Bladder Cancer Recurrence Research Articles

The Role of Fluorescence In Situ Hybridization in the Surveillance of Non-Muscle Invasive Bladder Cancer: An Updated Systematic Review and Meta-Analysis.

Background: Fluorescence in situ hybridization (FISH) has become a popular biomarker for subsequent monitoring the recurrence of non-muscle invasive bladder cancer (NMIBC), several studies have investigated the ability of FISH to detect recurrence in the surveillance of NMIBC. However, the results were inconsistent. Methods: We conducted a systematic literature search extensively on authenticated databases including PubMed/Medline, Embase, Web of Science, Ovid, and Cochrane Library. Meta-analysis was performed to find out the sensitivity and specificity of FISH in predicting recurrence of NMIBC. Results: 15 studies were ultimately included in this meta-analysis, a total of 2941 FISH evaluations from 2385 NMIBC patients were available. The pooled sensitivity of FISH was 68% (95% CI: 0.58–0.76), and the pooled specificity was 64% (95% CI: 0.53–0.74). Subgroup analyses were performed in 7 studies without Bacillus Calmette–Guerin (BCG) treatment, the pooled sensitivity was 82% (95% CI: 0.68–0.90), and the pooled specificity was 63% (95% CI: 0.37–0.82). And in 9 studies using “UroVysion standard” to define positive FISH results showed a pooled sensitivity of 60% (95% CI: 0.50–0.70) and specificity of 70% (95% CI: 0.61–0.78). Conclusions: The findings of this study indicate that FISH has a satisfactory sensitivity (68%) and specificity (64%) and could be a potential biomarker in the surveillance of NMIBC. Moreover, BCG treatment and different FISH methods may have an impact on the sensitivity and specificity, these factors should be taken into account when making clinical strategy.

488 TULA for Bladder Tumours in a University Teaching Hospital: Outcomes Over a 2-Year Period

Abstract Aim TULA (Transurethral laser ablation) of bladder tumours is a relatively non-invasive procedure that is carried out on a day-case basis under local anaesthesia, providing an attractive option for treating recurrent non-muscle invasive bladder cancer (NMIBC). However, data describing efficacy rates are limited. Method We carried out a retrospective audit of all TULA procedures carried out for bladder lesions between January 2018 and December 2019. Patients were identified using clinical coding and data collected using electronic case note data. Analysis was performed using Microsoft Excel. Results 48 patients were identified, 75% were male and the average age was 77. Performance status (PS) was formally documented in 6 patients, with a median of 2.5. A total of 77 TULA procedures were identified. 7 patients had TULA as primary treatment, all but one of these patients had significant co-morbidities. Biopsies were taken in 83% of procedures. Recurrence rate at 3 months was 29% (n=14). 18% (n=8) of patients went on to have repeat TULA and the remainder went on to have TURBT or biopsy and cystodiathermy. Of those patients with recurrence, 18% had disease progression. 1 patient required catheterisation and irrigation overnight, all other patients were discharged the same day. No patients required re-admission. Conclusions TULA is a safe, well tolerated procedure to treat low-grade, recurrent bladder tumours. It can also be used as a palliative procedure for high-grade lesions in patients with multiple co-morbidities. Future work includes collection of objective data on tolerance in the form of VAS pain scoring.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis from Urothelial Origin: a Case Report and Literature Review.

Urothelial carcinomas (UC) are the fourth most common tumours. Approximately, 50% of patients with invasive bladder cancer relapse after radical cistectomy (RC). In this report, we present the case of peritoneal carcinomatosis from bladder UC treated with cytoreductive surgery plus the administration of hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). A 34-year-old woman diagnosed with high-grade bladder cancer with peritoneal recurrence in 2017. She underwent cytoreductive surgery followed by HIPEC with mitomycin C. Histopathological results showed metastases from UC in the left ovary and right diaphragmatic peritoneum. In 2021, the patient underwent surgery after treatment with atezolizumab for abdominal wall recurrence. Today, the patient is alive and free of tumor recurrence 12months after the last surgery. Despite advances in surgical technique and patient selection, the risk of relapse remains high among patients with muscle-invasive bladder cancer. We face the case of a young female patient with local, peritoneal, and lymphatic recurrence of bladder cancer after RC who had a partial response to chemotherapy. The possibility of CRS + HIPEC is offered by the surgical oncology unit, referent in the management of peritoneal carcinomatosis. Surgery is capable of resecting residual tumor in patients with a partial response or who have been erroneously underdiagnosed. CRS + HIPEC might be a valid option to be considered in well-selected patients and to be performed in reference units. There is a need for more collaborative clinical trials and prospective studies addressing the role of surgery in patients with metastatic bladder cancer.

Integrated Urinalysis Devices Based on Interface-Engineered Field-Effect Transistor Biosensors Incorporated With Electronic Circuits.

