0 months. Nine patients achieved objective response, including 6 CR and 3 PR cases. The pathological ORR was 81.8%. Eight patients continued combined treatment after 3 months, maintaining a 72.7% bladder preservation rate at 16 months. One elderly patient progressed from ypT2N0M0 to ypT3N0M0 and underwent radical cystectomy but had no recurrence or metastasis 12 months postoperation. All patients reported varying degrees of treatment-related adverse reactions, which were largely manageable. ConclusionThe combination of RC48-ADC and PD-1 inhibitors proves to be a viable and safe option for bladder-sparing therapy, particularly for T2-stage MIBC patients who are ineligible for surgery and chemotherapy. This approach offers a promising new direction for bladder preservation or neoadjuvant therapy in MIBC patients.

Successful pre-surgical treatment with carboplatin and gemcitabine chemotherapy for a patient with muscle-invasive bladder cancer and severe renal dysfunction.

Radical cystectomy is the standard treatment for muscle-invasive bladder cancer, and pre-surgical treatment can improve survival. Carboplatin and gemcitabine chemotherapy is considered an effective, safe treatment for patients ineligible for cisplatin-based chemotherapy owing to reduced renal function. However, there is limited evidence on pre-surgical treatment with carboplatin and gemcitabine chemotherapy with glomerular filtration rates < 30mL/min. We discuss the treatment of a patient who did not undergo surgery owing to bladder tumor size of 12cm (cT3bN0M1a) and severe renal dysfunction (serum creatinine: 2.57mg/dL, estimated glomerular filtration rate: 20.2mL/min/1.73 m2). After the patient received two courses of carboplatin and gemcitabine chemotherapy, the bladder tumor size had reduced by 60%. No nausea or renal dysfunction was observed; febrile neutropenia improved with antibiotic therapy and granulocyte colony-stimulating factor. Then, he could undergo robot-assisted radical cystectomy after the pre-surgical chemotherapy treatment. Pre-surgical treatment with carboplatin and gemcitabine chemotherapy is a viable treatment option for patients with muscle-invasive bladder cancer and severe renal dysfunction.