Urinalysis is attractive in non-invasive early diagnosis of bladder cancer compared with clinical gold standard cystoscopy. However, the trace bladder tumor biomarkers in urine and the particularly complex urine environment pose significant challenges for urinalysis. Here, a clinically adoptable urinalysis device that integrates molecular-specificity indium gallium zinc oxide field-effect transistor (IGZO FET) biosensor arrays, a device control panel, and an internet terminal for directly analyzing five bladder-tumor-associated proteins in clinical urine samples, is reported for bladder cancer diagnosis and classification. The IGZO FET biosensors with engineered sensing interfaces provide high sensitivity and selectivity for identification of trace proteins in the complex urine environment. Integrating with a machine-learning algorithm, this device can identify bladder cancer with an accuracy of 95.0% in a cohort of 197 patients and 75 non-bladdercancer individuals, distinguishing cancer stages with an overall accuracy of 90.0% and assessing bladder cancer recurrence after surgical treatment. The non-invasive urinalysis device defines a robust technology for remote healthcare and personalized medicine.

Non-muscle invasive bladder cancer biomarkers beyond morphology

Non-muscle invasive bladder cancer (NMIBC) still represents a challenge in decision-making and clinical management since prognostic and predictive biomarkers of response to treatment are still under investigation. In addition to the risk factors defined by EORTC guidelines, histological features have also been considered key variables able to impact on recurrence and progression in bladder cancer. Conversely, the role of genomic rearrangements or expression of specific proteins at tissue level need further assessment in NMIBC. As with muscle-invasive cancer, NMIBC is a heterogeneous disease, characterized by genomic instability, varying rates of mutation and a wide range of protein tissue expression. In this Review, we summarized the recent evidence on prognostic and predictive tissue biomarkers in NMIBC, beyond morphological parameters, outlining how they could affect tumor biology and consequently its behavior during clinical care. Our aim was to facilitate clinical evaluation of promising biomarkers that may be employed to better stratify patients. We described the most common molecular events and immunohistochemical protein expressions linked to recurrence and progression. Moreover, we discussed the link between available treatments and molecular drivers that could be predictive of clinical response. In conclusion, we foster further investigations with particular focus on immunohistochemical evaluation of tissue biomarkers, a promising and cost-effective tool for daily practice.

High‐grade bladder cancer cells secrete extracellular vesicles containing miRNA‐146a‐5p and promotes angiogenesis

AbstractRecurrence is one of the major issues in bladder cancer (BCa). Novel technologies, such as the detection of microRNAs carried by extracellular vesicles (EVs) in urine, have been proposed as biomarkers for detecting recurrence in BCa. Although the usefulness of microRNAs in body fluids from cancer patients has been reported, it is also known that they play essential roles in cancer progression. We previously proposed miR‐146a‐5p as a prognostic marker in BCa, since its urinary expression was associated with grade and tumour depth. However, the specific mechanisms of miR‐146a‐5p remain unclear. Here, we show the proangiogenic effects of miR‐146a‐5p secreted by high‐grade BCa cells. The urinary miR‐146a‐5p level was higher in patients with high‐grade BCa than in those with low‐grade BCa. Similarly, tumours generated by miR‐146a‐overexpressing BCa cells in mice grew rapidly with high levels of angiogenesis. BCa‐derived EV treatment promoted the proliferation of endothelial cells via the inhibition of the demethylase TET2 and the subsequent increase in its downstream target c‐Myc. These findings demonstrate that secreted miR‐146a‐5p contributes to cancer progression by promoting angiogenesis. Therefore, miRNAs in EVs may become not only a diagnostic tool but also a target molecule for therapy.

The Role of Bladder Epicheck Test In Follow-Up of Patients with Non-Muscle Invasive Bladder Cancer.

EpiCheck is a new urinary test that analyses DNA methylation biomarkers in order to identify high-risk urothelial cancer MATERIALS AND METHODS: A prospective single centre study was performed. We analysed Epicheck results in a population of 231 patients in follow-up for non-muscle invasive bladder cancer. The primary endpoint was to evaluate sensitivity and specificity of Epicheck in detecting any type of bladder cancer recurrence. The secondary endpoint was to evaluate specificity and sensitivity of Epicheck in patients with high-risk recurrence and in patients recently treated with endovesical therapy (< 3 months). Negative predictive value (NPV) for cytology was 83 % while for bladder Epicheck it was 89 %, while positive predictive value (PPV) was 67 % and 73 % for cytology and Epicheck respectively. Considering only high grade non muscle invasive bladder cancer the sensitivity of Epicheck was 91 % and for cytology was 81 %, specificity was 85 % and 83 % and negative predictive value of Epicheck outreached 96 % compared to 92 % of cytology. Among patients with an ongoing or recent endovesical treatment it appears that sensitivity of Epicheck was 88% % compared to 73 % of cytology, specificity was 97 % and 85 % and NPV was 92 % compared to 82 % for cytology. The EpiCheck (test showed very high diagnostic values, higher than the currently, gold standard. The test might clinically improve the BCa management in terms of, reduced number of inconclusive/suspicious reports of cytology and endoscopy, reduced number of further examinations, reduced associated patient and economic.

Bacteria-inspired transformable nanoparticle targets and covers residual tumor against bladder cancer recurrence

The regrowth of residual tumor left by incomplete surgery leads to bladder cancer recurrence. Postoperative intravesical instillation in clinic shows unsatisfactory recurrence inhibition owing to rapid drug emptying and non-specific distribution. Here, inspired by intrinsic bacterial adhesion towards exposed wounds through fibronectin binding peptide, we develop a bacteria-inspired peptide-based nanoparticle that targets exposed fibronectin on the surgical bed with residual tumor. Upon binding, the nanoparticle simultaneously transforms into fibrous coating as drug depots for long-term release of encapsulated doxorubicin. The transformable nanoparticle retains 8.5-fold higher doxorubicin concentration than free one in bladders of live mice 3 days post-instillation. Reasonably, this formulation obviously suppresses tumor regrowth in an incomplete tumor resection model. Compared to the clinical doxorubicin treatment, it reduces the recurrence rate from 71% to 29% in a murine orthotopic bladder cancer model. This bacteria-inspired biomaterial provides a promising intravesical treatment but also opportunities for clinical management on cancer recurrence.

The prognostic value of urinary cytology after trimodal therapy (TMT) for muscle-invasive bladder cancer.

Urine cytology and cystoscopy are routinely employed during follow-up of patients after trimodal therapy (TMT) for muscle-invasive bladder cancer (MIBC). The significance of positive or equivocal cytology without visible disease recurrence on cystoscopy during follow-up is unknown, and studies informing outcomes in this scenario are lacking. This study aims to investigate the temporal trends of positive/equivocal cytology in the absence of visible disease recurrence and the association with bladder cancer recurrence and survival outcomes. One hundred and twenty-nine patients with available post-TMT cytology data and negative cystoscopy from a single academic institution between 2002 and 2017 with a median follow-up of 3.4 (range 0.1-14.2) years were analyzed. Cytology results, first post-TMT cytology positive/equivocal (CP) and negative (CN), were evaluated for association with disease recurrence and survival. Kaplan. Meier and competing risks methods were used to assess time-to-negative cytology in CP patients with ≥2 interval post-TMT cytology results (n = 33), time-to-recurrence, and disease-specific mortality (DSM) stratified by first post-TMT cytology result. At first follow-up (6-8 weeks post-TMT completion), CP was observed in 41 (32%) and CN in 88 (68%) of patients. With further follow-up of CP patients with ≥2 interval post-TMT cytology results, the probability of developing negative cytology was 57% (95% CI 42, 77) at 6 months post-TMT, and the median time-to-negative cytology was 3.2 months (95% CI 2.99, 5.80). The median time-to-recurrence was reduced in CP patients compared to CN (24.3 vs. 78.1 months, p = 0.1), corresponding with an apparent increase in the cumulative incidence of recurrence rate at 3 years in the CP vs. CN group (62% vs. 42%, p = 0.1). No significant difference was observed in the 3-year DSM rates. On univariable analysis, the hazards of recurrence and DSM for patients with CP were 1.5 (95% CI 0.9, 2.5, p = 0.1) and 2.1 (95% CI 0.9, 4.7, p = 0.07) respectively. This is the first study to investigate the significance of a positive/equivocal cytology without visible disease following TMT for MIBC. Positive cytology is common and does not preclude subsequent negative cytology supporting a watchful waiting approach rather than proceeding immediately to biopsy. However, cytology that remains positive at subsequent follow-up may be associated with adverse recurrence and survival outcomes.

Advances in Diagnosis and Therapy for Bladder Cancer.

Simple SummaryThe clinical management of bladder cancer has been developing in the past decade, including diagnostic tools and treatment options. Both monotherapy and combination therapy have been undoubtedly upgraded. Multiple diagnostic techniques and therapeutic strategies have been developed to meet the urgent clinical needs, resulting in the emergence of various explorations for cancer diagnosis and therapy. In this review, we mainly focus on the advances in the diagnosis and treatment of bladder cancer.Bladder cancer (BCa) is one of the most common and expensive urinary system malignancies for its high recurrence and progression rate. In recent years, immense amounts of studies have been carried out to bring a more comprehensive cognition and numerous promising clinic approaches for BCa therapy. The development of innovative enhanced cystoscopy techniques (optical techniques, imaging systems) and tumor biomarkers-based non-invasive urine screening (DNA methylation-based urine test) would dramatically improve the accuracy of tumor detection, reducing the risk of recurrence and progression of BCa. Moreover, intravesical instillation and systemic therapeutic strategies (cocktail therapy, immunotherapy, vaccine therapy, targeted therapy) also provide plentiful measures to break the predicament of BCa. Several exploratory clinical studies, including novel surgical approaches, pharmaceutical compositions, and bladder preservation techniques, emerged continually, which are supposed to be promising candidates for BCa clinical treatment. Here, recent advances and prospects of diagnosis, intravesical or systemic treatment, and novel drug delivery systems for BCa therapy are reviewed in this paper.

Abstract 1282: Elevated T cell exhaustion and immune cell infiltration is associated with BCG failure in patients with non-muscle invasive bladder cancer

Abstract Introduction: Gold standard treatment in patients with high-risk non-muscle invasive bladder cancer (NMIBC) includes Bacillus Calmette-Guérin (BCG), which activates the immune cells to kill remaining cancerous cells after surgical removal of the tumors. However, 40% of patients do not have a clinical benefit of BCG. The presence of immune cells, their functional state, as well as genomic alterations in the tumor and the normal appearing urothelial tissue, defined as field effect, may have significant impact on therapeutic outcome. Materials and methods: To investigate this, we analyzed samples from 156 patients diagnosed with NMIBC, including 237 tumors, 569 urine samples, and 305 biopsies of adjacent normal appearing urothelium. Patients had a median follow-up time of 8 years. 70 patients (45%) progressed to muscle-invasive bladder cancer or experienced early high grade recurrence within two years after ended BCG treatment, defined as BCG failure. Urinary levels of 92 immune-oncology related proteins were measured in pre- and post-treatment samples using the Olink proteomics platform. Total RNA- and whole exome sequencing (WES) data was generated from tumors before and after BCG. Clonal patient-specific mutations were selected for deep-targeted sequencing of the adjacent normal appearing biopsies. The level of field effect was defined as the mean of the variant allele frequency for mutations observed in normal biopsies. Results: We found that treatment with BCG activated the immune system regardless of clinical outcome. However, patients differed in urinary protein profile after BCG depending on their clinical response. Transcriptomic analysis of tumors showed that UROMOL2021 subtypes were significantly associated with outcome and clinical response (p=0.018). Paired tumors showed a shift in subtype to an immune infiltrated subtype (class 2b) after treatment in 36% of cases. Patients with BCG failure showed signs of immune exhaustion after treatment indicated by higher expression of the T cell exhaustion marker genes CTLA4 (p=0.0067), LAG3 (p=0.00012), TIM-3 (p=0.022), KLRG1 (p=0.028), and PD-1 (p=0.047), and higher immune cell infiltration (p=0.011). Genomic features such as mutational signatures and mutational load were not predictive of clinical response. Interestingly, BCG-responsive patients had a high level of field effect before BCG (p=0.0026), suggesting that field effect could lead to increased BCG efficacy. Conclusion: BCG treatment was associated with immune system activation reflected in both urine and tissue samples. In patients with BCG failure, we observed an immune exhausted phenotype after treatment, and we observed a high level of field effect before treatment in responsive patients. Collectively, this could indicate that increased immunogenicity and prolonged immune activation are key factors in BCG treatment responsiveness. Citation Format: Trine Strandgaard, Iver Nordentoft, Emil Christensen, Sia Lindskrog, Philippe Lamy, Karin Birkenkamp-Demtröder, Torben Steiniche, Jørgen Bjerggaard Jensen, Lars Dyrskjøt. Elevated T cell exhaustion and immune cell infiltration is associated with BCG failure in patients with 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 1282.

Abstract 517: Protein disulfide isomerase as a predictive biomarker for non-muscle invasive bladder cancer recurrence

Abstract INTRODUCTION AND OBJECTIVE: High recurrence rates found in non-muscle invasive bladder cancer (NMIBC) pose a financial and psychological burden for patients. We demonstrated that bladder cancer (BC) cells release protein disulfide isomerase (PDI), a redox-regulated ER-resident protein, via extracellular vesicles (EVs) when experiencing high levels of ER stress for their own survival. Chronic exposure to PDI-enriched BC EVs induced malignant transformation in recipient non-transformed cells. We hypothesized that the dynamic redox state in BC cells determines PDI cellular localization and tumors with elevated PDI preferentially incorporate PDI into EVs for removal. Furthermore, PDI expression levels and subcellular localization in tumors from NMIBC patients may predict NMIBC recurrence. METHODS: Retrospective chart review identified 122 patients with newly diagnosed low-grade NMIBC classified into 2 groups: recurrent (N=55) and non-recurrent (N=67) during follow-up period. Formalin fixed paraffin embedded tumor specimens from index transurethral resection of bladder tumor (TURBT) were obtained and a tissue microarray (TMA) was constructed. Immunofluorescent staining of TMA sections was conducted using antibodies against PDI and BiP, an ER stress marker. Stained tissues were photographed and tumor regions in each field were manually masked and confirmed by a genitourinary pathologist. Within each tumor region, total antibody labeling was determined by measuring the mean pixel intensity values with NIH ImageJ/Fiji. Manders coefficient was used to assess the colocalization of epitopes using JACoP plugin in ImageJ. RESULTS: Tumor tissues from patients that recurred expressed significantly higher levels of PDI and BiP. Moreover, high PDI and BiP expression predicted worse recurrence-free survival. These data suggest that tissues under higher levels of ER stress—as indicated by higher levels of PDI and BiP expression—have a higher risk of recurrence. Significantly higher levels of PDI were detected in non-ER cytosol in recurrent cohort tumors. CONCLUSIONS: This study provides a novel mechanism for BC recurrence and valuable clinical predictive biomarkers for NMIBC recurrence and progression. Future clinical applications targeting this pathway may be an avenue to prevent NMIBC recurrence. Citation Format: Kit L. Yuen, Chia-Hao Wu, Christopher R. Silvers, Alexis R. Steinmetz, Hiroshi Miyamoto, Edward M. Messing, Yi-Fen Lee. Protein disulfide isomerase as a predictive biomarker for non-muscle invasive bladder cancer recurrence [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 517.

Clinical determinants of recurrence in pTa bladder cancer following transurethral resection of bladder tumor.

BackgroundNon-muscle invasive bladder cancer can be controlled by transurethral resection of bladder (TURB), but suffers from frequent recurrences in 60–70% of cases. Although, recurrence interval after TURB influences treatment course and prognosis, its implication and risk factors have not been fully elucidated. We evaluated the risk factors of early (within 1 yr) and late (after 1 yr) recurrence of pTa bladder cancer and clinical significance of recurrence interval on disease progression and overall survival.MethodsIn this study, pTa bladder cancer patients enrolled in prospective patient registry system of Seoul National University, SUPER-UC, were retrospectively examined to determine the clinical risk factors for recurrence and its significance regarding to recurrence interval. A total of 1067 bladder cancer patients who underwent TURB between March 20 and June 2021 were included and classified into three groups of no recurrence, early, or late recurrence to be comparatively analyzed.ResultsEarly recurrence was associated with poorer cystectomy-free survival and overall survival than late recurrence. Risk factors for early recurrence included a high number of previous TURB, tumor multiplicity, tumor location, tumor shape, incompleteness of TURB, and high tumor grade. Otherwise, late recurrence was associated with low-grade tumors with insufficient TURB depth.ConclusionPatients with risk factors for early recurrence should be closely followed up with special cautions.

La dosis única de instilación intravesical postoperatoria inmediata de quimioterapia no es superior al lavado continuo con suero

Introduction and objectivesTo evaluate whether there is any difference between immediate postoperative instillation of intravesical chemotherapy (IPOIC) and continuous saline bladder irrigation(CSBI) in terms of bladder cancer(BC) recurrence in patients with primary low- or intermediate-risk non-muscle-invasive BC (NMIBC). Materials and methodsMedical records of 1482 patients who underwent transurethral resection of bladder tumor between March 1994 and August 2020 were reviewed retrospectively. Patients were divided into two groups according to IPOIC and/or CSBI administration status (Group 1: CSBI alone; Group 2: CSBI following IPOIC). Low- and intermediate-risk NMIBC patients were also divided into subgroups according to IPOIC and/or CSBI administration status. ResultsA total of 594 patients with primary NMIBC were included. Of the patients, 86 (14.5%) were female and 508 (85.5%) were male with a median age of 69 (60-78) years. The frequency of patients in group 1 and group 2 were 361 (60.8%) and 233 (39.2%), respectively. Recurrent disease was observed in 213 (35.9%) patients. There was no difference between the groups when they were compared for recurrent disease frequency, median time to first recurrence and frequency of recurrence within first 12 months (P=.064, P=.671, and P=.145, respectively). Disease recurrence rates in low-risk NMIBC patients was lower when they were treated with “CSBI following IPOIC” when compared to “CSBI alone” (P=.042). However, no difference was observed in low-risk NMIBC subgroups when they were compared for pathological features of recurrent tumors such as number, size, grade, stage, and presence of carcinoma in situ (P>.05, for each). Conclusions“CSBI following IPOIC” combination was not superior to “CSBI alone” for preventing adverse pathological outcomes in recurrent low- and intermediate-risk NMIBC.

Adherence to the WCRF/AICR Cancer Prevention Recommendations and Risk of Recurrence in Non-muscle Invasive Bladder Cancer

ObjectivesPatients with cancer are recommended to follow cancer prevention guidelines due to insufficient evidence for specific recommendations for cancer survivors. It is unclear if adherence to these recommendations lowers risk of recurrence among patients with non-muscle invasive bladder cancer (NMIBC). We examined whether the standardized lifestyle score measuring adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations was associated with risk of recurrence among NMIBC patients. MethodsThe study population included 979 patients newly diagnosed with NMIBC between 2014 and 2017 from the prospective cohort UroLife. Lifestyle was assessed shortly after diagnosis (reflecting the prediagnosis period) and 3 months postdiagnosis. The standardized 2018 WCRF/AICR score was constructed based on recommendations for BMI, physical activity, diet, and alcohol intake. We computed multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazard regression models. ResultsMedian follow-up time was 3.7 years and 315 first recurrences were observed. Patients with the highest versus lowest postdiagnosis WCRF/AICR scores had a statistically non-significant 23% lower risk of recurrence (HR 0.77, 95%CI: 0.53, 1.11). The same tendency was observed for the diet and alcohol sub-scores. No inverse associations were observed for the BMI or physical activity sub-scores and for the WCRF/AICR score at diagnosis. Each 1-point improvement in the WCRF/AICR score after diagnosis seemed to be associated with a lower recurrence risk (HR 0.86; 95% CI: 0.72, 1.01). ConclusionsGreater adherence to the WCRF/AICR cancer prevention recommendations and improvements therein after NMIBC diagnosis might be associated with a decreased recurrence risk. As a next step, we will extend our Cox models to include multiple recurrences which will improve the statistical power of our analyses. Funding SourcesWorld Cancer Research Fund International.

HALP score as a biomarker for nutritional status to predict overall survival in patients post radical cystectomy.

e16504 Background: Radical Cystectomy (RC) is the gold-standard treatment for recurrent high grade T1 or muscle-invasive bladder cancer. Nutritional status is a well-defined independent predictor of overall survival post-RC. Various prognostic biomarkers have been proposed as surrogates for nutritional status to help predict postoperative outcomes. These biomarkers include albumin, anemia, thrombocytopenia and sarcopenia. Recently, the Hemoglobin, Albumin, Lymphocyte, Platelet (HALP) score has been postulated as an all-encompassing biomarker and has been shown to predict overall survival (OS) post-RC in a single previous study. Due to the paucity of studies looking at HALP and RC outcomes, and optimal cutoffs for HALP have not been defined. Our study sought to analyze and optimize HALP thresholds for OS, as well as examine the Psoas Muscle Index (PMI) as a possible additional predictor that can be used with HALP. Methods: Seventy-three RC patients were evaluated from 2010 to 2021. Of 73 RC patients, 50 had sufficient pre-operative laboratory data to calculate HALP. Sixty-two patients had CT scans to analyze PMI, which was calculated using patient height and the psoas major muscle cross-sectional area measured at the L3 vertebral level. Patient date of surgery, tumor grade and stage, American Society of Anesthesiologists (ASA) Classification, survival status, and date of last contact were extracted from our institutional cancer registry. X-tile software was used to find optimal biomarker cutoffs for HALP. The Cox Proportional Hazards model was used to identify predictors of OS. Results: Median age was 67 (58-74) years, 58 (79.5%) were male, and 36 (49.3%) received neoadjuvant/adjuvant chemotherapy. Forty-seven (64.4%) had pathological stage ≥pT2, 25 (35.7%) had lymph-node involvement, and 4 (5.5%) had palliative surgery. Median HALP score was 28 (21 – 42). Median PMI was 569 (456 –700). Fifty-six (76.7%) had an ASA ≥ 3. Median follow up was 29.3 months (12.0– 51.9). Forty-eight (65.8%) were alive at last follow-up. HALP (continuous variable) was a significant predictor of OS on multivariable Cox regression analysis (HR 0.95, 95% CI 0.90 - 0.99) (P = 0.021), adjusting for age, sex, and node involvement; PMI and ASA were not significant. X-tile analysis showed an optimal HALP cutoff of 25.0. Patients with HALP &lt; 25 had inferior OS (median, 32.5 months) compared with those with HALP ≥ 25 (median, not reached) (P = 0.025). Conclusions: We conclude that patients with low HALP Score were shown to have a significantly inferior OS, with an optimum HALP cutoff of 25.0. We further suggest that the HALP score can be a reliable prognostic biomarker to assist in nutritional management before surgery. PMI was not a significant predictor of OS and did not add value to HALP score. Future studies may investigate better measures of sarcopenia, which could potentially be combined with HALP score to better predict OS in RC patients.

CCTG BL13 a randomized phase II trial assessing trimodality therapy with or without adjuvant durvalumab to treat patients with muscle-invasive bladder cancer (NCT03768570).

TPS4619 Background: Immunotherapy improves outcomes in the advanced (Bellmunt 2019; Powles 2020) as well as in the adjuvant setting post cystectomy (Bajorin 2021) for muscle invasive bladder cancer (MIBC) patients. Trimodality treatment (TMT) consisting of transurethral resection of bladder tumor (TURBT) followed by chemoradiotherapy (CRT) may be considered an alternative to radical cystectomy in MIBC. The role of radiotherapy and chemotherapy as immune system stimulants provides a rationale to evaluate the anticancer activity of checkpoint inhibitors in this patient population. Durvalumab, an anti PDL1 inhibitor, administered after CRT leads to improvement in PFS and OS in patients with locally advanced NSCLC, which further supports the rationale for this study (Antonia 2017, 2018). We hypothesized that durvalumab will improve outcomes in patients with MIBC when administered in the adjuvant setting after completion of trimodality therapy. Methods: CCTG BL13 is a Canadian Cancer Trials Group, randomized phase II trial in patients with stage T2-T4a N0M0, urothelial carcinoma treated with TURBT followed by radiotherapy with concurrent chemotherapy. Treatment arms consist of durvalumab 1500 mg IV q 4 weeks for 12 months versus surveillance. The primary objective: to compare disease free survival (DFS) between arms (RECIST 1.1, investigator assessed). Secondary endpoints include a non muscle-invasive bladder cancer recurrence rate (&lt; T2); locoregional control rate; overall survival; bladder intact DFS, patterns of disease recurrence; metastasis free survival; safety; quality of life ; economics evaluation. A pilot sub study (BL13F) has been activated and will evaluate the feasibility of electronic real-time patient self-reporting of immunotherapy related symptomatic adverse events using the SYMPTOM-IQ Tool on the uMotif Mobile Health Application (APP). Statistical Design: Randomization 1:1 balanced for stratification factors: ECOG PS; neoadjuvant chemotherapy; radiation field extent; T2 vs T3/T4; centre. Assuming a 2-year DFS rate 65% for patients on the control arm and estimated 12% improvement in the 2-year DFS rate (65% to 77% (HR 0.61)) with 80% power using a 1-sided 10% level test requires a sample size of 190 including 5% drop out rate. Conduct to Date: Study activation Dec 2018. Enrollment as of January 31 2022: 49. The DSMC reviewed and recommended trial continuation in November 2021. Clinical trial information: NCT03768570.

Assessment of Therapeutic Benefit and Option Strategy on Intravesical Instillation for Preventing Bladder Cancer Recurrence after Radical Nephroureterectomy in Patients with Upper Urinary Tract Urothelial Carcinoma.

Objective Upper urinary tract urothelial carcinoma (UUT-UC) is a very aggressive disease, characterized by 22%–50% of patients suffering from subsequent bladder recurrence after radical nephroureterectomy (RNU). Although the therapy of intravesical instillation is reported to be effective in preventing bladder recurrence, no study had been reported in Northeast China. The findings relating to the clinical effectiveness of intravesical instillation after RNU are somewhat controversial, and the best efficacy and least adverse effects of instillation drugs have not been widely accepted. Here, we aimed at evaluating the efficacy of intravesical instillation for the prevention intravesical recurrence systematically. Methods In this retrospective cohort study, from October 2006 to September 2017, 158 UUT-UC patients underwent RNU were divided into 4 groups: epirubicin (EPB) instillation group, hydroxycamptothecin (HCPT) instillation group, bacillus Calmette–Guerin (BCG) instillation group, and noninstillation group. Cox univariate and multivariate analyses were employed to identify the risk factors for intravesical recurrence-free survival (IVRFS). The nomogram model was also applied to predict patient outcomes. Subsequently, to evaluate the clinical significance of intravesical instillation comprehensively, several databases including PubMed, Ovid, and Embase were searched and data from published studies with our results were combined by direct meta-analysis. Moreover, a network meta-analysis comparing instillation therapies was conducted to evaluate the clinical efficacy of different instillation drugs. Results In our retrospective cohort study, the Kaplan–Meier survival curve demonstrated noninstillation groups were associated with worsened IVRFS. Meanwhile, multivariate analysis indicated that intravesical instillation was independent protective factors for IVRFS (hazard ratio [HR] = 0.731). Moreover, calibration plots, receiver operating characteristic (ROC) curves, area under the curve (AUC) values, and the C-index showed the priority of nomogram's predictive accuracy. Next, direct meta-analysis including 19 studies showed that intravesical instillation could prevent the recurrence of bladder cancer with a pooled risk ratio (RR) estimate of 0.53. Subgroup analysis by study type, year of intravesical recurrence, first instillation time, and instillation times also confirmed the robustness of the results. Moreover, intraoperative instillation was associated with a decrease in the risk of bladder recurrence compared with postoperative instillation. Then, a network meta-analysis including 7 studies indicated that pirarubicin (THP) (surface under the cumulative ranking curve [SUCRA] = 89.2%) is the most effective therapy to reduce the risk of bladder recurrence, followed by BCG (SUCRA = 83.5%), mitomycin C (MMC) (SUCRA = 53.6%), EPB (SUCRA = 52.6%), and HCPT (SUCRA = 5.1%) after the analysis of the value ranking. Conclusions A maintenance schedule of intravesical instillation prevents the recurrence of bladder cancer after RNU in UUT-UC patients effectively. Large, prospective trials are needed to further confirm its value. Compared with other chemotherapy regimens, THP may be a promising drug with favorable efficacy to prevent bladder recurrence. As included studies had moderate risk of bias, the results of network meta-analysis should be applied with caution.

The Role of NMP22 and CSTB Levels in Predicting Postoperative Recurrence of Bladder Cancer

Objective To investigate the value of preoperative urinary nuclear matrix protein 22 (NMP22) and Cystatin B (CSTB) expressions in evaluating the postoperative recurrence of bladder cancer. Methods The clinical case data of 102 patients with bladder cancer who underwent surgical treatment from January 2017 to January 2022 were collected, and the patients were divided into a recurrence group (n = 54) and nonrecurrence group (n = 48) according to whether the patients recurred after surgery, and the preoperative NMP22 and CSTB expression levels between the two groups were compared. Receiver operating curve (ROC) was used to analyze the evaluation value of preoperative NMP22 and CSTB expression in patients with bladder cancer postoperative recurrence. Logistic multivariate regression method was used to analyze the correlation between preoperative NMP22 and CSTB expression and postoperative bladder cancer recurrence. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of NMP22 and CSTB single detection and combined detection were evaluated for postoperative recurrence of bladder cancer. Results The preoperative expression levels of NMP22 and CSTB in the recurrence group were significantly higher than those in the nonrecurrence group (P < 0.05). The results of ROC curve analysis showed that the AUC of preoperative NMP22 and CSTB expression levels to assess postoperative recurrence of bladder cancer was 0.696 and 0.659, respectively (P < 0.05). Logistic multivariate regression analysis showed that preoperative NMP22 and CSTB overexpression was an independent risk factor for postoperative recurrence of bladder cancer (OR = 1.042, 2.307, P < 0.05). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of preoperative NMP22 combined with CSTB in evaluating bladder cancer recurrence after surgery were higher than those of preoperative NMP22 and CSTB alone, and the differences were statistically significant (P < 0.05). Conclusion Preoperative NMP22 and CSTB conveying is hardly interrelated to postoperative recurrence of bladder carcinoma and has certain appraisal worth for postoperative recurrence of bladder carcinoma, and the combined testing of the two has a taller appraisal worth. NMP22 combined with CSTB detection will help to detect postoperative recurrence of bladder cancer and formulate effective treatment measures in time.

13C Natural Isotope Abundance in Urothelium as a New Marker in the Follow-Up of Patients with Bladder Cancer.

Simple SummaryBladder cancer (BC) is a common urological cancer and has a high incidence of recurrence. Metabolic changes are one of the hallmarks of cancer. Differences in metabolic pathways between normal and cancerous tissues lead to a heterogeneous distribution of natural isotope abundance. We analyzed the isotope ratio of carbon, nitrogen, and sulfur in normal urothelium and bladder cancer samples and correlated these data with clinical parameters. We found that bladder cancers are 13C- and 15N-depleted when compared to normal urothelium. Furthermore, decreased 13C abundance in normal urothelium is correlated with shorter disease-free survival in bladder cancer patients. Determination of the isotopic signature of normal and cancerous bladder biopsies can provide important information about the risk of recurrence and improve patients’ management by avoiding invasiveness and unnecessary diagnostic procedures such as cystoscopy.Bladder cancer (BC) is the most common urological malignancy and has a high incidence of recurrence. BC cells alter their nutrient uptake and metabolic pathways in order to continue the production of sufficient levels of ATP and metabolic intermediates for proliferation and survival. Changes in metabolic pathways regarding the rate of the enzymatic reaction and transport lead to differences in the content of natural isotopes (13C, 15N, 34S) between normal and cancerous tissues. The assessment of the stable isotopes of carbon, nitrogen, and sulfur in normal urothelium and bladder cancer samples was performed using Isotope Ratio Mass Spectrometry (IRMS). The natural abundance of 15N and 13C was decreased in bladder cancer samples when compared to normal urothelium. No significant correlation was observed in BC specimens depending on the tumor grade and stage. Samples derived from bladder tumors and normal urothelium had a different pattern of 15N and 13C isotope abundance. Decreased 13C natural isotopes in the normal urothelium of BC patients were significantly associated with a shorter DFS. Our results suggest that isotopic analysis of normal urothelium of BC patients can be used to predict bladder cancer recurrence.